ECR 15 2020 by Radcliffe Cardiology

Volume 15 â&#x20AC;˘ 2020

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Cardiology

Lifelong Learning for Cardiovascular Professionals

Supporting life-long learning for cardiovascular professionals Guided by Editor-in-Chief Juan Carlos Kaski, Associate Editor Pablo Avanzas and an Editorial Board comprising of world-renowned physicians, European Cardiology Review is a peer-reviewed journal that publishes reviews, case reports and original research. Available online, European Cardiology Reviewâ&#x20AC;&#x2122;s articles are free-to-access, and aim to support continuous learning for physicians within the field.

Call for Submissions European Cardiology Review publishes invited contributions from prominent experts, but also welcomes speculative submissions of a superior quality. For further information on submitting an article, or for free online access to the journal, please visit: www.ECRjournal.com

Cardiology

Lifelong Learning for Cardiovascular Professionals

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Volume 15 • 2020

www.ECRjournal.com Official journal of

Editor-in-Chief Juan Carlos Kaski St George’s University of London, London

Associate Editor Pablo Avanzas

University Hospital of Oviedo, Oviedo

International Advisers Richard Conti

University of Florida, Gainesville

Wolfgang Koenig

Technical University of Munich, Munich

Giuseppe Mancia

University of Milano-Bicocca, Milan

Mario Marzilli

Hiroaki Shimokawa

Hypertension Maria Lorenza Muiesan

Epidemiology: Meta-analyses Gianluigi Savarese

University of Pisa, Pisa

Tohoku University, Sendai

Section Editors Cardiac Imaging John Baksi Royal Brompton Hospital, London

Arrhythmias David Calvo

Hospital Universitario Central de Asturias

Genetics and Cardiovascular Disease Eliecer Coto

Structural Heart Disease: Cardiac Intervention Giuseppe Ferrante

Humanitas Research Hospital, Humanitas University, Milan

Biomarkers of CV Risk Bruna Gigante

Cardiovascular Disease in Women Angela Maas

Radboud University, Nijmegen

Cardiomyopathies and Athletes Heart Disease Aneil Malhotra

University of Brescia, Brescia

Ischaemic Heart Disease Giampaolo Niccoli

Catholic University of the Sacred Heart, Rome

St George’s University of London, London

Karolinska Institute, Solna, Sweden

Karolinska Institutet, Karolinska University Hospital, Stockholm

Pharmacotherapy Juan Tamargo

Universidad Complutense, CIBERCV, Madrid

Genética Molecular-Laboratorio Medicina, HUCA, Oviedo

Editorial Board Ramón Arroyo-Espliguero

Carlo Di Mario

Koji Hasegawa

John McNeill

Anne Grete Semb

Head of Service, Hospital General Universitario, Guadalajara

Careggi University Hospital, Florence

National Hospital Organization Kyoto Medical Center, Fushimi-ku, Kyoto

Monash University, Melbourne

Diakonhjemme Hospital, Oslo, Norway

Debasish Banerjee

Thoraxcenter, Cardiovascular Research School COEUR, University Medical Centre Rotterdam, Rotterdam

Thomas Kahan

Noel Bairey Merz Cedars-Sinai Heart Institute, Los Angeles

Roxy Senior

St George’s University of London, London

Vinayak Bapat Columbia University Medical Centre, New York

Antoni Bayés-Genís Hospital Germans Trias i Pujol, Barcelona

John Beltrame

Perry Elliott

Danderyd University Hospital, Danderyd

Peter Ong Robert-Bosch-Krankenhaus, Stuttgart

Koichi Kaikita

University College, London

Kumamoto University, Kumamoto

Denis Pellerin

Albert Ferro

Mike G Kirby

St Bartholomew’s Hospital, London

King’s College London, London

University of Hertfordshire, Hatfield

Carl Pepine

Michael Fisher

Sreenivasa Rao Kondapally Seshasai

Piotr Ponikowski

University of Adelaide, Adelaide

Royal Liverpool University Hospital, Liverpool

Christopher Cannon

Augusto Gallino

Harvard Medical School, Boston

Ente Ospedaliero Cantonale, Bellinzona

Peter Collins

Robert Gerber

Imperial College, London

Conquest Hospital, Hastings

Derek Connolly

Bernard Gersh

Sandwell & West Birmingham Hospitals NHS Trust, Birmingham

Mayo Clinic, Minnesota

David Goldsmith

Alberto Cuocolo

St George’s University of London, London

University of Naples Federico II, Naples

Tommaso Gori

Gheorghe Andrei Dan

Royal Bournemouth Hospital, Bournemouth, UK

Patrizio Lancellotti University of Liège, Liège

Gaetano Lanza Università Cattolica del Sacro Cuore, Rome

Amir Lerman Mayo Clinic, Minnesota

Alberto Lorenzatti

University of Florida, Florida Wroclaw Medical University, Wroclaw

Eva Prescott Bispebjerg Hospital, Copenhagen

Axel Pries

Alejandro Recio

Imperial College, London

Olivia Manfrini

UICE-HP Cardiología, HU Virgen Macarena, Seville

Marcelo Di Carli

Kim Greaves

Eileen Handberg

Antoni Martínez-Rubio

Hippokration General Hospital, Athens

University of Florida, Florida

University Hospital of Sabadell, Sabadell

Iana Simova National Cardiology Hospital, Sofia

Jack Tan Wei Chieh National Heart Centre Singapore, Singapore

Dimitrios Tziakas

Macquarie University, Sydney

University of Hertfordshire, Hatfield, Hertfordshire

Polychronis Dilaveris

Italian National Research Council, Rome

Isabella Tritto

Diana Gorog

National University of Cordoba, Cordoba

Rosa Sicari

Hari Raju

National Research Council, Pisa

Felipe Martinez

St George’s University of London, London

University of Athens, Athens

Silvia Maffei

Sunshine Coast University Hospital, Queensland

Sanjay Sharma

Goethe University Hospital Frankfurt, Frankfurt

St George’s University of London, London

Brigham and Women’s Hospital, Harvard Medical School, Boston

St George’s University of London, London

Konstantinos Toutouzas

Robin Ray

University of Bologna, Bologna

Nesan Shanmugam

Valentina Puntmann

Johannes Gutenberg University Mainz, Mainz

Ranil de Silva

Imperial College, London

Charité Universitätsmedizin, Berlin

Hospital Córdoba, Cordoba

Colentina University Hospital, Bucharest

Cover image © AdobeStock

Dirk Duncker

Magdi Saba St George’s University of London, London

Ignacio J. Amat Santos Hospital Clínico Universitario de Valladolid, Spain

University of Perugia, Perugia Democritus University of Thrace, Xanthi

Mauricio Wajngarten University of São Paulo, São Paulo

Hiroshi Watanabe Hamamatsu University School of Medicine, Hamamatsu

Matthew Wright St Thomas’ Hospital, London

José Luis Zamorano Hospital Ramón y Cajal, Madrid

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Published by Radcliffe Cardiology, a division of Radcliffe Medical Media. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use thereof. Published content is for information purposes only and is not a substitute for professional medical advice. Where views and opinions are expressed, they are those of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Cardiology. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS, UK © 2020 All rights reserved ISSN: 1758–3756 • eISSN: 1758–3764 © RADCLIFFE CARDIOLOGY 2020

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• European Cardiology Review is an international, English language, peer-reviewed, open access journal that publishes articles continuously on www.ECRjournal.com. • European Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinions in cardiology medicine and practice. • European Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • European Cardiology Review provides comprehensive updates on a range of salient issues to support physicians in developing their knowledge and effectiveness in day-to-day clinical practice.

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Cardiology

Lifelong Learning for Cardiovascular Professionals Access at: www.ECRjournal.com

Contents

Latest Advances in Cardiac CT

Thomas D Heseltine, Scott W Murray, Balazs Ruzsics and Michael Fisher DOI: https://doi.org/10.15420/ecr.2019.14.2

Applications for Induced Pluripotent Stem Cells in Disease Modelling and Drug Development for Heart Diseases Shu Nakao, Dai Ihara, Koji Hasegawa and Teruhisa Kawamura DOI: https://doi.org/10.15420/ecr.2019.03

Spontaneous Coronary Artery Dissection: Mechanisms, Diagnosis and Management

Marcos Garcia-Guimarães, Teresa Bastante, Paula Antuña, César Jimenez, Francisco de la Cuerda, Javier Cuesta, Fernando Rivero, Diluka Premawardhana, David Adlam and Fernando Alfonso DOI: https://doi.org/10.15420/ecr.2019.01

New Perspectives on Atherogenic Dyslipidaemia and Cardiovascular Disease Alberto J Lorenzatti and Peter P Toth

DOI: https://doi.org/10.15420/ecr.2019.06

Emerging Strategies for the Management of Atherogenic Dyslipidaemia Anandita Agarwala and Michael D Shapiro DOI: https://doi.org/10.15420/ecr.2019.16

Will Direct Oral Anticoagulants Have a Chance in Prosthetic Valves? Mahmoud Abdelnabi, Abdallah Almaghraby and Yehia Saleh DOI: https://doi.org/10.15420/ecr.2019.1.3

Antithrombotic Treatment After Coronary Intervention: Agreement and Controversy Tamara García Camarero and José M de la Torre Hernández DOI: https://doi.org/10.15420/ecr.2019.25.2

Dual Antiplatelet Therapy in Coronary Artery Disease: Comparison Between ACC/AHA 2016 and ESC 2017 Guidelines

Christopher N Floyd

DOI: https://doi.org/10.15420/ecr.2019.09

Antithrombotic Therapy After Transcatheter Aortic Valve Implantation Leslie Marisol Lugo, Rafael Romaguera, Joan Antoni Gómez-Hospital and José Luis Ferreiro DOI: https://doi.org/10.15420/ecr.2019.10

Direct-acting Anticoagulants in Chronic Coronary Syndromes Emmanuel Sorbets and Philippe Gabriel Steg DOI: https://doi.org/10.15420/ecr.2018.24.2

Arrhythmogenic Cardiomyopathy: A Disease or Merely a Phenotype? Alexandros Protonotarios and Perry M Elliott DOI: https://doi.org/10.15420/ecr.2019.05

Coronary Artery Spasm: The Interplay Between Endothelial Dysfunction and Vascular Smooth Muscle Cell Hyperreactivity

Astrid Hubert, Andreas Seitz, Valeria Martínez Pereyra, Raffi Bekeredjian, Udo Sechtem and Peter Ong DOI: https://doi.org/10.15420/ecr.2019.20

Asymptomatic Left Ventricle Systolic Dysfunction

Jaskanwal D Sara, Takumi Toya, Riad Taher, Amir Lerman, Bernard Gersh and Nandan S Anavekar DOI: https://doi.org/10.15420/ecr.2019.14

Cardiology Masters Featuring: Prof Angela Maas DOI: https://doi.org/10.15420/ecr.2019.19

Effects of Statin Treatment on Patients with Angina and Normal or Nearly Normal Angiograms Olivia Manfrini, Peter Amaduzzi, Maria Bergami and Edina Cenko DOI: https://doi.org/10.15420/ecr.2019.15

Smoking Cessation as a Public Health Measure to Limit the Coronavirus Disease 2019 Pandemic Maki Komiyama and Koji Hasegawa

DOI: https://doi.org/10.15420/ecr.2020.11

Heart Failure Treatment by Device Antoni Bayés-Genis

DOI: https://doi.org/10.15420/ecr.2020.03

Interatrial Shunting for Treating Acute and Chronic Left Heart Failure

Leonardo Guimaraes, David del Val, Sebastien Bergeron, Kim O’Connor, Mathieu Bernier and Josep Rodés-Cabau DOI: https://doi.org/10.15420/ecr.2019.04

105

Destination Therapy with Left Ventricular Assist Devices in Non-transplant Centres: The Time is Right

Antoni Bayes-Genis, Christian Muñoz-Guijosa, Evelyn Santiago-Vacas, Santiago Montero, Cosme García-García, Pau Codina, Julio Núñez and Josep Lupón DOI: https://doi.org/10.15420/ecr.2019.29.2

MI with Non-obstructive Coronary Artery Presenting with STEMI: A Review of Incidence, Aetiology, Assessment and Treatment

109

Ying X Gue, Rahim Kanji, Sabiha Gati and Diana A Gorog DOI: https://doi.org/10.15420/ecr.2019.13

117

Recent Warnings about Antihypertensive Drugs and Cancer Risk: Where Do They Come From? Allegra Battistoni and Massimo Volpe

DOI: https://doi.org/10.15420/ecr.2019.21

122

Contemporary Management of Secondary Mitral Regurgitation Kashish Goel, Colin M Barker and JoAnn Lindenfeld DOI: https://doi.org/10.15420/ecr.2019.08

Ethical Issues in Decision-making Regarding the Elderly Affected by Coronavirus Disease 2019: An Expert Opinion David Martínez-Sellés, Helena Martínez-Sellés and Manuel Martinez-Sellés DOI: https://doi.org/10.15420/ecr.2020.14

Access at: www.ECRjournal.com

128

Imaging

Latest Advances in Cardiac CT Thomas D Heseltine,1 Scott W Murray,1,2 Balazs Ruzsics1 and Michael Fisher2,3 1. Royal Liverpool University Hospital, Liverpool, UK; 2. Liverpool Centre for Cardiovascular Science, Liverpool, UK; 3. Institute for Cardiovascular Medicine and Science, Liverpool Heart and Chest Hospital, Liverpool, UK

Abstract Recent rapid technological advancements in cardiac CT have improved image quality and reduced radiation exposure to patients. Furthermore, key insights from large cohort trials have helped delineate cardiovascular disease risk as a function of overall coronary plaque burden and the morphological appearance of individual plaques. The advent of CT-derived fractional flow reserve promises to establish an anatomical and functional test within one modality. Recent data examining the short-term impact of CT-derived fractional flow reserve on downstream care and clinical outcomes have been published. In addition, machine learning is a concept that is being increasingly applied to diagnostic medicine. Over the coming decade, machine learning will begin to be integrated into cardiac CT, and will potentially make a tangible difference to how this modality evolves. The authors have performed an extensive literature review and comprehensive analysis of the recent advances in cardiac CT. They review how recent advances currently impact on clinical care and potential future directions for this imaging modality.

Keywords Cardiac CT, coronary artery disease, atherosclerosis, fractional flow reserve CT, CT coronary angiography, machine learning, coronary artery calcium score, cardiovascular disease risk Disclosure: The authors have no conflicts of interest to declare. Received: 19 February 2019 Accepted: 7 August 2019 Citation: European Cardiology Review 2020;15:e01. DOI: https://doi.org/10.15420/ecr.2019.14.2 Correspondence: Thomas Heseltine, Royal Liverpool University Hospital, Liverpool L7 8XP, UK. E: thomas.heseltine@rlbuht.nhs.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

The impact of CT coronary angiography (CTCA) within diagnostic cardiology has been far-reaching and profound. The clinical utility of this modality is underpinned by excellent sensitivity (99%) and negative predicative value (97%) for detecting significant coronary artery disease.1 Over the past decade, technological advances in the form of increased gantry spin times and fast single heart beat scanning have driven improved temporal resolution together with lower radiation exposure. These advances have been realised through prospective ‘gating’ of the CT study. Coronary arteries are mobile throughout the cardiac cycle, and imaging during the phases where they are least mobile is paramount to image quality. This occurs typically at 50–80% of the R-R interval. The X-ray tube is only active for a specific duration of the cardiac cycle; for example, 50–80% of the R-R interval, thus reducing radiation exposure.2

single acquisition. The advantages of these techniques are that the X-ray tube is only on for a small amount of time and it alleviates stitching artefacts, as the whole image is acquired in one sequence. All the major CT vendors have recently introduced systems incorporating these advances. Rigorous heart rate control is also essential for keeping the effective radiation dose down. The effective dose given to an average patient doubles when their heart rate increases from <55 to 60 BPM. It doubles again with an increase to 65 BPM.3

Increased gantry spin times and multidetector technology have allowed the development of specific algorithms that allow whole heart scanning in a single heartbeat. For example, the time required for one rotation of an X-ray tube is reduced by increasing the gantry spin times and effectively halved by adding a second X-ray tube. This allows acquisition of the whole heart volume in a single beat at a specific point of the R-R interval. The patient is then moved rapidly through the z-axis to cover the whole heart in a single acquisition.

The culmination of recent advances led to a change in the National Institute for Health and Care Excellence (NICE) guidelines for assessment of chest pain of recent onset.2 CTCA is now recommended as the first-line investigation for patients with typical or atypical chest pain. This represents a dramatic change from previous versions of the guidance, with a move away from calculations of pretest probability and the previous emphasis on functional imaging. The radiological infrastructure within the UK is significantly behind other European health systems, and the change in NICE guidance will contribute significantly to increased demand. Significant investment, in both infrastructure and personnel, will be required over the next decade, and this will remain a challenge within the UK for many years to come. The British Society of Cardiac Imaging produced a report on the provision of cardiac CT that estimated a UK-wide shortfall of 43%.4

In addition, vendors offer models with an increased number of detector rows (256 and 320 slice), which allows coverage of the entire heart in a

The importance of CTCA as the principle non-invasive imaging modality in stable chest pain patients is highlighted in the 5-year outcomes from

Access at: www.ECRjournal.com

Latest Advances in Cardiac CT the Scottish Computed Tomography of the Heart (SCOT-HEART) study. When added to standard care, CTCA was associated with fewer cardiovascular disease (CVD) deaths or non-fatal MIs (HR 0.59; 95% CI [0.41–0.84]; p=0.004).5

Table 1: The Calculation of an Agatston Calcium Score Agatston Calcium Score Density in Hounsfield units (HU): • 1: 130–199 HU

In this review, we analyse the recent advances in CTCA, including how coronary artery calcium scoring (CACS) is being implemented to risk stratification algorithms; the development and refinement of CT-derived fractional flow reserve (FFR); plaque morphology and plaque characteristics, and how these may effect prognosis; and the development of machine learning (ML), and how these advances may impact clinical practice in the coming years.

• 2: 200–299 HU • 3: 300–399 HU • 4: >400 HU This weighted score is then multiplied by the area mm2. Source: Agatston et al. 1990.9

Figure 1: Example of Non-calcified Plaque with a Calcium Score of Zero

Coronary Artery Calcium Score: Precision Medicine and Risk Modification The pathological evolution of atherosclerosis is a dynamic process involving varying inflammatory insults to the arterial intima, which ultimately results in the development of coronary plaque.6 The evolution of atherosclerosis is highly variable, and there is a spectrum of atherosclerotic disease with distinct plaque characteristics. One common final pathway for plaque progression is calcification.7 Coronary artery calcification is associated with total atherosclerotic burden and advancing disease phenotypes.8 There are several methods used to quantify the burden of calcification, including the Agatston score, calcium volume and, more recently, calcium density. The Agatston score is the most established of these methods due to its good reproducibility and high accuracy. The Agatston calcium score was initially developed in the 1990s as a tool for quantifying the degree of calcium within the coronary arteries. Calcification within the coronary artery is defined as 130 HU and >1 mm2 in size. The method for calculating the Agatston score relies on calcium density and total area of calcification (Table 1). Early work was performed using single-beam electron beam CT, and later expanded to multidetector CT.9 Several large cohort studies have established CACS as a valuable tool to assess future CVD risk.10–12 The outcome of CACS is traditionally categorised into different strata reflecting the differing CVD risk. Unsurprisingly, the lowest risk of any coronary event is in the CACS 1–100 strata (HR 3.61), and the highest in those >300 (HR 9.67).10 Although the CACS technique has been in use for nearly two decades, there have been recent advances incorporating its use in regard to risk stratifying individuals. Unsurprisingly, it provides incremental benefit above traditional CVD risk prediction models, and is underpinned by the ability to potentially reclassify patients assessed by traditional CVD risk scores.13–17 Changes in risk prediction algorithms have traditionally been assessed by changes in the area under the receiver operating characteristic curve, but a more recent statistical method, the net reclassification index, is being preferentially used. The net reclassification index is the extent to which people are appropriately reclassified into higher or lower risk categories, and thus serves as a quantitative measure for the performance of risk prediction models when a new marker is added.18 The ability to reclassify patients is an important concept, as it allows increased precision of primary prevention medication prescribing and targeted risk reduction strategies. In addition to targeted medication, CACS remains a powerful mediator for lifestyle change.19 Recently, CACS has been added to traditional risk factors to create a risk prediction tool. The Astronaut Cardiovascular And Health

EUROPEAN CARDIOLOGY REVIEW

A: Multiplaner reformat of LAD. B: Stenosis grading tool in multiplanar reformat. C: Short axis view of lesion. D: Axial view showing positive remodelling of proximal LAD with moderate luminal stenosis.

Modification (Astro-CHARM) tool measures 10-year atherosclerotic CVD risk, and was developed using three large cohorts and validated against a fourth.20 The Astro-CHARM calculator again demonstrated the incremental value of added CACS above the Framingham Risk Score (improvement in C-statistic of 0.03 and net classification improvement of 0.12). A previous CVD risk calculator developed using Multi-Ethnic Study of Atherosclerosis (MESA) data was validated in an older cohort (mean age 65 years in MESA and mean age 51 years in Astro-CHARM).21 Statins are indicated in patients aged 50 years with a CVD risk profile >7.5–10%.22,23 Given that age is a significant independent CVD risk factor, the Astro-CHARM tool has potentially greater clinical utility.24 The development of integrated risk prediction tools enables enhanced decision-making around primary prevention medications and risk factor modification. The current European guidelines give CACS a level IIa recommendation for intermediate risk patients.23 In a review of the current evidence, Greenland et al. made specific recommendations regarding the CVD risk in the context of CACS. Essentially, if the 10-year risk of a CVD event is 7.5–20%, but the CACS is zero, then statin therapy may not be required due to the lack of impact on events.25 The scope for CACS ± CTCA to be used in high-risk patient groups in which the Framingham Risk Score may underestimate the true CVD risk is increasing. For example, CVD risk calculators in HIV (and other

Imaging Figure 2: An Example of CT-derived Fractional Flow Reserve

A: Fractional flow reserve results for the LAD, LCx and RCA. B and C: Multiplanar reconstruction of the LAD showing moderate stenosis.

Table 2: Comparison of Accuracy of CT-derived Fractional Flow Reserve Modality

Lesion

CT-derived FFR35 >50%

Sensitivity SpecificityPPV 86 (77–92)

CT-derived FFR32 Per patient 90

NPV

79 (72–84)

65 (56–74) 93 (87–96)

FFR = fractional flow reserve; NPV = negative predictive value; PPV = positive predictive value. Source: Thompson et al. 2015 and Nørgaard et al. 2014.32,35

chronic inflammatory diseases) are known to underestimate true CVD risk.26 Patients with HIV have been shown to have greater CACS than matched non-HIV patients, illustrating the greater burden of subclinical coronary atherosclerosis.27 There are currently no validated risk predication tools that incorporate CACS in these higher-risk populations. Recently data from the PROspective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) cohort have been reported around the prognostic benefit of a CACS of zero in patients (n=8,811) symptomatic of chest pain. Evaluating the performance of CACS to functional imaging, the investigators found that in symptomatic patients with CACS of zero the annualised event rate was <1%. Out of 133 events, there were 21 patients who had a CACS of zero (15.8%), and of those patients, only two had a severe non-calcified (>70%) stenosis. The risk of having an event with a severe non-calcified stenosis (>70%) with a CACS of zero was 1.4%. Of these 21 patients, approximately half had normal coronary arteries (52%), thus the event may actually have been secondary to a type 2 MI, embolism or coronary spasm (Figure 1). There were no data on plaque morphology. Having a positive CACS (≥1) was able to predict 83% of future CVD events, whereas a positive functional test only predicted 33%.28 These data add to historical evidence that CACS of zero is associated with a very low risk of CVD outcomes.29

CT Coronary Angiography and Functional Assessment Fractional flow reserve CT (CT-derived FFR) uses computational fluid dynamics to predict the functional significance of coronary artery lesions. In the current and only commercially available model, data

from standard CTCA data sets are transferred to the vendor’s server with a report emailed back within a few hours. The report demonstrates the coronary tree with CT-derived FFR results reported in all coronary segments (Figure 2). In a similar fashion to invasive FFR, <0.8 is considered functionally significant. The ability to combine both an anatomical and functional test is extremely appealing, and this technology is well validated in terms of accuracy and safety (Table 2).30–33 Invasive FFR is a well-established technique for quantifying lesion-specific ischaemia, and is comparable to functional imaging.34 To date, no trials with large numbers of patients have presented a comparison of myocardial functional imaging versus CTderived FFR. The technique has several constraints. First, good image quality is paramount. A recent series of CT-derived FFR reported the rate of unsuitable studies as high as 13%.35 In clinical practice, the rate of unsuitable data sets may be higher secondary to inappropriate heart rates (including AF), patients body habitus, poor contrast evolution and problems with artefacts (such as breathing and movement artefacts). Patient preparation and heart rate control has to be rigorous to obtain quality images to use CT-derived FFR. The advent of modern CT scanners will also enhance quality. Second, concerns remain around the diagnostic accuracy in the “FFR grey zone” – CTderived FFR 0.7–0.8. This was reported as 46.1% in a recent systematic review assessing 536 patients from five studies.36 Third, there are no data for patients having already undergone revascularisation. Currently, this service is limited to a few dedicated centres in the UK from a single vendor, HeartFlow. NICE have recently updated their guidance to suggest how CT-derived FFR may be considered for patients with recent-onset or stable chest pain.37 As this technology continues to mature, the initial results from the Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Care (ADVANCE) Registry unsurprisingly show that the strongest predictor of positive CT-derived FFR is stenosis >70%.38 Invasive studies of FFR have proven there is a disconnect between anatomical assessment of coronary stenosis and the physiological impact of those lesions.39 The ADVANCE Registry again demonstrates this disconnect, as despite stenosis >70% being the greatest predictor of CT-derived FFR <0.8, there was nearly one-third of severe lesions (28.4%) that were functionally insignificant. Similarly, in patients with non-obstructive coronary anatomy (stenosis grading 30–49%), there was a positive CTderived FFR rate of 20.8%. Very recently, the 1-year data from the ADVANCE Registry was published, demonstrating low rates of MI in CT-derived FFR >0.8 (0.19% of total FFR >0.8 group). In addition, 92.9% of individuals in which medical therapy was recommended remained free from revascularisation or major adverse cardiac events at 1 year.40 As the CT-derived FFR technology is refined over the coming years, it is expected to become increasingly available across the National Health Service. The economic impact of this has been considered by NICE when compared with invasive angiography. Conservative estimates show this test could be used in approximately 40,000 patients per year with savings per year of £9.1 million from reduced referral for functional investigation or invasive investigation.37 CT-derived FFR is certain to have an increasing presence in the diagnostic armoury of the cardiologist in the near future, particularly as it offers results on anatomy and physiology in a single test/single visit.

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Latest Advances in Cardiac CT As with all non-invasive cardiac imaging, patient selection will be paramount in delivering this service. In addition, centres will require robust systems for optimising CTCA data set acquisition to ensure quality images for CT-derived FFR analysis.

Figure 3: Multiplanar Reconstruction of the Right Coronary Artery Showing Different Plaque Morphologies and Severe Proximal Stenosis

Plaque Morphology Quantification The analysis of plaque morphology is becoming increasingly important. The ability of CTCA to visualise the entire vessel has several advantages in terms of assessing plaque. There has been extensive recent work on how plaque morphology may impact primary prevention, predictors of ischaemia and prognosis (Figure 3). The seminal work by Motoyama et al. established the CT-based concept of vulnerable plaque (VP) identification on CT, which confers a significantly heightened risk of acute coronary syndrome.41 They assessed 3,158 patients for three high-risk features that are readily identifiable on routine CTCA: low-attenuation plaque (<30 HU), positive remodelling of the coronary vessel (remodelling index of >1.1) and spotty calcification. The event rate was 16% over a median follow-up period of 3.9 years.41 High-risk plaque found on CTCA, specifically the plaque composition (necrotic core/fibrous plaque ratio) correlates with thin-cap fibroatheroma, which is seen on intravascular ultrasound.42 Positive remodelling and low-attenuation plaque have also been demonstrated to be associated with thin-cap fibroatheroma with macrophage infiltration on optical coherence tomography (Figure 4).43

A: Severe luminal stenosis in the proximal plaque complex. B: Reconstruction showing the entire Right Coronary Artery (RCA). C: Further demonstration of the RCA.

Figure 4: Example of Different Plaque Morphology on Coronary CT

Further work around vulnerable plaque in people with type 2 diabetes has recently been published that challenges the high-risk nature of vulnerable plaque morphology. In a series by Halon et al. that included 630 patients, it was shown that VP caused acute coronary syndrome in 3.5% of instances over a median follow-up period of 9.2 years compared with 0.6% of other plaques.44 In other words, 96.5% of VP never causes an event, and the risk attributable to VP was the same as stenosis >50%. The rate of statin therapy was similar at baseline and follow up between ACS cases and non-ACS cases (75â&#x20AC;&#x201C;80%). Although there are important differences in the demographics between these two studies, some of the difference in the event rate attributable to VP could be due to baseline statin use. In the Motoyama et al. cohort, the statin rate after initial CTCA was 38.9% compared with 80% in the Halon et al. cohort.41,44 Despite some disagreement on the exact magnitude of the risk conferred by VP, the detection of vulnerable plaque on CTCA is frequently regarded as an indication for aggressive primary prevention strategies. While statins are considered to help reduce the size of plaque and increase calcification, there does not seem to be major evidence that treating those patients with a CACS of zero confers any benefit in terms of hard cardiovascular endpoints. In a cohort of 13,644 patients, statin therapy was shown to reduce the CVD endpoints in patients with evidence of any coronary calcification (adjusted subhazard ratio 0.76), whereas in the CACS of zero group, there was no risk reduction (subhazard ratio 1).45 We do not yet know the impact of treating only non-calcified plaque with aspirin and statin therapies; however, this seems the obvious course to take. Beyond VP, there are a number of markers obtained on routine CTCA data sets that are used to attribute risk. There have been recent calls to standardise the reporting of CTCA and move away from a

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A: Multiplanar reconstruction of the RCA. B: Visualisation of the mixed plaque component in the mid-RCA. C: Example of the short axis view of the non-calcified aspect of the plaque. D: Short axis view of the calcified aspect of the plaque. E: Example of the napkin ring sign (another high risk plaque feature).

qualitative approach that is mostly employed clinically. This is outlined in the Coronary Artery Disease â&#x20AC;&#x201C; Reporting and Data System document, and may involve using semi-automated scoring systems alongside traditional luminal stenosis.46 Diameter stenosis, specifically obstructive coronary artery disease, is still the most clinically relevant tool that prompts referral for invasive assessment, and is the marker associated with adverse outcome (Figure 5).47 Other markers, such as segmental stenosis score and segmental involvement score, are used to quantify the burden of disease and both show prognostic value.48,49

Imaging Figure 5: Comparison of CT Coronary Angiography Finding to Invasive Coronary Angiography

patients, and found that total plaque volume >179 mm3 was associated with an increased risk of cardiac death (HR 2.3; 95% CI [1.09â&#x20AC;&#x201C;4.58]; p=0.022) for over a mean follow-up period of 5.2 years.53 This is unsurprising, as higher plaque volumes portrays more advanced disease phenotypes. Changes in plaque morphologies over serial CTCAs have the potential to show benefit from primary preventative strategies; the hypothesis being that one would be able to demonstrate to patients reduced plaque volume/VP/stenosis severity in response to specific interventions. Statin therapy is the single most significant pharmacological primary prevention medication, and is well documented to reduce events in secondary prevention cohorts and moderate- to high-risk primary prevention cohorts.54 The influence of statin therapy on coronary plaque has been previously described in intravascular ultrasound virtual histology studies that show reduction in total plaque volumes and increases in dense calcium plaque volumes, although there was no effect on lipid-rich cores.55 Also, the statin effect on coronary plaque is not uniform across agents or dosages.56

A: Axial view of the proximal LAD showing mixed plaque. B: Short axis view of the proximal LAD showing low attenuation non-calcified plaque C: Invasive coronary angiogram showing mild to moderate stenosis of the same coronary segment.

The addition of individual plaque characteristics to diameter stenosis can improve the prediction of functionally significant lesions. Sophisticated semi-automated systems are used to quantify plaque characteristics, such as AutoPlaque (Object Research Systems). These systems are limited to research tools and currently have limited scope in the clinical domain, but may well enter routine clinical practice in the foreseeable future. This disconnect between anatomical assessment and functional importance of a lesion is likely multifactorial. First, the grading of a stenosis may be inaccurate. Second, the location of the lesion and the amount of myocardium subtended is likely to have a role. Third, the plaque morphology at the site of stenosis is likely to portray underlying endothelial dysfunction. The metabolically active plaque confers more endothelial dysfunction, which may contribute to ischaemia secondary to reduced nitric oxide bioavailability.50 To this end, Doris et al. recently published an analysis of CT-derived FFR in non-severe lesions on CTCA. They demonstrated that the best predicator of total vessel ischaemia was total plaque volume (OR 2.09) compared with calcified plaque volume, non-calcified plaque volume and low-density non-calcified plaque volume (OR 1.36, 1.95 and 1.95, respectively).51 Total plaque volume has also been shown to be discriminatory of ischaemia when added to stenosis severity. Ă&#x2DC;verhus et al. recently published data demonstrating the superiority of total vessel plaque versus proximal plaque in predicating ischaemia. This substudy of the HeartFlow Analysis of Coronary Blood Flow Using Coronary CT Angiography (HFNXT) trial demonstrated improvement of the area under the curve of 0.83 versus 0.81 when whole vessel low-density non-calcified plaque volume was added to diameter stenosis versus proximal plaque. Stenosis severity alone had an area under the curve of 0.78.52 A whole vessel approach is more predicative of overall plaque burden, as it takes into account distal disease. Total plaque volume across the entire coronary tree is also associated with cardiac-related death. Hell et al. retrospectively assessed 2,748

On serial CTCA, total plaque volume has consistently been shown to be reduced and calcified plaque volume increased if a significant LDLlowering target is achieved.57 This progressive calcification in the setting of lipid-lowering therapy is yet to be fully elucidated, but the effect likely represents plaque stabilisation. This should not be confused with the fact that an increasing coronary artery calcification score confers an increasing risk, as discussed. Calcium on CACS is a surrogate for total plaque volume and the extent of potential disease. Increasing calcium arcs within a particular plaque is a sign of a more stable plaque.58,59 These facts call into question the utility of performing serial CACS on any patients taking statin medication without considering density. There are also newer models being developed to try and improve on the basic Agatston score.60

Machine Learning ML uses computer-based algorithms to make decisions based on multiple variables without having to know the relationship of those variables to the outcome at the outset of the learning period, or even which variables should be included in the predictive model. It has multiple applications in everyday life and is being increasingly applied to clinical imaging. The key ability of ML with diagnostic imaging is to analyse large data sets and extract the applicable data. With CTCA data sets, there is the potential to improve diagnoses and predicating functionally significant lesions. In addition, it will be able to automatically quantify markers, such as calcium scoring, epicardial fat volumes and liver Hounsfield units (to diagnose fatty liver), and plug these data into scoring systems.61 ML and its applications to CTCA has been previously very well reviewed.62 The integration of ML into clinical practice will bring exciting opportunities in terms of risk prediction. In a feasibility study, Motwani et al. analysed 10,030 patients from a large registry with 5-year followup data. They analysed 25 clinical and 44 CTCA parameters for predicting risk. ML was significantly better at predicting mortality than any individual clinical or CTCA-based risk factor (area under the curve for ML 0.79, Framingham Risk Score 0.61, segmental stenosis score 0.64 and segmental involvement score 0.64).63 Although that study did not take into account the more sophisticated risk stratification calculators (such as Astro-CHARM or MESA), it demonstrates the potential clinical utility of ML. ML has also been demonstrated to be superior at detection of ischaemic lesions by calculating CT perfusion

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Latest Advances in Cardiac CT and adding it to stenosis severity.64 ML-based fractional flow reserve has also been shown to perform well at predicting ischaemic lesions.65,66 The integration of ML into the clinical realm is likely to become reality in the coming decade. As electronic patient records are being increasingly used, the scope for ML is increasing. The potential benefit of ML is multifaceted, and would include enhanced precision of diagnoses and ischaemia, enhanced risk predication (from analysis of countless variables), and reduced healthcare costs from reduced reporting times.

Conclusion Techniques using CT have improved the landscape of non-invasive diagnostic cardiology significantly over the past decade. The short- and long-term future is set to yield significant leaps forward. CT-derived FFR is highly likely to become increasingly prevalent with the aim of increasing the accuracy of patients requiring invasive assessment/ revascularisation. In the subset of patients with previous percutaneous coronary intervention, CT perfusion techniques are currently being investigated. The ADVANCE study is currently recruiting with the aim of reporting the diagnostic accuracy of this technique.67 Potentially, the greatest role of CACS and CTCA is in a primary prevention setting. The addition of a calcium score to traditional risk calculators significantly enhances the accuracy of risk calculators (Astro-CHARM and MESA), which in turn allows a substantial proportion of individuals in the intermediate risk category to be reclassified up or down risk profiles. In addition, the traditional stratification systems for higher-risk populations, such as patients with chronic inflammatory diseases, have been shown to greatly underestimate coronary risk. It may be that CACS takes a more prominent role in achieving enhanced precision in CVD risk estimation in these groups. This will also allow targeted primary prevention strategies in the age of individualised medicine. There has been much debate very recently regarding a strategy of offering a CACS as a standalone test for the assessment of stable chest pain. The reported prognosis conferred by a calcium score of zero in symptomatic patients varies significantly between cohorts. In their substudy of the Coronary Artery Evaluation Using 64-Row Multidetector CT Angiography (CORE-64) data, Gottlieb et al. demonstrated that 19%

eijboom WB, Meijs MFL, Schuijf JD, et al. Diagnostic accuracy M of 64-slice computed tomography coronary angiography. a prospective, multicenter, multivendor study. J Am Coll Cardiol 2008;52:2135–44. https://doi.org/10.1016/j.jacc.2008.08.058; PMID: 19095130. Kelion AD, Nicol ED. The rationale for the primacy of coronary CT angiography in the National Institute for Health and Care Excellence (NICE) guideline (CG95) for the investigation of chest pain of recent onset. J Cardiovasc Comput Tomogr 2018;112:516– 22. https://doi.org/10.1016/j.jcct.2018.09.001; PMID: 30269897. Castellano IA, Nicol ED, Bull RK, et al. A prospective national survey of coronary CT angiography radiation doses in the United Kingdom. J Cardiovasc Comput Tomogr 2017:11;4:268–73. https://doi.org/10.1016/j.jcct.2017.05.002; PMID: 28532693. British Society of Cardiovascular Imaging, Royal College of Radiologists. Fatal heart conditions going undetected due to lack of scanning services. 8 November 2018. https://bsci.org.uk/ wp-content/uploads/2019/01/idor_2018_uk_release.pdf (accessed 18 December 2019). SCOT-HEART Investigators. Coronary CT angiography and 5-year risk of myocardial infarction. N Engl J Med 2018;379:924–33. https://doi.org/10.1056/NEJMoa1805971; PMID: 30145934. Libby P, Bornfeldt KE, Tall AR. Atherosclerosis: successes, surprises, and future challenges. Circ Res 2016;118:531–4. https://doi.org/10.1161/CIRCRESAHA.116.308334; PMID: 26892955. Demer LL, Watson KE, Boström K. Mechanism of calcification in atherosclerosis. Trends Cardiovasc Med 1994;4:45–9. https://doi. org/10.1016/1050-1738(94)90025-6; PMID: 21244909. Johnson RC, Leopold JA, Loscalzo J. Vascular calcification. Circ

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of patients with a calcium score of zero had a stenosis >50%. In addition 12.5% of the zero calcium arm went on for revascularisation.68 In contrast, Mittal et al. reported an all-cause mortality of 1.4% in patients with zero calcium, with none of the patients dying of a coronary event. Although 1.7% of the zero CACS group had >50% stenosis, flow-limiting disease was only proven in 0.3%.69 There are important differences between these two studies, not least the differing pretest probabilities and recruitment setting. Other large cohorts have published varying incidences of NCP and outcome data, but we use these two examples to highlight the significant variation. Proponents of a CACS-only diagnostic strategy will highlight the reduced scan time, radiation and contrast risk to patients, and reduced healthcare costs, which are important concepts in the current age. Further research needs to be performed to analyse the diagnostic and prognostic prowess of a CACS-only strategy in stable chest pain. This is especially important given recent UK guideline changes incorporating CTCA as first-line investigation of stable chest pain. As with all evolving technologies, there are limitations to these emerging technologies. CT-derived FFR is still in its infancy. The applicability of this technique to routine clinical CTCA data set needs to be proven given the rejection rate of up to 13% in registry studies.35 The delivery of modern CT hardware incorporating improved spatial resolution may go some of the way to alleviate this issue. Although the latest ADVANCE 1-year outcomes demonstrate an excellent prognosis in FFR values >0.8, there remains questions to be answered regarding the accuracy with up to 20% positive FFR values in unobstructed coronary arteries. One recent study by Ghekiere et al. compares CTderived FFR with invasive estimated FFR and stress cardiac magnetic resonance in 37 patients with intermediate lesions. A positive correlation was found with semiquantitative measures of ischaemia on cardiac magnetic resonance and CT-derived FFR (r=−0.63).70 Further fully powered studies comparing CT-derived FFR and other functional modalities will be performed to confirm the accuracy of this technology. Ultimately, the use of CTCA and CACS is set to show strong growth. As techniques are refined, an ever-increasing scope for precision medicine will come to the fore, and in our view, these benefits will be strongly supported and amplified by the exciting advances in ML.

Res 2006; 99:1044–59. https://doi.org/10.1161/01. RES.0000249379.55535.21; PMID: 17095733. Agatston AS, Janowitz WR, Hildner FJ, et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15:827–32. https://doi.org/10.1016/07351097(90)90282-T; PMID: 2407762. Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008;358:1336–45. https://doi.org/10.1056/ NEJMoa072100; PMID: 18367736. Raggi P, Gongora MC, Gopal A, et al. Coronary artery calcium to predict all-cause mortality in elderly men and women. J Am Coll Cardiol 2008;52:17–23. https://doi.org/10.1016/j. jacc.2008.04.004; PMID: 18582630. Budoff MJ, Shaw LJ, Liu ST, et al. Long-term prognosis associated with coronary calcification. Observations from a registry of 25,253 patients. J Am Coll Cardiol 2007;49:1860–70. https://doi. org/10.1016/j.jacc.2006.10.079; PMID: 17481445. Hoffmann U, Massaro JM, D’Agostino RB, et al. Cardiovascular event prediction and risk reclassification by coronary, aortic, and valvular calcification in the Framingham Heart Study. J Am Heart Assoc 2016;5:e003144. https://doi.org/10.1161/ JAHA.115.003144; PMID: 26903006. Paixao ARM, Ayers CR, El Sabbagh A, et al. Coronary artery calcium improves risk classification in younger populations. JACC Cardiovasc Imaging 2015;8:1285–93. https://doi. org/10.1016/j.jcmg.2015.06.015; PMID: 26476504. Yeboah J, Young R, McClelland RL, et al. Utility of nontraditional risk markers in atherosclerotic cardiovascular disease risk assessment. J Am Coll Cardiol 2016;67:139–47. https://doi.

org/10.1016/j.jacc.2015.10.058; PMID: 26791059. 16. K avousi M, Elias-Smale S, Rutten JHW, et al. Evaluation of newer risk markers for coronary heart disease risk classification. Ann Intern Med 2012;156:438. https://doi.org/10.7326/0003-4819156-6-201203200-00006; PMID: 22431676. 17. Polonsky TS, McClelland RL, Jorgensen NW, et al. Coronary artery calcium score and risk classification for coronary heart disease prediction. JAMA 2010;303:1610–6. https://doi. org/10.1001/jama.2010.461; PMID: 20424251. 18. Kerr KF, Wang Z, Janes H, et al. Net reclassification indices for evaluating risk-prediction instruments: a critical review. Epidemiology 2014;25:114–21. https://doi.org/10.1097/ EDE.0000000000000018; PMID: 24240655. 19. Chang AM, Litt HI, Snyder BS, et al. Impact of coronary computed tomography angiography findings on initiation of cardioprotective medications. Circulation 2017;136:2195–7. https://doi.org/10.1161/CIRCULATIONAHA.117.029994; PMID: 29180497. 20. Khera A, Budoff MJ, O’Donnell CJ, et al. Astronaut Cardiovascular Health and Risk Modification (Astro-CHARM) coronary calcium atherosclerotic cardiovascular disease risk calculator. Circulation 2018;138:1819–27. https://doi.org/10.1161/ CIRCULATIONAHA.118.033505; PMID: 30354651. 21. Mcclelland RL, Jorgensen NW, Budoff M, et al. Ten-year coronary heart disease risk prediction using coronary artery calcium and traditional risk factors: derivation in the MESA (Multi-Ethnic Study of Atherosclerosis) with validation in the HNR (Heinz Nixdorf Recall) study and the DHS (Dallas Heart Study). J Am Coll Cardiol 2015;66:1643–53. https://doi.org/10.1016/j. jacc.2015.08.035; PMID: 26449133.

Imaging 22. B lum CB, Eckel RH, Goldberg AC, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:1–45. https://doi.org/10.1161/01.cir.0000437738.63853.7a; PMID: 24222016. 23. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2016;37:2315–81. https://doi.org/10.1093/eurheartj/ ehw106; PMID: 27222591. 24. Dhingra R, Vasan RS. Age as a risk factor. Med Clin North Am 2012;96:87–91. https://doi.org/10.1016/j.mcna.2011.11.003; PMID: 22391253. 25. Greenland P, Blaha MJ, Budoff MJ, et al. Coronary calcium score and cardiovascular risk. J Am Coll Cardiol 2018;72:434–47. https://doi.org/10.1016/j.jacc.2018.05.027; PMID: 30025580. 26. Triant VA, Perez J, Regan S, et al. Cardiovascular risk prediction functions underestimate risk in HIV infection. Circulation 2018;137:2203–14. https://doi.org/10.1161/ CIRCULATIONAHA.117.028975; PMID: 29444987. 27. Chow D, Young R, Valcour N, et al. HIV and coronary artery calcium score: comparison of the Hawaii Aging with HIV Cardiovascular Study and Multi-Ethnic Study of Atherosclerosis (MESA) cohorts HHS Public Access. HIV Clin Trials 2015;16:130–8. https://doi.org/10.1179/1528433614Z.0000000016; PMID: 26038953. 28. Budoff MJ, Mayrhofer T, Ferencik M, et al. Prognostic value of coronary artery calcium in the PROMISE study (Prospective Multicenter Imaging Study for Evaluation of Chest Pain). Circulation 2017;136:1993–2005. https://doi.org/10.1161/ CIRCULATIONAHA.117.030578; PMID: 28847895. 29. Sarwar A, Shaw LJ, Shapiro MD, et al. Diagnostic and prognostic value of absence of coronary artery calcification. JACC Cardiovasc Imaging 2009;2:675–88. https://doi.org/10.1016/j. jcmg.2008.12.031; PMID: 19520336. 30. Nørgaard BL, Hjort J, Gaur S, et al. Clinical use of coronary ctaderived ffr for decision-making in stable CAD. JACC Cardiovasc Imaging 2017;10:541–50. https://doi.org/10.1016/j. jcmg.2015.11.025; PMID: 27085447. 31. Lu MT, Ferencik M, Roberts RS, et al. Noninvasive FFR derived from coronary ct angiography: management and outcomes in the PROMISE trial. JACC Cardiovasc Imaging 2017;10:1350–8. https://doi.org/10.1016/j.jcmg.2016.11.024; PMID: 28412436. 32. Thompson AG, Raju R, Blanke P, et al. Diagnostic accuracy and discrimination of ischemia by fractional flow reserve CT using a clinical use rule: results from the Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography study. J Cardiovasc Comput Tomogr 2015;9:120–8. https://doi.org/10.1016/j.jcct.2015.01.008; PMID: 25819194. 33. Douglas PS, Pontone G, Hlatky MA, et al. Clinical outcomes of fractional flow reserve by computed tomographic angiographyguided diagnostic strategies vs. usual care in patients with suspected coronary artery disease: the prospective longitudinal trial of FFR(CT): outcome and resource impacts study. Eur Heart J 2015;36:3359–67. https://doi.org/10.1093/eurheartj/ehv444; PMID: 26330417. 34. Lima RSL, Watson DD, Goode AR, et al. Incremental value of combined perfusion and function over perfusion alone by gated SPECT myocardial perfusion imaging for detection of severe three-vessel coronary artery disease. J Am Coll Cardiol 2003;42:64–70. https://doi.org/10.1016/S0735-1097(03)00562-X; PMID: 12849661. 35. Nørgaard BL, Leipsic J, Gaur S, et al. Diagnostic performance of noninvasive fractional flow reserve derived from coronary computed tomography angiography in suspected coronary artery disease: the NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps). Am J Coll Cardiol 2014;63:1145–55. https://doi.org/10.1016/j.jacc.2013.11.043; PMID: 24486266. 36. Cook CM, Petraco R, Shun-Shin MJ, et al. Diagnostic accuracy of computed tomography-derived fractional flow reserve. JAMA Cardiol 2017;2:803. https://doi.org/10.1001/ jamacardio.2017.1314; PMID: 28538960. 37. National Institute for Health and Care Excellence. HeartFlow FFRCT for estimating fractional flow reserve from coronary CT angiography. London: NICE; 2017. https://www.nice.org.uk/ guidance/mtg32 (accessed 29 November 2019). 38. Kitabata H, Leipsic J, Patel MR, et al. Incidence and predictors of lesion-specific ischemia by FFR CT: learnings from the

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53.

54.

international ADVANCE registry. J Cardiovasc Comput Tomogr 2018;12:95–100. https://doi.org/10.1016/j.jcct.2018.01.008; PMID: 29422416. Curzen N, Rana O, Nicholas Z, et al. Does routine pressure wire assessment influence management strategy at coronary angiography for diagnosis of chest pain? The RIPCORD study. Circ Cardiovasc Interv 2014;7:248–55. https://doi.org/10.1161/ CIRCINTERVENTIONS.113.000978; PMID: 24642999. Patel MR, Nørgaard BL, Fairbairn TA, et al. 1-year impact on medical practice and clinical outcomes of FFRCT: The ADVANCE Registry. JACC Cardiovasc Imaging 2019. https://doi.org/10.1016/j. jcmg.2019.03.003; PMID: 31005540; epub ahead of press. Motoyama S, Ito H, Sarai M, et al. Plaque characterization by coronary computed tomography angiography and the likelihood of acute coronary events in mid-term follow-up. J Am Coll Cardiol 2015;66:337–46. https://doi.org/10.1016/j.jacc.2015.05.069; PMID: 26205589. Obaid DR, Calvert PA, Brown A, et al. Coronary CT angiography features of ruptured and high-risk atherosclerotic plaques: correlation with intra-vascular ultrasound. J Cardiovasc Comput Tomogr 2017;11:455–61. https://doi.org/10.1016/j. jcct.2017.09.001; PMID: 28918858. Nakazato R, Otake H, Konishi A, et al. assessment of plaque characterization on coronary ct angiography for identification of high-risk coronary artery lesions: a direct comparison to optical coherence tomography. J Am Coll Cardiol 2014;63:A1161. https:// doi.org/10.1016/S0735-1097(14)61161-X. Halon DA, Lavi I, Barnett-Griness O, et al. Plaque morphology as predictor of late plaque events in patients with asymptomatic type 2 diabetes: a long-term observational study. JACC: Cardiovascular Imaging 2019;12:1353–63. https://doi. org/10.1016/j.jcmg.2018.02.025; PMID: 29778864. Mitchell JD, Fergestrom N, Gage BF, et al. Impact of statins on cardiovascular outcomes following coronary artery calcium scoring. J Am Coll Cardiol 2018;72:3233–42. https://doi. org/10.1016/j.jacc.2018.09.051; PMID: 30409567. Perna AF, Castaldo P, Ingrosso D, De Santo NG. Homocysteine, a new cardiovascular risk factor, is also a powerful uremic toxin. J Nephrol 1999;12:230–40. https://doi.org/10.1016/j. jcct.2016.04.005; PMID: 27318587. Al-Mallah MH, Qureshi W, Lin FY, et al. Does coronary CT angiography improve risk stratification over coronary calcium scoring in symptomatic patients with suspected coronary artery disease? Results from the prospective multicenter international CONFIRM registry. Eur Hear J Cardiovasc Imaging 2014;15:267–74. https://doi.org/10.1093/ehjci/jet148; PMID: 23966421. Ayoub C, Erthal F, Abdelsalam MA, et al. Prognostic value of segment involvement score compared to other measures of coronary atherosclerosis by computed tomography: A systematic review and meta-analysis. J Cardiovasc Comput Tomogr 2017;11:258–67. https://doi.org/10.1016/j. jcct.2017.05.001; PMID: 28483581. Min JK, Shaw LJ, Devereux RB, et al. Prognostic value of multidetector coronary computed tomographic angiography for prediction of all-cause mortality. J Am Coll Cardiol 2007;50:1161– 70. https://doi.org/10.1016/j.jacc.2007.03.067; PMID: 17868808. Ahmadi A, Kini A, Narula J. Discordance Between Ischemia and Stenosis, or PINSS and NIPSS: are we ready for new vocabulary? JACC Cardiovasc Imaging 2015;8:111–4. https://doi. org/10.1016/j.jcmg.2014.11.010; PMID: 25592703. Doris MK, Otaki Y, Arnson Y, et al. Non-invasive fractional flow reserve in vessels without severe obstructive stenosis is associated with coronary plaque burden. J Cardiovasc Comput Tomogr 2018;12:379–84. https://doi.org/10.1016/j. jcct.2018.05.003; PMID: 29784622. Øvrehus KA, Gaur S, Leipsic J, et al. CT-based total vessel plaque analyses improves prediction of hemodynamic significance lesions as assessed by fractional flow reserve in patients with stable angina pectoris. J Cardiovasc Comput Tomogr 2018;12:344– 9. https://doi.org/10.1016/j.jcct.2018.04.008; PMID: 29866619. Hell MM, Motwani M, Otaki Y, et al. Quantitative global plaque characteristics from coronary computed tomography angiography for the prediction of future cardiac mortality during long-term follow-up. Eur Heart J Cardiovasc Imaging 2017;18:1331–9. https://doi.org/10.1093/ehjci/jex183; PMID: 28950315. Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2021–31. https://doi.org/10.1056/ NEJMoa1600176; PMID: 27040132.

55. B anach M, Serban C, Sahebkar A, et al. Impact of statin therapy on coronary plaque composition: a systematic review and meta-analysis of virtual histology intravascular ultrasound studies. BMC Med 2015;13:229. https://doi.org/10.1186/s12916015-0459-4; PMID: 26385210. 56. Hou J, Xing L, Jia H, et al. Comparison of intensive versus moderate lipid-lowering therapy on fibrous cap and atheroma volume of coronary lipid-rich plaque using serial optical coherence tomography and intravascular ultrasound imaging. Am J Cardiol 2016;117:800–6. https://doi.org/10.1016/j. amjcard.2015.11.062; PMID: 26778524. 57. Tamarappoo B, Otaki Y, Doris M, et al. Improvement in LDL is associated with decrease in non-calcified plaque volume on coronary CTA as measured by automated quantitative software. J Cardiovasc Comput Tomogr 2018;12:385–90. https://doi. org/10.1016/j.jcct.2018.05.004; PMID: 29793847. 58. Murray SW, Patel B, Stables RH, et al. Site-specific intravascular ultrasound analysis of remodelling index and calcified necrosis patterns reveals novel blueprints for coronary plaque instability. Cardiovasc Diagn Ther 2014;4:287–98. 59. Murray SW, Stables RH, Garcia-Garcia HM, et al. Construction and validation of a plaque discrimination score from the anatomical and histological differences in coronary atherosclerosis: the Liverpool IVUS-V-HEART (Intra Vascular UltraSound-Virtual-Histology Evaluation of Atherosclerosis Requiring Treatment) study. EuroIntervention 2014;10:815–23. https://doi.org/10.4244/EIJV10I7A141; PMID: 24472736. 60. Fuhr P, Rooke S. Is it time for a change in cybersecurity? InTech 2017;64:10–5. 61. Commandeur F, Goeller M, Betancur J, et al. Deep learning for quantification of epicardial and thoracic adipose tissue from non-contrast CT. IEEE Trans Med Imaging 2018;37:1835-46. https://doi.org/10.1109/TMI.2018.2804799; PMID: 29994362. 62. Singh G, Al’Aref SJ, Van Assen M, et al. Machine learning in cardiac CT: Basic concepts and contemporary data. J Cardiovasc Comput Tomogr 2018;12:192–201. https://doi.org/10.1016/j. jcct.2018.04.010; PMID: 29754806. 63. Motwani M, Dey D, Berman DS, et al. Machine learning for prediction of all-cause mortality in patients with suspected coronary artery disease: a 5-year multicentre prospective registry analysis. Eur Heart J 2017;38:500–7. https://doi. org/10.1093/eurheartj/ehw188; PMID: 27252451. 64. Han D, Lee JH, Rizvi A, et al. Incremental role of resting myocardial computed tomography perfusion for predicting physiologically significant coronary artery disease: A machine learning approach. J Nucl Cardiol 2018;25:223–33. https://doi. org/10.1007/s12350-017-0834-y; PMID: 28303473. 65. von Knebel Doeberitz PL, De Cecco CN, Schoepf UJ, et al. Coronary CT angiography-derived plaque quantification with artificial intelligence CT fractional flow reserve for the identification of lesion-specific ischemia. Eur Radiol 2019;29:2378–87. https://doi.org/10.1007/s00330-018-5834-z; PMID: 30523456. 66. Coenen A, Kim YH, Kruk M, et al. Diagnostic accuracy of a machine-learning approach to coronary computed tomographic angiography-based fractional flow reserve. Circ Cardiovasc Imaging 2018;11:e007217. https://doi.org/10.1161/ CIRCIMAGING.117.007217; PMID: 29914866. 67. Andreini D, Mushtaq S, Pontone G, et al. Rationale and design of advantage (additional diagnostic value of CT perfusion over coronary CT angiography in stented patients with suspected in-stent restenosis or coronary artery disease progression) prospective study. J Cardiovasc Comput Tomogr 2018;12:411–7. https://doi.org/10.1016/j.jcct.2018.06.003; PMID: 29933938. 68. Gottlieb I, Miller JM, Arbab-Zadeh A, et al. The absence of coronary calcification does not exclude obstructive coronary artery disease or the need for revascularization in patients referred for conventional coronary angiography. J Am Coll Cardiol 2010;55:627–34. https://doi.org/10.1016/j.jacc.2009.07.072; PMID: 20170786. 69. Mittal TK, Pottle A, Nicol E, et al. Prevalence of obstructive coronary artery disease and prognosis in patients with stable symptoms and a zero-coronary calcium score. Eur Heart J Cardiovasc Imaging 2017;18:922-9. https://doi.org/10.1093/ehjci/ jex037; PMID: 28379388. 70. Ghekiere O, Bielen J, Leipsic J, et al. Correlation of FFR-derived from CT and stress perfusion CMR with invasive FFR in intermediate-grade coronary artery stenosis. Int J Cardiovasc Imaging 2019;35:559–68. https://doi.org/10.1007/s10554-0181464-4; PMID: 30284138.

EUROPEAN CARDIOLOGY REVIEW

Heart Disease

Applications for Induced Pluripotent Stem Cells in Disease Modelling and Drug Development for Heart Diseases Shu Nakao,1,2,3 Dai Ihara,1,2 Koji Hasegawa3 and Teruhisa Kawamura1,2,3 1. Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Japan; 2. Global Innovation Research Organization, Ritsumeikan University, Kusatsu, Japan; 3. Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan

Abstract Induced pluripotent stem cells (iPSCs) are derived from reprogrammed somatic cells by the introduction of defined transcription factors. They are characterised by a capacity for self-renewal and pluripotency. Human (h)iPSCs are expected to be used extensively for disease modelling, drug screening and regenerative medicine. Obtaining cardiac tissue from patients with mutations for genetic studies and functional analyses is a highly invasive procedure. In contrast, disease-specific hiPSCs are derived from the somatic cells of patients with specific genetic mutations responsible for disease phenotypes. These disease-specific hiPSCs are a better tool for studies of the pathophysiology and cellular responses to therapeutic agents. This article focuses on the current understanding, limitations and future direction of disease-specific hiPSC-derived cardiomyocytes for further applications.

Keywords Induced pluripotent stem cell, cardiomyocyte, genetic disease, drug screening, gene editing Disclosure: This work was supported by grants from JSPS KAKENHI (to TK and SN) and an Inamori Foundation Research Grant for Natural Sciences (to SN). TK is the group leader of the research project supported by Ritsumeikan Global Innovation Research Organization (R-GIRO). All other authors have no conflicts of interest to declare. Acknowledgements: The authors thank Steven H DeVries (Ophthalmology & Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, US) for helpful suggestions during writing of the manuscript. The authors also thank all members of the Laboratory of Stem Cell and Regenerative Medicine for helpful discussions. Received: 21 May 2019 Accepted: 9 August 2019 Citation: European Cardiology Review 2020;15:e02. DOI: https://doi.org/10.15420/ecr.2019.03 Correspondence: Teruhisa Kawamura, 1–1-1 Noji-higashi, Kusatsu, Shiga 525-8577, Japan. E: kawater@fc.ritsumei.ac.jp Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Induced Pluripotent Stem Cells and Their Potential Applications Induced pluripotent stem cells (iPSCs) are generated from somatic cells, such as skin fibroblasts, by ectopic expression of defined reprogramming factors. Within a few years of the first report of the generation of mouse iPSCs, several laboratories reportedly reproduced these cells using other cell types and species using similar approaches.1–4 This early attention on reproducible methods for the production of iPSCs from mammalian cells accelerated research into iPSC technology for clinical applications. iPSCs show unlimited proliferation capacity and pluripotency, as observed in embryonic stem cells (ESCs), and thus have significant advantages as a cell source for producing sufficient numbers of any cell type. In contrast with ESCs, human (h) iPSCs can be established from differentiated cells without destroying human embryos, thereby overcoming related ethical issues. Thus, iPSCs have been extensively investigated worldwide for applications in disease modelling, drug screening and regenerative medicine (Figure 1).2,5 When hiPSCs are derived from patients with a genetic disease caused by a mutation, such patient-derived iPSCs are called disease-specific hiPSCs. As disease-specific hiPSCs contain the same genetic information

as the patient, including mutations corresponding to the altered gene function,6,7 disease-specific hiPSCs could potentially be a powerful tool for modelling human disease. Particularly in cardiovascular research, obtaining a sufficient number of cardiomyocytes (CMs) from patients is challenging due to the highly invasive procedures required to extract them. Further, the low proliferation capacity of CMs limits researchers’ ability to maintain these cells in culture. Being able to generate iPSCderived CMs (hiPSC-CMs) from a specific patient overcomes this problem, and enables identification of typical cellular responses to pathological stress and therapeutic agents because these cells potentially reflect the biological responses of an individual patient’s own CMs (Figure 1). Recent genetic research has led to the identification of gene mutations responsible for hereditary heart diseases. Investigations into the pathophysiology of those inherited diseases often use animal models that partially mirror the disease conditions. However, animal studies are low throughput, time consuming and relatively expensive. Moreover, there are interspecies differences between humans and the experimental animals in terms of molecular and physiological properties (e.g. ion channel expression profile, heart rate), as well as in the cellular responses to pathological stress. Therefore, experimental results

Access at: www.ECRjournal.com

Heart Disease Figure 1: Human Induced Pluripotent Stem Cell Applications in Cardiovascular Medicine Patients with inherited heart disease

Somatic cells (skin fibroblasts, blood cells)

Somatic cell reprogramming Viral or non-viral vector-mediated gene introduction Disease-specific patient-derived iPSC lines

CRISPR/Cas9-based gene editing

Differentiation

NGG

iPSC-derived cardiomyocytes (disease model in a dish)

Disease-specific novel therapies

Drug screening Against disease-relevant and drug-targeted molecules

Regeneration therapy Phenotypic analysis (+/− gene editing) • Cellular electrophysiology • Gene expression profiling • Functional assays (Ca2+ regulation, contraction force)

Cas9 = CRISPR-associated 9; CRISPR = clustered regularly interspaced short palindromic repeat; iPSC = induced pluripotent stem cell.

obtained from animal models do not perfectly recapitulate the conditions occurring in humans, and are less reliable for the purpose of extrapolation. In contrast, disease-specific hiPSCs could be a valuable tool in research on inherited diseases and for testing therapeutic agents. hiPSCs are created from somatic cells, which can be easily collected from accessible patient tissues, such as skin and blood. Owing to their self-renewal property, hiPSCs could be used to produce a sufficient number of specific cell types following appropriate differentiation methods for further experiments in vitro.

Human Induced Pluripotent Stem Cells for Modelling Inherited Arrhythmias Advances in cardiovascular research have increased our understanding of the molecular mechanisms underlying various genetic diseases. Comprehensive genetic studies have identified causal mutations responsible for phenotypes of inherited cardiovascular diseases such as long QT syndrome (LQTS), Brugada syndrome and cardiomyopathies. LQTS is characterised by a significantly prolonged QT interval attributable to delayed repolarisation in the ventricular myocardium. Some types of LQTS cause life-threatening arrhythmias in response to stimuli such as swimming and sudden loud noise. Genetic studies have found a number of gene loci responsible for LQTS in families with a high incidence of the disease. Despite an absence of clinical symptoms under sedentary conditions in patients with LQTS, once ventricular tachyarrhythmias are triggered by specific stimuli, patients with LQTS are prone to exhibit syncope. Sustained arrhythmias ultimately lead to VF, resulting in sudden cardiac death. Several studies on patients with LQTS have identified a number of mutations in genes encoding cardiac ion channels, which are membrane proteins regulating the generation and propagation of action potential.8–10 However, these mutations are not always responsible for the observed symptoms, even when the patients are exposed to the stimuli that trigger electrophysiological changes. Effects of the stimuli or therapeutic agents, as well as the incidence of cardiac events, vary considerably among individual patients. Therefore,

to address issues related to proarrhythmic mechanisms in individuals with inherited LQTS, patient-derived hiPSC-CMs with the corresponding mutation(s) could serve as powerful tools for in vitro experiments. Previous studies characterising mutations of the alpha-subunit of the potassium voltage-gated channel subfamily Q member 1 (KCNQ1; also known as KVLQT1 and KV7.1) using patient-derived iPSC-CMs revealed that impaired membrane trafficking of Ks channels and reduced delayed rectifier potassium channel current (IKr) cause LQT1.9,11,12 Itzhaki et al. introduced reprogramming factors into dermal fibroblasts obtained from patients with a mutation in the alpha-subunit of potassium voltage-gated channel subfamily H member 2 (KCNH2; responsible for IKr) causing LQT2.13 Spontaneously beating hiPSC-CMs carrying this mutation were used for functional analysis and exhibited a prolonged QT interval similar to that in LQTS patients. Similar studies using hiPSC-CMs derived from a patient with a missense mutation in KCNH2 also exhibited action potential prolongation, smaller IKr, early afterdepolarisations and arrhythmias. These changes were recovered or exaggerated by pharmacological agents or selective RNA interference in disease-specific hiPSC-CMs.13–16 Disease-specific hiPSC-CMs from patients and families with Timothy syndrome (LQT8) that have a mutation located in calcium voltage-gated channel subunit alpha1 C (CACNA1C; responsible for the L-type calcium current, ICa,L) have been established and assessed for mutationassociated phenotypes in vitro.10,17,18 An LQT8 model using patientspecific hiPSC-CMs reflected cellular electrical abnormalities, including prolonged action potential duration, delayed afterdepolarisations and altered Ca2+ transients. In contrast, roscovitine, an inhibitor of cyclindependent kinase 5, a key mediator involved in the regulation of CaV1.2 channels, enhanced ICa,L inactivation, shortened action potential duration, restored the irregular Ca2+ transient and decreased the frequency of abnormal depolarisations in LQT8 hiPSC-CMs.10,17,18 Furthermore, other inherited arrhythmias have been investigated using disease-specific hiPSC-CMs, including various types of LQTS – mutations in sodium voltage-gated channel alpha subunit 5 (SCN5A), potassium inwardly rectifying channel subfamily J member 2 (KCNJ2), calmodulin 1 (CALM1) or calmodulin 2 (CALM2), short QT syndrome (KCNH2 mutation), Brugada syndrome type 1 (SCN5A mutation) and catecholaminergic polymorphic ventricular tachycardia (mutations in ryanodine receptor 2 (RYR2) or calsequestrin 2 [CASQ2]).19–40 These cells recapitulated cellular electrophysiological changes in the heart of patients. Table 1 summarises the different studies that have used hiPSC-CMs as models to investigate inherited arrhythmias.

Human Induced Pluripotent Stem Cells for Modelling of Inherited Cardiomyopathies In addition to inherited arrhythmias, there are some incidences of cardiomyopathies in families carrying specific genetic variant(s) that are responsible for causing the disease. Dilated cardiomyopathy (DCM) is a major type of cardiomyopathy that is characterised by systolic dysfunction and dilated cardiac chambers comprised of thin myocardial walls.41 Most cases of DCM without any identifiable cause (e.g. coronary artery disease, systemic hypertension, viral infection) are diagnosed as ‘idiopathic’ DCM. Based on family history and clinical findings, including sudden cardiac death, heart failure and abnormal echocardiography, previous clinical studies have proposed that familial transmission of idiopathic DCM is

EUROPEAN CARDIOLOGY REVIEW

IPSC Applications in Heart Diseases

Disease Phenotype KCNQ1 (R190Q)

Causal Genes (Mutations)

Reduced IKs, APD prolongation, drug-induced FPD prolongation

Reduced IKs, APD prolongation, irregular KCNQ1 localisation, increased susceptibility to isoproterenolinduced tachyarrhythmia

Cellular Phenotypes in iPSC-CMs

ML277 (KV channel activator) partially restored IKs and APD Egashira et al.11 Ma et al.12

Isoproterenol-induced EAD was prevented by propranolol (beta-blocker)

Drug Responses

Morettin et al.9

References

APD/FPD prolongation

Reduced IKr, APD prolongation, EADs

Reduced IKr, APD prolongation, EADs, triggered activity

The cellular phenotype was reversed by mexiletine (NaV blocker)

N/A

LUF7346 (hERG modulator) normalised IKs and APD

EADs were induced by E4031 (hERG blocker), APD prolongation and EAD were reduced by nicorandil and PD118057 (hERG activators), isoproterenol-induced EADs were blocked by nadolol and propranolol (beta-blockers)

Terrenoire et al.26

Malan et al.24

Ma et al.23

Fatima et al.20

Sala et al.16

Matsa et al.15

Hypersensitivity to arrhythmogenic drugs including sotalol Lahti et al.14 (beta-blocker)

EADs were completely blocked by nifedipine (Ca2+ blocker), Itzhaki et al.13 abolished by pinacidil (KATP channel agonist), inhibited by ranolazine (late INa inhibitor)

Sala et al.16

KCNQ1 (exon 7 deletion)

Table 1: Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Models of Inherited Arrhythmias Disease LQT1

LQT with broad-based T wave by reduced IKs, polymorphic ventricular tachycardia, often triggered by sympathetic activation (e.g. swim exercise, emotions)

LUF7346 (hERG modulator) normalised IKs and APD

Reduced IKr, APD prolongation

Sodium current irregularities were rescued by mexiletine and ranolazine (NaV blockers)

Isoproterenol-induced EAD was prevented by propranolol (beta-blocker)

Enhanced INa, APD prolongation

Enhanced INa,L was reduced by increased pacing and mexiletine (NaV blocker)

Davis et al.19

KCNQ1 (R594Q, R190Q) Reduced IKs activation, APD prolongation, abnormal subcellular KCNQ1 R190Q localisation

APD prolongation, EADs, shorter INa inactivation time

SCN5A (V240M, R535Q) APD prolongation, delayed INa time to peak and inactivation time

KCNH2 (N006I)

INa irregularities, delayed repolarisation, fatal arrhythmia

N/A

KCNH2 (A614V)

SCN5A (F1473C)

Decreased INa density and upstroke velocity, APD prolongation, increased persistent INa

LQT2

SCN5A (1795insD)

Irregular Ca2+ release

Cellular phenotype was improved by flecainide and pilsicainide (NaV blockers) and KB-R7943 (INCX inhibitor)

CALM2 (N98S)

CALM (D130G)

CALM1 (F142L)

CACNA1C (G406R)

CACNA1C (G1216A)

APD prolongation, altered Ca2+ transients, defective ICa,L inactivation, rescued by mutant gene suppression

QT prolongation, higher sensitivity to isoproterenol, altered rete dependency, defective ICa,L inactivation

Irregular contractions, excessive Ca2+ influx, APD prolongation, irregular Ca2+ transients

APD prolongation, DADs, abnormal Ca2+ transients, irregular and slow contraction

N/A

QT prolongation was reversed by verapamil (Ca2+ blocker)

Ca2+ defects and abnormal channel inactivation were improved by roscovitine (CDK5 inhibitor)

Cellular phenotype was rescued by roscovitine (CDK5 inhibitor)

Yamamoto et al.27

Limpitikul et al.22

Rocchetti et al.25

Yazawa et al.10 and Song et al.17

Yazawa et al.18

Kuroda et al.21

SCN5A (R1644H)

SCN5A (V1763M)

KCNH2 (G1681A)

KCNH2 (R176W)

LQT accompanied by bradycardia, conduction disease and/or Brugada syndrome

KCNJ2 (R218W, R67W, R218Q)

LQT with bifid T wave by reduced IKr, ventricular tachyarrhythmias triggered by sudden noise at rest; higher incidence in women

LQT3 (Overlap syndrome)

LQT accompanied by periodic paralysis, skeletal developmental abnormalities

LQT3

LQT7 (Andersenâ&#x20AC;&#x201C; Tawil syndrome)

Dysfunction in multiple organs characterised by congenital cardiac defects, immune deficiency, autism and LQT with enhanced ICa,L

LQT14

LQT associated with calmodulin-1 mutation enhancing ICa,L

LQT with late peaking T wave by enhanced INa,L, lethal events often at rest

LQT8 (Timothy syndrome)

LQT15

LQT associated with calmodulin-2 mutation enhancing ICa,L

(Continued)

Lower beating rate, APD prolongation, defective ICa,L inactivation, rescued by gene correction of mutant allele

EUROPEAN CARDIOLOGY REVIEW

Shortened QT, sudden cardiac death

Coved-type ST elevation followed by a descending negative T wave in V1 to V3 on ECG, risk of malignant ventricular arrhythmias, reduced INa

Stress-induced ventricular tachyarrhythmias in structurally normal hearts

Short QT syndrome

Brugada syndrome 1

CPVT1

CPVT2

Cellular Phenotypes in iPSC-CMs Increased KCNH2 expression, increased IKr density, shortened APD, irregular and abnormal Ca2+ transients, arrhythmic activity induced by carbachol (cholinergic activator) Reduced INa density, restored by wild-type gene expression Reduced INa and maximal upstroke AP velocity, abnormal Ca2+ transients, variable beating intervals Reduced INa density DADs, altered and irregular Ca2+ transients, abnormal Ca2+ response after cAMP-induced phosphorylation

Isoproterenol or forskolin (adrenergic stimulation)enhanced DADs and triggered activity, EADs, irregular Ca2+ transients

Isoproterenol-induced diastolic Ca2+ elevation, reduced SR Ca2+ content, DADs, increased frequency and duration of Ca2+ release, arrhythmias Abnormal Ca2+ transients, EADs, reduced SR Ca2+ content, increased non-alternating variability of Ca2+ transients in response to isoproterenol and adrenaline, decreased AP upstroke velocity Less developed ultrastructure, isoproterenol-induced arrhythmias and increased diastolic Ca2+ levels Altered Ca2+ transients, low SR Ca2+ content, Ca2+ leak, isoproterenol-induced irregular Ca2+ waves, prolonged Ca2+ sparks and DADs Increased diastolic Ca2+ waves, pacing-induced DADs Isoproterenol-induced DADs, EADs, oscillatory arrhythmic prepotentials, increased diastolic intracellular Ca2+ levels, irregular Ca2+ transients, reduced threshold for store overload-induced Ca2+ release, myofibril disorganisation, SR abnormalities, reduced caveolae

Causal Genes (Mutations) KCNH2 (N588K)

PKP2 (c.2484C>T) SCN5A (R620H, R811H) SCN5A (R367H) RYR2 (F2483I)

RYR2 (M4109R)

RYR2 (S406L)

RYR2 (P2328S)

RYR2 (R420Q) RYR2 (L3741P)

RYR2 (I4587V) CASQ2 (D307H)

JTB-519 (RyR stabiliser) and carvedilol suppressed abnormal Ca2+ cycling

Propranolol, carvedilol (beta-blockers), riluzole and flecainide (NaV blockers) inhibited isoproterenol-induced arrhythmia

S107 (RyR2 stabiliser) reduced DADs

Cellular phenotype was rescued by flecainide (NaV blocker)

N/A

Dantrolene (RyR inhibitor) restored normal Ca2+ spark properties and rescued the arrhythmogenic phenotype

Irregular Ca2+ transients was improved by propranolol (beta-blocker)

DADs were eliminated by flecainide (NaV blocker) and thapsigargin (SERCA inhibitor)

Abnormal Ca2+ response after repolarisation was abolished by forskolin (adenylyl cyclase agonist)

DADs were induced by isoproterenol

N/A

Quinidine (multiple channel inhibitor) prolonged APD and carbachol-induced arrhythmias

Drug Responses

Jung et al.34 Maizels et al.36 Novak et al.37,38

Sasaki et al.40

Preininger et al.39

Novak et al.37

Jung et al.,34 Kujala et al.35

Jung et al.34

Itzhaki et al.33

Fatima et al.32

Selga et al.31

Liang et al.30

Cerrone et al.29

El-Battrawy et al.28

References

AP = action potential; APD = action potential duration; CACNA1C = calcium voltage-gated channel subunit alpha1 C; CALM1 = calmodulin 1; CALM2 = calmodulin 2; cAMP = cyclic adenosine monophosphate; CASQ2 = calsequestrin 2; CDK5 = cyclin-dependent kinase 5; CM = cardiomyocyte; CPVT = catecholaminergic polymorphic ventricular tachycardia; DAD = delayed afterdepolarisation; EAD = early afterdepolarisation; FPD = field potential duration; hERG = pore-forming subunit of rapidly activating delayed rectifier potassium channel; iPSC-CM = induced pluripotent stem cell-derived cardiomyocyte; ICa,L = voltage-gated L-type calcium channel current; IKr = rapid delayed rectifier potassium current; IKs = slow delayed rectifier potassium current; INa = sodium current; INa,L = late sodium current; INCX = sodium-calcium exchanger current; KCNH2 = potassium voltage-gated channel subfamily H member 2; KCNQ1 = potassium voltage-gated channel subfamily Q member 1; KV = voltage-gated potassium channel; LQT = long QT; N/A = not applicable; NaV = voltage-gated sodium channel; PKP2 = plakophilin 2; RyR2 = ryanodine receptor 2; SCN5A = sodium voltage-gated channel alpha subunit 5; SERCA = sarcoplasmic/endoplasmic reticulum calcium ATPase; SR = sarcoplasmic reticulum.

Disease Phenotype

Disease

Table 1: Cont.

Heart Disease

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IPSC Applications in Heart Diseases observed in 20–50% of patients.42–44 When idiopathic DCM is identified in two or more family members, it is defined as familial DCM (FDC). FDC is largely caused by autosomal dominant mutations in key cardiac genes encoding sarcomere-related proteins, cytoskeletal proteins, mitochondrial proteins, nuclear membrane proteins and calcium regulators.43,45,46 These loss-of-function mutations lead to the abnormal morphology and function of the heart that is seen in idiopathic DCM. Moreover, recently developed high-throughput gene analyses have revealed that inherited DCM is associated with mutations in more than 100 gene loci.47 Although the pathophysiology of FDC is heterogeneous, the effect of each individual mutation has been unclear in the context of FDC. To address this, human CMs are ideal for in vitro functional analysis of mutations associated with FDC, but, as mentioned earlier, it is difficult to acquire a renewable source of cardiac cells. Compared with animal models and non-CMs expressing DCM mutant proteins, hiPSC-CMs are expected to exhibit responses similar to those observed in native human myocardium. For example, individual families carry a mutation that causes an arginine-to-tryptophan substitution at amino acid position 173 in the cardiac troponin T (cTnT) protein.48 Patient-specific hiPSCs were produced using minimally invasive procedures from skin fibroblasts of family members, and hiPSC-CMs were generated and tested to investigate the mechanisms underlying FDC. The FDC hiPSCCMs exhibited reduced Ca2+ influx and contractility, despite normal electrophysiological properties. These cells also showed the characteristic patchy structure of myofilaments, which was enhanced upon noradrenaline stimulation and stretching, leading to systolic dysfunction.48 This is consistent with the fact that the tendency towards DCM is enhanced by increases in inotropic effects and hypertension. These findings explain the involvement of cTnT dysfunction in the development of DCM. Thus, FDC hiPSC-CMs recreate, at least in part, the pathophysiology of FDC in human patients. Other causal gene mutations responsible for inherited cardiomyopathies, including DCM, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy/dysplasia, have been reported.49–57 Table 2 lists studies that have used hiPSC-CMs as models for investigating inherited cardiomyopathies. Although numerous studies have summarised the characteristic features of familial heart diseases using patient-specific hiPSC-CMs, as described above, it is still challenging to fully recapitulate the disease phenotype using iPSC-CM-based disease modelling, primarily because hiPSC-CMs exhibit immature functions and morphology. For example, an incomplete ion channel profile (e.g. lack of IK1, corresponding to slower action potential kinetics and a relatively positive diastolic potential) and subcellular structure (e.g. the absence of or underdeveloped T-tubule and sarcomere formation) are commonly observed in hiPSC-CMs.58–60 The gene expression profile of hiPSC-CMs also resembles that of foetal CMs and is distinct from that of adult CMs.60,61 The immaturity of hiPSC-CMs in terms of function and gene expression profile may result in controversial findings, particularly in the investigation of late-onset cardiac diseases that largely require adult CM-like cells for disease modelling. In an in vitro study using hiPSC-CMs to investigate the pathophysiology of late-onset Pompe disease, which is characterised by slow progression of muscle weakness, although patient-specific hiPSC-CMs exhibited

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typical features associated with the disease, such as intracellular glycogen accumulation and mitochondrial dysfunction, they did not fully exhibit the autophagic abnormalities that are observed in vivo.62,63 This may be overcome by using fully differentiated hiPSC-CMs assembled along with a complete subcellular system for muscle contraction, Ca2+ cycling, metabolism and protein recycling. Recent studies have contributed to the development of protocols for the maturation of hiPSC-CMs using electrical and/or mechanical stimulation, a 3D culture system with scaffold materials, coculture with fibroblasts or CMs in vitro and in vivo and a combination of these techniques, leading to improvement in contractility, Ca2+ handling and electrophysiological properties.64–68 Lack of chamber-specific characteristics is another major concern regarding the use of hiPSC-CMs for disease modelling. As the structure, haemodynamic stress, developmental origin and protein expression profile are quite distinctive among the cardiac chambers,59,69,70 the molecular features of individual CMs in each chamber would also differ. Some inherited arrhythmias and cardiomyopathies have chamberspecific characteristics. Clinical phenotypes of Brugada syndrome and ARVC/D likely originate from the right ventricular outflow tract. However, disease models based on hiPSC-CMs may not fully recapitulate the characteristic features of any specific region of the heart. A differentiated hiPSC-CM cluster usually consists of electrophysiologically heterogeneous subtypes including ventricular-, atrial- and nodal-like myocytes. The ventricular-like hiPSC-CMs exhibit properties analogous to those of human ventricular myocytes (e.g. steep upstroke (Phase 0) and plateau phase (Phase 4) of action potentials), whereas the nodal-type hiPSC-CMs exhibit slower action potential kinetics and depolarising diastolic potential.71 This mixed subtype of hiPSC-CMs leads to a wide range of results rather than being representative of a specific subtype of CMs. The development of protocols for subtype-specific and/or chamber-specific differentiation of hiPSC-CMs will accelerate research to identify the chamber-specific phenotypes associated with heart diseases. Although some genetic heart diseases are rare, many of them lead to life-threatening conditions. Therefore, further intensive research using disease-specific hiPSC-CMs should be promoted to gain insights into the underlying mechanisms and to identify potential therapeutic targets of these genetic diseases in order to develop novel therapeutic approaches for individual patients.

Human Induced Pluripotent Stem Cells as a Tool for Drug Screening Currently, the development of new drugs requires multiple processes, including screening of numerous putative drug compounds based on chemical structure and in vitro assays of pharmacological activity, followed by analyses of pharmacokinetics and safety in vitro and in vivo and, finally, clinical trials in humans. In most cases, these processes take many years until the candidate compounds are tested in humans.72 Even though the effectiveness of compounds may be promising in cell culture and animal experiments, problems identified in clinical trials assessing the effects of these compounds on the QT interval (known as a thorough QT/QTc study) following pharmacokinetics examination in humans may halt the further development of these compounds. However, if human cardiac cells were widely available, drug testing in human CMs might provide effective and safe drug candidates rapidly and economically, because the response to compounds tested using in vitro experiments with human CMs could resemble that of the human body.

Dilation and impaired contraction of LV or both ventricles presenting various arrhythmias, leading to sudden death

Thickened LV causing diastolic dysfunction

Inherited disease characterised by skin, facial and cardiac anomalies

Hypotonia and signs of heart failure by the age of 3â&#x20AC;&#x201C;5 months; accumulation of membrane-bound and cytoplasmic glycogen and rupture of lysosomes, aberrant mitochondria, accumulation of autophagic vesicles leading to cardiomyopathy

Desmosomal dysfunction; ventricular arrhythmias; fatty or fibrofatty replacement of myocardium with thinning of the RV wall

DCM

HCM

HCM (Leopard syndrome)

HCM (Pompe disease)

ARVC/D

Cellular phenotypes Reduced contraction force, compromised contraction, sarcomeric structural irregularities, reduced beating rate, abnormal Ca2+ transients, abnormal sarcomeric alpha-actinin distribution Diffuse abnormal desmin aggregations, diminished Ca2+ reuptake, reduced beating rate, failed sustained response to isoproterenol hiPSC-CM hypertrophy, elevated intracellular Ca2+ levels, irregular Ca2+ transients Nuclear bleb formation, micronucleation, nuclear senescence, electrical stimulation-induced cellular apoptosis

CM hypertrophy, NFATC4 nuclear accumulation, increased Ras/MAPK phosphorylation Glycogen accumulation, abnormal mitochondria ultrastructure, accumulation of autophagosomes, cellular respiration irregularities

Reduced density of PKP2, plakoglobin and connexin-43, FPD prolongation, widened and distorted desmosomes, lipid droplet clusters, increased lipid content in adipogenic differentiation media Irregular PKP2 nuclear accumulation, diminished beta-catenin activity in cardiogenic conditions, abnormal PPAR-gamma activation, Ca2+ handling defects Reduced expression of PKP2 and plakoglobin, disorganised myofibrils, increased lipid content in adipogenic differentiation media

Causal genes (mutations) TNNT2 (R173W)

DES (A285V)

MYH7 (R663H)

LMNA (R225X, Q354X, T518fs, c.50-51insGCCA)

PTPN11 (T426M) GAA (C1935A/C1935A, C1935A/G2040+1T, G1062G/ C1935A)

PKP2 (c.972InsT/N, A324fs335X)

PKP2 (c.2484C>T, c.2013delC)

PKP2 (L614P)

N/A

Lipid accumulation was prevented by 6-bromoindirubin-3Â˘-oxime (glycogen synthase kinase-3-beta inhibitor)

rhGAA enzyme and 2-3-methyladenine (autophagy inhibitor) normalised glycogen content; 3-l-carnitine increased O2 consumption and suppressed mitochondrial structural phenotype

N/A

Nuclear blebbing and electrical stimulation-induced apoptosis in R225X iPSC-CMs were rescued by PTC124 (ataluren, promoting read-through of the premature stop codon)

U0126 and selumetinib (AZD6244; ERK1/2 and MEK1/2 inhibitors) attenuated electric stimulationinduced proapoptotic effects

Myocyte hypertrophy, Ca2+ handling abnormalities and arrhythmia were rescued by verapamil and diltiazem (Ca2+ blockers)

N/A

Metoprolol (beta-blocker) improved abnormal functions

Drug responses

Lee et al.53

Lan et al.52

Huang et al.51

Dellefave et al.47

Mestroni et al.46

Tse et al.,49 Carvajal-Vergara et al.50

Sun et al.48

Morita et al.45

Grunig et al.44

References

ARVC/D = arrhythmogenic right ventricular cardiomyopathy/dysplasia; CM = cardiomyocyte; DCM = dilated cardiomyopathy; DES = desmin; ERK = extracellular signal-regulated kinase; FPD = field potential duration; GAA = acid alpha-glucosidase; HCM = hypertrophic cardiomyopathy; hiPSC-CM = human induced pluripotent stem cell-derived cardiomyocyte; LMNA, lamin A/C; LV = left ventricle; MAPK = mitogen-activated protein kinase; MEK = mitogen-activated protein kinase kinase; MYH7 = myosin heavy chain 7; N/A = not applicable; NFATC4 = nuclear factor of activated T cells cytoplasmic 4; PKP2 = plakophilin 2; PPAR-gamma = peroxisome proliferator-activated receptor-gamma; PTPN11 = protein tyrosine phosphatase non-receptor type 11; rh = recombinant human; RV = right ventricle; TNNT2 = troponin T2, cardiac type.

Disease phenotype

Disease

Table 2: Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Models of Inherited Cardiomyopathies

Heart Disease

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IPSC Applications in Heart Diseases Disease-specific hiPSC-derived CMs potentially exhibit similar physiological characteristics as diseased cells in patients, and may be a useful tool to predict the benefits and side-effects of drug candidates in patients. Drug screening using hiPSC-CMs to detect side effects such as drug-induced QT prolongation and ventricular tachyarrhythmias could contribute to the early withdrawal of therapeutic compounds with undesirable cardiac effects before the initiation of in vivo experiments and clinical trials.72,73 Other than the development of new drugs, the cardiac side effects of some already marketed drugs, including anti-arrhythmic drugs and non-cardiac drugs such as antihistamines, antipsychotics and anti-infective drugs, have been widely recognised. These drugs have the potential to cause torsade de pointes, in combination with other endogenous and environmental factors.73 Drug testing using hiPSC-CMs may also be applicable in this context. Although hiPSC-CMs share some characteristics with adult human ventricular myocytes, hiPSC-CMs are commonly known to exhibit the features of foetal ‘immature’ CMs in terms of their gene expression profile, structure and electrophysiology, as noted above. hiPSC-CMs express cardiac-specific genes (e.g. those encoding cTnT, alpha-myosin heavy chain) and exhibit ion channel activity (e.g. similar INa, IKr and ICa,L current density to that in adult ventricular CMs);12–14,16,71,74–83 however, morphologically they are more rounded or multiangular in shape and smaller in size, with disorganised myofibrils and a lack of t-tubules, which contribute to the slower kinetics of the Ca2+ transient.38,76,83–87 These important differences should be considered when using hiPSCCMs in drug screening. Further investigations are needed to develop optimal methods for more efficient differentiation into functional CMs that exhibit the typical properties of adult CMs.

Figure 2: Principle of Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/ CRISPR-associated (Cas) 9-Based Gene Editing CRISPR complex binding to target DNA Target DNA

Cas9

NGG

Guide RNA Double-strand break

Non-homologous end joining

Homology-directed repair

Deletions (frame shift)

Wild-type

Mutant or Donor templates

or Insertion (frame shift) NNNN

NNNN

Gene correction

Gene inactivation

Mutagenesis

NGG = protospacer-adjacent motif (N can be any nucleotide base).

Figure 3: Gene Editing in Human Induced Pluripotent Stem Cell for Cardiac Applications Conventional approach

Gene Editing to Create Disease-Specific Human Induced Pluripotent Stem Cells Comprehensive genetic studies have identified causal mutations responsible for genetic heart diseases. hiPSC-CMs have emerged as a highly effective tool for modelling such diseases. Although it is technically possible to induce disease-specific hiPSC-CMs, patientderived somatic cells may not be readily available, especially in the case of rare diseases. In addition, interclonal variation is seen among hiPSC clones, resulting from different genetic backgrounds associated with individual cells.

Healthy donors

Disease patients

Wild-type iPSC lines

Disease-specific iPSC lines

Variable genetic background

Isogenic approach Single healthy donor

Single disease patient Gene editing

Clustered regularly interspaced short palindromic repeat (CRISPR)/ CRISPR-associated protein (Cas) 9 is a gene-editing technology that can solve the challenges associated with the genetic variability.88,89 CRISPR is a DNA sequence found in bacterial genomes; it is thought to be derived from viruses, is known to protect bacteria from repeated viral infections and acts as a basic adaptive immune system for prokaryotes. Cas9 is a DNA-cutting enzyme that recognises CRISPR sequences and causes site-specific DNA double-strand breaks (Figure 2). Recent advances in CRISPR/Cas9-based gene editing have markedly improved the efficiency and specificity of the method and expanded its applications, including knockout, repression and activation of genes of interest.90

iPSC = induced pluripotent stem cell.

In phenotypic analysis of monogenic inherited diseases, this technology is also applicable to either disease-associated mutagenesis in wildtype hiPSCs or to the correction of pathogenic gene mutations in disease-specific hiPSCs (Figure 3).89 Analysis of disease-specific hiPSCs versus wild-type hiPSCs established from healthy donor cells as a

control may result in unreliable outcomes due to the different genetic backgrounds of the disease-specific hiPSCs and control cells. However, CRISPR/Cas9-based gene editing enables the preparation of an isogenic control by normalising a disease-relevant mutation in disease-specific hiPSCs or by inducing the mutation in wild-type hiPSCs so that diseased

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Wild-type Mutagenesis iPSCs

Mutant iPSCs

Wild-type Gene iPSCs correction

Mutant iPSCs

Differentiation to cardiomyocytes

Wild-type cardiomyocytes

Mutant cardiomyocytes

Isogenic cells

Phenotypic analysis

Heart Disease and control cells with the same genetic background are obtained. In addition, CRISPR/Cas9-based gene editing could allow the production of isogenic cells with intact and/or corrected variant alleles in noncoding regions including enhancers that may reveal the role of mutations in the transcriptional regulation of genes responsible for a disease phenotype. This method shows promise for the proper evaluation of the involvement of mutated genes in disease phenotype following in vitro differentiation (Figure 3). Polygenic diseases, which differ from monogenic inherited diseases in that more than one gene is involved in their dysfunction, impose another limitation on the use of hiPSCs. Polygenic diseases are thought to be caused by a combination of multiple mutations, each of which has a small effect, with or without extrinsic factors. Although gene editing has been used to edit multiple regions of the genome, a major challenge towards using hiPSCs to investigate polygenic diseases is identification of the corresponding mutations and understanding how each mutation contributes to the pathogenesis of these multifactorial diseases. Moreover, in some cases, environmental factors may strongly affect disease phenotypes, making experimental conditions and further analysis more complicated. Comprehensive reviews are available for detailed information regarding the use of gene editing in iPSC research.89,91

Consideration of Human Induced Pluripotent Stem Cells for Application in Disease Modelling and Clinical Use Despite extensive benefits, there are still many unsolved issues regarding the use of hiPSCs in further applications. One of the major issues is that the quality of individual hiPSC lines is variable, even when an hiPSC line is derived from one individual. Classical iPSC reprogramming methods using retroviral or lentiviral vectors may cause random insertional mutations in the host genome, resulting in alteration of subsequent cell phenotypes.92 Recent advances in reprogramming strategies using non-integrating, virus-free and vector-free methods are overcoming this issue.93,94 However, it is still technically difficult to eliminate the risk of gene mutations during the reprogramming process because forced expression of reprogramming factors can induce DNA damage.95 In fact, protein-coding point mutations acquired during or after reprogramming were identified in multiple hiPSC lines, some of which exhibit unpredictable phenotypes.96 Thus, accumulating evidence regarding the mechanism underlying the reprogramming of iPSCs is expected to provide insights into how the quality of hiPSC lines may be

T akahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007;131:861–72. https://doi.org/10.1016/j. cell.2007.11.019; PMID: 18035408. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126:663–76. https://doi. org/10.1016/j.cell.2006.07.024; PMID: 16904174. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007;318:1917–20. https://doi.org/10.1126/science.1151526; PMID: 18029452. Park IH, Zhao R, West JA, et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 2008;451:141–6. https://doi.org/10.1038/nature06534; PMID: 18157115. Takahashi K, Yamanaka S. A decade of transcription factormediated reprogramming to pluripotency. Nat Rev Mol Cell Biol 2016;17:183–93. https://doi.org/10.1038/nrm.2016.8; PMID: 26883003. Muller R, Lengerke C. Patient-specific pluripotent stem cells:

stabilised and standardised for use as a cell source for further experiments and clinical application. Precise investigations into the pathophysiology of inherited diseases using patient-derived iPSCs require improved protocols that allow highly efficient differentiation of hiPSCs into a specific cell type, because the differentiation efficiency in current experiments remains significantly lower than what is desired. The characteristic variability of cells differentiated from disease-specific hiPSCs is a considerable hurdle that research into pathophysiology must overcome. Epigenetic modifications are presumably one of the causes of phenotype variability. Optimised sorting methods to collect only a desired cell type from the heterogeneous cell population need to be developed. Current research efforts are advancing cardiac differentiation protocols to generate spontaneously beating CM-like cell clusters, but the clusters of differentiated cells that are heterogeneous also contain other mesodermal derivatives, such as smooth muscle cells and endothelial cells, as well as undifferentiated cells, which may increase the risk of tumourigenesis. Pathophysiological studies using disease-specific hiPSCs allow us to determine the cellular characteristics of a disease, but do not recreate the function of the whole organ within the body. Although complex bioengineering approaches, such as organoid formation and 3D culture systems, are available,97,98 it is difficult to use these methods in the heart because CMs in the heart are predominantly situated in a highly organised structure comprising vessels, nerves, mesenchymal cells, extracellular matrix and myocytes. In addition, CMs are continuously exposed to dynamically changing neuroendocrine factors and mechanical stresses. Therefore, it should be considered that studies using disease-specific hiPSC-CMs fundamentally provide simplified information regarding the pathophysiology in patients with a familial disease. Nevertheless, the experimental data from these cells may reveal responses that mirror actual phenomena in human patients, and are thus valuable for gaining an understanding of the inherited disease.

Conclusion Disease-specific hiPSC-CMs, which carry the same genomic information as patients with inherited diseases, can undoubtedly be of use in research to address the pathophysiology of monogenic inherited diseases, the drug responsiveness of patients for personalised medicine and drug development by providing a cell source for screening compounds and drug safety testing. A combination of disease-specific hiPSC-CMs and gene-editing technologies may further advance our understanding of genetic diseases and drug development in cardiovascular medicine.

promises and challenges. Nat Rev Endocrinol 2009;5:195–203. https://doi.org/10.1038/nrendo.2009.18; PMID: 19352317. iller R, Greenhough S, Park IH, Sullivan GJ. Modelling human S disease with pluripotent stem cells. Curr Gene Ther 2013;13:99–110. https://doi.org/10.2174/156652321131302000 4; PMID: 23444871. 8. Matsa E, Rajamohan D, Dick E, et al. Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation. Eur Heart J 2011;32:952–62. https://doi.org/10.1093/eurheartj/ ehr073; PMID: 21367833. 9. Moretti A, Bellin M, Welling A, et al. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med 2010;363:1397–409. https://doi.org/10.1056/ NEJMoa0908679; PMID: 20660394. 10. Yazawa M, Hsueh B, Jia X, et al. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 2011;471:230–4. https://doi.org/10.1038/ nature09855; PMID: 21307850. 11. Egashira T, Yuasa S, Suzuki T, et al. Disease characterization using LQTS-specific induced pluripotent stem cells. Cardiovasc 7.

Res 2012;95:419–29. https://doi.org/10.1093/cvr/cvs206; PMID: 22739119. 12. M a D, Wei H, Lu J, et al. Characterization of a novel KCNQ1 mutation for type 1 long QT syndrome and assessment of the therapeutic potential of a novel IKs activator using patientspecific induced pluripotent stem cell-derived cardiomyocytes. Stem Cell Res Ther 2015;6:39. https://doi. org/10.1186/s13287-015-0027-z; PMID: 25889101. 13. Itzhaki I, Maizels L, Huber I, et al. Modelling the long QT syndrome with induced pluripotent stem cells. Nature 2011;471:225–9. https://doi.org/10.1038/nature09747; PMID: 21240260. 14. Lahti AL, Kujala VJ, Chapman H, et al. Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture. Dis Model Mech 2012;5:220–30. https://doi.org/10.1242/dmm.008409; PMID: 22052944. 15. Matsa E, Dixon JE, Medway C, et al. Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes. Eur Heart J 2014;35:1078–87. https://doi.org/10.1093/eurheartj/

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IPSC Applications in Heart Diseases eht067; PMID: 23470493. 16. S ala L, Yu Z, Ward-van Oostwaard D, et al. A new hERG allosteric modulator rescues genetic and drug-induced longQT syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells. EMBO Mol Med 2016;8:1065–81. https://doi.org/10.15252/emmm.201606260; PMID: 27470144. 17. Song L, Park SE, Isseroff Y, et al. Inhibition of CDK5 alleviates the cardiac phenotypes in Timothy syndrome. Stem Cell Rep 2017;9:50–7. https://doi.org/10.1016/j.stemcr.2017.05.028; PMID: 28648896. 18. Yazawa M, Dolmetsch RE. Modeling Timothy syndrome with iPS cells. J Cardiovasc Transl Res 2013;6:1–9. https://doi. org/10.1007/s12265-012-9444-x; PMID: 23299782. 19. Davis RP, Casini S, van den Berg CW, et al. Cardiomyocytes derived from pluripotent stem cells recapitulate electrophysiological characteristics of an overlap syndrome of cardiac sodium channel disease. Circulation 2012;125:3079– 91. https://doi.org/10.1161/CIRCULATIONAHA.111.066092; PMID: 22647976. 20. Fatima A, Kaifeng S, Dittmann S, et al. The disease-specific phenotype in cardiomyocytes derived from induced pluripotent stem cells of two long QT syndrome type 3 patients. PLoS One 2013;8:e83005. https://doi.org/10.1371/ journal.pone.0083005; PMID: 24349418. 21. Kuroda Y, Yuasa S, Watanabe Y, et al. Flecainide ameliorates arrhythmogenicity through NCX flux in Andersen–Tawil syndrome-iPS cell-derived cardiomyocytes. Biochem Biophys Rep 2017;9:245–56. https://doi.org/10.1016/j. bbrep.2017.01.002; PMID: 28956012. 22. Limpitikul WB, Dick IE, Tester DJ, et al. A precision medicine approach to the rescue of function on malignant calmodulinopathic long-QT syndrome. Circ Res 2017;120:39– 48. https://doi.org/10.1161/CIRCRESAHA.116.309283; PMID: 27765793. 23. Ma D, Wei H, Zhao Y, et al. Modeling type 3 long QT syndrome with cardiomyocytes derived from patient-specific induced pluripotent stem cells. Int J Cardiol 2013;168:5277–86. https:// doi.org/10.1016/j.ijcard.2013.08.015; PMID: 23998552. 24. Malan D, Zhang M, Stallmeyer B, et al. Human iPS cell model of type 3 long QT syndrome recapitulates drug-based phenotype correction. Basic Res Cardiol 2016;111:14. https://doi. org/10.1007/s00395–016–0530–0. https://doi.org/10.1007/ s00395-016-0530-0; PMID: 26803770. 25. Rocchetti M, Sala L, Dreizehnter L, et al. Elucidating arrhythmogenic mechanisms of long-QT syndrome CALM1F142L mutation in patient-specific induced pluripotent stem cell-derived cardiomyocytes. Cardiovasc Res 2017;113:531–41. https://doi.org/10.1093/cvr/cvx006; PMID: 28158429. 26. Terrenoire C, Wang K, Tung KW, et al. Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics. J Gen Physiol 2012;141:61–72. https:// doi.org/10.1085/jgp.201210899; PMID: 23277474. 27. Yamamoto Y, Makiyama T, Harita T, et al. Allele-specific ablation rescues electrophysiological abnormalities in a human iPS cell model of long-QT syndrome with a CALM2 mutation. Hum Mol Genet 2017;26:1670–7. https://doi.org/10.1093/hmg/ddx073; PMID: 28335032. 28. El-Battrawy I, Lan H, Cyganek L, et al. Modeling short QT syndrome using human-induced pluripotent stem cell-derived cardiomyocytes. J Am Heart Assoc 2018;7:e007394. https:// doi.org/10.1161/JAHA.117.007394; PMID: 29574456. 29. Cerrone M, Lin X, Zhang M, et al. Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype. Circulation 2014;129:1092– 103. https://doi.org/10.1161/CIRCULATIONAHA.113.003077; PMID: 24352520. 30. Liang P, Sallam K, Wu H, et al. Patient-specific and genomeedited induced pluripotent stem cell-derived cardiomyocytes elucidate single-cell phenotype of Brugada syndrome. J Am Coll Cardiol 2016;68:2086–96. https://doi.org/10.1016/j. jacc.2016.07.779; PMID: 27810048. 31. Selga E, Sendfeld F, Martinez-Moreno R, et al. Sodium channel current loss of function in induced pluripotent stem cellderived cardiomyocytes from a Brugada syndrome patient. J Mol Cell Cardiol 2018;114:10–9. https://doi.org/10.1016/j. yjmcc.2017.10.002; PMID: 29024690. 32. Fatima A, Xu G, Shao K, et al. In vitro modeling of ryanodine receptor 2 dysfunction using human induced pluripotent stem cells. Cell Physiol Biochem 2011;28:579–92. https://doi. org/10.1159/000335753; PMID: 22178870. 33. Itzhaki I, Maizels L, Huber I, et al. Modeling of catecholaminergic polymorphic ventricular tachycardia with patient-specific human-induced pluripotent stem cells. J Am Coll Cardiol 2012;60:990–1000. https://doi.org/10.1016/j. jacc.2012.02.066; PMID: 22749309. 34. Jung CB, Moretti A, Mederos y Schnitzler M, et al. Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia. EMBO Mol Med 2012;4:180–91. https://doi. org/10.1002/emmm.201100194; PMID: 22174035. 35. Kujala K, Paavola J, Lahti A, et al. Cell model of catecholaminergic polymorphic ventricular tachycardia reveals early and delayed afterdepolarizations. PLoS One 2012;7:e44660. https://doi.org/10.1371/journal.pone.0044660;

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PMID: 22962621. 36. M aizels L, Huber I, Arbel G, et al. Patient-specific drug screening using a human induced pluripotent stem cell model of catecholaminergic polymorphic ventricular tachycardia type 2. Circ Arrhythm Electrophysiol 2017;10:pii:e004725. https:// doi.org/10.1161/CIRCEP.116.004725; PMID: 28630169. 37. Novak A, Barad L, Lorber A, et al. Functional abnormalities in iPSC-derived cardiomyocytes generated from CPVT1 and CPVT2 patients carrying ryanodine or calsequestrin mutations. J Cell Mol Med 2015;19:2006–18. https://doi.org/10.1111/ jcmm.12581; PMID: 26153920. 38. Novak A, Barad L, Zeevi-Levin N, et al. Cardiomyocytes generated from CPVTD307H patients are arrhythmogenic in response to beta-adrenergic stimulation. J Cell Mol Med 2012;16:468–82. https://doi.org/10.1111/j.1582-4934.2011. 01476.x; PMID: 22050625. 39. Preininger MK, Jha R, Maxwell JT, et al. A human pluripotent stem cell model of catecholaminergic polymorphic ventricular tachycardia recapitulates patient-specific drug responses. Dis Model Mech 2016;9:927–39. https://doi.org/10.1242/ dmm.026823; PMID: 27491078. 40. Sasaki K, Makiyama T, Yoshida Y, et al. Patient-specific human induced pluripotent stem cell model assessed with electrical pacing validates S107 as a potential therapeutic agent for catecholaminergic polymorphic ventricular tachycardia. PLoS One 2016;11:e0164795. https://doi.org/10.1371/journal. pone.0164795; PMID: 27764147. 41. Maron BJ, Towbin JA, Thiene G, et al. Contemporary definitions and classification of the cardiomyopathies. Circulation 2006;113:1807–16. https://doi.org/10.1161/ CIRCULATIONAHA.106.174287; PMID: 16567565. 42. Baig MK, Goldman JH, Caforio ALP, et al. Familial dilated cardiomyopathy: cardiac abnormalities are common in asymptomatic relatives and may represent early disease. J Am Coll Cardiol 1998;31:195–201. https://doi.org/10.1016/S07351097(97)00433-6; PMID: 9426040. 43. Burkett EL, Hershberger RE. Clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol 2005;45:969–81. https://doi.org/10.1016/j.jacc.2004.11.066; PMID: 15808750. 44. Grunig E, Tasman JA, Kucherer H, et al. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol 1998;31:186–94. https://doi.org/10.1016/S07351097(97)00434-8; PMID: 9426039. 45. Morita H, Seidman J, Seidman CE. Genetic causes of human heart failure. J Clin Invest 2005;115:518–26. https://doi. org/10.1172/JCI24351; PMID: 15765133. 46. Mestroni L, Rocco C, Gregori D, et al. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group. J Am Coll Cardiol 1999;34:181–90. https://doi.org/10.1016/S07351097(99)00172-2; PMID: 10400009. 47. Dellefave L, McNally EM. The genetics of dilated cardiomyopathy. Curr Opin Cardiol 2010;25:198–204. https:// doi.org/10.1097/HCO.0b013e328337ba52; PMID: 20186049. 48. Sun N, Yazawa M, Liu JW, et al. Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. Sci Transl Med 2012;4:130ra47. https://doi. org/10.1126/scitranslmed.3003552; PMID: 22517884. 49. Tse HF, Ho JC, Choi SW, et al. Patient-specific inducedpluripotent stem cells-derived cardiomyocytes recapitulate the pathogenic phenotypes of dilated cardiomyopathy due to a novel DES mutation identified by whole exome sequencing. Hum Mol Genet 2013;22:1395–403. https://doi.org/10.1093/ hmg/dds556; PMID: 23300193. 50. Carvajal-Vergara X, Sevilla A, D’Souza SL, et al. Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature 2010;465:808–12. https://doi.org/10.1038/ nature09005; PMID: 20535210. 51. Huang HP, Chen PH, Hwu WL, et al. Human Pompe diseaseinduced pluripotent stem cells for pathogenesis modeling, drug testing and disease marker identification. Hum Mol Genet 2011;20:4851–64. https://doi.org/10.1093/hmg/ddr424; PMID: 21926084. 52. Lan F, Lee AS, Liang P, et al. Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell 2013;12:101–13. https://doi.org/10.1016/j. stem.2012.10.010; PMID: 23290139. 53. Lee YK, Lau YM, Cai ZJ, et al. Modeling treatment response for lamin A/C related dilated cardiomyopathy in human induced pluripotent stem cells. J Am Heart Assoc 2017;6:pii:e005677. https://doi.org/10.1161/JAHA.117.005677; PMID: 28754655. 54. Siu CW, Lee YK, Ho JC, et al. Modeling of lamin A/C mutation premature cardiac aging using patient-specific induced pluripotent stem cells. Aging (Albany NY) 2012;4:803–22. https://doi.org/10.18632/aging.100503; PMID: 23362510. 55. Caspi O, Huber I, Gepstein A, et al. Modeling of arrhythmogenic right ventricular cardiomyopathy with human induced pluripotent stem cells. Circ Cardiovasc Genet 2013;6:557–68. https://doi.org/10.1161/ CIRCGENETICS.113.000188; PMID: 24200905. 56. Kim C, Wong J, Wen JY, et al. Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. Nature 2013;494:105–10. https://doi.org/10.1038/nature11799;

PMID: 23354045. 57. M a D, Wei H, Lu J, et al. Generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes as a cellular model of arrhythmogenic right ventricular cardiomyopathy. Eur Heart J 2013;34:1122–33. https://doi.org/10.1093/ eurheartj/ehs226; PMID: 22798562. 58. Cordeiro JM, Nesterenko VV, Sicouri S, et al. Identification and characterization of a transient outward K+ current in human induced pluripotent stem cell-derived cardiomyocytes. J Mol Cell Cardiol 2013;60:36–46. https://doi.org/10.1016/j. yjmcc.2013.03.014; PMID: 23542310. 59. Doll S, Dressen M, Geyer PE, et al. Region and cell-type resolved quantitative proteomic map of the human heart. Nat Commun 2017;8:1469. https://doi.org/10.1038/s41467-01701747-2; PMID: 29133944. 60. Karakikes I, Ameen M, Termglinchan V, Wu JC. Human induced pluripotent stem cell-derived cardiomyocytes: insights into molecular, cellular, and functional phenotypes. Circ Res 2015;117:80–8. https://doi.org/10.1161/ CIRCRESAHA.117.305365; PMID: 26089365. 61. Yang X, Pabon L, Murry CE. Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Res 2014;114:511–23. https://doi. org/10.1161/CIRCRESAHA.114.300558; PMID: 24481842. 62. Fukuda T, Ahearn M, Roberts A, et al. Autophagy and mistargeting of therapeutic enzyme in skeletal muscle in Pompe disease. Mol Ther 2006;14:831–9. https://doi. org/10.1016/j.ymthe.2006.08.009; PMID: 17008131. 63. Raben N, Ralston E, Chien YH, et al. Differences in the predominance of lysosomal and autophagic pathologies between infants and adults with Pompe disease: implications for therapy. Mol Genet Metab 2010;101:324–31. https://doi. org/10.1016/j.ymgme.2010.08.001; PMID: 20801068. 64. Veerman CC, Kosmidis G, Mummery CL, et al. Immaturity of human stem-cell-derived cardiomyocytes in culture: fatal flaw or soluble problem? Stem Cells Dev 2015;24:1035–52. https:// doi.org/10.1089/scd.2014.0533; PMID: 25583389. 65. Denning C, Borgdorff V, Crutchley J, et al. Cardiomyocytes from human pluripotent stem cells: from laboratory curiosity to industrial biomedical platform. Biochim Biophys Acta 2016;1863:1728–48. https://doi.org/10.1016/j. bbamcr.2015.10.014; PMID: 26524115. 66. Mathur A, Ma Z, Loskill P, et al. In vitro cardiac tissue models: Current status and future prospects. Adv Drug Deliv Rev 2016;96:203–13. https://doi.org/10.1016/j.addr.2015.09.011; PMID: 26428618. 67. Cho GS, Lee DI, Tampakakis E, et al. Neonatal transplantation confers maturation of PSC-derived cardiomyocytes conducive to modeling cardiomyopathy. Cell Rep 2017;18:571–82. https:// doi.org/10.1016/j.celrep.2016.12.040; PMID: 28076798. 68. Nunes SS, Miklas JW, Liu J, et al. Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Nat Methods 2013;10:781–7. https://doi. org/10.1038/nmeth.2524; PMID: 23793239. 69. Rana MS, Christoffels VM, Moorman AF. A molecular and genetic outline of cardiac morphogenesis. Acta Physiol (Oxf) 2013;207:588–615. https://doi.org/10.1111/apha.12061; PMID: 23297764. 70. Srivastava D. Making or breaking the heart: from lineage determination to morphogenesis. Cell 2006;126:1037–48. https://doi.org/10.1016/j.cell.2006.09.003; PMID: 16990131. 71. Ma J, Guo L, Fiene SJ, et al. High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents. Am J Physiol Heart Circ Physiol 2011;301:H2006–17. https://doi.org/10.1152/ajpheart.00694.2011; PMID: 21890694. 72. Gromo G, Mann J, Fitzgerald JD. Cardiovascular drug discovery: a perspective from a research-based pharmaceutical company. Cold Spring Harb Perspect Med 2014;4:a014092. https://doi.org/10.1101/cshperspect.a014092; PMID: 24890831. 73. Ritter JM. Cardiac safety, drug-induced QT prolongation and torsade de pointes (TdP). Br J Clin Pharmacol 2012;73:331–4. https://doi.org/10.1111/j.1365-2125.2012.04193.x; PMID: 22329611. 74. Bellin M, Casini S, Davis RP, et al. Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome. EMBO J 2013;32:3161–75. https://doi.org/10.1038/ emboj.2013.240; PMID: 24213244. 75. Doss MX, Di Diego JM, Goodrow RJ, et al. Maximum diastolic potential of human induced pluripotent stem cell-derived cardiomyocytes depends critically on I(Kr). PLoS One 2012;7:e40288. https://doi.org/10.1371/journal.pone.0040288; PMID: 22815737. 76. Hwang HS, Kryshtal DO, Feaster TK, et al. Comparable calcium handling of human iPSC-derived cardiomyocytes generated by multiple laboratories. J Mol Cell Cardiol 2015;85:79–88. https:// doi.org/10.1016/j.yjmcc.2015.05.003; PMID: 25982839. 77. Iost N, Virag L, Opinicariu M, et al. Delayed rectifier potassium current in undiseased human ventricular myocytes. Cardiovasc Res 1998;40:508–15. https://doi.org/10.1016/ S0008-6363(98)00204-1; PMID: 10070491. 78. Ivashchenko CY, Pipes GC, Lozinskaya IM, et al. Humaninduced pluripotent stem cell-derived cardiomyocytes exhibit temporal changes in phenotype. Am J Physiol Heart Circ

Heart Disease

79.

80.

81.

82.

83.

84.

Physiol 2013;305:H913–22. https://doi.org/10.1152/ ajpheart.00819.2012; PMID: 23832699. Jost N, Acsai K, Horvath B, et al. Contribution of I Kr and I K1 to ventricular repolarization in canine and human myocytes: is there any influence of action potential duration? Basic Res Cardiol 2009;104:33–41. https://doi.org/10.1007/s00395-0080730-3; PMID: 18604626. Lee S, Lee HA, Choi SW, et al. Evaluation of nefazodoneinduced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol 2016;296:42–53. https://doi.org/10.1016/j.taap.2016.01.015; PMID: 26821276. Zhang J, Wilson GF, Soerens AG, et al. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res 2009;104:e30–41. https://doi.org/10.1161/ CIRCRESAHA.108.192237; PMID: 19213953. Zhang M, D’Aniello C, Verkerk AO, et al. Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue. Proc Natl Acad Sci USA 2014;111:e5383–92. https://doi.org/10.1073/pnas.1419553111; PMID: 25453094. Zhang XH, Haviland S, Wei H, et al. Ca2+ signaling in human induced pluripotent stem cell-derived cardiomyocytes (iPSCM) from normal and catecholaminergic polymorphic ventricular tachycardia (CPVT)-afflicted subjects. Cell Calcium 2013;54:57–70. https://doi.org/10.1016/j.ceca.2013.04.004; PMID: 23684427. Dick E, Rajamohan D, Ronksley J, Denning C. Evaluating the

85.

86.

87.

88.

89.

90.

91.

utility of cardiomyocytes from human pluripotent stem cells for drug screening. Biochem Soc Trans 2010;38:1037–45. https://doi.org/10.1042/BST0381037; PMID: 20659000. Itzhaki I, Rapoport S, Huber I, et al. Calcium handling in human induced pluripotent stem cell derived cardiomyocytes. PLoS One 2011;6:e18037. https://doi.org/10.1371/journal. pone.0018037; PMID: 21483779. Spencer CI, Baba S, Nakamura K, et al. Calcium transients closely reflect prolonged action potentials in iPSC models of inherited cardiac arrhythmia. Stem Cell Rep 2014;3:269–81. https://doi.org/10.1016/j.stemcr.2014.06.003; PMID: 25254341. Devalla HD, Gelinas R, Aburawi EH, et al. TECRL, a new lifethreatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT. EMBO Mol Med 2016;8:1390–408. https://doi.org/10.15252/ emmm.201505719; PMID: 27861123. Jinek M, Chylinski K, Fonfara I, et al. A programmable dualRNA-guided DNA endonuclease in adaptive bacterial immunity. Science 2012;337:816–21. https://doi.org/10.1126/ science.1225829; PMID: 22745249. Hockemeyer D, Jaenisch R. Induced pluripotent stem cells meet genome editing. Cell Stem Cell 2016;18:573–86. https:// doi.org/10.1016/j.stem.2016.04.013; PMID: 27152442. Wang F, Qi LS. Applications of CRISPR genome engineering in cell biology. Trends Cell Biol 2016;26:875–88. https://doi. org/10.1016/j.tcb.2016.08.004; PMID: 27599850. Soldner F, Jaenisch R. Stem cells, genome editing, and the path to translational medicine. Cell 2018;175:615–32. https://

doi.org/10.1016/j.cell.2018.09.010; PMID: 30340033. 92. S aha K, Jaenisch R. Technical challenges in using human induced pluripotent stem cells to model disease. Cell Stem Cell 2009;5:584–95. https://doi.org/10.1016/j. stem.2009.11.009; PMID: 19951687. 93. de Almeida PE, Ransohoff JD, Nahid A, Wu JC. Immunogenicity of pluripotent stem cells and their derivatives. Circ Res 2013;112:549–61. https://doi.org/10.1161/ CIRCRESAHA.111.249243; PMID: 23371903. 94. Okano H, Nakamura M, Yoshida K, et al. Steps toward safe cell therapy using induced pluripotent stem cells. Circ Res 2013;112:523–33. https://doi.org/10.1161/ CIRCRESAHA.111.256149; PMID: 23371901. 95. Kawamura T, Suzuki J, Wang YV, et al. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 2009;460:1140–4. https://doi.org/10.1038/nature08311; PMID: 19668186. 96. Gore A, Li Z, Fung HL, et al. Somatic coding mutations in human induced pluripotent stem cells. Nature 2011;471:63–7. https://doi.org/10.1038/nature09805; PMID: 21368825. 97. Masumoto H, Ikuno T, Takeda M, et al. Human iPS cellengineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration. Sci Rep 2014;4:6716. https://doi.org/10.1038/srep06716; PMID: 25336194. 98. Mills RJ, Parker BL, Quaife-Ryan GA, et al. Drug screening in human PSC-cardiac organoids identifies pro-proliferative compounds acting via the mevalonate pathway. Cell Stem Cell 2019;24:895–907.e6. https://doi.org/10.1016/j. stem.2019.03.009; PMID: 30930147.

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Heart Disease

Spontaneous Coronary Artery Dissection: Mechanisms, Diagnosis and Management Marcos Garcia-Guimarães,1,2 Teresa Bastante,1 Paula Antuña,1 César Jimenez,1 Francisco de la Cuerda,1 Javier Cuesta,1 Fernando Rivero,1 Diluka Premawardhana,2 David Adlam2 and Fernando Alfonso1 1. Cardiology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria La Princesa, Centro de Investigación en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; 2. Cardiology Department, Glenfield General Hospital, Leicester, UK

Abstract Spontaneous coronary artery dissection (SCAD) is a relatively infrequent cause of acute coronary syndrome that usually affects young to middle-aged women. Mainly because of its low prevalence, until recently, most of the evidence on this condition was derived from case reports and small series. Over the last 5 years, more robust evidence has become available from larger retrospective and prospective cohorts of patients with SCAD. The increase in knowledge and recognition of this entity has led to the publication of expert consensus on both sides of the Atlantic. However, new data are continuously accumulating from larger cohorts of patients with SCAD, bringing new light to this little-understood condition. The aim of this article is to update the knowledge on SCAD, including new information from recent studies published since the consensus documents from the European Society of Cardiology and the American Heart Association.

Keywords Spontaneous coronary artery dissection, fibromuscular dysplasia, optical coherence tomography, intravascular ultrasound, percutaneous coronary intervention Disclosure: The authors have no conflicts of interest to declare. Funding: This project has been partially funded by a Rio Hortega grant by Insituto de Salud Carlos III, Madrid, Spain. Received: 13 May 2019 Accepted: 21 August 2019 Citation: European Cardiology Review 2020;15:e03. DOI: https://doi.org/10.15420/ecr.2019.01 Correspondence: Fernando Alfonso, Departamento de Cardiología, Hospital Universitario de La Princesa, IIS-IP, CIBER-CV, Universidad Autónoma de Madrid, c/ Diego de León 62, Madrid 28006, Madrid, Spain. E: falf@hotmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Spontaneous coronary artery dissection (SCAD) can be defined as the acute development of a false lumen within the coronary artery wall that may lead to flow limitation by compression of the true coronary lumen. This definition of SCAD excludes coronary dissections that are secondary to atherosclerotic disease, produced by the extension of an aortic dissection, iatrogenic or related to a trauma.1,2

Physiopathology Two mechanisms have been proposed to explain the development of the false lumen in SCAD. Under the “inside-out” hypothesis, the cause is a disruption of the endothelial-intimal layer, which allows blood from the lumen to enter the vessel wall, leading to the formation of an intramural haematoma (IMH). Under the “outside-in” hypothesis the primary event is a bleeding episode within the coronary artery wall (at the level of the vasa vasorum), which generates an IMH without intimal disruption. Both mechanisms can lead to haematoma extension and compression of the true lumen, resulting in myocardial ischaemia in the territory of the affected coronary artery.3 Some authors suggest that the outside-in hypothesis might be the primary event in the majority of SCAD cases. In some patients, rising pressure in this primarily produced IMH would lead to the development of an intimal disruption, which explains cases with double lumen on angiography and/or evidence of intimo-medial dissections with

intracoronary imaging (ICI). In keeping with this, Waterbury et al. analysed predictors of SCAD progression in patients who had initially been treated in a conservative manner.4 Interestingly, they found that 20% of lesions initially defined as IMH on repeated coronary angiogram progressed to a double lumen on angiography.

Epidemiology The true incidence of SCAD is unknown. Since the first case reported by Pretty in 1931, and for the next eight decades, most of the evidence came from isolated case reports and small series of patients.5 A classic study series described a prevalence of between 0.07 and 1.1% among patients referred for coronary angiography.6–8 With the standardisation of an early invasive approach in the context of acute coronary syndrome (ACS), coupled with the development of techniques, such as high-sensitivity troponin and the increased use of ICI, more cases have been diagnosed.3 In a 2016 study, the prevalence of SCAD as the underlying substrate of ACS was approximately 4%.9 This prevalence is higher in young- to middle-aged women (aged ≤50 years), where SCAD is the substrate for acute MI in approximately 24–35% of the cases.10,11 SCAD mainly affects women. In three of the largest series on SCAD, the percentage of women is around 81–96%, with a mean age at diagnosis of the index event between 45 and 52 years.12–15

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Heart Disease Figure 1: Fibromuscular Dysplasia in Spontaneous Coronary Artery Dissection

A and B: Angio-CT showing signs of multifocal fibromuscular dysplasia (FMD) with zones of stenosis alternating with dilatation in right renal artery (A) and both bilateral carotid arteries (B) in a 67-year-old woman with spontaneous coronary artery dissection (SCAD). C: Angiogram of the brachial artery confirming the typical string-of-beads appearance of multifocal FMD in a 70-year-old patient with SCAD. D-F: Selective angiograms with signs of multifocal FMD in right external iliac artery (D) and both left (E) and right (F) renal arteries in a 60-year-old woman with previous SCAD.

Conditions Related to Spontaneous Coronary Artery Dissection A long list of conditions has been related to SCAD, either as predisposing factors that make a coronary artery wall structure more prone to dissection, or as factors that precipitate acute episodes of SCAD.

Danlos syndrome, Alport syndrome and Nail-patella syndrome. 21–24 Mayo Clinic investigators tested 59 patients with diagnosis of SCAD for these genetic mutations related to collagen disorders. They found only 5% of pathogenic mutations related to collagen disorders.25 Similarly, contemporary SCAD series systematically showed a low prevalence (1–2%) of these disorders.13,18

Fibromuscular Dysplasia During the last decade, the association of this condition with SCAD has received major attention. Fibromuscular dysplasia (FMD) is a nonatherosclerotic and non-inflammatory idiopathic arteriopathy. A relationship (even when not confirmed as causative) has been found between these two entities (Figure 1). Among the different series, the prevalence of FMD in patients with SCAD has ranged between 25% and 86%. This variability is explained by the differences in the type of technique used for screening and/or the number of territories screened.13,16–18 In the first large prospective cohort published, Saw et al. reported signs of FMD in 31% of the total cohort, with this percentage rising to 57% in patients with a complete screening.15 Some authors have described the presence of ‘stigmas’ of FMD on the coronary arteries of patients with SCAD on both angiography and ICI.19,20 While this theory is plausible, more data are needed to corroborate these preliminary findings. The question of whether SCAD and FMD are independent, overlapping entities or manifestations of the same disorder remains unclear, although there is now evidence of a common genetic variant linking these conditions.

Collagen Vascular Disorders Based on the first description of isolated cases of SCAD associated with some of these entities, a relationship of SCAD with some collagen vascular disorders has been proposed. Among the conditions cited in these reports are Marfan syndrome, Ehlers-

Chronic Inflammatory Systemic Diseases SCAD has been associated with some chronic inflammatory systemic diseases. Previous case reports suggested a potential relationship between SCAD and systemic lupus erythematosus, inflammatory bowel disease and sarcoidosis.26–33 In the Canadian registry, the prevalence of these disorders was 11.9%.34 Furthermore, a vasculitic inflammatory mechanism, mainly mediated by eosinophils from the adventitial and peri-adventitial layers, has been suggested as the potential primary event leading to subsequent SCAD. Data from anatomopathological studies showed the presence of this peri-arterial eosinophilic infiltrate in patients with SCAD and confirmed its absence in patients with iatrogenic or traumatic dissections.35

Hypothyroidism A potential association between SCAD and thyroid dysfunction (mainly hypothyroidism) has recently been suggested.36 Theoretically, a thyroid hormone deficit might lead to a modification in the structure of the coronary artery wall, making it more prone to SCAD. In a study by Camacho et al., which included 73 patients with SCAD, the prevalence of hypothyroidism was 26%, significantly higher than that found in a matched control group of patients with ACS. Furthermore, patients with SCAD and hypothyroidism had more distal lesions and more tortuous coronary arteries. However, this association has not been yet confirmed in other studies on SCAD.

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Spontaneous Coronary Artery Dissection Pregnancy Pregnancy and the peripartum period have been classically linked to an increased risk of SCAD. Based on the first descriptions of case reports, SCAD was initially considered as a peripartum condition. However, a recent series showed that peripartum SCAD (P-SCAD) is infrequent, accounting for fewer than 5% of SCAD cases.15 On the other hand, SCAD is the main cause of acute MI during pregnancy and peripartum period.37 A hormone-mediated mechanism, related to both progesterone and oestrogens, has been suggested. Hormonal changes during pregnancy might lead to a weakening of the coronary artery wall and, under certain circumstances, favour the SCAD mechanism. Studies have showed that women with P-SCAD are a high-risk subgroup of patients with SCAD. P-SCAD more frequently affects proximal segments and present with multi-vessel involvement.38,39 In a recently published prospective Canadian cohort study, P-SCAD was related to a higher risk of adverse events both in hospital and within 30 days of discharge.15

Figure 2: Angiographic Patterns in Spontaneous Coronary Artery Dissection

Genetics Apart from cases related to connective tissue disorders or FMD, it seems that SCAD is not strongly familial. To date, few studies have focused on this. Goel et al. found five cases of familial SCAD in 412 patients included in the Mayo Clinic SCAD Registry, with both dominant and recessive patterns of inheritance.40 Recently, Adlam et al. described the first genetic variant associated with SCAD.41 The common variant rs9349379 in the locus PHACTR1/EDN1 has been associated with FMD, SCAD, coronary artery disease and MI. In this study, patients carrying the rs9349379-A allele had an increased risk of FMD and SCAD. Even though this study is a milestone in the field of SCAD, more studies are needed to unravel the relevance of genetics in the context of SCAD.

Precipitating Factors Several factors have been linked to the acute onset of SCAD.5 In the Canadian cohort study, a precipitant factor was found in 57% of patients, with emotional stressors (41%) being the most frequent, followed by physical stressors (24%).13 Data from the same cohort showed different patterns of precipitating factors in men and women with SCAD. In men, isometric physical exercise was the most frequent factor (44%), while in women it was the presence of an emotional stress (54.8%).42

Clinical Presentation The proportion of patients with SCAD presenting as ST-segment elevation MI versus non-ST-segment elevation MI varies widely between different series (26-49%).13,14,43 Other clinical presentations, such as ventricular tachycardia or ventricular fibrillation are infrequent (4– 10%).13,43 Presentation as out-of-hospital sudden cardiac death was 3% in the Italian cohort.14 Symptoms at the time of presentation described in the Canadian cohort are fairly typical of MI, with the vast majority of patients presenting with chest pain (96%), half of them with pain radiating to left upper limb. Other symptoms, such as nausea/vomiting (24%) and sweating (21%), were frequently seen.44

Diagnosis Coronary Angiography Invasive coronary angiography is still the main technique used in the diagnosis of SCAD.1,2 The advent of ICI revealed that a large majority of SCAD cases do not show a double lumen pattern on angiography. This finding led to a specific classification of SCAD by angiographic

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Coronary angiographic projections showing: A: an image of double lumen at first marginal branch of the left circumflex coronary artery in a 49-year-old woman compatible with type 1 spontaneous coronary artery dissection; B: a smooth stenosis at mid-left anterior descending (LAD) coronary artery with distal vessel calibre normalisation compatible with type 2a intramural haematoma; C: Smooth long stenosis from mid-to-distal LAD compatible with type 2b intramural haematoma; D: Focal stenosis at a septal branch of LAD that mimics atherosclerotic lesion compatible with type 3 spontaneous coronary artery dissection.

patterns, different from those of iatrogenic dissections induced by balloon angioplasty.45 This classification includes three main angiographic patterns (Figure 2). Type 1 lesions are defined by the presence of a double lumen image. Type 2 lesions are defined by the presence of a lumen narrowing, with a lesion length usually over 20 mm. Type 2 lesions are classified in two subtypes: type 2a, when the distal vessel recovers the normal size; and type 2b, when the IMH extends distally to the end of the coronary artery. Last, type 3 lesions are defined by an abrupt lumen narrowing with distal vessel size recovering that limits a focal lesion (length <20 mm), mimicking an atherosclerotic lesion. In the Canadian cohort (which included 168 patients with SCAD), Saw et al. observed that 67% of patients had type 2 lesions, 29% had type 1 lesions and 4% had type 3 lesions.13 Following this, other authors have defined type 4 lesions as a total occlusion (TIMI grade flow 0) of the vessel segment on initial presentation. In this context, making a diagnosis of SCAD is complex, as it requires the presence of some signs of SCAD immediately after vessel flow restoration during percutaneous coronary intervention (PCI) or, on follow-up, after confirming the healing of the vessel with normal distal flow, having ruled out causes of coronary embolism.46 In addition to this angiographic classification, other angiographic characteristics have been associated with SCAD. It usually affects more distal segments than atherosclerotic disease. Furthermore, the left anterior descending coronary artery is the most frequently involved vessel. Patients with SCAD have more tortuous vessels than controls without coronary artery disease.12 Motreff et al. described some morphological clues in SCAD.47 First, atherosclerotic lesions are usually absent on the coronary arteries that are not affected by SCAD. Second, the start and/or end of the SCAD lesion often coincides with the presence of a sidebranch. Third, there are

Heart Disease Figure 3: Intracoronary Imaging

Intravascular Ultrasound The standard IVUS technology of 20-40 MHz (spatial resolution ~150 μm) allows SCAD confirmation. Because it has greater penetration than OCT, IVUS may enable a better visualisation of the entire IMH, although in-depth visualisation is not usually an issue for a condition that mostly affects distal coronary territories. However, this technique does not usually allow assessment of subtle anatomic features, such as localised fenestrations, an intimal flap or true luminal thrombus. The first description about the role of IVUS in the diagnosis and management of SCAD was published in 2008 by Arnold et al. in a small series of four SCAD patients.53 Since then, some papers (mostly case reports and small series of patients) have described the usefulness of IVUS for: diagnostic confirmation of SCAD; as a guiding tool during PCI; and to confirm IMH has completely resolved on follow-up.54–59 The experience with high-definition 60 MHz IVUS (with a spatial resolution closer to that of OCT) is anecdotal and limited to a case description.60

Optical Coherence Tomography

A and B: IVUS images in spontaneous coronary artery dissection, confirming the presence of the IVUS catheter within the true lumen and clearly depicting the presence of an anechoic FL; C and D: Optical coherence tomography images in spontaneous coronary artery dissection; C clearly depicts the presence of the catheter within the TL with and near 180º IMH. D: Optical coherence tomography high spatial resolution enables the clear definition of the ED of the dissection. ED = entry door; FL = false lumen; IMH = intramural haematoma; IVUS = intravascular ultrasound; TL = true lumen. *Wire artefact.

unique patterns described as looking like a stick insect or a radish, which are produced by external lumen compression by the IMH. Another angiographic characteristic linked to SCAD is a broken-line appearance, defined as the development of sharp angles in an otherwise tortuous but smooth coronary artery segment.48,49 Anecdotally, the association between SCAD and segments of myocardial bridging has been described.50

Intracoronary Imaging During the last few years, ICI has been found to help in the diagnosis of SCAD and in guiding PCI when this is needed. Where there is diagnostic uncertainty (e.g. where SCAD mimics atherosclerotic disease as in type 3 lesions), ICI has a unique role in confirming the diagnosis of SCAD (Figure 3). In this context, the benefits of ICI should be balanced against potential complications due to the necessity of instrumentation within an injured coronary vessel, which could make it more prone to further dissection. Compared to intravascular ultrasound (IVUS), optical coherence tomography (OCT) in this context may have some theoretical limitations due to: the necessity of contrast injection, which could potentially lead to expansion of the IMH by hydraulic pressure; and the difficulty of assessment in flow-limiting lesions. Previous studies have described the absence of complications related to the use of OCT to confirm SCAD where it was suspected from an angiographic pattern.51 However, Jackson et al. found complications related to OCT in five out of 63 patients with SCAD, even though none of these complications led to an adverse outcome.52 Although ICI, IVUS and OCT can be used to confirm a diagnosis of SCAD, most experts recommend OCT over IVUS, mainly because its better spatial resolution enables clinicians to determine the presence or absence and the extent of the intimo-medial flap.

With its near-histological spatial resolution, OCT can detect the presence and extension of the IMH and can clearly characterise the existence of an intimo-medial flap or fenestration. Alfonso et al. first described the utility of this technique in the context of SCAD.51 In this study, OCT was used to confirm the diagnosis in 11 out of 17 consecutive patients with clinical suspicion of SCAD. OCT proved to be able to identify the rupture site (the entry tear), visualise the intimo-medial membrane and comprehensively assess the characteristics, extent and distribution of the true and false lumen/IMH. The technique could also be used to disclose the involvement of related side branches and the presence of thrombus in the false or the true lumen. Other studies have confirmed the utility of OCT as a diagnostic tool as well as for guiding PCI.61–64 Jackson et al. described unique OCT findings in a larger series of 65 SCAD patients. Interestingly, OCT showed an intimo-medial dissection/fenestration in only 37% of the lesions.52 During follow-up, OCT can be used to confirm vessel healing. Indeed, in some patients, a completely normal artery – intima, media and adventitia – can clearly be visualised, demonstrating the vessel wall has been restored to its original condition.51

Coronary CT Angiography The attraction of non-invasive coronary CT angiography (CCTA) in the acute setting where SCAD is suspected is its potential for avoiding invasive procedures within a coronary artery wall prone to secondary iatrogenic dissection. However, the spatial resolution of CCTA may lead to problems in detecting SCAD lesions, which frequently affect distal segments, sometimes do not produce significant lumen stenosis and where contrast may not penetrate the false lumen. Eleid et al. reported three cases where acute CCTA failed to lead to a diagnosis of SCAD that was later on confirmed on coronary angiography.65 The same group reported retrospective findings on CCTA of patients in the acute phase of SCAD. The most frequent findings were the presence of an abrupt luminal narrowing, followed by IMH identification (similar on CCTA analysis to non-calcified atherosclerotic plaque). However, prospective information on how CCTA compares with the gold-standard coronary angiogram in the acute setting is still lacking. Nonetheless, CCTA has emerged as a useful technique for non-invasive angiographic follow-up. Roura et al. reported results of CCTA in 24 patients with SCAD 3–6 months after the initial event. The study showed the dissection had healed in 83% of the patients.66

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Spontaneous Coronary Artery Dissection Table 1: Differential Diagnoses of Spontaneous Coronary Artery Dissection

Atherosclerotic acute coronary syndrome

Similarities

Differences

• Clinical presentation

• Male sex predominance

• A ngiographic appearance in type 3 spontaneous coronary artery dissection lesions

• O lder patients than spontaneous coronary artery dissection

• A cute and chronic recanalised atherosclerotic thrombus • High prevalence of cardiovascular risk factors may mimic type 1 double lumen spontaneous coronary artery • N o known association with fibromuscular dysplasia dissection • Less coronary tortuosity Takotsubo cardiomyopathy

• Clinical presentation

• O lder patients than spontaneous coronary artery dissection

• Female sex predominance • Frequently preceded by psychosocial/emotional stress • P redominance of the theoretical left anterior descending coronary artery territory Coronary embolism

• Predominance of distal coronary segments • Late angiographic healing

Coronary spasm

• Sometimes multifocal/multi-vessel involvement

• N o diagnostic findings on coronary angiogram/ intracoronary imaging

• P resence of high-risk conditions of systemic embolism: atrial fibrillation, prosthetic heart valves, dilated cardiomyopathy with apical thrombus, infective endocarditis, myxoma or hypercoagulable state • D ifferences in clinical profile (typically angina at rest, during the night) • Male sex predominance

FMD Screening Because of the association between SCAD and FMD described above, systematic screening of SCAD survivors has been recommended.1 Nevertheless, there is still no consensus on the appropriate imaging modality or whether follow-up imaging should be contemplated. Furthermore, it remains to be confirmed whether this screening would significantly alter patient management or outcomes. Available data reflect the presence of a sensitivity gradient in the detection of FMD among different imaging techniques, including invasive angiography, computed tomography angiography (CTA) and MR angiography. The Canadian cohort initially included a high percentage of invasive angiographic screening of the renal and iliac arteries. Angiography was shown to be the most sensitive method for detecting FMD, with a prevalence in this cohort as high as 86% of patients with SCAD.3 However, recently published data on the prospective cohort from the same group reported a lower FMD prevalence (31%), probably related to the lower percentage of patients having invasive screening (44%).67 On the other hand, the Mayo group reported the presence of extra-coronary vascular abnormalities (EVA), including FMD, in 69% of 39 patients with SCAD, using a comprehensive CTA protocol consisting of a single study of the neck, chest, abdomen and pelvis.68 Toggweiler et al. were the first to describe the utility of whole-body MR angiography to detect the presence of EVA in patients with SCAD, and found a 25% prevalence of renal EVA in 12 SCAD survivors.69 The temporal evolution of FMD in patients with SCAD is still unknown; this process might be dynamic with changes over time. However, the role of long-term surveillance beyond a single FMD screening in SCAD is unknown.

Differential Diagnosis Both atherosclerotic ACS and conditions involved in the physiopathology of MI with non-obstructive coronary arteries (MINOCA) should be included in the differential diagnosis of SCAD.70-72 Similarities and disparities between SCAD and these conditions are summarised in Table 1.

Acute Management Medical Therapies Until recently, the treatment frequently adopted in SCAD had been essentially the same as that recommended for ACS due to

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atherosclerotic disease. With the previously described underlying physiopathology (basically involving a weaker coronary artery wall and a primary bleeding event leading to an IMH), the rationale for potent antiplatelet therapy and lipid-lowering drugs seems unclear. On the other hand, some hypothesis-generating observational data has suggested that some medications may modify the risk of recurrences in SCAD survivors.

Thrombolysis, Antiplatelet and Anticoagulant Agents Information about safety and efficacy of thrombolysis in the context of SCAD is lacking and mostly comes from isolated case reports, ranging from successful results to dissection extension and even coronary rupture.73–76 It seems reasonable to avoid thrombolytic therapy where SCAD is suspected, as the European Society of Cardiology-Acute Cardiovascular Care Association position paper recommends.1 The use of antiplatelet therapies and the duration of therapy are still controversial. The rationale to add dual antiplatelet therapy in the specific context of SCAD is based on the idea of the existence of the associated thrombus within the true lumen in selected SCAD cases. A previous study reported the presence of thrombus within the true lumen in three out of 11 OCT-confirmed SCAD cases.51 Recent data on a larger cohort of SCAD patients with OCT seem to corroborate these findings, showing the presence of some amount of thrombus in the true lumen in 36% of fenestrated and 14% of non-fenestrated SCAD lesions.52 However, it is hard to justify that this usually tiny amount of intraluminal thrombus may play a major role in SCAD-related ischaemia. On the contrary, the thrombus probably plays a minor role as an epiphenomenon in SCAD. Some authors still recommend dual antiplatelet therapy (with aspirin plus clopidogrel) during the acute phase with continuing life-long aspirin therapy in conservatively managed SCAD patients. In patients where PCI with stent implantation is performed, 12-month dual antiplatelet therapy (avoiding potent P2Y12 inhibitors other than clopidogrel) is recommended by current guidelines.77 More information about different regimens and duration of dual antiplatelet therapy is needed. Data on the use of anticoagulant therapy in the context of SCAD are lacking. In the context of ACS (a common presentation of SCAD),

Heart Disease Table 2: Suggestions to Avoid Complications During Percutaneous Coronary Interventions in Spontaneous Coronary Artery Dissection • A void the use of Amplatz guiding catheters and guide catheter extension systems to prevent iatrogenic dissection. • Special focus to keep coaxial non-deep catheter intubation. • Use non-hydrophilic guidewires. • W hen a relevant side-branch is involved, wiring is recommended before percutaneous coronary intervention to avoid side-branch occlusion by haematoma extension. • T here is a low threshold for intracoronary imaging-guided percutaneous coronary intervention use: • It confirms position of the guidewire within the true lumen. • I t permits proper device selection (length and diameter) and stent optimisation. • I n flow-limiting lesions, the objective must be to restore coronary flow. Avoid aesthetic percutaneous coronary intervention. • Device dilatation should be done gently (avoid high pressure inflation). • C utting or scoring balloons, with or without stenting, may help to fenestrate high-pressure haematomas. • T hree-stent technique (sandwich stenting) may prevent spontaneous coronary artery dissection extension by first enclosing the haematoma borders. • I f feasible, avoid stent post-dilatation. If performed,the preference is for short balloons, low-pressure inflations and avoid geographic miss.

anticoagulant therapy with heparin or fondaparinux should be discontinued as soon as the diagnosis of SCAD is confirmed in the absence of any other indication for anticoagulant therapy.2

Percutaneous Coronary Interventions While conservative management constitutes the preferred approach in the majority of SCAD patients, PCI may be required in some specific situations such as in the presence of ongoing or recurrent ischaemia, total vessel occlusion, haemodynamic/electric instability or high-risk anatomies where a great territory is at risk (as with left main or proximal involvement). PCI has poorer results in the treatment of SCAD than in atherosclerotic disease. The Mayo Clinic cohort study described a 53% rate of procedural PCI failure.43 In the prospective Canadian cohort, 30% of PCI procedures were unsuccessful.15 Furthermore, these interventions in weaker coronary artery walls have been associated with an increased risk of iatrogenic dissections or IMH propagation.80,81 Many strategies have been postulated as the preferable technique in the context of SCAD. However, head-to-head studies comparing different strategies have not been performed. With the high rate of total healing described above, a more conservative approach with the objective of restoring the distal coronary flow may be potentially beneficial. Thereby, in some cases, gentle, low-calibre balloon angioplasty can be enough to restore distal flow, avoiding the implantation of a permanent metallic layer in a young patient with no significant atherosclerotic burden. This is also the rationale underlying the isolated use of scoring or cuttings balloons to fenestrate the IMH, with the aim of reducing the compression of the true lumen.58,82 When stent implantation is considered, it seems reasonable to use current generation drug-eluting stents (DES) over bare metal stents. In this regard, Conrotto et al. analysed the results of DES versus bare metal stents in 238 patients with SCAD.83 The DES group showed a nonsignificant trend towards a lower primary endpoint, that was mainly driven by a reduction in target vessel revascularisation.

Statins The rationale for lipid-lowering therapies in a condition not related to cholesterol deposition seems weak. Furthermore, retrospective data from the Mayo Clinic group even suggest a slightly higher risk of recurrence in patients taking statins.78 Current guidelines recommend treatment with statins only for primary prevention.1,2

Beta-blockers The potential benefit of beta-blockers in SCAD has been extrapolated from experience in acute aortic dissection and atherosclerotic-ACS. Moreover, data from a large cohort showed a lower risk of recurrences in SCAD survivors taking beta-blockers.34 Based on this observational data, most experts recommend long-term treatment with beta-blockers for SCAD survivors.2

The use of bioresorbable scaffolds (BRS) in the context of SCAD has clear appeal. The gradual and complete resorption of scaffolds over time would avoid the presence of a permanent metal layer when the coronary vessel wall is completely healed and, potentially, would obviate the risk of very-late device restenosis or thrombosis. A small series showed the good performance of first-generation BRS in the context of SCAD on mid- to long-follow-up.84,85 However, these firstgeneration poly-L-lactide acid-based BRS are no longer available, owing to the observed higher incidence of thrombosis compared with second-generation, everolimus DES. Data on other BRS, such as as magnesium BRS, are still anecdotical.86,87 Table 2 summarises several suggestions to avoid complications in SCAD PCI.

Coronary Artery Bypass Grafting

Revascularisation Conservative Management Observational data shows that most patients with SCAD have a benign clinical course when managed with a conservative, watchful waiting strategy without PCI.3 This is coupled with the evidence of a high percentage of complete vessel healing at follow-up in SCAD survivors. The Canadian group described spontaneous healing in all 79 SCAD patients who had a repeat angiogram ≥26 days after the index event.13 The same group has recently reported angiographic healing in 86% of SCAD lesions, a percentage that increased to 95% in patients who had a repeat angiogram >30 days after the event.79 These findings, combined with reported high rates of complications and suboptimal results with PCI, lead to the current recommendation of conservative management in the absence of recurrent or ongoing ischaemia, highrisk anatomy or haemodynamic/electric instability.1,2,43,67

Coronary artery bypass grafting may be necessary in the context of PCI failure with ongoing ischaemia and in some high-risk anatomic scenarios such as left main or multi-vessel proximal involvement. To date, available data on the results of bypass grafting in SCAD is limited to small case series. In general, these series described good acute results.43,88,89 Of note, the Mayo Clinic paper showed a high prevalence (~70%) of late bypass graft occlusion, presumably due to competitive flow from the healed native coronary vessel.43

Exercise Recommendations and Cardiac Rehabilitation Because of the association between SCAD episodes and acute physical stressors (especially isometric physical exercise) acting as a precipitating factor, concern has arisen about the prescription of physical activity in SCAD survivors. In the absence of robust data, it

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Spontaneous Coronary Artery Dissection seems reasonable to keep an active lifestyle after SCAD, avoiding highintensity exercise and competitive sports.2 However, case reports have showed excellent outcomes in patients resuming high-intensity competitive sport activity.90 The current American Heart Association statement recommends that all SCAD survivors should be referred to a cardiac rehabilitation programme.2 In the absence of robust evidence of the prognostic benefit of cardiac rehabilitation on SCAD, Krittanawong et al. demonstrated that cardiac rehabilitation after SCAD is safe and reported physical and emotional benefits in a majority of SCAD survivors.91. The Canadian group also reported benefits of a specific SCAD rehabilitation program in the first 70 SCAD patients referred in terms of less chest pain, higher exercise capacity, better performance on depression questionnaires and a reduced incidence of major adverse cardiovascular events (MACE) on follow-up.92

Pregnancy in SCAD Survivors Data evaluating the risk of SCAD recurrence with future pregnancies is scarce. To date, only one small series describes one pregnancy-related recurrence among eight SCAD survivors at a median follow-up of 36 months.93 With this limited data, it does not seem reasonable to give a general recommendation to SCAD survivors to avoid pregnancy. Pregnancy after SCAD should be considered high risk, and patients should be closely monitored and receive adequate information about the potential increased risk of SCAD recurrence associated with pregnancy.

Follow-up: Prognosis and Risk of Recurrences Reported mortality in SCAD is generally low. The Mayo Clinic group reported a 10-year mortality of 7.7% after SCAD.78 The Canadian group described a 1.2% mortality at median follow-up of 3.1 years.34 Lettieri et al. described a 5.6% 6-year mortality after SCAD.14 In the Japanese series, the mortality rate was 1.6% at median follow-up of 2.8 years.10 However, morbidity is significant after SCAD. Saw et al. described inhospital major adverse events in 8.8% of 750 SCAD patients.67 The

dlam D, Alfonso F, Maas A, et al. European Society of A Cardiology, Acute Cardiovascular Care Association, SCAD study group: a position paper on spontaneous coronary artery dissection. Eur Heart J 2018:3353–68. https://doi.org/10.1093/ eurheartj/ehy080; PMID: 29481627. 2. Hayes SN, Kim CESH, Saw J, et al. Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association. Circulation 2018;137:e523–57. https://doi.org/10.1161/ CIR.0000000000000564; PMID: 29472380. 3. Saw J, Mancini GBJ, Humphries KH. Contemporary review on spontaneous coronary artery dissection. J Am Coll Cardiol 2016;68:297–312. https://doi.org/10.1016/j.jacc.2016.05.034; PMID: 27417009 4. Waterbury TM, Tweet MS, Hayes SN, et al. Early natural history of spontaneous coronary artery dissection. Circ Cardiovasc Interv 2018;11:e006772. https://doi.org/10.1161/ CIRCINTERVENTIONS.118.006772; PMID: 30354594. 5. Pretty HC. Dissecting aneurysm of coronary artery in a woman aged 42: rupture. Br Med J 1931;1:667. 6. Hering D, Piper C, Hohmann C, et al. Prospective study of the incidence, pathogenesis and therapy of spontaneous, by coronary angiography diagnosed coronary artery dissection. Zeitschrift für Kardiol 1998;87:961–70 [in German]. https://doi. org/10.1007/s003920050253; PMID: 10025069. 7. Vanzetto G, Berger-Coz E, Barone-Rochette G, et al. Prevalence, therapeutic management and medium-term prognosis of spontaneous coronary artery dissection: results from a database of 11,605 patients. Eur J Cardio-Thoracic Surg 2009;35:250–4. https://doi.org/10.1016/j.ejcts.2008.10.023; PMID: 19046896. 8. Mortensen KH, Thuesen L, Kristensen IB, Christiansen EH. Spontaneous coronary artery dissection: a Western Denmark Heart Registry Study. Catheter Cardiovasc Interv 2009;74:710–7. https://doi.org/10.1002/ccd.22115; PMID: 19496145. 9. Nishiguchi T, Tanaka A, Ozaki Y, et al. Prevalence of spontaneous coronary artery dissection in patients with acute coronary syndrome. Eur Hear J Acute Cardiovasc Care 2016;5:263–70. https://doi.org/10.1177/2048872613504310; PMID: 24585938. 10. Nakashima T, Noguchi T, Haruta S, et al. Prognostic impact of spontaneous coronary artery dissection in young female

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composite was mainly driven by recurrent MI (4%), severe ventricular arrhythmia (4%) and unplanned revascularisation (3%). Overall, 30-day MACE in the same series was 8.8%, driven by recurrent MI (6%) and unplanned revascularisation (3%). In a previous paper by the same group with a longer follow-up, the overall MACE rate was 19.9% at median follow-up at 3.1 years, mostly driven by recurrent MI (16.8%) and recurrent SCAD (10.4%).34 The Mayo Clinic group reported a 10year rate of MACE as high as 47.4%, with 17% rate of recurrence during a median follow-up of 3.9 years.78 Lettieri et al. described a 6-year MACE rate of 14.6%, driven by recurrent MI (5.2%) and repeated revascularisation (4.6%).14 In the paper by Nakashima et al., the 5-year MACE rate was 37%, with 22% SCAD recurrence at median follow-up of 2.8 years.10 Observational data by Saw et al. found that hypertension and beta-blocker treatment seem to modify the risk of recurrence.34 Eleid et al. noted that increased coronary tortuosity might be associated with a higher risk of recurrence.12

Patient Groups Recently, due to a greater awareness of this condition, SCAD survivor groups have been set up. Initiatives such as Beat SCAD (https:// beatscad.org.uk) in the UK or SCAD Alliance (https://www.scadalliance. org) in North America support patients and families affected by the condition.

Conclusion SCAD is nowadays a well-known cause of ACS. Despite great advances in the recognition of this elusive disease in the last few years, significant gaps remain in our knowledge of the physiopathology, diagnosis, management and prognosis of this condition. In a sporadic and infrequent clinical entity such as SCAD (where randomised clinical trials are unlikely), information from further prospective registries and collaborative studies are required to advance in the knowledge of this fascinating condition.

patients with acute myocardial infarction: a report from the Angina Pectoris-Myocardial Infarction Multicenter Investigators in Japan. Int J Cardiol 2016;207:341–8. https://doi. org/10.1016/j.ijcard.2016.01.188; PMID: 26820364. Saw J, Aymong E, Mancini GBJ, et al. Nonatherosclerotic coronary artery disease in young women. Can J Cardiol 2014;30:814–19. https://doi.org/10.1016/j.cjca.2014.01.011; PMID: 24726091. Eleid MF, Guddeti RR, Tweet MS, et al. Coronary artery tortuosity in spontaneous coronary artery dissection angiographic characteristics and clinical implications. Circ Cardiovasc Interv 2014;7:656–62. https://doi.org/10.1161/ CIRCINTERVENTIONS.114.001676; PMID: 25138034. Saw J, Aymong E, Sedlak T, et al. Spontaneous coronary artery dissection association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes. Circ Cardiovasc Interv 2014;7:645–55. https://doi.org/10.1161/ CIRCINTERVENTIONS.114.001760; PMID: 25294399. Lettieri C, Zavalloni D, Rossini R, et al. Management and longterm prognosis of spontaneous coronary artery dissection. Am J Cardiol 2015;116:66–73. https://doi.org/10.1016/j. amjcard.2015.03.039; PMID: 25937347. Saw J, Starovoytov A, Humphries K, et al. Canadian spontaneous coronary artery dissection cohort study: in-hospital and 30-day outcomes. Eur Heart J 2019;40:1188–97. https://doi.org/10.1093/eurheartj/ehz007; PMID: 30698711. Saw J, Ricci D, Starovoytov A, et al. Spontaneous coronary artery dissection: prevalence of predisposing conditions including fibromuscular dysplasia in a tertiary center cohort. JACC Cardiovasc Interv 2013;6:44–52. https://doi.org/10.1016/j. jcin.2012.08.017; PMID: 23266235. Rogowski S, Maeder MT, Weilenmann D, et al. Spontaneous coronary artery dissection: angiographic follow-up and longterm clinical outcome in a predominantly medically treated population. Catheter Cardiovasc Interv 2017;89:59–68. https:// doi.org/10.1002/ccd.26383; PMID: 26708825. Prasad M, Tweet MS, Hayes SN, et al. Prevalence of extracoronary vascular abnormalities and fibromuscular dysplasia in patients with spontaneous coronary artery dissection. Am J Cardiol 2015;115:1672–77. https://doi. org/10.1016/j.amjcard.2015.03.011; PMID: 25929580. Michelis KC, Olin JW, Kadian-Dodov D, et al. Coronary artery

20.

21.

22.

23.

24.

25.

26.

27.

28.

manifestations of fibromuscular dysplasia. J Am Coll Cardiol 2014;64:1033–46. https://doi.org/10.1016/j.jacc.2014.07.014; PMID: 25190240. Saw J, Bezerra H, Gornik HL, et al. Angiographic and intracoronary manifestations of coronary fibromuscular dysplasia. Circulation 2016;133:1548–59. https://doi. org/10.1161/CIRCULATIONAHA.115.020282; PMID: 26957531. Sato C, Wakabayashi K, Suzuki H. Natural course of isolated spontaneous coronary artery dissection in Marfan syndrome. Int J Cardiol 2014;177:20–2. https://doi.org/10.1016/j. ijcard.2014.09.061; PMID: 25499326. Nakamura M, Yajima J, Oikawa Y, et al. Vascular Ehlers-Danlos syndrome – all three coronary artery spontaneous dissections. J Cardiol 2009;53:458–62. https://doi.org/10.1016/j. jjcc.2008.09.007; PMID: 19477391. Anuwatworn A, Sethi P, Steffen K, et al. Spontaneous coronary artery dissection: a rare manifestation of Alport syndrome. Case Rep Cardiol 2017;2017:1–3. https://doi. org/10.1155/2017/1705927; PMID: 28884028. Nizamuddin SL, Broderick DK, Minehart RD, Kamdar BB. Spontaneous coronary artery dissection in a parturient with Nail-Patella syndrome. Int J Obstet Anesth 2015;24:69–73. https://doi.org/10.1016/j.ijoa.2014.07.010; PMID: 25433575. Henkin S, Negrotto SM, Tweet MS, et al. Spontaneous coronary artery dissection and its association with heritable connective tissue disorders. Heart 2016;102:876–81. https://doi. org/10.1136/heartjnl-2015-308645; PMID: 26864667. Nisar MK, Mya T. Spontaneous coronary artery dissection in the context of positive anticardiolipin antibodies and clinically undiagnosed systemic lupus erythematosus. Lupus 2011;20:1436–38. https://doi.org/10.1177/0961203311406765; PMID: 21768175. Rekik S, Lanfranchi P, Jacq L, Bernasconi F. Spontaneous coronary artery dissection in a 35 year-old woman with systemic lupus erythematosus successfully treated by angioplasty. Heart Lung Circ 2013;22:955–8. https://doi. org/10.1016/j.hlc.2013.01.015; PMID: 23465651. Reddy S, Vaid T, Ganiga Sanjeeva NC, Shetty RK. Spontaneous coronary artery dissection as the first presentation of systemic lupus erythematosus. BMJ Case Rep 2016;2016:bcr2016216344. https://doi.org/10.1136/bcr-2016216344; PMID: 27558190.

Heart Disease 29. K othari D, Ruygrok P, Gentles T, Occleshaw C. Spontaneous coronary artery dissection in an adolescent man with systemic lupus erythematosus. Intern Med J 2007;37:342–3. https://doi.org/10.1111/j.1445-5994.2007.01345.x; PMID: 17504287. 30. Sharma AK, Farb A, Maniar P, et al. Spontaneous coronary artery dissection in a patient with systemic lupus erythematosis. Hawaii Med J 2003;62:248–53. PMID: 14702766. 31. Aldoboni AH, Hamza EA, Majdi K, et al. Spontaneous dissection of coronary artery treated by primary stenting as the first presentation of systemic lupus erythematosus. J Invasive Cardiol 2002;14:694–6. PMID: 12403902. 32. Kanaroglou S, Nair V, Fernandes JR. Sudden cardiac death due to coronary artery dissection as a complication of cardiac sarcoidosis. Cardiovasc Pathol 2015;24:244–6. https://doi. org/10.1016/j.carpath.2015.01.001; PMID: 25638512. 33. Srinivas M, Basumani P, Muthusamy R, Wheeldon N. Active inflammatory bowel disease and coronary artery dissection. Postgrad Med J 2005;81:68–70. https://doi.org/10.1136/ pgmj.2004.018952; PMID: 15640436. 34. Saw J, Humphries K, Aymong E, et al. Spontaneous coronary artery dissection: clinical outcomes and risk of recurrence. J Am Coll Cardiol 2017;70:1148–58. https://doi.org/10.1016/j. jacc.2017.06.053; PMID: 28838364. 35. Pitliya A, Datta S, Kalayci A, et al. Eosinophilic inflammation in spontaneous coronary artery dissection: a potential therapeutic target? Med Hypotheses 2018;121:91–4. https://doi. org/10.1016/j.mehy.2018.09.039; PMID: 30396503. 36. Camacho Freire SJ, Díaz Fernández JF, Gheorghe LL, et al. Spontaneous coronary artery dissection and hypothyroidism. Rev Española Cardiol (Eng Ed) 2019;72:625–33. https://doi. org/10.1016/j.rec.2018.06.031; PMID: 30097393. 37. Elkayam U, Jalnapurkar S, Barakkat MN, et al. Pregnancyassociated acute myocardial infarction: a review of contemporary experience in 150 cases between 2006 and 2011. Circulation 2014;129:1695–702. https://doi.org/10.1161/ CIRCULATIONAHA.113.002054; PMID: 24753549. 38. Tweet MS, Hayes SN, Codsi E, et al. Spontaneous coronary artery dissection associated with pregnancy. J Am Coll Cardiol 2017;70:426–35. https://doi.org/10.1016/j.jacc.2017.05.055; PMID: 28728686. 39. Havakuk O, Goland S, Mehra A, Elkayam U. Pregnancy and the risk of spontaneous coronary artery dissection: an analysis of 120 contemporary cases. Circ Cardiovasc Interv 2017;10:1–13. https://doi.org/10.1161/CIRCINTERVENTIONS.117.004941; PMID: 28302642. 40. Goel K, Tweet M, Olson TM, et al. Familial spontaneous coronary artery dissection. JAMA Intern Med 2015;175:821. https://doi.org/10.1001/jamainternmed.2014.8307; PMID: 25798899. 41. Adlam D, Olson TM, Combaret N, et al. Association of the PHACTR1/EDN1 genetic locus with spontaneous coronary artery dissection. J Am Coll Cardiol 2019;73:58–66. https://doi. org/10.1016/j.jacc.2018.09.085; PMID: 30621952. 42. Fahmy P, Prakash R, Starovoytov A, et al. Pre-disposing and precipitating factors in men with spontaneous coronary artery dissection. JACC Cardiovasc Interv 2016;9:866–8. https://doi. org/10.1016/j.jcin.2016.02.024; PMID: 27101917. 43. Tweet MS, Eleid MF, Best PJM, et al. Spontaneous coronary artery dissection: revascularization versus conservative therapy. Circ Cardiovasc Interv 2014;7:777–86. https://doi. org/10.1161/CIRCINTERVENTIONS.114.001659; PMID: 25406203. 44. Luong C, Starovoytov A, Heydari M, et al. Clinical presentation of patients with spontaneous coronary artery dissection. Catheter Cardiovasc Interv 2017;89:1149–54. https://doi. org/10.1002/ccd.26977; PMID: 28244197. 45. Saw J. Coronary angiogram classification of spontaneous coronary artery dissection. Catheter Cardiovasc Interv 2014;84:1115–22. https://doi.org/10.1002/ccd.25293; PMID: 24227590. 46. Al-Hussaini A, Adlam D. Spontaneous coronary artery dissection. Heart 2017;103:1043–51. https://doi.org/10.1136/ heartjnl-2016-310320; PMID: 28363899. 47. Motreff P, Malcles G, Combaret N, et al. How and when to suspect spontaneous coronary artery dissection: novel insights from a single-centre series on prevalence and angiographic appearance. EuroIntervention 2017;12:e2236–43. https://doi.org/10.4244/EIJ-D-16-00187; PMID: 27973331. 48. Alfonso F, Bastante T. Spontaneous coronary artery dissection: novel diagnostic insights from large series of patients. Circ Cardiovasc Interv 2014;7:638–41. https://doi.org/10.1161/ CIRCINTERVENTIONS.114.001984; PMID: 25336602. 49. Alfonso F. Spontaneous coronary artery dissection. Circulation 2012;126:667–70. https://doi.org/10.1161/ CIRCULATIONAHA.112.122093; PMID: 22800852. 50. De-Giorgio F, Grassi VM, Abbate A, et al. Causation or coincidence? A case of sudden death due to spontaneous coronary artery dissection in presence of myocardial bridging. Int J Cardiol 2012;159:e32–4. https://doi.org/10.1016/j. ijcard.2011.11.056; PMID: 22192277. 51. Alfonso F, Paulo M, Gonzalo N, et al. Diagnosis of spontaneous coronary artery dissection by optical coherence tomography. J Am Coll Cardiol 2012;59:1073–9. https://doi.org/10.1016/j. jacc.2011.08.082; PMID: 22421300. 52. Jackson R, Al-Hussaini A, Joseph S, et al. Spontaneous

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59.

60.

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coronary artery dissection. JACC Cardiovasc Imaging 2019;12:2475–88. https://doi.org/10.1016/j.jcmg.2019.01.015; PMID: 30878439. Arnold JR, West NE, van Gaal WJ, et al. The role of intravascular ultrasound in the management of spontaneous coronary artery dissection. Cardiovasc Ultrasound 2008;6:24. https://doi. org/10.1186/1476-7120-6-24; PMID: 18513437. Kalra A, Aggarwal A, Kneeland R, Traverse JH. Percutaneous coronary intervention in spontaneous coronary artery dissection: role of intravascular ultrasound. Cardiol Ther 2014;3:61–6. https://doi.org/10.1007/s40119-014-0029-4; PMID: 25139465. Mahmood MM, Austin D. IVUS and OCT guided primary percutaneous coronary intervention for spontaneous coronary artery dissection with bioresorbable vascular scaffolds. Cardiovasc Revasc Med 2017;18:53–7. https://doi.org/10.1016/j. carrev.2016.09.005; PMID: 27717579. Paulo M, Sandoval J, Lennie V, et al. Combined use of OCT and IVUS in spontaneous coronary artery dissection. JACC Cardiovasc Imaging 2013;6:830–2. https://doi.org/10.1016/j. jcmg.2013.02.010; PMID: 23747066. Cerrato E, Tomassini F, Rolfo C, et al. Spontaneous coronary artery dissection treated with biovascular scaffolds guided by intravascular ultrasounds imaging. Cardiovasc Interv Ther 2017;32:186–9. https://doi.org/10.1007/s12928-016-0391-3; PMID: 27023796. Ito T, Shintani Y, Ichihashi T, et al. Non-atherosclerotic spontaneous coronary artery dissection revascularized by intravascular ultrasonography-guided fenestration with cutting balloon angioplasty. Cardiovasc Interv Ther 2017;32:241–3. https://doi.org/10.1007/s12928-016-0397-x; PMID: 27142197. Tsutsui H, Chino C, Komatsu M, et al. Resolution of spontaneous coronary artery dissection within 3 weeks detected by computed tomography angiography and intravascular ultrasound. Cardiovasc Interv Ther 2017;32:77–81. https://doi.org/10.1007/s12928-015-0373-x; PMID: 26700028. Song L, Mintz GS, Kadohira T, et al. Spontaneous coronary artery dissection with intra-adventitial hematoma detected by high-definition intravascular ultrasound. Coron Artery Dis 2016;27:707–8. https://doi.org/10.1097/ MCA.0000000000000427; PMID: 27608321. Garcia-Guimaraes M, Bastante T, Cuesta J, et al. Multifaceted presentation of recurrent spontaneous coronary artery dissection: angiography and optical coherence tomography findings. Circ Cardiovasc Interv 2017;10:e004696. https://doi. org/10.1161/CIRCINTERVENTIONS.116.004696; PMID: 28108456. Fabris E, Kennedy MW, Sinagra G, et al. Optical coherence tomography for strategy planning and staged optimization of spontaneous coronary artery dissection. Eur Hear J Cardiovasc Imaging 2017;18:939. https://doi.org/10.1093/ehjci/jex058; PMID: 28398579. Ramalho AR, Silva Marques J, Oliveira Santos M, Matos V. Optical coherence tomography-guided full plastic jacket in spontaneous coronary artery dissection. JACC Cardiovasc Interv 2017;10:413–14. https://doi.org/10.1016/j.jcin.2016.10.028; PMID: 28161260. Nishiguchi T, Tanaka A, Taruya A, et al. Prognosis of spontaneous coronary artery dissection treated by percutaneous coronary intervention with optical coherence tomography. J Cardiol 2017;70:524–9. https://doi.org/10.1016/j. jjcc.2017.03.009; PMID: 28504113. Eleid MF, Tweet MS, Young PM, et al. Spontaneous coronary artery dissection: challenges of coronary computed tomography angiography. Eur Hear J Acute Cardiovasc Care 2017;7:609–13. https://doi.org/10.1177/2048872616687098; PMID: 28139136. Roura G, Ariza-Solé A, Rodriguez-Caballero IF, et al. Noninvasive follow-up of patients with spontaneous coronary artery dissection with CT angiography. JACC Cardiovasc Imaging 2016;9:896–7. https://doi.org/10.1016/j.jcmg.2015.06.011; PMID: 26476501. Saw J, Starovoytov A, Humphries K, et al. Canadian spontaneous coronary artery dissection cohort study: in-hospital and 30-day outcomes. Eur Heart J 2019;40:1188–97. https://doi.org/10.1093/eurheartj/ehz007; PMID: 30698711. Liang JJ, Prasad M, Tweet MS, et al. A novel application of CT angiography to detect extracoronary vascular abnormalities in patients with spontaneous coronary artery dissection. J Cardiovasc Comput Tomogr 2014;8:189–97. https://doi. org/10.1016/j.jcct.2014.02.001; PMID: 24939067. Toggweiler S, Puck M, Thalhammer C, et al. Associated vascular lesions in patients with spontaneous coronary artery dissection. Swiss Med Wkly 2012;142:w13538. https://doi. org/10.4414/smw.2012.13538; PMID: 22389212. Niccoli G, Scalone G, Crea F. Acute myocardial infarction with no obstructive coronary atherosclerosis: mechanisms and management. Eur Heart J 2015;36:475–81. https://doi. org/10.1093/eurheartj/ehu469; PMID: 25526726. Agewall S, Beltrame JF, Reynolds HR, et al. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. Eur Heart J 2017;38:143–53. https://doi. org/10.1093/eurheartj/ehw149; PMID: 28158518. Duran JM, Naderi S, Vidula M, et al. Spontaneous coronary artery dissection and its association with takotsubo syndrome: Novel insights from a tertiary center registry. Catheter Cardiovasc Interv 2019. https://doi.org/10.1002/ccd.28314;

PMID: 31037831; epub ahead of press. 73. S iddiqui F, Briasoulis A, Siddiqui S, et al. Spontaneous distal right coronary artery dissection in a patient with massive pulmonary embolism. Am J Ther 2016;23:e249–51. https://doi. org/10.1097/MJT.0000000000000108; PMID: 25079507. 74. Leclercq F, Messner-Pellenc P, Carabasse D, et al. Successful thrombolysis treatment of a spontaneous left main coronary artery dissection without subsequent surgery. Eur Heart J 1996;17:320–1. https://doi.org/10.1093/oxfordjournals. eurheartj.a014853; PMID: 8732390. 75. Andreou AY, Georgiou PA, Georgiou GM. Spontaneous coronary artery dissection: report of two unsuspected cases initially treated with thrombolysis. Exp Clin Cardiol 2009;14:e89– 92. PMID: 20198198. 76. Jović Z, Obradović S, Djenić N, et al. Does thrombolytic therapy harm or help in ST elevation myocardial infarction (STEMI) caused by the spontaneous coronary dissection? Vojnosanit Pregl 2015;72:536–40. https://doi.org/10.2298/VSP1506536J; PMID: 26226727. 77. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur Heart J 2018;39:213–60. https://doi.org/10.1093/eurheartj/ehx419; PMID: 28886622. 78. Tweet MS, Hayes SN, Pitta SR, et al. Clinical features, management, and prognosis of spontaneous coronary artery dissection. Circulation 2012;126:579–88. https://doi. org/10.1161/CIRCULATIONAHA.112.105718; PMID: 22800851. 79. Hassan S, Prakash R, Starovoytov A, Saw J. Natural history of spontaneous coronary artery dissection with spontaneous angiographic healing. JACC Cardiovasc Interv 2019;12:518–27. https://doi.org/10.1016/j.jcin.2018.12.011; PMID: 30826233. 80. Prakash R, Starovoytov A, Heydari M, et al. Catheter-induced iatrogenic coronary artery dissection in patients with spontaneous coronary artery dissection. JACC Cardiovasc Interv 2016;9:1851–3. https://doi.org/10.1016/j.jcin.2016.06.026; PMID: 27609262. 81. García-Guimaraes M, Bastante T, Cuesta J, Alfonso F. Hybrid percutaneous treatment of iatrogenic coronary artery dissection complicating a spontaneous coronary artery dissection. EuroIntervention 2018;14:e1038–9. https://doi. org/10.4244/EIJ-D-18-00035; PMID: 29400651. 82. Alkhouli M, Cole M, Ling FS. Coronary artery fenestration prior to stenting in spontaneous coronary artery dissection. Catheter Cardiovasc Interv 2016;88:E23–7. https://doi.org/10.1002/ ccd.26161; PMID: 26333193. 83. Conrotto F, D’Ascenzo F, Cerrato E, et al. Safety and efficacy of drug eluting stents in patients with spontaneous coronary artery dissection. Int J Cardiol 2017;238:105–9. https://doi. org/10.1016/j.ijcard.2017.03.027; PMID: 28318654. 84. Ielasi A, Cortese B, Tarantini G, et al. Sealing spontaneous coronary artery dissection with bioresorbable vascular scaffold implantation: data from the prospective “registro Absorb Italiano” (RAI Registry). Int J Cardiol 2016;212:44–6. https://doi.org/10.1016/j.ijcard.2016.03.043; PMID: 27019047. 85. Macaya F, Salinas P, Gonzalo N, et al. Long-term follow-up of spontaneous coronary artery dissection treated with bioresorbable scaffolds. EuroIntervention 2019;14:1403–5. https://doi.org/10.4244/EIJ-D-18-00519; PMID: 30222118. 86. Quadri G, Tomassini F, Cerrato E, Varbella F. First reported case of magnesium-made bioresorbable scaffold to treat spontaneous left anterior descending coronary artery dissection. Catheter Cardiovasc Interv 2017;90:768–72. https:// doi.org/10.1002/ccd.27214; PMID: 28766909. 87. Quadri G, Cerrato E, Rolfo C, Varbella F. Spontaneous coronary artery dissection treated with magnesium-made bioresorbable scaffold: 1-year angiographic and optical coherence tomography follow-up. Catheter Cardiovasc Interv 2019;93:E130– 3. https://doi.org/10.1002/ccd.27971; PMID: 30419604. 88. Vanzetto G, Berger-Coz E, Barone-Rochette G, et al. Prevalence, therapeutic management and medium-term prognosis of spontaneous coronary artery dissection: results from a database of 11,605 patients. Eur J Cardiothorac Surg 2009;35:250–4. https://doi.org/10.1016/j.ejcts.2008.10.023; PMID: 19046896. 89. Unal M, Korkut AK, Kosem M, et al. Surgical management of spontaneous coronary artery dissection. Texas Heart Inst J 2008;35:402–5. PMID: 19156232. 90. Weber N, Weber A, Carbone P, et al. High-intensity, sportspecific cardiac rehabilitation training of a 22-year-old competitive cyclist after spontaneous coronary artery dissection. Proc (Bayl Univ Med Cent) 2018;31:207–9. https://doi. org/10.1080/08998280.2017.1415509; PMID: 29706822. 91. Krittanawong C, Tweet MS, Hayes SE, et al. Usefulness of cardiac rehabilitation after spontaneous coronary artery dissection. Am J Cardiol 2016;117:1604–9. https://doi. org/10.1016/j.amjcard.2016.02.034; PMID: 27055757. 92. Chou AY, Prakash R, Rajala J, et al. The first dedicated cardiac rehabilitation program for patients with spontaneous coronary artery dissection: description and initial results. Can J Cardiol 2016;32:554–60. https://doi.org/10.1016/j.cjca.2016.01.009; PMID: 26923234. 93. Tweet MS, Hayes SN, Gulati R, et al. Pregnancy after spontaneous coronary artery dissection: a case series. Ann Intern Med 2015;162:598–600. https://doi.org/10.7326/L140446; PMID: 25894037.

EUROPEAN CARDIOLOGY REVIEW

Risk Factors and Cardiovascular Disease Prevention

New Perspectives on Atherogenic Dyslipidaemia and Cardiovascular Disease Alberto J Lorenzatti1,2 and Peter P Toth3,4 1. DAMIC Medical Institute, Rusculleda Foundation for Research, Cordoba, Argentina; 2. Department of Cardiology, Cordoba Hospital, Cordoba, Argentina; 3. CGH Medical Center, Sterling, IL, US; 4. Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, US

Abstract Over the past few decades, atherogenic dyslipidaemia has become one of the most common phenotypic presentations of lipid abnormalities, being strongly and unequivocally associated with an increased risk of cardiovascular (CV) disease. Despite the excellent results achieved from statin and non-statin management of LDL cholesterol and CV events prevention, there still remains a significant residual risk, associated with the prevalence of non-LDL cholesterol lipid patterns characterised by elevated triglyceride levels, low HDL cholesterol, a preponderance of small and dense LDL particles, accumulation of remnant lipoproteins and postprandial hyperlipidaemia. These qualitative and quantitative lipid modifications are largely associated with insulin resistance, type 2 diabetes and obesity, the prevalence of which has grown to epidemic proportions throughout the world. In this review, we analyse the pathophysiology of this particular dyslipidaemia, its relationship with the development of atherosclerotic CV disease and, finally, briefly describe the therapeutic approaches, including changes in lifestyle and current pharmacological interventions to manage these lipid alterations aimed at preventing CV events.

Keywords Apolipoprotein B, atherogenic dyslipidaemia, atherosclerosis, ezetimibe, fibrate, lipoprotein, omega-3 fatty acid, proprotein convertase subtilisin/kexin type 9, statin, triglycerides Disclosure: AJL has recevied grants from Amgen, Novo-Nordisk and Resverlogix and personal fees from Sanofi, Pfizer and Kowa outside the submitted work. PPT has received personal fees from Amarin, Amgen, Merck, Novo-Nordisk, Sanofi, Kowa and Resverlogix outside the submitted work. Acknowledgement: The authors thank Thomas Dayspring (Chief Academic Officer, True Health, Richmond, VA, US) for kindly rendering the figures. Received: 17 June 2019 Accepted: 27 August 2019 Citation: European Cardiology Review 2020;15:e04. DOI: https://doi.org/10.15420/ecr.2019.06 Correspondence: Alberto J Lorenzatti, Av Colon 2057, X5003DCE, Cordoba, Argentina. E: alorenzatti@damic.com.ar Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

We are witnessing an epidemic global increase in the prevalence of obesity and its clinical consequences (e.g. insulin resistance and diabetes). This epidemic has been potentiated and sustained by the widespread adoption of unhealthy lifestyles in broad swathes of the population and is characterised by a sedentary lifestyle and an imbalance between the type and characteristics of nutrition, dominated by an excess of calorie intake. Its effects have come to offset the decline in cardiovascular (CV) mortality achieved in recent years as a result of marked therapeutic advances.1,2 The prevalence of atherogenic dyslipidaemia (AD) has increased considerably. AD is characterised by the coexistence of profound qualitative and quantitative modifications in lipid metabolism. The excess of non-LDL particles is a distinctive feature, with an increase in triglyceride (TG)-rich lipoproteins (TRL), low HDL cholesterol levels, accumulation of lipoprotein remnants (i.e. small very LDL [VLDL] and intermediate-density lipoprotein [IDL]), a preponderance of numerous small and dense (sd) LDL particles and postprandial hyperlipidaemia.3â&#x20AC;&#x201C;5 The management of AD requires therapeutic lifestyle modification coupled with pharmacological intervention aimed at reducing CV risk. Because of the range of cardiometabolic alterations these patients present with, trying to attenuate their CV risk can pose formidable management issues.6,7

ÂŠ RADCLIFFE CARDIOLOGY 2020

Atherogenic Dyslipidaemia and its Relationship with Atherosclerotic Cardiovascular Disease The increasing prevalence of obesity is directly associated with the increase in type 2 diabetes (T2D) and metabolic syndrome (MS), which, in turn, are associated with lipoprotein abnormalities described as AD. AD is causally linked to the development and progression of atherosclerotic CV disease (ASCVD).8,9 The relationship between AD and ASCVD is supported by prospective longitudinal cohorts, clinical evidence and genetic linkage studies. As an example, the best predictor of risk of MI at the population level in the INTERHEART study was the apolipoprotein (apo) B100/apoA-I ratio, reflecting the correlation between all apoB (atherogenic lipoproteins) and HDL (representing the classically anti-atherogenic particles).10 In addition, a huge registry of almost 140,000 patients hospitalised in the US due to acute coronary syndromes (ACS) showed that more than half had LDL cholesterol levels <2.59 mmol/l, whereas mean HDL cholesterol and TG values were <1.03 and >1.81 mmol/l, respectively.11,12 In these patients the LDL cholesterol level was not reflecting the real burden of atherogenic lipoproteins; this was more aptly quantified by non-HDL cholesterol (total cholesterol minus HDL cholesterol), a better predictor of CV risk in these individuals. The evidence goes beyond epidemiological studies. The relationship between AD and ASCVD has also been demonstrated in prospective

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Risk Factors and Cardiovascular Disease Prevention randomised clinical trials using statins. Even when treated with statins, patients with the AD phenotype have a higher risk of CV events than those without AD.13,14 The Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis in Myocardial Infarction (PROVE IT-TIMI 22) trial showed that among patients receiving high-intensity statins after an ACS, those with TG <1.69 mmol/l (adjusted by HDL cholesterol and LDL cholesterol levels) had a lower risk of coronary events (HR 0.80; 95% CI [0.66–0.97]; p=0.025) than those with TG exceeding this threshold.15 Similarly, in the Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) and Treating to New Targets (TNT) studies, even in patients who reached LDL cholesterol <1.81 mmol/l, the risk increased 63% (p<0.001) when comparing the highest quintile of TG levels with the lowest one.16 Long-term (>20 years) follow-up of the Bezafibrate Infarction Prevention (BIP) study showed a significant association between elevated TG and all-cause mortality.17 In addition, in a meta-analysis of prospective studies in patients treated with statins, increased TG concentrations were independently correlated with coronary disease and predicted recurrent ischaemic events in patients with a history of ACS treated with statins.11,18,19 Some studies have shown that the association between plasma TG concentrations and CV risk is attenuated when adjusted for other lipid parameters. In a meta-analysis by the Emerging Risk Factors Collaboration, which included data from 302,430 individuals, there was a significant association between TG concentrations and CV risk, but this association was attenuated after adjusting for HDL cholesterol and non-HDL cholesterol.20 In some respects, the case can be made that because non-HDL cholesterol includes lipoproteins that can carry TGs, this likely represents an ‘over-adjustment’ of two highly interrelated risk factor covariates. However, in a more recent analysis, among approximately 46,000 high-risk patients on statin therapy whose LDL cholesterol was well controlled, TG >169 mmol/l was independently and significantly correlated with CV events even after adjusting for LDL cholesterol, non-HDL cholesterol and HDL cholesterol.21 TRL particles (precursors of LDL, including small VLDL and IDL) can be estimated in clinical practice as total cholesterol minus LDL cholesterol minus HDL cholesterol. TRLs are associated with increased CV risk.22,23 Varbo et al. showed that each 1 mmol/l increase in TRLs is associated with a 2.8-fold increase in CV risk independent of the HDL cholesterol level.24 Directly measured TRLs were correlated with an increased risk for ASCVD events in both the Framingham Heart Study and the Jackson Heart Study.25 TRLs are also potently proinflammatory, which likely contributes to their overall atherogenic profile.26 Highlighting the importance of TRLs, postprandial TG concentrations are a stronger predictor of CV events than fasting TG levels. Although most individuals are in a postprandial state during most hours of the day, changes in postprandial TG levels can have a significant effect on the development of atherosclerosis.27–29 In summary, there is convincing evidence that AD is highly atherogenic, although the true significance of each component in this context is incompletely characterised and understood. Human genetic evidence suggests that TRLs contribute causally to the development of ASCVD.12 Gene variants leading to higher levels of plasma apoB-containing lipoproteins, including TRL, consistently increase ASCVD risk.30

Lipoprotein lipase (LPL) plays a critical role in the disposal of TGs carried with chylomicrons and apoB100-containing lipoproteins. LPL is tethered to vascular endothelial cells via glycosylphosphatidylinositol-anchored HDL-binding protein 1 and hydrolyses TGs within the core of TRLs (Figure 1). LPL activity can be regulated by changes in nuclear expression of the gene for LPL, but it is also responsive to a variety of effector molecules. LPL is inhibited by apoCIII and activated by apoCII and apoA-V.31 Angiopoietin-like protein (ANGPTL) 3 and ANGPTL4 exert inhibitory effects via distinct mechanisms. ANGPTL3 stimulates cleavage of LPL from GP1HBP by proprotein convertase subtilisin/kexin types 3 and 6, rendering it inactive.32 LPL monomers are catalytically inactive; the active form is an LPL dimer. In contrast, ANGPTL4 competitively inhibits LPL by inducing the dissociation of its constituent dimers.33 The severity of diabetes can also affect the dimeric integrity of this enzyme.34 The genetics of LPL and the effector molecules that regulate its activity support the conclusion that TGs are an independent risk factor for ASCVD. Loss-of-function mutations in apoCIII result in lower mean serum TG levels than in patients who express normal levels of this enzyme that are correlated with significant reductions in ASCVD risk.35,36 Similarly, a variety of genetic polymorphisms giving rise to reduced activity of ANGPTL3 and ANGPTL4 result in lower mean TG levels and lower risk for ASCVD compared with wild-type controls.37–39 Patients with loss-of-function mutations in apoA-V have higher TG concentrations and augmented risk for ASCVD and ischaemic stroke.40,41 Consistent with these changes, gain-of-function mutations and loss-of-function mutations in LPL are correlated with lower TGs/ lower ASCVD risk and higher TGs/higher ASCVD risk, respectively.35 Epidemiological data associate low HDL cholesterol with heightened ASCVD risk, although a more recent analysis has questioned this.19,42-44 It was long believed that treating low serum HDL cholesterol concentrations would reduce residual risk. However, clinical outcomes trials targeting low HDL cholesterol with different pharmacological interventions failed to reduce CV endpoints, and, similarly, genetic studies do not support a protective role of HDL cholesterol in humans.45-49 Together, these findings imply that HDL cholesterol may be considered a metabolic marker of increased CV risk rather than a therapeutic target. It will be some time before the HDL proteome and lipidome are understood well enough to tailor therapeutic interventions that affect ASCVD risk.50,51 The Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome (AEGIS-II; NCT03473223) is a large Phase III trial testing the capacity of an infusible human apoAI preparation to reduce the risk of CV events in patients with a history of ACS. The trial will also evaluate the efficacy of CSL112 (apoA-I [human]) in inducing atherosclerotic plaque regression by promoting reverse cholesterol transport.

Abnormalities in Lipid Metabolism: The Perfect Storm The aforementioned phenotypic characteristics of AD reflect an abnormal metabolism of TRL, conditioned by both genetic and acquired factors that also affect HDL and LDL particles.52 In the setting of insulin resistance, insulin has reduced capacity to inhibit hormone-sensitive lipase in adipose tissue. This leads to a constitutive release of fatty acid from visceral adipose tissue stores. The liver can dispose of this fatty acid in multiple ways:

EUROPEAN CARDIOLOGY REVIEW

Atherogenic Dyslipidaemia and Cardiovascular Disease Figure 1: Regulation of Triglyceride-Enriched Lipoprotein Lipolysis

ApoCII

Muscle/adipose vasculature ApoE

ApoCIII ApoCI

ApoA-V

ANGPTL4

ApoB TG-rich lipoprotein

LPL

HSPG

HSPG ApoA-V

ANGPTL 9 family (3,8)

HSPG

LPL

ApoE

LPL

3 ApoCII

GPIHBP1

4 ApoA-V

ApoB

5 ApoCIII

LDLR

7 ApoCII ApoCI

HSPG

GPIHBP1

1. Apolipoprotein (apo) CIII stimulates hepatic triglyceride (TG)-rich lipoprotein production. 2. ApoCII is an essential cofactor and activator of lipoprotein lipase (LPL), which is anchored to heparan sulphate proteoglycan (HSPG) and glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1). These receptors are crucial for maintaining LPL activity. 3. GPIHBP1 seizes LPL in the interstitial space and shuttles it across endothelial cells to the luminal surface; it also tethers LPL to the capillary endothelium. 4. ApoA-V binds to HSPG and activates LPL. 5. ApoCIII inhibits LPL-mediated lipolysis by both displacing the LPL activator apoCII from the lipoprotein surface and blocking the interaction of apoCII with LPL (steric hindrance). 6. ApoCI inhibits LPL activity by preventing binding of LPL to TG-rich lipoproteins and by rendering LPL more susceptible to inhibition by angiopoietin-like protein (ANGPTL) 4. 7. ApoE2 can interfere with LPL. 8. ApoCIII inhibits receptor-mediated hepatic clearance of TG-rich lipoproteins. 9. ANGPTL3, ANGPTL4 and ANGPTL8 are members of a family of secreted proteins that inhibit LPL. Source: Sathiyakumar et al. 2018.155 Reproduced with permission from Elsevier.

• It can be oxidised in the mitochondrial matrix. • It can be reassimilated into TG and secreted in VLDL particles. • Some can be shunted toward gluconeogenesis by activation of phosphoenolpyruvate carboxykinase, which will exacerbate the hyperglycaemia of insulin resistance. • If all pathways become saturated, excess TG will be stored in the liver and manifest as hepatic steatosis. In addition to the overproduction and increased hepatic secretion of VLDLs, there is reduced capacity to lipolyse TRLs because of decreased LPL activity. Insulin resistance can reduce nuclear expression of LPL, leading to increased production of apoCIII and decreased production of apoCII.53 Secondary to both hepatic overproduction of TRL and their reduced catabolism, there is a considerable increase in TRLs in the serum. As TRLs accumulate in serum, the activity of cholesterol ester transfer protein (CETP) increases. CETP catalyses the neutral lipid of exchange of TG out of TRLs for cholesterol from both HDLs and LDLs (Figure 2).54 As the HDLs and LDLs become more enriched with TG, they become better substrates for lipolysis by hepatic lipase. Hepatic lipase catabolises HDL and promotes the wasting of apoA-I by the kidney. Hepatic lipase also converts large, buoyant LDLs into smaller (sdLDL) and more numerous ones, rendering the LDL fraction more atherogenic.55 HDL cholesterol levels decrease via other mechanisms as well. There is an insulin response element in the gene for apoA-I, the primary apolipoprotein constituent of HDL particles.56,57 As the liver becomes more insulin resistant, less apoA-I is produced and there is less HDL biogenesis.

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Adipocytes express the ATP-binding membrane cassette transport protein A1 (ABCA1). Insulin resistance downregulates expression of ABCA1 on the surface of adipocytes and reduces HDL formation by these cells.58–60 Chylomicrons are enriched with apoA-I. Insulin resistance reduces the release of this apoA-I in serum by inhibiting LPL. In addition, within the milieu of insulin resistance or diabetes, HDL particle concentrations are not only quantitatively reduced, but also tend to be dysfunctional and thus are not able to perform their primary functions, including reverse cholesterol transport and inhibition of oxidative and inflammatory phenomena.61 The sdLDL particles are highly atherogenic.62 There is accumulating evidence that smaller LDL particles are more atherogenic than larger, more buoyant ones. In addition, sdLDL: • Is more susceptible to oxidation (oxidised LDL is avidly scavenged by activated macrophages in the subendothelial space, giving rise to foam cell cells);63 • Contains apoB100, which undergoes conformational alteration as the particle decreases in volume and size, resulting in lower affinity for, and clearance by, the LDL receptor;64 and • Has increased affinity for proteoglycans in the subendothelial space, exacerbating lipoprotein retention.5 An increase in the hepatic content of TG also promotes an increase in the size of the TRL pool and augmentation of VLDL biosynthesis and secretion. All these observations help explain the extensive and more premature development of ASCVD in patients with insulin resistance and AD.65–67

Risk Factors and Cardiovascular Disease Prevention Figure 2: Molecular Dynamics of Atherogenic Dyslipidaemia

ApoB

Small LDL

TG-rich LDL

Artery

Hepatic lipase

MTP CE

LDL receptor

CETP ApoA-I

ApoA-V ApoCII

ApoA-I catabolism Hepatic and

CETP

HDL

Megalin /cubilin

endothelial lipase

Smaller HDL

ApoE

TG-rich VLDL Lipoprotein lipase

VLDL remnant

CE = cholesteryl ester CETP = cholesteryl ester transfer protein FC = free cholesterol MTP = microsomal TG transfer protein TG = triglyceride

Hepatocytes produce and secrete triglyceride (TG)-rich VLDL. In the setting of insulin resistance with reduced lipoprotein lipase activity, cholesterol ester transfer protein is activated, which catalyses a 1:1 stoichiometric exchange of cholesterol from LDL and HDL particles for TGs from VLDLs of various sizes. As the LDL and HDL particles become more enriched with TG, they become better substrates for lipolysis by hepatic lipase. The result of hepatic lipase-driven lipolysis is to produce increased numbers of smaller, denser LDLs and catabolise HDL. As the HDL is catabolised, apolipoprotein (apo) A-I is released, bound to either cubulin or megalin in the renal ultrafiltrate, and eliminated via the urine.

In summary, changes in lipid metabolism in the setting of insulin resistance or diabetes are profound and include an excess of apoB, including remnants, HDL, which is decreased in quantity and function, and changes in LDL size and particle number. These metabolic changes, coupled with the pro-oxidative, proinflammatory and prothrombotic state of insulin resistance, predispose to the development of accelerated atherogenesis in ‘cardiometabolic’ patients.

Apolipoprotein B and Non-HDL Cholesterol as Risk Markers ApoB measurement represents an estimation of all atherogenic lipoproteins, namely VLDL, IDL, LDL and lipoprotein(a) (Lp(a)), because they all contain a molecule of apoB100. In the same way, each chylomicron particle or its remnants contain a molecule of apoB48 (a truncated form of apoB100). In AD there is overproduction not only of VLDL, but also of apo B. In patients with cardiometabolic risk, the total number of sdLDL particles is increased, and hence apoB is elevated. Neither the sdLDL concentration nor the apoB level is reflected in LDL cholesterol measurements.68 Among patients with insulin resistance, LDL cholesterol is frequently low or ‘normal’, despite increases in apoB. Non-HDL cholesterol is a simple and practical calculation (total cholesterol minus HDL cholesterol) that represents an estimation of the cholesterol concentration within all atherogenic lipoproteins. It is defined as a secondary treatment target in most international dyslipidaemia guidelines.69–72 Using sophisticated techniques, the number of particles of each lipoprotein class and its subclasses can be quantified, but its application in daily clinical practice is an area of continuing investigation.73 Non-HDL cholesterol and apoB are better therapeutic targets in patients with AD.74 In that sense, most guidelines established for patients at very high risk, include objectives of LDL cholesterol <1.81 mmol/l, non-HDL cholesterol <2.59 mmol/l and apoB <1.56 µmol/l, and in those at high risk of LDL cholesterol <2.59 mmol/l, non-HDL cholesterol <3.36 mmol/l and apoB <1.75 µmol/l. In addition, therapeutic effort should be made

to reduce TG burden in serum through lifestyle modification and medication as indicated.75

Non-pharmacological Interventions: Therapeutic Changes in Lifestyle Healthy Eating Favourable therapeutic changes in lifestyle constitute the basic approach and the cornerstone of AD treatment. The greatest benefit is obtained with a reduction in saturated and trans-fats intake, along with an increase in consumption of mono- and polyunsaturated fats. It is essential to reduce the excess of carbohydrates in the diet, especially refined sugars.76,77 The Mediterranean diet seems to be more effective than a low-fat diet; the Mediterranean diet has been shown to significantly reduce the total cholesterol:HDL cholesterol ratio and nonHDL cholesterol, and to reduce clinical events and CV mortality.78,79 Both low-fat and low-carbohydrate diets affect lipid levels. The low-fat diet has little effect in decreasing total cholesterol and LDL cholesterol, whereas the low-carbohydrate diet shows more favourable effects on TG and HDL cholesterol. In addition, the consumption of sea fish or omega-3 fatty acids has favourable effects. In conclusion, lowering the dietary carbohydrate content or losing weight appears to attenuate AD, whereas reducing the total fat or saturated fat content has little effect.80 Weight loss is associated with significant relief of insulin resistance.

Regular Physical Activity The effects of physical activity on serum lipids have been widely studied. Regular aerobic exercise is associated with increased skeletal muscle and systemic tissue insulin sensitisation.81,82 As this occurs, HDL cholesterol tends to increase and TGs and sdLDL decrease.83,84 Regular physical activity is a key recommendation in the approach to AD.85 Unfortunately, despite the benefits, long-term adherence to lifestyle changes is often difficult to sustain over time.86

Current Pharmacological Interventions Statins Statins are first-line drugs in the treatment of AD. They comprise a pharmacological group that inhibit the rate-limiting step of cholesterol biosynthesis catalysed by 3¢-hydroxy-3¢-methylglutaryl coenzyme A. By decreasing intrahepatocyte concentrations of cholesterol, the statins activate the nuclear transcription factor sterol regulatory element binding protein-1c, which increases the cell surface expression of LDL receptors (LDLR). Thus, statins reduce circulating levels of LDL cholesterol by: • decreasing cholesterol biosynthesis and VLDL secretion; and • increasing the clearance of LDL particles from the circulation. In addition, statins can reduce plasma TGs by 15–20% and increase HDL cholesterol by up to 15%.87,88 However, the effect of statins on sdLDL has not been completely clarified.89 A recent meta-analysis of six statin trials, including 802 subjects, demonstrated that statins significantly reduce circulating levels of apoCIII, which likely contributes to their modest TG-lowering capacity.90 In addition to their lipid-lowering effects, the statins exert cholesterol-independent pleiotropic actions, which have been widely studied and contribute to the stabilisation of atherosclerotic plaques and reverse endothelial dysfunction, among

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Atherogenic Dyslipidaemia and Cardiovascular Disease other effects.91 The beneficial effects of statins have been extensively demonstrated in both primary and secondary prevention studies because they incontrovertibly reduce risk for MI, ischemic stroke, revascularisation by both percutaneous transluminal coronary angioplasty and coronary artery bypass grafting, as well as cardiovascular and all-cause mortality.92,93 There is some concern that treatment of dyslipidaemia with statins increases the incidence of diabetes. As first reported by Ridker et al. in the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), rosuvastatin therapy is associated with an increased risk for new-onset diabetes.94 A subsequent metaanalysis showed that statins increase the risk for diabetes by approximately 9%.95 However, this does require some contextualisation. As shown in JUPITER, compared with placebo, statin therapy accelerates time to onset of diabetes by only 5.4 weeks and, for those with risk factors for diabetes, 134 vascular events or deaths were prevented for every 54 new cases of diabetes diagnosed.96 Thus, the benefit:risk ratio of statin therapy is quite favourable. Subsequent work showed that the greater the number of components of MS a patient has, the higher the risk for statin-induced diabetes.97 In general, patients with MS have the highest risk for statin-accelerated diabetes. The mechanism(s) for this are as yet unknown. With low-dose statin therapy 1,000 patients have to be treated for 1 year in order to see one new case of diabetes; with moderate- to high-dose statin therapy, 500 patients have to be treated for 1 year to see one new case of diabetes.98 Statin therapy should not be withheld out of concern that it may precipitate diabetes; it has been shown that diabetics derive every bit as much benefit from statin therapy as do non-diabetics.99 Moreover, it has been suggested that patients with features of MS may derive particular benefit from statin therapy.100

actually been shown to be nephroprotective and does not adversely affect renal function.110,111 The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial also failed to meet its primary endpoint in patients on statins randomised to either fenofibrate or placebo.112 However, at baseline, both HDL cholesterol and TG levels were very near normal. In meta-analyses, fibrates show a reduction in CV morbidity and mortality, but not in total mortality.113,114 In another metaanalysis, fibrates decreased major CV events by 13%, but this benefit was evident only in subjects with increased TG (>2.26 mmol/l).115 It is in the setting of AD where fibrates are most effective. As fibrates are weak PPAR-alpha agonists with limited efficacy and dose-related adverse events, a new generation of highly specific PPARalpha agonists, known as selective PPAR-alpha modulators, have been developed that preserve the beneficial effects of fibrates and eliminate the unwanted side effects. Recently, pemafibrate was introduced; it is >2,500-fold more potent than fibric acid, with a greater lipid-modifying efficacy and an improved safety and tolerability profile.116 Pemafibrate is being evaluated in the CV outcomes trial, Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT), studying a high-risk diabetic population on statin therapy.117

Cholesterol Absorption Inhibition: Ezetimibe Ezetimibe reduces the absorption of dietary and biliary cholesterol along the brush border of jejunal enterocytes. Ezetimibe inhibits the transmembrane sterol transporter Niemann–Pick C1-like protein.118 This reduces the amount of cholesterol delivered to the liver and stimulates increased expression of LDLR along the hepatocyte cell surface.119 As monotherapy, ezetimibe reduces LDL cholesterol by approximately 15–20%, but it is most commonly used in combination with a statin, where it provides additive benefit for reducing LDL cholesterol, non-HDL cholesterol and apoB and is safe.120–122

Fibrates Fibrates are weak agonists of the nuclear transcription factor peroxisome proliferator-activated receptor (PPAR) alpha and regulate the expression of genes that influence lipid metabolism. Fibrates were found to improve glucose homeostasis via activation of PPAR-alpha and increases in adiponectin levels.101 Fibrates lower TGs by 25–50%, increase HDL cholesterol 5–30%, reduce LDL cholesterol up to 20% and decrease sdLDL particles, postprandial TGs and TRLs.102,103 In both the Helsinki Heart Study (primary prevention) and the Veterans Administration Low HDL Intervention Trial (secondary prevention), gemfibrozil significantly reduced risk of the primary composite endpoint.104,105 However, because gemfibrozil reduces statin glucuronidation and can potentiate the risk of rhabdomyolysis, gemfibrozil should not be used in combination with a statin.106,107 Fenofibrate is substantially safer than gemfibrozil when combined with a statin.108 Fenofibrate therapy has been evaluated in two prospective randomised studies of patients with diabetes. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, fenofibrate as monotherapy failed to reduce the primary composite endpoint, but did reduce the risk for MI, stroke, revascularisation and multiple microangiopathic endpoints, including retinopathy, nephropathy and neuropathy.109 In a subgroup analysis of patients with TGs >2.26 mmol/l and HDL cholesterol <1.03 mmol/l, fenofibrate significantly reduced the primary composite endpoint by 27%. Although fenofibrate may increase serum creatinine concentrations, it has

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Recently, the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE IT) demonstrated that ezetimibe provides an incremental reduction in CV events among patients with a previous ACS and being treated with a statin.123 It has been successfully used in patients who do not tolerate statins and in those who are not at goal with adequate doses of statins.119 Ezetimibe can be combined with any statin, at the usual single dose of 10 mg/day, with no significant side effects reported, except for occasionally mild elevation of liver enzymes or myalgia. In a recent meta-analysis of eight studies including 80,790 diabetics and 85,555 non-diabetics, with a mean follow-up of 45 months, the risk for ASCVD events was significantly less with ezetimibe–statin combination therapy than statin monotherapy in both diabetic (relative risk 0.69; 95% CI [0.67–0.73]; p<0.00001) and non-diabetic (RR 0.68; 95% CI [0.52–0.90]; p=0.006) subjects.124 In a post hoc analysis of IMPROVE IT, the diabetic subgroup on ezetimibe plus simvastatin achieved a significantly lower mean LDL cholesterol than the group on placebo plus simvastatin (1.27 versus 1.73 mmol/l, respectively; p<0.001), and the RR reduction for MI and stroke in diabetics was 24% and 39%, respectively. Thus, the benefit of adding ezetimibe to statin appeared to be enhanced in patients with diabetes.125

Omega-3 Fatty Acids The omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) are long-chain polyunsaturated fatty

Risk Factors and Cardiovascular Disease Prevention acids that inhibit the synthesis of VLDL and TG in the liver. Although the combination of EPA and DHA reduces serum TGs and VLDL, it also induces an elevation in LDL cholesterol that is proportional to the baseline TG level.126,127 No recent study in the statin era has been able to demonstrate CV risk reduction using combinations of EPA and DHA.128 The Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH) trial is currently testing whether or not a combination of EPA and DHA will affect the risk for ASCVD events in high-risk diabetic patients on a statin background. The Japan EPA Lipid Intervention Study (JELIS) treated Japanese patients on low-dose statin therapy with 1.8 g EPA or placebo.129 The addition of EPA did provide incremental risk addition beyond statin therapy, but patients were not blinded to therapy and the doses of statin used were quite low (oral simvastatin 5 mg once daily, or oral pravastatin 10 mg, once daily). In addition, the only endpoint that achieved statistical significance was unstable angina requiring hospitalisation. JELIS did not achieve significant reductions in endpoints such as non-fatal MI or stroke, CV mortality or need for revascularisation. Hence, given these limitations, this approach did not become very widely adopted. Recently, the Reduction of Cardiovascular Events with Icosapent Ethyl– Intervention Trial (REDUCE-IT) showed that treatment of high-risk individuals (58% with diabetes) with 4 g EPA ethyl ester daily (mean TG 2.40 mmol/l, mean LDL cholesterol 1.68 mmol/l) resulted in relative reductions of 25% in the incidence of major adverse cardiac events (MACE) and 20% in CV mortality against a statin background. Entry criteria for the REDUCE-IT trial included age >45 years with established CV disease or age >50 years with diabetes and one or more additional risk factor, fasting TG 1.69–5.63 mmol/l, LDL cholesterol 1.06–2.59 mmol/l and a stable dose of statin for ≥4 weeks. This benefit was independent of both baseline TG and LDL cholesterol.130 The precise mechanisms by which EPA exerts these benefits remains under active investigation, although it is likely that the inhibition of oxidative processes and the augmented production of downstream effectors such as resolvins and protectins play beneficial roles.131

Proprotein Convertase Subtilisin/ Kexin Type 9 Inhibitors Evolocumab and alirocumab, monoclonal antibodies (mAbs) that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), have been approved for use and are available in a number of countries. They are indicated for use with or without combination statin therapy to reduce LDL cholesterol in patients with established ASCVD or heterozygous familial hypercholesterolaemia. PCSK9 regulates the expression of LDLRs by shuttling LDLR into the lysosome for proteolytic destruction.132 Hence, when plasma PCSK9 is increased or exhibits augmented functionality, the density of hepatocyte surface LDLR is reduced, plasma LDL cholesterol increases and the risk for ASCVD increases.133 In contrast, when PCSK9 is inhibited by mAbs directed against it, cell surface expression of LDLR is increased and plasma LDL cholesterol decreases due to increased clearance.134,135 The inhibition of PCSK9 with mAbs results in a profound decrease in LDL cholesterol of approximately 50–70%. These agents also induce significant reductions in non-HDL cholesterol, apoB and Lp(a).136 The magnitude of the reduction in Lp(a) with the PCSK9 mAbs is proportional to the baseline level.137,138 Patients with low Lp(a) typically experience no to small changes in this lipoprotein. The mechanism(s) by which these agents

reduce Lp(a) is a matter of intense debate.139,140 The PCSK9 mAbs are available for biweekly or monthly subcutaneous injection and have a favourable safety profile. Two landmark studies have been conducted with CV endpoints including thousands of patients randomised to a PCSK9 inhibitor or placebo against statin backgrounds. The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) study randomised 27,564 patients with established ASCVD to either evolocumab or placebo against a statin background. LDL cholesterol decreased 59% (mean level achieved in the active treatment group: 0.78 mmol/l). The risk for the primary (HR 0.85; 95% CI [0.79–0.92]; p<0.001) and secondary composite endpoints 20% (HR 0.80; 95% CI [0.73–0.88]; p<0.001) were substantially reduced after an average follow-up of 2.2 years.141 Evolocumab significantly reduced CV risk in patients with diabetes and did not increase the risk of new-onset diabetes.142 Evolocumab therapy was not correlated with an increased risk for cognitive impairment even when LDL cholesterol was reduced to less than 0.26 mmol/l.143 The Odyssey Outcomes study included 18,924 patients who were between 1 and 12 months after an ACS; 89% were treated with highintensity statins but did not reach their LDL cholesterol goal (<1.81 mmol/l) and mean baseline LDL cholesterol was 2.25 mmol/l. Patients were randomised to alirocumab 75/150 mg twice weekly versus placebo.144 LDL cholesterol decreased 54.7% in those treated with alirocumab, and the mean follow-up was 2.8 years. The primary endpoint, a combination of coronary death, non-fatal MI, fatal or nonfatal stroke and hospitalisation for unstable angina, decreased 15% (HR 0.85; 95% CI [0.78–0.93]; p=0.0003). Of great interest in this trial was the observation that alirocumab reduced the risk for the primary composite endpoint significantly more in diabetic patients than in patients with prediabetes or those who were normoglycaemic (2.3% absolute risk reduction versus 1.2% and 1.2%, respectively).145 In a variety of patient types with AD, alirocumab and evolocumab demonstrate excellent capacity on top of statins for reducing atherogenic lipoproteins other than LDL cholesterol.146–148 Both evolocumab and alirocumab reduce serum concentrations of VLDL, remnant lipoproteins and LDL particle numbers.149,150 In the FOURIER trial, the reduction in Lp(a) potentiated by evolocumab provided incremental risk reduction over and above LDL cholesterol reduction, an important advance in dyslipidaemia management.137 Although a Mendelian randomisation study suggested that there may be a signal for increased risk of diabetes with a PCSK9 mAb, to date there is no evidence that either evolocumab or alirocumab increases the risk for impaired glucose tolerance, impaired fasting glucose or diabetes.151–154

Conclusion Despite statin therapy, among patients with AD LDL cholesterol reduction is inadequate because significant residual risk remains. At least some of this risk is attributable to inadequate LDL cholesterol reduction. Clearly, however, mounting evidence suggests that inadequate reduction of other apoB-containing lipoproteins also contributes to residual risk. In the setting of insulin resistance, patients experience a large increase in apoB-containing lipoproteins characterised by elevated levels of VLDL, TRLs and LDL particles. These changes occur in response to increased hepatic TG and VLDL production, inhibition of LPL, activation of CETP and hepatic lipase and reduced clearance of apoB-containing lipoproteins. AD is also

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Atherogenic Dyslipidaemia and Cardiovascular Disease characterised by substantial changes in HDL metabolism at the level of multiple organs and cell types. The contributions of low HDL, HDL dysfunction and impaired reverse cholesterol transport to the net effect of AD are matters of continuing investigation. In order to better reduce residual risk among patients with AD and TGs >2.26 mmol/l, it is generally accepted that non-HDL cholesterol and apoB are better targets of therapy, and their aggressive reduction is a clinical priority. Among the established therapies, statins are the first-line treatment. Ezetimibe and the PCSK9 mAbs constitute important additional therapies that should be used in patients who fail to reach their LDL

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L ahey R, Khan SS. Trends in obesity and risk of cardiovascular disease. Curr Epidemiol Rep 2018;5:243–51. https://doi. org/10.1007/s40471-018-0160-1; PMID: 30705802. Zobel EH, Hansen TW, Rossing P, von Scholten BJ. Global changes in food supply and the obesity epidemic. Curr Obes Rep 2016;5:449–55. https://doi.org/10.1007/s13679-016-02338; PMID: 27696237. Stone GW, Maehara A, Lansky AJ, et al. A prospective naturalhistory study of coronary atherosclerosis. N Engl J Med 2011;364:226–35. https://doi.org/10.1056/NEJMoa1002358; PMID: 21247313. Chapman MJ, Ginsberg HN, Amarenco P, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345–61. https://doi.org/10.1093/eurheartj/ehr112; PMID: 21531743. Ponte-Negretti CI, Isea-Perez JE, Lorenzatti AJ, et al. Atherogenic dyslipidemia in Latin America: prevalence, causes and treatment: expert’s position paper made by the Latin American Academy for the Study of Lipids (ALALIP) endorsed by the Inter-American Society of Cardiology (IASC), the South American Society of Cardiology (SSC), the Pan-American College of Endothelium (PACE), and the International Atherosclerosis Society (IAS). Int J Cardiol 2017;243:516–22. https://doi.org/10.1016/j.ijcard.2017.05.059; PMID: 28552520. Catapano AL, Reiner Z, De Backer G, et al. ESC/EAS guidelines for the management of dyslipidaemias. The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis 2011;217:3–46. https://doi.org/10.1016/j. atherosclerosis.2011.06.028; PMID: 21882396. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis 2016;253:281–344. https://doi.org/10.1016/j.atherosclerosis.2016.08.018; PMID: 27594540. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005;365(9468):1415–28. https://doi.org/10.1016/S01406736(05)66378-7; PMID: 15836891. Ginsberg HN. Insulin resistance and cardiovascular disease. J Clin Invest 2000;106:453–8. https://doi.org/10.1172/JCI10762; PMID: 10953019. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937–52. https://doi.org/10.1016/S01406736(04)17018-9; PMID: 15364185. Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 2013;45:1345–52. https://doi. org/10.1038/ng.2795; PMID: 24097064. Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in Get With The Guidelines. Am Heart J 2009;157:111–7.e2. https://doi.org/10.1016/j. ahj.2008.08.010; PMID: 19081406. Guyton JR, Slee AE, Anderson T, et al. Relationship of lipoproteins to cardiovascular events: the AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes). J Am Coll Cardiol 2013;62:1580–4. https://doi. org/10.1016/j.jacc.2013.07.023; PMID: 23916935. Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. Dyslipidaemia of obesity, metabolic syndrome and type 2 diabetes mellitus: the case for residual risk reduction after statin treatment. Open Cardiovasc Med J 2011;5:24–34. https:// doi.org/10.2174/1874192401105010024; PMID: 21660248. Miller M, Cannon CP, Murphy SA, et al. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2008;51:724–30. https://doi.org/10.1016/j.

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cholesterol goal with statins alone or in statin-intolerant subjects. Fenofibrate can be considered in patients with AD, especially in those with high TG and low HDL cholesterol despite the use of statins in adequate doses. Although studies with CV outcomes have been inconsistent in demonstrating benefits with fibrates, post hoc analyses of the subgroups with AD (high TG and low HDL) consistently demonstrate ASCVD risk reduction. Based on the REDUCE-IT trial, EPA monotherapy constitutes an exciting, highly efficacious approach to reducing ASCVD events in patients with established ASCVD or T2D with additional CV disease risk factors and controlled LDL cholesterol on statin therapy but who still have TGs >1.69 mmol/l.

jacc.2007.10.038; PMID: 18279736. 16. F aergeman O, Holme I, Fayyad R, et al. Plasma triglycerides and cardiovascular events in the Treating to New Targets and Incremental Decrease in End-Points through Aggressive Lipid Lowering trials of statins in patients with coronary artery disease. Am J Cardiol 2009;104:459–63. https://doi. org/10.1016/j.amjcard.2009.04.008; PMID: 19660594. 17. Klempfner R, Erez A, Sagit BZ, et al. Elevated triglyceride level is independently associated with increased all-cause mortality in patients with established coronary heart disease: twentytwo-year follow-up of the Bezafibrate Infarction Prevention Study and Registry. Circ Cardiovasc Qual Outcomes 2016;9:100–8. https://doi.org/10.1161/CIRCOUTCOMES.115.002104; PMID: 26957517. 18. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 2007;115:450–8. https://doi.org/10.1161/ CIRCULATIONAHA.106.637793; PMID: 17190864. 19. Schwartz GG, Abt M, Bao W, et al. Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins. J Am Coll Cardiol 2015;65:2267– 75. https://doi.org/10.1016/j.jacc.2015.03.544; PMID: 26022813. 20. Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993–2000. https://doi.org/10.1001/jama.2009.1619; PMID: 19903920. 21. Toth PP, Philip S, Hull M, Granowitz C. Association of elevated triglycerides with increased cardiovascular risk and direct costs in statin-treated patients. Mayo Clin Proc 2019;94:1670– 80. https://doi.org/10.1016/j.mayocp.2019.03.028; PMID: 31405751. 22. Toth PP. Triglyceride-rich lipoproteins as a causal factor for cardiovascular disease. Vasc Health Risk Manag 2016;12:171–83. https://doi.org/10.2147/VHRM.S104369; PMID: 27226718. 23. Reiner Ž. Hypertriglyceridaemia and risk of coronary artery disease. Nat Rev Cardiol 2017;14:401–11. https://doi. org/10.1038/nrcardio.2017.31; PMID: 28300080. 24. Varbo A, Benn M, Tybjaerg-Hansen A, et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36. https://doi.org/10.1016/j. jacc.2012.08.1026; PMID: 23265341. 25. Joshi PH, Khokhar AA, Massaro JM, et al. Remnant lipoprotein cholesterol and incident coronary heart disease: the Jackson Heart and Framingham Offspring Cohort Studies. J Am Heart Assoc 2016;5:pii:e002765. https://doi.org/10.1161/ JAHA.115.002765; PMID: 27130348. 26. Varbo A, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation 2013;128:1298–309. https://doi.org/10.1161/CIRCULATIONAHA.113.003008; PMID: 23926208. 27. Masuda D, Yamashita S. Postprandial hyperlipidemia and remnant lipoproteins. J Atheroscler Thromb 2017;24:95–109. https://doi.org/10.5551/jat.RV16003; PMID: 27829582. 28. Bansal S, Buring JE, Rifai N, et al. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007;298:309–16. https://doi.org/10.1001/ jama.298.3.309; PMID: 17635891. 29. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299–308. https://doi.org/10.1001/jama.298.3.299; PMID: 17635890. 30. Musunuru K, Kathiresan S. Surprises from genetic analyses of lipid risk factors for atherosclerosis. Circ Res 2016;118:579–85. https://doi.org/10.1161/CIRCRESAHA.115.306398; PMID: 26892959. 31. Willer CJ, Sanna S, Jackson AU, et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008;40:161–9. https://doi.org/10.1038/ ng.76; PMID: 18193043.

32. L iu J, Afroza H, Rader DJ, Jin W. Angiopoietin-like protein 3 inhibits lipoprotein lipase activity through enhancing its cleavage by proprotein convertases. J Biol Chem 2010;285:27561–70. https://doi.org/10.1074/jbc.M110.144279; PMID: 20581395. 33. Sukonina V, Lookene A, Olivecrona T, Olivecrona G. Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissue. Proc Natl Acad Sci USA 2006;103:17450–5. https://doi. org/10.1073/pnas.0604026103; PMID: 17088546. 34. Wang Y, Puthanveetil P, Wang F, et al. Severity of diabetes governs vascular lipoprotein lipase by affecting enzyme dimerization and disassembly. Diabetes 2011;60:2041–50. https://doi.org/10.2337/db11-0042; PMID: 21646389. 35. TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371:22–31. https://doi.org/10.1056/ NEJMoa1307095; PMID: 24941081. 36. Natarajan P, Kohli P, Baber U, et al. Association of APOC3 lossof-function mutations with plasma lipids and subclinical atherosclerosis: the Multi-Ethnic BioImage Study. J Am Coll Cardiol 2015;66:2053–5. https://doi.org/10.1016/j. jacc.2015.08.866; PMID: 26516010. 37. Stitziel NO, Khera AV, Wang X, et al. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol 2017;69:2054–63. https://doi.org/10.1016/j.jacc.2017.02.030; PMID: 28385496. 38. Dewey FE, Gusarova V, O’Dushlaine C, et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N Engl J Med 2016;374:1123–33. https://doi.org/10.1056/ NEJMoa1510926; PMID: 26933753. 39. Helgadottir A, Gretarsdottir S, Thorleifsson G, et al. Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease. Nat Genet 2016;48:634–9. https://doi.org/10.1038/ng.3561; PMID: 27135400. 40. Au A, Griffiths LR, Irene L, et al. The impact of APOA5, APOB, APOC3 and ABCA1 gene polymorphisms on ischemic stroke: evidence from a meta-analysis. Atherosclerosis 2017;265:60–70. https://doi.org/10.1016/j.atherosclerosis.2017.08.003; PMID: 28865324. 41. Chasman DI, Pare G, Zee RY, et al. Genetic loci associated with plasma concentration of LDL-C, HDL-C, triglycerides, ApoA1, and ApoB among 6382 Caucasian women in genome-wide analysis with replication. Circ Cardiovasc Genet 2008;1:21–30. https://doi.org/10.1161/CIRCGENETICS.108.773168; PMID: 19802338. 42. Castelli WP. Cholesterol and lipids in the risk of coronary artery disease – the Framingham Heart Study. Can J Cardiol 1988;4(Suppl A):5A–10A. PMID: 3179802. 43. Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989;79:8–15. https://doi.org/10.1161/01.CIR.79.1.8; PMID: 2642759. 44. Bartlett J, Predazzi IM, Williams SM, et al. Is isolated low highdensity lipoprotein cholesterol a cardiovascular disease risk factor? New insights from the Framingham Offspring Study. Circ Cardiovasc Qual Outcomes 2016;9:206–12. https://doi. org/10.1161/CIRCOUTCOMES.115.002436; PMID: 27166203. 45. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109–22. https://doi.org/10.1056/NEJMoa0706628; PMID: 17984165. 46. Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255–67. https://doi. org/10.1056/NEJMoa1107579; PMID: 22085343. 47. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013;34:1279–91. https://doi.org/10.1093/eurheartj/eht055; PMID: 23444397. 48. Lincoff AM, Nicholls SJ, Riesmeyer JS, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J

Risk Factors and Cardiovascular Disease Prevention

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

Med 2017;376:1933–42. https://doi.org/10.1056/ NEJMoa1609581; PMID: 28514624. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet 2012;380:572–80. https://doi. org/10.1016/S0140-6736(12)60312-2; PMID: 22607825. Toth PP, Barylski M, Nikolic D, et al. Should low high-density lipoprotein cholesterol (HDL-C) be treated? Best Pract Res Clin Endocrinol Metab 2014;28:353–68. https://doi.org/10.1016/j. beem.2013.11.002; PMID: 24840264. Toth PP, Barter PJ, Rosenson RS, et al. High-density lipoproteins: a consensus statement from the National Lipid Association. J Clin Lipidol 2013;7:484–525. https://doi. org/10.1016/j.jacl.2013.08.001; PMID: 24079290. Xiao C, Dash S, Morgantini C, et al. Pharmacological targeting of the atherogenic dyslipidemia complex: the next frontier in CVD prevention beyond lowering LDL cholesterol. Diabetes 2016;65:1767–78. https://doi.org/10.2337/db16-0046; PMID: 27329952. Bobik A. Apolipoprotein CIII and atherosclerosis: beyond effects on lipid metabolism. Circulation 2008;118:702–4. https:// doi.org/10.1161/CIRCULATIONAHA.108.794081; PMID: 18695202. Barter PJ, Brewer HB Jr, Chapman MJ, et al. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol 2003;23:160–7. https://doi.org/10.1161/01.ATV.0000054658.91146.64; PMID: 12588754. Lewis GF, Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res 2005;96:1221–32. https://doi.org/10.1161/01. RES.0000170946.56981.5c; PMID: 15976321. Bays HE, Toth PP, Kris-Etherton PM, et al. Obesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association. J Clin Lipidol 2013;7:304–83. https://doi. org/10.1016/j.jacl.2013.04.001; PMID: 23890517. Mooradian AD, Haas MJ, Wong NCW. Transcriptional control of apolipoprotein A-I gene expression in diabetes. Diabetes 2004;53:513–20. https://doi.org/10.2337/diabetes.53.3.513; PMID: 14988232. Chung S, Sawyer JK, Gebre AK, et al. Adipose tissue ATP binding cassette transporter A1 contributes to high-density lipoprotein biogenesis in vivo. Circulation 2011;124:1663–72. https://doi.org/10.1161/CIRCULATIONAHA.111.025445; PMID: 21931081. McGillicuddy FC, Reilly MP, Rader DJ. Adipose modulation of high-density lipoprotein cholesterol. Circulation 2011;124:1602– 5. https://doi.org/10.1161/CIRCULATIONAHA.111.058453; PMID: 21986773. Zhang Y, McGillicuddy FC, Hinkle CC, et al. Adipocyte modulation of high-density lipoprotein cholesterol. Circulation 2010;121:1347–55. https://doi.org/10.1161/ CIRCULATIONAHA.109.897330; PMID: 20212278. Farbstein D, Levy AP. HDL dysfunction in diabetes: causes and possible treatments. Expert Rev Cardiovas Ther 2012;10:353–61. https://doi.org/10.1586/erc.11.182; PMID: 22390807. Packard C, Caslake M, Shepherd J. The role of small, dense low density lipoprotein (LDL): a new look. Int J Cardiol 2000;74(Suppl 1):S17–22. https://doi.org/10.1016/S0167-5273(99)00107-2; PMID: 10856769. Chait A, Brazg RL, Tribble DL, Krauss RM. Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. Am J Med 1993;94:350–6. https://doi. org/10.1016/0002-9343(93)90144-E; PMID: 8475928. McNamara JR, Small DM, Li Z, Schaefer EJ. Differences in LDL subspecies involve alterations in lipid composition and conformational changes in apolipoprotein B. J Lipid Res 1996;37:1924–35. PMID: 8895058. Ivanova EA, Myasoedova VA, Melnichenko AA, Grechko AV, Orekhov AN. Small dense low-density lipoprotein as biomarker for atherosclerotic diseases. Oxid Med Cell Longev 2017;2017:1273042. https://doi.org/10.1155/2017/1273042; PMID: 28572872. Diffenderfer MR, Schaefer EJ. The composition and metabolism of large and small LDL. Curr Opin Lipidol 2014;25:221–6. https:// doi.org/10.1097/MOL.0000000000000067; PMID: 24811298. Julius U, Dittrich M, Pietzsch J. Factors influencing the formation of small dense low-density lipoprotein particles in dependence on the presence of the metabolic syndrome and on the degree of glucose intolerance. Int J Clin Pract 2007;61:1798–804. https://doi. org/10.1111/j.1742-1241.2007.01507.x; PMID: 17935544. Sacks FM. The apolipoprotein story. Atheroscler Suppl 2006;7:23–7. https://doi.org/10.1016/j. atherosclerosissup.2006.05.004; PMID: 16822722. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 – executive summary. J Clin Lipidol 2014;8:473–88. https://doi.org/10.1016/j.jacl.2014.07.007; PMID: 25234560. Rabar S, Harker M, O’Flynn N, Wierzbicki AS. Lipid modification and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: summary of updated NICE guidance. BMJ (Clin Res Ed) 2014;349:g4356.

https://doi.org/10.1136/bmj.g4356; PMID: 25035388. 71. C atapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J 2016;37:2999–3058. https://doi.org/10.1093/eurheartj/ehw272; PMID: 27567407. 72. Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract 2017;23(Suppl 2):1–87. https://doi.org/10.4158/EP171764. APPGL; PMID: 28437620. 73. Kuller L, Arnold A, Tracy R, et al. Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the cardiovascular health study. Arterioscler Thromb Vasc Biol 2002;22:1175–80. https://doi.org/10.1161/01. ATV.0000022015.97341.3A; PMID: 12117734. 74. Barter PJ, Ballantyne CM, Carmena R, et al. Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel. J Intern Med 2006;259:247–58. https://doi. org/10.1111/j.1365-2796.2006.01616.x; PMID: 16476102. 75. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2008;51:1512–24. https://doi.org/10.1016/j. jacc.2008.02.034; PMID: 18402913. 76. Van Horn L, McCoin M, Kris-Etherton PM, et al. The evidence for dietary prevention and treatment of cardiovascular disease. J Am Diet Assoc 2008;108:287–331. https://doi. org/10.1016/j.jada.2007.10.050; PMID: 18237578. 77. Sacks FM, Lichtenstein AH, Wu JHY, et al. Dietary fats and cardiovascular disease: a presidential advisory from the American Heart Association. Circulation 2017;136:e1–23. https:// doi.org/10.1161/CIR.0000000000000510; PMID: 28620111. 78. Shai I, Schwarzfuchs D, Henkin Y, et al. Weight loss with a lowcarbohydrate, Mediterranean, or low-fat diet. N Engl J Med 2008;359:229–41. https://doi.org/10.1056/NEJMoa0708681; PMID: 18635428. 79. Guasch-Ferre M, Babio N, Martinez-Gonzalez MA, et al. Dietary fat intake and risk of cardiovascular disease and all-cause mortality in a population at high risk of cardiovascular disease. Am J Clin Nutr 2015;102:1563–73. https://doi.org/10.3945/ ajcn.115.116046; PMID: 26561617. 80. Musunuru K. Atherogenic dyslipidemia: cardiovascular risk and dietary intervention. Lipids 2010;45:907–14. https://doi. org/10.1007/s11745-010-3408-1; PMID: 20524075. 81. Liu X, Yuan H, Niu Y, et al. The role of AMPK/mTOR/S6K1 signaling axis in mediating the physiological process of exercise-induced insulin sensitization in skeletal muscle of C57BL/6 mice. Biochim Biophys Acta 2012;1822:1716–26. https://doi.org/10.1016/j.bbadis.2012.07.008; PMID: 22846606. 82. Lim S, Choi SH, Jeong I-K, et al. Insulin-sensitizing effects of exercise on adiponectin and retinol-binding protein-4 concentrations in young and middle-aged women. J Clin Endocrinol Metab 2008;93:2263–8. https://doi.org/10.1210/ jc.2007-2028; PMID: 18334592. 83. Halverstadt A, Phares DA, Wilund KR, et al. Endurance exercise training raises high-density lipoprotein cholesterol and lowers small low-density lipoprotein and very low-density lipoprotein independent of body fat phenotypes in older men and women. Metabolism 2007;56:444–50. https://doi.org/10.1016/j. metabol.2006.10.019; PMID: 17378998. 84. Trejo-Gutierrez JF, Fletcher G. Impact of exercise on blood lipids and lipoproteins. J Clin Lipidol 2007;1:175–81. https://doi. org/10.1016/j.jacl.2007.05.006; PMID: 21291678. 85. Kodama S, Tanaka S, Saito K, et al. Effect of aerobic exercise training on serum levels of high-density lipoprotein cholesterol: a meta-analysis. Arch Intern Med 2007;167:999– 1008. https://doi.org/10.1001/archinte.167.10.999; PMID: 17533202. 86. Bassi N, Karagodin I, Wang S, et al. Lifestyle modification for metabolic syndrome: a systematic review. Am J Med 2014;127:1242.e1–10. https://doi.org/10.1016/j. amjmed.2014.06.035; PMID: 25004456. 87. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97. https://doi.org/10.1001/jama.285.19.2486; PMID: 11368702. 88. Sirtori CR. The pharmacology of statins. Pharmacol Res 2014;88:3–11. https://doi.org/10.1016/j.phrs.2014.03.002; PMID: 24657242. 89. Rizzo M, Berneis K. The clinical relevance of low-densitylipoproteins size modulation by statins. Cardiovasc Drugs Ther 2006;20:205–17. https://doi.org/10.1007/s10557-006-8283-x; PMID: 16775666. 90. Sahebkar A, Simental-Mendía LE, Mikhailidis DP, et al. Effect of statin therapy on plasma apolipoprotein CIII concentrations: a systematic review and meta-analysis of randomized controlled trials. J Clin Lipidol 2018;12:801–9. https://doi.org/10.1016/j. jacl.2018.01.008; PMID: 29580713. 91. Oesterle A, Laufs U, Liao JK. Pleiotropic effects of statins on

the cardiovascular system. Circ Res 2017;120:229–43. https:// doi.org/10.1161/CIRCRESAHA.116.308537; PMID: 28057795. 92. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78. https://doi.org/10.1016/ S0140-6736(05)67394-1; PMID: 16214597. 93. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010;376:1670–81. https://doi. org/10.1016/S0140-6736(10)61350-5; PMID: 21067804. 94. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–207. https://doi.org/10.1056/NEJMoa0807646; PMID: 18997196. 95. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735–42. https://doi.org/10.1016/S01406736(09)61965-6; PMID: 20167359. 96. Ridker PM, Pradhan A, MacFadyen JG, et al. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 2012;380:565–71. https://doi.org/10.1016/S01406736(12)61190-8; PMID: 22883507. 97. Waters DD, Ho JE, DeMicco DA, et al. Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials. J Am Coll Cardiol 2011;57:1535– 45. https://doi.org/10.1016/j.jacc.2010.10.047; PMID: 21453832. 98. Preiss D, Seshasai SRK, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy. JAMA 2011;305:2556–64. https://doi.org/10.1001/ jama.2011.860; PMID: 21693744. 99. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy of cholesterol-lowering therapy in 18 686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008;371:117–25. https://doi.org/10.1016/S01406736(08)60104-X; PMID: 18191683. 100. Ballantyne CM, Olsson AG, Cook TJ, et al. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation 2001;104:3046–51. https://doi. org/10.1161/hc5001.100624; PMID: 11748098. 101. Simental-Mendia LE, Simental-Mendia M, Sanchez-Garcia A, et al. Effect of fibrates on glycemic parameters: a systematic review and meta-analysis of randomized placebo-controlled trials. Pharmacol Res 2018;132:232–41. https://doi. org/10.1016/j.phrs.2017.12.030; PMID: 29292213. 102. Staels B, Dallongeville J, Auwerx J, et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998;98:2088–93. https://doi.org/10.1161/01.CIR.98.19.2088; PMID: 9808609. 103. Ferrari R, Aguiar C, Alegria E, et al. Current practice in identifying and treating cardiovascular risk, with a focus on residual risk associated with atherogenic dyslipidaemia. Eur Heart J Suppl 2016;18(Suppl_C):C2–12. https://doi.org/10.1093/ eurheartj/suw009; PMID: 28533705. 104. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primaryprevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317:1237–45. https://doi.org/10.1056/ NEJM198711123172001; PMID: 3313041. 105. Robins SJ, Collins D, Wittes JT, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA 2001;285:1585–91. https://doi.org/10.1001/jama.285.12.1585; PMID: 11268266. 106. Prueksaritanont T, Zhao JJ, Ma B, et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J Pharmacol Exp Ther 2002;301:1042–51. https://doi.org/10.1124/ jpet.301.3.1042; PMID: 12023536. 107. Prueksaritanont T, Tang C, Qiu Y, et al. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos 2002;30:1280–7. https://doi.org/10.1124/ dmd.30.11.1280; PMID: 12386136. 108. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin. Am J Cardiol 2005;95:120–2. https://doi.org/10.1016/j. amjcard.2004.08.076; PMID: 15619408. 109. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849–61. https://doi. org/10.1016/S0140-6736(05)67667-2; PMID: 16310551. 110. Ansquer JC, Foucher C, Rattier S, et al. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebocontrolled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis 2005;45:485–93. https://doi.org/10.1053/j.ajkd.2004.11.004; PMID: 15754270. 111. Dalton RN, Crimet D, Ansquer JC. The Effect of Fenofibrate on Glomerular Filtration Rate (GFR) and Other Renal Function Tests. A Double-Blind Placebo-Controlled Cross-Over Study in Healthy Subjects. Philadelphia, PA: American Society of Nephrology, 2005.

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Atherogenic Dyslipidaemia and Cardiovascular Disease 112. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563–74. https://doi.org/10.1056/NEJMoa1001282; PMID: 20228404. 113. Saha SA, Arora RR. Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus – a pooled meta-analysis of randomized placebo-controlled clinical trials. Int J Cardiol 2010;141:157–66. https://doi.org/10.1016/j. ijcard.2008.11.211; PMID: 19232762. 114. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010;375:1875–84. https://doi.org/10.1016/S01406736(10)60656-3; PMID: 20462635. 115. Wang D, Liu B, Tao W, et al. Fibrates for secondary prevention of cardiovascular disease and stroke. Cochrane Database Syst Rev 2015;10:CD009580. https://doi.org/10.1002/14651858. CD009580.pub2; PMID: 26497361. 116. Fruchart JC. Selective peroxisome proliferator-activated receptor alpha modulators (SPPARMalpha): the next generation of peroxisome proliferator-activated receptor alpha-agonists. Cardiovasc Diabetol 2013;12:82. https://doi. org/10.1186/1475-2840-12-82; PMID: 23721199. 117. Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J 2018;206:80–93. https://doi. org/10.1016/j.ahj.2018.09.011; PMID: 30342298. 118. Garcia-Calvo M, Lisnock J, Bull HG, et al. The target of ezetimibe is Niemann–Pick C1-like 1 (NPC1L1). Proc Natl Acad Sci USA 2005;102:8132–7. https://doi.org/10.1073/ pnas.0500269102; PMID: 15928087. 119. Wierzbicki AS, Doherty E, Lumb PJ, et al. Efficacy of ezetimibe in patients with statin-resistant and statin-intolerant familial hyperlipidaemias. Curr Med Res Opin 2005;21:333–8. https://doi. org/10.1185/030079905X28872; PMID: 15811200. 120. Toth PP, Catapano A, Tomassini JE, Tershakovec AM. Update on the efficacy and safety of combination ezetimibe plus statin therapy. Clin Lipidol 2010;5:655–84. https://doi.org/10.2217/ clp.10.49. 121. Morrone D, Weintraub WS, Toth PP, et al. Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis 2012;223:251–61. https://doi.org/10.1016/j. atherosclerosis.2012.02.016; PMID: 22410123. 122. Toth PP, Morrone D, Weintraub WS, et al. Safety profile of statins alone or combined with ezetimibe: a pooled analysis of 27 studies including over 22,000 patients treated for 6–24 weeks. Int J Clin Pract 2012;66:800–12. https://doi.org/10.1111/ j.1742-1241.2012.02964.x; PMID: 22805272. 123. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387–97. https://doi.org/10.1056/NEJMoa1410489; PMID: 26039521. 124. Miao XY, Liu HZ, Jin MM, et al. A comparative meta-analysis of the efficacy of statin–ezetimibe co-therapy versus statin monotherapy in reducing cardiovascular and cerebrovascular adverse events in patients with type 2 diabetes mellitus. Eur Rev Med Pharmacol Sci 2019;23:2302–10. https://doi. org/10.26355/eurrev_201903_17279; PMID: 30915779. 125. Giugliano RP, Cannon CP, Blazing MA, et al. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation 2018;137:1571– 82. https://doi.org/10.1161/CIRCULATIONAHA.117.030950; PMID: 29263150. 126. von Schacky C, Harris WS. Cardiovascular benefits of omega-3

EUROPEAN CARDIOLOGY REVIEW

fatty acids. Cardiovasc Res 2007;73:310–5. https://doi. org/10.1016/j.cardiores.2006.08.019; PMID: 16979604. 127. Jain AP, Aggarwal KK, Zhang PY. Omega-3 fatty acids and cardiovascular disease. Eur Rev Med Pharmacol Sci 2015;19:441– 5. PMID: 25720716. 128. Siscovick DS, Barringer TA, Fretts AM, et al. Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease: a science advisory from the American Heart Association. Circulation 2017;135:e867–84. https://doi.org/10.1161/ CIR.0000000000000482; PMID: 28289069. 129. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised openlabel, blinded endpoint analysis. Lancet 2007;369:1090–8. https://doi.org/10.1016/S0140-6736(07)60527-3; PMID: 17398308. 130. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2018;380:11–22. https://doi.org/10.1056/NEJMoa1812792; PMID: 30415628. 131. Kohli P, Levy BD. Resolvins and protectins: mediating solutions to inflammation. Br J Pharmacol 2009;158:960–71. https://doi. org/10.1111/j.1476-5381.2009.00290.x; PMID: 19594757. 132. Reiner Z. PCSK9 inhibitors – past, present and future. Expert Opin Drug Metab Toxicol 2015;11:1517–21. https://doi.org/10.151 7/17425255.2015.1075506; PMID: 26329686. 133. Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154–6. https://doi.org/10.1038/ng1161; PMID: 12730697. 134. Lüscher TF. LDL-cholesterol targets: perspectives for the use of PCSK9 inhibitors. Eur Heart J 2016;37:1337–40. https://doi. org/10.1093/eurheartj/ehw150; PMID: 27134243. 135. Stoekenbroek RM, Kastelein JJ, Huijgen R. PCSK9 inhibition: the way forward in the treatment of dyslipidemia. BMC Med 2015;13:258. https://doi.org/10.1186/s12916-015-0503-4; PMID: 26456772. 136. Banerjee Y, Santos RD, Al-Rasadi K, Rizzo M. Targeting PCSK9 for therapeutic gains: have we addressed all the concerns? Atherosclerosis 2016;248:62–75. https://doi.org/10.1016/j. atherosclerosis.2016.02.018; PMID: 26987067. 137. O’Donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation 2019;139:1483–92. https://doi.org/10.1161/ CIRCULATIONAHA.118.037184; PMID: 30586750. 138. Gaudet D, Kereiakes DJ, McKenney JM, et al. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/ kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from Phase 2 trials). Am J Cardiol 2014;114:711–5. https://doi.org/10.1016/j. amjcard.2014.05.060; PMID: 25060413. 139. Shapiro MD, Minnier J, Tavori H, et al. Relationship between low-density lipoprotein cholesterol and lipoprotein(a) lowering in response to PCSK9 inhibition with evolocumab. J Am Heart Assoc 2019;8:e010932. https://doi.org/10.1161/ JAHA.118.010932; PMID: 30755061. 140. Raal FJ, Giugliano RP, Sabatine MS, et al. PCSK9 inhibitionmediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor’s role. J Lipid Res 2016;57:1086–96. https://doi.org/10.1194/jlr.P065334; PMID: 27102113. 141. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22. https://doi.org/10.1056/ NEJMoa1615664; PMID: 28304224. 142. Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients

with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the Fourier randomised controlled trial. Lancet Diabetes Endocrinol 2017;5:941–50. https://doi.org/10.1016/ S2213-8587(17)30313-3; PMID: 28927706. 143. Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med 2017;377:633–43. https://doi.org/10.1056/NEJMoa1701131; PMID: 28813214. 144. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–107. https://doi.org/10.1056/ NEJMoa1801174; PMID: 30403574. 145. Ray KK, Colhoun HM, Szarek M, et al. Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial. Lancet Diabetes Endocrinol 2019;7:618–28. https://doi. org/10.1016/S2213-8587(19)30158-5; PMID: 31272931. 146. Ray KK, Leiter LA, Müller-Wieland D, et al. Alirocumab vs usual lipid-lowering care as add-on to statin therapy in individuals with type 2 diabetes and mixed dyslipidaemia: the ODYSSEY DM-DYSLIPIDEMIA randomized trial. Diabetes Obes Metab 2018;20:1479–89. https://doi.org/10.1111/dom.13257; PMID: 29436756. 147. Lorenzatti AJ, Eliaschewitz FG, Chen Y, et al. Randomised study of evolocumab in patients with type 2 diabetes and dyslipidaemia on background statin: primary results of the BERSON clinical trial. Diabetes Obes Metab 2019;21:1455–63. https://doi.org/10.1111/dom.13680; PMID: 30821053. 148. Rosenson RS, Daviglus ML, Handelsman Y, et al. Efficacy and safety of evolocumab in individuals with type 2 diabetes mellitus: primary results of the randomised controlled BANTING study. Diabetologia 2019;62:948–58. https://doi. org/10.1007/s00125-019-4856-7; PMID: 30953107. 149. Toth PP, Sattar N, Blom DJ, et al. Effect of evolocumab on lipoprotein particles. Am J Cardiol 2018;121:308–14. https://doi. org/10.1016/j.amjcard.2017.10.028; PMID: 29221604. 150. Toth PP, Hamon SC, Jones SR, et al. Effect of alirocumab on specific lipoprotein non-high-density lipoprotein cholesterol and subfractions as measured by the vertical auto profile method: analysis of 3 randomized trials versus placebo. Lipids Health Dis 2016;15:28. https://doi.org/10.1186/s12944-0160197-4; PMID: 26872608. 151. Schmidt AF, Swerdlow DI, Holmes MV, et al. PCSK9 genetic variants and risk of type 2 diabetes: a Mendelian randomisation study. Lancet Diabetes Endocrinol 2017;5:97–105. https://doi.org/10.1016/S2213-8587(16)30396-5; PMID: 27908689. 152. de Carvalho LSF, Campos AM, Sposito AC. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and incident type 2 diabetes: a systematic review and metaanalysis with over 96,000 patient-years. Diabetes Care 2018;41:364–7. https://doi.org/10.2337/dc17-1464; PMID: 29180351. 153. Colhoun HM, Ginsberg HN, Robinson JG, et al. No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies. Eur Heart J 2016;37:2981–9. https://doi.org/10.1093/eurheartj/ehw292; PMID: 27460890. 154. Toth PP, Descamps O, Genest J, et al. Pooled safety analysis of evolocumab in over 6000 patients from double-blind and open-label extension studies. Circulation 2017;135:1819–31. https://doi.org/10.1161/CIRCULATIONAHA.116.025233; PMID: 28249876. 155. Sathiyakumar V, Kapoor K, Jones SR, et al. Novel therapeutic targets for managing dyslipidemia. Trends Pharmacol Sci 2018; 39:733–47. https://doi.org/10.1016/j.tips.2018.06.001; PMID: 29970260.

Guest Editorial

Emerging Strategies for the Management of Atherogenic Dyslipidaemia Anandita Agarwala1 and Michael D Shapiro2 1. Division of Cardiology, Washington University School of Medicine, St Louis, MO, US; 2. Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Wake Forest University Baptist Medical Center, Winston-Salem, NC, US

Disclosure: MDS sits on the scientific advisory boards of Amgen and Regeneron. AA has no conflicts of interest to declare. Received: 29 October 2019 Accepted: 29 October 2019 Citation: European Cardiology Review 2020;15:e05. DOI: https://doi.org/10.15420/ecr.2019.16 Correspondence: Michael D Shapiro, Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Wake Forest University Baptist Medical Center, Winston-Salem, NC 27157, US. E: mdshapir@wakehealth.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

therogenic dyslipidaemia encompasses a broad variety of lipid phenotypes. While LDL cholesterol is a well-known risk factor for atherosclerotic cardiovascular disease (ASCVD), there are additional atherogenic lipoproteins that may be targeted to further reduce ASCVD risk. In their comprehensive review, Lorenzatti and Toth emphasise that, even when LDL cholesterol levels are optimised, ASCVD risk remains in a substantial subset of individuals.1 Some of this residual cardiovascular risk is due to suboptimal levels of other atherogenic lipids and lipoproteins, including triglycerides, HDL cholesterol, non-HDL cholesterol (total cholesterol minus HDL cholesterol), and apolipoprotein B (ApoB). The 2018 American College of Cardiology/American Heart Association (ACC/AHA) Multi-Society Cholesterol Guideline and the recent 2019 European Society of Cardiology (ESC) guideline for the management of dyslipidaemias prioritise LDL cholesterol as the primary target of lipid-lowering therapy, principally with the use of maximally tolerated statin therapy.2,3 Both guidelines emphasise intense (≥50%) LDL cholesterol lowering and define specific values of LDL cholesterol to trigger additional recommendations. Moreover, if adequate LDL cholesterol reduction is not achieved despite lifestyle modifications and maximally tolerated statin therapy, consideration of non-statin therapy is warranted. There are several key differences between the European and American guidelines, the first of which lies in the definition and treatment thresholds for very high risk patients. Table 1 outlines the similarities and differences in the definition of very high risk patients between the ACC/AHA and ESC guidelines. Second, in a departure from the ACC/AHA guideline, which recommends an LDL cholesterol threshold of 1.8 mmol/l before considering non-statin therapies, the ESC guideline recommends treating to a more aggressive therapeutic threshold of 1.42 mmol/l, thereby suggesting that non-statin therapies should be considered even where LDL cholesterol levels are 1.42– 1.81 mmol/l.3 Finally, regarding several high-risk medical conditions, known to be risk-enhancing factors or risk modifiers, there are notable differences between the two guideline documents. As well as sharing many of the risk-enhancing factors described in the ACC/AHA guideline, the ESC guideline includes social deprivation, (central)

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obesity, physical inactivity, psychosocial stress, psychiatric disorders, HIV treatments, AF, left ventricular hypertrophy, chronic kidney disease, obstructive sleep apnoea and non-alcoholic fatty liver disease as risk modifiers.3,4 Both guidelines consider atherogenic lipoproteins beyond LDL cholesterol. Persistently elevated triglycerides (≥4.53 mmol/l) and elevated ApoB concentrations (≥3.37 mmol/l) are considered riskenhancing factors in the 2018 ACC/AHA guideline. Their presence in intermediate risk or select borderline risk patients should inform the clinician-patient decision and facilitate shared decision making with regards to initiating or intensifying statin therapy.2 The ESC guideline recommends secondary goals for both non-HDL cholesterol (<2.20, 2.60, and 3.37 mmol/l) and ApoB (<1.68, 2.07, and 2.60 mmol/l) in individuals at very high, high, and moderate risk respectively. While no specific thresholds have been set for triglycerides, a triglyceride concentration <3.89 mmol/l is considered reasonable.3 Beyond the atherogenic lipoproteins already mentioned, there is another atherogenic biomarker that merits discussion. The association between elevated plasma concentrations of lipoprotein(a) [Lp(a)] and ASCVD is well established and there may be an emerging role for the assessment and treatment of elevated Lp(a) in clinical practice.5–10 Lp(a) levels ≥1.3 mmol/l or ≥125 nmol/l are considered a risk-enhancing factor in the 2018 ACC/AHA guideline and the presence of elevated levels can be used to reclassify ASCVD risk.2 Currently, there are no evidence-based therapies to target elevated Lp(a) lowering, although some experts have advocated the potential use of niacin and/or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which can modestly reduce plasma concentrations of Lp(a).11–13 An antisense oligonucleotide-based therapy directed at apolipoprotein(a) is in the late stages of development and is poised to be tested within the context of a randomised cardiovascular outcomes trial. A recent Phase IIB study demonstrated reductions of up to 80% in Lp(a) with this therapy.14 Beyond targeting Lp(a), a number of additional novel therapeutics for the treatment of atherogenic dyslipidaemia are on the horizon (Table 2). While LDL cholesterol lowering has, understandably, remained the mainstay in the primary and secondary prevention of ASCVD, a

Management of Atherogenic Dyslipidaemia Table 1: Classifying Patients at Very High Risk

Table 2: Emerging Therapies for Atherogenic Dyslipidaemia

2018 ACC/AHA Guideline

2019 ESC Guideline

Drug

Mechanism of Action Anticipated Effect

Bempedoic acid (ETC-1002)16–19

Adenosine triphosphate citrate lyase inhibitor

↓LDL-C, non-HDL-C, ApoB, and hs-CRP

Acute coronary syndrome (within the past 12 months)

Inclisiran (ALN-PCSSC)20–23

PCSK9 siRNA

↓PCSK9, ApoB, LDL-C, non–HDL-C, VLDL-C

History of MI

AKCEA-APO(a)-LRx14,24

ApoA antisense oligonucleotides

↓Lp(a)

History of ischaemic stroke Symptomatic peripheral arterial disease (history of claudication with anklebrachial index <0.85, previous revascularisation or amputation)

Volanesorsen (ISIS 304801, ISIS-ApoCIIIRx and IONIS-ApoCIIIRx)25-27

ApoC3 antisense

↓TG, TC, ApoB, non-HDL-C, VLDL-C ↑HDL-C

One major ASCVD event with two or more high-risk conditions*

IONIS-ANGPTL328,29

ANGPTL3 antisense oligonucleotides

↓TG, VLDL-C, non-HDL-C, LDL-C, HDL-C

Epanova30,31

Omega-3 in free fatty acid form

↓ TG

Evinacumab (REGN1500)32–34

ANGPTL3 monoclonal antibody

↓TG, non-HDL-C, LDL-C, TC, and HDL-C

Documented ASCVD (clinical or unequivocal diagnosis by imaging)

Type 2 diabetes with either end-organ damage or at least three major risk factors, or early-onset type 1 diabetes of long duration (>20 years)

Severe chronic kidney disease with estimated glomerular filtration rate of <30 ml/min/1.73m2

Familial hypercholesterolaemia with either ASCVD or another major risk factor

HeartScore15 of ≥10% for 10-year risk of fatal cardiovascular disease

Differences in classification of very high risk patients in the 2018 American College of Cardiology/American Heart Association and 2019 European Society of Cardiology guidelines. High-risk conditions are defined as age ≥65 years, heterozygous familial hypercholesterolaemia, history of coronary artery bypass graft or percutaneous coronary intervention outside major atherosclerotic cardiovascular disease events, type 1 diabetes, hypertension, chronic kidney disease with estimated glomerular filtration rate 15–59 ml/ min/1.73m2, current smoking, persistently elevated LDL cholesterol ≥ 2.60 mmol/l despite maximally tolerated statin therapy, history of congestive heart failure.

comprehensive assessment of all atherogenic lipoproteins is merited. Mitigation of ASCVD risk should be targeted in the following manner:

L orenzatti AJ, Toth PP. New perspectives on atherogenic dyslipidaemia and cardiovascular disease. Eur Cardiol 2020;15:e04. https://doi.org/10.15420/ecr.2019.06. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/ AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139:e1082–143. https://doi.org/10.1161/ CIR.0000000000000625; PMID: 30586774. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Atherosclerosis 2019;290:140–205. https://doi.org/10.1016/j. atherosclerosis.2019.08.014; PMID: 31591002. Agarwala A, Liu J, Ballantyne CM, Virani SS. The use of risk enhancing factors to personalize ASCVD risk assessment: evidence and recommendations from the 2018 AHA/ACC Multi-Society Cholesterol Guidelines. Curr Cardiol Risk Rep 2019;13:18. https://doi.org/10.1007/s12170-019-0616-y. Burgess S, Ference BA, Staley JR, et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol 2018;3:619–27. https://doi.org/10.1001/ jamacardio.2018.1470; PMID: 29926099. Cook NR, Mora S, Ridker PM. Lipoprotein(a) and cardiovascular risk prediction among women. J Am Coll Cardiol 2018;72:287– 96. https://doi.org/10.1016/j.jacc.2018.04.060; PMID: 30012322. Erqou S, Kaptoge S, Perry PL, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009;302:412–23. https://doi. org/10.1001/jama.2009.1063; PMID: 19622820. Verbeek R, Hoogeveen RM, Langsted A, et al. Cardiovascular disease risk associated with elevated lipoprotein(a) attenuates at low low-density lipoprotein cholesterol levels in a primary

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10.

11.

12.

13.

14.

15.

16.

ANGPTL3 = angiopoietin-like 3; ApoB = apolipoprotein B; HDL-C = HDL cholesterol; LDL-C = LDL cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9; siRNA = small interfering RNA; TC = total cholesterol; TG = triglycerides; VLDL-C = very LDL cholesterol.

lifestyle modifications; targeting and surpassing LDL cholesterol therapeutic thresholds; and selective evaluation and treatment of additional measures of the atherogenic lipoprotein burden, including triglycerides, non-HDL cholesterol, ApoB and Lp(a). The key to managing atherogenic dyslipidaemia lies in emphasising the foundational importance of therapeutic lifestyle changes and the apt usage of pharmacological agents. Fortunately, it appears that the effective therapeutic armamentarium is likely to increase. Meanwhile, we eagerly await the results of cardiovascular outcome studies testing several novel lipid-lowering therapeutics that have the potential to revolutionise the pharmacological management of atherogenic dyslipidaemia.

prevention setting. Eur Heart J 2018;39:2589–96. https://doi. org/10.1093/eurheartj/ehy334; PMID: 29931232. irani SS, Brautbar A, Davis BC, et al. Associations between V lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2012;125:241–9. https://doi.org/10.1161/ CIRCULATIONAHA.111.045120; PMID: 22128224. Wilson DP, Jacobson TA, Jones PH, et al. Use of lipoprotein(a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association. J Clin Lipidol 2019;13:374–92. https://doi.org/10.1016/j. jacl.2019.04.010; PMID: 31147269. Gaudet D, Kereiakes DJ, McKenney JM, et al. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/ kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol 2014;114:711–5. https://doi.org/10.1016/j. amjcard.2014.05.060; PMID: 25060413. O’Donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation 2019;139:1483–92. https://doi.org/10.1161/ CIRCULATIONAHA.118.037184; PMID: 30586750. Warden BA, Minnier J, Watts GF, Fazio S, Shapiro MD. Impact of PCSK9 inhibitors on plasma lipoprotein(a) concentrations with or without a background of niacin therapy. J Clin Lipidol 2019;13:580–5. https://doi.org/10.1016/j.jacl.2019.04.008; PMID: 31130489. Langsted A, Nordestgaard BG. Antisense oligonucleotides targeting lipoprotein(a). Curr Atheroscler Rep 2019;21:30. https://doi.org/10.1007/s11883-019-0792-8; PMID: 31111240. Conroy RM, Pyörälä K, Fitzgerald AP, et al. Estimation of tenyear risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003;24:987–1003. https://doi.org/10.1016/ S0195-668X(03)00114-3; PMID: 12788299. Ballantyne CM, Banach M, Mancini GBJ, et al. Efficacy and

17.

18.

19.

20.

21.

22.

23.

safety of bempedoic acid added to ezetimibe in statinintolerant patients with hypercholesterolemia: a randomized, placebo-controlled study. Atherosclerosis 2018;277:195–203. https://doi.org/10.1016/j.atherosclerosis.2018.06.002; PMID: 29910030. Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol 2019:2047487319864671. https://doi. org/10.1177/2047487319864671; PMID: 31357887. Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol N Engl J Med 2019;380:1022–32. https://doi.org/10.1056/NEJMoa1803917; PMID: 30865796. Laufs U, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J Am Heart Assoc 2019;8:e011662. https:// doi.org/10.1161/JAHA.118.011662; PMID: 30922146. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017;376:1430–40. https://doi.org/10.1056/ NEJMoa1615758; PMID: 28306389. Ray KK, Stoekenbroek RM, Kallend D, et al. Effect of an siRNA therapeutic targeting PCSK9 on atherogenic lipoproteins. Circulation 2018;138:1304–16. https://doi.org/10.1161/ CIRCULATIONAHA.118.034710; PMID: 29735484. ClinicalTrials.gov. Inclisiran for subjects With ACSVD or ACSVDrisk equivalents and elevated low-density lipoprotein cholesterol (ORION-11). https://clinicaltrials.gov/ct2/show/ NCT03400800 (accessed 15 December 2019). Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers:

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25.

26.

27.

a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet 2014;383:60–68. https://doi.org/10.1016/S01406736(13)61914-5; PMID: 24094767. ClinicalTrials.gov. Phase 2 study of ISIS 681257 (AKCEA-APO(a)LRx) in patients with hyperlipoproteinemia(a) and cardiovascular disease. https://clinicaltrials.gov/ct2/show/ NCT03070782 (accessed 15 December 2019). Alexander VJ, Xia S, Hurh E, et al. N-acetyl galactosamineconjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. Eur Heart J 2019;40:2785–96. https://doi.org/10.1093/eurheartj/ehz209; PMID: 31329855. Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med 2015;373:438–47. https://doi.org/10.1056/ NEJMoa1400283; PMID: 26222559. Schmitz J, Gouni-Berthold I. APOC-III antisense oligonucleotides: a new option for the treatment of

28.

29.

30.

31.

hypertriglyceridemia. Curr Med Chem 2018;25:1567–76. https:// doi.org/10.2174/0929867324666170609081612; PMID: 28595549. Xu YX, Redon V, Yu H, et al. Role of angiopoietin-like 3 (ANGPTL3) in regulating plasma level of low-density lipoprotein cholesterol. Atherosclerosis 2018;268:196–206. https://doi. org/10.1016/j.atherosclerosis.2017.08.031; PMID: 29183623. Graham MJ, Lee RG, Brandt TA, et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med 2017;377:222–32. https://doi.org/10.1056/ NEJMoa1701329; PMID: 28538111. ClinicalTrials.gov. Outcomes study to assess STatin Residual risk reduction with EpaNova in HiGh CV risk patienTs with Hypertriglyceridemia (STRENGTH). https://clinicaltrials.gov/ct2/ show/NCT02104817 (accessed 15 December 2019). Nicholls SJ, Lincoff AM, Bash D, et al. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of

triglycerides and low levels of high-density lipoprotein cholesterol: rationale and design of the STRENGTH trial. Clin Cardiol 2018;41:1281–8. https://doi.org/10.1002/clc.23055; PMID: 30125052. 32. Gusarova V, Alexa CA, Wang Y, et al. ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. J Lipid Res. 2015;56:1308–17. https://doi.org/10.1194/jlr.M054890; PMID: 25964512. 33. Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med 2017;377:211–21. https://doi.org/10.1056/ NEJMoa1612790; PMID: 28538136. 34. Ahmad Z, Banerjee P, Hamon S, et al. Inhibition of angiopoietin-like protein 3 with a monoclonal antibody reduces triglycerides in hypertriglyceridemia. Circulation 2019;140:470–486. https://doi.org/10.1161/ CIRCULATIONAHA.118.039107; PMID: 31242752.

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Pharmacotherapy

Will Direct Oral Anticoagulants Have a Chance in Prosthetic Valves? Mahmoud Abdelnabi,1 Abdallah Almaghraby2 and Yehia Saleh2,3 1. Cardiology and Angiology Unit, Department of Clinical and Experimental Internal Medicine, Medical Research Institute, University of Alexandria, Egypt; 2. Department of Cardiology, Faculty of Medicine, University of Alexandria, Egypt; 3. Michigan State University, East Lansing, MI, US

Abstract Although there are abundant data highlighting the safety and efficacy of direct oral anticoagulants, to date, recent guidelines have limited their use to stroke prevention in patients with non-valvular AF, as well as in the prevention and treatment of venous thromboembolism and pulmonary embolism. Encouraging data about the off-label use of direct oral anticoagulants have been shown in several other indications, such as intracardiac thrombi, left ventricular thrombi and left atrial appendage, but a large sector of patients are still not addressed, such as valvular and prosthetic patients.

Keywords Prosthetic valves, direct oral anticoagulants, vitamin K antagonist, left ventricular thrombi, rivaroxaban Disclosure: The authors have no conflicts of interest to declare. Received: 3 January 2019 Accepted: 19 September 2019 Citation: European Cardiology Review 2020;15:e06 DOI: https://doi.org/10.15420/ecr.2019.1.3 Correspondence: Mahmoud Hassan Abdelnabi, Cardiology and Angiology Unit, Department of Clinical and Experimental Internal Medicine, Medical Research Institute, University of Alexandria, Egypt. E: mahmoud.hassan.abdelnabi@outlook.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

itamin K antagonist (VKA) oral anticoagulants have been ruling the field of anticoagulation for cardiovascular indications for years now. Recently, this dominance has been threatened by the introduction of direct oral anticoagulants (DOACs), with abundant data highlighting their safety and efficacy. To date, recent guidelines have limited the use of DOACs to stroke prevention in patients with non-valvular AF and in the prevention and treatment of venous thromboembolism and pulmonary embolism. Although DOACs represent a major advance in oral anticoagulation, there are several limitations for their use, such as prosthetic valves, mitral stenosis and left ventricular thrombi. Given that patients with moderate-to-severe mitral stenosis have been excluded from all pivotal trials, the American College of Cardiology and the European Society of Cardiology currently recommend using warfarin over DOACs in AF patients with moderate-to-severe mitral stenosis.1,2 However, recently, in a large retrospective analysis comparing DOACs with warfarin in mitral stenosis, Kim et al. concluded that DOACs showed a lower incidence of thromboembolic events and intracranial haemorrhage in comparison with warfarin.3 Based on the previous promising results, a prospective clinical trial for the evaluation of the superiority of DOACs in moderate-to-severe mitral stenosis is required. However, the geographical distribution of rheumatic heart disease has always been a hindering factor in conducting a large prospective study. Regarding left ventricular thrombi, due to a lack of prospective clinical trials, warfarin is the only approved medication so far. Nonetheless, several case reports and case series showed the efficacy of DOACs in left ventricular thrombi.4,5 In addition, several prospective trials are examining the use of different DOACs in patients with left ventricular thrombi.

Regarding prosthetic valves, the European Society of Cardiology recommends lifelong oral anticoagulation using VKA in mechanical valve patients. Moreover, low-dose aspirin (75–100 mg/day) in addition to VKA should be considered after thromboembolism, despite an adequate international normalised ratio. For patients with bioprosthesis, oral anticoagulation using a VKA should be considered for the first 3 months after surgical implantation of a mitral or tricuspid bioprosthesis. However, after surgical implantation of an aortic bioprosthesis, low-dose aspirin (75–100 mg/day) should only be considered for the first 3 months.6 Hence, to date, there is no place in the guidelines for DOACs in prosthetic valves. Several trials were conducted to evaluate the efficacy and safety of DOACs in prosthetic valves, such as the Randomised, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement (RE-ALIGN), which was prematurely terminated due to safety concerns. The RE-ALIGN study concluded that in patients with mechanical mitral or aortic valves, dabigatran was not only less effective than warfarin for thromboembolic prevention, but was also associated with an increased risk of bleeding; therefore, it should not be used in mechanical valve patients.7 Possible explanations for the increase in thromboembolic complications with dabigatran included inadequate plasma levels of the drug and dabigatran’s mechanism of action, which differs from warfarin.7 Despite the unfavourable outcomes of the RE-ALIGN study, several retrospective analyses and prospective studies were conducted to evaluate the safety and efficacy of different DOACs in prosthetic valves, such as the Dabigatran Versus Warfarin After Bioprosthesis

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Pharmacotherapy Valve Replacement for the Management of Atrial Fibrillation Postoperatively (DAWA) study, which aimed to evaluate the efficacy and safety of dabigatran in patients with bioprosthetic mitral and/or aortic valve replacement and AF. Due to inconclusive results and low enrolment rates, the study was terminated.8 Duraes et al. conducted a pilot study to evaluate the effect of the use of rivaroxaban for anticoagulation in seven patients with unstable international normalised ratios at least 3 months following isolated mechanical mitral valve replacement, and concluded that the use of rivaroxaban for 90 days in mechanical mitral valve prosthesis was not associated with thromboembolic or bleeding events. Hence, rivaroxaban use in mechanical prostheses may be feasible, efficacious and safe. However, larger-scale randomised controlled clinical trials are required to evaluate this possibility before it is adopted as an alternative to warfarin in this patient population.9 Transcatheter aortic valve replacement (TAVR) has recently been approved for low-risk patients with severe aortic stenosis, thus the number of TAVR procedures within the next decade is expected to rise significantly. Currently, for TAVR patients, the European Society of Cardiology recommends dual antiplatelet therapy for the first 3–6 months, followed by lifelong single antiplatelet therapy for patients who do not require oral anticoagulation for other reasons. Nonetheless, single antiplatelet therapy may be considered after TAVR in the case of high bleeding risk.6 However, in a retrospective study, several patients who underwent a successful TAVR were noted to have reduced leaflet motion on CT. Interestingly, after therapeutic anticoagulation, the reduced aortic valve leaflet motion was resolved; hence, it was presumed that valve thrombosis was contributing to the pathogenesis.10

January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2019;16:e66–93. https://doi. org/10.1016/j.jacc.2019.01.011; PMID: 30703431. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. https://doi.org/10.1093/ejcts/ezw313; PMID: 27663299. Kim JY, Kim SH, Myong JP, et al. Outcomes of direct oral anticoagulants in patients with mitral stenosis. J Am Coll Cardiol 2019;73:1123–31. https://doi.org/10.1016/j.jacc.2018.12.047; PMID: 30871695. Abdelnaby M, Almaghraby A, Abdelkarim O, et al. The role of rivaroxaban in left ventricular thrombi. Anatol J Cardiol 2019;21:47–50. https://doi.org/10.14744/

Consecutively, several trials investigated DOACs in patients undergoing TAVR. The Global Study Comparing a Rivaroxaban-based Antithrombotic Strategy to an Antiplatelet Strategy After Transcatheter Aortic Valve Replacement to Optimise Clinical Outcomes (GALILEO) assessed whether a rivaroxaban-based regimen is superior in reducing death or first antithrombotic events compared with an antiplatelet-based regimen in patients undergoing a successful TAVI procedure. It was halted, because data showed that rivaroxaban was associated with greater risks of all-cause mortality, thromboembolic events and bleeding in patients who had undergone TAVR.11 To further investigate the role of anticoagulation in TAVR patients, the Anti-Thrombotic Strategy After Trans-Aortic Valve Implantation for Aortic Stenosis (ATLANTIS) is an on-going clinical trial to test the superiority of an apixaban-based strategy versus dual antiplatelet therapy strategy in patients who have undergone a successful TAVI procedure to reduce the risk of post-TAVI thromboembolic and bleeding complications.12 To date, the limited evidence about the safety and efficacy of DOACs in prosthetic valve patients make it difficult to define solid recommendations for their use in this population. Currently, the available data demonstrated that DOACs use (specifically dabigatran) in mechanical valve patients is neither safe nor effective. Also, prospective and retrospective data analyses of DOACs use in patients with bioprosthetic valves are contradictory. Further research is required to justify whether the use of DOACs for thromboembolic prevention in prosthetic valves is safe and efficient. The question still stands, will DOACs have a chance in prosthetic valves or will warfarin, with all its drawbacks, always be the only available option?

AnatolJCardiol.2018.48313; PMID: 30587707. Mujer M, Kandola SK, Saleh Y. Rarecase of biventricular thrombi complicating pulmonary embolism. BMJ Case Rep 2019;12. https://doi.org/10.1136/bcr-2019-229698; PMID: 31061185. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739–91. https://doi.org/10.1093/eurheartj/ ehx391; PMID: 28886619. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013;369:1206–14. https://doi.org/10.1056/ NEJMoa1300615; PMID: 23991661. Duraes AR, de Souza Roriz P, de Almeida Nunes B, et al. Dabigatran versus warfarin after bioprosthesis valve replacement for the management of atrial fibrillation postoperatively: DAWA pilot study. Drugs R D 2016;16:149–54. https://doi.org/10.1007/s40268-016-0124-1; PMID: 26892845.

Durães AR, de SL Bitar Y, Lima MLG, et al. Usefulness and safety of rivaroxaban in patients following isolated mitral valve replacement with a mechanical prosthesis. Am J Cardiol 2018;122:1047–50. https://doi.org/10.1016/j. amjcard.2018.06.015; PMID: 30098707. 10. Makkar RR, Fontana G, Jilaihawi H, et al. Possible subclinical leaflet thrombosis in bioprosthetic aortic valves. N Engl J Med 2015;373:2015–24. https://doi.org/10.1056/NEJMoa1509233; PMID: 26436963. 11. Windecker S, Tijssen J, Giustino G, et al. Trial design: rivaroxaban for the prevention of major cardiovascular events after transcatheter aortic valve replacement: rationale and design of the GALILEO study. Am Heart J 2017;184:81–7. https:// doi.org/10.1016/j.ahj.2016.10.017; PMID: 27892890. 12. Collet J-P, Berti S, Cequier A, et al. Oral anti-Xa anticoagulation after trans-aortic valve implantation for aortic stenosis: the randomized ATLANTIS trial. Am Heart J 2018;200:44–50. https:// doi.org/10.1016/j.ahj.2018.03.008; PMID: 29898848.

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Pharmacotherapy

Antithrombotic Treatment After Coronary Intervention: Agreement and Controversy Tamara García Camarero and José M de la Torre Hernández Department of Interventional Cardiology, Hospital Universitario Marques de Valdecilla, IDIVAL, Santander, Spain

Abstract Percutaneous revascularisation has evolved dramatically in the past few decades. The approach to the management of ischaemic heart disease has changed due to the development of new devices and techniques as well as the availability of new drugs and treatment strategies. Its use in combination with antiplatelet therapies has been essential to protect against stent thrombosis. The length of time this combination therapy is used has been modified in recent years and has been the subject of extensive research. The effect of prolonging the time it is taken or shortening it has been evaluated in different clinical conditions. In practice, the decisions regarding antithrombotic therapy after percutaneous coronary intervention are informed by the patient’s profile and the characteristics of the procedures performed. In this article, we review the use of antiplatelet/anticoagulant therapy after percutaneous coronary intervention focusing on trials and guidelines addressing variable durations for combination regimens and the alternatives.

Keywords Coronary artery disease, percutaneous coronary intervention, drug-eluting stent, antithrombotic therapy, bleeding, thrombosis Disclosure: The authors received unrestricted grants for research from Boston Scientific, Abbott Vascular, St Jude Medical, Biotronik and Biosensors. They have also received consulting fees from Medtronic, Astra-Zeneca, Biotronik, Boston Scientific and Abbott Vascular. Received: 8 April 2019 Accepted: 15 August 2019 Citation: European Cardiology Review 2020;15:e07. DOI: https://doi.org/10.15420/ecr.2019.25.2 Correspondence: José de la Torre Hernández, Hospital Universitario Marques de Valdecilla, Unidad de Cardiología Intervencionista, Valdecilla Sur, 39008 Santander, Spain. E: he1thj@humv.es Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

The use of dual antiplatelet therapy (DAPT) after stent implantation in a percutaneous coronary intervention (PCI) is the standard treatment. The first randomised controlled trial (RCT) to establish the superiority of DAPT versus oral anticoagulant treatment among patients undergoing PCI was the Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial, published in 1996.1 Since then, more than 35 RCTs have been carried out, with more than 225,000 participants, to assess different aspects of DAPT in this context, including the ideal approach of antiplatelet drug and the optimal duration of treatment. With the advent of the first bare metal stents (BMS), it was established that DAPT was needed for a month by studies such as the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS).2 Until clopidogrel was approved by the FDA in 1997, the drug used together with acetylsalicylic acid (ASA) was ticlopidine. The duration of treatment with DAPT was extended to 3 months after the approval of the first drug-eluting stents (DES) containing sirolimus, and to 6 months after the release of paclitaxel DES. These periods were established without any clinical evidence. The length was extended to 12 months after the findings of wide registries documenting a sustained risk of late stent thrombosis beyond 6 months.3,4 This risk was not identified by the first clinical trials for DES.5 The concern raised among the medical community regarding late and very late thrombosis events with the use of these first-generation DES created the need to assess prolonged DAPT regimens.

Subsequently, with the introduction of second and third generation DES, such as thinner struts, the -limus drugs, and more biocompatible or biodegradable polymers, which have decreased the risk of late and very late thrombosis to numbers similar or even lower than the BMS, there has been a drift in the approach to DAPT.6,7 Although DAPT continues to play a key role in reducing the risk of late and very late thrombosis, the significant related risk of bleeding implies that, currently, prolonged 12-month DAPT is not generally justified. On the other hand, there is sustained evidence that DAPT can reduce long-term cardiovascular events independently of the prevention of stent thrombosis, by preventing thrombotic events of atheromatous plaques, especially in patients who have had acute coronary syndrome (ACS).8,9 DAPT has moved from a local focus on the prevention of stent thrombosis to be considered part of a global strategy of treatment that provides the patient with overall protection against vascular thrombotic events, especially cardiac but also cerebral. Studies carried out in recent years aimed to establish the minimum safe duration of DAPT for the new DES as well as considering the potential benefit of continuing DAPT over 12 months in certain patients. These studies are summarised in Table 1. In 2016, the American College of Cardiology and the American Heart Association published an update of the clinical practice guidelines on

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Pharmacotherapy Table 1: Most Important Studies Comparing Different Periods of Dual Antiplatelet Therapy Study

Comparison

Drugs

Patients (n) Stent

Clinical Setting

Primary Endpoint

Bleeding

EXCELLENT, 201213

6 versus 12 months

ASA + clopidogrel

1,443

DES

Stable/ACS

No difference

12 months higher (p>0.5)

PRODIGY, 201214

6 versus 24 months

ASA + clopidogrel

2,013

DES/BMS

Stable/ACS

No difference

24 months higher TIMI major (p<0.5)

ISAR-SAFE, 201415

6 versus 12 months

ASA + clopidogrel

4,005

DES

Stable/ACS

No difference

12 months higher BARC ≥2 (p<0.5)

ITALIC, 201416

6 versus 24 months

ASA + clopidogrel (99%) 1,894

DES

Stable/ACS

No difference

–

6 versus 12 months

ASA + clopidogrel (99%) 1,399

DES

Stable/unstable angina

No difference

SECURITY,

201417

RESET, 201218

3 versus 12 months

ASA + clopidogrel

2,117

DES

Stable/ACS

No difference

OPTIMIZE, 201319

3 versus 12 months

ASA + clopidogrel

3,119

DES

Stable/low-risk ACS

No difference

12 months higher (p>0.5)

DAPT, 201421

30 versus 12 months

ASA + thienopyridine

9,961

DES

After 12 asymptomatic months

30 months better (p<0.5)

30 months higher (p>0.5)

DES-LATE, 201322

36 versus 12 months

ASA + clopidogrel

5,045

DES

After 12 asymptomatic months

No difference

ARCTIC-Interruption, 201423

18–24 versus 12 months

ASA + thienopyridine

1,259

DES

After 12 asymptomatic months

No difference

Longer higher (p<0.5)

IVUS-XPL, 201650

6 versus 12 months

ASA + clopidogrel

1,400

DES

Stable/ACS

No difference

NIPPON, 201651

6 versus 18 months

ASA + clopidogrel

3,773

DES

Stable/ACS

No difference

OPTIDUAL,

201652

12 versus ≥12 months

ASA + clopidogrel

1,398

DES

Stable/ACS

No difference

DAPT-STEMI, 201827

6 versus 12 months

ASA + P2Y112 inhibitor

1,100

Secondgeneration DES

STEMI

No difference

SMART-DATE, 201829

6 versus 12 months

ASA + P2Y12 inhibitor

2,712

Secondgeneration DES

ACS

6 months higher MI rate (p<0.5)

No difference

SMART-CHOICE, 201930

3 versus 12 months

ASA + P2Y12 inhibitor 2,993 (monotherapy with P2Y12 inhibitor)

DES

Stable/ACS

3 months non-inferior

P2Y12 inhibitor monotherapy better (p<0.5)

ACS = acute coronary syndrome; ASA = acetylsalicylic acid; BARC = Bleeding Academic Research Consortium; BMS = bare metal stent; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; STEMI = ST-elevation MI; TIMI = thrombolysis in MI

the duration of DAPT in patients with coronary artery disease (CAD).10 These guidelines were developed based on the results of a systematic review of all the studies carried out on this topic.11 More recently, the European Society of Cardiology (ESC), in collaboration with the European Association of Cardiothoracic Surgery, published an update of the guidelines on DAPT in CAD.12 Both documents show a high degree of consensus, but in this article we will focus on the recommendations in the European guidelines. Since the publication of these two practice guidelines, several studies have been published which address similar questions and many others are in the inclusion or follow-up phase and the findings will probably have an impact on future guidelines. We will, therefore, comment on some of these most interesting studies. The clinical context in which the patient is being treated must always be considered when making a decision about the type of antiplatelet drug and the duration of treatment, so we will discuss patients undergoing percutaneous revascularisation in a stable situation separately from those revascularised in the setting of ACS. Moreover, the management of patients undergoing percutaneous revascularisation

who also have a high risk of bleeding or need chronic oral anticoagulation require a separate mention.

DAPT After Percutaneous Revascularisation in Stable Coronary Artery Disease There are no clinical trials that assess the duration of DAPT exclusively in stable patients, so all the recommendations have been drawn from subgroups from wider trials. There is also a lack of trials that evaluate the use of prasugrel or ticagrelor as an alternative to clopidogrel in the stable context, although their use is accepted in selected patients who have unsatisfactory previous use or clinical resistance to clopidogrel, drug allergy or a high risk of ischaemia.

DAPT for at Least 12 Months Versus 3–6 Months Several trials have aimed to assess this aspect, all with very similar results, and have led to the proposed recommendations. The Efficacy of Xience/promus versus Cypher in rEducing Late Loss after stENTing (EXCELLENT) compared a strategy of 6 months versus 12 months of DAPT (ASA and clopidogrel).13 It included 1,443 patients treated with DES. At 1 year, the 12-month group had a target

EUROPEAN CARDIOLOGY REVIEW

Antithrombotic Treatment After Coronary Intervention vessel failure rate slightly lower than the 6-month group (4.3% versus 4.8%), at the expense of a non-significant increase in bleeding. The findings were independent from the clinical context (stable versus unstable). The Prolonging Dual-Antiplatelet Treatment After Grading StentInduced Intimal Hyperplasia Study (PRODIGY) compared a strategy of 6 months versus 24 months of DAPT (ASA and clopidogrel). It included 2,013 patients randomised to four different stents (one BMS and three DES). At 2 years, no significant differences were found in the combined primary endpoint of major adverse coronary events (MACE) but there was higher significant bleeding in the 24-month group, even more so in the subgroup of patients with stable CAD.14 The Intracoronary Stenting and Antithrombotic Regimen: Safety And EFficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) compared a strategy of 6 versus 12 months of DAPT (ASA and clopidogrel).15 It included 4,005 patients treated with DES. and included both stable and unstable patients. It concluded that the 12-month strategy did not provide any benefit over the 6-month strategy. The Is There A LIfe for Drug-eluting Stents (DES) After Discontinuation of Clopidogrel (ITALIC) and Second Generation DrugEluting Stent Implantation Followed by Six- Versus Twelve-Month Dual Antiplatelet Therapy (SECURITY) trials had a similar design and results to ISAR-SAFE.16,17 The REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation (RESET) trial compared a strategy of 3 versus 12 months of DAPT (ASA and clopidogrel).18 It included 2,117 patients treated with zotarolimus DES. There were no significant differences in MACE between the two groups. The Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice (OPTIMIZE) trial compared a strategy of 3 versus 12 months of DAPT (ASA and clopidogrel).19 It included 3,119 patients treated with zotarolimus DES. There were no significant differences in MACE between the groups. A meta-analysis comparing the strategy of 12 months of DAPT after the implantation of a DES versus no more than 6 months of DAPT concluded that the 1-year strategy does not provide any advantage in terms of survival, stent thrombosis or acute MI and substantially increases the risk of major bleeding.20

DAPT for 12 Months Versus Longer Treatment Strategies The main characteristics and results of trials that address 12 months of DAPT treatment versus longer treatment strategies are summarised here. The Dual Antiplatelet Therapy (DAPT) study compared a strategy of 12 months versus 30 months of DAPT.21 It included 9,961 patients treated with DES without ischaemic or haemorrhagic events in the first year of treatment after stent implantation. In the 30-month arm, there was a significant decrease in thrombosis (0.4% versus 1.4%, p <0.001) and major adverse cardiac and cerebrovascular events (4.3% versus 5.9%, p<0.001). This is associated with a significant increase in the risk of bleeding (2.5% versus 1.6%, p<0.001) and an almost significant increase in mortality from any cause.

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Three independent meta-analyses that included the results of the Optimal Duration of Clopidogrel Therapy With DES to Reduce Late Coronary Arterial Thrombotic Event (DES-LATE; 5,045 patients) and the Assessment by a Double Randomisation of a Conventional Antiplatelet Strategy Versus a Monitoring-Guided strategy for Drug Eluting Stent Implantation and, of Treatment Interruption Versus Continuation 1 Year After Stenting-Interruption (ARCTIC-Interruption; 1,259 patients) trials reached conclusions consistent with a possible increase in global mortality with the prolongation of DAPT.22,23 These studies show that maintaining long-term DAPT in patients with stable CAD treated with DES confers a benefit in terms of secondary prevention of ischaemic events and reduction of stent thrombosis, but at the expense of an increased risk of bleeding and a potential increase in global mortality. Taking all this into account, the class I level A recommendation is that maintenance of DAPT is not systematically recommended beyond 6 months and the duration should be individualised according to the patient’s risk profile. It will be necessary to assess the patient’s ischaemic and bleeding risk in the medium to long term, for which several tools have been developed. Those recommended in the European guidelines are the PRECISE-DAPT score and the DAPT score. The PRECISE-DAPT score decides the duration of DAPT at the time of stent implantation.24 The DAPT score can be used to make decisions to prolong DAPT after an uneventful first year post-PCI. Of note, the type of stent implanted is important when assessing the benefit of extending DAPT beyond one year. This benefit is clearer in patients with firstgeneration DES, although these are no longer used. There have been no studies assessing the optimal duration of DAPT after implantation of bioabsorbable scaffolds, but there is evidence of an increased risk of stent thrombosis in the first month and in the long term, which is why, in patients treated with these stents, it seems reasonable to recommend DAPT for at least 12 months, and even prolong it when the risk of bleeding is low.

DAPT After Percutaneous Revascularisation in Acute Coronary Syndrome The usefulness of DAPT with ASA and clopidogrel for 1 year in patients with ACS has been amply demonstrated.8,9 There are also studies that demonstrate the superiority of ticagrelor (PLATelet inhibition and patient Outcomes [PLATO] trial) and prasugrel (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction [TRITON-TIMI]) versus clopidogrel in this context.25,26 Although both prasugrel and ticagrelor significantly increase the risk of major TIMI bleeding not related to surgery, the risk–benefit ratios are favourable, with a number needed to treat to prevent a primary outcome of 46 and 53, respectively, and the number needed to harm of 167 for both drugs. For these reasons, the recommendation is to prescribe DAPT for 1 year after ACS has been established, preferably with ticagrelor or prasugrel, unless there are contraindications (class I level C).

DAPT for 12 Months Versus 3–6 Months Following the idea that longer DAPT exposes the patient to higher bleeding risk and therefore poorer prognosis and in line with the studies that seek to shorten the duration of DAPT in stable patients, a line of research is also arising in the setting of ACS.

Pharmacotherapy The Dual Antiplatelet Therapy after drug-eluting stent implantation in ST-elevation MI (DAPT-STEMI) trial was designed to show that limiting DAPT to 6 months in patients with event-free ST-elevation MI (STEMI) results in a non-inferior clinical outcome (composite of all-cause mortality, any MI, any revascularisation, stroke and TIMI major bleeding at 18 months after randomisation) versus DAPT for 12 months.27 There were 1,100 patients enrolled. The authors concluded that the shortterm strategy was non-inferior in the long term in patients with eventfree STEMI at 6 months after primary PCI with second generation DES. A later meta-analysis included 17,941 patients from three RCTs and eight RCT sub-analysis allocated to two groups according to the DAPT strategy. It concluded that a short duration of DAPT may be safely considered, with similar rates of recurrent thrombotic complications compared with the standard 12 months, and similar mortality.28 After this meta-analysis was published, new data have been released addressing this same topic. The Safety of 6-month Duration of Dual Antiplatelet Therapy After Acute Coronary Syndromes (SMART-DATE) trial aimed to prove that a 6-month duration of DAPT is non-inferior to a conventional 12-month or longer duration of DAPT at preventing the occurrence of major adverse cardiac and cerebrovascular events at 18 months after second-generation DES implantation in patients with ACS.29 A total of 2,712 patients were included and randomised. The authors found an increased risk of MI with the short-term strategy and concluded that prolonged DAPT in patients with ACS without excessive risk of bleeding should remain the standard of care. The P2Y12 Inhibitor Monotherapy Versus Extended DAPT in Patients Treated with Bioresorbable Scaffold (SMART-CHOICE) trial compared the efficacy and safety of P2Y12 inhibitor monotherapy versus aspirin plus P2Y12 antagonist following 3-month of DAPT in patients undergoing PCI with DES. Of the 2,993 patients included, 58% had ACS. The results showed that short-duration DAPT (3 months) followed by P2Y12 inhibitor monotherapy is non-inferior to longer-duration DAPT (12 months) among unselected patients undergoing PCI with a DES.30 The results of all the above-mentioned studies were published after the ESC guidelines were published. Therefore, no specific mention on this strategy is made apart from the 6 months recommendation in patients at high risk of bleeding.

DAPT for 12 Months Versus More Than 12 Months Patients with ACS have a high cardiovascular risk beyond the first year and intensive DAPT has been shown to be effective in reducing the rate of new recurrent ischaemic events. The riskâ&#x20AC;&#x201C;benefit balance is not so clear and several trials have been developed to try to clarify the issue. The Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin (PEGASUS) study included 21,162 patients with a previous MI (between 1 and 3 years before the start of the study) and a high-risk profile. Monotherapy with ASA was compared with two DAPT regimens with ASA and ticagrelor (60 mg or 90 mg). Although the main combined result of efficacy (cardiovascular death, MI and stroke at 3 years) was significantly better in the ticagrelor groups (7.85% with 90 mg and 7.77% with 60 mg versus 9.04% in ASA monotherapy), a significant increase in TIMI bleeding was also observed (2.6% with 90 mg, 2.3% with 60 mg and 1.06% in ASA monotherapy). Therefore, it is not possible to obtain a net benefit with 90 mg ticagrelor and the benefits are marginal with 60 mg ticagrelor.31

For these reasons, the generalised use of DAPT with ASA and ticagrelor beyond a year after an ACS is discouraged and more individualised use is advocated, considering the ischaemic and haemorrhagic risks of each particular patient. The DAPT study compared 12 months versus 30 months of DAPT (ASA and either clopidogrel or prasugrel).21 A non-pre-specified analysis of the sub-group who had an MI (3,567 patients) found a significant reduction in thrombosis in the 30-month group (0.5% versus 1.9%; p<0.001), as well as of new infarction (2.2% versus 5.2%; p<0.001), at the expense of an increase in moderate or severe bleeding, according to the Global Use of Strategies to Open Occluded Arteries (GUSTO) scale (1.9% versus 0.8%; p=0.005) and the same mortality rate for all causes. Recently, a meta-analysis including clinical trials that assess the use of DAPT (clopidogrel, prasugrel or ticagrelor) beyond 12 months after ACS has been carried out. The conclusions are similar: reduction in cardiovascular events at the expense of an increase in bleeding with neutral or negative impact on overall mortality.32 Although these findings seem to show a consistent class effect among the three P2Y12 receptor inhibitors, the use of 60 mg ticagrelor is recommended in patients with a low risk of bleeding in whom it is decided to continue with DAPT after 1 year. This recommendation is based on the fact that ticagrelor is the most widely studied drug and has the most complete trials.

DAPT Duration in Patients with a High Risk of Bleeding The majority of clinical trials exclude patients with a high risk of bleeding, although the definition of high bleeding risk had not been well established until the recently published Academic Research Consortium for High Bleeding Risk definitions.33 Nevertheless, the evaluation of shorter DAPT strategies allows inferring results applicable to this patient group. A meta-analysis, with data from six trials, compared the strategy of 12 months of DAPT versus 3 or 6 months in 4,758 patients after an ACS.34 Reduction of DAPT to 6 months resulted in a nonsignificant increase in the risk of thrombosis or MI, while reducing DAPT to 3 months significantly increased this risk. There are some studies that have shown safety with 3 months of DAPT, but they were performed with outdated DES. However, there are ongoing studies with current DES and registries that guarantee the safety of new generation DES with 3 months of DAPT. To date, only one trial has specifically assessed the population of patients with the highest bleeding risk, the Prospective Randomized Comparison of the BioFreedom Biolimus A9 Drug-Coated Stent versus the Gazelle Bare-Metal Stent in Patients at High Bleeding Risk (LEADERS FREE) trial.35 In this study, 2,466 patients with medium-high or high bleeding risk were randomised to BioFreedom (polymer-free DES) or BMS with a 1-month DAPT in both cases. The BioFreedom stent arm was better in terms of safety and efficacy. A class IIb recommendation has been made for 1-month DAPT linked to this stent. Therefore, the ESC guidelines suggest that the withdrawal of DAPT after 3 months in stable patients (class IIa level B) and after 6 months in ACS patients (class IIa level C) in the presence of a high bleeding risk could be considered. The reduction of DAPT to 1 month could be considered

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Antithrombotic Treatment After Coronary Intervention in stable cases with increased bleeding risk, but it should be linked to the use of the above-mentioned stent. A tool that could aid decision making regarding DAPT duration after PCI would be useful and the PRECISE-DAPT score might play a key role. After the input of five simple items, it gives the likelihood of the patient’s out-of-hospital bleeding risk. A cutoff value of >25 could identify those patients at higher risk of bleeding.24 There are several ongoing trials examining the safety of very short-term DAPT in patients with a high-risk of bleeding after new generation DES PCI. These include Bioresorbable Polymer-Coated EES in Patients at High Bleeding Risk Undergoing PCI Followed by 1-Month DAPT (POEM; NCT03112707); Resolute Onyx in One Month Dual Antiplatelet Therapy for High-Bleeding Risk Patients (Onyx-ONE; NCT03344653); XIENCE 28 (NCT03815175 and NCT03355742) and Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Prolonged DAPT Regimen (MASTER-DAPT; NCT03023020). The results of these trials would enhance the amount of evidence in this setting and would probably change the recommendations in future guidelines.

Role of De-escalation in DAPT The risk of ischaemic complications is most likely just after PCI and the risk gradually decreases. The same happens after an ACS. Hence, the hypothesis that, during the chronic phase, once the disease stabilises, the level of platelet anti-aggregation required might be lower than in the acute phase. The following trials tested this hypothesis. The Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes (TROPICALACS) trial studied patients undergoing PCI after ACS. After 1 week of DAPT with prasugrel and ASA, the participants were randomised to prasugrel or clopidogrel for 12 months. The results of a subsequent platelet aggregation test were used to guide the therapy in the latter group. The results indicate non-inferiority of the de-escalation therapy compared with maintenance therapy.36 The Timing of Platelet Inhibition after Acute Coronary Syndrome (TOPIC) trial involved 645 patients who had a PCI following an ACS, and after an uneventful 1-month period of ASA and a newer P2Y12, were randomised to continue their DAPT regimen or switch to ASA and clopidogrel. After 1 year of follow-up, there were a similar amount of ischaemic events in both groups, with a significant reduction in bleeding complications in the de-escalation group.37 Information on how to de-escalate (switching from prasugrel or ticagrelor to clopidogrel) is found in the 2017 ESC guidelines and in the international expert consensus on switching platelet P2Y12 receptorinhibiting therapies.12,38

Acetylsalicylic Acid-free Strategy There is a growing feeling that the era of lifelong ASA treatment might be over, and some studies are trying to assess this topic. The goal of the Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation (GLOBAL-LEADERS) trial was to evaluate 1 month of aspirin plus ticagrelor followed by 23 months of ticagrelor monotherapy compared with 1 year of dual antiplatelet therapy (aspirin plus either clopidogrel or ticagrelor) followed by 1 year of aspirin

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monotherapy among 15,968 patients undergoing PCI with a BES. The composite outcome, components of the primary outcome and major bleeding were similar between treatment groups. The experimental strategy of a shorter duration of DAPT did not increase ischaemic events.39 The goal of the Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent-2 (STOPDAPT-2) trial was to evaluate 1 month of DAPT compared with 12 months of DAPT among patients undergoing PCI in stable and unstable settings) with a cobalt chromium everolimus-eluting stent.40 The 3,045 participants were randomised to either 1 month of DAPT followed by clopidogrel monotherapy for 5 years or 12 months of DAPT followed by aspirin monotherapy for 5 years. The authors concluded that 1 month of DAPT followed by clopidogrel monotherapy was superior to 12 months of DAPT followed by aspirin monotherapy at preventing net adverse clinical events (non-inferior at preventing ischaemic events and superior at preventing bleeding). The SMART-CHOICE trial is also aligned with this ‘off-ASA’ strategy. Other ongoing trials are also assessing ASA-free strategies – Ticagrelor With Aspirin or Alone in High-risk Patients after Coronary Intervention (TWILIGHT; NCT02270242), Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus Stent for Acute Coronary Syndrome (TICO; NCT02494895) and Acetyl Salicylic Elimination Trial (ASET; NCT03469856).

DAPT in Patients with Indication for Oral Anticoagulation It is estimated that about 6–8% of patients who undergo PCI also have an indication to continue chronic therapy with oral anticoagulantion (OAC) due to different pathologies, such as AF, mechanical valvular prosthesis or previous pulmonary embolism. The association of DAPT with OAC increases the risk of haemorrhagic complications up to threefold. It is especially important for this subgroup of patients to make an adequate stratification of both ischaemic and bleeding risk, as well as the need for chronic anticoagulation. They should follow OAC only when there is a clear indication (CHA2DS2-VASc ≥1 in men and ≥2 in women, mechanical valvular prosthesis, pulmonary embolism or recent or recurrent deep vein thrombosis). The haemorrhagic risk is not static and therefore attention should be paid to the reversible bleeding risk factors present in the different scores or algorithms (HAS-BLED score for major bleeding risk). No predictive risk model developed for patients with OAC has been prospectively validated, so its usefulness in improving the clinical outcomes of patients is questionable. There are a number of considerations that must be acknowledged to decide the most appropriate approach for these patients.

Type of Antiplatelet Treatment There are no trials that have assessed the efficacy or safety of triple therapy (DAPT and OAC) with prasugrel or ticagrelor, but there are worrying data showing increased bleeding in various registries. Therefore, it is recommended to avoid ticagrelor and prasugrel in triple therapy.

Duration of Triple Therapy and Triple Versus Dual Therapy The following trials have evaluated the duration of triple therapy and triple versus dual therapy.

Pharmacotherapy Figure 1: A Proposed Algorithm to Guide Dual Antiplatelet Therapy Duration After Percutaneous Coronary Intervention with Drug-eluting Stents

Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) trial included 2,124 patients with non-valvular AF undergoing PCI. They were divided into three branches: dual therapy with a P2Y12 inhibitor and 15 mg rivaroxaban once daily for 12 months; triple therapy with DAPT plus 2.5 mg rivaroxaban twice daily for 1, 6 or 12 months; and triple therapy with DAPT plus vitamin K antagonist (VKA) for 1, 6 or 12 months. At 12 months, rates of clinically significant bleeding were significantly lower in the two rivaroxaban arms, compared with triple therapy with DAPT and VKA.42

Bleeding risk DAPT duration 1 month PRECISE DAPT score ≥25

1 month

3 months

6 months

Neither of these studies has sufficient power to assess significant differences in the rate of ischaemic events (stroke or thrombosis). 3 months

6 months

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Ischaemic-thrombotic risk ACS

Stable angina Simple PCI

Complex PCI

Simple PCI

Complex PCI

Complex PCI, at least one: 3 vessels, >3 stents, bifurcation with 2 stents, total stent length >60 mm, CTO The different colours for time durations are roughly in relation with the level of evidence supporting the indication: green I, purple IIa and orange IIb. ACS = acute coronary syndrome; CTO = chronic total occlusion; PCI = percutaneous coronary intervention.

Figure 2: A Proposed Algorithm to Guide Duration of Antithrombotic Regimens After Percutaneous Coronary Intervention with Drug-eluting Stents in Patients Requiring Chronic Oral Anticoagulation Bleeding risk Dual therapy (clopidogrel + DOAC) duration 3 months

PRECISE DAPT score ≥25

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6 months

3 months

6 months

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(1st month

triple)

Ischaemic-thrombotic risk Stable angina Simple PCI

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Complex PCI

The What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing (WOEST) trial saw 573 patients randomised after PCI to dual therapy with clopidogrel and OAC versus triple therapy with ASA, clopidogrel and OAC for 1 or 12 months (depending on the use of BMS or DES). The dual therapy arm showed a significant reduction in total bleeding and overall mortality without differences in major bleeding or cardiovascular events.41 The Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral

The Triple Therapy in Patients on Oral Anticoagulation after Drug Eluting Stent Implantation (ISAR-TRIPLE) included 614 patients undergoing PCI receiving OAC.43 They were randomised to receive triple therapy (ASA, clopidogrel and VKA) for 6 weeks or 6 months. There were no significant differences between groups in any aspect. These three studies consistently show that the rate of bleeding peaks a month after the start of triple therapy and that the rate of haemorrhagic events doubles that of coronary ischaemic events (infarction or thrombosis). The Evaluation of Dual Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with AF That Undergo a PCI with Stenting (REDUAL PCI) trial included 2,725 patients with AF undergoing PCI. They were assigned to three different arms: at least 6 months of dual therapy with 150 mg of dabigatran twice daily and a P2Y12 inhibitor; at least 6 months of dual therapy with 110 mg of dabigatran twice daily and a P2Y12 inhibitor; and triple therapy with VKA, AAS and a P2Y12 inhibitor for 1 month (BMS) or 3 months (DES), continuing later with dual therapy. The authors found a significant decrease in haemorrhagic events in the two dual therapy arms compared with triple therapy while maintaining safety (not inferiority to VKA).44 A meta-analysis including the four trials mentioned above compared the safety and efficacy of dual versus triple antithrombotic therapy in patients on OAC secondary to AF undergoing PCI. A total of 5,317 patients were included. The study concludes that the dual therapy showed a 47% reduction in TIMI major or minor bleeding with comparable outcomes for MACE.45 The Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation (AUGUSTUS) trial included 4,616 patients with AF and recent ACS or PCI with planned use of P2Y12 inhibitor for at least 6 months. They were randomised in a 1:1 fashion to either apixaban 5 mg twice daily or vitamin K antagonist (VKA) or aspirin 81 mg daily or matching placebo. At 6 months’ follow-up, adding apixaban to a P2Y12 inhibitor resulted in lower rates of bleeding compared with VKA with a lower rate of death or rehospitalisation. The addition of aspirin resulted in greater bleeding without any difference in efficacy in both arms.46 Several other similar trials are currently in the inclusion phase. Of note, the Edoxaban Treatment Versus Vitamin K Antagonist in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (ENTRUST-AF-PCI) aimed to assess the role of edoxaban in people with AF following PCI.47 Its results have been recently released. The authors randomised 1,506 patients to either standard triple antithrombotic

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Antithrombotic Treatment After Coronary Intervention regimen (VKA-based) or dual antithrombotic therapy with 60 mg edoxaban and a P2Y12 inhibitor. The edoxaban-based dual antithrombotic therapy was non-inferior for bleeding compared with VKA-based triple antithrombotic regimen, without significant differences in ischaemic events.

ischaemia, such as previous stent thrombosis, PCI of the only permeable coronary artery, diabetes with diffuse coronary disease, renal insufficiency, more than three stents implanted, more than three lesions treated, bifurcation treated with two stents technique, total length of stent >60 mm or treatment of a chronic occlusion.

The ESC guidelines propose two strategies that are selected based on the balance of ischaemic and haemorrhagic risks:

Type of Stent The choice of a new generation DES over a BMS in patients with OAC indication is well established.

• Triple therapy with ASA, clopidogrel and OAC for 1 month, extendable to 6 months in patients with higher ischaemic risk and lower risk of bleeding. • Dual therapy with clopidogrel and OAC from the beginning in cases of higher bleeding risk and lower ischaemic risk.

We have developed an algorithm at the Hospital Universitario Marqués de Valdecilla that we propose as a tool to help decide the duration of DAPT after PCI (Figures 1 and 2).

However, the results of REDUAL-PCI and AUGUSTUS trials were known after the publication of the guidelines, and these, along with the other studies mentioned above, seem to suggest the end the use of triple therapy for patients with non-valvular AF undergoing PCI.

There are two different algorithms depending on the need of chronic anticoagulation. The protocols consider the bleeding risk assessed with the PRECISE-DAPT score and the presence of certain comorbidities as well as the ischaemic risk assessed with the clinical presentation and the PCI complexity. We consider a PCI to be complex when at least one of the following is present:

The 2018 North American Perspective Update on antithrombotic therapy in patients undergoing PCI recommends a shorter (only periprocedural) period of triple therapy in most settings.48

Definitive Suspension of Antiplatelet Therapy Data on the appropriate time to discontinue antiplatelet therapy in patients on chronic treatment with OAC are scarce. It is recommended that it is discontinued in patients who have remained stable for 1 year after the PCI, based on studies that show that this strategy is safer. The Optimizing Antithrombotic Care in Patients With AtriaL fibrillatiON and Coronary stEnt (OAC-ALONE) study compared OAC alone with combined OAC and single antiplatelet treatment among patients with AF beyond 1 year after PCI in a 1:1 randomisation. The primary endpoint was a composite of all-cause death, MI, stroke or systemic embolism. Due to an insufficient sample size (696 patients), the noninferiority goal was not established. However, the International Society of Thrombosis and Haemostasis stated that major bleeding was lower in the only OAC group, suggesting that OAC alone might be reasonable for patients with AF beyond 1 year after coronary stenting.49 Dual therapy with an antiplatelet drug and an OAC is limited for patients who meet some criterion which indicate they have a high risk of

chomig A, Neumann FJ, Kastrati A, et al. A randomized S comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084–9. https://doi.org/10.1056/ NEJM199604253341702; PMID: 8598866. Bertrand ME, Rupprecht HJ, Urban P, et al. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation 2000;102:624–9. https://doi. org/10.1161/01.CIR.102.6.624; PMID: 10931801. Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet 2007;369:667–78. https://doi.org/10.1016/S0140-6736(07)60314-6; PMID: 17321312. de la Torre-Hernández JM, Alfonso F, Hernández F, et al. ESTROFA Study Group. Drug-eluting stent thrombosis: results from the multicenter Spanish registry ESTROFA (Spanish Study on Thrombosis of Pharmacoactive stents). J Am Coll Cardiol 2008;51:986–90. https://doi.org/10.1016/j.jacc.2007.10.057; PMID: 18325436.

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• • • • •

PCI over three vessels. The use of more than three stents. A two-stent strategy in a bifurcation Total length of stent >60 mm. The treatment of a chronic total occlusion.

The different colours for time durations are roughly related to the level of evidence supporting the indication. It is designed to guide the clinician in the final decision, and it is meant to be thought of as a continuum.

Conclusion PCI has evolved dramatically in recent years and it has changed the approach in the management of ischaemic heart disease. This has been due to the development of new devices and antithrombotic therapies. We have reviewed the indications and modalities of antiaggregant-anticoagulant therapy after PCI in different scenarios. The multiple trials carried out have modified the approach of this therapy from a routine general approach that did not consider individual variables of the patients to a more comprehensive approach that takes into account the balance of ischaemic-thrombotic and haemorrhagic risks, informed from patient variables, coronary heart disease symptoms and features of the PCI procedure.

auri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in M randomized clinical trials of drug-eluting stents. N Engl J Med 2007;356:1020–9. https://doi.org/10.1056/NEJMoa067731; PMID: 17296821. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet 2012;379:1393–402. https://doi.org/10.1016/S01406736(12)60324-9; PMID: 22445239. Bangalore S, Toklu B, Amoroso N, et al. Bare metal stents, durable polymer drug eluting stents, and biodegradable polymer drug eluting stents for coronary artery disease: mixed treatment comparison meta-analysis. Br Med J 2013;347:f6625. https://doi.org/10.1136/bmj.f6625; PMID: 24212107. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527–33. https://doi. org/10.1016/S0140-6736(01)05701-4; PMID: 11520521. Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411–20. https://doi.org/10.1001/ jama.288.19.2411; PMID: 12435254.

10. L evine GN, Bates ER, Bittl JA, et al. ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;68:1082–115. https://doi.org/10.1016/j.jacc.2016.03.513; PMID: 27036918. 11. Bittl JA, Baber U, Bradley SM, et al. Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2016;68:1116–39. https://doi.org/10.1016/j.jacc.2016.03.512; PMID: 27036919. 12. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213–60. https://doi.org/10.1093/eurheartj/ehx419. PMID: 28886622. 13. Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of

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drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation 2012;125:505–13. https://doi.org/10.1161/CIRCULATIONAHA.111.059022; PMID: 22179532. Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012;125:2015–26. https://doi.org/10.1161/CIRCULATIONAHA.111.071589; PMID: 22438530. Schulz-Schüpke S, Byrne RA, Ten Berg JM, et al. ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting. Eur Heart J 2015;36:1252–63. https://doi.org/10.1093/eurheartj/ ehu523; PMID: 25616646. Gilard M, Barragan P, Noryani AA, et al. 6- versus 24-month dual antiplatelet therapy after implantation of drug-eluting stents in patients nonresistant to aspirin: the randomized, multicenter ITALIC trial. J Am Coll Cardiol 2015;65:777–86. https://doi.org/10.1016/j.jacc.2014.11.008; PMID: 25461690. Colombo A, Chieffo A, Frasheri A, et al. Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. J Am Coll Cardiol 2014;64:2086–97. https://doi. org/10.1016/j.jacc.2014.09.008; PMID: 25236346. Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET trial (REal safety and efficacy of 3 month dual antiplatelet therapy following endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012;60:1340–8.https://doi.org/10.1016/j. jacc.2012.06.043; PMID: 22999717. Feres F, Costa RA, Abizaid A, et al. Three vs. twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA 2013;310:2510–22. https:// doi.org/10.1001/jama.2013.282183; PMID: 24177257. Palmerini T, Benedetto U, Bacchi-Reggiani L, et al. Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials. Lancet 2015;385:2371–82. https://doi.org/10.1016/S01406736(15)60263-X; PMID: 25777667. Mauri L, Kereiakes DJ, Yeh RW et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155–66. https://doi.org/10.1056/NEJMoa1409312; PMID: 25399658. Lee CW, Ahn JM, Park DW et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation 2014;129:304–12. https://doi.org/10.1161/CIRCULATIONAHA.113.003303; PMID: 24097439. Collet JP, Silvain J, Barthélémy O et al. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. Lancet 2014;384:1577–85. https://doi.org/10.1016/S01406736(14)60612-7; PMID: 25037988. Costa F, van Klaveren D, James S, et al. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials. Lancet 2017;389:1025–34. https://doi.org/10.1016/S01406736(17)30397-5; PMID: 28290994. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–15. https://doi.org/10.1056/ NEJMoa0706482; PMID: 17982182. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57. https://doi.org/10.1056/ NEJMoa0904327; PMID: 19717846. Kedhi E, Fabris E, van der Ent M, et al. Six months versus 12

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

months dual antiplatelet therapy after drug-eluting stent implantation in ST-elevation myocardial infarction (DAPTSTEMI): randomised, multicentre, non-inferiority trial. Br Med J 2018;363:k3793. https://doi.org/10.1136/bmj.k3793; PMID: 30279197. Verdoia M, Kedhi E, Ceccon C, et al. Duration of dual antiplatelet therapy and outcome in patients with acute coronary syndrome undergoing percutaneous revascularization: A meta-analysis of 11 randomized trials. Int J Cardiol 2018;264:30–8. https://doi.org/10.1016/j. ijcard.2018.02.095; PMID: 29776573. Hahn JY, Song YB, Oh JH, et al. 6-month versus 12-month or longer dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (SMART-DATE): a randomised, open-label, non-inferiority trial. Lancet 2018;391:1274–84. https://doi.org/10.1016/S01406736(18)30493-8; PMID: 29544699. Hahn JY, Song YB, Oh JH, et al. Effect of P2Y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients undergoing percutaneous coronary intervention: the SMART-CHOICE randomized clinical trial. JAMA 2019;321:2428–37. https://doi.org/10.1001/ jama.2019.8146; PMID: 31237645. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791–800. https://doi.org/10.1056/ NEJMoa1500857; PMID: 25773268. Udell JA, Bonaca MP, Collet JP, et al. Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials. Eur Heart J 2016;37:390–9. https://doi. org/10.1093/eurheartj/ehv443; PMID: 26324537. Urban P, Mehran R, Colleran R, et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention. Circulation 2019;140:240–61. https://doi. org/10.1161/CIRCULATIONAHA.119.040167; PMID: 31116032. Palmerini T, Della Riva D, Benedetto U, et al. Three, six or twelve months of dual antiplatelet therapy after drug-eluting stent implantation in patients with or without acute coronary syndromes: an individual patient data pairwise and network meta-analysis of six randomized trials and 11 473 patients. Eur Heart J 2017;38:1034–43. https://doi.org/10.1093/eurheartj/ ehw627; PMID: 28110296. Urban P, Meredith IT, Abizaid A, et al. Polymer-free drug-coated coronary stents in patients at high bleeding risk. N Engl J Med 2015;373:2038–47. https://doi.org/10.1056/NEJMoa1503943; PMID: 26466021. Sibbing D, Aradi D, Jacobshagen C, et al. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet 2017;390:1747–57. https://doi.org/10.1016/S01406736(17)32155-4; PMID: 28855078. Cuisset T, Deharo P, Quilici J, et al. Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study. Eur Heart J 2017;38:3070–8. https://doi.org/10.1093/eurheartj/ehx175; PMID: 28510646. Angiolillo DJ, Rollini F, Storey RF, et al. International expert consensus on switching platelet P2Y12 receptor-inhibiting therapies. Circulation 2017;136:1955–75. https://doi. org/10.1161/CIRCULATIONAHA.117.031164; PMID: 29084738. Vranckx P, Valgimigli M, Jüni P, et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, openlabel, randomised superiority trial. Lancet 2018;392:940–9. https://doi.org/10.1016/S0140-6736(18)31858-

0; PMID: 30166073. 40. W atanabe H, Domei T, Morimoto T, et al. Effect of 1-month dual antiplatelet therapy followed by clopidogrel vs 12-month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving PCI: The STOPDAPT-2 randomized clinical trial. JAMA 2019;321:2414–27. https://doi.org/10.1001/ jama.2019.8145; PMID: 31237644. 41. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381:1107–15. https://doi.org/10.1016/S01406736(12)62177-1; PMID: 23415013. 42. Gibson CM, Mehran R, Bode C. An open-label, randomized, controlled, multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI). Am Heart J 2015;169:472–8.e5. https://doi. org/10.1016/j.ahj.2014.12.006; PMID: 25819853. 43. Fiedler KA, Maeng M, Mehilli J, et al. Duration of triple therapy in patients requiring oral anticoagulation after drug-eluting stent implantation: the ISAR-TRIPLE Trial. J Am Coll Cardiol 2015;65:1619–29. https://doi.org/10.1016/j.jacc.2015.02.050; PMID: 25908066. 44. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med 2017;377:1513–24. https://doi.org/10.1056/ NEJMoa1708454; PMID: 28844193. 45. Golwala HB, Cannon CP, Steg PG, et al. Safety and efficacy of dual vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of randomized clinical trials. Eur Heart J 2018;39:1726–35a. https://doi.org/10.1093/ eurheartj/ehy162; PMID :29668889. 46. Lopes RD, Heizer G, Aronson R, et al. Antithrombotic therapy after acute coronary syndrome or pci in atrial fibrillation. N Engl J Med 2019;380:1509–24. https://doi.org/10.1056/ NEJMoa1817083; PMID: 30883055. 47. Vranckx P, Valgimigli M, Eckardt L. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet 2019;394:1335–43. https://doi.org/10.1016/S01406736(19)31872-0; PMID: 31492505. 48. Angiolillo DJ, Goodman SG, Bhatt DL, et al. Antithrombotic therapy in patients with atrial fibrillation treated with oral anticoagulation undergoing percutaneous coronary intervention. Circulation 2018;138:527–36. https://doi. org/10.1161/CIRCULATIONAHA.118.034722; PMID: 30571525. 49. Matsumura-Nakano Y, Shizuta S, Komasa A, et al. Open-label randomized trial comparing oral anticoagulation with and without single antiplatelet therapy in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after coronary stent implantation. Circulation 2019;139:604–16. https://doi.org/10.1161/CIRCULATIONAHA.118.036768; PMID: 30586700. 50. Hong SJ, Shin DH, Kim JS, et al. 6-month versus 12-month dualantiplatelet therapy following long everolimus-eluting stent implantation: The IVUS-XPL randomized clinical trial. JACC Cardiovasc Interv 2016;9:1438–46. https://doi.org/10.1016/ j.jcin.2016.04.036; PMID: 27212028. 51. Nakamura M, Iijima R, Ako J, et al. Dual antiplatelet therapy for 6 versus 18 months after biodegradable polymer drugeluting stent implantation. JACC Cardiovasc Interv 2017;10:1189–98. https://doi.org/10.1016/j.jcin.2017.04.019; PMID: 28641838. 52. Helft G, Steg PG, Le Feuvre C, et al. Stopping or continuing clopidogrel 12 months after drug-eluting stent placement: the OPTIDUAL randomized trial. Eur Heart J 2016;37:365–74. https:// doi.org/10.1093/eurheartj/ehv481; PMID: 26364288.

EUROPEAN CARDIOLOGY REVIEW

Expert Opinion

Dual Antiplatelet Therapy in Coronary Artery Disease: Comparison Between ACC/AHA 2016 and ESC 2017 Guidelines Christopher N Floyd 1. King’s College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, Department of Clinical Pharmacology, London, UK; 2. Biomedical Research Centre, Clinical Research Facility, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Abstract Dual antiplatelet therapy (DAPT) is integral to the management of coronary artery disease (CAD) but there remains uncertainty as to the optimal approach for balancing an individual’s risk of atherothrombotic events versus their risk of bleeding complications. A myriad of clinical trials have investigated how factors such as antiplatelet selection or duration of treatment can affect outcomes in both stable CAD and acute coronary syndromes. To aid clinicians in the challenge of applying trial findings to the circumstances of individual patients, the American College of Cardiology/American Heart Association and European Society of Cardiology have released focused updates on prescribing DAPT in CAD. While the two guidelines agree on many issues, there are some differences in the recommendations. This article highlights those differences and provides comment on their aetiology.

Keywords Antiplatelet, bleeding, acute coronary syndrome, stent, thrombosis, guidelines Disclosure: The author has no conflicts of interest to declare. Received: 3 July 2019 Accepted: 4 November 2019 Citation: European Cardiology Review 2020;15:e08. DOI: https://doi.org/10.15420/ecr.2019.09 Correspondence: Christopher Floyd, Clinical Research Facility, Fourth Floor, St Thomas’ Hospital, London SE1 7EH, UK. E: christopher.floyd@kcl.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Antiplatelet therapy represents a key pharmacological pillar for the prevention of atherothrombotic events. Aspirin, the primogenial antiplatelet agent, has been shown to reduce the incidence of recurrent major adverse cardiovascular events (MACE) by approximately onefifth.1 Dual antiplatelet therapy (DAPT), usually aspirin in combination with a P2Y12 inhibitor, provides greater platelet inhibition resulting in an incremental reduction in the risk of MACE but at the cost of an increased risk of major bleeding. Prescribers are faced with the challenge of identifying where this risk:benefit ratio lies for each individual patient, and producing a tailored approach based on clinical presentation, management strategy and patient characteristics. To assist clinicians in the challenge of applying trial findings to the circumstances of individual patients, the American College of Cardiology/American Heart Association (ACC/AHA) and European Society of Cardiology (ESC) released focused updates on prescribing DAPT in coronary artery disease (CAD).2,3 To aid clinical decision-making, the updates provide helpful flowcharts that stratify patients according to presentation (stable CAD versus acute coronary syndrome [ACS]), management strategy (conservative versus interventional), and perceived bleeding risk. Differences between the two publications can be largely attributed to the 17 months between publications and, to a lesser extent, differences in the methodology for grading evidence, and the scope of each update. With no paradigm-shifting publications in this intervening period, it is unlikely

that following one set of recommendations would lead to substantially different patient outcomes compared with the other.

Duration of DAPT: Ischaemic Versus Bleeding Risk The two guidelines generally agree on the two key issues faced by clinicians: the selection and the duration of P2Y12 inhibition. In broad terms, prasugrel and ticagrelor are recommended for those at higher risk of ischaemic events (ACS compared with CAD) given that pharmacokinetic factors result in greater platelet inhibition compared with clopidogrel.4 The standard duration of DAPT for patients with ACS is ≥12 months, and ≥6 months for those with CAD undergoing intervention. These durations may be lengthened or shortened depending on perceived ischaemic or bleeding risk, and the decisionmaking behind such decisions is a major focus of the two updates. The ACC/AHA update includes a list of clinical and procedural factors associated with increased ischaemic risk, increased risk of stent thrombosis and increased bleeding risk, but acknowledges that many patients will have risk factors across categories and hence identifying where the balance lies for each individual remains challenging. Both updates present the DAPT score as a tool for assessing the risk:benefit ratio of >12 months DAPT after percutaneous coronary intervention (PCI).5,6 The DAPT score can be used after the completion of 12 months of uneventful DAPT after PCI (i.e. those free from repeat ischaemic events or moderate/severe bleeding) and is calculated by summation of points

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Expert Opinion attributed to nine variables, as follows.6 For the first variable, age, the score awards −2 points for age ≥75 years, −1 point for age 65 to <75 years and 0 points for age <65 years; it then awards 1 point each for current cigarette smoker; diabetes; MI at presentation; prior PCI or MI; paclitaxeleluting stent; and stent diameter <3 mm; and then 2 points each for congestive heart failure or left ventricular ejection fraction <30%; and vein graft stent. The score ranges from −2 to 10 points, with a score ≥2 indicating longer DAPT, and a score <2 indicating standard DAPT.6 The later publication date for the ESC update enabled it to also include the Predicting Bleeding Complication in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISEDAPT) score, which uses five patient-derived variables (haemoglobin; white blood cell count; age; creatinine clearance; and prior bleeding) to determine whether shorter (3–6 months) or standard/longer (12–24 months) DAPT may be beneficial after PCI based on bleeding risk.7 This score uses a nomogram to provide a decision-making cut-off regarding shorter or standard/longer DAPT. Although it is more challenging to calculate manually (available at http://www.precisedaptscore.com), it does have the advantage that it is performed at the time of coronary stenting, rather than after 12 months of DAPT. Decisions regarding the duration of DAPT therefore do not rely on assessments at follow-up appointments, which may not always occur in a timely manner. Crucially, neither the DAPT nor the PRECISE-DAPT scores have been tested in prospective randomised controlled trials (RCTs), and many of the RCTs comparing the different durations of DAPT have wide noninferiority margins and low rates of ischaemic events. Consequently, most recommendations for the duration of DAPT are graded as class II (i.e. a particular duration should ‘be considered’ or ‘is reasonable’), highlighting the lack of conclusive evidence.

Prevention of Gastrointestinal Bleeding Gastrointestinal (GI) bleeding represents the most common serious bleeding complication from long-term antiplatelet therapy, and so coprescription of proton pump inhibitors (PPIs) is recommended.8 The ACC/AHA recommends PPIs only for those at risk of bleeding (prior GI bleeding, advanced age and concomitant use of warfarin, steroids or non-steroidal anti-inflammatory drugs), whereas the ESC recommends PPIs for all prescribed DAPT. The difference in the recommendations is due to their respective interpretation of a large clinical trial that demonstrated a pharmacokinetic interaction between clopidogrel and omeprazole, but without an impact on cardiovascular events.9 However, given the known cytochrome pharmacokinetic interaction, it remains prudent to avoid co-prescription of clopidogrel with omeprazole/ esomeprazole if possible.4 No such interaction has been identified between PPIs and prasugrel or ticagrelor.

Utility of Platelet Function Testing The personalisation of antiplatelet therapy based on platelet function testing has been an aspiration following observations that high and low platelet reactivity while prescribed P2Y12 inhibitors predicts ischaemic 1.

ntithrombotic Trialists’ (ATT) Collaboration. Aspirin in the A primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849–60. https://doi. org/10.1016/S0140-6736(09)60503-1; PMID: 19482214. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;68:1082–115. https://doi.org/10.1016/j.jacc.2016.03.513;

and bleeding risk, respectively.10 Despite significant progresses in understanding the aetiology of poor response to antiplatelet agents,11,12 the updates are unable to make recommendations following neutral results from RCTs using platelet function-guided therapy, and a lack of RCTs investigating genome-led strategies.13–15 Since publication of the two guidelines, several studies investigating antiplatelet de-escalation (usually from prasugrel or ticagrelor to clopidogrel) have been reported. The 2018 ESC guidelines on myocardial revascularisation state that de-escalation based on platelet function testing may be considered as an alternative to 12 months of potent platelet inhibition, for which bleeding risk is high.16 However, it refers back to a 2017 consensus statement, which, although offering advice regarding drug dose/timings when switching, does not provide any practical advice on patient selection for the use of platelet function testing.17 This uncertainty around the clinical utility of platelet function testing and the efficacy of antiplatelet de-escalation is reflected in a recent meta-analysis highlighting that although de-escalation from ticagrelor to clopidogrel commonly occurs in real-world practice, the profile of patients suitable for de-escalation, the impact of de-escalation on adverse clinical outcomes, and how this is affected by the timing after index ACS warrant further large-scale investigation.18

Combination Antiplatelet and Anti-thrombotic Therapy Combination of antiplatelet therapy and anti-thrombotic therapy is increasingly indicated given that AF and CAD commonly co-exist, and this adds additional complexity to the risk:benefit assessment.19,20 This topic lies outside the scope of the ACC/AHA update, and although recommendations were made by the ESC update this has largely been superseded by a recent European consensus document that recommends use of the CHA2DS2-VASc and HAS-BLED scores when assessing risk:benefit ratio in AF, and a general preference for prescribing clopidogrel rather than prasugrel or ticagrelor.21 In individuals with high atherothrombotic risk and low bleeding risk, triple therapy (aspirin, clopidogrel and oral anticoagulant) can be prescribed for up to 6 months, with dual therapy (clopidogrel plus oral anticoagulant) continued for up to 12 months after PCI. When there are concerns about high bleeding risk, the duration of triple therapy can be shortened to 1 month or removed altogether. In all cases, once 12 months of dual therapy has been completed, individuals can continue oral anticoagulant as monotherapy.21

Future Recommendations The evidence base for antiplatelet therapy continues to develop; and recently published or ongoing studies investigating the routine use of anticoagulants, aspirin dosing regimens, P2Y12 monotherapy, direct prasugrel versus ticagrelor comparisons, and switching between P2Y12 inhibitors will all inform future updates and continue the push towards personalised medicine as our understanding of individual risk:benefit ratio evolves.

PMID: 27036918. algimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused V update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213–60. https://doi.org/10.1093/eurheartj/ehx419; PMID: 28886622. Floyd CN, Passacquale G, Ferro A. Comparative pharmacokinetics and pharmacodynamics of platelet

adenosine diphosphate receptor antagonists and their clinical implications. Clin Pharmacokinet 2012;51:429–42. https://doi. org/10.2165/11630740-000000000-00000; PMID: 22568693. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155–66. https://doi.org/10.1056/NEJMoa1409312; PMID: 25399658. Yeh RW, Secemsky EA, Kereiakes DJ, et al. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016;315:1735–49. https://doi.

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Dual Antiplatelet Therapy in CAD

10.

11.

org/10.1001/jama.2016.3775; PMID: 27022822. osta F, van Klaveren D, James S, et al. Derivation and C validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials. Lancet 2017;389:1025–34. https://doi.org/10.1016/S01406736(17)30397-5; PMID: 28290994. Agewall S, Cattaneo M, Collet JP, et al. Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy. Eur Heart J 2013;34:1708–13, 13a–13b. https://doi.org/10.1093/eurheartj/ eht042; PMID: 23425521. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010;363:1909–17. https://doi.org/10.1056/NEJMoa1007964; PMID: 20925534. Aradi D, Kirtane A, Bonello L, et al. Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J 2015;36:1762–71. https://doi.org/10.1093/eurheartj/ehv104; PMID: 25896078. Floyd CN, Ferro A. Mechanisms of aspirin resistance.

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12.

13.

14.

15.

Pharmacol Ther 2014;141:69–78. https://doi.org/10.1016/j. pharmthera.2013.08.005; PMID: 23993980. Floyd CN, Ferro A. Antiplatelet drug resistance: molecular insights and clinical implications. Prostaglandins Other Lipid Mediat 2015;120:21–7. https://doi.org/10.1016/j. prostaglandins.2015.03.011; PMID: 25868910. Collet JP, Cuisset T, Range G, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012;367:2100–9. https://doi.org/10.1056/NEJMoa1209979; PMID: 23121439. Trenk D, Stone GW, Gawaz M, et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 2012;59:2159–64. https://doi.org/10.1016/j.jacc.2012.02.026; PMID: 22520250. Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 2011;305:1097–105. https://doi. org/10.1001/jama.2011.290; PMID: 21406646.

16. N eumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy394; PMID: 30165437. 17. Angiolillo DJ, Rollini F, Storey RF, et al. International expert consensus on switching platelet P2Y12 receptor-inhibiting therapies. Circulation 2017;136:1955–75. https://doi. org/10.1161/CIRCULATIONAHA.117.031164; PMID: 29084738. 18. Angiolillo DJ, Patti G, Chan KT, et al. De-escalation from ticagrelor to clopidogrel in acute coronary syndrome patients: a systematic review and meta-analysis. J Thromb Thrombolysis 2019;48:1–10. https://doi.org/10.1007/s11239-019-01860-7; PMID: 31004312. 19. Bhatnagar P, Wickramasinghe K, Williams J, et al. The epidemiology of cardiovascular disease in the UK 2014. Heart 2015;101:1182–9. https://doi.org/10.1136/ heartjnl-2015-307516; PMID: 26041770. 20. Floyd CN, Ferro A. Indications for anticoagulant and antiplatelet combined therapy. BMJ 2017;359:j3782. https:// doi.org/10.1136/bmj.j3782; PMID: 28982662. 21. Lip GYH, Collet JP, Haude M, et al. Management of antithrombotic therapy in AF patients presenting with ACS and/or undergoing PCI. Eur Heart J 2018;39:2847–50. https:// doi.org/10.1093/eurheartj/ehy396; PMID: 30137444.

Pharmacotherapy

Antithrombotic Therapy After Transcatheter Aortic Valve Implantation Leslie Marisol Lugo,1 Rafael Romaguera,2 Joan Antoni Gómez-Hospital3 and José Luis Ferreiro3 1. Dobney Hypertension Centre, School of Medicine – Royal Perth Hospital Unit/Medical Research Foundation, University of Western Australia, Perth, Australia; 2. Heart Diseases Institute, Hospital Universitario de Bellvitge – IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain; 3. Department of Cardiology, Hospital Universitario de Bellvitge – IDIBELL, CIBER-CV, L’Hospitalet de Llobregat, Barcelona, Spain

Abstract The development of transcatheter aortic valve implantation has represented one of the greatest advances in the cardiology field in recent years and has changed clinical practice for patients with aortic stenosis. Despite the continuous improvement in operators’ experience and techniques, and the development of new generation devices, thromboembolic and bleeding complications after transcatheter aortic valve implantation remain frequent, and are a major concern due to their negative impact on prognosis in this vulnerable population. In addition, the optimal antithrombotic regimen in this scenario is not known, and current recommendations are mostly empirical and not evidence based. The present review aims to provide an overview of the current status of knowledge, including relevant on-going randomised trials, on antithrombotic treatment strategies after transcatheter aortic valve implantation.

Keywords Antithrombotic therapy, antiplatelet therapy, anticoagulant therapy, transcatheter aortic valve implantation, transcatheter aortic valve replacement, aortic stenosis Disclosure: JLF has received honoraria for lectures from Eli Lilly, Daiichi Sankyo, AstraZeneca, Roche Diagnostics, Pfizer, Abbott, Boehringer Ingelheim and Bristol-Myers Squibb; consulting fees from AstraZeneca, Eli Lilly, Ferrer, Boston Scientific and Pfizer; and research grants from AstraZeneca. LML has received a grant from the National Council on Science and Technology, Mexico (CONACYT). All other authors have no conflicts of interest to declare. Received: 19 July 2019 Accepted: 10 October 2019 Citation: European Cardiology Review 2020;15:e09. DOI: https://doi.org/10.15420/ecr.2019.10 Correspondence: José Luis Ferreiro, Heart Diseases Institute, Bellvitge University Hospital – IDIBELL, Feixa Llarga St, 08907, L’Hospitalet de Llobregat, Barcelona, Spain. E: jlferreiro@bellvitgehospital.cat Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Transcatheter aortic valve implantation (TAVI) is the therapy of choice for patients with symptomatic severe aortic stenosis who are unsuitable for surgical aortic valve replacement and for elderly patients with high operative risk.1,2 It is also considered to be a more than valid and reasonable alternative to surgical aortic valve replacement for patients with moderate to high surgical risk.3,4 Of note, two recently published trials assessing TAVI in low-risk patients have shown that TAVI is at least non-inferior and is likely to be superior to surgery in major outcomes in this scenario.5,6 Overall, these findings suggest that indications for TAVI will be expanded and the number of patients treated with this technique will continue to grow exponentially in the near future. Improvements in patient assessment, new generation devices and greater operators’ experience have certainly contributed to an increase in the efficacy and safety of the procedure over the years. Despite this, thromboembolic and bleeding complications after TAVI remain prevalent and affect morbidity and mortality. Indeed, TAVI interventions are associated with the occurrence of thrombotic and haemorrhagic events, which can occur periprocedurally or during the short- or longterm follow up after the index procedure.7,8 Given the observed important rise in the number of interventions, it is of utmost relevance to determine the optimal antithrombotic strategy after TAVI. In this scenario, an accurate assessment of the balance between thrombotic and bleeding risk, which can be augmented if an unnecessarily potent

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antithrombotic regimen is chosen, is critical. The aim of this article is to provide a brief and comprehensive overview of the current status of knowledge on antithrombotic treatment strategies following TAVI procedures, focusing on guidelines recommendations and the available evidence to support them, and of currently on-going trials that are evaluating different antithrombotic regimens in this scenario.

Adverse Events After Transcatheter Aortic Valve Implantation Both thromboembolic and bleeding events after TAVI are major concerns due to their prognostic impact. These complications may be associated with procedural issues, but also with underlying risk factors in the long term, taking into consideration that these procedures are often performed in elderly and frail patients with several comorbidities. Early thromboembolic events can be considered mainly procedural, and due to device positioning and implantation. Periprocedural complications include cerebrovascular events (CVEs), systemic embolisation and MI. Of note, several factors and phenomena occurring during TAVI and in the early postprocedural period contribute to create a prothrombotic environment. These include: native leaflets are not removed and may be mechanically damaged during TAVI, which may lead to embolisation of small valve fragments and to the exposure in the bloodstream of molecules that help increasing thrombogenicity

Antithrombotic Therapy After TAVI and inflammation (unlike normal valves, stenotic valve leaflets are rich in tissue factor and thrombin); changes in the flow patterns that may predispose to thrombus formation; and other mechanisms occurring during positioning and implantation (aortic wall injury, air embolism, rapid pacing or haemodynamic instability that may lead to cerebral hypoperfusion, etc.).7–10 CVEs are undoubtedly among the most feared complications of TAVI, since they have a considerable impact on morbidity and mortality.11–13 The greatest risk of suffering a clinically apparent stroke is within 24–48 hours after TAVI, but remains high for up to 2–3 months. The rates of CVEs (including transient ischaemic attacks and strokes) are highly variable among published studies, ranging from approximately 2–6% at 30 days, and reaching 7–9% at 1 year of follow-up.11,13 Acute events can be clearly attributed to procedural issues (i.e. device manipulation, repeated positioning or post-valve deployment balloon dilatation), whereas the main underlying cause of subacute (1–30 days) and late (>30 days) events is the presence of AF. The prevalence of AF among TAVI candidates (usually elderly patients) ranges approximately 20– 50%, and is the major predictor of late CVEs in this population.14,15 In addition, 10–30% of patients develop new-onset AF after TAVI, which is less frequent with the transfemoral approach. Remarkably, newonset AF is often undiagnosed, and it represents an important predictor of subacute CVEs. Overall, TAVI patients with AF have a high baseline cardioembolic risk, and both pre-existing and new-onset AF appear to be associated not only with CVEs, but also with mortality, although controversial results can be found in the scientific literature.14–17 Therefore, efforts should be made to properly diagnose and treat AF, which may frequently require chronic anticoagulation therapy, in this subset of patients. The incidence of MI after TAVI is relatively low (1–2%) and mostly restricted to the periprocedural period, thus, it may reflect myocardial injury during the procedure. A higher degree of myocardial injury has been associated with increased mortality in some studies, but other investigations failed to observe a prognostic impact in TAVI patients.18–21 Nevertheless, it is relevant to identify coronary artery disease in TAVI candidates, since both conditions frequently coexist (30–70%) and the severity of coronary artery disease might impact prognosis after TAVI.22–24 The decision about revascularisation, its completeness and timing (staged or concomitant procedures) should be made on a case-by-case basis for patients undergoing TAVI. Regardless, a period of dual antiplatelet therapy (DAPT) after coronary revascularisation is mandatory, which has also evident implications in the decision-making process of selecting the antithrombotic treatment regimen after TAVI.25,26 The spectrum of bioprosthetic leaflet thrombosis comprises subclinical imaging findings, such as early reduced leaflet motion and hypoattenuated leaflet thickening, to clinically apparent valve thrombosis with elevated gradients and clinical manifestations (i.e. heart failure, valve dysfunction and stroke or systemic embolisms).27,28 Its pathogenesis is not completely known, although several mechanisms are involved, including surface, haemostatic and haemodynamic factors.29 The presence of hypoattenuated leaflet thickening and reduced leaflet motion is not infrequent after TAVI (up to 10–15% of cases). A retrospective observational study reported that reduced leaflet motion could be associated with a higher risk of stroke.30 However, it remains uncertain whether these imaging abnormalities are clinically meaningful

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or just represent a subclinical finding. Fortunately, clinical valve thrombosis is an infrequent phenomenon with an estimated incidence of 0.03–0.07% per year,7 although a single-centre study reported an overall incidence of 2.8%, with a median time of diagnosis of approximately 6 months after the procedure.30 Of note, predictors of clinical valve thrombosis are the use of a balloon-expandable device (compared with self-expanding or mechanically expanded devices), a valve-in-valve procedure and treatment with antiplatelet agents alone.30 Interestingly, the use of oral anticoagulation (OAC) has consistently shown to be effective in reducing valve thickening and transvalvular gradients in the majority of cases of subclinical or clinical valve thrombosis, although the risk–benefit balance remains to be determined.28,30 Bleeding events also play a major role in short- and long-term prognosis after TAVI, and its severity can be categorised, for the sake of standardisation, according to the Valve Academic Research Consortium criteria.31 Indeed, early and late haemorrhagic events have a negative impact on cardiovascular mortality.32,33 Early (<30 days) major bleeding complications after TAVI are frequent (10–15%), and represent a strong independent predictor of early mortality.32 They are mostly due to vascular or access-site complications, with pericardial bleeding being less common. The improvement in operators’ experience and in new generation devices (reduction in sheaths size) is leading to a reduction in the events related with the procedural technique. Remarkably, late (>30 days) bleeding events are associated with an important increase in mortality risk of more than threefold.33 Regarding late outcomes, nonaccess-site bleeding has a greater impact on prognosis, with gastrointestinal haemorrhages being the most frequent location. Importantly, late bleeding complications may be attributed to the baseline risk of patients undergoing TAVI, but antithrombotic regimens also play a role in this vulnerable population.34

Antithrombotic Therapy There is clearly insufficient evidence nowadays regarding optimal adjunct antithrombotic therapy after TAVI, which is reflected in the large heterogeneity of drug regimens that are used in clinical practice.35 In fact, two different hypotheses – the antiplatelet and the antithrombin hypotheses – have been postulated to support the use of antiplatelet and anticoagulant agents, respectively. Unfortunately, it remains unclear whether thromboembolic complications after TAVI are mainly due to platelet- or thrombin-mediated clot formation. An accurate evaluation of the fine balance between a potential prevention of thromboembolic complications without unnecessarily increasing the risk of bleeding is crucial to determine the optimal antithrombotic therapy in this high-risk population (Figure 1). In this section, we summarise current guideline recommendations, most of them empirically based, and available evidence regarding the efficacy and safety of antiplatelet and anticoagulant agents after TAVI.

Guidelines Recommendations The recommendations of the European Society of Cardiology and American College of Cardiology/American Heart Association regarding antithrombotic therapy after TAVI are not uniform.1,2 This is far from surprising, as they are mostly based on relatively small non-randomised studies and expert consensus. Current guidelines recommendations on postprocedural antithrombotic strategies are summarised in Table 1. European guidelines advocate the use of DAPT with aspirin and clopidogrel for the first 3–6 months, followed by lifelong single

Pharmacotherapy Figure 1: Potential Complications and Putative Benefits and Limitations of Antithrombotic Strategies in Transcatheter Aortic Valve Implantation Patients

Cerebrovascular events

MI TAVI procedure

Antiplatelet Therapy: Available Evidence

Leaflet thrombosis

Bleeding events Antithrombotic therapy after TAVI No other indication for OAC

Other indication for OAC

• Lower risk of bleeding than DAPT or OAC • No differences with DAPT in ischaemic outcomes with available data

• Default strategy as per guidelines • Potential for reducing both CVEs and leaflet thrombosis • If AF, DOACs can also be used • Empirical, but mostly widely used (unclear if more beneficial OAC strategy (default strategy as per than VKA) • Limitation: high bleeding DAPT guidelines) • May be necessary if recent ACS or PCI risk population • No clear benefit over SAPT • No clear benefit over OAC • Potential benefit or reducing leaflet OAC • Increases rick of bleeding + thrombosis and valve dysfunction OAC • May be necessary in APT • No evidence so far of fewer comorbidities that require APT CVEs compared with APT • Increases risk of bleeding SAPT

ACS = acute coronary syndrome; APT = antiplatelet therapy; CVE = cerebrovascular event; DAPT = dual antiplatelet therapy (aspirin + clopidogrel); DOAC = direct oral anticoagulant; OAC = oral anticoagulation; PCI = percutaneous coronary intervention; SAPT = single antiplatelet therapy; TAVI = transcatheter aortic valve implantation; VKA = vitamin K antagonist.

Table 1. Summary of Current Guidelines Recommendations for Antithrombotic Therapy After Transcatheter Aortic Valve Implantation Class and Level of Evidence

Guideline

Recommendations

ESC/EACTS guidelines (2017)

Dual antiplatelet therapy should be IIa, C considered for the first 3–6 months after TAVI, followed by lifelong single antiplatelet therapy in patients who do not need oral anticoagulation for other reasons Single antiplatelet therapy may be IIa, C considered after TAVI in the case of high bleeding risk

ACC/AHA guidelines (2017 Update)

antiplatelet therapy (SAPT) as the default strategy for patients without any other indication for OAC, whereas SAPT may be considered for patients with high bleeding risk.1 US guidelines suggest DAPT with clopidogrel for the first 6 months in addition to lifelong aspirin, whereas OAC with a vitamin K antagonist (VKA) is proposed for at least 3 months after TAVI for patients at low risk of bleeding to diminish the risk of valve thrombosis.2 Both guidelines agree in recommending lifelong OAC for patients with other indications for OAC (the most frequent being AF), although no clear statement is provided with regards to the need for concomitant antiplatelet therapy in these patients.1,2

Clopidogrel 75 mg daily may be IIb, B-NR reasonable for the first 6 months after TAVR in addition to life-long aspirin 75 mg to 100 mg daily Anticoagulation with a VKA to achieve an IIb, C INR of 2.5 may be reasonable for at least 3 months after TAVR in patients at low risk of bleeding

ACC = American College of Cardiology; AHA: American Heart Association; EACTS = European Association for Cardio-Thoracic Surgery; ESC = European Society of Cardiology; INR = international normalised ratio; TAVI = transcatheter aortic valve implantation; TAVR = transcatheter aortic valve replacement.

The most widely adopted postprocedural antithrombotic regimen for TAVI patients, in the absence of an indication for OAC, is DAPT with aspirin (indefinitely) and clopidogrel (3–6 months). This strategy is empirical and based, first and foremost, on current recommendations for patients undergoing percutaneous coronary interventions.25 Further, anatomopathological analyses have suggested that neointimal tissue invasion and full endothelialisation of the valve stent frame occur approximately 3 months after the procedure, with a decrease in thromboembolic events thereafter, which might support this antithrombotic strategy.36 Recent evidence, however, has questioned the usefulness and safety of DAPT over SAPT with aspirin. Three small randomised trials have compared DAPT (3 or 6 months) with aspirin monotherapy after TAVI (Figure 2).37–39 None of them found a significant benefit of DAPT in terms of the prevention of thromboembolic events, although the studies were clearly not powered to detect differences in ischaemic outcomes due to their small sample size. The Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation (ARTE) trial was the largest of these studies. ARTE compared 3 months of DAPT with SAPT plus aspirin in 222 patients with no indication for OAC after implantation of a balloon-expandable device, although it was stopped prematurely due to funding issues and slow recruitment.39 The net primary endpoint (death, MI, stroke or transient ischaemic attack, or major or life-threatening bleeding) numerically tended to occur more frequently in the DAPT group (15.3% versus 7.2%; p=0.065) at 3 months after the procedure. Of note, no statistically significant differences were observed in individual ischaemic endpoints or mortality, whereas DAPT was associated with a greater rate of major or life-threatening bleeding events compared with SAPT (10.8% versus 3.6%; p=0.038).39 This was corroborated in a patient-level meta-analysis of these three randomised trials (n=421), in which DAPT was associated with a higher risk of major or life-threatening bleeding events compared with aspirin monotherapy at 30 days of follow up (11.4% versus 5.2%; OR 2.24; 95% CI [1.12–4.46]; p=0.022) without showing any beneficial effect on ischaemic events.40 A recently published mechanistic investigation showed a better pharmacodynamic efficacy of ticagrelor compared with clopidogrel (both in association with aspirin) in TAVI patients with suboptimal response to clopidogrel, as measured with the VerifyNow PRUTest (Werfen). The study was not powered to evaluate differences in clinical endpoints, and the high level of platelet inhibition achieved with ticagrelor should actually suggest caution before prescribing a potent antiplatelet agent in this elderly population with a high risk of bleeding.

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Antithrombotic Therapy After TAVI Figure 2: Outcomes of Randomised Clinical Trials Comparing Dual Versus Single Antiplatelet Therapy with Aspirin After Transcatheter Aortic Valve Implantation A

Ischaemic events (all-cause death, stroke or TIA, or MI)

Major or life-threatening bleeding

20 17.9

15.0

15 11.7

8.3

10.8

10.0 7.7

4.5

3.3

8.3

3.6

0 Ussia et al.

SAT-TAVI DAPT

ARTE

Ussia et al.

Aspirin

SAT-TAVI DAPT

ARTE

Aspirin

A: Ischaemic events (all-cause death, stroke or transient ischaemic attack, or MI) outcomes at 30 days. B: Major or life-threatening bleeding at 30 days.37â&#x20AC;&#x201C;39 DAPT = dual antiplatelet therapy (aspirin and clopidogrel); TAVI = transcatheter aortic valve implantation; TIA = transient ischaemic attack.

Nevertheless, an interesting reflection can be drawn from this trial, as a very high percentage of suboptimal responders to clopidogrel (>70%) was observed and, thus, it questions again the usefulness of the addition of clopidogrel to aspirin in this setting.41 Overall, cumulative data from observational and small randomised investigations considered together do not support current common practice of DAPT after TAVI, as it has not been proven superior in reducing thromboembolic events compared with SAPT with aspirin, which could be a safer and similarly effective option.42 Some on-going trials that are mentioned below are presently testing this hypothesis and will provide important insights on the subject.

Anticoagulant Therapy: Available Evidence The above-mentioned effectiveness of OAC in preventing and treating subclinical and clinical leaflet thrombosis that has been reported in observational studies has provided the rationale for suggesting an OAC-based strategy after TAVI, as recommended in the US guidelines.2,28,30 However, the evidence supporting this recommendation is weak and several doubts may arise, such as the duration of OAC that should be prescribed, the actual prognostic relevance of subclinical leaflet thrombosis or, more importantly, the impact on haemorrhagic events. Interestingly, in a recent report of the large nationwide FRANCE-TAVI registry, OAC at discharge (administered to >70% of cases due to AF) was independently associated with a lower risk of valve dysfunction and, conversely, with a higher risk of all-cause mortality.43 Indeed, the uncertainty of the trade-off between the potential benefit of preventing an infrequent entity, such as clinical valve thrombosis, and the potential harm of prolonged OAC in patients without AF precludes the use of long-term OAC as a default strategy for patients undergoing TAVI. The management of antithrombotic therapy after TAVI for patients with other indications for long-term OAC, with AF being the most frequent aetiology, is particularly challenging. As commented previously, the presence of AF is very common in patients undergoing TAVI, and is associated with an increased risk of cerebrovascular events and

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mortality.14,17 Of note, the addition of antiplatelet therapy to OAC does not appear to reduce the incidence of thromboembolic events and actually increases the risk of major or life-threatening bleeding.44,45 Hence, if no other reason for associating antiplatelet agents is present (e.g. recent percutaneous coronary intervention), available evidence suggests that OAC alone without concomitant antiplatelet therapy may be the preferred antithrombotic treatment for TAVI patients with AF. The use of direct oral anticoagulants (DOACs) appears particularly attractive due to their favourable safety profile when compared with VKA, particularly for patients at high risk of bleeding or if combination with antiplatelet drugs is required.46,47 However, the evidence regarding the usefulness of DOACs after TAVI is extremely scarce to date, and is mostly based on small subgroup analyses of observational studies. According to available data, DOACs may have a similar efficacy as VKA in preventing thromboembolic events after TAVI, and also for treatment of subclinical leaflet thrombosis.28,48 A small study even suggested that apixaban might confer a benefit (composite endpoint at 30 days of all-cause mortality, all stroke, lifethreatening bleeding, acute kidney injury, coronary obstruction, major vascular complications and valve dysfunction requiring re-intervention) compared with VKA for patients with AF after transfemoral TAVI.49 Conversely, a recently published multicentre registry evaluating the impact of the type of anticoagulant agent for TAVI patients (n=962) in need of OAC therapy showed a higher risk of ischaemic events (composite endpoint of all-cause mortality, MI and any cerebrovascular event) with the use of DOACs compared with VKA at 1 year of follow up without noticing differences in bleeding risk.50 Hence, further investigations are warranted to determine the true usefulness of DOACs in this scenario and, in fact, several on-going studies are evaluating the efficacy and safety of DOACs for TAVI patients with and without other indications for OAC.

On-going Studies Current recommendations of practice guidelines regarding antithrombotic therapy after TAVI, as previously mentioned, are not fully evidence based. However, this is a very active field of research

Pharmacotherapy Figure 3: On-going Randomised Trials Evaluating Antithrombotic Strategies After Transcatheter Aortic Valve Implantation TAVI patients

With or without other indication for OAC

No other indication for OAC

Antiplatelet-based strategies PTOLEMAIOS

(aspirin + ticagrelor versus aspirin + clopidogrel)

TIC TAVI

(ticagrelor versus aspirin+ clopidogrel)

Anticoagulant-based strategies GALILEO

(aspirin + rivaroxaban versus aspirin + clopidogrel)

AUREA

Antiplatelet and anticoagulant-based strategies POPular-TAVI

(aspirin + clopidogrel versus aspirin/ OAC + clopidogrel versus OAC)

(VKA versus aspirin + clopidogrel)

Anticoagulant-based strategies ATLANTIS

(apixaban versus aspirin + clopidogrel/ apixaban versus VKA)

Other indication for OAC

Anticoagulant-based strategies AVATAR

(OAC versus aspirin + OAC)

ENVISAGE-TAVI AF (edoxaban versus VKA)

ADAPT-TAVR

(edoxaban versus aspirin + clopidogrel)

LRT 2.0

(aspirin + VKA versus aspirin)

Trials are classified according to the presence or absence of an indication other than transcatheter aortic valve implantation for oral anticoagulation in the study population and to the type of antithrombotic strategy tested in the experimental arm of each study. Only trials registered on ClinicalTrials.gov are included in the figure. OAC = oral anticoagulation; TAVI = transcatheter aortic valve implantation; VKA = vitamin K antagonist.

with several on-going randomised trials (Figure 3). A detailed description of these investigations is beyond the scope of this article, but it is worthwhile commenting briefly on some of them due to their special interest (Table 2). The Antiplatelet Therapy for Patients Undergoing Transcatheter Aortic Valve Implantation (POPular-TAVI; NCT02247128) trial will provide important insights into the management of antithrombotic treatment for TAVI patients. POPular-TAVI will assess the safety in terms of bleeding (primary endpoint) and the efficacy of the following regimens: aspirin monotherapy compared with DAPT with aspirin plus clopidogrel in a cohort of patients without an indication for OAC prior to TAVI (n=684); and OAC alone compared with OAC plus clopidogrel in a cohort of patients with an indication for OAC prior to TAVI (n=316). In patients without other indications for OAC, some small studies are evaluating the possible benefit of ticagrelor in this scenario, either in association with aspirin, in the Trial to Assess the Safety and Efficacy of Prophylactic TicagrelOr With Acetylsalicylic Acid Versus CLopidogrel With Acetylsalicylic Acid in the Development of Cerebrovascular EMbolic Events During TAVI (PTOLEMAIOS; NCT02989558) trial, or in monotherapy in the Safety Profile Evaluation of TICagrelor Alone Compared to a Combination of Lysine Acetylsalicylate-Clopidogrel in the Context of Transcatheter Aortic Valve Implantation (TICTAVI; NCT02817789) study. Several studies are trying to assess the usefulness of anticoagulationbased strategies in TAVI patients without any other known indication for OAC. Of note, the Global Study Comparing a rivAroxaban-based Antithrombotic Strategy to an antipLatelet-based Strategy After Transcatheter aortIc vaLve rEplacement to Optimize Clinical Outcomes

(GALILEO; NCT02556203) trial, which was evaluating the usefulness of a reduced dose of rivaroxaban (10 mg daily) in association with aspirin compared with standard DAPT, had to be prematurely terminated after enrolling 1,644 patients due to increased risks of all-cause mortality, thromboembolic events and bleeding in the rivaroxaban arm. The study has been recently published and its findings evidently cast doubts on the need for anticoagulant therapy in TAVI patients without any other indication for OAC (e.g. AF, mechanic valves, etc.).51 Other small-scale investigations will provide more information into the matter, such as the Dual Antiplatelet Therapy Versus Oral Anticoagulation for a Short Time to Prevent Cerebral Embolism After TAVI (AUREA; NCT01642134) and the Anticoagulant Versus Dual Antiplatelet Therapy for Preventing Leaflet Thrombosis and Cerebral Embolisation After Transcatheter Aortic Valve Replacement (ADAPTTAVR; NCT03284827) trials, which are comparing the effectiveness of VKA and edoxaban in monotherapy, respectively, versus standard DAPT with aspirin and clopidogrel. Of note, the results of the AUREA trial have been recently reported (but not published at the time this manuscript was written), showing that OAC with VKA failed to reduce the incidence of new subclinical ischaemic cerebral lesions, assessed by magnetic resonance imaging at 6 days and 3 months after TAVI, when compared with DAPT. Another small study, the Strategies to Prevent Transcatheter Heart Valve Dysfunction in Low Risk Transcatheter Aortic Valve Replacement (LRT 2.0; NCT03557242), is evaluating the effect of adding VKA to aspirin compared with aspirin monotherapy. Two relevant large trials are presently exploring the usefulness of DOACs following TAVI: the Anti-Thrombotic Strategy After Trans-Aortic

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Antithrombotic Therapy After TAVI Table 2. Ongoing Randomised Clinical Trials of Antithrombotic Therapy in Transcatheter Aortic Valve Implantation Patients

Trial

Estimated Treatment Arms Enrolment

Key Inclusion and Exclusion Criteria Primary Outcome

PTOLEMAIOS (NCT02989558)

Aspirin + ticagrelor versus Inclusion: TAVI patients with high risk aspirin + clopidogrel (EuroSCORE ≥18 or considered inoperable) for surgical valve replacement Exclusion: Any condition requiring the use of anticoagulants

Confirmed high intensity transient signals as assessed with transcranial Doppler between the two groups during the TAVI procedure

TICTAVI (NCT02817789)

308

Ticagrelor versus aspirin + Inclusion: Patient eligible for TAVI as clopidogrel recommended by French healthcare system authority Exclusion: Need for chronic anticoagulation or previous PCI or ACS requiring DAPT

VARC2 composite endpoint (all-cause mortality, all stroke, life-threatening or disabling bleeding, acute kidney injury, coronary artery obstruction requiring intervention, major vascular complication, valve-related dysfunction requiring a new procedure) at 30 days

GALILEO (NCT02556203)

1,644*

Aspirin + rivaroxaban versus aspirin + clopidogrel

Inclusion: Successful TAVI of an aortic valve stenosis (either native of valve-in-valve) Exclusion: Any indication for continued treatment with any OAC and any ongoing absolute indication for DAPT unrelated to the TAVI procedure

Efficacy: Composite of all-cause death and adjudicated any stroke, MI, symptomatic valve thrombosis, pulmonary embolism, deep vein thrombosis, or symptomatic valve thrombosis at 25 months. Safety: Composite of life-threatening or disabling bleeding (BARC types 5 and 3b/3c) or major bleeding (BARC type 3a) at 25 months

AUREA (NCT01642134)

123†

VKA versus aspirin + clopidogrel

Inclusion: TAVI patients with symptomatic New areas of cerebral infarction by MRI 3 months degenerative severe aortic stenosis after TAVI rejected for conventional surgical aortic valve replacement due to unacceptable high risk Exclusion: Patients on chronic OAC treatment or those that cannot undergo DAPT or OAC for 3 months due to any new post-TAVI indication

ADAPT-TAVR (NCT03284827)

220

Edoxaban versus aspirin + Inclusion: Successful TAVI on either native clopidogrel valve or valve-in-valve with any approved/ marketed device Exclusion: Any indication for chronic OAC

Leaflet thrombosis on 4D, volume-rendered cardiac CT imaging at 6 months

LRT 2.0 (NCT03557242)

200

Aspirin + VKA versus aspirin

Inclusion: Low-risk (risk of death ≤3% by STS score) TAVI patients Exclusion: Other indications for OAC, bicuspid aortic valve or valve-in-valve procedures

Composite of all-cause mortality, all stroke, life-threatening and major bleeding, major vascular complications, hospitalisations for valve-related symptoms or worsening congestive heart failure, hypoattenuated leaflet thickening, at least moderately restricted leaflet motion or haemodynamic dysfunction at 30 days

POPular-TAVI (NCT02247128)

1,000

No prior OAC indication: Aspirin + clopidogrel versus aspirin Prior OAC indication: OAC + clopidogrel versus OAC

Inclusion: TAVI patients with and without other indication for long-term OAC. Exclusion: DES implantation or BMS implantation within 3 and 1 months prior to TAVI procedure, respectively

All (BARC) bleeding complications at 1 year after TAVI. Co-primary endpoint: Non-procedure related bleeding complications at 1 year after TAVI

ATLANTIS (NCT02664649)

1,510

No prior OAC indication: apixaban versus aspirin ± clopidogrel Prior OAC indication: apixaban versus VKA

Inclusion: Patients undergoing a clinically successful TAVI procedure Exclusion: Mechanical heart valve or necessary use of prasugrel or ticagrelor

Composite of death, MI, stroke, systemic embolism, intracardiac or bioprosthesis thrombus, any episode of deep vein thrombosis or pulmonary embolism, life-threatening or disabling or major bleeding at 1 year

AVATAR (NCT02735902)

170

OAC versus aspirin + OAC

Inclusion: Successful TAVI in patients requiring OAC Exclusion: Coronary stenting for less than 12 months and patients with high risk of bleeding

Composite of death from any cause, myocardial infarction, stroke all causes, valve thrombosis and haemorrhage ≥2 as defined by the VARC 2 at 12 months

ENVISAGE-TAVI AF (NCT02943785)

1,400

Edoxaban versus VKA

Inclusion: Successful TAVI in patients requiring OAC due to AF Exclusion: Comorbidities at high risk of bleeding

Composite of all-cause death, myocardial infarction), ischemic stroke, systemic embolic events, valve thrombosis, and ISTH major bleeding at 36 months. Co-primary endpoint: ISTH major bleeding at 36 months

*Prematurely terminated. †Completed (presented but not yet published). ACS = acute coronary syndrome; BARC = Bleeding Academic Research Consortium; BMS = bare metal stent; DAPT = dual antiplatelet therapy; ISTH = International Society on Thrombosis and Haemostasis; OAC = oral anticoagulation; PCI = percutaneous coronary intervention; TAVI = transcatheter aortic valve implantation; VARC = Valve Academic Research Consortium; VKA = vitamin K antagonist.

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Pharmacotherapy Valve Implantation for Aortic Stenosis (ATLANTIS; NCT02664649) study is evaluating the efficacy and safety of full-dose apixaban 5 mg twice daily (dose adjustment according to the drug label) compared either with VKA in patients with an indication other than TAVI for OAC or with standard of care antiplatelet therapy (DAPT or SAPT) in subjects without OAC indication; and the Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients with Atrial Fibrillation (ENVISAGE TAVI AF; NCT02943785) trial, which is comparing an edoxaban-based regimen with a VKA-based regimen in AF patients with indication for OAC after TAVI. For patients with a concomitant indication for anticoagulation, the value, if any, of adding aspirin to OAC (VKA or DOAC) compared with OAC alone is being tested in the Anticoagulation Alone Versus Anticoagulation and Aspirin Following Transcatheter Aortic Valve Interventions (AVATAR; NCT02735902) trial. Finally, a significant proportion of AF patients undergoing TAVI is at increased risk of bleeding complications and, thus, may also have an absolute or relative contraindication for OAC. In this population, a nonpharmacological approach with concomitant TAVI and left atrial appendage occlusion could be an attractive option. The efficacy and safety of this strategy is being evaluated in the WATCHMAN for

10.

11.

12.

13.

aumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS B Guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739–91. https://doi.org/10.1093/eurheartj/ ehx391; PMID: 28886619. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;70:252–89. https://doi.org/10.1016/j. jacc.2017.03.011; PMID: 28315732. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609–20. https://doi.org/10.1056/ NEJMoa1514616; PMID: 27040324. Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or transcatheter aortic-valve replacement in intermediaterisk patients. N Engl J Med 2017;376:1321–31. https://doi. org/10.1056/NEJMoa1700456; PMID: 28304219. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aorticvalve replacement with a balloon-expandable valve in lowrisk patients. N Engl J Med 2019;380:1695–705. https://doi. org/10.1056/NEJMoa1814052; PMID: 30883058. Popma JJ, Deeb GM, Yakubov SJ, et al. Transcatheter aorticvalve replacement with a self-expanding valve in lowrisk patients. N Engl J Med 2019;380:1706–15. https://doi. org/10.1056/NEJMoa1816885; PMID: 30883053. Vranckx P, Windecker S, Welsh RC, et al. Thrombo-embolic prevention after transcatheter aortic valve implantation. Eur Heart J 2017;38:3341–50. https://doi.org/10.1093/eurheartj/ ehx390; PMID: 29020333. Ranasinghe MP, Peter K, McFadyen JD. Thromboembolic and Bleeding Complications in Transcatheter Aortic Valve Implantation: Insights on Mechanisms, Prophylaxis and Therapy. J Clin Med 2019;8:pii: E280. https://doi.org/10.3390/ jcm8020280; PMID: 30823621. Nusca A, Bressi E, Colaiori I, et al. Antiplatelet therapy in valvular and structural heart disease interventions. Cardiovasc Diagn Ther 2018;8:678–93. https://doi.org/10.21037/ cdt.2018.06.08; PMID: 30498690. Gargiulo G, Collet JP, Valgimigli M. Antithrombotic therapy in TAVI patients: changing concepts. EuroIntervention 2015;11 Suppl W:W92–5. https://doi.org/10.4244/EIJV11SWA28; PMID: 26384206. Bosmans J, Bleiziffer S, Gerckens U, et al. The incidence and predictors of early- and mid-term clinically relevant neurological events after transcatheter aortic valve replacement in real-world patients. J Am Coll Cardiol 2015;66:209–17. https://doi.org/10.1016/j.jacc.2015.05.025; PMID: 26184612. Tchetche D, Farah B, Misuraca L, et al. Cerebrovascular events post-transcatheter aortic valve replacement in a large cohort of patients: a FRANCE-2 registry substudy. JACC Cardiovasc Interv 2014;7:1138–45. https://doi.org/10.1016/j. jcin.2014.04.018; PMID: 25240554. Nombela-Franco L, Webb JG, de Jaegere PP, et al. Timing, predictive factors, and prognostic value of cerebrovascular events in a large cohort of patients undergoing transcatheter aortic valve implantation. Circulation 2012;126:3041–53.

Patients With Atrial Fibrillation Undergoing Transcatheter Aortic Valve Replacement (WATCH-TAVR; NCT03173534) and the Comparison of Left Atrial Appendage Occlusion Versus Standard Medical Therapy in Patients in AF Undergoing TAVI (TAVI/LAAO; NCT03088098) trials.

Conclusion The introduction of TAVI has represented an important breakthrough in cardiology and has changed the clinical practice for patients with aortic stenosis. Since the number of procedures is growing, it is crucial to determine the optimal antithrombotic therapy after TAVI, which to date remains a challenge due to the scarce available evidence. DAPT with aspirin and clopidogrel is the most commonly used strategy for patients without other indications for OAC, although recent evidence has questioned this approach, suggesting that SAPT with aspirin may be sufficient and less harmful in terms of bleeding in this setting. For patients with an indication for OAC other than TAVI (mostly AF), monotherapy with OAC appears to be the most suitable strategy. In the absence of contraindications, the use of DOACs in this scenario is appealing due to their better safety profile compared with VKA, but this hypothesis needs to be confirmed by dedicated studies. The results of several on-going trials will provide interesting insights on the subject in the upcoming years.

https://doi.org/10.1161/CIRCULATIONAHA.112.110981; PMID: 23149669. 14. T arantini G, Mojoli M, Urena M, et al. Atrial fibrillation in patients undergoing transcatheter aortic valve implantation: epidemiology, timing, predictors, and outcome. Eur Heart J 2017;38:1285–93. https://doi.org/10.1093/eurheartj/ehw456; PMID: 27744287. 15. Sannino A, Gargiulo G, Schiattarella GG, et al. A meta-analysis of the impact of pre-existing and new-onset atrial fibrillation on clinical outcomes in patients undergoing transcatheter aortic valve implantation. EuroIntervention 2016;12:e1047–56. https://doi.org/10.4244/EIJY15M11_12; PMID: 26610809. 16. Gargiulo G, Capodanno D, Sannino A, et al. New-onset atrial fibrillation and increased mortality after transcatheter aortic valve implantation: A causal or spurious association? Int J Cardiol 2016;203:264–6. https://doi.org/10.1016/j. ijcard.2015.10.133; PMID: 26519681. 17. Amat-Santos IJ, Rodés-Cabau J, Urena M, et al. Incidence, predictive factors, and prognostic value of new-onset atrial fibrillation following transcatheter aortic valve implantation. J Am Coll Cardiol 2012;59:178–88. https://doi.org/10.1016/j. jacc.2011.09.061; PMID: 22177537. 18. Paradis JM, Maniar HS, Lasala JM, et al. Clinical and functional outcomes associated with myocardial injury after transfemoral and transapical transcatheter aortic valve replacement: a subanalysis from the PARTNER trial (Placement of Aortic Transcatheter Valves). JACC Cardiovasc Interv 2015;8:1468–79. https://doi.org/10.1016/j. jcin.2015.06.018; PMID: 26404200. 19. Yong ZY, Wiegerinck EM, Boerlage-van Dijk K, et al. Predictors and prognostic value of myocardial injury during transcatheter aortic valve implantation. Circ Cardiovasc Interv 2012;5:415–23. https://doi.org/10.1161/ CIRCINTERVENTIONS.111.964882; PMID: 22668556. 20. Köhler WM, Freitag-Wolf S, Lambers M, et al. Preprocedural but not periprocedural high-sensitive troponin T levels predict outcome in patients undergoing transcatheter aortic valve implantation. Cardiovasc Ther 2016;34:385–96. https://doi. org/10.1111/1755-5922.12208; PMID: 27380819. 21. Nara Y, Watanabe Y, Kataoka A, et al. Incidence, predictors, and midterm clinical outcomes of myocardial injury after transcatheter aortic-valve implantation. Int Heart J 2018;59:1296–302. https://doi.org/10.1536/ihj.17-645; PMID: 30369574. 22. Stefanini GG, Stortecky S, Cao D, et al. Coronary artery disease severity and aortic stenosis: clinical outcomes according to SYNTAX score in patients undergoing transcatheter aortic valve implantation. Eur Heart J 2014;35:2530–40. https://doi.org/10.1093/eurheartj/ehu074; PMID: 24682843. 23. Witberg G, Lavi I, Harari E, et al. Effect of coronary artery disease severity and revascularization completeness on 2-year clinical outcomes in patients undergoing transcatether aortic valve replacement. Coron Artery Dis 2015;26:573–82. https://doi.org/10.1097/MCA.0000000000000284; PMID: 26180996. 24. Van Mieghem NM, van der Boon RM, Faqiri E, et al. Complete revascularization is not a prerequisite for success in current transcatheter aortic valve implantation practice. JACC

Cardiovasc Interv 2013;6:867–75. https://doi.org/10.1016/j. jcin.2013.04.015; PMID: 23871511. 25. L ugo LM, Ferreiro JL. Dual antiplatelet therapy after coronary stent implantation: Individualizing the optimal duration. J Cardiol 2018;72:94–104. https://doi.org/10.1016/j. jjcc.2018.03.001; PMID: 29602648. 26. Angiolillo DJ, Ferreiro JL. Antiplatelet and anticoagulant therapy for atherothrombotic disease: the role of current and emerging agents. Am J Cardiovasc Drugs 2013;13:233–50. https://doi.org/10.1007/s40256-013-0022-7; PMID: 23613159. 27. Makkar RR, Fontana G, Jilaihawi H, et al. Possible subclinical leaflet thrombosis in bioprosthetic aortic valves. N Engl J Med 2015;373:2015–24 https://doi.org/10.1056/NEJMoa1509233; PMID: 26436963. 28. Chakravarty T, Søndergaard L, Friedman J, et al. Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study. Lancet 2017;389:2383– 92. https://doi.org/10.1016/S0140-6736(17)30757-2; PMID: 28330690. 29. Dangas GD, Weitz JI, Giustino G, et al. Prosthetic heart valve thrombosis. J Am Coll Cardiol 2016;68:2670–89. https://doi. org/10.1016/j.jacc.2016.09.958; PMID: 27978952. 30. Jose J, Sulimov DS, El-Mawardy M, et al. Clinical bioprosthetic heart valve thrombosis after transcatheter aortic valve replacement: incidence, characteristics, and treatment outcomes. JACC Cardiovasc Interv 2017;10:686–97. https://doi. org/10.1016/j.jcin.2017.01.045; PMID: 28385406. 31. Kappetein AP, Head SJ, Généreux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol 2012;60:1438–54. https://doi.org/10.1016/j.jacc.2012.09.001; PMID: 23036636. 32. Généreux P, Cohen DJ, Williams MR, et al. Bleeding complications after surgical aortic valve replacement compared with transcatheter aortic valve replacement: insights from the PARTNER I Trial (Placement of Aortic Transcatheter Valve). J Am Coll Cardiol 2014;63:1100–9. https:// doi.org/10.1016/j.jacc.2013.10.058; PMID: 24291283. 33. Généreux P, Cohen DJ, Mack M, et al. Incidence, predictors, and prognostic impact of late bleeding complications after transcatheter aortic valve replacement. J Am Coll Cardiol 2014;64:2605–15. https://doi.org/10.1016/j.jacc.2014.08.052; PMID: 25524339. 34. Piccolo R, Pilgrim T, Franzone A, et al. Frequency, timing, and impact of access-site and non-access-site bleeding on mortality among patients undergoing transcatheter aortic valve replacement. JACC Cardiovasc Interv 2017;10:1436–46. https://doi.org/10.1016/j.jcin.2017.04.034; PMID: 28728657. 35. Cerrato E, Nombela-Franco L, Nazif TM, et al. Evaluation of current practices in transcatheter aortic valve implantation: the WRITTEN (WoRldwIde TAVI ExperieNce) survey. Int J Cardiol 2017;228:640–7. https://doi.org/10.1016/j.ijcard.2016.11.104; PMID: 27883975. 36. Noble S, Asgar A, Cartier R, et al. Anatomo-pathological analysis after CoreValve Revalving system implantation. EuroIntervention 2009;5:78–85. https://doi.org/10.4244/ EIJV5I1A12; PMID: 19577986. 37. Ussia GP, Scarabelli M, Mulè M, et al. Dual antiplatelet therapy

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Antithrombotic Therapy After TAVI

38.

39.

40.

41.

versus aspirin alone in patients undergoing transcatheter aortic valve implantation. Am J Cardiol 2011;108:1772–6. https://doi.org/10.1016/j.amjcard.2011.07.049; PMID: 21907949. Stabile E, Pucciarelli A, Cota L, et al. SAT-TAVI (single antiplatelet therapy for TAVI) study: a pilot randomized study comparing double to single antiplatelet therapy for transcatheter aortic valve implantation. Int J Cardiol 2014;174:624–7. https://doi.org/10.1016/j.ijcard.2014.04.170; PMID: 24809922. Rodés-Cabau J, Masson JB, Welsh RC, et al. Aspirin versus aspirin plus clopidogrel as antithrombotic treatment following transcatheter aortic valve replacement with a balloon-expandable valve: the ARTE (Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation) randomized clinical trial. JACC Cardiovasc Interv 2017;10:1357–65. https://doi.org/10.1016/j.jcin.2017.04.014; PMID: 28527771. Maes F, Stabile E, Ussia GP, et al. Meta-analysis comparing single versus dual antiplatelet therapy following transcatheter aortic valve implantation. Am J Cardiol 2018;122:310–5. https:// doi.org/10.1016/j.amjcard.2018.04.006; PMID: 29861051. Jimenez Diaz VA, Tello-Montoliu A, Moreno R, et al.

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42.

43.

44.

45.

Assessment of Platelet REACtivity After Transcatheter Aortic Valve Replacement: The REAC-TAVI Trial. JACC Cardiovasc Interv 2019;12:22–32. https://doi.org/10.1016/j.jcin.2018.10.005; PMID: 30621974. Hu X, Yang FY, Wang Y, et al. Single versus dual antiplatelet therapy after transcatheter aortic valve implantation: a systematic review and meta-analysis. Cardiology 2018;141:52– 65. https://doi.org/10.1159/000490307; PMID: 30368490. Overtchouk P, Guedeney P, Rouanet S, et al. Long-term mortality and early valve dysfunction according to anticoagulation use: the FRANCE TAVI Registry. J Am Coll Cardiol 2019;73:13–21. https://doi.org/10.1016/j. jacc.2018.08.1045; PMID: 30153483. Geis NA, Kiriakou C, Chorianopoulos E, et al. Feasibility and safety of vitamin K antagonist monotherapy in atrial fibrillation patients undergoing transcatheter aortic valve implantation. EuroIntervention 2017;12:2058–66. https://doi. org/10.4244/EIJ-D-15-00259; PMID: 28433958. Abdul-Jawad Altisent O, Durand E, Muñoz-García AJ, et al. Warfarin and antiplatelet therapy versus warfarin alone for treating patients with atrial fibrillation undergoing transcatheter aortic valve replacement. JACC Cardiovasc Interv 2016;9:1706–17. https://doi.org/10.1016/j.jcin.2016.06.025;

PMID: 27539691. 46. R uff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955–62. https://doi. org/10.1016/S0140-6736(13)62343-0; PMID: 24315724. 47. Ruiz-Nodar JM, Ferreiro JL. Antithrombotic therapy after percutaneous revascularization in patients on chronic oral anticoagulation treatment. REC Interv Cardiol 2019;1:41–50. https://doi.org/10.24875/RECICE.M19000010. 48. Geis NA, Kiriakou C, Chorianopoulos E, et al. NOAC monotherapy in patients with concomitant indications for oral anticoagulation undergoing transcatheter aortic valve implantation. Clin Res Cardiol 2018;107:799–806. https://doi. org/10.1007/s00392-018-1247-x; PMID: 29644411. 49. Seeger J, Gonska B, Rodewald C, et al. Apixaban in patients with atrial fibrillation after transfemoral aortic valve replacement. JACC Cardiovasc Interv 2017;10:66–74. https://doi. org/10.1016/j.jcin.2016.10.023; PMID: 27916486. 50. Jochheim D, Barbanti M, Capretti G, et al. Oral anticoagulant type and outcomes after transcatheter aortic valve replacement. JACC Cardiovasc Interv 2019;12:1566–76. https:// doi.org/10.1016/j.jcin.2019.03.003; PMID: 31202946.

Risk Factors and Cardiovascular Disease Prevention

Direct-acting Anticoagulants in Chronic Coronary Syndromes Emmanuel Sorbets1,2 and Philippe Gabriel Steg2,3,4,5,6 1. Hôtel-Dieu, Assistance Publique – Hôpitaux de Paris, Université de Paris, Paris, France; 2. Royal Brompton Hospital, National Heart and Lung Institute, Imperial College, London, UK; 3. Département Hospitalo-Universitaire FIRE, Paris, France; 4. Laboratory for Vascular Translational Science, INSERM U-1148, Paris, France; 5. French Alliance for Cardiovascular Clinical Trials, F-CRIN Network, France; 6. Université de Paris, Hôpital Bichat, Assistance Publique – Hôpitaux de Paris, Paris, France

Abstract Direct-acting oral anticoagulants (DOACs) are easier to use, safer than and as effective as vitamin K antagonists (VKA) in the treatment of non-valvular AF (NVAF). Because of their favourable safety profile and easier use than VKAs, DOACs as anti-thrombotic therapy may have a role in the management of chronic coronary syndromes (CCS). To date, few studies have evaluated DOACs in this setting. Initial studies have focused on patients receiving DOACs for NVAF undergoing acute or elective percutaneous coronary intervention who additionally require dual antiplatelet therapy (DAPT). Rivaroxaban 15 mg once daily plus a P2Y12 inhibitor compared with a VKA regimen was associated with a reduction of bleedings (HR 0.59; 95% CI [0.47–0.76]; p<0.001). Rivaroxaban 2.5 mg twice daily plus DAPT up to 12 months followed by rivaroxaban 15 mg once daily plus P2Y12 inhibitor showed similar results. Dabigatran 110 mg twice daily plus a P2Y12 inhibitor versus a VKA regimen was associated with a reduction of bleedings (HR 0.52; 95% CI [0.42–0.63]; p<0.001), after a mean follow-up of 14 months. A dabigatran 150 mg regimen showed similar results. Apixaban 5 mg twice daily plus a P2Y12 inhibitor versus a VKA regimen confirmed at 6 months the safety of DOACs with a reduction of bleedings (HR 0.69; 95% CI [0.58–0.81]; p<0.001 for non-inferiority and superiority). Edoxaban 60 mg once daily plus a P2Y12 inhibitor was non-inferior to a VKA regimen on bleeding outcomes (major bleeding or non-major clinically relevant non-major bleeding) after a 12-month follow-up (HR 0.83; 95% CI [0.65–1.05]; p=0.001 for non-inferiority; p=0.1154 for superiority). Meta-analysis of these four trials confirmed the safety of DOACs regarding bleeding outcomes, but showed a trend toward stent thrombosis for dual antithrombotic therapy using DOACs versus triple antithrombotic therapy using VKAs. DOACs may show promise in the management of high-risk patients with chronic coronary syndromes. In these patients, rivaroxaban 2.5 mg twice daily in addition to aspirin was shown to reduce the composite outcome of cardiovascular death, stroke or MI compared to aspirin alone (HR 0.76; 95% CI [0.66–0.86]; p<0.001). All-cause death, cardiovascular death and stroke were also significantly lower. This benefit was at the cost of an increase in non-fatal bleeding.

Keywords Chronic coronary syndromes, direct oral anticoagulants, secondary prevention, non-valvular AF, percutaneous coronary intervention Disclosure: ES has received fees for lecture and consulting from AstraZeneca, Bayer, BMS, MSD, Novartis, Roche Diagnostics and Servier. PGS discloses research grants from Bayer, Merck, Sanofi, and Servier and speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, BoehringerIngelheim, Bristol-Myers-Squibb, Lilly, Merck, Novartis, Novo-Nordisk, Pfizer, Regeneron, Sanofi and Servier. Received: 16 October 2018 Accepted: 23 October 2019 Citation: European Cardiology Review 2020;15:e10. DOI: https://doi.org/10.15420/ecr.2018.24.2 Correspondence: Gabriel Steg, Université de Paris, Hôpital Bichat, Assistance Publique – Hôpitaux de Paris, Paris, France. E: gabriel.steg@aphp.fr Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Despite improvements in the management of coronary artery disease over the last decades, ischaemic heart disease remains the leading cause of mortality worldwide and the leading cause of premature death.1,2 Patients with chronic coronary syndromes (CCS) encompass a heterogeneous population, including those with demonstrable coronary artery disease by anatomical testing or evidence of ischaemia, prior MI and prior revascularisation. Most patients with CCS are free of angina, but some may have demonstrable ischaemia (silent ischaemia).3 Antiplatelet therapy, particularly aspirin, remains the cornerstone of the management of CCS for the prevention of atherothrombotic events.4–6 Additional therapies to improve platelet inhibition and reduce ischaemic events have been developed, but are often associated with an increase in bleeding events. P2Y12 receptor inhibition by clopidogrel alone as a substitute for aspirin failed to improve ischaemic outcomes in the coronary artery disease population, and the combination of clopidogrel

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and aspirin increased bleeding.7,8 New P2Y12 inhibitors, such as prasugrel and ticagrelor, reduced the risk of major cardiovascular outcomes when used for over 1 year after MI, but also increased the risk of bleeding.9,10 Ongoing trials are evaluating which patients with CCS may benefit most from these new P2Y12 inhibitors.11,12 Vitamin K antagonists (VKAs) have been used for many decades in patients with coronary syndromes for the prevention of atherothrombotic events, showing effectiveness in reducing the recurrence of major cardiovascular outcomes.13,14 However, increased bleeding related to a narrow therapeutic index requiring long-term careful monitoring and dose adjustment has resulted in VKAs being replaced by aspirin.15 Direct-acting oral anticoagulants (DOACs) have a favourable benefit/risk ratio (i.e. ischaemia/bleeding ratio) and easier use than VKAs, which could impact on the management of CCS, in the same way they have

DOACs in Chronic Coronary Syndromes transformed the management of non-valvular AF (NVAF) and venous thromboembolism. To date, few studies have evaluated DOACs in this setting. Initial studies have focused on patients receiving DOACs for NVAF undergoing acute or elective percutaneous coronary intervention (PCI) who additionally required dual antiplatelet therapy (DAPT).

Direct-acting Oral Anticoagulants in Non-valvular AF and Percutaneous Coronary Intervention Almost 10% of patients with CCS also have AF.16,17 Of those with AF, 25–35% also have a coronary syndrome.18–20 PCI is commonly needed in patients with NVAF treated with DOACs. The management of anticoagulant and antiplatelet therapies may be challenging. Several studies have evaluated this scenario.

Rivaroxaban and the PIONEER AF-PCI Trial The Open-label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Patients With AF Who Undergo PCI (PIONEER AF-PCI) was the first randomised study to evaluate patients treated with either rivaroxaban or warfarin for NVAF who would also need DAPT after PCI.21 The primary outcome was safety (major bleeds, minor bleeds or bleeding requiring medical attention) and the secondary outcome was efficacy (composite of cardiovascular death, MI or stroke). Between 2013 and 2015, 2,124 patients with NVAF who had undergone PCI with stent placement were recruited. They were at a low thromboembolic risk (average CHA2DS2VASc score 1.6) and without any prior stroke or transient ischaemic attack (TIA) when enrolled. Almost half were known to have CCS. This open-label trial randomised patients in a 1:1:1 ratio to receive: • Rivaroxaban 15 mg once daily plus single antiplatelet therapy (SAPT) with a P2Y12 inhibitor (clopidogrel 75 mg once daily, ticagrelor 90 mg twice daily, or prasugrel 10 mg once daily) for 12 months. • Rivaroxaban 2.5 mg twice daily, with stratification to a prespecified duration of DAPT (for 1, 6 or 12 months) including low-dose aspirin (75–100 mg once daily) plus a P2Y12 inhibitor (clopidogrel 75 mg once daily, ticagrelor 90 mg twice daily, or prasugrel 10 mg once daily). After stopping aspirin, rivaroxaban was increased to 15 mg once daily (or 10 mg in the event of renal insufficiency) and the P2Y12 inhibitor was continued at the same dose. • VKA as the control group, with stratification to a prespecified duration of DAPT (given by each investigator; 1, 6 or 12 months), including low-dose aspirin (75–100 mg once daily) plus a P2Y12 inhibitor (clopidogrel 75 mg once daily, ticagrelor 90 mg twice daily or prasugrel 10 mg once daily).

Figure 1: PIONEER AF-PCI Trial: Inclusion and Main Exclusion Criteria and Study Design Inclusion criteria: • NVAF requiring a PCI Main exclusion criteria: • Previous stroke or transient ischaemic attack • Gastrointestinal bleeding <12 months Study design

Follow-up: 12 months n=709

Rivaroxaban 15 mg once daily + clopidogrel 75 mg once daily/ticagrelor 90 mg twice daily/prasugrel 10 mg once daily

n=709 Rivaroxaban 2.5 mg once daily + clopidogrel 75 mg once daily/ ticagrelor 90 mg twice daily/ Rivaroxaban 15 mg once daily prasugrel 10 mg once daily + aspirin 75–100 mg once daily + aspirin 75–100 mg once daily 1, 3, 6 months*

Randomisation ≤72 hours post-PCI 1:1:1 n=2,114

n=706 VKA (INR 2–3) + clopidogrel 75 mg once daily/ ticagrelor 90 mg twice daily/ prasugrel 10 mg once daily + aspirin 75–100 mg once daily 1, 3, 6 months

VKA (INR 2–3) + aspirin 75–100 mg once daily

*Aspirin as a third therapy prespecified for 1, 3 or 6 months INR = international normalised ratio; NVAF = non-valvular AF; PCI = percutaneous coronary intervention; VKA = vitamin K antagonist.

There was no significant difference in the secondary efficacy outcome between the arms and no more in-stent thrombosis in the two rivaroxaban regimens compared with the VKA regimen.23 Despite being an exploratory and underpowered study, the results of PIONEER-AF suggested an equivalence of rivaroxaban and VKA regimens.

Dabigatran and the RE-DUAL PCI Trial The non-inferiority Evaluation of Dual Therapy with Dabigatran vs. Triple Therapy with Warfarin in Patients with AF that Undergo a PCI With Stenting (RE-DUAL PCI) trial evaluated dabigatran in patients requiring oral anticoagulation for NVAF and DAPT for a PCI with stent insertion.24 In contrast to PIONEER AF-PCI, patients with stroke or TIA over 1 month previously were randomised. They were at a higher thromboembolic risk with a mean CHA2DS2-VASc score of 3.5. Between 2014 and 2016, 2,725 patients were enrolled. Nearly half were patients with CCS. This open-label trial randomised subjects to one of three regimens in a 1:1:1 ratio to receive:

Randomisation was done up to 72 hours after the PCI, with conventional DAPT (including loading doses) up to 72 hours. For each group, clopidogrel was the most common P2Y12 inhibitor, used in >93% of cases (Figure 1).

• Dabigatran 110 mg twice daily plus SAPT with either clopidogrel 75 mg once daily or ticagrelor 90 mg twice daily for the entire follow-up. • Dabigatran 150 mg twice daily plus SAPT with either clopidogrel 75 mg once daily or ticagrelor 90 mg twice daily, for the entire follow-up. • Warfarin, plus DAPT with aspirin <100 mg once daily and either clopidogrel 75 mg once daily or ticagrelor 90 mg twice daily. The duration of aspirin was 1 month for bare-metal stents and 3 months for drug-eluting stents.

At 12 months, the intention-to-treat analysis showed a significant reduction in bleeding for both rivaroxaban regimens compared with the VKA group. The HR for the primary safety composite outcome (including major bleeding, minor bleeding or bleeding requiring medical attention) was lower in the rivaroxaban 15 mg once daily regimen compared with the VKA regimen (HR 0.59; 95% CI [0.47–0.76]; p<0.001).22 The HR for the primary bleeding outcome was also lower in the rivaroxaban 2.5 mg twice daily group compared to the VKA regimen (HR 0.63; 95% CI [0.50– 0.80]; p<0.001).23

Randomisation was done up to 120 hours after the PCI, with conventional DAPT up to 120 hours after the index PCI. Clopidogrel was the most common P2Y12 inhibitor, used in almost 90% of cases. No prasugrel was used in this trial (Figure 2). Mean follow-up was 14 months. The primary composite endpoint was the occurrence of major bleeding or clinically relevant non-major bleeding.25 The intention-totreat analysis showed a significant reduction of bleeding in both dabigatran arms compared with warfarin. The HR for the primary bleeding outcome was lower in the 110 mg dabigatran + DAPT group

EUROPEAN CARDIOLOGY REVIEW

Risk Factors and Cardiovascular Disease Prevention Figure 2: RE-DUAL PCI Trial: Inclusion and Main Exclusion Criteria and Study Design

in each dabigatran regimen – for that purpose 8,500 patients would have needed to be enrolled as initially designed – it strongly suggested that DOAC strategies are as effective as VKA strategies.

Inclusion criteria: • NVAF requiring a PCI Main exclusion criteria: • Stroke or major bleeding ≤1 month Study design

Apixaban and the AUGUSTUS Trial

Mean follow-up: 14 months n=981

Dabigatran 110 mg twice daily + clopidogrel 75 mg once daily/ticagrelor 90 mg twice daily*

n=763 Randomisation ≤120 hours post-PCI 1:1:1 n=2,725

Dabigatran 150 mg twice daily + clopidogrel 75 mg once daily/ticagrelor 90 mg twice daily* n=981 Warfarin (INR 2–3) + clopidogrel 75 mg once daily/ ticagrelor 90 mg twice daily* + aspirin 100 mg once daily 1 or 3 months†

Warfarin (INR 2–3) + clopidogrel 75 mg once daily/ ticagrelor 90 mg twice daily*

*>86% clopidogrel Aspirin as a third therapy 1 month for bare-metal stent, 3 months for drug-eluting stent

†

INR = international normalised ratio; NVAF = non-valvular AF; PCI = percutaneous coronary intervention.

At 6 months, the primary safety outcome, including major and clinically relevant bleeding, was lower in the apixaban group versus warfarin: 241 (10.5%) versus 332 (14.7%), respectively (HR 0.69; 95% CI [0.58–0.81]; p<0.001 for non-inferiority and superiority). The incidence of bleeding was higher in the aspirin arm versus placebo (HR 1.89; 95% CI [1.59– 2.24]; p<0.001). No significant interaction was observed between the two randomisation factors.

Figure 3: AUGUSTUS Trial: Inclusion and Main Exclusion Criteria and Study Design Inclusion criteria: • NVAF requiring DOAC • ACS and/or PCI with planned P2Y12 inhibitor for 6 months Main exclusion criteria: • DOAC for other condition than NVAF • Severe renal insufficiency • Prior intracranial haemorrhage Study design

Follow-up: 6 months Aspirin Apixaban 5 mg twice daily* + P2Y12 inhibitor

n=2,306 Matched placebo

Randomisation ≤14 hours post ACS or PCI

Open-label

Double-blind

Aspirin

n= 4,614 Warfarin (INR 2–3) + P2Y12 inhibitor

n=2,308 Matched placebo

• Aspirin for all patients on day of ACS or PCI • P2Y12: >90% clopidogrel

The Apixaban Versus Warfarin in Patients with AF and Acute Coronary Syndrome or PCI (AUGUSTUS) trial, enrolled >4,600 patients with NVAF (mean CHA2DS2-VASc score 3.9) and without severe renal insufficiency within 14 days after an acute coronary syndrome and/or a PCI.27 They were randomised using a two-by-two factorial design to receive: apixaban (with usual doses) versus warfarin (open label) and aspirin 81 mg versus placebo (double blind) for 6 months (Figure 3). At 6 months, patients received antiplatelet and anticoagulant therapy according to the local standard of care. Clopidogrel was the main P2Y12 inhibitor used (92.6%). The median time from the index event (acute coronary syndrome or PCI) to randomisation was 6 days (interquartile range 3–10) while all patients received aspirin. A total of 37.3% had acute coronary syndrome and underwent PCI, 23.9% had medically managed acute coronary syndrome and 38.8% underwent elective PCI.

*Apixaban 5 mg twice daily or 2.5 mg twice daily according to usual guidelines in NVAF

ACS = acute coronary syndrome; DOAC = direct oral anti-coagulant; INR = international normalised ratio; NVAF = non-valvular AF; PCI = percutaneous coronary intervention.

than in the group receiving triple therapy with warfarin (HR 0.52; 95% CI [0.42–0.63]; p<0.001 for non-inferiority). Similarly it was lower in the dabigatran 150 mg + DAPT group (HR 0.72; 95% CI [0.58–0.88]; p<0.001 for non-inferiority) than in the group receiving triple therapy with warfarin. These results were consistent across several bleeding definitions.26 The composite efficacy endpoint of thromboembolic events (MI, stroke or systemic embolism), death, or unplanned revascularisation was similar between the treatment arms (HR 1.04; 95% CI [0.84–1.29]; p=0.005 for non-inferiority).26

The secondary outcome of a composite of all-cause death or all-cause hospitalisation was lower in the apixaban group versus warfarin: 541 (23.5%) versus 632 (27.4%), respectively (HR 0.83; 95% CI [0.74–0.93]; p=0.002). This was driven by a lower incidence of hospitalisation and stroke. This secondary outcome was similar in the aspirin versus placebo arm (HR 1.08; 95% CI [0.96–1.21]). There was no interaction between the two randomisation factors. All-cause death, MI and urgent PCI were similar between groups. Thus, the AUGUSTUS trial further supported the safety of DOAC compared with warfarin in patients with NVAF requiring PCI and the safety of adjunctive SAPT with a P2Y12 receptor antagonist over DAPT with aspirin. While this trial confirmed the beneficial effect of apixaban on stroke, it was insufficiently powered to demonstrate a different effect on coronary outcomes (recurrent MI, stent thrombosis and urgent PCI). Consequently, when concerns about coronary ischaemic risk prevail over concerns about bleeding risk, 1–6 months of triple therapy (oral anticoagulant + aspirin + clopidogrel) followed by dual therapy (oral anticoagulant + clopidogrel) are recommended to cover the period when the risk of stent thrombosis is presumed to exceed the risk of bleeding. When concerns about bleeding risk prevail over concerns about coronary ischaemic risk, a limited triple therapy ≤1 week (oral anticoagulant + aspirin + clopidogrel) followed by dual therapy (oral anticoagulant + clopidogrel) are recommended.28

Edoxaban and the ENTRUST AF-PCI Trial RE-DUAL PCI confirmed that dabigatran was safer than warfarin regarding the occurrence of bleeding. Despite this trial also being underpowered to completely rule out an increase of ischaemic events

The Edoxaban Treatment Versus Vitamin K Antagonist in Patients With AF Undergoing PCI (ENTRUST AF-PCI) trial assessed edoxaban in patients with NVAF requiring PCI (CHA2DS2-VASc score 4.0).29

EUROPEAN CARDIOLOGY REVIEW

DOACs in Chronic Coronary Syndromes Overall 1,506 patients (52% after an acute coronary syndrome and 48% after elective PCI) were randomised up to 5 days after PCI in two arms. The experimental regimen was edoxaban 60 mg once daily (or 30 mg once daily if creatinine clearance was ≤50 ml/min, weight was ≤60 kg, or if the patient received P-glycoprotein inhibitors). The control arm was triple therapy with VKA + P2Y12 inhibitor + low-dose aspirin (aspirin was prescribed from 1 to 12 months according to the ischaemic/ bleeding risk; Figure 4). After a 12-month follow-up, the primary outcome (major bleeding or nonmajor but clinically relevant bleeding) occurred in 128 of 751 patients (annualised event rate 20.7%) with the edoxaban regimen and 152 of 755 patients (annualised event rate 25.6%) patients with the VKA regimen, resulting in a HR of 0.83 (95% CI [0.65–1.05]; p=0.001 for non-inferiority; p=0.1154 for superiority) for edoxaban. At 12 months, there was no difference in the main efficacy endpoint (composite of cardiovascular death, stroke, systemic embolic events, MI, definite stent thrombosis) with an annualised event rate of 7.3% for patients receiving the edoxaban regimen compared with 6.9% for patients receiving the VKA regimen, resulting in a HR of 1.06 (95% CI [0.71–1.69]) for edoxaban. The ENTRUST AF-PCI trial was the fourth trial showing the safety of a dual therapy combining a DOAC with a P2Y12 inhibitor (mainly clopidogrel) on bleeding outcomes. However, this trial – similar to the three previously described – was underpowered to demonstrate a potential efficacy on ischaemic coronary events.

Figure 4: ENTRUST AF-PCI Trial: Inclusion and Main Exclusion Criteria and Study Design Inclusion criteria: • Successful PCI with stent (at least 25% of ACS) • NVAF requiring DOAC for at least 12 months Main exclusion criteria: • Known bleeding diathesis Study design

Follow-up: 12 months n=751

Randomisation 4 hours to 5 days after sheath removal

n=755

Edoxaban 60 mg once daily* + clopidogrel 75 mg once daily/ticagrelor 90 mg twice daily/prasugrel 10 mg once daily†

Open-label

Vitamin K antagonist + clopidogrel 75 mg once daily/ticagrelor 90 mg twice daily/prasugrel 10 mg once daily† Aspirin 1–12 months

* Edoxaban 30 mg once daily if: • CrCl ≤50 ml/min • Bodyweight ≤60 kg • P-gp inhibitors †

>90% clopidogrel

ACS = acute coronary syndrome; CrCl = creatinine clearance; DOAC = direct oral anti-coagulant; NVAF = non-valvular AF; PCI = percutaneous coronary intervention; P-gp = p-glycoprotein.

Meta-analysis of the Four Randomised Clinical Trials

demonstrate that dabigatran reduces inflammation, improves cell endothelial function, decreases oxidative stress and reduces atheromatous plaque initiation and progression.32,33 Similar findings have been reported for rivaroxaban.34,35

A meta-analysis of the four trials (PIONEER AF-PCI, RE-DUAL PCI, AUGUSTUS and ENTRUST AF-PCI) assessed the dual antithrombotic therapy using DOACs with SAPT versus triple antithrombotic therapy using VKA with DAPT.29 The results confirmed the safety of dual antithrombotic therapy with DOAC over triple antithrombotic therapy with VKA on bleeding outcomes with a risk ratio of 0.62 (95% CI [0.47– 0.81]; p=0.0005; Figure 5).

These experimental findings have yet to be translated clinically. In patients with NVAF, rivaroxaban treatment was associated with a lower total and calcified plaque volume evaluated by coronary CT angiography compared with warfarin, which may explain cardiovascular event reduction associated with rivaroxaban treatment.36 A similar study using apixaban is currently ongoing.37

This meta-analysis showed a trend towards an increased risk of stent thrombosis with a risk ratio of 1.55 (95% CI [0.99–2.41]; p=0.06) for dual antithrombotic therapy using DOACs versus triple antithrombotic therapy using VKA (Figure 5). These results are in line with European Society of Cardiology (ESC) guidelines, where aspirin in addition to clopidogrel is recommended after PCI for patients with oral anticoagulant (DOAC or VKA), with the duration of aspirin depending on the ischaemic and bleeding risks. One year after PCI, oral anticoagulant without antiplatelet therapy is recommended. 28

Direct-acting Oral Anticoagulants and Atherosclerotic Plaque Progression DOACs could become an additional treatment of the secondary prevention of CCS, not only because of their antithrombotic effect but also because of their potential to limit atheromatous plaque progression. Experimental data suggest that thrombin may have pleiotropic actions including inducing oxidative stress, increasing endothelial dysfunction, vascular inflammation, leucocyte adhesion, rolling, and migration on the activated endothelium and may participate in the early stages of atherosclerotic plaque formation as well as accelerating plaque progression and destabilisation.30,31 Experimental studies evaluating the effect of DOACs on the growth of the atherosclerotic plaque in hypercholesterolaemic ApoE−/− mice

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Direct-acting Oral Anticoagulants as Secondary Prevention in Chronic Coronary Syndromes The COMPASS Trial DOACs are easier to use, safer than and as effective as VKAs for thromboprophylaxis in patients with NVAF. Therefore, the question regarding the role of oral anticoagulants in the secondary prevention of atherothrombotic events has been raised. To date, the only published results in humans are for rivaroxaban. The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial evaluated whether low-dose rivaroxaban alone or in addition to aspirin was safer and more effective than aspirin monotherapy in stable cardiovascular disease.38 Between 2013 and 2016, this double-blind trial enrolled 27,395 patients with stable cardiovascular disease, including 90% with CCS and 27% with peripheral arterial disease (PAD). To be enrolled, patients had to be at a high cardiovascular risk. If patients were ≥65 years old, no additional inclusion criteria were needed. Patients <65 years old required the presence of atherosclerosis involving at least two vascular beds or two or more additional risk factors: current smoker, diabetes, moderate chronic renal insufficiency, heart failure or non-lacunar ischaemic stroke (≥1 month previously; Figure 6).

Risk Factors and Cardiovascular Disease Prevention Figure 5: Meta-analysis on the Safety and Efficacy of Dual-acting Antiplatelet Therapy + SAPT Versus Vitamin K Antagonist + Dual-acting Antiplatelet Therapy Major bleeding (ISTH) or clinically relevant non-major bleeding DOAC + SAPT Events/patients

VKA + DAPT Events/patients

Risk ratio (95% CI)

117/696

178/697

0.66 (0.53–0.81)

RE-DUAL PCI

305/1,744

264/981

0.65 (0.56–0.75)

AUGUSTUS

84/1,143

210/1,123

0.39 (0.31–0.50)

ENTRUST AF-PCI

128/751

152/755

0.85 (0.68–1.05)

804/3,556

0.62 (0.47–0.81)

PIONEER AF-PCI

Total

634/4,344

Heterogeneity: tau =0.07; chi =22.84, df=3 (p<0.0001); Test for overall effect: Z=3.47 (p=0.0005) 2

I2=87%

Risk ratio (95% CI)

0.1

Favours DOAC + SAPT

Favours VKA + DAPT

Stent thrombosis DOAC + SAPT Events/patients PIONEER AF-PCI

VKA + DAPT Events/patients

5/694

4/695

1.25 (0.34–4.64)

RE-DUAL PCI

22/1,744

8/981

1.55 (0.69–3.46)

AUGUSTUS

21/1,153

12/1,154

1.75 (0.87–3.54)

8/751

6/755

1.34 (0.47–3.84)

56/4,342

30/3,585

1.55 (0.99–2.41)

ENTRUST AF-PCI

Total

Heterogeneity: tau2=0.00; chi2=0.29, df=3 (p=0.96); I2=0% Test for overall effect: Z=1.92 (p=0.06)

Risk ratio (95% CI)

0.1

Favours DOAC + SAPT

DAPT = dual-acting antiplatelet therapy; DOAC = direct oral anti-coagulant; ISTH = International Society on Thrombosis and Haemostasis; SAPT = single antiplatelet therapy; VKA = vitamin K antagonist. Source: Adapted from Vranckx et al. 2019.29 Used with permission from Elsevier.

Figure 6: COMPASS Trial: Inclusion and Main Exclusion Criteria and Study Design

Inclusion criteria: • Stable CAD or PAD • If ≥65 years, no additional criterion • If <65 years: atherosclerosis in ≥2 vascular beds • If <65 or ≥2 additional risk factors: – current smoking – diabetes – eGFR <60 ml/min – heart failure – non-lacunar ischaemic stroke ≥1 month Main exclusion criteria: • Haemorrhagic or lacunar ischaemic stroke Study design n=9,152

Run-in (aspirin)

Randomisation 1:1:1 N=27,395

n=9,117

n=9,126

Rivaroxaban 2.5 mg twice daily + aspirin 100 mg once daily

Rivaroxaban 5 mg twice daily

Aspirin 100 mg once daily

Expected follow-up of 3–4 years Early termination with a mean follow-up of 23 months

CAD = coronary artery disease; eGFR = estimated glomerular filtration rate; PAD = peripheral artery disease.

Patients were randomised in a 1:1:1 ratio to receive one of the following three regimens: • Rivaroxaban 2.5 mg twice daily + aspirin 100 mg once daily, long term. • Rivaroxaban 5 mg twice daily, long term. • Aspirin 100 mg once daily (control). The study was prematurely stopped by the data safety monitoring board following interim analysis that showed a significant improvement in the primary composite endpoint, as well as all-cause death. The primary efficacy composite outcome of cardiovascular death, stroke or MI, was significantly lower in the rivaroxaban 2.5 mg twice daily + aspirin group than in the aspirin monotherapy group (4.1% and 5.4%, respectively; HR 0.76; 95% CI [0.66–0.86]; p<0.001). These results were driven by a decrease in cardiovascular death and stroke. The rate of all-cause death was also significantly lower (Figure 7).39 The main safety outcome was major bleeding defined by modified ISTH criteria including all bleeding that led to presentation at an acute care facility or hospitalisation. It was higher in the rivaroxaban 2.5 mg twice daily + aspirin group than in the aspirin monotherapy group (3.1% and 1.9%, respectively; HR 1.70; 95% CI [1.40–2.05]; p<0.001). This outcome was driven by bleeding leading to acute care facility presentation or blood transfusion. Importantly, there was no significant difference in the rate of fatal bleeding, intracranial bleeding, or symptomatic bleeding into a critical organ (Figure 7).39

EUROPEAN CARDIOLOGY REVIEW

DOACs in Chronic Coronary Syndromes The subjective net clinical benefit outcome taking into account cardiovascular death, stroke, MI, fatal bleeding or symptomatic bleeding into a critical organ was in favour of rivaroxaban + aspirin therapy (HR 0.80; 95% CI [0.70–0.91]; p<0.00.1; Figure 7) compared to aspirin alone.39 However, the benefit/risk ratio was unfavourable for rivaroxaban 5 mg twice-daily monotherapy compared with aspirin monotherapy. There was no significant improvement in the efficacy outcome but there was a significant increase in major bleeding, advocating against this strategy (Figure 7).39 The substudy of patients with CCS in the COMPASS trial, comprising 90.6% of the entire population and performed using the same design, showed similar results.40 Therefore, despite early termination – possibly overestimating the treatment effect – the findings of the COMPASS study suggested that rivaroxaban 2.5 mg twice daily may become an additional treatment for CCS in selected patients at high ischaemic risk.

Figure 7: Outcomes of the COMPASS Trial Rivaroxaban + aspirin versus aspirin HR (95% CI)

The main exclusion criteria were AF, recent acute MI or revascularisation (<21 days), stroke (<3 months), bleeding risk, anaemia (haemoglobin <8 g/dl) or thrombocytopaenia (platelets <50,000/µl). A total of 5,022 patients were enrolled from 2013 to 2017 in this double-blind multicentre trial, and randomly assigned to receive rivaroxaban 2.5 mg twice daily or placebo in addition to standard care therapy.There was no significant difference in the occurrence of the primary efficacy outcome (composite of MI, stroke and all-cause death) and the secondary safety outcome (fatal or major bleeding) over a median follow-up of 21.1 months.

Direct-acting Oral Anticoagulants in International Guidelines The 2019 ESC Guidelines for the diagnosis and management of CCS provide the following recommendations:28 • When oral anticoagulation is initiated in a patient with NVAF, a DOAC is recommended in preference to a VKA (recommendation IA). • Aspirin 75–100 mg daily (or clopidogrel 75 mg daily) may be considered in addition to long-term oral anticoagulant therapy in patients with NVAF and CCS at high risk of recurrent MI (prior MI, multivessel disease, diabetes, chronic kidney disease with estimated glomerular filtration rate <60 ml/min/1.73m2, PAD) NVAF, but not high risk of bleeding (recommendation IIaB). • For PCI in patients with DOAC, it is recommended that periprocedural aspirin and clopidogrel are administered to patients undergoing PCI (recommendation IC). • After PCI, in patients eligible for a DOAC, it is recommended that a DOAC (apixaban 5 mg twice daily, dabigatran 150 mg twice daily,

EUROPEAN CARDIOLOGY REVIEW

HR (95% CI)

0.76 (0.66 –0.86)

<0.001

0.90 (0.79–1.03)

0.12

0.82 (0.71–0.96) 0.78 (0.64–0.96) 0.86 (0.70–1.05) 0.58 (0.44–0.76)

0.01 0.02 0.14 <0.001

0.97 (0.97–1.12) 0.96 (0.79–1.17) 0.89 (0.73–1.08) 0.82 (0.65–1.05)

0.67 0.69 0.24 0.12

1.70 (1.40–2.05) 1.78 (1.41–2.23) 1.49 (0.67–3.33) 1.16 (0.67–2.00) 2.15 (1.60–2.89)

<0.001 <0.001 0.32 0.60 <0.001

1.51 (1.25–1.84) 1.52 (1.20–1.92) 1.40 (0.62–3.15) 1.95 (1.09–2.96) 1.40 (1.02–1.93)

<0.001 <0.001 0.41 0.02 0.04

Minor bleedings:

1.70 (1.52–1.90)

<0.001

1.50 (1.34–1.68)

<0.001

Net clinical benefit:

0.80 (0.70–0.91)

<0.001

0.94 (0.84–1.07)

0.36

Primary outcome: CV death, MI, stroke Secondary outcomes: All-cause death CV death MI Stroke Major bleedings: Modified ISTH criteria ISTH criteria Fatal bleeding Intracranial Gastrointestinal

* For secondary outcomes, prespecified significant p value <0.0025

CV = cardiovascular; ISTH = International Society on Thrombosis and Haemostasis.

The COMMANDER HF Trial Decompensated heart failure is associated with an activation of thrombin-related pathways. Thus, patients with CCS with worsening heart failure may be a subpopulation that benefits from the addition of a DOAC. The Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure (COMMANDER HF) assessed the association of low dose of rivaroxaban and aspirin in patients with CCS and chronic heart failure (left ventricular ejection fraction ≤40%) and recent decompensation.41

Rivaroxaban versus aspirin

•

edoxaban 60 mg once daily, or rivaroxaban 20 mg once daily) is used in preference to a VKA in combination with antiplatelet therapy (recommendation IA). After PCI, when rivaroxaban or dabigatran are used and concerns about high bleeding risk prevail over concerns about stent thrombosis or ischaemic stroke, lower DOAC doses should be considered for the duration of concomitant SAPT or DAPT as follows: rivaroxaban 15 mg once daily, dabigatran 110 mg twice daily (recommendation IIaB). After PCI, early cessation (≤1 week) of aspirin and continuation of dual therapy with an oral anticoagulant and clopidogrel should be considered if the risk of stent thrombosis is low, or if concerns about bleeding risk prevail over concerns about the risk of stent thrombosis irrespective of the type of stent used (recommendation IIaB). After PCI, triple therapy with aspirin, clopidogrel, and an oral anticoagulant for ≥1 month should be considered when the risk of stent thrombosis outweighs the bleeding risk, with the total duration (≤6 months) decided according to assessment of these risks (recommendation IIaC). The use of ticagrelor or prasugrel is not recommended as part of triple antithrombotic therapy with aspirin and an oral anticoagulant (recommendation III).

Conclusion In patients with NVAF treated with DOACs, switching to a VKA regimen is not required when a PCI is needed. Short-term triple antithrombotic therapy (DOAC + aspirin + clopidogrel) up to 3 months followed by dual antithrombotic therapy (DOAC + clopidogrel) up to 1 year seems to be the best strategy, compared with triple antithrombotic therapy (VKA + aspirin + clopidogrel). DOACS may become an accepted secondary prevention therapy as suggested by the COMPASS study. However, before DOACs become a cornerstone of the management of selected patients with CCS, further studies are needed to address some issues. Identifying which patients will derive the highest ischaemic benefit with the lowest haemorrhagic risk needs to be determined. The additional benefit on the recurrence of major cardiovascular events and death with rivaroxaban in such patients is offset by the higher rate of bleeding events. In that case patients should not move to this strategy, particularly if they are stable, asymptomatic and risk the occurrence of both major and minor bleeding.

Risk Factors and Cardiovascular Disease Prevention The potential use of DOACs in combination with new antiplatelet drugs is not known. Moreover adherence may be challenging because of the need for a twice-daily dosing regimen. All these factors will have to be discussed individually with each patient for optimal individualised care that improves both outcomes and quality of life (i.e. taking into consideration the ischaemia/bleeding ratio).

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13.

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aghavi M, Wang H, Lozano R, et al. Global, regional, and N national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015;385:117–71. https://doi.org/10.1016/S01406736(14)61682-2; PMID: 25530442. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006;3:e442. https://doi.org/10.1371/journal.pmed.0030442; PMID: 17132052. Sorbets E, Greenlaw N, Ferrari R, et al. Rationale, design and baseline characteristics of the CLARIFY registry of outpatients with stable coronary artery disease. Clin Cardiol 2017;40:797–806. https://doi.org/10.1002/clc.22730; PMID: 28561986. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34:2949–3003. https://doi.org/10.1093/ eurheartj/eht296; PMID: 23996286. Fihn SD, Gardin JM, Abrams J, et al. ACCF/AHA/ACP/AATS/ PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease. Circulation 2012;126:e354-471. https://doi.org/10.1161/ CIR.0b013e318277d6a0; PMID: 23166211. Antithrombotic Trialists Collaboration. Collaborative metaanalysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71–86. https://doi.org/10.1136/ bmj.324.7329.71; PMID: 11786451. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events. CAPRIE Steering Committee. Lancet 1996;348:1329–39. https://doi.org/10.1016/S0140-6736(96)09457-3; PMID: 8918275. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706–17. https://doi. org/10.1056/NEJMoa060989; PMID: 16531616. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155–66. https://doi.org/10.1056/NEJMoa1409312; PMID: 25399658. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791–800. https://doi.org/10.1056/ NEJMoa1500857; PMID: 25773268. Steg PG, Bhatt DL, Simon T, et al. Ticagrelor in patients with stable coronary disease and diabetes. N Engl J Med 2019;381:1309–20. https://doi.org/10.1056/NEJMoa1908077; PMID: 31475798. Bhatt DL, Steg PG, Mehta SR, et al. Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial. Lancet 2019;394:1169–80. https://doi.org/10.1016/S01406736(19)31887-2; PMID: 31484629. Anand SS, Yusuf S. Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis. JAMA 1999;282:2058–67. https://doi.org/10.1001/jama.282.21.2058; PMID: 10591389. Hurlen M, Abdelnoor M, Smith P, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med 2002;347:969–74. https://doi.org/10.1056/NEJMoa020496; PMID: 12324552. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849–60. https://doi.org/10.1016/S0140-

Another issue will be the cost of this additional new therapy. Given the high number patients potentially eligible for low dose rivaroxaban in addition to aspirin,42 the clinical/cost ratio compared with the low cost of the aspirin alone will have to be evaluated. This is particularly relevant given that the absolute risk reduction is quite low (the number needed to treat to avoid one primary outcome is 77).

6736(09)60503-1; PMID: 19482214. 16. S teg PG, Greenlaw N, Tardif JC, et al. Women and men with stable coronary artery disease have similar clinical outcomes: insights from the international prospective CLARIFY registry. Eur Heart J 2012;33:2831–40. https://doi.org/10.1093/eurheartj/ ehs289; PMID: 22922505. 17. Ruff CT, Bhatt DL, Steg PG, et al. Long-term cardiovascular outcomes in patients with atrial fibrillation and atherothrombosis in the REACH Registry. Int J Cardiol 2014;170:413–8. https://doi.org/10.1016/j.ijcard.2013.11.030; PMID: 24321327. 18. Lip GY, Windecker S, Huber K, et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions. Eur Heart J 2014;35:3155–79. https://doi.org/10.1093/eurheartj/ehu298; PMID: 25154388. 19. Lip GY, Laroche C, Dan GA, et al. A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry. Europace 2014;16:308–19. https://doi.org/10.1093/ europace/eut373; PMID: 24351881. 20. Bernard A, Fauchier L, Pellegrin C, et al. Anticoagulation in patients with atrial fibrillation undergoing coronary stent implantation. Thromb Haemost 2013;110:560–8. https://doi. org/10.1160/TH13-04-0351; PMID: 23846210. 21. Gibson CM, Mehran R, Bode C, et al. An open-label, randomized, controlled, multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI). Am Heart J 2015;169:472–8. https://doi. org/10.1016/j.ahj.2014.12.006; PMID: 25819853. 22. Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009;374:29–38. https://doi.org/10.1016/S01406736(09)60738-8; PMID: 19539361. 23. Gibson CM, Mehran R, Bode C, et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med 2016;375:2423–34. https://doi.org/10.1056/NEJMoa1611594; PMID: 27959713. 24. Cannon CP, Gropper S, Bhatt DL, et al. Design and rationale of the RE-DUAL PCI Trial: A prospective, randomized, phase 3b study comparing the safety and efficacy of dual antithrombotic therapy with dabigatran etexilate versus warfarin triple therapy in patients with nonvalvular atrial fibrillation who have undergone percutaneous coronary intervention with stenting. Clin Cardiol 2016;39:555–64. https:// doi.org/10.1002/clc.22572; PMID: 27565018. 25. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005;3:692–4. https://doi.org/10.1111/j.1538-7836.2005.01204.x; PMID: 15842354. 26. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med 2017;377:1513–24. https://doi.org/10.1056/ NEJMoa1708454; PMID: 28844193. 27. Lopes RD, Heizer G, Aronson R, et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med 2019;380:1509–24. https://doi.org/10.1056/ NEJMoa1817083; PMID: 30883055. 28. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

diagnosis and management of chronic coronary syndromes. Eur Heart J 2019:ehz425. https://doi.org/10.1093/eurheartj/ ehz425; PMID: 31504439. Vranckx P, Valgimigli M, Eckardt L, et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet 2019;394:1335–43. https://doi.org/10.1016/ S0140-6736(19)31872-0; PMID: 31492505. Borissoff JI, Spronk HM, Heeneman S, et al. Is thrombin a key player in the ‘coagulation-atherogenesis’ maze? Cardiovasc Res 2009;82:392–403. https://doi.org/10.1093/cvr/cvp066; PMID: 19228706. Hirano K. The roles of proteinase-activated receptors in the vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol 2007;27:27–36. https://doi.org/10.1161/01. ATV.0000251995.73307.2d; PMID: 17095716. Pingel S, Tiyerili V, Mueller J, et al. Thrombin inhibition by dabigatran attenuates atherosclerosis in ApoE deficient mice. Arch Med Sci 2014;10:154–60. https://doi.org/10.5114/ aoms.2014.40742; PMID: 24701228. Preusch MR, Ieronimakis N, Wijelath ES, et al. Dabigatran etexilate retards the initiation and progression of atherosclerotic lesions and inhibits the expression of oncostatin M in apolipoprotein E-deficient mice. Drug Des Devel Ther 2015;9:5203–11. https://doi.org/10.2147/DDDT.S86969; PMID: 26392754. Hara T, Fukuda D, Tanaka K, et al. Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice. Atherosclerosis 2015;242:639–46. https://doi.org/10.1016/j. atherosclerosis.2015.03.023; PMID: 25817329. Zhou Q, Bea F, Preusch M, et al. Evaluation of plaque stability of advanced atherosclerotic lesions in apo E-deficient mice after treatment with the oral factor Xa inhibitor rivaroxaban. Mediators Inflamm 2011;2011:432080. https://doi. org/10.1155/2011/432080; PMID: 21772662. Lee J, Nakanishi R, Li D, et al. Prospective randomized trial of rivaroxaban versus warfarin in the evaluation of progression of coronary artery calcification. J Am Coll Cardiol 2018;71:1684. https://doi.org/10.1016/S0735-1097(18)32225-3. Osawa K, Nakanishi R, Win TT, et al. Rationale and design of a randomized trial of apixaban vs warfarin to evaluate atherosclerotic calcification and vulnerable plaque progression. Clin Cardiol 2017;40:807–13. https://doi. org/10.1002/clc.22746; PMID: 28703931. Bosch J, Eikelboom JW, Connolly SJ, et al. Rationale, design and baseline characteristics of participants in the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) trial. Can J Cardiol 2017;33:1027–35. https://doi. org/10.1016/j.cjca.2017.06.001; PMID: 28754388. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377:1319–30. https://doi.org/10.1056/NEJMoa1709118; PMID: 28844192. Connolly SJ, Eikelboom JW, Bosch J, et al. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018;391:205–18. https://doi.org/10.1016/S01406736(17)32458-3; PMID: 29132879. Zannad F, Anker SD, Byra WM, et al. Rivaroxaban in patients with heart failure, sinus rhythm, and coronary disease. N Engl J Med 2018;379:1332–42. https://doi.org/10.1056/ NEJMoa1808848; PMID: 30146935. Darmon A, Bhatt DL, Elbez Y, et al. External applicability of the COMPASS trial: an analysis of the reduction of atherothrombosis for continued health (REACH) registry. Eur Heart J 2018;39:750–7a. https://doi.org/10.1093/eurheartj/ ehx658; PMID: 29186454.

EUROPEAN CARDIOLOGY REVIEW

Heart Failure

Arrhythmogenic Cardiomyopathy: A Disease or Merely a Phenotype? Alexandros Protonotarios1,2 and Perry M Elliott1,2 1. Institute of Cardiovascular Science, University College London, London, UK; 2. Inherited Cardiovascular Disease Unit, Barts Heart Centre, London, UK

Abstract Arrhythmogenic cardiomyopathy (AC) is a clinical entity that has evolved conceptually over the past 30 years. Advances in cardiac imaging and the introduction of genetics into everyday practice have revealed that AC comprises multiple phenotypes that are dependent on genetic or acquired factors. In this study, the authors summarise the approach to the identification of the AC phenotype and its underlying causes. They believe that AC represents a paradigm for personalised medicine in cardiology and that better stratification of the disease will enhance the development of mechanism-based treatments.

Keywords Arrhythmogenic cardiomyopathy, phenotype, disease, genetics, treatment Disclosure: The authors have no conflicts of interest to declare. Received: 17 June 2019 Accepted: 10 October 2019 Citation: European Cardiology Review 2020;15:e11. DOI: https://doi.org/10.15420/ecr.2019.05 Correspondence: Perry Elliott, UCL Institute for Cardiovascular Science, Paul O’Gorman Building, University College London, 72 Huntley St, London WC1E 6DD, UK. E: perry.elliott@ucl.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Until the 20th century, conventional medicine relied almost exclusively on observable characteristics to classify and treat human disease.1 Even in the modern era, physicians define diseases using phenotypic similarities and employ relatively simple algorithms to interpret diagnostic tools and plan treatment. The advent of low-cost genetic sequencing and its introduction into clinical care provides new insights into pathogenesis and improves the recognition of inherited diseases and complex associated entities. In this article, we review a relatively new concept, arrhythmogenic cardiomyopathy (AC), and explain why it is an exemplar for a more nuanced approach to diagnosis that promises more effective treatments.

The Paradigm of Arrhythmogenic Right Ventricular Cardiomyopathy In 1982, Marcus et al. described a group of patients with right ventricular dysplasia who presented with ventricular tachycardias of left bundle branch block configuration, T-wave inversion in the right precordial leads and structural abnormalities of the right ventricle (RV).2 In cases of sudden death, histological examination showed fibrofatty replacement of the right ventricular myocardium combined with signs of myocardial degeneration and necrosis, with and without inflammation, which led to the adoption of the term ‘arrhythmogenic right ventricular cardiomyopathy’ (ARVC), rather than ‘dysplasia’ to describe this new potentially lethal myocardial disorder.3 The familial nature of the disease was recognised very early and inspired the identification of the first genetic mutation in ARVC, which was a two-nucleotide pair deletion in the junction plakoglobin (JUP) gene in patients with Naxos disease, a recessive syndromic form of ARVC associated with palmoplantar keratoderma and woolly hair.4,5 Around the same time, a recessive mutation in the desmoplakin (DSP)

gene was identified as the cause of an autosomal recessive cardiocutaneous syndrome in Ecuadorian families known as Carvajal syndrome.6–8 Both JUP and DSP are key components of the myocyte intercalated disc, and candidate gene evaluation in families with more common dominant forms of ARVC soon revealed mutations in DSP and other desmosomal genes, including plakophilin-2 (PKP-2), desmocollin-2 (DSC-2) and desmoglein-2 (DSG-2), forming the concept of ARVC as a disease of the desmosome.9

The Emergence of Nosological Confusion Even in early reports of ARVC, fibrous/fibrofatty lesions were found in the left ventricular myocardium, as well as the right.2,3 Electrocardiograms from patients with ARVC often demonstrated features consistent with left ventricular involvement and cardiac imaging occasionally demonstrated coexistent wall motion abnormalities, dilation and systolic dysfunction.2,5 With the widespread use of cardiac MRI to assess patients with suspected ARVC, it became apparent that subtle left ventricle (LV) disease in the form of myocardial fibrosis is almost the norm, particularly in patients with mutations in DSP and DSG2.10 In response to this, many investigators started to use terms such as ‘arrhythmogenic left ventricular cardiomyopathy’, and even more confusingly, ‘left-dominant arrhythmogenic cardiomyopathy’, to describe this broader spectrum of disease. However, this effort to preserve the concept of ARVC as originally described in the 1980s and 1990s has become increasingly tenuous with the demonstration of overlapping phenotypes, such as dilated cardiomyopathy and non-desmosomal gene mutations, such as phospholamban (PLN), transmembrane protein 43 (TMEM43), filamin C (FLNC), desmin, cadherin 2 (CDH2), lamin A/C (LMNA) and titin (TTN) in individuals fulfilling current diagnostic criteria for ARVC, as well as other phenotypes (Figure 1).11–17

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Heart Failure Figure 1: The Type of Ventricular Involvement in Genetic Subgroups with Arrhythmogenic Cardiomyopathy RV Disease

LV Disease

• Structural abnormalities of the myocardium, including regional or global systolic dysfunction or myocardial scar in either ventricle, unexplained by ischaemic heart disease, hypertension or an acute inflammatory trigger, such as viral infection or exposure to a toxic agent. • Frequent ventricular ectopy, sustained or non-sustained ventricular tachycardia (VT) or unexplained cardiac arrest. • A family history of sudden cardiac death or cardiomyopathy and a history of myocarditis presentation are also key features (Figure 2).

TTN LMNA

PKP-2

DES

DSC-2

When defined in this way, the term AC serves as the first step towards disease classification and elucidation of aetiology. Contemporary studies show that AC encompasses a broad spectrum of genetic and non-genetic diseases, each with its own characteristic features and clinical course. A detailed description of all contenders for the label of AC is beyond the scope of this article, but two groups deserve emphasis due to their potential to cause premature death (often in young people) and their influence on therapy.

DSP

JUP

PLN

DSG-2 THEM43

FLNC CDH2

Arrhythmogenic Dilated Cardiomyopathy

A schematic representation of the type of ventricular involvement (left or right) in the different genetic subgroups that present with a phenotype of arrhythmogenic cardiomyopathy. CDH2 = cadherin 2; DES = desmin; DSC-2 = desmocollin-2; DSG2 = desmoglein-2; DSP = desmoplakin; FLNC = filamin C; JUP = junction plakoglobin; LMNA = lamin A/C; LV = left ventricle; PKP-2 = plakophilin-2; PLN = phospholamban; RV = right ventricle; TMEM43 = transmembrane protein 43; TTN = titin. Source: Elliott et al. 2019.61 Adapted with permission from John Wiley and Sons.

Figure 2: Clinical Presentations and Differential Diagnoses Structural abnormalities of the myocardium, including regional or global systolic dysfunction or myocardial scar in either ventricle DDx: Ischaemic heart disease Hypertension Congenital heart disease Toxic causes of cardiomyopathy Athlete’s heart

Frequent ventricular ectopy, VT or cardiac arrest

Although diagnostic criteria for the expanded AC spectrum do not yet exist, it is possible to summarise the key components of the AC phenotype:

DDx: Ischaemic heart disease Channelopathies Idiopathic VT forms Arrhythmogenic cardiomyopathy

DDx: Infectious myocarditis

Previous history of myocarditis

DDx: Channelopathies Other genetic cardiomyopathies Family history of sudden cardiac death or cardiomyopathy Various clinical presentations to the clinical setting of patients with arrhythmogenic cardiomyopathy and the respective differential diagnoses. DDx = differential diagnosis; VT = ventricular tachycardia.

The Arrhythmogenic Cardiomyopathy Phenotype Phenotypes describe a set of identifiable clinical characteristics that help to distinguish affected individuals from unaffected. The term AC represents an evolution of diagnostic terms describing disease of the LV and RV, but it was only recently that the term was formally used to describe this disorder.18

It is important to appreciate that, by definition, the AC phenotype overlaps with that of dilated cardiomyopathy (DCM). DCM is currently defined only by LV size and function. However, a subgroup of patients characterised by syncope, rapid non-sustained ventricular tachycardia, increased ventricular ectopy and a family history of sudden cardiac death has been described.19 The term ‘arrhythmogenic DCM’ has been used to describe these cases, but in practice it aligns with the definition of AC.20 Arrhythmogenic DCM includes many genetic forms that are characterised mainly by dilatation and dysfunction of the LV. Examples include disease caused by mutations in desmosomal genes, such as DSP and LMNA encoding the nuclear envelope protein lamin AC.21,22 The latter may also present with conduction abnormalities (atrioventricular node and/or left bundle branch disease) and clinical or subclinical skeletal myopathy. An increased risk of sudden cardiac death has also been identified in cases with mutations in desmosomal genes and LMNA, as compared to other genetic and non-genetic causes of DCM.23,24

Myocardial Inflammation Ever since the first reports of AC, inflammatory cell infiltrates have been described in patients diagnosed at post-mortem, with the highest incidence in patients with more diffuse disease.3,25–29 Inflammatory infiltrates are also described in the transgenic models of AC.30,31 The subepicardial distribution of the typical AC lesions is very similar to that reported in myocarditis, and on occasion, patients with AC seek medical attention with symptoms of chest pain and palpitations accompanied by electrocardiographic changes and cardiac biomarkers consistent with myocarditis.32,33 These ‘hot phases’ can be the initial presentation of AC, sometimes preceding the development of classical ECG, imaging and histological features.34–37 18F-fluorodeoxyglucose PET can be positive in a subset of symptomatic AC patients, particularly in cases with left-dominant AC.32 Cardiac MRI in AC often demonstrates patterns of subepicardial scarring with a predilection for the inferior and lateral walls of the

EUROPEAN CARDIOLOGY REVIEW

Arrhythmogenic Cardiomyopathy: Disease or Phenotype? Figure 3: Algorithmic Representation of the Evaluation and Management of Arrhythmogenic Cardiomyopathy Establishment of AC phenotype

Symptoms/ problem

Palpitations Syncope Aborted SCD Previous myocarditis FHx of AC, myocarditis, SCD

Establishment of AC cause and management

Initial clinical assessment

Physical examination (skin–hair abnormalities, myopathy) ECG (de- or repolarisation abnormalities) Holter (burden of VE and VT) ECHO (ventricular structure/ function) Cardiac MRI (focus on RV abnormalities and tissue characterisation)

Standard/ symptomatic management Exercise restriction Beta-blockade Anti-arrhythmics ICD implantation VT ablation Heart failure management Heart transplantation Psychological support

The future

Genetic/other testing

Cause-oriented treatment

Extended gene panel Family screening FDG-PET scanning Endomyocardial biopsy

Anti-inflammatory treatment Gene therapy Pre-implantation diagnosis Cellular pathway modulators

AC = arrhythmogenic cardiomyopathy; ECHO = echocardiography; FDG = 18F-fluorodeoxyglucose; FHx = family history; RV = right ventricle; SCD = sudden cardiac death; VE = ventricular ectopy; VT = ventricular tachycardia.

LV, similar to that seen following myocarditis. 36–38 There are two studies showing raised cytokine levels in the blood of patients compared to controls.38,39 Cardiac sarcoidosis can show marked resemblance to genetic forms of AC, and the differential diagnosis is sometimes only made at a histological level.32 Furthermore, a link at the molecular level is also present, as both giant cell myocarditis and sarcoidosis exhibit a similar pattern of reduced plakoglobin staining in the absence of any mutations in the desmosomal genes.38 Finally, there is recent evidence of cardiac autoimmunity in a study of AC reporting anti-desmoglein antibodies associated with the extent of the disease.40 Importantly, this was a consistent finding among desmosomal and non-desmosomal forms of the disease.40

Arrhythmia Risk Stratification Risk stratification in AC is critical, as ICDs provide a life-saving therapy for patients prone to haemodynamically unstable ventricular arrhythmias.41 It is uncontentious that patients with previous unstable ventricular arrhythmias are at high risk of recurrence and an ICD is always recommended for secondary prevention.41 Although there have been numerous studies on arrhythmic risk stratification in affected individuals, and particularly family members from cascade screening with no previous arrhythmic events, the timing of ICD implantation remains a challenge.42–45 A new prediction model for ventricular arrhythmias (https://arvcrisk.com) has been recently developed and published by a multi-centre cohort. However, this is based only on individuals with a definite diagnosis of ARVC based on the 2010 Task Force criteria, and its utility remains obscure for the leftdominant forms.42

Approach to Diagnosis Identifying phenotypes and defining the discrepancies between them might seem as an overly academic and mundane task; however, these concepts and their application are fundamental to treatment decisions and guide clinical and basic research. The phenotypic spectrum encompassed by ‘classic’ ARVC, biventricular AC and left-dominant AC challenges the development of a single set of diagnostic criteria. However, a stepwise approach to first identify the broad AC phenotype, as defined above, and then to characterise the genetic and non-genetic causes is possible in everyday practice, although the involvement of different specialities, such as clinical genetics, microbiology, immunology and haematology, is also essential in specific cases (Figure 3). In this way, it is possible to move beyond the crude phenotypes currently used to define disease (e.g. heart failure with reduced or preserved ejection fraction) towards personalised algorithms for investigation and management.

Opportunities for Improved Management and New Therapies The elucidation of specific subtypes of AC offers opportunities for tailored therapies. Examples where this is already possible include arrhythmia risk stratification, myocarditis treatment and the role of exercise.

EUROPEAN CARDIOLOGY REVIEW

In a recent report, the Heart Rhythm Society provided consensus recommendations on the management of different forms of AC using a genotype-guided approach.18 Evidence of increased arrhythmic risk in cases with only mildly impaired LV systolic function exist for specific genes, such as PLN, LMNA and FLNC, and ICD implantation should be considered, irrespective of symptoms, in such cases.18 In the case of LMNA, additional parameters, such as male sex and non-sustained VT, can guide decision-making.

Myocarditis Treatment As mentioned previously, myocardial inflammation is an important component of the AC spectrum.32,46 Identification of specific forms of inflammation, such as sarcoidosis, can be challenging, as a definite diagnosis can be reached only by endomyocardial biopsy, but is critical as it can dictate further management with corticosteroid therapy and long-term immunosuppression.47–49 The effects of anti-inflammatory therapy in gene-positive individuals presenting with a ‘hot phase’ remains to be investigated. The increasing recognition of myocardial inflammation as a mechanism of disease progression in genetic forms of AC raises several possibilities in regards to therapeutic approaches.37 Although conventional treatment options for myocarditis, such intravenous immunoglobulin, corticosteroids, cyclosporine and azathioprine, can be considered, they

Heart Failure remain largely non-selective in terms of the mechanisms and the sites of inflammation that they target.50,51 The elucidation of the cellular mechanisms in the various genetic forms of AC will be crucial in the identification of the potential causes of inflammatory induction that can be targeted therapeutically.

The Role of Exercise It is common to elicit a history of high-intensity exercise among individuals affected by classic ARVC. Furthermore, patients with ARVC who were athletes have been found to have increased risk of sudden death compared with non-athletes.52 Desmosomal mutation carriers who participate in endurance and frequent exercise have a higher incidence of ventricular tachyarrhythmias and heart failure compared to those who are less athletic.53 A history of vigorous exercise seems to have an even greater effect in patients without an identifiable mutation, and patients seem to have greater benefit from exercise restriction.54,55 Further research is warranted to better understand the role of exercise in other subtypes of AC and non-desmosomal mutation carriers to prescribe exercise restriction more effectively.

mutation carriers.56,57 The inhibition of GSK3B led to rescue of the phenotype when administered early in transgenic mice with mutant DSG2 or JUP.31 In disease caused by LMNA mutations, a selective p38 mitogenactivated protein kinase inhibitor, ARRY-797, has shown reversal of cardiac dysfunction in a transgenic murine model of LMNA. A Phase III clinical trial is now underway in patients with DCM caused by LMNA mutations (NCT03439514). Examples of other molecular-targeted treatments include gene therapy enabling trans-splicing in a LMNA-related muscular dystrophy mouse model with partial rescue of the mutant phenotype.58 Antisensemediated exon skipping can remove mutant exons with frameshift or nonsense variants in cardiomyopathy genes, and has been used to eliminate TTN truncating variants in patient-derived induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM).59 Gene correction using transcription activator-like effector nucleases has successfully corrected PLN variants in iPSC-CM by establishing the biallelic expression of the normal PLN transcripts.60

Future Developments in Mechanism-based Therapies

Conclusion

Recent studies have revealed a key role of the glycogen synthase kinase-3 beta (GSK3B) in the pathogenesis of AC.31 In the hearts of patients with AC, it has been shown that GSK3B translocates from the cytoplasm, where it is present in controls, to the intercalated disc.31 This observation was consistent among all cases with desmosomal gene mutations, including DSP, but less consistent in FLNC and PLN

In the era of ‘-omic’ technologies and precision medicine, there are increasing opportunities to redefine diseases and test new therapies. AC serves as a prime example of a heterogeneous family of disorders in which there are multiple genetic and non-genetic causes amenable to existing and developing therapies that promise to slow, reverse and perhaps prevent disease.

Protonotarios A, Elliott PM. Arrhythmogenic cardiomyopathies (ACs): diagnosis, risk stratification and management. Heart 2019;105:1117–28. https://doi.org/10.1136/ heartjnl-2017-311160; PMID: 30792239. 2. Marcus FI, Fontaine GH, Guiraudon G, et al. Right ventricular dysplasia: a report of 24 adult cases. Circulation 1982;65:384– 98. https://doi.org/10.1161/01.cir.65.2.384; PMID: 7053899. 3. Basso C, Thiene G, Corrado D, et al. Arrhythmogenic right ventricular cardiomyopathy. Dysplasia, dystrophy, or myocarditis? Circulation 1996;94:983–91. https://doi. org/10.1161/01.cir.94.5.983; PMID: 8790036. 4. McKoy G, Protonotarios N, Crosby A, et al. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet 2000;355:2119–24. https://doi. org/10.1016/S0140-6736(00)02379-5; PMID: 10902626. 5. Protonotarios N, Tsatsopoulou A, Patsourakos P, et al. Cardiac abnormalities in familial palmoplantar keratosis. Br Heart J 1986;56:321–6. https://doi.org/10.1136/hrt.56.4.321; PMID: 2945574. 6. Norgett EE, Hatsell SJ, Carvajal-Huerta L, et al. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet 2000;9:2761–6. https://doi.org/10.1093/hmg/9.18.2761; PMID: 11063735. 7. Carvajal-Huerta L. Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy. J Am Acad Dermatol 1998;39:418–21. https://doi.org/10.1016/s01909622(98)70317-2; PMID: 9738775. 8. Kaplan SR, Gard JJ, Carvajal-Huerta L, et al. Structural and molecular pathology of the heart in Carvajal syndrome. Cardiovasc Pathol 2004;13:26–32. https://doi.org/10.1016/ S1054-8807(03)00107-8; PMID: 14761782. 9. Karmouch J, Protonotarios A, Syrris P. Genetic basis of arrhythmogenic cardiomyopathy. Curr Opin Cardiol 2018;33:276–81. https://doi.org/10.1097/ HCO.0000000000000509; PMID: 29543670. 10. Sen-Chowdhry S, Syrris P, Ward D, et al. Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression. Circulation 2007;115:1710– 20. https://doi.org/10.1161/CIRCULATIONAHA.106.660241; PMID: 17372169. 11. van der Zwaag PA, van Rijsingen IA, Asimaki A, et al. Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur J Heart Fail 2012;14:1199–

207. https://doi.org/10.1093/eurjhf/hfs119; PMID: 22820313. 12. Merner ND, Hodgkinson KA, Haywood AF, et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet 2008;82:809–21. https://doi.org/10.1016/j.ajhg.2008.01.010; PMID: 18313022. 13. van Tintelen JP, Van Gelder IC, Asimaki A, et al. Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene. Heart Rhythm 2009;6:1574–83. https://doi.org/10.1016/j. hrthm.2009.07.041; PMID: 19879535. 14. Ortiz-Genga MF, Cuenca S, Dal Ferro M, et al. Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies. J Am Coll Cardiol 2016;68:2440–51. https://doi.org/10.1016/j.jacc.2016.09.927; PMID: 27908349. 15. Quarta G, Syrris P, Ashworth M, et al. Mutations in the lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy. Eur Heart J 2012;33:1128–36. https://doi. org/10.1093/eurheartj/ehr451; PMID: 22199124. 16. Mayosi BM, Fish M, Shaboodien G, et al. Identification of cadherin 2 (CDH2) mutations in arrhythmogenic right ventricular cardiomyopathy. Circ Cardiovasc Genet 2017;10: e001605. https://doi.org/10.1161/CIRCGENETICS.116.001605; PMID: 28280076. 17. Taylor M, Graw S, Sinagra G, et al. Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes. Circulation 2011;124:876–85. https://doi. org/10.1161/CIRCULATIONAHA.110.005405; PMID: 21810661. 18. Towbin JA, McKenna WJ, Abrams DJ, et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm 2019;16:e301–72. https://doi.org/10.1016/j.hrthm.2019.05.007; PMID: 31078652. 19. Spezzacatene A, Sinagra G, Merlo M, et al. Arrhythmogenic phenotype in dilated cardiomyopathy: natural history and predictors of life-threatening arrhythmias. J Am Heart Assoc 2015;4:e002149. https://doi.org/10.1161/JAHA.115.002149; PMID: 26475296. 20. Pinto YM, Elliott PM, Arbustini E, et al. Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J 2016;37:1850–8. https:// doi.org/10.1093/eurheartj/ehv727; PMID: 26792875. 21. Elliott P, O’Mahony C, Syrris P, et al. Prevalence of desmosomal protein gene mutations in patients with dilated

cardiomyopathy. Circ Cardiovasc Genet 2010;3:314–22. https:// doi.org/10.1161/CIRCGENETICS.110.937805; PMID: 20716751. 22. Captur G, Arbustini E, Bonne G, et al. Lamin and the heart. Heart 2018;104:468–79. https://doi.org/10.1136/ heartjnl-2017-312338; PMID: 29175975. 23. Merlo M, Cannata A, Gobbo M, et al. Evolving concepts in dilated cardiomyopathy. Eur J Heart Fail 2018;20:228–39. https:// doi.org/10.1002/ejhf.1103; PMID: 29271570. 24. Gigli M, Merlo M, Graw SL, et al. Genetic risk of arrhythmic phenotypes in patients with dilated cardiomyopathy. J Am Coll Cardiol 2019;74:1480–90. https://doi.org/10.1016/j. jacc.2019.06.072; PMID: 31514951. 25. Fontaine G, Fontaliran F, Lascault G, et al. Congenital and acquired right ventricular dysplasia. Arch Mal Coeur Vaiss 1990;83:915–20 [in French]. PMID: 2114851. 26. Lobo FV, Heggtveit HA, Butany J, et al. Right ventricular dysplasia: morphological findings in 13 cases. Can J Cardiol 1992;8:261–8. PMID: 1576560. 27. Burke AP, Farb A, Tashko G, Virmani R. Arrhythmogenic right ventricular cardiomyopathy and fatty replacement of the right ventricular myocardium: are they different diseases? Circulation 1998;97:1571–80. https://doi.org/10.1161/01. cir.97.16.1571; PMID: 9593562. 28. Fornes P, Ratel S, Lecomte D. Pathology of arrhythmogenic right ventricular cardiomyopathy/dysplasia – an autopsy study of 20 forensic cases. J Forensic Sci 1998;43:777–83. PMID: 9670499. 29. Campuzano O, Alcalde M, Iglesias A, et al. Arrhythmogenic right ventricular cardiomyopathy: severe structural alterations are associated with inflammation. J Clin Pathol 2012;65:1077– 83. https://doi.org/10.1136/jclinpath-2012-201022; PMID: 22944624. 30. Pilichou K, Remme CA, Basso C, et al. Myocyte necrosis underlies progressive myocardial dystrophy in mouse dsg2related arrhythmogenic right ventricular cardiomyopathy. J Exp Med 2009;206:1787–802. https://doi.org/10.1084/ jem.20090641; PMID: 19635863. 31. Chelko SP, Asimaki A, Andersen P, et al. Central role for GSK3beta in the pathogenesis of arrhythmogenic cardiomyopathy. JCI Insight 2016;1:85923. https://doi. org/10.1172/jci.insight.85923; PMID: 27170944. 32. Protonotarios A, Wicks E, Ashworth M, et al. Prevalence of (18) F-fluorodeoxyglucose positron emission tomography abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy. Int J Cardiol 2019;284:99–104. https://doi. org/10.1016/j.ijcard.2018.10.083; PMID: 30409737. 33. Charron P, Elliott PM, Gimeno JR, et al. The Cardiomyopathy Registry of the EURObservational Research Programme of the

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Arrhythmogenic Cardiomyopathy: Disease or Phenotype?

34.

35.

36.

37.

38.

39.

40.

41.

42.

European Society of Cardiology: baseline data and contemporary management of adult patients with cardiomyopathies. Eur Heart J 2018;39:1784–93. https://doi. org/10.1093/eurheartj/ehx819; PMID: 29378019. Bauce B, Basso C, Rampazzo A, et al. Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations. Eur Heart J 2005;26:1666–75. https://doi.org/10.1093/eurheartj/ehi341; PMID: 15941723. Patrianakos AP, Protonotarios N, Nyktari E, et al. Arrhythmogenic right ventricular cardiomyopathy/dysplasia and troponin release. Myocarditis or the ‘hot phase’ of the disease? Int J Cardiol 2012;157:e26–8. https://doi.org/10.1016/j. ijcard.2011.09.017; PMID: 21962611. Mavrogeni S, Protonotarios N, Tsatsopoulou A, et al. Naxos disease evolution mimicking acute myocarditis: the role of cardiovascular magnetic resonance imaging. Int J Cardiol 2013;166:e14–5. https://doi.org/10.1016/j.ijcard.2012.12.078; PMID: 23336952. Lopez-Ayala JM, Pastor-Quirante F, Gonzalez-Carrillo J, et al. Genetics of myocarditis in arrhythmogenic right ventricular dysplasia. Heart Rhythm 2015;12:766–73. https://doi. org/10.1016/j.hrthm.2015.01.001; PMID: 25616123. Asimaki A, Tandri H, Duffy ER, et al. Altered desmosomal proteins in granulomatous myocarditis and potential pathogenic links to arrhythmogenic right ventricular cardiomyopathy. Circ Arrhyth Electrophysiol 2011;4:743–52. https://doi.org/10.1161/CIRCEP.111.964890; PMID: 21859801. Campian ME, Verberne HJ, Hardziyenka M, et al. Assessment of inflammation in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Eur J Nucl Med Mol Imaging 2010;37:2079–85. https://doi.org/10.1007/s00259-0101525-y; PMID: 20603720. Chatterjee D, Fatah M, Akdis D, et al. An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis. Eur Heart J 2018;39:3932– 44. https://doi.org/10.1093/eurheartj/ehy567; PMID: 30239670. Corrado D, Wichter T, Link MS, et al. Treatment of arrhythmogenic right ventricular cardiomyopathy/dysplasia: an international task force consensus statement. Eur Heart J 2015;36:3227–37. https://doi.org/10.1093/eurheartj/ehv162; PMID: 26216920. Cadrin-Tourigny J, Bosman LP, Nozza A, et al. A new prediction model for ventricular arrhythmias in arrhythmogenic right

EUROPEAN CARDIOLOGY REVIEW

ventricular cardiomyopathy. Eur Heart J 2019;40:1850–8. https:// doi.org/10.1093/eurheartj/ehz103; PMID: 30915475. 43. Lie OH, Rootwelt-Norberg C, Dejgaard LA, et al. Prediction of life-threatening ventricular arrhythmia in patients with arrhythmogenic cardiomyopathy: a primary prevention cohort study. JACC Cardiovasc Imaging 2018;11:1377–86. https://doi. org/10.1016/j.jcmg.2018.05.017; PMID: 30031702. 44. Vischer AS, Castelletti S, Syrris P, et al. Risk score for the exclusion of arrhythmic events in arrhythmogenic right ventricular cardiomyopathy at first presentation. Int J Cardiol 2019;290:100–5. https://doi.org/10.1016/j.ijcard.2019.04.090; PMID: 31104822. 45. Maupain C, Badenco N, Pousset F, et al. Risk stratification in arrhythmogenic right ventricular cardiomyopathy/dysplasia without an implantable cardioverter-defibrillator. JACC Clin Electrophysiol 2018;4:757–68. https://doi.org/10.1016/j. jacep.2018.04.017; PMID: 29929669. 46. Philips B, Madhavan S, James CA, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy and cardiac sarcoidosis: distinguishing features when the diagnosis is unclear. Circ Arrhythm Electrophysiol 2014;7:230–6. https://doi.org/10.1161/ CIRCEP.113.000932; PMID: 24585727. 47. Yazaki Y, Isobe M, Hiroe M, et al. Prognostic determinants of long-term survival in Japanese patients with cardiac sarcoidosis treated with prednisone. Am J Cardiol 2001;88:1006–10. https://doi.org/10.1016/s00029149(01)01978-6; PMID: 11703997. 48. Sadek MM, Yung D, Birnie DH, et al. Corticosteroid therapy for cardiac sarcoidosis: a systematic review. Can J Cardiol 2013;29:1034–41. https://doi.org/10.1016/j.cjca.2013.02.004; PMID: 23623644. 49. Ballul T, Borie R, Crestani B, et al. Treatment of cardiac sarcoidosis: a comparative study of steroids and steroids plus immunosuppressive drugs. Int J Cardiol 2019;276:208–11. https://doi.org/10.1016/j.ijcard.2018.11.131; PMID: 30527995. 50. Tschope C, Cooper LT, Torre-Amione G, Van Linthout S. Management of myocarditis-related cardiomyopathy in adults. Circ Res 2019;124:1568–83. https://doi.org/10.1161/ CIRCRESAHA.118.313578; PMID: 31120823. 51. Stephenson E, Savvatis K, Mohiddin SA, Marelli-Berg FM. T-cell immunity in myocardial inflammation: pathogenic role and therapeutic manipulation. Br J Pharmacol 2017;174:3914–25. https://doi.org/10.1111/bph.13613; PMID: 27590129. 52. Corrado D, Basso C, Rizzoli G, et al. Does sports activity

53.

54.

55.

56.

57.

58.

59.

60.

61.

enhance the risk of sudden death in adolescents and young adults? J Am Coll Cardiol 2003;42:1959–63. https://doi. org/10.1016/j.jacc.2003.03.002; PMID: 14662259. James CA, Bhonsale A, Tichnell C, et al. Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. J Am Coll Cardiol 2013;62:1290–7. https://doi.org/10.1016/j.jacc.2013.06.033; PMID: 23871885. Sawant AC, Bhonsale A, te Riele AS, et al. Exercise has a disproportionate role in the pathogenesis of arrhythmogenic right ventricular dysplasia/cardiomyopathy in patients without desmosomal mutations. J Am Heart Assoc 2014;3:e001471. https://doi.org/10.1161/JAHA.114.001471; PMID: 25516436. Wang W, Orgeron G, Tichnell C, et al. Impact of exercise restriction on arrhythmic risk among patients with arrhythmogenic right ventricular cardiomyopathy. J Am Heart Assoc 2018;7:e008843. https://doi.org/10.1161/ JAHA.118.008843; PMID: 29909402. Begay RL, Graw SL, Sinagra G, et al. Filamin C truncation mutations are associated with arrhythmogenic dilated cardiomyopathy and changes in the cell-cell adhesion structures. JACC Clin Electrophysiol 2018;4:504–14. https://doi. org/10.1016/j.jacep.2017.12.003; PMID: 30067491. Te Rijdt WP, Asimaki A, Jongbloed JDH, et al. Distinct molecular signature of phospholamban p.Arg14del arrhythmogenic cardiomyopathy. Cardiovasc Pathol 2018;40:2–6. https://doi. org/10.1016/j.carpath.2018.12.006; PMID: 30763825. Azibani F, Brull A, Arandel L, et al. Gene therapy via transsplicing for LMNA-related congenital muscular dystrophy. Mol Ther Nucleic Acids 2018;10:376–86. https://doi.org/10.1016/j. omtn.2017.12.012; PMID: 29499949. Gramlich M, Pane LS, Zhou Q, et al. Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy. EMBO Mol Med 2015;7:562–76. https://doi. org/10.15252/emmm.201505047; PMID: 25759365. Karakikes I, Stillitano F, Nonnenmacher M, et al. Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy. Nat Commun 2015;6:6955. https://doi.org/10.1038/ ncomms7955; PMID: 25923014. Elliott PM, Anastasakis A, Asimaki A, et al. Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report. Eur J Heart Fail 2019;21:955–64. https://doi. org/10.1002/ejhf.1534; PMID: 31210398.

Ischaemic Heart Disease

Coronary Artery Spasm: The Interplay Between Endothelial Dysfunction and Vascular Smooth Muscle Cell Hyperreactivity Astrid Hubert, Andreas Seitz, Valeria Martínez Pereyra, Raffi Bekeredjian, Udo Sechtem and Peter Ong Robert-Bosch-Krankenhaus, Department of Cardiology, Stuttgart, Germany

Abstract Patients with angina pectoris, the cardinal symptom of myocardial ischaemia, yet without significant flow-limiting epicardial artery stenosis represent a diagnostic and therapeutic challenge. Coronary artery spasm (CAS) is an established cause for anginal chest pain in patients with angiographically unobstructed coronary arteries. CAS may occur at the epicardial level and/or in the microvasculature. Although the underlying pathophysiological mechanisms of CAS are still largely unclear, endothelial dysfunction and vascular smooth muscle cell (VSMC) hyperreactivity seem to be involved as major players, although their contribution to induce CAS is still seen as controversial. This article will look at the role and possible mechanistic interplay between an impaired endothelial and VSMC function in the pathogenesis of CAS.

Keywords Coronary artery spasm, angina pectoris, unobstructed coronary arteries, endothelial dysfunction, vascular smooth muscle cell hyperreactivity Disclosure: The authors have no conflicts of interest to declare. Received: 9 December 2019 Accepted: 6 January 2020 Citation: European Cardiology Review 2020;15:e12. DOI: https://doi.org/10.15420/ecr.2019.20 Correspondence: Peter Ong, Robert-Bosch-Krankenhaus, Department of Cardiology, Auerbachstrasse 110, 70376 Stuttgart, Germany. E: Peter.Ong@rbk.de Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Coronary artery spasm (CAS) is an established cause for anginal chest pain, the cardinal symptom of myocardial ischaemia, in patients with angiographically unobstructed coronary arteries. Evidence from large clinical studies has revealed that about 50% of patients undergoing diagnostic coronary angiography for suspected coronary artery disease (CAD) had either normal or near normal coronary arteries (<20% stenosis) or non-obstructive CAD (<50% stenosis).1,2 Abnormal coronary vasomotion occurred in about 60% of patients with unobstructed coronary arteries who underwent acetylcholine (ACh) provocation testing during coronary angiography, an established method for the assessment of CAS.3,4 These functional vasoconstrictor disorders may occur at the epicardial level, known as focal or diffuse pronounced epicardial spasm, and/or in the microvasculature, known as microvascular spasm.2 An overview of the current diagnostic criteria of CAS is shown in Table 1.5,6 Due to the heterogeneous clinical presentation of these patients regarding rest- and/or exercise-related angina, severity and frequency of symptoms, presence of coronary atherosclerosis, spasm localisation, the diagnosis and treatment of CAS are still challenging. The lack of a consistent definition of epicardial spasm in previous studies, for example regarding the degree of vasoconstriction for a positive CAS provocation test, further impedes the understanding of the underlying pathophysiological mechanisms. Nevertheless, several mechanisms have been proposed based on experimental and clinical studies. Central players involved in all scenarios are endothelial cells and vascular smooth muscle cells (VSMC), which can be influenced by extrinsic factors such as oxidative stress and inflammation (often induced by established cardiovascular risk factors, such as

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hypertension, hypercholesterinaemia, diabetes, obesity and smoking), as well as genetic mutations/polymorphisms and the autonomic nervous system (Figure 1).7–9 The interplay of both the endothelium and the VSMC layer plays a crucial role in the regulation of coronary vascular tone and two schools of thought exist that see either endothelial dysfunction or VSMC hyperreactivity as primary contributors to CAS.8,10,11 The aim of this article is to summarise the current knowledge and possible interplay of an impaired endothelial and VSMC function in the pathogenesis of CAS.

Normal and Abnormal Coronary Vasomotor Function Under physiological conditions, the interplay between the endothelium and the VSMC layer is crucial for adequate regulation of coronary vascular tone. Both cell types are influenced by various stimuli derived from haemodynamic (e.g. blood pressure and blood flow) and metabolic (e.g. adenosine and oxygen partial pressure) changes, as well as by the autonomic innervation and circulating vasoactive substances ,such as ACh, adenosine, serotonin and histamine, acting differently on the endothelium and VSMCs. The endothelium is much more than a passive barrier between blood and the vessel wall. By acting as signal transducers of haemodynamic forces (caused by the blood flow) and circulating substances, endothelial cells contribute to coronary tone modulation. In response to these vasoactive stimuli, endothelial cells are capable of synthesising and releasing a variety of autacoids with vasodilating properties, such as nitric oxide (NO), prostacyclin (PGI2) and endothelium-derived hyperpolarising factor (EDHF), but also with vasoconstricting potential, such as endothelin-1. Corresponding to the physiological situation and vasodilating/ vasoconstricting properties of

Pathophysiological Mechanisms of Coronary Artery Spasm Figure 1: Proposed Mechanistic Interplay Between Endothelial Dysfunction and Vascular Smooth Muscle Cell Hyperreactivity in the Pathogenesis of Coronary Artery Spasm

Vasoactive stimuli (e.g. ACh, adenosine, serotonin, histamine)

Endothelium Triggering factors Endothelial dysfunction

• Autonomic nervous system • Genetic factors

Vasodilators (e.g. NO, EDHF) Vasoconstrictors (e.g. ET-1)

VSMCs

VSMC hyperreactivity Triggering factors • Chronic low-grade inflammation • Oxidative stress

Due to dysfunctions of signal transduction involved in VSMC contraction • On receptor level and ion channels • Intracellular G-proteins and enzymes (e.g. Rho-kinase, protein kinase C)

Susceptibility for CAS

ACh = acetylcholine; CAS = coronary artery spasm; EDHF = endothelium-derived hyperpolarising factor; ET-1 = endothelin-1; VSMC = vascular smooth muscle cell.

these endothelial-derived substances, VSMCs respond with changes to their contractile state. Simultaneously, circulating vasoactive substances may also lead to vasoconstriction through direct VSMC activation.8,10,12 In normal coronary vasomotor function, providing an intact endothelial integrity and adequate VSMC reactivity, the net effect of these set of conditions favours vasodilation. In the presence of impaired endothelial function and/or VSMC hyperreactivity, the net effect of circulating vasoactive substances can be vasoconstriction and this could favour CAS. In 1980, Furchgott and Zawadzki demonstrated in isolated rabbit thoracic aortas that relaxation of arterial VSMCs in response to ACh requires the presence of endothelial cells and that the complete loss of endothelial cells by rubbing off the intimal surface or intraluminal exposure to collagenase resulted in the complete loss of vasorelaxation in response to ACh.13 The link between the increased vasoconstricting potential of coronary arteries in response to ACh and susceptibility to CAS was confirmed by clinical trials.14,15 Shimizu et al. observed vasoconstriction >50% in response to intracoronary ACh infusion in all examined patients with vasospastic angina without epicardial stenosis, while healthy controls showed neither ischaemic ECG changes nor vasoconstriction >50% during ACh provocation testing. In most asymptomatic controls, only mild vasoconstriction (0–25%) or even vasodilation was observed. Vasodilation in response to ACh was more frequent in relatively young controls indicating that age-related physiological impairment of endothelial function may favour the vasoconstrictive potential of the coronary vasculature despite angiographically unobstructed coronary

EUROPEAN CARDIOLOGY REVIEW

arteries.14 This observation was confirmed by Okumura et al. who also saw a predominantly vasodilatory effect of ACh in young control subjects, whereas patients with CAS showed a significantly and diffusely enhanced vasoconstrictor response to ACh.15 However, these observations do not tell us whether the observed constricting effect of ACh is mainly mediated via a dysfunctional or even absent endothelium or an increased sensitivity of VSMC.

Role of Endothelial Dysfunction in the Pathogenesis of Coronary Artery Spasm Endothelial dysfunction comprises a spectrum of pathological conditions involving an imbalance between endothelium-derived substances mediating vasodilation, antimitogenic and antithrombogenic properties and substances with vasoconstricting, prothrombotic and proliferative potential.16 In particular, an involvement of NO and endothelin-1 as typical substances synthesised by the endothelium in the pathogenesis of CAS on the epicardial as well as the microvascular level, is supported by various animal and clinical studies. Furthermore, immunohistological findings in endomyocardial biopsies of symptomatic patients with unobstructed coronary arteries revealed an increased expansion of activated endothelial cells, indicating impaired endothelial integrity in patients with microvascular spasm.17

Role of Nitric Oxide Since NO is one of the most important endothelium-derived vasodilators, impaired NO bioavailability plays a crucial role in endothelial dysfunction. In the setting of CAS, several clinical studies suggested an impaired endothelial NO bioactivity in epicardial coronary

Ischaemic Heart Disease Table 1: Clinical Presentation, Definition and Diagnostic Criteria of Coronary Artery Spasm Clinical Characteristics Heterogeneous clinical presentation regarding: • Rest- and/or exercise-related angina • And/or dyspnoea • Severity and frequency of symptoms • Presence/absence of coronary atherosclerotic changes

Coronary Reactivity Testing in Response to Intracoronary Acetylcholine • Ischaemic electrocardiographic changes (≥1 mm ST-segment depression or elevation) • Reproduction of patient’s usual symptoms

Epicardial Spasm Focal: • Diameter reduction ≥90% within the borders of one coronary segment Diffuse: • Diameter reduction ≥90% in ≥2 adjacent coronary segments

Microvascular Spasm • Epicardial vasoconstriction <90%

arteries of patients with CAS.18,19 Besides, the clinically observed strong vasodilatory effect of the NO donor nitro-glycerine in patients with CAS is also likely to be related to a reduced bioavailability of endogenous NO, which results in a higher basal tone and decreased coronary diameter.15,18 The association of predisposition for CAS with mutations, such as T-786-C, and polymorphisms, such as NOS4a and Glu298Asp, in the endothelial NO-synthase gene (NOS3) further supports the contribution of an impaired endothelial NO bioactivity and endothelial dysfunction in the pathogenesis of CAS.20–2 However, CAS may not only occur at the epicardial but also at the microvascular level. In this regard, experimental ex vivo studies in rat and human arteries indicate the existence of a vessel size depending on the heterogeneity of endothelial vasodilator functions with a predominate contribution of NO to vascular relaxation in relatively large, conduit arteries, such as the aorta and epicardial coronary arteries, while EDHF plays a greater role in resistance arteries, such as the coronary microvessels.11,23,24

Role of Endothelin-1 Endothelin-1 (ET-1), one of the most potent vasoconstrictors, is increased in the coronary and systemic circulation in patients with coronary endothelial dysfunction. Several clinical studies demonstrated higher ET-1 plasma levels in the coronary sinus – baseline as well as during CAS provocation – in patients with a positive epicardial CAS provocation test indicated by vasoconstriction in response to ACh, compared with patients with a normal vasodilatory response.25–27 Although the endothelium is a major source of ET-1, it has been shown that ET-1 is also expressed in macrophages and intimal VSMCs in atherosclerotic tissue specimens from patients who underwent percutaneous revascularisation.28 Furthermore, expression of endothelin-converting enzyme-1 (ECE-1), the key enzyme in ET-1 processing, was ascertained in neointimal VSMCs in rat balloon-denuded arteries as well as in VSMCs and macrophages in human coronary atherosclerotic lesions.29 Experimental and clinical studies provide further evidence that ET-1 is also involved in the pathogenesis of coronary microvascular spasm. In a porcine coronary microvascular spasm model, repeated endothelial

denudation of epicardial coronary arteries increased the plasma levels of ET-1 in coronary sinus blood compared with the control group without endothelial denudation, while the chronic administration of an ETA receptor antagonist prevented the coronary microvascular vasoconstrictive response to ACh.30 In a placebo-controlled clinical trial in patients with coronary microvascular dysfunction (defined by a ≤50% increase in coronary blood flow [CBF] in response to the maximal dose of ACh compared with baseline CBF) and non-obstructed CAD, Reriani et al. demonstrated an improvement of microvascular endothelial function after long-term (>6 months) treatment with the ETA receptor antagonist atrasentan.31 Ford et al. used a case-control study to compare peripheral endothelial function and vascular reactivity in patients with epicardial spasm (defined as VSA; vasospastic angina) or coronary microvascular dysfunction (defined as MVA; microvascular angina) with control subjects who had stable chest pain but a normal intracoronary vasoreactivity test result. For the functional ex vivo wire myographybased experiments small resistance arteries (diameter <400 µm) were dissected from gluteal subcutaneous fat biopsies. Reduced vasorelaxation in response to ACh and increased vasoconstrictive response to ET-1 was found in VSA and MVA patients compared with control subjects, indicating a generalised systemic microvascular dysfunction in these patients. This study identifies ET-1 as a potential mediator of endothelial dysfunction and enhanced vasoconstriction in VSA and MVA.32

Role of Vascular Smooth Muscle Cell Hyperreactivity in the Pathogenesis of Coronary Artery Spasm Vascular tone, defined as the ratio of baseline/maximal vessel diameter, is related to the contractile state of VSMCs. Various mechanisms and stimuli act through activation and inactivation of intracellular pathways involved in the phosphorylation of myosin light chain (MLC) resulting in VSMC contraction. When there is a background of overproduction of contractile stimulators such as ET-1 or absence of relaxing factors such as NO, any additional otherwise innocent contractile stimulus might result in CAS. However, CAS could also be elicited by a low concentration of a contractile stimulus acting on an abnormally sensitive receptor on the VSMCs. Theoretically, dysfunctions in all components of signal transduction involved in the complex regulation of VSMC contraction may contribute to VSMC hyperreactivity, including receptors and ion channels as well as intracellular G-proteins, such as RhoA, and enzymes, such as Rho-kinase and protein kinase C).8,10 A central role of abnormalities located at the level of the VSMCs in the pathogenesis of CAS is also supported by clinical evidence demonstrating that CAS can be provoked by a variety of substances, such as ACh, dopamine, serotonin and histamine, acting directly on VSMCs through different intracellular mechanisms.33–36 Although the cellular and molecular mechanisms triggering VSMC hypercontraction and CAS are still incompletely understood, an increased Rho-kinase activity within the VSMC seems to be substantially involved in the pathogenesis of CAS.37–39 Animal models for CAS demonstrated an upregulation of Rho-kinase in spastic segments of coronary arteries, whereas the Rho-kinase-inhibitor hydroxyfasudil prevented dose-dependently coronary hyperconstrictions.37,38 Fasudil also markedly attenuates ACh-induced coronary vasoconstriction in the clinical setting by preventing the occurrence of chest pain and ischaemic ECG changes in patients with CAS.39 It also ameliorates myocardial

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Pathophysiological Mechanisms of Coronary Artery Spasm ischaemia in patients with microvascular dysfunction.40 However, little is known about mechanisms leading to upregulation and increased activity of Rho-kinase. In this regard, inflammatory mechanisms have been proposed as important contributors causing upregulation of Rhokinase. In a porcine model chronic focal application of interleukin-1-beta (IL-1-beta), a major inflammatory cytokine, induces coronary intimal lesions at the site of treatment. Focal vasospasm can be provoked at these sites in response to intracoronary serotonin and histamine.41 In further studies using the same porcine model, serotonin-induced hypercontractions at the IL-1-beta-treated site were dose-dependently inhibited by the Rho-kinase inhibitors hydroxyfasudil and Y-27632.37,38 Moreover, upregulation of Rho-kinase expression in the spastic segment seems to be involved in inducing VSMC hypercontraction by inhibition of MLC phosphatase through phosphorylation of the myosinbinding subunit.38 The role of Rho-kinase upregulation by inflammatory pathways is further supported by Hiroki et al. demonstrating that inflammatory stimuli, such as angiotensin II and interleukin-1-beta, upregulate the expression and activation of Rho-kinase in human VSMCs both at RNA- and protein-levels in a time- and concentrationdependent manner. The PKC/NF-κB signalling pathway is apparently involved in the inflammatory stimuli-induced upregulation of Rhokinase both in vitro and in vivo.42

Endothelial Dysfunction Versus Vascular Smooth Muscle Cell Hyperreactivity Although there is consistent evidence that endothelial dysfunction is involved in the pathogenesis of CAS, an exclusive role of endothelial dysfunction is challenged by several clinical observations. First, endothelial dysfunction is often associated with common cardiovascular risk factors, such as hypertension, diabetes, dyslipidaemia and atherosclerosis, whereas the prevalence for CAS is comparatively much lower. Thus, it is not surprising that ACh-induced CAS is seen less frequently in patients with chest pain, hypertension and uncontrolled blood pressure or diabetes than in patients without these risk factors.43,44 Moreover, it could be shown by using substance P for the assessment of endothelial-dependent vasodilation, which in contrast to ACh has no direct vasoconstricting action on VSMCs, that endothelium-dependent vasodilation may even be preserved in the spastic segments of epicardial coronary arteries in patients with CAS suggesting that focal vasospasm may result from focal hyperactivity of VSMC.45,46 Clinical findings by Kaski et al. support the hypothesis that focal CAS in patients with variant angina primarily arises from VSMC hyperreactivity to vasoactive stimuli. This study showed that in patients with documented spontaneous CAS, ergonovine-induced CAS was seen at the same site. This indicates that in the presence of a generalised stimulus affecting all coronary arteries, CAS may only occur at a site of local coronary hyperreactivity.47 Distinguishing between endothelial and VSMC dysfunction and the influence on the development of CAS is further hampered by the various angiographic constellations associated with this condition. Most of the findings listed above that indicate a major role for local VSMC abnormalities were obtained in patients with variant angina. This condition is commonly associated with focal sub-occlusive or occlusive spasm.48 However, this angiographic constellation is only infrequently encountered in patients with CAS. When challenged by ACh, a pattern of distally pronounced diffuse spasm of the entire coronary artery is much more commonly encountered.49 The second most frequent finding is microvascular spasm which is characterised by

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angiographically mild constriction of the epicardial coronary arteries associated with the reproduction of chest pain and often pronounced ST segment depression.50 In the latter two types of spasm we know much less about the respective contribution of abnormalities in endothelial cells and VSMC. Precise characterisation of the clinical picture, the angiographic appearance of the coronary arteries at baseline and the reaction to provocative testing is a cornerstone of understanding the pathophysiology behind CAS. It is likely that the pathophysiology behind CAS is as variable as the clinical presentation and the angiographic patterns.

Role of Chronic Low-grade Inflammation Accumulating evidence from experimental studies indicate that inflammatory conditions, in particular, via an involvement of Rho-kinase upregulation, may play an important role in the pathogenesis of CAS. An association of CAS with inflammation is also suggested in the clinical setting. Biomarkers of inflammation, such as high-sensitivity C-reactive protein (hs-CRP) and soluble CD40 ligand, are increased in patients with coronary vasospastic angina and unobstructed coronary arteries compared with patients with non-vasospastic angina.51–53 Even minor elevations of hs-CRP serum level are significantly and independently associated with CAS, suggesting that a chronic lowgrade inflammatory state may also contribute to CAS susceptibility.52 The observation that cigarette smoking is significantly and independently associated with CAS occurrence and there is an association of increased hs-CRP levels with smoking further supports an involvement of chronic low-grade inflammation in CAS.54 However, inflammation can work as a trigger for both endothelial dysfunction and VSMC hyperreactivity. The exposure of the endothelium to circulating proinflammatory mediators in infective or inflammatory states is associated with impaired endothelial function and inflammation has also been considered as a cardiovascular risk factor.55,56 Elevated CRP levels were identified as a significant independent predictor of a blunted systemic endothelial vasodilator capacity in patients with CAD, while normalisation of CRP levels was associated with a significant improvement of the endotheliumdependent vascular function.57 On the other hand it was shown in an experimental porcine model with chronic IL-1-beta treatment that endothelium-mediated coronary vasodilatation in response to bradykinin, substance P, as well as an increase in coronary blood flow, was preserved at the spastic inflammatory site. Further ex vivo organ chamber experiments confirmed increased serotonin-induced contractions at the IL-1-beta-treated spastic site regardless of the presence or absence of the endothelium, suggesting a primary contribution of VSMC hypercontractions in this model of CAS.58 Based on these observations, it is likely that endothelial dysfunction may provide the background on which additional stimuli manage to produce CAS. Endothelial dysfunction alone could not explain the phasic clinical presentation of patients with vasospasm proven by invasive provocation testing. These patients typically report attacks of resting angina either superimposed on normal exercise tolerance (variant angina) or dyspnoea with exertion, which is more often found in microvascular spasm. Thus, it needs additional triggers, which are not well understood, to explain this pattern of angina in patients with CAS. Endothelial dysfunction, which is a constant condition, alone would probably not explain the sudden occurrence of ≥90% vasoconstriction during coronary spasm provocation test (corresponding to the definition of epicardial CAS according to the

Ischaemic Heart Disease Japanese Circulation Society guidelines) with concomitant reproduction of their usual symptoms at home.5 However, the presence of VSMC hyperreactivity coupled with yet to be identified endogenous triggers seems to be sufficient to explain this phasic angina pattern in patients with CAS. The importance of a primary contribution of functional VSMC impairment is further supported by the clinical observation of cases with recurrent epicardial vasospastic angina refractory to nitrates, which would normally be substituted for insufficient production of endothelial NO.59

Conclusion Due to the heterogeneous clinical presentations of patients with CAS, it is likely that there are several underlying mechanisms involved in its pathogenesis rather than a single mechanism of action. Based on the current knowledge, the presence of VSMC hyperreactivity to vasoactive

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Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography. N Engl J Med 2010;362:886–95. https://doi.org/10.1056/NEJMoa0907272; PMID: 20220183. Ong P, Athanasiadis A, Borgulya G, et al. High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries). J Am Coll Cardiol 2012;59:655–62. https://doi.org/10.1016/j. jacc.2011.11.015; PMID: 22322081. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2019;41:407–77. https://doi.org/10.1093/eurheartj/ ehz425; PMID: 31504439. Ford TJ, Stanley B, Good R, et al. Stratified medical therapy using invasive coronary function testing in angina: The CorMicA Trial. J Am Coll Cardiol 2018;72:2841–55. https://doi. org/10.1016/j.jacc.2018.09.006; PMID: 30266608. JCS Joint Working Group. Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina) (JCS 2013). Circ J 2014;78:2779–801. https:// doi.org/10.1253/circj.CJ-66-0098; PMID: 25273915. Ong P, Camici PG, Beltrame JF, et al. International standardization of diagnostic criteria for microvascular angina. Int J Cardiol 2018;250:16–20. https://doi.org/10.1016/j. ijcard.2017.08.068; PMID: 29031990. Granger DN, Rodrigues SF, Yildirim A, et al. Microvascular responses to cardiovascular risk factors. Microcirculation 2010;17:192–205. https://doi. org/10.1111/j.1549-8719.2009.00015.x; PMID: 20374483. Lanza GA, Careri G, Crea F. Mechanisms of coronary artery spasm. Circulation 2011;124:1774–82. https://doi.org/10.1161/ CIRCULATIONAHA.111.037283; PMID: 22007100. Ong P, Aziz A, Hansen HS, et al. Structural and functional coronary artery abnormalities in patients with vasospastic angina pectoris. Circ J 2015;79:1431–8. https://doi.org/10.1253/ circj.CJ-15-0520; PMID: 26084380. Pries AR, Badimon L, Bugiardini R, et al. Coronary vascular regulation, remodelling, and collateralization: mechanisms and clinical implications on behalf of the working group on coronary pathophysiology and microcirculation. Eur Heart J 2015;36:3134–46. https://doi.org/10.1093/eurheartj/ehv100; PMID: 26112888. Shimokawa H. 2014 Williams Harvey Lecture: importance of coronary vasomotion abnormalities-from bench to bedside. Eur Heart J 2014;35:3180–93. https://doi.org/10.1093/eurheartj/ ehu427; PMID: 25354517. Busse R, Fleming I, Hecker M. Signal transduction in endothelium-dependent vasodilatation. Eur Heart J 1993;14(Suppl I):2–9. PMID: 8293777. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373–6. https://doi. org/10.1038/288373a0; PMID: 6253831. Shimizu H, Lee JD, Ogawa K, et al. Coronary artery vasoreactivity to intracoronary acetylcholine infusion test in patients with chest pain syndrome. Intern Med 1992;31:22–7. https://doi.org/10.2169/internalmedicine.31.22; PMID: 1568038. Okumura K, Yasue H, Matsuyama K, et al. Diffuse disorder of coronary artery vasomotility in patients with coronary spastic angina. J Am Coll Cardiol 1996;27:45–52. https://doi. org/10.1016/0735-1097(95)00432-7; PMID: 8522709. Flammer AJ, Anderson T, Celermajer DS, et al. The assessment of endothelial function: from research into clinical practice. Circulation 2012;126:753–67. https://doi.org/10.1161/ CIRCULATIONAHA.112.093245; PMID: 22869857. Lindemann H, Petrovic I, Hill S, et al. Biopsy-confirmed endothelial cell activation in patients with coronary

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

stimuli seems to be required to explain the phasic clinical pattern seen in patients with CAS. Endothelial dysfunction could provide the background for development of CAS by increasing coronary vascular tone. However, this rather constant milieu provided by the endothelium alone cannot explain the phasic occurrence of angina which is associated with ≥90% vasoconstriction. Abnormalities at the level of the VSMC are also likely to be required to fully explain the clinical picture encountered in patients with the different forms of CAS. Rhokinase inhibitors, acting directly at the level of the VSMCs by inhibition of Rho-kinase mediated vasoconstriction as well as ETA receptor antagonists, counteracting the increased production of endothelin-1 by dysfunctional endothelial cells, are potential approaches to successfully treat CAS. However, further studies elucidating the underlying pathophysiology of the various forms of CAS are urgently needed before targeted pharmacological therapies can be designed.

microvascular dysfunction. Coron Artery Dis 2018;29:216–22. https://doi.org/10.1097/MCA.0000000000000599; PMID: 29315085. Kugiyama K, Yasue H, Okumura K, et al. Nitric oxide activity is deficient in spasm arteries of patients with coronary spastic angina. Circulation 1996;94:266–71. https://doi.org/10.1161/01. CIR.94.3.266; PMID: 8759065. Kugiyama K, Ohgushi M, Motoyama T, et al. Nitric oxidemediated flow-dependent dilation is impaired in coronary arteries in patients with coronary spastic angina. J Am Coll Cardiol 1997;30:920–6. https://doi.org/10.1016/S07351097(97)00236-2; PMID: 9316519. Nakayama M, Yasue H, Yoshimura M, et al. T-786-C mutation in the 5‘-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 1999;99:2864–70. https://doi.org/10.1161/01.CIR.99.22.2864; PMID: 10359729. Chang K, Baek SH, Seung KB, et al. The Glu298Asp polymorphism in the endothelial nitric oxide synthase gene is strongly associated with coronary spasm. Coron Artery Dis 2003;14:293–9. https://doi.org/10.1097/01. mca.0000073080.69657.71; PMID: 12826928. Kaneda H, Taguchi J, Kuwada Y, et al. Coronary artery spasm and the polymorphisms of the endothelial nitric oxide synthase gene. Circ J 2006;70:409–13. https://doi.org/10.1253/ circj.70.409; PMID: 16565556. Shimokawa H, Yasutake H, Fujii K, et al. The importance of the hyperpolarizing mechanism increases as the vessel size decreases in endothelium-dependent relaxations in rat mesenteric circulation. J Cardiovasc Pharmacol 1996;28:703–11. https://doi.org/10.1097/00005344-199611000-00014; PMID: 8945685. Urakami-Harasawa L, Shimokawa H, Nakashima M, et al. Importance of endothelium-derived hyperpolarizing factor in human arteries. J Clin Invest 1997;100: 2793–9. https://doi. org/10.1172/JCI119826; PMID: 9389744. Lerman A, Holmes DR, Bell MR, et al. Endothelin in coronary endothelial dysfunction and early atherosclerosis in humans. Circulation 1995;92:2426–31. https://doi.org/10.1161/01. CIR.92.9.2426; PMID: 7586341. Matsuyama K, Yasue H, Okumura K, et al. Increased plasma level of endothelin-1-like immunoreactivity during coronary spasm in patients with coronary spastic angina. Am J Cardiol 1991;68:991–5. https://doi.org/10.1016/0002-9149(91)90484-3; PMID: 1927939. Toyo-oka T, Aizawa T, Suzuki N, et al. Increased plasma level of endothelin-1 and coronary spasm induction in patients with vasospastic angina pectoris. Circulation 1991;83:476–83. https://doi.org/10.1161/01.CIR.83.2.476; PMID: 1825037. Zeiher AM, Goebel H, Schächinger V, et al. Tissue endothelin-1 immunoreactivity in the active coronary atherosclerotic plaque. A clue to the mechanism of increased vasoreactivity of the culprit lesion in unstable angina. Circulation 1995;91:941–7. https://doi.org/10.1161/01.CIR.91.4.941; PMID: 7850978. Minamino T, Kurihara H, Takahashi M, et al. Endothelinconverting enzyme expression in the rat vascular injury model and human coronary atherosclerosis. Circulation 1997;95:221– 30. https://doi.org/10.1161/01.CIR.95.1.221; PMID: 8994440. Osugi T, Saitoh SI, Matumoto K, et al. Preventive effect of chronic endothelin type A receptor antagonist on coronary microvascular spasm induced by repeated epicardial coronary artery endothelial denudation in pigs. J Atheroscler Thromb 2010;17:54– 63. https://doi.org/10.5551/jat.2147; PMID: 20075598. Reriani M, Raichlin E, Prasad A, et al. Long-term administration of endothelin receptor antagonist improves coronary endothelial function in patients with early atherosclerosis. Circulation 2010;122:958–66. https://doi.org/10.1161/ CIRCULATIONAHA.110.967406; PMID: 20733096.

32. Ford TJ, Rocchiccioli P, Good R, et al. Systemic microvascular dysfunction in microvascular and vasospastic angina. Eur Heart J 2018;39:4086–97. https://doi.org/10.1093/eurheartj/ehy529; PMID: 30165438. 33. Yasue H, Horio Y, Nakamura N, et al. Induction of coronary artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nervous system in the pathogenesis of coronary artery spasm. Circulation 1986;74:955–63. https://doi.org/10.1161/01.CIR.74.5.955; PMID: 3769179. 34. Crea F, Chierchia S, Kaski JC, et al. Provocation of coronary spasm by dopamine in patients with active variant angina pectoris. Circulation 1986;74:262–9. https://doi.org/10.1161/01. CIR.74.2.262; PMID: 3731418. 35. McFadden EP, Clarke JG, Davies GJ, et al. Effect of intracoronary serotonin on coronary vessels in patients with stable angina and patients with variant angina. N Engl J Med 1991;324:648–54. https://doi.org/10.1056/ NEJM199103073241002; PMID: 1994247. 36. Ginsburg R, Bristow MR, Kantrowitz N, et al. Histamine provocation of clinical coronary artery spasm: Implications concerning pathogenesis of variant angina pectoris. Am Heart J 1981;102:819–22. https://doi.org/10.1016/0002-8703(81)900302; PMID: 6795908. 37. Shimokawa H. Rho-kinase-mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm. Cardiovasc Res 1999;43:1029– 39. https://doi.org/10.1016/S0008-6363(99)00144-3; PMID: 10615430. 38. Kandabashi T, Shimokawa H, Miyata K, et al. Inhibition of myosin phosphatase by upregulated rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1beta. Circulation 2000;101:1319–23. https://doi. org/10.1161/01.CIR.101.11.1319; PMID: 10725293. 39. Masumoto A, Mohri M, Shimokawa H, et al. Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation 2002;105: 1545–7. https://doi.org/10.1161/hc1002.105938; PMID: 11927519. 40. Fukumoto Y, Mohri M, Inokuchi K, et al. Anti-ischemic effects of fasudil, a specific Rho-kinase inhibitor, in patients with stable effort angina. J Cardiovasc Pharmacol 2007;49:117–21. https://doi.org/10.1097/FJC.0b013e31802ef532; PMID: 17414222. 41. Shimokawa H, Ito A, Fukumoto Y, et al. Chronic treatment with interleukin-1 beta induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of plateletderived growth factor. J Clin Invest 1996;97:769–76. https://doi. org/10.1172/JCI118476; PMID: 8609234. 42. Hiroki J, Shimokawa H, Higashi M, et al. Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells. J Mol Cell Cardiol 2004;37:537–46. https://doi. org/10.1016/j.yjmcc.2004.05.008; PMID: 15276023. 43. Chen K-Y, Rha S-W, Li Y-J, et al. Impact of hypertension on coronary artery spasm as assessed with intracoronary acetylcholine provocation test. J Hum Hypertens 2010;24:77–85. https://doi.org/10.1038/jhh.2009.40; PMID: 19458625. 44. Li Y-J, Hyun MH, Rha S-W, et al. Diabetes mellitus is not a risk factor for coronary artery spasm as assessed by an intracoronary acetylcholine provocation test: angiographic and clinical characteristics of 986 patients. J Invasive Cardiol 2014;26:234–9; PMID: 24907077. 45. Egashira K, Inou T, Yamada A, et al. Preserved endotheliumdependent vasodilation at the vasospastic site in patients with variant angina. J Clin Invest 1992;89:1047–52. https://doi. org/10.1172/JCI115646; PMID: 1371774. 46. Yamamoto H, Yoshimura H, Noma M, et al. Preservation of endothelium-dependent vasodilation in the spastic segment of the human epicardial coronary artery by substance P. Am Heart J 1992;123:298–303. https://doi.org/10.1016/0002-

EUROPEAN CARDIOLOGY REVIEW

Pathophysiological Mechanisms of Coronary Artery Spasm 8703(92)90638-C; PMID: 1371034. 47. Kaski JC, Maseri A, Vejar M, et al. Spontaneous coronary artery spasm in variant angina is caused by a local hyperreactivity to a generalized constrictor stimulus. J Am Coll Cardiol 1989;14:1456–63. https://doi.org/10.1016/0735-1097(89)903823; PMID: 2809004. 48. Beltrame JF, Crea F, Kaski JC, et al. International standardization of diagnostic criteria for vasospastic angina. Eur Heart J 2017;38:2565–8. https://doi.org/10.1093/eurheartj/ ehv351; PMID: 26245334. 49. Ong P, Athanasiadis A, Sechtem U. Patterns of coronary vasomotor responses to intracoronary acetylcholine provocation. Heart 2013;99:1288–95. https://doi.org/10.1136/ heartjnl-2012-302042; PMID: 23442537. 50. Ong P, Athanasiadis A, Borgulya G, et al. Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive white patients with unobstructed coronary arteries. Circulation 2014;129:1723–30. https://doi.org/10.1161/ CIRCULATIONAHA.113.004096; PMID: 24573349.

EUROPEAN CARDIOLOGY REVIEW

51. Hung MJ, Cherng WJ, Yang NI, et al. Relation of high-sensitivity C-reactive protein level with coronary vasospastic angina pectoris in patients without hemodynamically significant coronary artery disease. Am J Cardiol 2005;96:1484–90. https:// doi.org/10.1016/j.amjcard.2005.07.055; PMID: 16310426. 52. Itoh T, Mizuno Y, Harada E, et al. Coronary spasm is associated with chronic low-grade inflammation. Circ J 2007;71:1074–8. https://doi.org/10.1253/circj.71.1074; PMID: 17587713. 53. Ong P, Carro A, Athanasiadis A, et al. Acetylcholine-induced coronary spasm in patients with unobstructed coronary arteries is associated with elevated concentrations of soluble CD40 ligand and high-sensitivity C-reactive protein. Coron Artery Dis 2015;26:126–32. https://doi.org/10.1097/ MCA.0000000000000181; PMID: 25405929. 54. Hung MY, Hsu KH, Hung MJ, et al. Interaction between cigarette smoking and high-sensitivity C-reactive protein in the development of coronary vasospasm in patients without hemodynamically significant coronary artery disease. Am J Med Sci 2009;338:440–6. https://doi.org/10.1097/ MAJ.0b013e3181b9147f; PMID: 20010154.

55. Vallance P, Collier J, Bhagat K. Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link? Lancet 1997;349:1391–2. https://doi.org/10.1016/S01406736(96)09424-X; PMID: 9149715. 56. Willerson JT, Ridker PM. Inflammation as a cardiovascular risk factor. Circulation 2004;109(21 Suppl 1):II2–10. https://doi. org/10.1161/01.CIR.0000129535.04194.38; PMID: 15173056. 57. Fichtlscherer S, Rosenberger G, Walter DH, et al. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation 2000;102:1000–6. https://doi.org/10.1161/01. CIR.102.9.1000; PMID: 10961964. 58. Miyata K, Shimokawa H, Yamawaki T, et al. Endothelial vasodilator function is preserved at the spastic/inflammatory coronary lesions in pigs. Circulation 1999;100:1432–7. https:// doi.org/10.1161/01.CIR.100.13.1432; PMID: 10500045. 59. Freeman WR, Peter T, Mandel WJ. Verapamil therapy in variant angina pectoris refractory to nitrates. Am Heart J 1981;102:358– 62. https://doi.org/10.1016/0002-8703(81)90309-4; PMID: 6791484.

Heart Failure

Asymptomatic Left Ventricle Systolic Dysfunction Jaskanwal D Sara,1 Takumi Toya,1,2 Riad Taher,1 Amir Lerman,1 Bernard Gersh1 and Nandan S Anavekar1 1. Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, US; 2. Division of Cardiology, National Defense Medical College, Tokorozawa, Japan

Abstract Heart failure is a common debilitating illness, associated with significant morbidity and mortality, rehospitalisation and societal costs. Current guidelines and position statements emphasise the management of patients with overt symptomatic disease, but the increasing prevalence of congestive heart failure underscores the need to identify and manage patients with early left ventricular dysfunction prior to symptom onset. Asymptomatic left ventricular systolic dysfunction (ALVSD), classified as stage B heart failure, is defined as depressed left ventricular systolic function in the absence of clinical heart failure. Early initiation of therapies in patients with presumed ALVSD has been shown to lead to better outcomes. In this article, the authors clarify issues surrounding the definition and natural history of ALVSD, outline clinical tools that may be of value in identifying patients with ALVSD and highlight potential opportunities for future investigations to better address aspects of our understanding of this complex syndrome.

Keywords Asymptomatic, heart failure, left ventricular dysfunction, systolic impairment Disclosure: The authors have no conflicts of interest to declare. Received: 21 October 2019 Accepted: 6 January 2020 Citation: European Cardiology Review 2020;15:e13. DOI: https://doi.org/10.15420/ecr.2019.14 Correspondence: Nandan Anavekar, Department of Cardiovascular Diseases, Mayo College of Medicine, 200 First Street SW, Rochester, MN 55905, US. E: anavekar.nandan@mayo.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Heart failure (HF) affects more than 6 million people in the US and results in more than 1 million hospitalisations per year.1 In patients aged ≥65 years, there are more hospitalisations for a primary diagnosis of HF than any other condition.2 HF is a debilitating illness, associated with significant morbidity and mortality, rehospitalisation and societal costs.3 Current guidelines and position statements emphasise the management of patients with overt symptomatic disease, but the aging of the population and the increasing prevalence of congestive HF underscores the need for a shift towards effective prevention and management of patients with left ventricular (LV) dysfunction prior to the development of symptoms. HF is considered a progressive disorder characterised by four stages: • Stage A, at high risk of developing HF; • Stage B, structural heart disease without symptoms of HF; and • Stage C/D, structural heart disease with symptoms related to HF.4 Asymptomatic LV systolic dysfunction (ALVSD), classified as stage B HF, is defined as depressed LV systolic function in the absence of clinical HF (Figure 1). The early initiation of therapies in patients with presumed ALVSD has been shown to lead to better outcomes.5,6 Nevertheless, there is considerable uncertainty surrounding the current definition of ALVSD, its prevalence and clinical importance and the clinical tools that may be of value in guiding management. In this article, we clarify these issues and highlight potential opportunities for future investigations to better address aspects of our understanding of this complex syndrome.

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Prevalence and Prognosis of Asymptomatic Left Ventricular Systolic Dysfunction In the Cardiovascular Health Study, echocardiography was performed in 5,649 subjects,7 7.3% of whom were classified as having ALVSD with an LV ejection fraction (EF) <55%.8 This was a population-based longitudinal study among adults aged ≥65 years with a history of coronary artery disease and stroke who were sampled from Medicare eligibility lists in predetermined geographic regions of the US. The study was undertaken in 1989 and advances in risk factor management and pharmacotherapy have changed the clinical profile of cardiovascular patients since then. Nevertheless, that study permitted evaluation of cardiovascular risk factors in older adults, as well as in particular groups that had previously been under-represented in epidemiological studies, such as women, which accounted for almost 50% of the Cardiovascular Health Study cohort. In another population-based sample of 2,029 participants aged >45 years, 23% had stage B HF, characterised by asymptomatic cardiac structural or functional abnormalities with an LVEF <50%.9 Among patients with stage B HF, the risk of all-cause mortality was fourfold greater in men than in women after adjusting for age (p=0.01), and there was a tendency for an 1.8-fold increased risk of all-cause mortality for those with stage B HF after adjusting for age and sex compared with patient with stage A HF (p=0.08). Further, deterioration from stage B to stage C HF was associated with a significant increase in all-cause mortality (HR 9.6; 95% CI [6.8–13.6]; p<0.0001).9 That study was based on residents from Olmsted County (MN, US), which comprises >90%

Asymptomatic Systolic Dysfunction white people of northern European descent, representing a largely homogeneous and select racial group. Further, observations from the Framingham Study revealed that subjects with ALVSD had a nearly fourfold increased risk of death than subjects with a normal LVEF >50%.10 In another study, compared with individuals with a normal LVEF (≥55%), ALVSD was associated with an increased risk of incident HF (HR 1.60; 95% CI [1.35–1.91]), cardiovascular mortality (HR 2.13; 95% CI [1.81–2.51]) and all-cause mortality (HR 1.46; 95% CI [1.29–1.64]), albeit with a lower risk than individuals with symptomatic LV systolic dysfunction.8 That study included patients with a mean age of 73.0 (SD ±5.6) years who were followed for a median duration of 11.7 years. In addition, in a meta-analysis that included 11 studies evaluating 25,369 patients with ALVSD followed-up for a mean period of 7.9 years, the investigators found an adjusted relative risk of 4.6 for progression to overt HF.11 The risk of progression to overt HF was higher in patients with an LVEF <40% than in those with a mid-range LVEF of 40–49% (HR 7.8 vs. 3.3, respectively).10 These individuals are not only at risk of progressing to stage C/D HF, but are also at an increased risk of death. Further studies including younger and more diverse populations that also follow-up patients for longer periods of time could contribute more to our understanding of the natural history of ALVSD and the role played by conventional cardiovascular risk factors, including hypertension and diabetes, the presence of coronary artery disease and the implementation of cardiovascular pharmacotherapy. Nevertheless, there appears to be a significant association between ALVSD and conversion to clinically overt HF, as well as increased mortality, underscoring the importance of detecting ALVSD early. Detection of ALVSD could allow for the early initiation of interventions such as pharmacological therapy to mitigate the progression of disease and improve outcomes in this group.11 However, at present routine echocardiography to screen for ALVSD is not recommended, and has not been shown to be cost-effective.12 Consequently, alternative cheaper, non-invasive tools that could assist in the identification of patients with or at risk of developing ALVSD could be of value.

Imaging Techniques to Assess Asymptomatic Left Ventricular Systolic Dysfunction Congestive HF is often the end stage of progressive deterioration of LV function, which can remain asymptomatic for many years. In fact, ALVSD is considered to be as common in the general population as overt congestive HF.13 Numerous challenges arise when attempting to classify ALVSD as a homogeneous syndrome. In particular, studies defining ALVSD in patients have focused exclusively on LVEF, which can lead to a number of challenges. First, studies have used multiple different cut-offs as their definition for impaired LVEF, ranging from more typically <50% to less frequently <35%, creating a heterogeneous group of individuals who are likely to have different phenotypes, risk for progression and prognosis despite having no symptoms. Although decreases in LVEF indeed correlate with worse clinical outcomes,14,15 the inverse relationship between LVEF and mortality plateaus at an LVEF of 40–45%, above which LVEF may not be directly related to mortality.15 Second, this definition focuses purely on systolic function, and moreover defines systolic function solely on the basis of LVEF, which

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Figure 1: Summary of an Approach to the Management of Heart Failure Through its Different Stages Stage A

Stage B

Stage C

Stage D

High risk of developing HF

Asymptomatic cardiac structural or functional abnormalities with an LVEF <50%

Structural heart disease with symptoms related to HF

Progressive and/or persistent features of HF despite optimised medical therapy

Risk factors

Pharmacological therapy

• Age • Hypertension • Diabetes • Family history of HF

• Early implementation of HF-directed pharmacotherapy • ACE inhibitors • Beta-blockers • ? SGLT2 inhibitors in diabetics

ALVSD

Diagnostic tools

Prognostic tools

• Conventional echocardiography • GLS with speckletracking analysis of 2D echocardiography

• Serum BNP/NT-pro BNP levels • ECG combined with machine learning • Peripheral endothelial function ACE = angiotensin-converting enzyme; ALVSD = asymptomatic left ventricular systolic dysfunction; BNP = B-type natriuretic peptide; GLS = global longitudinal strain; HF = heart failure; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal pro B-type natriuretic peptide; SGLT2 = sodium–glucose cotransporter 2.

represents only a single facet of ventricular function. This approach creates an arbitrary separation between systole and diastole, rather than evaluating cardiac function throughout the entirety of the cardiac cycle, and excludes the potential role of diastolic function, which, in itself, has prognostic value.16,17 Third, LVEF can change substantially depending on loading conditions of the LV, and thus does not necessarily reflect intrinsic myocardial contractile property.18 Fourth, although LVEF has remained a cornerstone of therapeutic decisions relevant to myocardial performance, it can remain normal despite the presence of significant LV dysfunction related to other coexisting factors, including LV hypertrophy and/or decreased cavity size, leading, in turn, to a reduced stroke volume.19 Thus, a definition limited to LVEF could overlook the broader evaluation of ventricular function. The assessment of global longitudinal strain (GLS) from speckle-tracking analysis of 2D echocardiography has become a clinically feasible adjunct to LVEF for the assessment of myocardial function. In fact, GLS correlates with mortality independent of and incremental to LVEF in patients with HF with a reduced EF and following an acute MI.20–22 In a meta-analysis including 5,721 patients across 16 studies, the investigators showed that GLS was a stronger predictor than LVEF of all-cause mortality, as well as a composite of cardiac death, HF hospitalisation and malignant arrhythmias, and could, in fact, add incremental predictive value for mortality in individuals with an LVEF >35%.23 In addition, GLS has been proposed as the test of choice for monitoring asymptomatic cardiotoxicity related to chemotherapy, where impairments in GLS have been shown to precede and predict reductions in LVEF.24,25 Reduced myocardial deformational characteristics have also been demonstrated as the only sign of LV dysfunction in other groups at risk of HF. For example, in individuals with hypertension and a normal LVEF, independent of LV hypertrophy and diastolic dysfunction, reduced longitudinal strain confers an elevated cardiovascular risk.26,27 In asymptomatic individuals with diabetes, of whom up to one-third have an abnormal GLS with normal LVEF and diastolic function, GLS predicts

Heart Failure worse outcomes in individuals with a normal LVEF.28–30 Further, in individuals with valvular heart disease, there is increasing evidence to suggest that GLS may be of independent predictive value over and above LVEF.31–33 Thus, although evaluating GLS may be technically challenging, its practical incorporation as a material index of myocardial function could enhance the ability to identify individuals with ALVSD across a range of cardiac diseases, and potentially with greater accuracy than currently used LVEF. Further studies are required to evaluate the potential utility of GLS in this regard. Other issues related to identifying individuals with putative ALVSD include the fact that studies have relied largely on echocardiography, which has its own limitations with interobserver variability associated with differences in operator expertise and quality of image acquisition, as well as systemic limitations related to geometric assumptions and LV cavity border tracing. Alternative imaging modalities to identify ALVSD, such as cardiac MRI (CMR) and multigated acquisition scans, have featured less frequently in studies. Despite not carrying the same issues related to operator dependence, these techniques have their unique modalityspecific limitations and provide measurements of LVEF that correlate differentially with those obtained using other imaging techniques. CMR in particular has been regarded as the gold standard to measure ventricular volumes and mass using a simple acquisition of a 2D stack of contiguous short-axis cines with full biventricular coverage, primarily due to its accuracy and reproducibility.34,35 GLS can be quantified using CMR, and correlates well with GLS measured by echocardiography.36 Although the clinical utility of CMR has developed rapidly as a consequence of remarkable advances in technology and imaging techniques, high cost and limited availability remain barriers to the widespread expansion and application of this modality when considering screening for ALVSD in the general population. Thus, improved clarification of the definition of ALVSD in terms of which modality is used and which parameter of systolic and/or diastolic function is evaluated is important and holds additional important benefits. These benefits include: • improving patient selection for clinical trials, which, going forward, could further enhance understanding of this syndrome; • potential reclassification of individuals with stage B HF, which, in turn, could influence decisions regarding the optimal timing and frequency of consultation with specialist cardiology clinics; • determining the nature and timing of pharmacotherapy with the view of preventing disease progression and reducing the risk of adverse events; and • determining when invasive studies, such as coronary angiography, and invasive treatments, such as implantable cardiac device implantation, may be necessary. Further studies are required to clarify the potential role of these interventions.

Non-imaging Tools to Assess Asymptomatic Left Ventricular Systolic Dysfunction Individuals with ALVSD in whom treatment may be prognostically useful should be followed to assess clinical response and to identify those with disease progression. Moreover, clinical tools that offer an ‘abridged’ assessment(s) of cardiac function that could be used during follow-up, to assist with prognostication and to determine whether therapeutic goals are being met would be useful. To date, there have

been a number of studies that have shown promising associations between non-invasive indices of cardiac function and ALVSD, which could potentially fulfil this role.

Serum B-type Natriuretic Peptide Patients with ALVSD have evidence of secondary neurohormonal activation with higher concentrations of noradrenaline, atrial natriuretic peptide and B-type natriuretic peptide (BNP) than controls, but with levels that are lower than those in individuals with symptomatic HF.13,37–39 A previous study provided evidence of a significant association between elevated N-terminal pro BNP (NT-proBNP) concentrations and ALVSD in high-risk groups including those with diabetes or peripheral and cerebrovascular diseases.40,41 However, the largest communitybased investigation using a BNP-based screening strategy to identify ALVSD yielded suboptimal diagnostic utility, with an area under the curve (AUC) of 0.72 in men and 0.56 in women.42 The recently published St Vincent’s Screening To Prevent Heart Failure Study (STOP-HF) randomised trial compared usual primary care against a BNP-based screening strategy among 1,374 participants with cardiovascular risk factors (mean age ± SD: 64.8 ± 10.2 years).43 In that study, the BNP-based screening strategy, using a cut-off value of 50 pg/ml, was associated with reduced combined rates of LV systolic dysfunction, diastolic dysfunction and clinically overt HF among individuals with stage A/B HF.43 Another prospective study involving diabetic patients (mean duration ± SD: 15 ± 12 years, mean HbA1c ± SD: 7.0 ± 1.1%) without known structural heart disease and an NT-proBNP cut-off value >125 pg/ml randomised individuals to either intensified treatment with aggressive up-titration of a renin–angiotensin system antagonist and beta-blocker therapy at a cardiac outpatient clinic or standard care at a diabetes care unit alone.44 Those in the intensified group had a reduced risk of hospitalisation and death due to cardiovascular disease at 2 years.44 Based on the results of these studies, the 2017 American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Failure Society of America focused update of the 2013 ACC Foundation/AHA guideline for the management of heart failure gave class IIa recommendation on the use of a BNP/NT-proBNP-based screening strategy for individuals with stage A/B HF.4 Further studies are necessary to determine the cost-effectiveness of such an approach.

Electrocardiography In a recently published paper, investigators from the Mayo Clinic reported that the application of artificial intelligence to the standard ECG was successfully able to identify individuals with LV dysfunction (LVEF ≤35%).45 After training a convolutional neural network using features from a resting 12-lead ECG in 44,959 patients, the investigators tested their application on an independent set of 52,870 patients and were able to identify individuals with an LVEF ≤35% when diagnosed with an echocardiogram with an AUC, sensitivity, specificity and accuracy of 0.93, 86.3%, 85.7% and 85.7%, respectively. Interestingly, patients who were misclassified as having an abnormal ECG by the artificial intelligence algorithm, despite having a normal LVEF (LVEF >50%) at baseline were found to have a fourfold increased risk of future LV impairment, defined as an LVEF ≤35%, than those with a negative ECG.45 An enhanced understanding of what specific abnormalities the algorithm identifies would be essential going forward. Further, how precisely the artificial intelligence-based application will become

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Asymptomatic Systolic Dysfunction distributed on a population level and whether its detection algorithm will need to be calibrated in large-scale local training samples first before it can be clinically applied remain to be seen. It is likely that the algorithm will first need to undergo further validation in other populations, as well as refinement to detect milder, although nonetheless clinically relevant, LV dysfunction. Nevertheless, ECGbased screening offers promise in providing a ubiquitous and costeffective tool to predict future deterioration of LV function in asymptomatic individuals. Identified individuals could then be encouraged to undergo echocardiography and/or could be advised to have more frequent clinical follow-up than may otherwise be indicated.

Management of Asymptomatic Left Ventricular Systolic Dysfunction

Non-invasive Tools to Measure Peripheral Endothelial Dysfunction

Nevertheless, among the limited data available to address the potential utility of intervening with treatment in patients with ALVSD, the Studies of Left Ventricular Dysfunction (SOLVD) prevention trial showed that the use of enalapril in patients with ALVSD brings about a significant improvement in mortality and morbidity.5 The Trandolapril Cardiac Evaluation (TRACE) trial also showed that the use of trandolapril reduced the risk of mortality in patients with a reduced LVEF (<35%) after MI.60 With further stratification based on patient symptoms, the use of trandolapril was also associated with a significant reduction in mortality, even in patients with ALVSD.60 Among patients with ALVSD, both the SOLVD prevention trial and the Survival and Ventricular Enlargement (SAVE) trial showed that administration of beta-blockers in addition to angiotensin-converting enzyme inhibitors reduced mortality and hospitalisation.1,6 The roles of other HF medication, including digoxin, aldosterone antagonists and direct renin inhibitors, have not been evaluated in patients with ALVSD.

Endothelial dysfunction precedes atherosclerosis and independently leads to adverse cardiovascular events.46 Endothelial dysfunction can be measured peripherally and non-invasively using various tools, including flow-dependent hyperaemia with ultrasound and reactive hyperaemia-peripheral arterial tonometry (RH-PAT), using devices such as EndoPAT (Itamar Medical Ltd, Caesarea, Israel). The association between peripheral endothelial dysfunction (PED) and overt HF has been shown in several studies and supports the notion of vascular–cardiac coupling. In one study following 362 patients with HF and a reduced LVEF for 3 years, a significant association was found between PED and HF-related events, including the composite of cardiovascular death and HF hospitalisation.47 In another study, the authors found that baseline PED predicted HF-related hospitalisation in patients who had implanted cardiac resynchronisation therapy for HF.48 However, the association between PED and ALVSD has not been previously investigated. Regardless of the presence of CAD, HF is associated with endothelial dysfunction due to reduced levels of synthesis, release and/or response to nitric oxide (NO).49–51 Impaired NO-mediated vasodilatory reserve contributes to exercise intolerance by increasing LV afterload and abnormal skeletal muscle signalling.52,53 In mice, a lack of endotheliumderived NO signalling may be associated with reduced capillary density in cardiac muscle through insufficient activation of vascular endothelial growth factor, leading to systolic dysfunction.54 Impaired endotheliummediated vasodilation in HF is a generalised abnormality that occurs in both the peripheral and coronary circulation.55 Previously, we demonstrated that coronary microvascular endothelial dysfunction is present in patients with ALVSD.56 Another study showed that impaired endothelial-dependent vasodilation, measured using forearm blood flow in response to intra-arterial methacholine, was present and near maximal in individuals with mild HF (New York Heart Association class I and II), further evidence that endothelial dysfunction may be an early finding in HF.57 Thus, given the central role of NO bioavailability and activity in the assessment of PED using indices such as RH-PAT, for example, growing evidence suggests that the effects of impaired endothelial-derived NO contribute to the pathophysiology of LV systolic dysfunction and the progression of HF from its early stages.58 Thus, these patients may benefit from the initiation of therapy targeted at the NO pathway to address endothelial dysfunction and, in turn, potentially mitigate the progression to overt HF. The precise relationship between PED and ALVSD needs to be clarified with large prospective trials, and only then can the potential utility of measuring peripheral endothelial function as a screening tool for ALSVD be determined.

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Identifying HF before the onset of symptoms could enable the implementation of therapy at a point along the natural history of the disease that may slow or terminate progression. Indeed, detecting subclinical LV impairment as a surrogate of future development of HF could form a useful clinical model to guide clinicians on the optimal timing of initiating therapy. To date, a screening process to identify individuals with ALVSD has not been endorsed, and further studies evaluating risk–benefit ratios with regard to treatment efficacy and cost implications are required.59

Thus, the SAVE and SOLVD trials both demonstrated that early pharmacological treatment for ALVSD is effective. However, these studies are dated and defined LV impairment as an LVEF of <35–40%. There is a lack of evidence regarding early pharmacological intervention for ALVSD with an LVEF of 40–49%. The Prospective Comparison of ARNi (angiotensin receptor–neprilysin inhibitor) with ARB (angiotensin receptor blocker) Global Outcomes in Heart Failure with Preserved Ejection Fraction (PARAGON-HF) trial, in which the effect of the ARNi sacubitril in combination with valsartan was tested for patients with stage C/D HF and an LVEF >45%, failed to show a reduction in HF hospitalisation and cardiovascular death.61 However, lower LVEF was associated with a reduction in HF hospitalisation and cardiovascular death in this population, indicating the potential benefit of sacubitril–valsartan in patients with more severe LVEF reduction.61 Further trials, including contemporary populations and therapeutics, are required to determine the best approaches to managing patients with ALVSD. A useful approach would be to compare early intervention(s) against clinical surveillance, including potentially more frequent follow-up than may be otherwise indicated, without the implementation of additional therapy, to determine the most cost-effective approach to managing these individuals. Previously, clinicians considered pharmacotherapy for abbreviated periods of time, guided either by prognostication tools and/or serial clinical evaluation, or for predetermined time intervals in a bid to achieve an acceptable balance between risk mitigation and harms from undue medical therapy. However, the Therapy withdrawal in REcovered Dilated cardiomyopathy – Heart Failure (TRED-HF) trial demonstrated that withdrawal of pharmacological therapy in patients with dilated cardiomyopathy after recovery of HF symptoms and LVEF

Heart Failure >50% led to relapse of HF in 40%, suggesting the need of lifelong treatment.62 Thus, at present, no data justify the withdrawal of pharmacological therapy for patients with recovered ALVSD. The role of sodium–glucose cotransporter 2 inhibitors in this population needs investigation because these medications have shown a significant reduction in rates of HF hospitalisation in diabetic patients, including those with no known HF, and also in diabetic patients with multiple cardiovascular risk factors but without established cardiovascular disease or HF.63–65 Recently, the Dapagliflozin and Prevention of Adverse outcomes in Heart Failure (DAPA-HF) trial showed a significant reduction of mortality and HF hospitalisation even in non-diabetic patients, although only individuals with symptomatic LV systolic impairment were included in that study.66 Nevertheless, the study highlighted the potentially promising effects of SGLT2 inhibitors in patients with HF regardless of the presence of diabetes. Further studies regarding the effects of SGLT2 inhibitors on the natural history of ALVSD in patients with and without diabetes are needed to clarify their role in these groups. Identifying ALVSD could facilitate the early initiation of cardioprotective therapy, which could contribute to efforts in reversing the widespread HF epidemic. Nevertheless, ongoing consideration must be given to resource allocation, distribution of specialist medical centres and the number and timing of patient visits that may be required for the large number of individuals in the wider community deemed to be ‘at risk’ but who have no conventional indications for imaging. This, in turn, will

Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics – 2015 update: a report from the American Heart Association. Circulation 2015;131:e29–322. https://doi. org/10.1161/CIR.0000000000000152; PMID: 26078378. 2. DeFrances CJ, Podgornik MN. 2004 National hospital discharge survey. Adv Data 2006;(371):1–19. PMID: 16703980. 3. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2129–200. https://doi.org/10.1093/ eurheartj/ehw128; PMID: 27206819. 4. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failur. Circulation 2017;136:e137–61. https://doi.org/10.1016/j.jacc.2017.04.025; PMID: 28461007. 5. SOLVD Investigators, Yusuf S, Pitt B, et al. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685–91. https://doi. org/10.1056/NEJM199209033271003; PMID: 1463530. 6. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left-ventricular dysfunction after myocardial-infarction – results of the Survival And Ventricular Enlargement trial. N Engl J Med 1992;327:669–77. https://doi.org/10.1056/ NEJM199209033271001; PMID: 1386652. 7. Fried LP, Borhani NO, Enright P, et al. The Cardiovascular Health Study: design and rationale. Ann Epidemiol 1991;1:263–76. https://doi.org/10.1016/1047-2797(91)90005-W; PMID: 1669507. 8. Pandhi J, Gottdiener JS, Bartz TM, et al. Comparison of characteristics and outcomes of asymptomatic versus symptomatic left ventricular dysfunction in subjects 65 years old or older (from the Cardiovascular Health Study). Am J Cardiol 2011;107:1667–74. https://doi.org/10.1016/j. amjcard.2011.01.051; PMID: 21575752. 9. Ammar KA, Jacobsen SJ, Mahoney DW, et al. Prevalence and prognostic significance of heart failure stages: application of the American College of Cardiology/American Heart Association heart failure staging criteria in the community. Circulation 2007;115:1563–70. https://doi.org/10.1161/ CIRCULATIONAHA.106.666818; PMID: 17353436. 10. Wang TJ, Evans JC, Benjamin EJ, et al. Natural history of asymptomatic left ventricular systolic dysfunction in the community. Circulation 2003;108:977–82. https://doi. org/10.1161/01.CIR.0000085166.44904.79; PMID: 12912813. 11. Echouffo-Tcheugui JB, Erqou S, Butler J, et al. Assessing the risk of progression from asymptomatic left ventricular dysfunction to overt heart failure: a systematic overview and meta-analysis. JACC Heart Fail 2016;4:237–48. https://doi. org/10.1016/j.jchf.2015.09.015; PMID: 26682794.

require wider health economic considerations, as well as those pertaining to clinical decision making alluded to above, when determining the optimal way to evaluate and manage patients in the early phases of the HF process.

Conclusion ALVSD is common, and is associated with a significantly increased risk of progression to overt HF and death. A definition of ALVSD remains elusive secondary to challenges posed by heterogeneity of descriptions used in the literature coupled with heterogeneity in the non-invasive techniques used to study the phenomenon. These uncertainties underpin some of the knowledge gaps related to contemporary appraisal of ventricular function. Addressing these issues is integral to translating the identification of subclinical ventricular dysfunction into an opportunity to intervene with the potential to affect clinical outcomes. Screening asymptomatic individuals with echocardiography or CMR is currently not recommended, nor is it cost effective, and how these individuals may be recognised in the first instance remains undetermined. Non-invasive screening tools such as ECG evaluation with machine learning, laboratory assessment with serum BNP concentrations and measurements of PED offer promise in this regard, and could assist with prognostication, but each carries a number of caveats that will need to be addressed. Finally, individuals with ALVSD may potentially benefit from the early implementation of HF-directed pharmacotherapy, although the precise nature and timing of these approaches will need to be clarified in larger prospective studies using contemporary populations.

12. Galasko GI, Barnes SC, Collinson P, et al. What is the most cost-effective strategy to screen for left ventricular systolic dysfunction: natriuretic peptides, the electrocardiogram, handheld echocardiography, traditional echocardiography, or their combination? Eur Heart J 2006;27:193–200. https://doi. org/10.1093/eurheartj/ehi559; PMID: 16267076. 13. McDonagh TA, Morrison CE, Lawrence A, et al. Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet 1997;350:829–33. https://doi. org/10.1016/S0140-6736(97)03033-X; PMID: 9310600. 14. Gottdiener JS, McClelland RL, Marshall R, et al. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The Cardiovascular Health Study. Ann Intern Med 2002;137:631–9. https://doi.org/10.7326/00034819-137-8-200210150-00006; PMID: 12379062. 15. Curtis JP, Sokol SI, Wang Y, et al. The association of left ventricular ejection fraction, mortality, and cause of death in stable outpatients with heart failure. J Am Coll Cardiol 2003;42:736–42. https://doi.org/10.1016/S0735-1097(03)007897; PMID: 12932612. 16. Aljaroudi W, Alraies MC, Halley C, et al. Impact of progression of diastolic dysfunction on mortality in patients with normal ejection fraction. Circulation 2012;125:782–8. https://doi. org/10.1161/CIRCULATIONAHA.111.066423; PMID: 22261198. 17. Moller JE, Sondergaard E, Poulsen SH, Egstrup K. Pseudonormal and restrictive filling patterns predict left ventricular dilation and cardiac death after a first myocardial infarction: a serial color M-mode Doppler echocardiographic study. J Am Coll Cardiol 2000;36:1841–6. https://doi.org/10.1016/ S0735-1097(00)00965-7; PMID: 11092654. 18. Cikes M, Solomon SD. Beyond ejection fraction: an integrative approach for assessment of cardiac structure and function in heart failure. Eur Heart J 2016;37:1642–50. https://doi. org/10.1093/eurheartj/ehv510; PMID: 26417058. 19. Potter E, Marwick TH. Assessment of left ventricular function by echocardiography: the case for routinely adding global longitudinal strain to ejection fraction. JACC Cardiovasc Imaging 2018;11:260–74. https://doi.org/10.1016/j.jcmg.2017.11.017; PMID: 29413646. 20. Zhang KW, French B, May Khan A, et al. Strain improves risk prediction beyond ejection fraction in chronic systolic heart failure. J Am Heart Assoc 2014;3:e000550. https://doi. org/10.1161/JAHA.113.000550; PMID: 24419736. 21. Sengelov M, Jorgensen PG, Jensen JS, et al. Global longitudinal strain is a superior predictor of all-cause mortality in heart failure with reduced ejection fraction. JACC Cardiovasc Imaging 2015;8:1351–9. https://doi.org/10.1016/j.jcmg.2015.07.013; PMID: 26577264. 22. Hung CL, Verma A, Uno H, et al. Longitudinal and circumferential strain rate, left ventricular remodeling, and

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prognosis after myocardial infarction. J Am Coll Cardiol 2010;56:1812–22. https://doi.org/10.1016/j.jacc.2010.06.044; PMID: 21087709. Stanton T, Leano R, Marwick TH. Prediction of all-cause mortality from global longitudinal speckle strain: comparison with ejection fraction and wall motion scoring. Circ Cardiovasc Imaging 2009;2:356–64. https://doi.org/10.1161/ CIRCIMAGING.109.862334; PMID: 19808623. Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2014;27:911–39. https://doi.org/10.1016/j.echo.2014.07.012; PMID: 25172399. Thavendiranathan P, Poulin F, Lim KD, et al. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol 2014;63:2751–68. https://doi.org/10.1016/j.jacc.2014.01.073; PMID: 24703918. Szelenyi Z, Fazakas A, Szenasi G, et al. The mechanism of reduced longitudinal left ventricular systolic function in hypertensive patients with normal ejection fraction. 2015;33:1962–9. https://doi.org/10.1097/ HJH.0000000000000624; PMID: 26154942. Lee WH, Liu YW, Yang LT, Tsai WC. Prognostic value of longitudinal strain of subepicardial myocardium in patients with hypertension. J Hypertens 2016;34:1195–200. https://doi. org/10.1097/HJH.0000000000000903; PMID: 27035737. Holland DJ, Marwick TH, Haluska BA, et al. Subclinical LV dysfunction and 10-year outcomes in type 2 diabetes mellitus. Heart 2015;101:1061–6. https://doi.org/10.1136/ heartjnl-2014-307391; PMID: 25935767. Kiencke S, Handschin R, von Dahlen R, et al. Pre-clinical diabetic cardiomyopathy: prevalence, screening, and outcome. Eur J Heart Fail 2010;12:951–7. https://doi.org/10.1093/eurjhf/ hfq110; PMID: 20581103. Liu JH, Chen Y, Yuen M, et al. Incremental prognostic value of global longitudinal strain in patients with type 2 diabetes mellitus. Cardiovasc Diabetol 2016;15:22. https://doi. org/10.1186/s12933-016-0333-5; PMID: 26842466. Yingchoncharoen T, Gibby C, Rodriguez LL, et al. Association of myocardial deformation with outcome in asymptomatic aortic stenosis with normal ejection fraction. Circ Cardiovasc Imaging 2012;5:719–25. https://doi.org/10.1161/ CIRCIMAGING.112.977348; PMID: 23008423. Citro R, Baldi C, Lancellotti P, et al. Global longitudinal strain predicts outcome after MitraClip implantation for secondary mitral regurgitation. J Cardiovasc Med (Hagerstown) 2017;18:669– 78. https://doi.org/10.2459/JCM.0000000000000526;

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Asymptomatic Systolic Dysfunction PMID: 28509760. 33. Ewe SH, Haeck MLA, Ng ACT, et al. Detection of subtle left ventricular systolic dysfunction in patients with significant aortic regurgitation and preserved left ventricular ejection fraction: speckle tracking echocardiographic analysis. Eur Heart J Cardiovasc Imaging 2015;16:992–9. https://doi.org/10.1093/ ehjci/jev019; PMID: 25733208. 34. Grothues F, Smith GC, Moon JC, et al. Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy. Am J Cardiol 2002;90:29–34. https://doi.org/10.1016/S00029149(02)02381-0; PMID: 12088775. 35. Grothues F, Moon JC, Bellenger NG, et al. Interstudy reproducibility of right ventricular volumes, function, and mass with cardiovascular magnetic resonance. Am Heart J 2004;147:218–23. https://doi.org/10.1016/j.ahj.2003.10.005; PMID: 14760316. 36. Obokata M, Nagata Y, Wu VC, et al. Direct comparison of cardiac magnetic resonance feature tracking and 2D/3D echocardiography speckle tracking for evaluation of global left ventricular strain. Eur Heart J Cardiovasc Imaging 2016;17:525– 32. https://doi.org/10.1093/ehjci/jev227; PMID: 26377901. 37. Francis GS, Benedict C, Johnstone DE, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 1990;82:1724–9. https://doi.org/10.1161/01. CIR.82.5.1724; PMID: 2146040 38. Benedict CR, Shelton B, Johnstone DE, et al. Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. SOLVD Investigators. Circulation 1996;94:690–7. https://doi. org/10.1161/01.CIR.94.4.690; PMID: 8772689. 39. Tsutamoto T, Wada A, Maeda K, et al. Plasma brain natriuretic peptide level as a biochemical marker of morbidity and mortality in patients with asymptomatic or minimally symptomatic left ventricular dysfunction. Comparison with plasma angiotensin II and endothelin-1. Eur Heart J 1999;20:1799–807. https://doi.org/10.1053/euhj.1999.1746; PMID: 10581138. 40. Struthers AD, Morris AD. Screening for and treating leftventricular abnormalities in diabetes mellitus: a new way of reducing cardiac deaths. Lancet 2002;359:1430–2. https://doi. org/10.1016/S0140-6736(02)08358-7; PMID: 11978359. 41. Kelly R, Struthers AD. Screening for left ventricular systolic dysfunction in patients with stroke, transient ischaemic attacks, and peripheral vascular disease. QJM 1999;92:295–7. https://doi.org/10.1093/qjmed/92.6.295; PMID: 10616704. 42. Vasan RS, Benjamin EJ, Larson MG, et al. Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction: the Framingham Heart Study. JAMA 2002;288:1252–9. https://doi.org/10.1001/ jama.288.10.1252; PMID: 12215132.

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43. Ledwidge M, Gallagher J, Conlon C, et al. Natriuretic peptidebased screening and collaborative care for heart failure: the STOP-HF randomized trial. JAMA 2013;310:66–74. https://doi. org/10.1001/jama.2013.7588; PMID: 23821090. 44. Huelsmann M, Neuhold S, Resl M, et al. PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial. J Am Coll Cardiol 2013;62:1365–72. https://doi.org/10.1016/j.jacc.2013.05.069; PMID: 23810874. 45. Attia ZI, Kapa S, Lopez-Jimenez F, et al. Screening for cardiac contractile dysfunction using an artificial intelligence-enabled electrocardiogram. Nat Med 2019;25:70–74. https://doi. org/10.1038/s41591-018-0240-2; PMID: 30617318. 46. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 2003;23:168–75. https://doi.org/10.1161/01. ATV.0000051384.43104.FC; PMID: 12588755. 47. Fujisue K, Sugiyama S, Matsuzawa Y, et al. Prognostic significance of peripheral microvascular endothelial dysfunction in heart failure with reduced left ventricular ejection fraction. Circ J 2015;79:2623–31. https://doi. org/10.1253/circj.CJ-15-0671; PMID: 26489455. 48. Yufu K, Shinohara T, Ebata Y, et al. Endothelial function predicts new hospitalization due to heart failure following cardiac resynchronization therapy. Pacing Clin Electrophysiol 2015;38:1260–6. https://doi.org/10.1111/pace.12698; PMID: 26227741. 49. Kubo SH, Rector TS, Bank AJ, et al. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation 1991;84:1589–96. https://doi.org/10.1161/01. CIR.84.4.1589; PMID: 1914099. 50. Katz SD, Krum H, Khan T, Knecht M. Exercise-induced vasodilation in forearm circulation of normal subjects and patients with congestive heart failure: role of endotheliumderived nitric oxide. J Am Coll Cardiol 1996;28:585–90. https:// doi.org/10.1016/0735-1097(96)00204-5; PMID: 8772743. 51. Katz SD, Khan T, Zeballos GA, et al. Decreased activity of the L-arginine–nitric oxide metabolic pathway in patients with congestive heart failure. Circulation 1999;99:2113–7. https://doi. org/10.1161/01.CIR.99.16.2113; PMID: 10217650. 52. Borlaug BA, Olson TP, Lam CS, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 2010;56:845–54. https://doi. org/10.1016/j.jacc.2010.03.077; PMID: 20813282. 53. Guazzi M, Samaja M, Arena R, et al. Long-term use of sildenafil in the therapeutic management of heart failure. J Am Coll Cardiol 2007;50:2136–44. https://doi.org/10.1016/j. jacc.2007.07.078; PMID: 18036451. 54. Giordano FJ, Gerber HP, Williams SP, et al. A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function. Proc Natl Acad Sci USA 2001;98:5780–5. https://doi.org/10.1073/pnas.091415198; PMID: 11331753.

55. Hornig B, Maier V, Drexler H. Physical training improves endothelial function in patients with chronic heart failure. Circulation 1996;93:210–4. https://doi.org/10.1161/01. CIR.93.2.210; PMID: 8548890. 56. Prasad A, Higano ST, Al Suwaidi J, et al. Abnormal coronary microvascular endothelial function in humans with asymptomatic left ventricular dysfunction. Am Heart J 2003;146:549–54. https://doi.org/10.1016/S00028703(03)00364-8; PMID: 12947377. 57. Bank AJ, Lee PC, Kubo SH. Endothelial dysfunction in patients with heart failure: relationship to disease severity. J Card Fail 2000;6:29–36. https://doi.org/10.1016/S1071-9164(00)00009-9; PMID: 10746816. 58. Nohria A, Gerhard-Herman M, Creager MA, et al. Role of nitric oxide in the regulation of digital pulse volume amplitude in humans. J Appl Physiol (1985) 2006;101:545–8. https://doi. org/10.1152/japplphysiol.01285.2005; PMID: 16614356. 59. American College of Cardiology Foundation Appropriate Use Criteria Task Force; American Society of Echocardiography; American Heart Association, et al. ACCF/ASE/AHA/ASNC/ HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 appropriate use criteria for echocardiography. J Coll Am Cardiol 2011;57:1126– 66. https://doi.org/10.1016/j.jacc.2010.11.002; PMID: 21349406. 60. Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995;333:1670–6. https://doi.org/10.1056/ NEJM199512213332503; PMID: 7477219 61. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin– neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 2019;381:1609–20. https://doi. org/10.1056/NEJMoa1908655; PMID: 31475794. 62. Halliday BP, Wassall R, Lota AS, et al. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet 2019;393:61–73. https://doi. org/10.1016/S0140-6736(18)32484-X; PMID: 30429050. 63. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. https://doi.org/10.1056/ NEJMoa1504720; PMID: 26378978. 64. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–57. https://doi.org/10.1056/ NEJMoa1611925; PMID: 28605608. 65. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–57. https://doi.org/10.1056/NEJMoa1812389; PMID: 30415602. 66. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. https://doi.org/10.1056/ NEJMoa1911303; PMID: 31535829.

Cardiology Masters

Featuring: Prof Angela Maas

In the Cardiology Masters section of European Cardiology Review, we bring you an insight into the career of a key contributor to the field of cardiology. In this edition, we feature Prof Angela Maas. Citation: European Cardiology Review 2020;15:e14. DOI: https://doi.org/10.15420/ecr.2019.19 Prof Angela Maas has been practising clinical cardiology since 1988. For the last 25 years, she has specialised in heart disease in women. Her major research areas are female-specific risk factors, such as pre-eclampsia and early menopause and the impact of sex differences on traditional cardiovascular risk factors. In 2003, Prof Maas established the first outpatient clinic for women in the Netherlands. Prof Maas studied medicine at the University of Groningen, specialising in cardiology at Sint Antonius Hospital. In 2006, she obtained her PhD at Utrecht University. She has been a professor of cardiology for women at Radboud University Medical Centre since 2012. She is an important partner in the EUGenMed programme, which is working to develop a roadmap for the implementation of sex in biomedical sciences and health research. She is the author of Hearts for Women, in which she highlighted female-specific heart complaints, Gynecardiology Handbook: Female Specific Cardiology in Clinical Practice and Manual of Gynecardiology: Female-Specific Cardiology. Prof Maas also initiated the Dutch SCAD Registry. She has received many awards, including the Hermesdorf award from Radboud University, Nijmegen, and the Corrie Hermann Prize from the Dutch Society of Female Physicians, and she was made an Officer in the Order of Oranje-Nassau in 2017.

hen I was a young girl, my father was a family care physician with a home office in our basement. His patients came to our house and I was mesmerised by the whole idea. I’d try to sneak a look in the window of his office, or take him a cup of tea, because I simply had to know what was going on down there. Who were these strange people who came to our house to be treated by my father? What did they look like? I figured they must be a very special kind of species. So I was a little surprised, and maybe a little disappointed, when I began to realise that they looked just like any other person. Now, as I look back at my career, I realise that many of my peers in cardiology may have had a similar experience when patients presented with symptoms that contradicted everything they knew to be true about heart disease. Who were these strange creatures with issues that weren’t covered in any of the books? I, too, had been practising cardiology for a few years before I finally began to understand again that there was nothing strange about them. True, we hadn’t learned about their symptoms in medical school, but they looked like normal people – and they were normal people.

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The only difference was that they were women.

Shared Experience Some years after I had peered into my basement window to see what my father was doing, I, too, decided to become a physician. This delighted him, naturally. I was the second of five children in my family, and the only one to go into medicine. He was proud of all of us, of course, but my career choice created a special empathy. He encouraged me from the start, and he was there for me again when I most needed encouragement, years later, when I found myself fighting some unexpected uphill battles. He had his own battles along the way, having experienced the sting of derision from his peers, because he was interested in homeopathy. Homeopathy, many general care physicians insisted, was nonsense. Whether it is or isn’t, I don’t really know. It is not my area of interest or expertise. But his experience helped us bond later, when I, too, was derided for wanting to change the way medicine was practised. Not that I’d started out wanting to change anything. Early on, I just wanted to be a part of the medical world and to fit in.

Cardiology Masters: Prof Angela Maas Figure 1: As a Medical Student in 1976

Figure 2: Prof Maas was Awarded the Corrie Hermann Prize by the Dutch Society of Female Physicians in 2010

Early Training

Cardiology was very male-oriented. It was a men’s community that focused on men’s diseases. This also led to some confusion. I had female patients I wanted to understand and help, but they didn’t seem to fit in with the male-oriented models I’d studied. This was an era of growing enlightenment for women, and my increasingly confident female patients were very upfront about what they were experiencing. They had many questions, but I had very few answers for them.

I always loved school, my grades were good, and I chose the subjects I knew I needed to get into medical school. I was helped by what seemed to be almost boundless energy. My friends used to shake their heads in amazement, because I seemed to never wear down. I was always on the front lines, ready to embrace the next intrigue. Your level of energy is something different, they would say. I was just as enthusiastic in med school. On holidays, I always worked as a nurse. I wanted to be hands-on and to learn as much as I could. Plus, I knew I had to decide what direction I wanted to go in, and I was eager to figure it out. It wasn’t until my last year of medical school that I finally chose cardiology. Why? I think because cardiology is about making decisions fast, and that suited my character. With internal medicine, doctors may think for weeks about something. That’s not my style. Like many young doctors from the Netherlands, I did my residency on the Caribbean island of Curaçao. The University of Groningen, where I did my training, had an informal agreement with Curaçao for medical students, and I was eager to spend a few years overseas. I was lucky to have the opportunity. The experience was as eyeopening as it was educational. The patients were poor, and I saw first-hand that many parts of the world did not have the same highstandard healthcare system that we enjoy in the Netherlands and other developed nations.

Lukewarm Welcome An even bigger eye-opener awaited me. When I returned home in 1988 and began practising, I quickly realised that the cardiology community was not very welcoming to women. It was a bit of a jolt. As a student, I had been very involved with the second-wave feminist movement. I had actively participated in seminars and discussion groups that focused on the need for women to find their own directions, to earn their own money, and to make their own decisions.

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Initially, I succumbed to the attitudes around me. I should emphasise here that I don’t think male cardiologists are bad people, by any means. Virtually every male cardiologist I know is kind. But the dominant group culture isn’t as kind. And I cringe a little now when I remember that I laughed at some of my female patients because they had ‘stupid’ symptoms. These weren’t the symptoms we’d studied in all the books. These women didn’t have obstructions. The symptoms they described didn’t add up, so we dismissed them. That was normal at the time.

Unnerving Exchange It was 1991, 3 years into my career, when a confluence of events helped me realise that neither the person I’d become, nor the physician I’d become, were who I wanted to be. It was around that time that the first literature on sex differences in cardiology disease began to appear, including the seminal book, The Female Heart, by Marianne Legato and Carol Colman. Against this backdrop, I also found myself unnerved one day by an exchange that took place on an otherwise normal day in my office. A middle-aged woman – frustrated to breaking point by the repeated dismissiveness of physicians who refused to take her seriously – finally shouted at me in tears: “Why don’t you explain my complaints?” Before long, I was reading everything I could about female hearts and the cardiological differences between men and women. And it all

Cardiology Masters Figure 3: Prof Maas in 2014

Figure 4: Prof Maas and Her Husband Ernst Faber

began to come together. There were enormous gaps in my knowledge, and I had to fill them. But it seemed as if no one in my country could help me. No one seemed interested.

As the heart ages, women experience more stiffness of the myocardium, which often leads to symptoms such as shortness of breath and a different kind of heart failure than the reduced ejection fraction and pattern of heart failure we are used to seeing in men.

Eventually, I found myself at odds with virtually the entire Dutch cardiology community. To many, female cardiology was still a non-issue. After all, the whole community had been focused on obstructive cardiology disease for more than 40 years, and women have far less obstructive cardiology disease than men. I had to pry myself away from the dominant attitudes of the time and seek what I now knew to be a broader truth.

Welcome Support Fortunately, my husband, Ernst, a cardiologist who I met when we happened to sit next to each other at a cardiology dinner in 1985, was there for me as this next chapter of my life unfolded. He knew what I was up against, and he’d ask me, what do you want to change, and how important is this to you? He became both a sounding board and an extremely supportive partner. Among other things, he often took over the care of our two sons, so I could travel abroad and pursue what had become to me a vital path. He’s retired now and still very supportive. Among other things, he takes care of all the food preparation in our home, so I can maintain my demanding schedule. I submerged myself in the new and growing research community on women’s heart disease, and I earned a PhD while taking part in a worldwide study of female cardiology. In my practice, I began to focus more and more on female patients, and eventually, in 2003, I stopped seeing male patients altogether. I explained to my befuddled colleagues that it was something I needed to do. Women’s heart issues were clearly different, and I wanted to know why some were more at risk than others. Of course, many answers had already begun to emerge. Women have less muscle mass than men. Their arteries are smaller. As people age, men usually have more obstructive kinds of coronary disease and aortic stenosis – issues that can be treated relatively easily with a stent or a bypass. But women are much more likely to have non-obstructive coronary diseases – issues that are more difficult, if not impossible, to treat with coronary interventions.

All of these are very typical for women between 40 and 70 years. The bottom line is that women and men have distinctly different occurrences of heart disease throughout their lives, and we, as cardiologists, must finally come to understand those differences. Those who can’t, or won’t, accept that these serious sex and gender differences exist, will end up misdiagnosing and mistreating their female patients, or failing to treat them at all.

The Right Direction Fortunately, we have made enormous progress. But we still have a long way to go. For one, we need to address a large disparity in numbers of practitioners. In Holland, women now account for about 25–30% of all cardiologists. But women are less than 10% of all cardiology professors. Women also hold a vastly disproportionately low percentage of leadership positions at the large teaching hospitals. And not a single woman in Dutch cardiology is the leader of an entire department. Not one. Since my awakening, I have been striving to provide not just better care for female patients, but also to facilitate better positions for female cardiologists. But the challenge can be nuanced. Ironically, some women who go into cardiology do so because they’re attracted by the macho culture. So, we cannot assume that all female cardiologists will have a special interest in female patients. In fact, as a professor, I hear concerns and some hesitancy about the culture from both female and male students. The concerns are valid. It’s usually easier when you’re a young physician just starting out to keep your mouth shut than it is to speak up. We need to see the culture for what it is and keep challenging ourselves to move forward. I’m heartened that Prof Barbara Casadei is now President of the European Society of Cardiology. She is a great example of how things are improving. She’s extremely brave, and she now has the power to help effect change. Most of all, she’s a great example for younger female cardiologists.

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Cardiology Masters: Prof Angela Maas Moving Forward In the meantime, I’m focusing on research and teaching, as well as focusing on women in my own outpatient facility. I’ve recently published my third book, Hearts for Women, and I have four important research subjects that I’m working on with PhD students at the Radboud University Medical Center in Nijmegen, where I am a professor of women’s cardiac health. First, we are working with gynaecologists, looking at high-risk women who have experienced pre-eclampsia. Second, we are working with women who have specific types of coronary symptoms, such as coronary artery dissections. Those have become increasingly prevalent in younger women who’ve given birth and/or who are dealing with the stresses of our current society. Third, we are looking at middle-aged women with microvascular angina. And last, we are researching cardiooncology in breast cancer patients. The fourth area is an interesting example of unintended consequences, and I have a chapter on cardiac damage related to breast cancer in my new book. Physicians are treating breast cancer very well, and mortality has declined enormously over the past decades. But we’re also paying a price. We are seeing more and more cardiovascular damage as a result, sometimes as long as 10–20 years after treatment. It is not yet widely recognised, so when patients complain of fatigue, their physicians may brush it off, attributing it to their breast cancer many years earlier, instead of taking a closer look. As a result, heart failure often remains underdiagnosed years after women are treated for breast cancer. We know that angiogenesis inhibitors cause hypertension, and that when you do not treat high blood pressure for many years, you are bound to have heart problems. To combat this, we need to take a closer look at individual patients, we need to do more genotyping of tumours, and we need to try to tailor treatments accordingly. New chemotherapy agents and additional therapies can also help. I hope and believe that our perspective will change in the coming years. When we empower women in healthcare, we elevate the importance of these topics related to women’s health because women are likely to be

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more interested in them. With more women in leadership positions, these will be higher on the agenda. My own experience is instructive. I’ve been asked to join various scientific committees, and am also now a senior reviewer of the Lancet Commission on Women and Health. I’m currently involved in the creation of a position paper about global cardiovascular health in women, and I was elected last year to be a Dutch delegate to the UN, starting in 2020. In October 2020, I’ll be giving a short lecture at the UN in New York, about the need to empower women working in healthcare. Currently, 70% of healthcare workers worldwide are women, but only 25% of leadership positions are filled by women.

Persistence Pays It has not always been easy, by any means, but I have persisted. You have to be strong to honestly assess and, if necessary, change, your behaviour, especially when doing so puts you in conflict with your environment. I am proud that I have helped to improve care for female patients, and I hope I have helped to change the culture a bit. But change always happens more slowly than you want, and it is always made by many people, not just by one person. Still, in the last 5 years we’ve made more progress than was made in the preceding 20 years. I’m pleased to have been a part of it. There are also plenty of female cardiology pioneers elsewhere in Europe and in the US, who have been brave enough to go against the mainstream and to fight to change the ways women are diagnosed and treated. We have a shared experience and it is important for female cardiologists to support each other: to be heart sisters, to discuss our experiences and those of our colleagues; and, above all, to make sure we understand and practise the right science. This is our message: women are still undervalued and undertreated in cardiology. To bring about change, we have to be one force, we have to create understanding; and ultimately, we have to make a difference.

Ischaemic Heart Disease

Effects of Statin Treatment on Patients with Angina and Normal or Nearly Normal Angiograms Olivia Manfrini, Peter Amaduzzi, Maria Bergami and Edina Cenko Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy

Abstract This article offers an updated and comprehensive overview of major findings on the effects of statin treatment in patients with chronic angina but without any epicardial coronary artery with obstructive lesion.

Keywords Statins, non-obstructive coronary artery disease, cardiac syndrome X, coronary microvascular dysfunction, vasospastic angina Disclosure: The authors have no conflict of interest to declare. Received: 25 October 2019 Accepted: 8 January 2020 Citation: European Cardiology Review 2020;15:e15. DOI: https://doi.org/10.15420/ecr.2019.15 Correspondence: Olivia Manfrini, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via Massarenti 9 (Padiglione 11), 40128 Bologna, Italy. E: olivia.manfrini@unibo.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Statins are commonly used in patients with hypercholesterolaemia and in those with cardiovascular diseases – that is, peripheral artery disease and coronary artery disease (CAD) – for the prevention of atheromatous plaque development, progression and complications, with the aim of reducing subsequent major adverse cardiovascular events (MACE), i.e. cardiac death, acute MI, stroke and heart failure. The beneficial role of these drugs is partially driven by their lipidlowering effect but is also due to their pleiotropic effects on the molecular pathways involved in inflammation and oxidative stress.1,2 Statins reduce NADPH-oxidase activity and subunit isoprenylation as well as promoting endothelial nitric oxide synthase activity directly and via the induction of tetrahydrobiopterin synthesis, effects that seem to be reversed by the addition of mevalonate, a product of beta-hydroxy beta-methylglutaryl-coenzyme A reductase.3–8 The molecular actions statins have on inflammation and endothelial function have resulted in several studies investigating their use in patients with chest pain/discomfort and normal or slightly abnormal coronary arteriograms. These patients have a poor quality of life and recent analyses have shown their prognosis is not so benign as previously thought.9–16 Patients with angina (i.e. chest pain/discomfort) and non-obstructive CAD (1–49% lumen stenosis) are at increased risk for MACE compared with the asymptomatic population.13,16 With the widespread use of coronary angiography and other imaging techniques, there is increasing evidence that, even among those with acute coronary syndrome, the proportion of the patients at increased risk of MACE is greater than originally thought.13–18 This article provides a comprehensive overview of major findings on the effects of statin treatment in patients with chronic angina and epicardial coronary arteries without obstructive (>50%) lumen stenosis.

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Effect of Statin Therapy on ‘Soft’ Endpoints Several small observational studies and randomised clinical trials have evaluated the effects of statin treatment on the occurrence of angina, exercise capacity, endothelial function and coronary flow reserve (CFR). Initial studies in the late 1990s analysed the effect of statins in patients with non-obstructive CAD and hypercholesterolaemia.19,20 In 1999, Baller et al. enrolled 23 patients (five women) with angina, normal or slightly abnormal angiograms (the latter defined as the presence of ≤30% stenosis) and LDL cholesterol >3.89 mmol/l (mean 4.27 ± 0.8 mmol/l), analysing their myocardial blood flow before and after 6 months of lipid-lowering therapy with simvastatin. The authors found that simvastatin treatment improved participants’ overall coronary vasodilator capacity in addition to lowering serum cholesterol concentration. In fact, treatment resulted in an increase in CFR (from 2.2 ± 0.6 to 2.64 ± 0.6; p<0.01) and maximal coronary flow under pharmacological stress with dipyridamole (from 182 ± 36 ml/min × 100 g to 238 ± 58 ml/min × 100 g; p<0.001) and decreased the minimum coronary resistance (from 0.51 ± 0.12 mmHg to 0.40 ± 0.14 mmHg; p<0.001). In addition to this, the symptoms of angina regressed in most patients. In light of these results, the authors concluded that intensive lipid-lowering treatment with simvastatin provided vasoprotection in patients in the early stages of coronary atherosclerosis and could potentially prevent disease progression.19 In the same year, Mansur et al. published the first randomised control study of the effect of statin therapy on positive exercise stress tests in patients with severe hypercholesterolaemia (total serum cholesterol >7.77 mmol/l) and normal coronary angiograms.20 Patients with diabetes and hypertension were excluded. After 12 weeks of diet (American Heart Association step 1 diet), the 43 patients were randomly

Statins in Non-obstructive Coronary Artery Disease assigned to treatment with diet alone or with diet and a statin (20 mg lovastatin daily or 10 mg simvastatin daily) for a further 16 weeks. Diet alone produced little change in cholesterol and no change in exercise resistance whereas the addition of a statin decreased total and LDL cholesterol levels and improved exercise-induced myocardial ischaemia. After 16 weeks, the number of patients that still had a positive exercise test was significantly lower in the statin group than in the diet-only group (13% versus 75%; p=0.01). The authors hypothesised that, since normal angiograms (smooth coronary arteries at angiography) were an inclusion criterion, the increase in exercise capacity could have been the consequence of improved coronary endothelial function secondary to the reduction in cholesterol plasma concentrations obtained with statin treatment.20 This supported the theory of microvascular dysfunction as a possible cause of myocardial ischaemia and led them to introduce the concept of statins as a possible treatment for endothelial dysfunction. Since these two pioneer investigations on the effect of statins on myocardial ischaemia in patients with non-obstructive coronary arteries, several scientists have examined the consequences of statins on coronary endothelial function through the direct assessment of myocardial perfusion and coronary flow. They have also investigated peripheral endothelial function using markers, such as brachial flowmediated dilation (FMD), which is a surrogate of coronary endothelial function. Analysis of the effect of statin treatment has also provided some insight into the pathogenesis of cardiac syndrome X. In the late 1990s and early 2000s, patients with angina, transient myocardial ischaemia and normal angiograms were often considered to be suffering from cardiac syndrome X (CSX).21–23 This diagnosis underlines the fact that the causes of myocardial ischaemia were still unclear. In 2003, a single-blind, randomised, placebo-controlled study looked at the effects of statin therapy versus placebo in 40 patients with CSX.24 Patients with left ventricular hypertrophy, hypertension, diabetes and LDL cholesterol ≥4.15 mmol/l were excluded from the study. At baseline, FMD was significantly impaired in all patients; however, after 3 months FMD had significantly improved in the pravastatin group (9.7 ± 8.6% versus 16.3 ± 6.8%, p=0.006) but there was no significant change in the placebo group (9.0 ± 7.9% versus 8.8 ± 5.5%, p=0.35). There were also significant improvements in the time needed for 1 mm ST-segment depression (from 267 ± 105 seconds to 419 ± 162 seconds; p=0.001) and total duration of exercise (from 530 ± 162 seconds to 585 ± 165 seconds; p=0.001) and an improvement in the Canadian Cardiovascular Society Angina grading scale in the pravastatin group but not the placebo group. It is interesting to note that a moderate association between changes in FMD and time to 1 mm ST-segment depression was observed (r=0.525, p=0.04), suggesting an underlying relationship between endothelial function and myocardial ischaemia.24 Houghton et al. assessed the effects that cholesterol lowering with a statin had on coronary resistance in a small observational study of six patients with a history of chest pain and normal angiograms.25 This study deserves to be mentioned because it provided important insight into the possible mechanisms of myocardial ischaemia in patients with normal epicardial coronary arteries. Coronary endothelium-independent and dependent vasodilatation were examined using intracoronary administration of adenosine and acetylcholine, respectively, and coronary blood flow was measured with an intracoronary flow Doppler wire. After 6 months of 20 mg pravastatin daily, the authors found no

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significant differences in adenosine-mediated increase in coronary blood flow compared to baseline (i.e. there were no changes in endothelium-independent vasodilation) but a significant difference in acetylcholine infusion peak (endothelium-dependent vasodilation), which rose from 97 ± 13% to 160 ± 16% (p=0.01). There was also a strong correlation (r=-0.87, p=0.02) between improvement in coronary flow reserve (CFR) and reduction in LDL cholesterol, suggesting that endothelial function may depend upon circulating lipid profiles, among other factors.25 In conclusion, the study proved that endothelial function was significantly improved with pravastatin. Soon after this, another prospective single-blind study provided further insight into the benefits of statin treatment and added to our understanding of the pathophysiology of myocardial ischaemia in patients with normal angiograms.26 Pizzi et al. examined the effects of atorvastatin 40 mg per day plus ramipril 10 mg per day versus placebo in 45 patients with CSX. After 6 months, patients in the intervention group had fewer episodes of chest pain (4.4 ± 2.9 versus 9.2 ± 2.7 episodes per month; p=0.004), improved time to peak exercise (from 450 ± 82.2 seconds to 555.3 ± 84.6 seconds, p=0.045) and significantly increased FMD (from 2.2 ± 1.3% to 4.2 ± 1.7%; p=0.001), while there were no significant changes in the placebo group. The authors found a significant correlation between FMD and time to peak exercise (r=0.29; p<0.01), reinforcing the notion that endothelial function may be the underlying cause of ischaemia in these patients. Moreover, in the dualtherapy group, the levels of superoxide dismutase – which is one of the major antioxidant enzymes of the vessel wall – decreased from 268.4 ± 53.7 U/ml to 188.1 ± 29.6 U/ml during follow-up (p<0.001). The levels of this enzyme had a negative correlation with changes in FMD (r=0.38; p=0.01), exercise capacity (r=0.22; p=0.03) and Seattle Angina Questionnaire score (r=0.46; p<0.01), suggesting that in patients with CSX, the benefit of dual therapy may be related to a reduction in oxidative stress.26 Unfortunately, since the treatment group received both an angiotensin-converting enzyme inhibitor and a statin, the authors were unable to determine whether both or only one of the drugs was responsible for the beneficial effects. Fábián et al. studied the effects of statins on endothelial function and exercise-induced ischaemia in 40 CSX patients randomised to 20 mg simvastatin per day or placebo for 3 months.27 Similar to previous studies, simvastatin reduced total cholesterol, improved brachial FMD (from 4.01 ± 0.91% to 6.12 ± 0.79%; p<0.0001) and time to 1 mm ST segment depression (from 4.45 ± 0.39 minutes to 5.33 ± 0.27 minutes; p<0.0001) in comparison to placebo. Zhang et al. reported on the effects of 3 months of treatment on 68 CSX patients randomised to a statin, a calcium-channel blocker or dual therapy (statin plus calcium-channel blocker).28 All three groups showed significant (p<0.05) improvements in CFR (fluvastatin +23.2% versus diltiazem +12.4% versus fluvastatin–diltiazem +29.1%) and time to ST segment depression (fluvastatin from 241 ± 97 seconds to 410 ± 140 seconds; diltiazem from 258 ± 91 seconds to 392 ± 124 seconds; fluvastatin–diltiazem from 250 ± 104 seconds to 446 ± 164 seconds). The greatest improvements were recorded in the fluvastatin and dual therapy groups, suggesting the statin had played a dominant role.28 Remarkably, a significant increase in nitric oxide and reduction in endothelin-1 was observed in the two groups receiving statins, indicating that the pleiotropic effects of this drug are fundamental for improved coronary endothelial function in patients with normal angiograms.

Ischaemic Heart Disease A more recent double-blind, placebo-controlled clinical trial randomised 58 patients (40 women and 18 men) with angina pectoris, evidence of inducible ischaemia, non-obstructive CAD (<50% lumen stenosis) and normal total cholesterolaemia (<8 mmol/l) to atorvastatin 20 mg per day or placebo for 6 months to determine the effect of atorvastatin on endothelial function.29 A significant improvement in brachial FMD among patients in the statin group (although FMD never met the criteria for normal endothelial function) but no change in the placebo group at 3- and 6-month follow-up was observed, demonstrating that even moderate doses of atorvastatin improve the endothelial function of peripheral arteries in patients with normal serum total cholesterol, inducible myocardial ischaemia and non-obstructive CAD. Further insights into the role of statins in coronary circulation were elucidated by Caliskan et al., who explored the effect of 20 mg atorvastatin per day in 20 patients with normal epicardial angiograms but slow coronary flow (i.e. late coronary opacification during angiography, defined as corrected thrombolysis in MI frame count >2 standard deviations from the normal published range).30 Previous acute MI was an exclusion criterion in this study. CFR, using transthoracic Doppler echocardiography, was evaluated at baseline and after 8 weeks of statin treatment. At follow-up, the authors observed significant increases in CFR (from 1.95 ± 0.38 to 2.54 ± 0.56, p<0.001) and hyperaemic diastolic peak flow velocity (from 45.4 ± 12.7 cm/s to 53.0 ± 15.8 cm/s, p=0.01) and a significant decrease in diastolic peak flow velocity (from 23.3 ± 5.6 cm/s to 20.7 ± 3.5 cm/s, p=0.02) in atorvastatin-treated patients, demonstrating that statin therapy significantly improves the microvascular function of patients with normal angiograms and slow coronary flow.30 Ulus et al. investigated the effects of statins on myocardial perfusion in patients with metabolic syndrome.31 At 6 months they found that, in patients with a myocardial perfusion defect on exercise stress technetium-99m single-photon emission CT and normal coronary arteries, 20 mg per day of atorvastatin significantly improved myocardial infusion (p<0.01), as measured by summed stress score, summed rest score and summed difference score. In summary, several small observational and randomised trials have shown that statin treatment has beneficial effects in patients with angina and non-obstructive coronary angiograms (with or without hypercholesterolaemia).19,20,24–31 These effects include improvements in endothelial and microvascular function, exercise capacity and myocardial perfusion, as well as a reduction in or regression of angina symptoms.19,20,24–31

Effect of Statin Therapy on ‘Hard’ Endpoints Several large observational studies designed to evaluate the effects of statins on ‘hard’ endpoints in non-obstructive CAD patients have been carried out in recent years. Results from the COroNary CT Angiography Evaluation for Clinical Outcomes (CONFIRM) registry provided evidence of an association between the presence and extent of non-obstructive CAD and mortality.32 Chow et al. identified 10,418 patients with stable CAD and normal coronary arteries (n=5,712) or non-obstructive CAD (1–49% lumen stenosis, n=4,706) using coronary CT angiography (CCTA).

Patients with non-obstructive CAD were more likely to be taking statins (43.2% versus 25.1%; p<0.001) and aspirin (46.2% versus 30.8%; p<0.001) at the time of CCTA when compared with patients with normal angiograms. After a median follow-up period of 27.2 months, statin therapy was associated with a significant improvement in survival in non-obstructive CAD patients (HR 0.45; 95% CI [0.27–0.75]), but not in patients with normal angiograms (HR 0.66; 95% CI [0.30–1.43]).32 No information was collected on the initiation or discontinuation of statin therapy after CCTA, thus patients with normal arteries may have discontinued statin therapy, thereby underestimating the benefit of statins in this subpopulation. Hwang et al. identified a cohort of 8,372 subjects with non-obstructive CAD (1–49% lumen stenosis) who were not on statin therapy from among 47,708 consecutive individuals who underwent CCTA for evaluation of CAD.33 Of the individuals with non-obstructive CAD, 1,983 started statin therapy while 6,389 did not. After a median follow-up of 27.6 months, statin use was associated with a significant reduction in all-cause mortality (HR 0.397; 95% CI [0.26–0.60]) and the composite of mortality and late coronary revascularisation (HR 0.43; 95% CI [0.31–0.60]). This association remained regardless of other factors, including age, sex, the presence of hypertension or diabetes, level of LDL cholesterol or C-reactive protein, coronary artery calcium score or glomerular filtration rate. In summary, two observational studies including a total of >18,700 patients with non-obstructive CAD have shown that statin use is associated with a significant reduction in all-cause mortality during a follow-up period of approximately 2.5 years.32,33 However, since these studies were not randomised trials, the results should be accepted with caution as they may have been influenced by patient selection.

Conclusion A number of studies exploring the effects of statin treatment on soft endpoints actually had pathophysiological endpoints that have helped us understand the causes of ischaemia in patients with non-obstructive CAD.19,20,24–31 It is currently recognised that myocardial ischaemia in these individuals is often the consequence of reduced coronary microvascular dilatory responses and increased coronary resistance due to endothelial dysfunction and/or vasomotor disorder (involving the microvascular and/or epicardial bed).34 Studies in patients with angina and non-obstructive CAD show that statins increase myocardial perfusion and improve symptoms in subjects with mild coronary atherosclerosis and even in those with normal angiograms.19,24,26,29 Current international guidelines suggest statin treatment for all patients with chronic coronary syndrome, including those with microvascular angina.34 Finally, preliminary data have shown that statin treatment improves survival in patients with mild coronary atherosclerosis (1–49% lumen stenosis) but not in those with normal angiograms (0% lumen stenosis).32,33 However, since patient enrolment in these studies was not randomised, further research (i.e. adequately powered randomised trials) is needed to clarify the protective role of statins on clinical outcomes in patients with chronic coronary syndrome without obstructive CAD.

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Statins in Non-obstructive Coronary Artery Disease 1.

idker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to R prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–207. https:// doi.org/ 10.1056/NEJMoa0807646; PMID: 18997196. 2. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–9. https://doi.org/10.1056/NEJM199610033351401; PMID: 8801446. 3. Margaritis M, Sanna F, Antoniades C. Statins and oxidative stress in the cardiovascular system. Curr Pharm Des 2017;23:7040–7. https://doi.org/10.2174/138161282366617092 6130338; PMID: 28950822. 4. Martínez-González J, Raposo B, Rodríguez C, et al. 3-hydroxy3-methylglutaryl coenzyme a reductase inhibition prevents endothelial NO synthase downregulation by atherogenic levels of native LDLs: balance between transcriptional and posttranscriptional regulation. Arterioscler Thromb Vasc Biol 2001;21:804–9. https://doi.org/10.1161/01.atv.21.5.804; PMID: 11348878. 5. Wassmann S, Laufs U, Müller K, et al. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol 2002;22:300–5. https://doi.org/10.1161/ hq0202.104081; PMID: 11834532. 6. Aoki C, Nakano A, Tanaka S, et al. Fluvastatin upregulates endothelial nitric oxide synthase activity via enhancement of its phosphorylation and expression and via an increase in tetrahydrobiopterin in vascular endothelial cells. Int J Cardiol 2012;156:55–61. https://doi.org/10.1016/j.ijcard.2010.10.029; PMID: 21093076. 7. Brandes RP, Beer S, Ha T, et al. Withdrawal of cerivastatin induces monocyte chemoattractant protein 1 and tissue factor expression in cultured vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2003;23:1794–800. https://doi. org/10.1161/01.ATV.0000092126.25380.BC; PMID: 12933532. 8. Wagner AH, Köhler T, Rückschloss U, et al. Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol 2000;20:61–9. https://doi.org/10.1161/01.atv.20.1.61; PMID: 10634801. 9. Atienza F, Velasco JA, Ridocci F, et al. Assessment of quality of life in patients with chest pain and normal coronary arteriogram (syndrome X) using a specific questionnaire. Clin Cardiol 1999;22:283–90. https://doi.org/10.1002/ clc.4960220406; PMID: 10198738. 10. Cox ID, Hann CM, Kaski JC. Low dose imipramine improves chest pain but not quality of life in patients with angina and normal coronary angiograms. Eur Heart J 1998;19:250–4. https://doi.org/10.1053/euhj.1997.0615; PMID: 9519318. 11. Bemiller CR, Pepine CJ, Rogers AK. Long-term observations in patients with angina and normal coronary arteriograms. Circulation 1973;47:36–43. https://doi.org/10.1161/01. cir.47.1.36; PMID: 4686602. 12. Bruschke AVG, Proudfit WL, Sones FM. Clinical course of patients with normal, and slightly or moderately abnormal coronary arteriograms. A follow-up study on 500 patients.

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13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

Circulation 1973;47:936–45. https://doi.org/10.1161/01. cir.47.5.936; PMID: 4705583. Jespersen L, Hvelplund A, Abildstrøm SZ, et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J 2012;33:734–44. https://doi. org/10.1093/eurheartj/ehr331; PMID: 21911339. Sharaf B, Wood T, Shaw L, et al. Adverse outcomes among women presenting with signs and symptoms of ischemia and no obstructive coronary artery disease: findings from the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE) angiographic core laboratory. Am Heart J 2013;166:134–41. https://doi. org/10.1016/j.ahj.2013.04.002; PMID: 23816032. Radico F, Zimarino M, Fulgenzi F, et al. Determinants of longterm clinical outcomes in patients with angina but without obstructive coronary artery disease: a systematic review and meta-analysis. Eur Heart J 2018;39:2135–46. https://doi. org/10.1093/eurheartj/ehy185; PMID: 29688324. Lanza GA, Crea F, Kaski JC. Clinical outcomes in patients with primary stable microvascular angina: is the jury still out? Eur Heart J Qual Care Clin Outcomes 2019;5:283–91. https://doi. org/10.1093/ehjqcco/qcz029; PMID: 31168622. Sedlak TL, Lee M, Izadnegahdar M, et al. Sex differences in clinical outcomes in patients with stable angina and no obstructive coronary artery disease. Am Heart J 2013;166:38–44. https://doi.org/10.1016/j.ahj.2013.03.015; PMID: 23816019. Bugiardini R, Manfrini O, De Ferrari GM. Unanswered questions for management of acute coronary syndrome: risk stratification of patients with minimal disease or normal findings on coronary angiography. Arch Intern Med 2006;166:1391–5. https://doi.org/10.1001/archinte.166.13.1391; PMID: 16832004. Baller D, Notohamiprodjo G, Gleichmann U, et al. Improvement in coronary flow reserve determined by positron emission tomography after 6 months of cholesterol-lowering therapy in patients with early stages of coronary atherosclerosis. Circulation 1999;99:2871–5. https://doi.org/10.1161/01. cir.99.22.2871; PMID: 10359730. Mansur AP, Serrano CV Jr, Nicolau JC, et al. Effect of cholesterol lowering treatment on positive exercise tests in patients with hypercholesterolaemia and normal coronary angiograms. Heart 1999;82:689–93. https://doi.org/10.1136/ hrt.82.6.689; PMID: 10573494. Maseri A, Crea F, Kaski JC, et al. Mechanism of angina pectoris in syndrome-X. J Am Coll Cardiol 1991;17:499–506. https://doi. org/10.1016/s0735-1097(10)80122-6; PMID: 1991909. Kaski JC. Pathophysiology and management of patients with chest pain and normal coronary arteriograms (cardiac syndrome X). Circulation 2004;109:568–72. https://doi. org/10.1161/01.CIR.0000116601.58103.62; PMID: 14769677. Bugiardini R, Pozzati A, Ottani F, et al. Vasotonic angina: a spectrum of ischemic syndromes involving functional abnormalities of the epicardial and microvascular coronary circulation. J Am Coll Cardiol 1993;22:417–25. https://doi.

org/10.1016/0735-1097(93)90045-3; PMID: 8166784. 24. K ayikcioglu M, Payzin S, Yavuzgil O, et al. Benefits of statin treatment in cardiac syndrome-X1. Eur Heart J 2003;24:1999– 2005. https://doi.org/10.1016/s0195-668x(03)00478-0; PMID: 14613735. 25. Houghton JL, Pearson TA, Reed RG, et al. Cholesterol lowering with pravastatin improves resistance artery endothelial function: report of six subjects with normal coronary arteriograms. Chest 2000;118:756–60. https://doi.org/10.1378/ chest.118.3.756; PMID: 10988199. 26. Pizzi C, Manfrini O, Fontana F, et al. Angiotensin-converting enzyme inhibitors and 3-hydroxy-3-methylglutaryl coenzyme A reductase in cardiac Syndrome X: role of superoxide dismutase activity. Circulation 2004;109:53–8. https://doi.org/10.1161/01.CIR.0000100722.34034.E4; PMID: 14699004. 27. Fábián E, Varga A, Picano E, et al. Effect of simvastatin on endothelial function in cardiac syndrome X patients. Am J Cardiol 2004;94:652–5. https://doi.org/10.1016/j. amjcard.2004.05.035; PMID: 15342302. 28. Zhang X, Li Q, Zhao J, et al. Effects of combination of statin and calcium channel blocker in patients with cardiac syndrome X. Coron Artery Dis 2014;25:40–4. https://doi. org/10.1097/MCA.0000000000000054; PMID: 24256699. 29. Kabaklić A, Fras Z. Moderate-dose atorvastatin improves arterial endothelial function in patients with angina pectoris and normal coronary angiogram: a pilot study. Arch Med Sci 2017;13:827–36. https://doi.org/10.5114/aoms.2017.68238; PMID: 28721151. 30. Caliskan M, Erdogan D, Gullu H, et al. Effects of atorvastatin on coronary flow reserve in patients with slow coronary flow. Clin Cardiol 2007;30:475–9. https://doi.org/10.1002/clc.20140; PMID: 17803205. 31. Ulus T, Parspour A, Cavusoglu Y, et al. Statins improve myocardial perfusion in metabolic syndrome patients who have perfusion defects on myocardial perfusion imaging and angiographically normal coronary arteries. Eur Rev Med Pharmacol Sci 2012;16:328–34. PMID: 22530349. 32. Chow BJ, Small G, Yam Y, et al; CONFIRM Investigators. Prognostic and therapeutic implications of statin and aspirin therapy in individuals with nonobstructive coronary artery disease: results from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry) registry. Arterioscler Thromb Vasc Biol 2015;35:981–9. https://doi.org/10.1161/ATVBAHA.114.304351; PMID: 25676000. 33. Hwang IC, Jeon JY, Kim Y, et al. Statin therapy is associated with lower all-cause mortality in patients with non-obstructive coronary artery disease. Atherosclerosis 2015;239:335–42. https://doi.org/10.1016/j.atherosclerosis.2015.01.036; PMID: 25682032. 34. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2019;41:407–77. https://doi.org/10.1093/eurheartj/ ehz425; PMID: 31504439.

COVID-19

Smoking Cessation as a Public Health Measure to Limit the Coronavirus Disease 2019 Pandemic Maki Komiyama and Koji Hasegawa National Hospital Organization Kyoto Medical Center, Kyoto, Japan

Abstract The novel coronavirus disease 2019 (COVID-19) has already evolved into a rapidly expanding pandemic. Risk factors for COVID-19, such as cardiovascular disease, chronic obstructive pulmonary disease and diabetes, are all strongly associated with smoking habits. The effects of cigarette smoking on the transmission of the virus and worsening of COVID-19 have been less addressed. Emerging data indicate that smoking history is the major determinant of worsening COVID-19 outcomes. Smoking cessation recovers airway ciliary clearance and immune function. Thus, smoking cessation awareness is strongly encouraged as a public health measure to limit the global impact of COVID-19.

Keywords Smoking, COVID-19, SARS-CoV-2, coronavirus, pandemic Disclosure: The authors have no conflicts of interest to declare. Received: 7 April 2020 Accepted: 8 April 2020 Citation: European Cardiology Review 2020;15:e16. DOI: https://doi.org/10.15420/ecr.2020.11 Correspondence: Koji Hasegawa, Division of Translational Research, National Hospital Organization Kyoto Medical Center, 612-8555, Kyoto, Japan. E: koj@kuhp.kyoto-u.ac.jp Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

The novel coronavirus disease 2019 (COVID-19) first occurred in December 2019 in Wuhan, Hubei Province, China, and has already evolved into a rapidly expanding pandemic. The WHO has declared COVID-19, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), to be a public health emergency of international concern.1 Until effective therapeutics and vaccines become available, minimising the spread of COVID-19 is a pressing global challenge. Approximately 80% of infected individuals remain asymptomatic or present only with minor symptoms, whereas 15% become moderately to severely ill with cough and shortness of breath, and 5% require intensive care. Elderly people with underlying diseases, such as cardiovascular disease, diabetes, hypertension, chronic respiratory disease and malignancies, are at greater risk of developing severe COVID-19. Behavioural measures, such as coughing etiquette, hand washing, social distancing and reducing physical contact, are recommended to prevent the spread of SARS-CoV-2. However, the effects of cigarette smoking on the transmission of the virus and worsening of COVID-19 have been less addressed. Smoking is a major risk factor for many respiratory infections, and could also accelerate disease progression in those infected.2 Previous studies have shown that smokers are more likely to contract influenza and exhibit more severe symptoms than nonsmokers.3 Additionally, with the previous Middle East respiratory syndrome coronavirus (MERSCoV) outbreaks, smoking was reported to be a risk factor for MERS-CoV infection and associated with high mortality.4 The mechanisms by which smoking increases the risk of worsening pneumonia include altered airway architecture, inhibition of airway ciliary clearance and reduced immune function.3

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There are several reasons why smoking adversely affects the immune system. First, smoking reduces CD4+ T-cells (helper T-cells), which promote antibody production in B-cells and activate killer T-cells to attack pathogens. Second, nicotine, a major component in tobacco products, which promotes the secretion of catecholamines and corticosteroids, could impair immune function and suppress the bodyâ&#x20AC;&#x2122;s ability to combat infections.5,6 Third, nicotine also reportedly inhibits the production of interleukin-22, which helps suppress lung inflammation and repair damaged cells.7 Thus, in COVID-19, as well as in other infectious diseases, the risk of infection and increased disease severity could be higher in smokers. However, although there are reports of age, sex and underlying diseases being factors driving SARS-CoV-2 transmission and disease deterioration, few studies have focused on the association with cigarette smoking. Unfortunately, the COVID-19 pandemic is still ongoing, and limited data on the clinical characteristics and prognostic factors of COVID-19 patients are available. However, emerging data appear to indicate an increased risk of infection, morbidity and mortality of SARS-CoV-2 in individuals with a history of smoking. According to the WHO, the mortality rate due to SARS-CoV-2 in China is higher among men (4.7%) than women (2.8%), which might reflect the large sex difference in smoking habits in China (52.1% in men and 2.7% in women).8,9 In Western countries, where infection transmission has recently soared, smoking tends to be higher among men, although the sex difference is not as great as in China. The European Centre for Disease Prevention and Control (ECDC) reported that COVID-19 deaths were more frequent among men; a higher smoking rate in men might be attributable to the higher mortality.10

ÂŠ RADCLIFFE CARDIOLOGY 2020

Smoking Cessation to Limit the COVID-19 Pandemic In a report on 1,099 infected individuals from China, 12.4% of current smokers and 23.8% of past smokers developed critical outcomes, including being admitted into an intensive care unit or fitted with a ventilator, or mortality. In comparison, only 4.7% of those who had never smoked developed critical outcomes.11 Additionally, the proportion of patients with severe symptoms was 21.2% among current smokers and 42.9% among past smokers, which was higher compared with those who had never smoked (14.5%).11 In this report, the analysis was just a simple comparison. Usually, past smokers were older than current smokers. Therefore, a high age in past smokers may contribute to their worsening outcomes. A small study from China using multivariate analysis identified the following four factors as being associated with COVID-19 deterioration: smoking history, body temperature of >37.3°C at the time of admission, respiratory failure and age ≥60 years.12 Among these, the OR for smoking history was highest at 14 (CI [1.6–45]; p=0.018), which was higher than the ORs for other factors associated with disease deterioration (8.5–9.0). As noted earlier, COVID-19 is considered to be severe and associated with a higher mortality rate in elderly patients with underlying diseases; it is worth noting that underlying diseases related to the severity of COVID-19, such as cardiovascular disease, chronic obstructive pulmonary disease and diabetes, are all strongly associated with smoking.13,14 COVID-19 is primarily a disease of the respiratory tract, and virus entry into cells, viral replication and virion release occur within the respiratory tract.15 Angiotensin-converting enzyme (ACE) 2 converts the vasoconstrictor angiotensin II to vasoprotective angiotensin.1–7 Multiple studies have shown that ACE-2 is a host receptor for SARS-CoV-2.16 SARS-CoV-2 enters cells through ACE-2 receptors present in mucosal epithelial cells and alveolar tissues in a clathrin-dependent process.

WHO. Coronavirus disease (COVID-19) outbreak. Geneva: WHO, 2020. https://www.who.int/emergencies/diseases/novelcoronavirus-2019 (accessed 14 April 2020). Groskreutz DJ, Monick MM, Babor EC, et al. Cigarette smoke alters respiratory syncytial virus-induced apoptosis and replication. Am J Respir Cell Mol Biol 2009;41:189–98. https://doi. org/10.1165/rcmb.2008-0131OC; PMID: 19131644. Arcavi L, Benowitz NL. Cigarette smoking and infection. Arch Intern Med 2004;164:2206–16. https://doi.org/10.1001/ archinte.164.20.2206; PMID: 15534156. Park JE, Jung S, Kim A, Park JE. MERS transmission and risk factors: a systematic review. BMC Public Health 2018;18:574. https://doi.org/10.1186/s12889-018-5484-8; PMID: 29716568. Ouyang Y, Virasch N, Hao P, et al. Suppression of human IL-1β, IL-2, IFN-γ, and TNF-α production by cigarette smoke extracts. J Allergy Clin Immunol 2000;106:280–7. https://doi.org/10.1067/ mai.2000.107751; PMID: 10932071. Nouri-Shirazi M, Guinet E. Evidence for the immunosuppressive role of nicotine on human dendritic cell functions. Immunology 2003;109:365–73. https://doi. org/10.1046/j.1365-2567.2003.01655.x; PMID: 12807482. Nguyen HM, Torres JA, Agrawal S, Agrawal A. Nicotine impairs the response on lung epithelial cells to IL-22. Mediator Inflamm 2020;6705428. https://doi.org/10.1155/2020/6705428; PMID: 32189996. WHOn. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). WHO: Geneva, 2020. https://www.who. int/docs/default-source/coronaviruse/who-china-joint-

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10.

11.

12.

13.

14.

15.

Cigarette smoking increases the expression of ACE-2 in pulmonary tissues, which could in part account for the increased risk of infection.17,18 Additionally, the WHO has noted that smokers perform repeated hand to face reciprocal movements, which contribute to increased opportunity for virus entry.19 ACE inhibitors and angiotensin-receptor blockers also increase the expression of ACE-2 receptors, which could increase the risk of COVID-19 infection. In fact, the ECDC reported that 74% of COVID-19 fatalities in Italy had concomitant hypertension, suggesting an association with these drugs.10 Many societies, including the European Society of Cardiology, have issued alerts that patients with cardiovascular diseases discontinue ACE inhibitors and angiotensinreceptor blockers.20 Switching to calcium antagonists has been suggested; however, further evidence for this is needed.21 Although only a few reports on smoking have been published to date and further accrual of evidence is warranted, smoking is likely to be an important and significant factor associated with COVID-19 severity. Cigarette smoking decreases lung function, and evidently poses a general risk factor for severe respiratory infections, thus there is an apparent association between cigarette smoking and COVID-19 severity. The detailed mechanism by which COVID-19 becomes more severe in patients with a history of cigarette smoking warrants further investigation. There is also a need for more evidence on the effect of second-hand smoke on the spread of SARS-CoV-2. However, according to published COVID-19 research reports, even at this stage, it might be well assumed that smokers are likely to be at serious risk for contracting SARS-CoV-2 infection. Smoking cessation recovers airway ciliary clearance and immune function as early as 1 month. Thus, smoking cessation awareness is strongly encouraged as part of public health measures to limit the global impact of COVID-19.

mission-on-covid-19-final-report.pdf (accessed 14 April 2020). WHO. WHO report on the global tobacco epidemic 2019. WHO: Geneva, 2020. https://www.who.int/tobacco/global_report/en/ (accessed 14 April 2020). European Centrr for Disease Prevention and Control. Coronavirus disease 2019 (COVID-19) pandemic: increased transmission in the EU/EEA and the UK – seventh update. ECDC: Stockholm, 2020. https://www.ecdc.europa.eu/sites/default/ files/documents/RRA-seventh-update-Outbreak-ofcoronavirus-disease-COVID-19.pdf (accessed 14 April 2020). Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020. https://doi. org/10.1056/NEJMoa2002032; PMID: 32109013; epub ahead of press. Liu W, Tao ZW, Lei W, et al. Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease. Chin Med J (Engl) 2020. https://doi. org/10.1097/CM9.0000000000000775; PMID: 32118640; epub ahead of press. Dong X, Cao YY, Lu XX, et al. Eleven faces of coronavirus disease 2019. Allergy 2020. https://doi.org/10.1111/all.14289; PMID: 32196678; epub ahead of press. Medical management and prevention instruction of chronic obstructive pulmonary disease during the coronavirus disease 2019 epidemic. Zhonghua Jie He He Hu Xi Za Zhi 2020 [in Chinese]. https://doi.org/10.3760/cma.j.cn11214720200227-00201; PMID: 32153171; epub ahead of press. Zou L, Ruan F, Huang M, et al. SARS-CoV-2 viral load in upper

16.

17.

18.

19.

20.

21.

respiratory specimens of infected patients. N Engl J Med 2020;382:1177–9. https://doi.org/10.1056/NEJMc2001737; PMID: 32074444. Zhou P, Yang X-L, Wang X-G, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270–3. https://doi.org/10.1038/s41586-0202012-7; PMID: 32015507. Liang W, Guan W, Chen R, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol 2020;21:335–7. https://doi.org/10.1016/S1470-2045(20)300966; PMID: 32066541. Xia Y, Jin R, Zhao J, et al. Risk of COVID-19 for cancer patients. Lancet Oncol 2020;21:e180. https://doi.org/10.1016/S14702045(20)30149-2; PMID: 32142622. WHO. Q&A on smoking and COVID-19. WHO: Geneva, 2020. https://www.who.int/news-room/q-a-detail/ q-a-on-smoking-and-covid-19 (accessed 14 April 2020). di Simone G. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers. European Society of Cardiology. 13 March 2020. https://www.escardio.org/Councils/Council-on-Hypertension(CHT)/News/position-statement-of-the-esc-council-onhypertension-on-ace-inhibitors-and-ang (accessed 14 April 2020). Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020;8:e21. https://doi.org/10.1016/S22132600(20)30116-8; PMID: 32171062.

Heart Failure

Heart Failure Treatment by Device Antoni Bayés-Genis Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain, and Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain

Disclosure: ABG was supported by CIBER Cardiovascular (CB16/11/00403). Citation: European Cardiology Review 2020;15:e17. DOI: https://doi.org/10.15420/ecr.2020.03 Correspondence: Antoni Bayés-Genis, Heart Institute, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n 08916, Barcelona, Spain. E: abayesgenis@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

“ Science can amuse and fascinate us all, but it is engineering that changes the world.” – Isaac Asimov, 1920–1992 Technological breakthroughs, particularly advances in devices, are changing the course of heart failure (HF) management. Implantable devices have been used for decades to treat heart disease. The first pacemaker was implanted over 60 years ago (October 1958), and implantable defibrillators were first used in the early 1980s. Cardiac resynchronisation therapy appeared at the turn of the century. However, the past few years have witnessed a surge in both the types of devices being tested for HF treatment and the optimism of experts about their usefulness. This HF Special Focus Section reviews novel devices used for advanced, symptomatic HF. Destination left ventricular assist devices (LVADs) in non-transplant centres, interatrial shunts to treat HF and MitraClip in HF are discussed by Bayés-Genis, Rodés-Cabau and Linderfeld. The history of mechanical circulatory support began in 1953, when John H Gibbon reported the first successful use of extracorporeal circulation by means of an oxygenator. In 1966, DeBakey implanted the first pneumatically driven LVAD,1 and in 1969, Cooley implanted the first total artificial heart, intended as a bridge to transplantation. 2 It was not until 1982 that the Jarvik-7 artificial heart was implanted for the first time with the intention of permanent treatment, although the patient died within 4 months of severe sepsis and multi-organ failure. 3 A shift from the concept of a complete artificial heart towards the development of single chamber pumps as cardiac support initiated the LVAD era. First-generation ventricular assist devices were either pneumatically or electrically driven membrane pumps, such as the Berlin Heart EXCOR (Berlin Heart) and Thoratec PVAD (Thoratec). In the past decade, LVAD systems have undergone substantial progress in size, durability, reliability and noise emission, such as the HeartMate 3 (Abbott Structural Heart). LVAD implantation became a new treatment option for end-stage HF, as destination therapy for patients either too old or not suitable for transplantation due to other medical conditions.

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Consequentially, an exponential increase in LVAD implantations has occurred in the past 5 years. The history of the MitraClip begins with advances in the surgical treatment of mitral regurgitation. The MitraClip technology draws on experience with surgical edge-to-edge mitral valve repair, which was first reported by Alfieri et al. in 1995.4 This technique involves the placement of sutures to anchor the free edge of a leaflet to its corresponding opposite leaflet, creating two valve orifices without the need for annuloplasty. Based on these findings, investigators at major academic institutions, in concert with private industry (Evalve; later Abbott Vascular), developed the MitraClip percutaneous transcatheter method to reapproximate the anterior and posterior mitral leaflets as a therapy for mitral regurgitation. This method was first described in pigs in 2003, and several trials have since tested the value of MitraClip in the treatment of severe mitral regurgitation, with controversial results. In this HF Special Focus Section, these data are discussed and put into a clinical context to better understand the real clinical value of MitraClip in 2020. The interatrial shunt is the newest of the three devices discussed in this special issue. Increased left atrial pressure leading to pulmonary congestion is the common mechanism precipitating symptom worsening and acute decompensation in chronic HF patients. Some evidence supports interatrial shunting to relieve the excess volume from the left to right atrium regulated by the interatrial pressure gradient. Two different interatrial shunt devices are currently being tested in large randomised clinical trials: the interatrial shunt device (Corvia Medical) and the V-Wave device (V-Wave). Both are intended for symptomatic HF; the interatrial shunt device is focused on heart failure with preserved ejection fraction, whereas the V-Wave device is being tested in both heart failure with preserved ejection fraction and heart failure with reduced ejection fraction.5 We have truly entered the era of devices in HF, and I believe there will be rapid progress on multiple fronts in the next few years. These

Guest Editorial devices would have been completely unimaginable a few decades ago, and exemplify the role that industry and technology play in modern medical care. Furthermore, while advances in devices are impressive, it is likely that we are only in the early stages of their development. These new devices may just be the second wave designed for different aspects

DeBakey ME. Left ventricular bypass pump for cardiac assistance. Clinical experience. Am J Cardiol 1971;27:3–11. https://doi.org/10.1016/0002-9149(71)90076-2; PMID: 5538711. Cooley DA, Liotta D, Hallman GL, et al. Orthotopic cardiac prosthesis for two-staged cardiac replacement. Am J Cardiol 1969;24:723–30.https://doi.org/10.1016/0002-9149(69)90460-3;

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of HF treatment, after implantable defibrillators and cardiac resynchronisation therapy. What we do now may be called a ‘passive’ bridge to recovery, where we place devices and hope that whatever is wrong with the heart naturally works itself out. What we may see in the future is an ‘active’ bridge to recovery, where we not only place the device, but administer cells, genes or new (or even old) drugs to help repair the heart.

PMID: 4899910. DeVries WC, Anderson JL, Joyce LD, et al. Clinical use of the total artificial heart. N Engl J Med 1984;310:273–8. https:// doi.g/10.1056/NEJM198402023100501; PMID: 6690950. Fucci C, Sandrelli L, Pardini A, et al. Improved results with mitral valve repair using new surgical techniques. Eur J

Cardiothorac Surg 1995;9:621–6. https://doi.org/10.1016/S10107940(05)80107-1;PMID: 8751250. Guimaraes L, Lindenfeld J, Sandoval J, et al. Interatrial shunting for heart failure current evidence and future perspectives. EuroIntervention 2019;15:164–71. https://doi.org/10.4244/EIJ-D18-01211; PMID: 3080393.

Heart Failure

Interatrial Shunting for Treating Acute and Chronic Left Heart Failure Leonardo Guimaraes, David del Val, Sebastien Bergeron, Kim O’Connor, Mathieu Bernier and Josep Rodés-Cabau Department of Cardiology, Quebec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada

Abstract The creation of an interatrial shunt has emerged as a new therapy to decompress the left atrium in patients with acute and chronic left heart failure (HF). Current data support the safety of this therapy, and promising preliminary efficacy results have been reported in patients who are refractory to optimal medical/device therapy. This article aims to provide an updated overview and clinical perspective on interatrial shunting for treating different HF conditions, and highlights the potential challenges and future directions of this therapy.

Keywords Heart failure, acute heart failure, chronic heart failure, interatrial shunt Disclosure: JR-C is a consultant for and has received research grants from V-Wave, and holds the Research Chair Fondation Famille Jacques Larivière for the Development of Structural Heart Disease Interventions. DdV was supported by a grant from the Alfonso Martín Escudero Foundation (Madrid, Spain). All other authors have no other conflicts of interest to declare. Received: 8 June 2019 Accepted: 9 August 2019 Citation: European Cardiology Review 2020;15:e18. DOI: https://doi.org/10.15420/ecr.2019.04 Correspondence: Josep Rodés-Cabau, Quebec Heart and Lung Institute, Laval University, 2725 Chemin Ste-Foy, Quebec City, Quebec, G1V 4G5, Canada. E: josep.rodes@criucpq.ulaval.ca Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Major advances in heart failure (HF) management have been achieved over the past three decades, yet it remains a syndrome with high morbidity and mortality, poor quality of life and high healthcare costs. Despite all advances in medical/device therapy, many HF patients continue to deteriorate, leading to poor quality of life and high rehospitalisation and mortality rates.1 The recent European Society of Cardiology HF pilot study showed that hospitalised and stable/ ambulatory HF patients had 12-month all-cause mortality rates of 17% and 7%, respectively, and 12-month rehospitalisation rates of 44% and 32%, respectively.2 Of note, an increase in left atrial (LA) pressure usually precedes the worsening of symptoms and acute HF decompensation in patients with left ventricular (LV) dysfunction.3 Acute HF has become the most common cause of hospitalisation in patients >65 years, and approximately 4–12% of patients present with cardiogenic shock, a severe condition with high morbidity and mortality rates.4,5 The creation of an interatrial shunt to decompress the left atrium in patients with acute or chronic HF has been used as an alternative therapy to improve symptoms and clinical outcomes.6–8 The aim of this review was to provide an updated overview and clinical perspective on interatrial shunting for treating HF, and to highlight the potential challenges and future directions of this therapy.

circulatory support (MCS) can improve forward flow and interrupt the inflammatory mechanism preventing organ damage related to the shock. Veno-arterial extracorporeal membrane oxygenation (VAECMO) remains the most effective percutaneous MCS to treat refractory cardiogenic shock.9 Nevertheless, the arterial cannula may increase LV afterload in these patients, raising LV end-diastolic and LA pressures, leading to increased LV wall stress and myocardial oxygen consumption, and further worsening LV failure and refractory pulmonary oedema.10,11 The intra-aortic balloon pump has been the most common technique to decompress the LV in such cases, but it has not been associated with improved survival.12 Atrial septostomy (AS) has recently been described as an option for LV decompression in adults treated with VA-ECMO who develop refractory pulmonary oedema or upper body hypoxaemia.13

Clinical Evidence The global experience of AS in patients treated with VA-ECMO is limited to small series and case reports. The main findings of AS in cardiogenic shock and VA-ECMO recipients to date are summarised in Table 1. AS was first described in paediatric patients treated with VA-ECMO who had signs of high LV/LA pressure or refractory pulmonary oedema. Haemodynamic data are limited, and some studies have evaluated the response of AS using non-invasive examintions, such as echocardiography, chest X-ray and respiratory parameters.

Interatrial Shunting for Acute Heart Failure The management of cardiogenic shock includes cardiovascular resuscitation and identification and treatment of the underlying cause. Vasoactive agents are needed to maintain the cardiac output, but can increase myocardial oxygen demand leading to myocardial ischaemia and increased risk of arrhythmias. The use of mechanical

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In a small series of four paediatric patients, the haemodynamic effect of AS was assessed by echocardiography and showed prompt normalisation of LA size and/or Doppler velocity values across the atrial septum, and improvements in LV function.14 A recent series of AS in 15 adults treated with VA-ECMO showed a significant drop in the

Interatrial Shunting and Heart Failure oxygenation index (from 9.9 ± 5.9 to 4.6 ± 3.0, p<0.001) and radiological improvement of pulmonary oedema following AS (Figure 1). Additional LA pressure measurements obtained in three patients showed a significant decrease in LA pressure values following the procedure (from a mean of 29 mmHg to 13 mmHg).15,16 Another recent series of nine adult patients evaluated the radiological response after AS and a more objective measure using vascular pedicle width (VPW).17 VPW consists of the distance (measured in millimetres) from a perpendicular line at the point at which the left subclavian artery exits the aorta to the point at which the superior vena cava crosses the right main bronchus and correlates with volume overload.18 Significant radiological improvement and a reduction in VPW (from 76.6 mm to 57.9 mm, p=0.021) were observed following AS. Additionally, all patients had improved respiratory parameters, with an increase of PaO2/FiO2 of >10fold, and a reduction in LA pressure (from 32 mmHg [interquartile range 28–42 mmHg] to 21 mmHg [interquartile range 13–28 mmHg]), and no changes in right atrial pressure.17 Overall, AS has been shown to be a relatively simple procedure with a high success rate among paediatric and adult patients treated with VA-ECMO who have refractory pulmonary oedema or upper body hypoxaemia.14–17 Apart from the acute effects of AS and the critical condition of patients receiving this treatment, the impact on clinical outcomes is difficult to establish due to the very limited number of patients and a lack of follow-up. LA decompression usually leads to a resolution of the pulmonary oedema and a shorter period of sedation and invasive ventilation. LV decompression improves subendocardial perfusion, decreases myocardial oxygen consumption and can contribute to LV recovery and ECMO weaning. While the reported inhospital mortality following AS in such patients is approximately 50%, a significant proportion of patients who survive undergo successful heart transplantation.15,17 In summary, AS in this particularly challenging population acts as a palliative treatment for complications induced by VA-ECMO or cardiogenic shock to gain time for LV recovery or heart transplantation.

Table 1: Demographic and Procedural Outcomes in Patients with Cardiogenic Shock Treated with Veno-arterial Extracorporeal Membrane Oxygenation Undergoing Atrial Septostomy Koenig et al.14 Lin et al.15 Prasad et al.17 n

Baseline characteristics Age (years)

4 days–5 years

51 (40–58)

46 (31–68)

Male sex (%)

–

Myocarditis/ICMP/ DCMP/VT/CA/AR

4/0/0/0/0/0

5/7/1/2/0/0

–

15/16

9/9

– –

29* 13*

32 (28–42) 21 (13–28)

– –

76.6 (68.5–91.7) 57.9 (56.4–71.2)

Veno-arterial 4–8 extracorporeal membrane oxygenation duration (days)

15 (10–22)

14 (10–21)

In-hospital death, n (%)

7 (46.7)

5 (55.6%)

Procedural characteristics Procedural success

4/4

Haemodynamic outcomes LAP (mmHg): • Baseline • Post-procedural VPW (mm): • Baseline • Post-procedural

Clinical outcomes

1 (25)

*Measured in three patients. Values are median (interquartile range) or range. AR = acute rejection; CA = cardiac arrest; DCMP = dilated cardiomyopathy; ICMP = ischaemic cardiomyopathy; LAP = left atrial pressure; VPW = vascular pedicle width; VT = ventricular tachycardia.

Figure 1: Radiological Improvement after Atrial Septostomy in a Patient with Cardiogenic Shock Treated with Venoarterial Extracorporeal Membrane Oxygenation

Technique AS usually starts with a standard right heart catheterisation, with pressure and cardiac output measurements. A transseptal puncture is performed at the level of the central segment of the fossa ovalis under fluoroscopy and transoesophageal/intracardiac echocardiography guidance, followed by the advancement of a long sheath across the interatrial septum to the left atrium. A balloon is then advanced through a stiff guidewire, and balloon dilation at the level of the interatrial septum using a non-compliant balloon is performed. Usually, large balloons (>10–15 mm, up to 27 mm; usually an Inoue-Balloon or peripheral balloon) have been used in VA-ECMO patients to create a very large and haemodynamically effective atrial septal defect.

Future Perspectives Patients with cardiogenic shock treated with VA-ECMO frequently need additional measures to decompress the LA. There are no data available comparing the different strategies to decompress the left heart, but surgical methods using a cannula connected to ECMO or the implant of another device, such as Impella, are likely to be more complex and expensive than AS. Also, it has been shown that bedside balloon AS in children undergoing echocardiographic guidance is feasible and prevents the transfer of these critical patients to the cath lab.14,19 In adult patients, AS has also been demonstrated to be simple, and could become one of the preferred strategies to overcome left heart

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A: Before atrial septostomy. B: After atrial septostomy. Source: Aiyagari et al. 2006.16 Reproduced with permission from Wolters Kluwer.

distension in such patients. However, to the best of our knowledge, no prospective observational or randomised studies are underway to prospectively evaluate the efficacy of the AS strategy in the context of cardiogenic shock or VA-ECMO.

Interatrial Shunt for Chronic Heart Failure HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) continue to be major public healthcare problems with an annual cost of >US$30 billion in the US.20 The National

Heart Failure Figure 2: Devices used for Interatrial Shunting in Patients with Chronic Heart Failure

A and B: InterAtrial Shunt Device. C and D: V-Wave device. E and F: Second-generation (valveless) V-Wave device. G,H: Atrial Flow Regulator. Source: A and B: Reproduced with permission from Corvia Medical Inc. C–F: Reproduced with permission from V-Wave. G and H: Reproduced with permission from Occlutech International AB.

Health and Nutritional Examination Survey estimates that 6.5 million Americans >20 years have HF, which is responsible for 900,000 hospitalisations every year.21 Furthermore, the projection from 2012 to 2030 estimates an increase close to 50%, resulting in more than 8 million people >18 years with HF.20 Despite decades of major advances in medical and device treatments, HF morbidity and mortality remain high, regardless of their aetiology. Increased LA pressure leading to pulmonary congestion is the common mechanism precipitating worsening of symptoms and acute decompensation in chronic HF patients.3 In addition, elevated pulmonary capillary wedge pressure (PCWP) during exercise has been associated with lower functional capacity, negatively impacting quality of life and prognosis.22,23 Implantable haemodynamic pressure monitoring has been demonstrated to decrease HF hospitalisation and improve outcomes by guiding dose titration of drugs, impacting LA pressure in HFrEF and HFpEF patients.3,24 Notwithstanding the benefits of device-guided therapy, most HF patients are elderly and present multiple comorbidities, which may challenge both the self-titration of medication and close medical follow-up. There is some evidence supporting interatrial shunting to relieve the volume excess from the left to right atrium regulated by the interatrial pressure gradient, and creating an on-demand, auto-regulating reduction in LA pressure. Pulmonary oedema due to decreased LV compliance and acute increase in LA pressure has been observed in patients undergoing atrial septal defect closure.25 One of the concerns of left-to-right shunting is the potential overloading of the right ventricle (RV) and an increase in pulmonary artery pressure (PAP). However, studies in the congenital field have shown that small shunts (usually atrial septal defects <10 mm) are not associated with any deleterious haemodynamic effect at long-term follow-up.26 Thus, some devices have been developed in order to create a controlled and permanent left-to-right shunt in HF patients.

Devices and Clinical Evidence InterAtrial Shunt Device The InterAtrial Shunt Device (IASD, Corvia Medical) is composed of a nitinol mesh with multiple legs and radiopaque markers, with a central hole (Figure 2A and Figure 2B). The disc and fenestration diameter are 19 mm and 8 mm, respectively.27 The IASD has been evaluated in patients with HFpEF. In the first evaluation of 11 patients with left ventricular ejection fraction (LVEF) >45% and New York Heart Association (NYHA) class III/IV, the device was successfully implanted in all patients (in one case, the device was initially maldeployed in the left atrium, recaptured with a snare without complications and a second device was successfully implanted).27 Following device implantation, there was a significant decrease (about 30%) in PCWP, with stable right atrial pressure (RAP) and PAP. This was associated with significant improvements in a 6-minute walk test (6MWT) distance, quality of life and NYHA class at 30-day follow-up (Table 2).27 The Reduce Elevated Left Atrial Pressure in Patients with HF (REDUCE LAP-HF) trial was a multicentre study of 64 patients with symptomatic HF (NYHA classes II–IV) and LVEF >40% who were treated with the IASD System II device.28 The device was successfully implanted in all patients, with no major periprocedural complications. At 6-month follow-up, repeat right catheterisation showed no significant changes in PCWP at rest, but there was a significant decrease in PCWP at peak exercise (mean reduction of 3 mmHg, p=0.01). There were no safety issues, and significant improvements in NYHA class, quality of life and exercise capacity were observed at 6 months (Table 2).28 A subsequent report from Kaye et al. showed that these improvements were maintained at 1-year follow-up.29 Shunt patency was properly evaluated by transthoracic echocardiography (TTE) in 48 of 64 patients, with no signs of occlusion/stenosis. In 16 patients (25%), TTE images were not considered adequate for patency assessment, highlighting the potential

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Interatrial Shunting and Heart Failure Table 2: Baseline, Procedural Characteristics and Clinical Outcomes of Patients with Chronic Heart Failure Undergoing Interatrial Shunting with a Permanent Device Søndergaard et al.27

Hasenfuß et al.28 REDUCE LAP-HF

Feldman et al.8 REDUCE LAP-HF I

Del Trigo et al.7

Rodés-Cabau et al.34

Age (years)

70.0 ± 11.9

69.0 ± 8.0

69.6 ± 8.3

62.0 ± 8.0

66.0 ± 9.0

Male sex, n (%)

5 (45.4)

22 (34.4)

14 (63.6)

9 (90%)

35 (92)

HFpEF/HFrEF

11/0

64/0

22/0

0/10

8/30

LVEF (%)

57.0 ± 9.0

47.0 ± 7.0

59.9 ± 9.0

25.0 ± 8.0

–

Device

IASD

V-Wave

Procedural success

11/11

64/66

20/21

10/10

38/38

12.0 ± 3.4 11.5 ± 2.8

9.0 ± 4.0 11.0 ± 5.0§

10.1 ± 2.3 10.6 ± 4.0

9.5 ± 4.0 8.0 ± 5.0

8.0 ± 4.0 9.0 ± 4.0

30.3 ± 7.1 26.5 ± 5.9

25.0 ± 7.0 –

30.2 ± 9.5 27.5 ± 5.4

29.0 ± 7.0 26.0 ± 11.0

30.0 ± 7.0 30.0 ± 10.0

19.1 ± 5.0 14.0 ± 3.3§

17.0 ± 5.0 17.0 ± 7.0

20.9 ± 7.9 18.7 ± 6.6

23.0 ± 5.0 17.0 ± 8.0§

21.0 ± 5.0 19.0 ± 7.0

– –

32.0 ± 8.0 29.0 ± 9.0§

37.3 ± 6.5 33.8 ± 6.4

– –

• Post-procedural

2.4 ± 0.4 –

– –

2.1 ± 0.3 2.4 ± 0.7

2.2 ± 0.4 2.3 ± 0.5

Device occlusion/stenosis (n)

0||

0†

19/36‡

322.0 ± 151.6 367.5 ± 123.1§

313.0 ± 105.0 345.0 ± 106.0§

– –

249.0 ± 106.0 319.0 ± 134.0§

290.0 ± 112.0 324.0 ± 105.0§

3.2 ± 0.4 2.4 ± 0.8

3 (2–3) 2 (2–3)§

3 2.5 ± 0.7

3 2.0 ± 0.5§

3.0 ± 0.2 –

53.0 ± 17.3 32.8 ± 18.7§

49.0 ± 20.0 36.0 ± 23.0§

– –

44.8 ± 9.4 79.1 ± 13.0§

– –

12.4 ± 6.2 24.8 ± 12.9§

– –

Immediate death (<24 hours)

Late death (>30 days) Follow-up

–

0 6 months

–

1 3 months

2 Median 28 months

Baseline characteristics

Procedural characteristics

Haemodynamic outcomes RAP (mmHg): • Baseline • Post-procedural PAP (mmHg): • Baseline • Post-procedural PWP at rest (mmHg): • Baseline • Post-procedural PWP at exercise (mmHg): • Baseline • Post-procedural CI (l/min/m2): • Baseline

Functional status and quality of life 6MWT (m): • Baseline • Post-procedural NYHA: • Baseline • Post-procedural MLWHF score: • Baseline • Post-procedural KCCQ: • Baseline • Post-procedural DASI: • Baseline • Post-procedural

Clinical outcomes

Values are mean ± standard deviation or median (interquartile range). *1-month follow-up; †3-month follow-up; ‡ median follow-up of 28 months (range: 18–48 months); §statistically significant; ||10 patients presented shunt patency and in one patient the shunt patency was unable to be assessed. 6MWT = 6-minute walk test; CI = cardiac index; DASI = Duke Activity Status Index; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; KCCQ = Kansas City Cardiomyopathy Questionnaire; LVEF = left ventricle ejection fraction; MLWHF = Minnesota Living with Heart Failure; NYHA = New York Heart Association; PAP=pulmonary artery pressure; PWP = pulmonary wedge pressure; RAP = right atrial pressure.

challenge of interatrial shunt evaluation using TTE. Recently, Kaye et al. determined the potential impact of IASD implantation on mortality in HFpEF patients after a median follow-up of 2 years.30 The observed mortality in IASD recipients (9.4%) was compared with the predicted

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mortality using the Meta-analysis Global Group in Chronic HF prognostic model at 1 and 3 years, showing that interatrial shunting was associated with a 33% reduction in the all-cause mortality rate (HR 0.67, 95% CI [0.09–0.89], p=0.02). Furthermore, IASD recipients who had HF

Heart Failure hospitalisations were not associated with subsequent increased mortality (p=0.31). The REDUCE LAP-HF I study was a randomised trial that included patients with LVEF >40% and NYHA classes III–IV.8 Forty-four patients were allocated (1:1) to receive the IASD System II device versus a sham procedure (control group). At 1-month follow-up, there were no significant differences between the groups for PCWP values at rest, but patients in the IASD group had a reduction of PCWP during exercise compared to a lack of changes in PCWP exercise values among the control group (p=0.01 for differences between groups; Table 2). Functional status and exercise capacity were similar in both groups at 1-month and 1-year follow-up.8,31 At 1-year follow-up, the IASD group exhibited a tendency towards a better NYHA class improvement compared to baseline (median −1 [interquartile range −1 to 0] versus 0 [−1 to 0], p=0.08) and less HF hospitalisations (rate per patient year 0.22, 95% CI [0.08–0.58] versus 0.63, 95% CI [0.33–1.21], p=0.06).31 Mild RV dilation was observed at 6 months in the IASD group compared with the control group (9.1 ml/m2 [interquartile range 5.8–11.0] versus −1.9 ml/m2 [interquartile range −4.4 to 3.8] , p=0.002), with no further dilation up to 1 year. No decrease in RV function and no evidence of shunt stenosis/occlusion were observed over time. Finally, major adverse cardiac, cerebrovascular or renal events were also similar between the groups, with a survival rate of 95% at 12 months (one death in each group). Additional evidence of the potential effect of interatrial shunting on right-side heart parameters was recently reported by Danial et al.32 An interatrial shunt was created with a 2 mm balloon in a total of 22 rats (healthy n=11, HFpEF n=11), and this translated into a reduction in LA volume and pulmonary artery diameter in rats with HFpEF. However, in healthy rats, interatrial shunting was associated with an RV overload and increased pulmonary artery diameter. Long-term clinical data are needed to provide definitive data on the potential impact of interatrial shunts on right ventricular function.

V-Wave Device The V-Wave device is an hourglass-shaped device made with nitinol and expanded polytetrafluoroethylene encapsulation, and three porcine pericardial leaflets sutured together with a PROLENE suture to ensure unidirectional left-to-right shunt (Figure 2C and Figure 2D). The lumen diameter of the V-Wave device is 5 mm.7 This device has been tested in patients with HFpEF and HFrEF. The newer generation device consists of a similar device, but without valve leaflets (valveless device) (Figure 2E and Figure 2F). After an initial in-human experience, this newer generation device will be used in a large randomised trial of HFrEF and HFpEF patients. The V-Wave device was the first interatrial shunt device implanted in a patient with HFrEF.33 Del Trigo et al. reported the initial experience with this device in 10 patients with HFrEF (mean LVEF 25%) and functional class III/IV, despite optimal medical/device therapy.7 The device was implanted in all patients with no complications, and a significant reduction in PCWP (mean 5 mmHg) was observed at 3-month follow-up, with no changes in RAP or PAP values. At 3-month follow-up, most patients were in NYHA classes I–II, with significant improvements in quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ; 44.8 ± 9.4 versus 79.1 ± 13.0, p<0.001), and the 6MWT distance increased by about 75 m (p=0.01 versus baseline).

The results of an initial multicentre experience with the V-Wave device were recently reported.34 The study included 38 patients (HFrEF n=30, HFpEF n=8) with NYHA class III–IV, despite optimal medical/device therapy.The V-Wave device was successfully implanted in all cases with only one major periprocedural complication (cardiac tamponade resolved with pericardiocentesis). No additional device-procedure related events occurred up to 1-year follow-up (primary endpoint). Significant improvements in functional status, exercise capacity and quality of life were observed within the first 3 months post-procedure, and were maintained at 1-year follow-up. There were no changes in haemodynamic parameters (as determined at rest) at 1-year follow-up, including PCWP, RAP and PAP (Table 2). After a median follow-up of 28 months (21–31 months), 10 patients (26%) had died (eight from cardiovascular causes), one patient received a left ventricular assist device as destination therapy at 15 months and another underwent heart transplantation at 27 months. The patency of the valved V-Wave device was evaluated by transoesophageal echocardiography at two time points: at 1–3 months and at 1 year after device implantation.34 All shunts were fully patent at 1–3 months, but shunt occlusion was observed in 14% of patients at 1-year follow-up. Additionally, some degree of shunt stenosis at the valve level occurred in 36% of patients, leading to an incidence of shunt stenosis or occlusion of 50% at 1 year. No thrombus (as evaluated by echocardiography) was detected in any of the patients. Interestingly, the potential cause of stenosis or occlusion was suggested from a stenotic shunt that was explanted during cardiac transplantation about 2 years after the procedure. The bioprosthetic leaflets were thickened and stenotic with neoendocardial hyperplasia (pannus). These data, along with the lack of thrombus, strongly suggest intrashunt valve deterioration as the main mechanism of shunt stenosis–occlusion. Following this initial experience, modifications were implemented in order to improve late device patency and continued efficacy, with valve removal being the most relevant feature of the newer (second) generation of the V-Wave shunt. In an animal model of 11 sheep, the valveless V-Wave shunt remained patent, with no late loss in lumen diameter at 5–6-month follow-up (V-Wave, unpublished data). In addition, the first-in-human experience with the valveless V-Wave shunt showed the patency of the shunt (no stenosis-occlusion) in all cases at the 1-year follow-up.35 The fact that half of the interatrial shunts were either stenotic or occluded in the initial V-Wave experience permitted a comparative analysis between patients with and without shunt stenosis or occlusion.34 Patients with full patent shunts exhibited significant improvements in haemodynamic parameters, such as PWCP, at followup (mean decrease of 4 mmHg, p=0.01 versus baseline), compared to the lack of changes in the shunt stenosis–occlusion group (p=0.03 for the comparison of PWCP changes between groups). Furthermore, patients with patent shunts had improved late clinical outcomes, with lower rates of death/left ventricular assistance/transplantation or HF rehospitalisation at 3-year follow-up (Figure 3). Of note, the Kaplan– Meier curves suggested relatively similar event rates (death, hospitalisation) for the two groups (patent versus stenotic-occluded shunts) during the first year of follow-up, before curves progressively separated at up to 3 years. In an exploratory analysis, clinical outcomes at up to 3-year follow-up in those patients included in the V-Wave initial experience appeared to be better than those observed in the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) trial,

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Interatrial Shunting and Heart Failure Figure 3: Clinical Events up to 3-year Follow-up, According to Shunt Patency (Stenotic/Occluded vs. Patent) 2.5

1.0 Cumulative hazard

Death, LVAD, transplant 0.8

HF hospitalisation 2.0

p=0.001

1.5

0.6 0.4

Patent

1.0

Patent

0.5

0.2

0.0

0.0 0 2.5 Cumulative hazard

Stenotic/occluded

p=0.008

Stenotic/occluded

36 5.0

Non HF hospitalisation

2.0

Stenotic/occluded

p=0.002

Stenotic/occluded

All events

4.0

1.5

p=0.002

3.0 Patent

1.0

2.0

0.5

1.0

0.0

Patent

0.0 0

Months No. at Risk 19 17

19 17

16 17

9 14

7 6

5 2

Months 9 14

7 6

5 3

19 17

16 17

Source: Rodés-Cabau et al. 2018.34 Reproduced with permission from Elsevier.

which had similar inclusion criteria and patient characteristics, particularly among those patients with full patent shunt at 1-year follow-up, even if the V-Wave group patients were older and exhibited a higher risk profile (Supplementary Material Figure 1).36

Atrial Flow Regulator The Atrial Flow Regulator (AFR; Occlutech) is a double disc device made of a nitinol wire mesh and a central orifice (Figure 2G and Figure 2H). The fenestration diameter varies from 4 to 10 mm, and there are three waist sizes: 2, 5 and 10 mm to suit the atrial septal thickness. The AFR device is being tested in patients with HFrEF and HFpEF in a small feasibility, currently ongoing clinical trial (Pilot Study to Assess Safety and Efficacy of a Novel Atrial Flow Regulator in Heart Failure Patients [PRELIEVE], NCT03030274). In summary, all of the tested devices to date have been demonstrated to be safe, with improvements in functional class and quality of life, despite a modest reduction in absolute wedge pressure values compared to baseline.

Technique For most devices, the procedure is performed under general or local anaesthesia, by transfemoral venous approach. Following transseptal puncture, a sheath (14–16 Fr) is advanced into the LA cavity, and the device is deployed using a dedicated delivery system. The left side of the device is initially opened, and the entire system is pulled back ensuring back tenting at the level of the interatrial septum. Then, the right side of the device is deployed and the device is finally released. Following device implantation, most studies to date have recommended aspirin associated with clopidogrel for 6 months in patients who are not under anticoagulation therapy, and in patients

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receiving anticoagulantion (warfarin or direct oral anticoagulant), aspirin is added to the antithrombotic regime.

Future Studies The ongoing and future studies on interatrial shunting in patients with HF are summarised in Supplementary Material Table 1. Several studies on the IASD are currently in the recruitment phase. The REDUCE LAPHFrEF trial (NCT03093961) is recruiting up to 10 HFrEF patients in NYHA classes III–IV to evaluate the safety and feasibility of the device in this specific population. Another study involving the IASD, the REDUCE LAP-HF II (NCT03088033) is a randomised controlled trial comparing the clinical efficacy of the device versus optimal medical treatment (with a sham procedure) in symptomatic patients with LVEF >40%. The estimated sample size consisted of 608 patients, with the primary composite endpoint of the incidence of and time-to-cardiovascular mortality or first non-fatal ischaemic stroke within 12 months; total rate (first plus recurrent) per patient year of HF admissions or healthcare facility visits for IV diuresis for HF within 12 months and time to first HF event; and change in baseline KCCQ total summary score at 12 months. Finally, the REDUCE LAP-HF III (NCT03191656) is planning to recruit 100 patients with preserved or mildly reduced LVEF, with the purpose of determining the benefits (functional status, quality of life) of this therapy at 12-month follow-up. Reducing Lung Congestion Symptoms in Advanced Heart Failure (RELIEVE-HF, NCT03499236) is a randomised controlled trial comparing the second-generation (valveless) V-Wave device with optimal medical therapy (with a sham procedure) in 500 patients with HFpEF or HFrEF. The primary endpoint is a hierarchical composite of death, heart transplant or left ventricular assist device implantation, HF hospitalisations and change

Heart Failure in 6MWT (time frame: follow-up duration at endpoint analysis ranges from a minimum of 12 to a maximum of 24 months).

Conclusion Interatrial shunting has emerged as a promising option for treating HF patients. The feasibility and acute efficacy of balloon dilation atrial septostomy have been shown in acute HF, particularly among patients with refractory pulmonary oedema treated with VA-ECMO. To date,

Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics – 2014 update: a report from the American Heart Association. Circulation 2014;129:e28–92. https://doi. org/10.1161/01.cir.0000442015.53336.12; PMID: 24446411. 2. Maggioni AP, Dahlstrom U, Filippatos G, et al. EURObservational Research Programme: regional differences and 1-year followup results of the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail 2013;15:808–17. https://doi.org/10.1093/eurjhf/ hft050; PMID: 23537547. 3. Ritzema J, Troughton R, Melton I, et al. Physician-directed patient self-management of left atrial pressure in advanced chronic heart failure. Circulation 2010;121:1086–95. https://doi. org/10.1161/CIRCULATIONAHA.108.800490; PMID: 20176990. 4. Adams KF Jr, Fonarow GC, Emerman CL, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005;149:209–16. https://doi.org/10.1016/j.ahj.2004.08.005; PMID: 15846257. 5. Follath F, Yilmaz MB, Delgado JF, et al. Clinical presentation, management and outcomes in the Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF). Intensive Care Med 2011;37:619–26. https://doi.org/10.1007/s00134-010-2113-0; PMID: 21210078. 6. Baruteau AE, Barnetche T, Morin L, et al. Percutaneous balloon atrial septostomy on top of venoarterial extracorporeal membrane oxygenation results in safe and effective left heart decompression. Eur Heart J Acute Cardiovasc Care 2018;7:70–9. https://doi.org/10.1177/2048872616675485; PMID: 27742755. 7. Del Trigo M, Bergeron S, Bernier M, et al. Unidirectional left-toright interatrial shunting for treatment of patients with heart failure with reduced ejection fraction: a safety and proof-ofprinciple cohort study. Lancet 2016;387:1290–7. https://doi. org/10.1016/S0140-6736(16)00585-7; PMID: 27025435. 8. Feldman T, Mauri L, Kahwash R, et al. Transcatheter interatrial shunt device for the treatment of heart failure with preserved ejection fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure]): a phase 2, randomized, sham-controlled trial. Circulation 2018;137:364–75. https://doi.org/10.1161/CIRCULATIONAHA.117.032094; PMID: 29142012. 9. Sayer GT, Baker JN, Parks KA. Heart rescue: the role of mechanical circulatory support in the management of severe refractory cardiogenic shock. Curr Opin Crit Care 2012;18:409– 16. https://doi.org/10.1097/MCC.0b013e328357f1e6; PMID: 22895213. 10. Kotani Y, Chetan D, Rodrigues W, et al. Left atrial decompression during venoarterial extracorporeal membrane oxygenation for left ventricular failure in children: current strategy and clinical outcomes. Artif Organs 2013;37:29–36. https://doi.org/10.1111/j.1525-1594.2012.01534.x; PMID: 23020884. 11. Bavaria JE, Ratcliffe MB, Gupta KB, et al. Changes in left ventricular systolic wall stress during biventricular circulatory assistance. Ann Thorac Surg 1988;45:526–32. https://doi. org/10.1016/s0003-4975(10)64525-0; PMID: 3365043. 12. Cheng R, Hachamovitch R, Makkar R, et al. Lack of survival benefit found with use of intraaortic balloon pump in extracorporeal membrane oxygenation: a pooled experience

clinical experience with interatrial shunting in chronic HF (HFrEF and HFpEF) has been limited to less than 200 patients using different devices, and demonstrating to be a feasible and safe therapy in those who remain symptomatic, despite optimal medical/device therapy. If further randomised trials (currently ongoing) could demonstrate improvements in clinical outcomes, device-mediated left-to-right atrial shunting would become an important new approach for treating patients with refractory HF.

of 1517 patients. J Invasive Cardiol 2015;27:453–8. PMID: 26208379. 13. Alkhouli M, Narins CR, Lehoux J, et al. Percutaneous decompression of the left ventricle in cardiogenic shock patients on venoarterial extracorporeal membrane oxygenation. J Card Surg 2016;31:177–82. https://doi. org/10.1111/jocs.12696; PMID: 26809382. 14. Koenig PR, Ralston MA, Kimball TR, et al. Balloon atrial septostomy for left ventricular decompression in patients receiving extracorporeal membrane oxygenation for myocardial failure. J Pediatr 1993;122:S95–9. https://doi. org/10.1016/s0022-3476(09)90051-8; PMID: 8501556. 15. Lin YN, Chen YH, Wang HJ, et al. Atrial septostomy for left atrial decompression during extracorporeal membrane oxygenation by inoue balloon catheter. Circ J 2017;81:1419–23. https://doi. org/10.1253/circj.CJ-16-1308; PMID: 28496031. 16. Aiyagari RM, Rocchini AP, Remenapp RT, Graziano JN. Decompression of the left atrium during extracorporeal membrane oxygenation using a transseptal cannula incorporated into the circuit. Crit Care Med 2006;34:2603–6. https://doi.org/10.1097/01.CCM.0000239113.02836.F1; PMID: 16915115. 17. Prasad A, Ghodsizad A, Brehm C, et al. Refractory pulmonary edema and upper body hypoxemia during veno-arterial extracorporeal membrane oxygenation-a case for atrial septostomy. Artif Organs 2018;42:664–9. https://doi. org/10.1111/aor.13082; PMID: 29344963. 18. Miller RR, Ely EW. Radiographic measures of intravascular volume status: the role of vascular pedicle width. Curr Opin Crit Care 2006;12:255–62. https://doi.org/10.1097/01. ccx.0000224871.31947.8d; PMID: 16672786. 19. Johnston TA, Jaggers J, McGovern JJ, O’Laughlin MP. Bedside transseptal balloon dilation atrial septostomy for decompression of the left heart during extracorporeal membrane oxygenation. Catheter Cardiovasc Interv 1999;46:197– 9. https://doi.org/10.1002/(SICI)1522726X(199902)46:2<197::AID-CCD17>3.0.CO;2-G; PMID: 10348543. 20. Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail 2013;6:606–19. https://doi.org/10.1161/ HHF.0b013e318291329a; PMID: 23616602. 21. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation 2018;137:e67–492. https://doi. org/10.1161/CIR.0000000000000558; PMID: 29386200. 22. Corra U, Mezzani A, Bosimini E, Giannuzzi P. Cardiopulmonary exercise testing and prognosis in chronic heart failure: a prognosticating algorithm for the individual patient. Chest 2004;126:942–50. https://doi.org/10.1378/chest.126.3.942; PMID: 15364777. 23. de Groote P, Dagorn J, Soudan B, et al. B-type natriuretic peptide and peak exercise oxygen consumption provide independent information for risk stratification in patients with stable congestive heart failure. J Am Coll Cardiol 2004;43:1584–9. https://doi.org/10.1016/j.jacc.2003.11.059; PMID: 15120815. 24. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

failure: a randomised controlled trial. Lancet 2011;377:658–66. https://doi.org/10.1016/S0140-6736(11)60101-3; PMID: 21315441. Beyer J. Atrial septal defect: acute left heart failure after surgical closure. Ann Thorac Surg 1978;25:36–43. https://doi. org/10.1016/s0003-4975(10)63484-4; PMID: 619810. Baumgartner H, Bonhoeffer P, De Groot NM, et al. ESC guidelines for the management of grown-up congenital heart disease (new version 2010). Eur Heart J 2010;31:2915–57. https://doi.org/10.1093/eurheartj/ehq249; PMID: 20801927. Søndergaard L, Reddy V, Kaye D, et al. Transcatheter treatment of heart failure with preserved or mildly reduced ejection fraction using a novel interatrial implant to lower left atrial pressure. Eur J Heart Fail 2014;16:796–801. https://doi. org/10.1002/ejhf.111; PMID: 24961390. Hasenfuß G, Hayward C, Burkhoff D, et al. A transcatheter intracardiac shunt device for heart failure with preserved ejection fraction (REDUCE LAP-HF): a multicentre, open-label, single-arm, phase 1 trial. Lancet 2016;387:1298–304. https:// doi.org/10.1016/S0140-6736(16)00704-2; PMID: 27025436. Kaye DM, Hasenfuss G, Neuzil P, et al. One-year outcomes after transcatheter insertion of an interatrial shunt device for the management of heart failure with preserved ejection fraction. Circ Heart Fail 2016;9:e003662. https://doi.org/10.1161/ CIRCHEARTFAILURE.116.003662; PMID: 27852653. Kaye DM, Petrie MC, McKenzie S, et al. Impact of an interatrial shunt device on survival and heart failure hospitalization in patients with preserved ejection fraction. ESC Heart Fail 2019;6:62–9. https://doi.org/10.1002/ehf2.12350; PMID: 30311437. Shah SJ, Feldman T, Ricciardi MJ, et al. One-year safety and clinical outcomes of a transcatheter interatrial shunt device for the treatment of heart failure with preserved ejection fraction in the Reduce Elevated Left Atrial Pressure in Patients With Heart Failure (REDUCE LAP-HF I) trial: a randomized clinical trial. JAMA Cardiol 2018;3:968–77. https://doi. org/10.1001/jamacardio.2018.2936; PMID: 30167646. Danial P, Dupont S, Escoubet B, et al. Pulmonary hemodynamic effects of interatrial shunt in heart failure with preserved ejection fraction in rats. EuroIntervention 2019; https://doi. org/10.4244/EIJ-D-18-01100; PMID: 31062698; epub ahead of press. Amat-Santos IJ, Bergeron S, Bernier M, et al. Left atrial decompression through unidirectional left-to-right interatrial shunt for the treatment of left heart failure: first-in-man experience with the V-Wave device. EuroIntervention 2015;10:1127–31. https://doi.org/10.4244/EIJY14M05_07; PMID: 24832489. Rodés-Cabau J, Bernier M, Amat-Santos IJ, et al. Interatrial shunting for heart failure: early and late results from the firstin-human experience with the V-Wave system. JACC Cardiovasc Interv 2018;11:2300–10. https://doi.org/10.1016/j. jcin.2018.07.001; PMID: 30391390. Guimaraes L, Bergeron S, Bernier M, et al. Initial experience with the second-generation V-Wave shunt for treating patients with chronic heart failure. EuroIntervention 2019, in press. https://doi.org/10.4244/EIJ-D-19-00291. Rodés-Cabau J. Lessons from the early clinical experience with a unidirectional interatrial shunting. Presented at EuroPCR 2018, Paris, France, 24 May 2018.

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Heart Failure

Destination Therapy with Left Ventricular Assist Devices in Non-transplant Centres: The Time is Right Antoni Bayes-Genis,1,2 Christian Muñoz-Guijosa,1,2 Evelyn Santiago-Vacas,1,2 Santiago Montero,1,2 Cosme García-García,1,2 Pau Codina,1,2 Julio Núñez3 and Josep Lupón1,2 1. Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; 2. Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain; 3. Servicio de Cardiología, Hospital Clínico Universitario de Valencia, Universidad de Valencia, INCLIVA, Valencia, Spain

Abstract For almost half a century, cardiac transplant has been the only long-term treatment for patients with end-stage heart failure. Implantable left ventricular assist devices (LVADs) have emerged as a new treatment option for advanced heart failure as destination therapy for patients either too old or not suitable for transplant. A meta-analysis presenting head-to-head comparisons of cardiac transplant versus LVAD as destination therapy (LVAD-DT) found no difference in 1-year mortality rates between LVAD-DT and cardiac transplant (OR 1.49; 95% CI [0.48– 4.66]; I2=82.8%). Moreover, a recent subanalysis from the Interagency Registry for Mechanically Assisted Circulatory Support found similar outcomes after LVAD-DT implantation in both transplant and non-transplant centres. The time is right for LVAD-DT in non-transplant centres, provided multidisciplinary heart failure teams and expertise are in place.

Keywords Cardiac transplant, left ventricular assist device, destination therapy, outcomes Disclosure: AB-G was supported by grants from the Ministerio de Educación y Ciencia (SAF2014-59892), Fundació La MARATÓ de TV3 (201502, 201516), CIBER Cardiovascular (CB16/11/00403 and 16/11/00420) and AdvanceCat 2014-2020. All other authors have no conflicts of interest to declare. Received: 15 April 2019 Accepted: 2 August 2019 Citation: European Cardiology Review 2020;15:e19. DOI: https://doi.org/10.15420/ecr.2019.29.2 Correspondence: Antoni Bayes-Genis, Heart Institute, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n 08916, Barcelona, Spain. E: abayesgenis@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

“The time is always right to do what is right.” – Martin Luther King Jr (1929–1968) Heart failure (HF) has increased at a fast pace during the 21st century to become the main cause of morbidity and mortality for patients with cardiovascular disorders in developed nations, leading to increasing healthcare costs and declining quality of life. The expected prevalence of HF was ~25 million in 2011, and was anticipated to rise to >40 million worldwide in 2018, according to market research reports and industry analysis. Data from the National Heart, Lung and Blood Institute indicate that HF incidence is ~21 per 1,000 people aged >65 years.1 The total costs for HF are projected to reach $69.7 billion by 2030, an increase of 127% from 2012.2 In Catalonia, the most recent prevalence data indicate that HF affects 155,883 patients (out of 7.5 million inhabitants).3 Over the past three decades, research has led to better management of HF using drugs, new devices and a more holistic approach in multidisciplinary HF clinics. This has led to improvements in survival, yet a percentage of patients with progressive HF continue to require cardiac transplant or mechanical circulatory support to prolong life.4 Approximately 50% of HF patients have reduced ejection fraction, and 10% of these patients experience refractory HF symptoms (New York

Heart Association functional class IIIb to IV, stage D). Cardiac transplant is currently, and has been for the past 50 years, the preferred long-term treatment for eligible patients with end-stage advanced HF. Nevertheless, the availability of donor hearts is limited and not all patients are eligible for cardiac transplant. In Catalonia, the number of patients with advanced HF is probably ~500–1000; however, cardiac transplant is only recommended for a limited number of eligible patients aged <70 years. The transplant rate in Catalonia has ranged between 55 and 70 hearts per year during the past two decades. These numbers illustrate the paucity of donor hearts for transplant, and the fact that most candidates ultimately do not receive a compatible graft. Implantable left ventricular assist devices (LVADs), which fully or partly support the left ventricle, are an alternative therapy for patients with end-stage advanced HF. A long-term LVAD is used as a bridge to transplant (BTT) while patients await a suitable heart, or as permanent destination therapy (DT) that provides both life prolongation and proper quality of life.

Cardiac Transplant: Pros and Cons Despite recent advances in mechanical circulatory support, cardiac transplant remains the treatment of choice for patients with advanced HF. The short- and long-term outcomes following cardiac

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Heart Failure transplant are remarkable, with a median survival of 10.7 years. 5 For transplant patients, there is a marked improvement in survival, quality of life and functional status. 6 During the past decades, there has been continuous improvement in morbidity and mortality, despite older and higher-risk recipients receiving transplants. However, graft failure, rejection and infection remain significant causes of morbidity and mortality, precluding better short- and longterm outcomes. The highest incidence of mortality occurs in the first 6 months post-transplant, with the perioperative hospitalisation period having the highest risk of death. After the first year, the mortality rate decreases to 3–4% per year.6 However, mid- to long-term mortality continues to be affected by progressive cardiac allograft vasculopathy, late graft failure, rejection, infectious complications and issues due to chronic immunosuppression, including malignancy. The ultimate goals of preventing rejection and finding alternatives to immunosuppression remain elusive. In addition, chronic kidney disease is common after heart transplant and is associated with increased mortality. Furthermore, up to 39% of cardiac transplant recipients will develop diabetes after transplant. The major factor limiting cardiac transplant has been the insufficient donor supply, which is currently limited to approximately 4,000 hearts annually worldwide.

Destination Therapy with Left Ventricular Assist Devices: Pros and Cons LVADs have revolutionised the management of patients with advanced HF, providing an alternative to cardiac transplant. LVADs were initially implanted as a BTT to reduce the high mortality rates among patients who were awaiting donor hearts. However, the paucity of donor organs, along with the substantial increases in the comorbidities and the age of the HF population, have led to LVADs being used as a DT for advanced HF. LVADs can be broadly classified as either pulsatile flow/positive displacement or continuous flow/rotary systems. Continuous flow systems have several advantages over pulsatile flow pumps, including a more compact size and improved surfaces, as well as reduced surgical trauma and thrombotic complications. Continuous flow pumps can be further classified into centrifugal and axial flow pumps. Centrifugal flow pumps are smaller than the axial pumps available, and have a tubular configuration that allows them to be implanted faster and even less invasively; therefore, they are probably more cost-effective.7 Third-generation implantable continuous-flow LVADs, incorporating improved pump technologies, have improved pump performance and patient healthcare. The recent Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial demonstrated that implantation of a fully magnetically levitated centrifugal-flow pump (HeartMate 3) was associated with better outcomes at 6 months than an axial-flow pump (HeartMate II), primarily because of the lower rate of reoperation for pump malfunction.8 The use of a LVAD as DT (LVAD-DT) was approved by the US Food and Drug Administration in 2010; since then, LVAD-DT implantations have rapidly increased. The proportion of patients allocated to LVAD-DT increased from 19.6% from 2008 to 2010, to 45.7% of all implants in 2014. The miniaturisation of devices, the evolution of device technology

and improvements in the operative techniques, as well as better patient selection and complication management have led to a significant improvement in survival rates. The 8th Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) report on >20,000 LVAD implantations from 2006 to 2016 found a 1-year survival rate of 81% and 2-year survival rate of 70%.9 Nowadays, LVAD therapy constitutes an established treatment option for well-selected patients with advanced HF. As a result, the number of transplant and non-transplant centres integrating LVAD programs in their facilities is rapidly expanding, and a further increase in device implantations is anticipated in the near future. Relevant recent literature demonstrates better event-free survival, symptoms and quality of life with LVAD-DT, as compared with optimal medical management.10–12 The Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management (ROADMAP) study found that 12-month survival was greater for LVAD-DT versus optimal medical management (80 ± 4% versus 63 ± 5%; p=0.022) in patients with New York Heart Association Class IIIb/IV. Health-related quality of life and depression improved from baseline more significantly with LVADs than with optimal medical management. Adverse events were higher in LVAD-DT patients, in the HeartMate II trial.10 Starling et al. extended these findings up to 2 years of follow up.11 More recently, the Medical Arm of Mechanically Assisted Circulatory Support (MedaMACS) Registry reported that survival was similar for medical and LVAD-DT in the overall cohort, which included the lower severity INTERMACS profiles 6 and 7, but survival was better with LVAD-DT among patients in INTERMACS profiles 4 and 5.12

Cardiac Transplant Versus Left Ventricular Assist Devices for Advanced Heart Failure Theochari et al. performed a meta-analysis of the available studies presenting head-to-head comparisons of cardiac transplant versus LVAD-BTT or LVAD-DT for late (>6 months) all-cause mortality.13 Eight studies were included that reported data on 7,957 patients. Seven studies compared cardiac transplant with LVAD-BTT, and five compared cardiac transplant with LVAD-DT, evaluating 1-year mortality. These studies found no difference in 1-year mortality rates between LVAD-BTT and cardiac transplant (OR 0.91; 95% CI [0.62– 1.32]; I2=21.2%) or between LVAD-DT and cardiac transplant (OR 1.49; 95% CI [0.48–4.66]; I2=82.8%; Figure 1). Although complications with LVAD therapy are not uncommon, most are manageable, and current outcomes clearly support the use of a LVAD in advanced HF. Nevertheless, although there are certainly limitations to cardiac transplant, median survival at present is much better with transplant (~12 years) than LVAD (3–4 years).14

Destination Left Ventricular Assist Devices in Non-transplant Centres Since the US Food and Drug Administration approval of LVAD-DT, the number of hospitals offering LVAD therapy has grown rapidly, with a rising number performed at centres without internal transplant programs. Brinkley et al. sought to determine whether the outcomes after LVADDT implantation were similar at transplant and non-transplant

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LVAD-DT in Non-transplant Centres

Assuming the appropriate infrastructure is in place (described below), the findings of these studies should mitigate concerns regarding a broader extension of LVAD-DT, as the expanded access to this restorative and life-saving therapy at non-transplant centres has maintained good patient outcomes.

Characteristics of a Left Ventricular Assist Device Destination Therapy Program In general, an LVAD-DT program is considered a challenging endeavour, yet it does not require the co-existence of a parallel in-hospital transplant program. The Essen Experience, recently reported by Papathanasiou and Luedike, provided the following advice.16 A LVAD-DT program should be part of a multidisciplinary HF clinic consisting (at least) of a cardiology and a cardiac surgery department with an adequate number of potential LVAD-DT candidates. Considering the multi-organ manifestations of advanced HF and the broad spectrum of non-surgical interventions indicated in this patient cohort, the candidate centre should perform interventional and surgical cardiac procedures, cardiac electronic device implantation, and intensive cardiovascular care. A dedicated outpatient clinic is part of the required infrastructure to provide high-quality, long-term care of ambulatory patients. The physician leadership team is the core of the LVAD-DT program. An experienced HF cardiologist and a cardiac surgeon with expertise in mechanical circulatory support should supervise all aspects of device implementation, including patient selection, staff training, quality controls and cost-effectiveness.

Figure 1: Forest Plot of the Odds Ratios for 1-year Mortality Between Cardiac Transplant and Left Ventricular Assist Device Destination Therapy Study author

OR (95% CI)

Weight

Ammirati, 2015

1.23 (0.68–2.22)

26.54

Droogne, 2014

1.06 (0.13–8.35)

14.73

Jakovljevic, 2015

0.17 (0.01–3.29)

9.84

Sorabella, 2015

1.02 (0.34–3.04)

22.64

Mishra, 2016

6.78 (3.59–12.79)

26.24

Overall (I2=82.8%; p=0.000)

1.49 (0.48–4.66)

100.00

Note: Weights are from random effects analysis Favours LVAD-DT Favours HTx There was no difference in 1-year mortality rates between left ventricular assist device as destination therapy (LVAD-DT) and cardiac transplant (HTx) among the five studies. Source: Theochari et al. 2018.13 Reproduced with permission from AME Publishing Company.

Figure 2: Kaplan–Meier Analysis of Freedom from Death or Major Adverse Events at Transplant and Non-transplant Centres 1 Major event-free survival

centres.15 The authors analysed all adult recipients of a primary, continuous-flow LVAD-DT between 2012 and 2014 from the INTERMACS registry. Subjects were classified according to their implanting centre as transplant (n=3,323) or non-transplant (n=260). Outcomes included overall survival, freedom from death or major adverse event, rates of individual adverse events, rehospitalisation and health-related quality of life. The 1-month (94.2%; 95% CI [95.0– 93.4] versus 94.2%; 95% CI [97.1–91.4]) and 12-month (76.4%; 95% CI [77.9–74.8] versus 71.3%; 95% CI [77.4–65.2]) survival rates were similar at transplant versus non-transplant centres (HR 0.88; 95% CI [0.70–1.12]). The risk remained similar after adjustment for baseline characteristics (HR 0.88; 95% CI [0.69–1.12]). The rates for freedom from death or major adverse event at 12 months (29.0%; 95% CI [30.6– 27.3] versus 29.8%; 95% CI [36.0–23.6]) were similar at transplant and non-transplant centres (adjusted HR 1.01; 95% CI [0.87–1.18]; Figure 2). The individual adverse event rates, rehospitalisation and postimplant health-related quality of life were also similar. The authors concluded that in a large, modern cohort of LVAD-DT recipients, outcomes after implantation were similar at transplant and nontransplant centres.15

0.75 0.50 0.25

p=0.473

0 0 Number at risk Non-transplant 232 Transplant 2,989

12 Months

91 1,140

44 656

23 383

10 220

Non-transplant

Transplant

Follow-up

Non-transplant

Transplant

1 month

66.1% (71.9–60.4)

60.6% (62.3–58.9)

3 months

53.6% (59.7–47.4) 42.0% (48.1–35.8)

48.8% (50.5–47.1) 40.0% (41.7–38.3)

6 months 12 months 24 months

29.8% (36.0–23.6)

17.2% (30.6–27.3)

20.0% (27.0–13.0)

17.2% (18.8–15.6)

Major adverse events included death, stroke, major bleeding, pump exchange, device infection, device malfunction and right heart failure. Source: Brinkley et al. 2018.15 Reproduced with permission from Wolters Kluwer Health.

site consulting service should be available for the end-of-life care of LVAD patients.

Conclusion A qualified team of surgeons, HF cardiologists and nurses familiar with the complexity of LVAD-DT should be organised. Staff training in special skills, and familiarity with the psychosocial, technical and pharmaceutical issues is of paramount importance for all parties. Rehabilitation physicians should be part of the caring team. A transplant centre affiliation is necessary for patients who are or may become eligible for LVAD-BTT and should be offered transplant candidacy. Participation in a palliative care network or at least an on-

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LVADs have transformed the treatment landscape of HF and are now adopted for long-term ambulatory support of patients with advanced disease. As the number of LVAD-DT implants is anticipated to rise, clinicians will need to integrate dedicated programs in their HF clinics and be actively involved in the care of patients on LVAD support. Indeed, all LVAD centres, regardless of their transplant capabilities, are required to have multidisciplinary HF teams to guide patient selection and assist in the long-term care of this unique population. The time is right for LVAD-DT in non-transplant centres.

Heart Failure 1.

Huffman MD, Berry JD, Ning H, et al. Lifetime risk for heart failure among white and black Americans. J Am Coll Cardiol 2013;61:1510–7. https://doi.org/10.1016/j.jacc.2013.01.022; PMID: 23500287. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics – 2018 update: a report from the American Heart Association. Circulation 2018,137:e67–492. https://doi: 10.1161/CIR.0000000000000558; PMID: 29386200. Cainzos-Achirica M, Capdevila C, Vela E, et al. Individual income, mortality and healthcare resource use in patients with chronic heart failure living in a universal healthcare system: a population-based study in Catalonia, Spain. Int J Cardiol 2019;277:250–7. https://doi.org/10.1016/j.ijcard.2018.10.099; PMID: 30413306. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. https://doi.org/10.1093/eurheartj/ehw128; PMID: 27206819. Stehlik J, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplant: Twenty-eighth Adult Heart Transplant Report – 2011. J Heart Lung Transplant 2011;30:1078–94. https://doi.org/10.1016/j.

healun.2011.08.003; PMID: 21962016. McCartney SL, Patel C, Del Rio JM. Long-term outcomes and management of the heart transplant recipient. Best Pract Res Clin Anaesthesiol 2017;31:237–48. https://doi.org/10.1016/j. bpa.2017.06.003; PMID: 29110796. 7. Olsen DB. The history of continuous-flow blood pumps. Artif Organs 2000;24:401–4. https://doi. org/10.1046/j.1525-1594.2000.06652.x; PMID: 10886055. 8. Mehra MR, Naka Y, Uriel N, et al. A fully magnetically levitated circulatory pump for advanced heart failure. N Engl J Med 2017;376:440–50. https://doi.org/10.1056/NEJMoa1610426; PMID: 27959709. 9. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: special focus on framing the impact of adverse events. J Heart Lung Transplant 2017;36;1080–6. https:// doi.org/10.1016/j.healun.2017.07.005; PMID: 28942782. 10. Estep JD, Starling RC, Horstmanshof DA, et al. Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: results from the ROADMAP Study. J Am Coll Cardiol 2015;66:1747–61. https://doi:10.1016/j.jacc.2015.07.075; PMID: 26483097. 11. Starling RC, Estep JD, Horstmanshof DA, et al. Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: the ROADMAP study 2-year results. JACC Heart Fail 6.

12.

13.

14.

15.

16.

2017;5:518–27. https://doi.org/10.1016/j.jchf.2017.02.016; PMID: 28396040. Ambardekar AV, Kittleson MM, Palardy M, et al. Outcomes with ambulatory advanced heart failure from the Medical Arm of Mechanically Assisted Circulatory Support (MedaMACS) Registry. J Heart Lung Transplant 2019;38:408–17. https://doi. org/10.1016/j.healun.2018.09.021; PMID: 30948210. Theochari CA, Michalopoulos G, Oikonomou EK, et al. Heart transplant versus left ventricular assist devices as destination therapy or bridge to transplant for 1-year mortality: a systematic review and meta-analysis. Ann Cardiothorac Surg 2018;7:3. https://doi.org/10.21037/acs.2017.09.18; PMID: 29492379. Goldstein DJ, Meyns B, Xie R, et al. Third annual report from the ISHLT Mechanically Assisted Circulatory Support Registry: a comparison of centrifugal and axial continuous-flow left ventricular assist devices. J Heart Lung Transplant 2019;38:352– 63. https://doi.org/10.1016/j.healun.2019.02.004; PMID: 30945637. Brinkley DM, DeNofrio D, Ruthazer R, et al. Outcomes after continuous-flow left ventricular assist device implantation as destination therapy at transplant versus nontransplant centers. Circ Heart Fail 2018;11:e004384. https://doi. org/10.1161/CIRCHEARTFAILURE.117.004384; PMID: 29540471. Papathanasiou M, Luedike P. The evolution of left ventricular assist devices. HeathManagement 2019;19:70–2.

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Myocardial Infarction

MI with Non-obstructive Coronary Artery Presenting with STEMI: A Review of Incidence, Aetiology, Assessment and Treatment Ying X Gue,1 Rahim Kanji,2 Sabiha Gati1 and Diana A Gorog1,2 1. University of Hertfordshire, Hertfordshire, UK; 2. National Heart and Lung Institute, Imperial College, London, UK

Abstract MI with non-obstructive coronary artery (MINOCA) is a condition previously thought to be benign that has recently been shown to have comparable mortality to that of acute coronary syndrome with obstructive coronary disease. The heterogeneity of the underlying aetiology makes the assessment, investigation and treatment of patients with MINOCA challenging. The majority of patients with MINOCA presenting with ST-segment elevation MI generally have an underlying coronary or myocardial cause, predominantly plaque disruption or myocarditis. In order to make the correct diagnosis, in addition to the cause of the presentation, a meticulous and methodical approach is required, with targeted investigations. Stratification of patients to guide investigations that are more likely to provide the diagnosis will allow the correct treatment to be initiated promptly. In this article, the authors review the contemporary incidence, aetiology, recommended assessment and treatment of patients with MINOCA presenting with ST-segment elevation MI.

Keywords MI with non-obstructive coronary artery, ST-segment elevation MI, acute coronary syndrome Disclosure: The authors have no conflicts of interest to declare. Received: 8 October 2019 Accepted: 25 February 2020 Citation: European Cardiology Review 2020;15:e20. DOI: https://doi.org/10.15420/ecr.2019.13 Correspondence: Diana Gorog, National Heart and Lung Institute, Imperial College, Dovehouse St, London SW3 6LY, UK. E: d.gorog@imperial.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Cardiovascular disease is the leading cause of death globally, with 85% of cardiovascular deaths attributed to acute coronary syndrome (ACS) and stroke.1 The development of coronary atherosclerosis and subsequent plaque disruption, predominantly from plaque rupture or erosion, is responsible for the majority of ACS presentations. Persistent occlusion of the coronary artery due to thrombus, leading to MI, classically presents with symptoms of chest pain and ECG evidence of ST-segment elevation. Approximately 90% of patients with MI have angiographic evidence of obstructive coronary artery disease (CAD), based on registry studies published more than 30 years ago.2,3 The realisation that obstructive CAD was causative in the majority of patients with ST-elevation MI (STEMI) led to the development of current management strategies, including primary percutaneous coronary intervention.4 In addition to revascularisation, targeted pharmacotherapy, including high-dose statins, aspirin, P2Y12 inhibitors, beta-blockers and angiotensinconverting enzyme inhibitors, has been shown to improve outcomes in patients with STEMI in large randomised controlled trials.5–10 However, most patients in these trials had obstructive CAD. Around 10% of patients presenting with classical signs and symptoms of ACS do not have evidence of obstructive CAD to account for their presentation, namely those with MI with non-obstructive coronary artery (MINOCA).11–13 This phenomenon has been historically overlooked and largely understudied in relation to prognosis and treatment. MINOCA was previously thought to carry a good prognosis;

however, there is growing interest in this group of patients, as increasing data are showing that this syndrome is not as benign as previously thought.11,14-16 This has led to the recent authoritative paper by the European Society of Cardiology (ESC) Working Group on Cardiovascular Pharmacotherapy describing and defining the condition in detail.17

MINOCA: Definition and Terminology To aid in appropriate evaluation, treatment and future research, the ESC Working Group on Cardiovascular Pharmacotherapy formalised the definition of MINOCA.17 The definition of MINOCA is predicated on the patient fulfilling all three main diagnostic criteria, namely: the Universal Definition of Acute MI; the presence of non-obstructive coronary artery on angiography (defined as no coronary artery stenosis ≥50%) in any potential infarct-related artery; and the absence of another specific, clinically overt cause for the acute presentation.17,18 With the Fourth Universal Definition of acute MI, the delineation of MI from myocardial injury is clearer, excluding diagnoses, such as myocarditis, where there is myocardial injury not attributable to an ischemic cause, from other causes of MINOCA.19,20 Very recently, the term troponin positive non-obstructive coronary arteries, which encompasses MINOCA, myocardial disorders and extracardiac causes, has been proposed.21 Irrespective of the nomenclature, the intention of the authors when they developed the position paper has not changed – to bring this not-so-benign condition to the attention of clinicians and to highlight the need for appropriate investigation and

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Myocardial Infarction management. As is the case with ‘heart failure’, MINOCA is not a definitive condition, but a working diagnosis that should prompt thorough investigation to ascertain the underlying aetiology.

STEMI MINOCA versus NSTEMI MINOCA STEMI occurs in the presence of transmural ischaemia due to transient or persistent complete occlusion of the infarct-related coronary artery. In patients presenting with non-ST-segment elevation MI (NSTEMI), the infarct is subendocardial. This pathophysiological difference also seems to be present within the MINOCA cohort. Registry data indicate that 6–11% of patients with acute MI have nonobstructive coronary arteries.11–13 Within the literature, MINOCA tends to present more commonly as NSTEMI than STEMI: the incidence of MINOCA reported in patients presenting with NSTEMI is about 8–10% and in STEMI cohorts it is 2.8–4.4%.22–25 This has resulted in an under-representation of STEMI MINOCA patients in the literature. Most studies examine undifferentiated ACS cohorts,5 with only a handful providing separate data.22–25 These studies indicate that the 1-year mortality of MINOCA presenting as STEMI is 4.5%, in contrast to the mortality of unselected MINOCA ACS patients who have a mortality of 4.7%.11,24,25 The underlying aetiology of MINOCA is similar among those presenting with STEMI and in all-comer MINOCA patients with ACS, with non-coronary aetiology responsible for presentation in 60–70% of individuals with STEMI24,25 and in 76% of unselected ACS patients.11

Clinical Features, Aetiology and Prognosis MINOCA tends to present more commonly as NSTEMI.11,26 The clinical characteristics of patients with MINOCA are distinct from patients with conventional CAD. They tend to be younger, with a lower prevalence of hyperlipidaemia, hypertension, diabetes and smoking.11,13,27–30 As with atherosclerotic CAD, MINOCA predominantly affects men; however, the male-to-female ratio is approximately 2.5:1 with MINOCA versus 4:1 with atherosclerotic coronary disease.11 MINOCA is a heterogenous entity and consequently creates a diagnostic challenge in identifying the aetiology, which among other things may include coronary dissection, plaque rupture with embolisation, myocarditis and takotsubo syndrome. A systematic approach is required to identify the underlying cause and initiate appropriate therapy. There have been many attempts at providing a clinical algorithm to aid physicians in evaluating and investigating these patients.17,20,31 These algorithms all underscore the same principle – namely understanding the possible mechanisms of myocardial injury, followed by investigations to determine the underlying cause. In the case of STEMI, the time for assessment prior to angiography is limited to obtaining a comprehensive history, examination and an ECG. In line with the ESC Working Group, the aetiology can be classified into three main categories: coronary, non-coronary cardiac and extra cardiac causes. MINOCA, irrespective of the underlying aetiology, is not a benign condition. A large systematic review and meta-analysis of 1,924 patients reported that all-cause mortality in unselected patients with MINOCA at 12 months was 4.7%.11 More recently, data from the 2003– 2013 SWEDEHEART registry revealed that over a mean follow-up of 4 years, 23.9% patients with MINOCA experienced another major adverse cardiac event.26 In a retrospective registry of patients presenting with STEMI, those with MINOCA were reported to have a mortality rate of 3.6% at 30 days and 4.5% at 1 year.24

Epicardial/Coronary Causes Plaque Disruption Atherosclerotic plaque disruption (usually plaque erosion or rupture) is the main cause of type 1 MI, which is responsible for the majority of STEMI presentations.19 However, it is also recognised that plaque disruption is not an uncommon cause of MINOCA.32–34 It is important to differentiate patients with ≥50% epicardial coronary artery stenosis from those without obstructive CAD. Furthermore, positive remodelling of the coronary arteries may result in compensatory enlargement of the culprit vessel, increasing the luminal size of atherosclerotic arteries. This may consequently result in the appearance of angiographically normal or minimally obstructed coronary arteries.35 Plaque disruption has been documented in patients with angiographically near-normal arteries, namely those with luminal irregularities.33,34 Therefore, it is possible that patients with mild luminal irregularities presenting with STEMI have underlying atherosclerosis with plaque disruption, thrombosis and transient occlusion from distal embolisation. In the presence of effective endogenous thrombolysis, such individuals may not exhibit angiographic evidence of significant plaque or visible thrombus.36 Appreciation of the importance of plaque rupture as the underlying pathomechanism in patients presenting with MINOCA has been facilitated with the use of intravascular ultrasound (IVUS) and optical coherence tomography (OCT) imaging. Advanced intracoronary imaging is frequently required to diagnose plaque disruption. Such techniques have shown evidence of plaque rupture in 37% of patients with ACS who had angiographically unobstructed coronary arteries.32 A small study combining IVUS and cardiac MRI has shown that the majority of patients with MINOCA with plaque disruption have cardiac MRI evidence of acute myocardial oedema, providing the much needed link between areas of plaque disruption and ensuing myocardial injury.33 It is estimated that one-third of MINOCA presentations are attributable to plaque disruption, although the proportion among those presenting with STEMI is less clear because they are under-represented in the studies (13–39% of subjects) and advanced imaging techniques are less often used in these scenarios.24,32,33

Coronary Dissection Spontaneous coronary artery dissection (SCAD) describes the acute spontaneous development of a false lumen within the coronary artery, compromising flow down the artery. This condition has a strong female preponderance, with a mean age of 44–53 years, and is associated with fibromuscular dysplasia and pregnancy, indicating that female sex hormones may play a role in its pathophysiology.37 The reported incidence of SCAD among patients presenting with ACS is between 2% and 4%.38,39 Diagnosis of SCAD is made during angiography, where it can be subclassified based on angiographic appearance.40 It is recommended that coronary instrumentation – including stenting – is avoided, where possible, particularly if epicardial coronary flow is normal.37 In cases where there is diagnostic uncertainty or where coronary intervention is required, intracoronary imaging with OCT or IVUS can be useful to make a definitive diagnosis and also to assess the outcome of intervention. On initial angiography, SCAD, in particular type 2 SCAD, can be easily missed. Careful review of fluoroscopy images, especially in patients who exhibit high-risk demographics (typically middle-aged peripartum women without traditional cardiac risk factors) or those who have high-risk clinical features (e.g. history of fibromuscular dysplasia,

EUROPEAN CARDIOLOGY REVIEW

MI with Non-obstructive Coronary Artery in STEMI connective tissue disorder, recent intensive exercise or emotional stress) could allow a diagnosis to be made and appropriate treatment to be initiated.40

Figure 1: Coronary Angiogram Showing Severe Coronary Artery Spasm

Coronary Vasospasm In 2015, the Coronary Vasomotion Disorders International Study Group defined the diagnostic criteria for vasospastic angina as: nitrateresponsive angina, transient ischaemic ECG changes and coronary artery spasm (Figure 1), defined as transient total or subtotal (>90%) occlusion either spontaneously or in response to a provocative stimulus.41 Vasospasm, like SCAD, is more prevalent in women. Risk factors include smoking and the use of drugs such as cocaine or betablockers in patients with vascular smooth muscle hyperreactivity.42â&#x20AC;&#x201C;46 Its transient nature and responsiveness to nitrates makes the diagnosis of coronary vasospasm in STEMI a challenge, as the frequent use of intra-arterial isosorbide mononitrate administration during radial cannulation to prevent peripheral vasospasm could essentially mask the diagnosis. For this reason, the use of a radial cocktail is prohibited during provocative vasospasm testing.42 The gold standard diagnostic test for coronary vasospasm is provocative spasm testing with the administration of a spasm-provoking stimulus, namely acetylcholine or ergonovine. The patient is required to experience chest pain and demonstrate ECG and angiographic changes in response to provocation before the test is deemed to be positive for the diagnosis of spasm.41 Invasive testing is relatively safe, with no irreversible complications in patients with a recent ACS, and therefore should be considered as part of the investigative workup of STEMI patients with MINOCA.47,48 Clearly it should be done outside of the acute presentation.

Coronary Thromboembolism Coronary embolism is the underlying cause in 3% of ACS presentations, but is often under-recognised because it is hard to differentiate from atherosclerotic ACS.49 Coronary thromboembolism can arise from either the left atrium or by means of paradoxical embolisation in the presence of septal defects in patients with hypercoagulable states, such as those with AF or those with hereditary thrombophilias. Non-thrombotic emboli can arise from valvular vegetations or cardiac tumours.50 In patients who exhibit a high thrombus burden at angiography without underlying coronary atherosclerosis, thromboembolism or thrombophilia should be strongly suspected (Figure 2).49 Unlike SCAD and coronary vasospasm, patients with coronary thromboembolism are more heterogenous and can have a wide variety of predisposing clinical characteristics. The most frequent predisposing condition is AF, followed by valvular heart disease, such as infective endocarditis or rheumatic heart disease.51 In one of the largest systematic reviews of patients with MINOCA, up to 14% of patients were reported to have had evidence of an inherited thrombotic disorder.11 In a more recent study, extensive thrombophilia testing revealed that 33% of MINOCA patients had inherited thrombophilia.52 These findings imply that coronary embolism might have previously been overlooked as the underlying cause of MINOCA in this cohort. The diagnosis of a thrombotic disorder as a cause of STEMI will change the management of these patients, usually mandating lifelong anticoagulation rather than the standard dual antiplatelet regimen prescribed for ACS.

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A: Left coronary artery showing ostial left mainstem spasm (arrow). B: Spasm of the proximal right coronary artery (arrow).

Figure 2: Coronary Angiogram from a Patient Presenting with ST-Elevation MI due to Coronary Thrombosis with Unobstructed Coronary Arteries

A: High thrombus burden (double arrow) with occluded distal left anterior descending artery (single arrow) with no perfusion (thrombolysis in MI 0 flow). B: Significant reduction of thrombus burden (arrow) on repeat angiography 72 hours later, showing underlying unobstructed smooth coronary artery with thrombolysis in MI 3 flow.

Non-coronary Cardiac Causes Takotsubo Cardiomyopathy Takotsubo or stress cardiomyopathy describes the transient impairment of left ventricular function (commonly sparing the basal myocardium), frequently precipitated by a stressful event.53 It typically occurs in postmenopausal women, most often (but not exclusively) with a precipitating acute emotional or physical stressor.53 For this reason, it has been thought to be a catecholamine-driven process. Approximately 2% of STEMI cases are considered attributable to takotsubo cardiomyopathy.54 Patients generally present with symptoms of chest pain and ECG changes consistent with ACS, together with troponin elevation. The troponin level is usually minimal in relation to the extent of N-terminal prohormone brain natriuretic peptide (NT-proBNP) elevation, demonstrating a mismatch between the markers of myocardial ischaemia and the extent of myocardial involvement.55,56 The Heart Failure Association of the ESC has defined the diagnostic criteria for takotsubo cardiomyopathy, which takes into consideration biomarkers and imaging. Patients should have transient regional wall motion abnormalities of the myocardium that recover on follow-up imaging, extending beyond a single epicardial coronary distribution with absence of coronary culprit lesions, in the context of new ECG changes, significantly raised NT-proBNP or BNP and a relatively small rise in troponin.56 The recommended first-line investigation is a transthoracic

Myocardial Infarction echocardiogram, as it can be used to assess the anatomical variant, complications and recovery. Cardiac MRI imaging, if performed early after the event, can accurately characterise regional wall motion abnormalities, myocardial oedema and patterns of injury with late gadolinium enhancement in patients with takotsubo syndrome. Furthermore, cardiac MRI allows differentiation from other causes, including myocarditis and infarction.56 Therefore, early assessment with biomarkers, echocardiography and, if available, cardiac MRI is recommended to determine and confirm the diagnosis.57,58

Myocarditis Inflammation of the myocardium secondary to a variety of infectious pathogens, autoimmune conditions or toxins may imitate an ACS. Individuals may present with symptoms of chest pain, ST-segment elevation, raised troponin level and impaired left ventricular systolic function.59 Owing to the wide spectrum of aetiology, the clinical characteristics of patients with myocarditis vary widely; therefore, making the correct diagnosis requires a high index of suspicion during presentation. The gold standard test for diagnosing and determining the aetiology of myocarditis is endomyocardial biopsy,59 although this is associated with a risk of complications – particularly in young individuals – and should be reserved for patients with haemodynamic compromise, severely impaired left ventricular function that is unresponsive to treatment and/or significant ventricular arrhythmias.60 In such individuals, early cardiac MRI can prove valuable in the diagnosis of myocarditis, with sequences for tissue characterisation.60–62 In cases of MINOCA where there is suspicion of myocarditis, cardiac MRI during acute admission can be extremely helpful in confirming or refuting the diagnosis.62,63

Extracardiac Causes Type 2 MI A mismatch between oxygen supply and demand, leading to ischaemic myocardial injury, is responsible for type 2 MI and should be differentiated from conventional atherosclerotic plaque disruption.19 Patients with type 2 MI tend to be older and have several comorbidities when compared to those with type 1 MI.64 Common causes of increased oxygen demand from cardiac myocytes include sustained tachyarrhythmias or reduced oxygen supply, for example in acute bleeding conditions or pulmonary embolism, where patients with otherwise mild or stable CAD could develop myocardial ischaemia. However, such a mismatch would have to be profound to cause MINOCA.

Aortic Syndromes Acute aortic dissection results from a tear within the wall of the aorta forming an intimal flap separating the false and true lumens. Classification is based upon the location and extent of the dissection. The incidence is higher in men and increases with age.65 Risk factors include uncontrolled hypertension, pre-existing aortic disease or connective tissue disorders, blunt chest trauma and intravenous drug abuse.65 Similar to ACS, patients commonly present with acute severe chest pain; however, the nature of the pain is dissimilar, usually manifesting as a sharp, tearing or ripping sensation.65 Only about 18% of aortic dissection presents with MI, particularly type A dissection.66 Coronary artery involvement may occur due to the flap occluding the coronary ostium or as a result of extension of the

dissection into the coronary artery. Early surgical intervention is recommended to improve survival, given the high mortality rate without intervention.65 In patients with MINOCA, the use of direct aortography may provide the diagnosis, although non-invasive investigations, such as echocardiography or CT aortography, are safer and recommended as first line.65

Assessment Initial Investigations As part of the investigative process, it is recommended that all patients who present with acute ST-elevation have emergency assessment of their clinical history with essential examination, an ECG or serial ECGs confirming ST-elevation or new-onset left bundle branch block, and coronary angiography with the option of proceeding to coronary angioplasty.4 Baseline blood tests should be taken before angiography, but cardiac catheterisation should not be deferred until the blood results become available. Following angiography, in the case of the patient without obstructive coronary disease, re-evaluation of the patient’s clinical history could prove valuable in helping identify the underlying diagnosis (Figure 3). Thorough review of the fluoroscopic images obtained during initial coronary angiography may reveal otherwise subtle changes. If there are any doubts, and provided it is safe to do so, further intracoronary imaging may be useful to confirm or refute differential diagnoses. Given the high incidence of plaque disruption documented with intravascular imaging in patients with MINOCA, the use of OCT or IVUS of atherosclerotic non-obstructive diseased vessels could prove useful in identifying the underlying pathology in patients with STEMI.32–34 In patients with a large thrombus burden and normal coronary arteries, thromboembolism should be considered and thrombophilia screening performed as part of diagnostic workup. Consideration of different thrombophilic disorders should prompt extensive testing for inherited thrombophilia. This includes testing for factor V Leiden, antiphospholipid syndrome, prothrombin G20210A mutation, proteins C and S and antithrombin III deficiency.52 Plaque disruption is extremely unlikely in patients with smooth, unobstructed coronaries without evidence of atherosclerotic disease at angiography, as shown in several studies involving intracoronary imaging.32–34 Therefore, clear distinction of patients according to degrees of coronary stenosis (i.e. 0% compared to 1–49%) may prove invaluable in identifying the underlying aetiology. During initial coronary angiography, the presence of coronary spasm helps clarify this diagnosis in patients presenting with STEMI and suspected MINOCA; however, occasionally provocative spasm testing may be required at a later stage to fulfil the aforementioned diagnostic criteria as a class I indication in patients with MINOCA.41 There are no data to support provocative testing in patients with STEMI and suspected MINOCA at the time of initial angiography. However, recent studies appear to show that provocative spasm testing is safe in ACS patients, with reversible complication rates comparable to diagnostic angiography (a serious adverse event rate of around 0.8%).67,68 Small studies demonstrate that during the acute phase there are no irreversible complications; bradyarrhythmias occur in 5–16% of cases, which is comparable to that seen in stable patients with non-obstructive coronary arteries (15%),and ventricular tachyarrhythmias are rare (<0.5%), but this is clearly not in the setting of STEMI.48,69 There are

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MI with Non-obstructive Coronary Artery in STEMI Figure 3: Investigative Algorithm for ST-Elevation MI Patients Presenting with MI with Non-obstructive Coronary Artery Patients with ST-segment elevation on ECG with cardiac chest pain fitting criteria for primary percutaneous coronary intervention with no contraindication to invasive angiography Consent and urgent angiography

Review history: consider clinical context for type 1 MI

Confirm with other imaging modalities and blood test(s)

Blood count, NT-proBNP, etc CT pulmonary angiogram, CT aorta

Review angiogram 1–49% stenosis

Consider missed obstructive coronary artery disease, i.e. plaque disruption, embolism, spontaneous coronary artery dissection, coronary vasospasm

0% stenosis

Consider non-coronary cardiac causes, i.e. myocarditis, takotsubo syndrome, embolisation

Inpatient

Immediate

No evidence of obstructive coronary artery disease

Consider intracoronary imaging, if safe Inflammatory markers, autoimmune screen, thrombophilia screen (antiphospholipid syndrome, factor V Leiden, protein C and S, antithrombin)

Confirm diagnosis of MINOCA with troponin

Transthoracic echocardiogram, endomyocardial biopsy

Outpatient

Consider early cardiac MRI to confirm diagnosis

Other confirmatory testing, if required, i.e. provocative spasm testing, repeat echocardiography or cardiac MRI

Continue evidence-based treatment as indicated CAD = coronary artery disease; MINOCA = MI with non-obstructive coronary artery; NT-proBNP = N-terminal prohormone of brain natriuretic peptide; SCAD = spontaneous coronary artery dissection.

important prognostic benefits to reaching a correct diagnosis and accurately identifying and treating patients with coronary vasospasm, therefore routine vasospasm provocation testing is strongly encouraged in patients with MINOCA.48,70

Follow-up Investigations Following cardiac catherisation in patients with a provisional diagnosis of MINOCA, other blood investigations to consider include a full blood count (checking for the presence of significant anaemia in the case of a type 2 MI), inflammatory markers and a thrombophilia screen. A detailed transthoracic echocardiogram can help elucidate potential features of myocarditis or valvular disease. Early cardiac MRI within the first 5–14 days of admission is recommended, where possible, to confirm a diagnosis of MI or other aetiologies of MINOCA (Figure 4).71–73 A recent study has shown that cardiac MRI can offer a definitive diagnosis in 88% of patients with MINOCA and, more importantly, changed the diagnosis in 47% of cases.74

Treatment In contrast to the definite aetiology and guidelines for the management of STEMI with CAD, in the 10% of patients who experience MI in the absence of obstructive CAD the aetiology often remains unclear, mainly because it is under-investigated and the optimal management is therefore often undecided.14 There are no prospective randomised trials of pharmacotherapies in patients with MINOCA. Retrospective data from the SWEDEHEART

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registry suggest that there is long-term prognostic benefit in treating such patients with statins, beta-blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, irrespective of the underlying aetiology.26 However, there appeared to be no significant benefit associated with the use of P2Y12 inhibitors. Thus, it appears that the use of routine secondary prevention medications post-ACS can still prove beneficial in MINOCA, despite a possibly unclear aetiology. The obvious limitation is that SWEDEHEART is a retrospective observational study where many confounders are present that are not accounted for. Furthermore, the majority of MINOCA presentations are attributable to plaque disruption and myocarditis,which may benefit from conventional secondary prevention pharmacotherapy, especially in the context of left ventricular systolic dysfunction.11,20,24 The use of dual antiplatelet therapy (DAPT) is more controversial, since in the SWEDEHEART registry the treatment of patients with DAPT was not shown to confer benefit.26 Furthermore, in the post-hoc analysis of the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events – Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7) study evaluating the use of DAPT in MINOCA and non-MINOCA patients, using high-dose DAPT with doubledose clopidogrel increased the risk of major adverse cardiovascular events (HR 3.57; p=0.013) without an increase in bleeding.75 With the limitations of being a post-hoc analysis with multiple confounders, this poses an interesting hypothesis that DAPT may actually be harmful when used in MINOCA patients.

Myocardial Infarction Figure 4: Cardiac Magnetic Resonance Images of Differentials for Patients Presenting with MI with Non-obstructive Coronary Artery

MINOCA: 1. Chest pain 2. Troponin-positive 3. ST-elevation MI

Takotsubo syndrome

Plaque disruption

Myocarditis

A: Four-chamber cine view demonstrating left ventricular apical ballooning in end-systole. B: Myocardial oedema/inflammation of the mid to apical left ventricular myocardium on T2-short-tau inversion recovery sequence (black arrows). C: Four-chamber cine view with normal-thickness left ventricular myocardium. D: Late gadolinium enhancement demonstrating a small subendocardial infarction in the apical septal wall (yellow arrow). E and F: Angiograms showing minor atheroma in the left anterior descending artery (orange arrows). G: Late gadolinium enhancement showing patchy enhancement in the mid and apical septum and basal and apical lateral wall (green arrows). H: T2-short-tau inversion recovery sequence demonstrating myocardial oedema in multiple regions of the left ventricular myocardium corresponding with regions of late gadolinium enhancement shown in G (blue arrows). MINOCA = MI with non-obstructive coronary artery; STEMI = ST-elevation MI.

Current and Future Studies

Conclusion

A number of studies are in the pipeline to investigate the optimal assessment and treatment options for patients with MINOCA. The Women’s Heart Attack Research Program – Imaging Study (HARP; NCT02905357) is a multicentre, prospective, observational study aiming to recruit 500 women with MINOCA who will undergo OCT at the time of diagnostic angiography and cardiac MRI to explore the proportion of plaque disruption and its correlation with cardiac MRI findings. Recruitment started in 2016 and the study has an estimated completion date of April 2020. The multicentre Randomized Evaluation of Beta Blocker and ACEI/ARB Treatment in MINOCA Patients (MINOCA-BAT; NCT03686695) trial is exploring the impact of betablockers and angiotensin-converting enzyme inhibitor or angiotensin receptor blockers on the composite endpoint of death from any cause and readmission due to acute MI, ischaemic stroke or heart failure. It is aiming to recruit 3,500 patients. Enrolment started in 2018 and the trial has an estimated completion date of 2025.

MINOCA is a condition with comparable in-hospital and long-term mortality to conventional ACS. The heterogeneity in aetiology often makes it a challenge for clinicians to investigate and treat this condition optimally. In STEMI patients with MINOCA, careful assessment of the history and examination findings during initial contact, with meticulous review of the coronary angiogram, can allow appropriate triaging. Routine biomarkers, including troponins and NT-proBNP, and early use of cardiac MRI imaging is advocated. Additional selective use of further testing that includes intracoronary assessment with IVUS/OCT, thrombophilia screening and vasoprovocation testing should be considered on an individual basis. Unless alternative causes are identified that mandate specific treatment, patients presenting with MINOCA should receive standard post-ACS pharmacotherapy.

WHO. Cardiovascular diseases (CVDs). Geneva: WHO, 2017. https://www.who.int/en/news-room/fact-sheets/detail/ cardiovascular-diseases-(cvds) (accessed 26 March 2020). DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303:897–902. https://doi.org/10.1056/NEJM198010163031601; PMID: 7412821.

Ongoing studies will hopefully yield new insight into the optimal management of this hitherto under-investigated condition.

DeWood MA, Stifter WF, Simpson CS, et al. Coronary arteriographic findings soon after non-Q-wave myocardial infarction. N Engl J Med 1986;315:417–23. https://doi. org/10.1056/NEJM198608143150703; PMID: 3736619. Ibanez B, James S, Agewall S, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients

presenting with ST-segment elevation of the European Sociey of Cardiology (ESC). Eur Heart J 2018;39:119–77. https://doi. org/10.1093/eurheartj/ehx393; PMID: 28886621. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–1278. https://doi.org/10.1016/ S0140-6736(05)67394-1; PMID: 16214597.

EUROPEAN CARDIOLOGY REVIEW

MI with Non-obstructive Coronary Artery in STEMI 6.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

Antithrombotic Trialists Collaboration, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849– 1860. https://doi.org/10.1016/S0140-6736(09)60503-1; PMID: 19482214. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–1057. https://doi.org/10.1056/ NEJMoa0904327; PMID: 19717846. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–2015. https://doi.org/10.1056/ NEJMoa0706482; PMID: 17982182. Freemantle N, Cleland J, Young P, et al. Beta blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 1999;318:1730–1737. https://doi.org/10.1136/ bmj.318.7200.1730; PMID: 10381708. ACE Inhibitor Myocardial Infarction Collaborative Group. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. Circulation 1998;97:2202–2212. https://doi.org/10.1161/01.cir.97.22.2202; PMID: 9631869. Pasupathy S, Air T, Dreyer RP, et al. Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries. Circulation 2015;131:861–70. https://doi.org/10.1161/CIRCULATIONAHA.114.011201; PMID: 25587100. Dokainish H, Pillai M, Murphy SA, et al. Prognostic implications of elevated troponin in patients with suspected acute coronary syndrome but no critical epicardial coronary disease: a TACTICS-TIMI-18 substudy. J Am Coll Cardiol 2005;45:19–24. https://doi.org/10.1016/j.jacc.2004.09.056; PMID: 15629367. Safdar B, Spatz ES, Dreyer RP, et al. Presentation, clinical profile, and prognosis of young patients with myocardial infarction with nonobstructive coronary arteries (MINOCA): results from the VIRGO study. J Am Heart Assoc 2018;7:e009174. https://doi.org/10.1161/JAHA.118.009174; PMID: 29954744. Kemp HG, Kronmal RA, Vlietstra RE, et al. Seven year survival of patients with normal or near normal coronary arteriograms: a CASS registry study. J Am Coll Cardiol 1986;7:479–83. https:// doi.org/10.1016/S0735-1097(86)80456-9; PMID: 3512658. Lichtlen PR, Bargheer K, Wenzlaff P. Long-term prognosis of patients with anginalike chest pain and normal coronary angiographic findings. J Am Coll Cardiol 1995;25:1013–8. https:// doi.org/10.1016/0735-1097(94)00519-V; PMID: 7897110. Bugiardini R, Bairey Merz CN. Angina with “normal” coronary arteries. JAMA 2005;293:477. https://doi.org/10.1001/ jama.293.4.477; PMID: 15671433. Agewall S, Beltrame JF, Reynolds HR, et al. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. Eur Heart J 2016;38:ehw149. https://doi. org/10.1093/eurheartj/ehw149; PMID: 28158518. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation 2012;126:2020–35. https:// doi.org/10.1161/CIR.0b013e31826e1058; PMID: 22923432. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction (2018). Circulation 2018;138:1–34. https://doi.org/10.1016/j.jacc.2018.08.1038; PMID: 30153967. Tamis-Holland JE, Jneid H, Reynolds HR, et al. Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: a scientific statement from the American Heart Association. Circulation 2019;139:E891–908. https://doi. org/10.1161/CIR.0000000000000670; PMID: 30913893. Pasupathy S, Tavella R, Beltrame JF. Myocardial infarction with nonobstructive coronary arteries (MINOCA): the past, present, and future management. Circulation 2017;135:1490–3. https:// doi.org/10.1161/CIRCULATIONAHA.117.027666; PMID: 28416521. Gehrie ER, Reynolds HR, Chen AY, et al. Characterization and outcomes of women and men with non–ST-segment elevation myocardial infarction and nonobstructive coronary artery disease: results from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) quality improvement initiative. Am Heart J 2009;158:688–94. https://doi.org/10.1016/j.ahj.2009.08.004; PMID: 19781432. Planer D, Mehran R, Ohman EM, et al. Prognosis of patients with non-ST-segment-elevation myocardial infarction and nonobstructive coronary artery disease. Circ Cardiovasc Interv 2014;7:285–93. https://doi.org/10.1161/ CIRCINTERVENTIONS.113.000606; PMID: 24847016. Gue YX, Corballis N, Ryding A, et al. MINOCA presenting with STEMI: incidence, aetiology and outcome in a contemporaneous cohort. J Thromb Thrombolysis 2019;48:533– 8. https://doi.org/10.1007/s11239-019-01919-5; PMID: 31327089. Widimsky P, Stellova B, Groch L, et al. Prevalence of normal coronary angiography in the acute phase of suspected ST-elevation myocardial infarction: experience from the PRAGUE studies. Can J Cardiol 2006;22:1147–52. https://doi. org/10.1016/S0828-282X(06)70952-7; PMID: 17102833. Lindahl B, Baron T, Erlinge D, et al. Medical therapy for

EUROPEAN CARDIOLOGY REVIEW

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

secondary prevention and long-term outcome in patients with myocardial infarction with nonobstructive coronary artery disease. Circulation 2017;135:1481–9. https://doi.org/10.1161/ CIRCULATIONAHA.116.026336; PMID: 28179398. Rakowski T, De Luca G, Siudak Z, et al. Characteristics of patients presenting with myocardial infarction with nonobstructive coronary arteries (MINOCA) in Poland: data from the ORPKI national registry. J Thromb Thrombolysis 2019;47:462– 6. https://doi.org/10.1007/s11239-018-1794-z; PMID: 30565147. Patel MR, Chen AY, Peterson ED, et al. Prevalence, predictors, and outcomes of patients with non-ST-segment elevation myocardial infarction and insignificant coronary artery disease: results from the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines (CRUSADE) initiative. Am Heart J 2006;152:641–7. https://doi.org/10.1016/j. ahj.2006.02.035; PMID: 16996828. Daniel M, Agewall S, Caidahl K, et al. Effect of myocardial infarction with nonobstructive coronary arteries on physical capacity and quality-of-life. Am J Cardiol 2017;120:341–6. https://doi.org/10.1016/j.amjcard.2017.05.001; PMID: 28610801. Barr PR, Harrison W, Smyth D, et al. Myocardial infarction without obstructive coronary artery disease is not a benign condition (ANZACS-QI 10). Hear Lung Circ 2018;27:165–74. https://doi.org/10.1016/j.hlc.2017.02.023; PMID: 28408093. Scalone G, Niccoli G, Crea F. Pathophysiology, diagnosis and management of MINOCA: an update. Eur Hear J Acute Cardiovasc Care 2019;8:54–62. https://doi.org/10.1177/2048872618782414; PMID: 29952633. Ouldzein H, Elbaz M, Roncalli J, et al. Plaque rupture and morphological characteristics of the culprit lesion in acute coronary syndromes without significant angiographic lesion: analysis by intravascular ultrasound. Ann Cardiol Angeiol (Paris) 2012;61:20–6. https://doi.org/10.1016/j.ancard.2011.07.011; PMID: 21903196. Reynolds HR, Srichai MB, Iqbal SN, et al. Mechanisms of myocardial infarction in women without angiographically obstructive coronary artery disease. Circulation 2011;124:1414– 25. https://doi.org/10.1161/CIRCULATIONAHA.111.026542; PMID: 21900087. Opolski MP, Spiewak M, Marczak M, et al. Mechanisms of myocardial infarction in patients with nonobstructive coronary artery disease: results from the optical coherence tomography study. JACC Cardiovasc Imaging 2018;12:2210–21. https://doi. org/10.1016/j.jcmg.2018.08.022; PMID: 30343070. Stiel GM, Stiel LSG, Schofer J, et al. Impact of compensatory enlargement of atherosclerotic coronary arteries on angiographic assessment of coronary artery disease. Circulation 1988;80:1603–9. https://doi.org/10.1161/01. CIR.80.6.1603; PMID: 2598424. Gorog DA, Lip GYH. Impaired spontaneous/endogenous fibrinolytic status as new cardiovascular risk factor? J Am Coll Cardiol 2019;74:1366–75. https://doi.org/10.1016/j. jacc.2019.07.030; PMID: 31488274. Adlam D, Alfonso F, Maas A, et al. European Society of Cardiology, acute cardiovascular care association, SCAD study group: a position paper on spontaneous coronary artery dissection. Eur Heart J 2018;39:3353–68. https://doi. org/10.1093/eurheartj/ehy080; PMID: 29481627. Mortensen KH, Thuesen L, Kristensen IB, et al. Spontaneous coronary artery dissection: a Western Denmark Heart Registry study. Catheter Cardiovasc Interv 2009;74:710–7. https://doi. org/10.1002/ccd.22115; PMID: 29481627. Nishiguchi T, Tanaka A, Ozaki Y, et al. Prevalence of spontaneous coronary artery dissection in patients with acute coronary syndrome. Eur Heart J Acute Cardiovasc Care 2016;5:263–70. https://doi.org/10.1177/2048872613504310; PMID: 24585938. Saw J. Coronary angiogram classification of spontaneous coronary artery dissection. Catheter Cardiovasc Interv 2014;84:1115–22. https://doi.org/10.1002/ccd.25293; PMID: 24227590. Beltrame JF, Crea F, Kaski JC, et al. International standardization of diagnostic criteria for vasospastic angina. Eur Heart J 2017;38:2565–8. https://doi.org/10.1093/eurheartj/ ehv351; PMID: 26245334. Beijk MA, Vlastra WV, Delewi R, et al. Myocardial infarction with non-obstructive coronary arteries: a focus on vasospastic angina. Neth Heart J 2019;27:237–45. https://doi.org/10.1007/ s12471-019-1232-7; PMID: 30689112. Takaoka K, Yoshimura M, Ogawa H, et al. Comparison of the risk factors for coronary artery spasm with those for organic stenosis in a Japanese population: role of cigarette smoking. Int J Cardiol 2000;72:121–6. https://doi.org/10.1016/S01675273(99)00172-2; PMID: 10646952. Kolodgie FD, Virmani R, Cornhill JF, et al. Increase in atherosclerosis and adventitial mast cells in cocaine abusers: an alternative mechanism of cocaine-associated coronary vasospasm and thrombosis. J Am Coll Cardiol 1991;17:1553–60. https://doi.org/10.1016/0735-1097(91)90646-Q; PMID: 2033185. Robertson RM, Wood AJ, Vaughn WK, et al. Exacerbation of vasotonic angina pectoris by propranolol. Circulation 1982;65:281–5. https://doi.org/10.1161/01.CIR.65.2.281; PMID: 6797752.

46. Lanza G, Careri G, Circulation FC, et al. Mechanisms of coronary artery spasm. Am Hear Assoc 2011;124:1774–82. https://doi.org/10.1161/CIRCULATIONAHA.111.037283; PMID: 22007100. 47. Ong P, Athanasiadis A, Borgulya G, et al. Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive white patients with unobstructed coronary arteries. Circulation 2014;129:1723–30. https://doi.org/10.1161/ CIRCULATIONAHA.113.004096; PMID: 24573349. 48. Montone RA, Niccoli G, Fracassi F, et al. Patients with acute myocardial infarction and non-obstructive coronary arteries: safety and prognostic relevance of invasive coronary provocative tests. Eur Heart J 2018;39:91–8. https://doi. org/10.1093/eurheartj/ehx667; PMID: 29228159. 49. Raphael CE, Heit JA, Reeder GS, et al. Coronary embolus: an underappreciated cause of acute coronary syndromes. JACC Cardiovasc Interv 2018;11:172–80. https://doi.org/10.1016/j. jcin.2017.08.057; PMID: 29348012. 50. He DK, Zhang YF, Liang Y, et al. Risk factors for embolism in cardiac myxoma: a retrospective analysis. Med Sci Monit 2015;21:1146–54. https://doi.org/10.12659/MSM.893855; PMID: 25900256. 51. Shibata T, Kawakami S, Noguchi T, et al. Prevalence, clinical features, and prognosis of acute myocardial infarction attributable to coronary artery embolism. Circulation 2015;132:241–50. https://doi.org/10.1161/ CIRCULATIONAHA.114.015134; PMID: 26216084. 52. Stepien K, Nowak K, Wypasek E, et al. High prevalence of inherited thrombophilia and antiphospholipid syndrome in myocardial infarction with non-obstructive coronary arteries: comparison with cryptogenic stroke. Int J Cardiol 2019;290:1–6. https://doi.org/10.1016/j.ijcard.2019.05.037; PMID: 31133433. 53. Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155:408–17. https://doi. org/10.1016/j.ahj.2007.11.008; PMID: 18294473. 54. Gianni M, Dentali F, Grandi AM, et al. Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review. Eur Heart J 2006;27:1523–9. https://doi.org/10.1093/eurheartj/ ehl032; PMID: 16720686. 55. Fröhlich GM, Schoch B, Schmid F, et al. Takotsubo cardiomyopathy has a unique cardiac biomarker profile: NT-proBNP/myoglobin and NT-proBNP/troponin T ratios for the differential diagnosis of acute coronary syndromes and stress induced cardiomyopathy. Int J Cardiol 2012;154:328–32. https:// doi.org/10.1016/j.ijcard.2011.09.077; PMID: 22044675. 56. Lyon AR, Bossone E, Schneider B, et al. Current state of knowledge on Takotsubo syndrome: a position statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2016;18:8–27. https://doi.org/10.1002/ejhf.424; PMID: 26548803. 57. Bhatia S, Anstine C, Jaffe AS, et al. Cardiac magnetic resonance in patients with elevated troponin and normal coronary angiography. Heart 2019;105:1231–6. https://doi. org/10.1136/heartjnl-2018-314631; PMID: 30948519. 58. Dastidar AG, Baritussio A, De Garate E, et al. Prognostic role of cardiac MRI and conventional risk factors in myocardial infarction with nonobstructed coronary arteries. JACC Cardiovasc Imaging 2019;12:1973–82. https://doi.org/10.1016/j. jcmg.2018.12.023; PMID: 30772224. 59. Caforio ALP, Pankuweit S, Arbustini E, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013;34:2636–48. https://doi.org/10.1093/ eurheartj/eht210; PMID: 23824828. 60. Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease. A scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. J Am Coll Cardiol 2007;50:1914–31. https://doi.org/10.1016/j.jacc.2007.09.008; PMID: 17980265. 61. Tornvall P, Gerbaud E, Behaghel A, et al. Myocarditis or “true” infarction by cardiac magnetic resonance in patients with a clinical diagnosis of myocardial infarction without obstructive coronary disease: a meta-analysis of individual patient data. Atherosclerosis 2015;241:87–91. https://doi.org/10.1016/j. atherosclerosis.2015.04.816; PMID: 25967935. 62. Patriki D, Gresser E, Manka R, et al. Approximation of the incidence of myocarditis by systematic screening with cardiac magnetic resonance imaging. JACC Hear Fail 2018;6:573–9. https://doi.org/10.1016/j.jchf.2018.03.002; PMID: 29885953. 63. Lurz P, Eitel I, Adam J, et al. Diagnostic performance of CMR imaging compared with EMB in patients with suspected myocarditis. JACC Cardiovasc Imaging 2012;5:513–24. https://doi. org/10.1016/j.jcmg.2011.11.022; PMID: 22595159. 64. Saaby L, Poulsen TS, Hosbond S, et al. Classification of myocardial infarction: frequency and features of type 2 myocardial infarction. Am J Med 2013;126:789–97. https://doi. org/10.1016/j.amjmed.2013.02.029; PMID: 23856021.

Myocardial Infarction 65. Erbel R, Aboyans V, Boileau C, et al. 2014 ESC guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. Eur Heart J 2014;35:2873–926. https://doi.org/10.1093/eurheartj/ehu281; PMID: 25173340. 66. Bossone E, Labounty TM, Eagle KA. Acute aortic syndromes: diagnosis and management, an update. Eur Heart J 2018;39:739–49. https://doi.org/10.1093/eurheartj/ehx319; PMID: 29106452. 67. Takagi Y, Yasuda S, Takahashi J, et al. Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association. Eur Heart J 2013;34:258–67. https://doi.org/10.1093/eurheartj/ ehs199; PMID: 22782943. 68. Ciliberti G, Seshasai SRK, Ambrosio G, et al. Safety of intracoronary provocative testing for the diagnosis of coronary artery spasm. Int J Cardiol 2017;244:77–83. https://doi. org/10.1016/j.ijcard.2017.05.109; PMID: 22782943.

69. Probst S, Seitz A, G Pirozzolo G, et al. Safety assessment and results of coronary spasm provocation testing in patients with MINOCA compared to patients with stable angina and unobstructed coronary arteries. Eur Heart J 2019;40(Suppl):ehz746.0724. https://doi.org/10.1093/eurheartj/ ehz746.0724. 70. Ong P, Athanasiadis A, Borgulya G, et al. 3-year follow-up of patients with coronary artery spasm as cause of acute coronary syndrome: the CASPAR (coronary artery spasm in patients with acute coronary syndrome) study follow-up. J Am Coll Cardiol 2011;57:147–52. https://doi.org/10.1016/j. jacc.2010.08.626; PMID: 21211685. 71. Assomull RG, Lyne JC, Keenan N, et al. The role of cardiovascular magnetic resonance in patients presenting with chest pain, raised troponin, and unobstructed coronary arteries. Eur Heart J 2007;28:1242–9. https://doi.org/10.1093/ eurheartj/ehm113; PMID: 17478458. 72. Monney PA, Sekhri N, Burchell T, et al. Acute myocarditis presenting as acute coronary syndrome: role of early cardiac

magnetic resonance in its diagnosis. Heart 2011;97:1312–8. https://doi.org/10.1136/hrt.2010.204818; PMID: 21106555. 73. Laraudogoitia Zaldumbide E, Pérez-David E, Larena JA, et al. The value of cardiac magnetic resonance in patients with acute coronary syndrome and normal coronary arteries. Rev Esp Cardiol 2009;62:976–83. https://doi.org/10.1016/s18855857(09)73263-3; PMID: 19712618. 74. Vago H, Szabo L, Horvath V, et al. Differential diagnosis of MINOCA patients: the contribution of early cardiac magnetic resonance imaging to the final diagnosis in patients with normal coronary angiography. Eur Heart J 2019;40(Suppl):ehz748.0146. https://doi.org/10.1093/eurheartj/ ehz748.0146. 75. Bossard M, Yusuf S, Tanguay J, et al. Recurrent cardiovascular events and mortality in relation to antiplatelet therapy in patients with myocardial infarction without obstructive coronary artery disease (MINOCA). Eur Heart J 2019;40(Suppl):ehz748.0154. https://doi.org/10.1093/eurheartj/ ehz748.0145.

EUROPEAN CARDIOLOGY REVIEW

Pharmacotherapy

Recent Warnings about Antihypertensive Drugs and Cancer Risk: Where Do They Come From? Allegra Battistoni1 and Massimo Volpe1,2 1. Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy; 2. IRCCS Neuromed, Pozzilli, Italy

Abstract The recent decrease in mortality related to cardiovascular diseases has largely been due to the more effective treatment of cardiovascular risk factors and secondary prevention therapies. More people than ever are now on long-term medications. Hypertension, which is one of the most common cardiovascular risk factors, requires life-long treatment. Recent evidence has focused attention on the risk of cancer that may be associated with the long-term use of antihypertensive therapy. This article summarises available evidence surrounding three recent events in this setting. Even though this is a crucial patient safety issue, there are no conclusive answers at this time and further studies are required.

Keywords Hypertension, cancer, cancer risk, skin cancer, thiazide Disclosure: The authors have no conflicts of interest to disclose. Received: 31 December 2019 Accepted: 17 February 2020 Citation: European Cardiology Review 2020;15:e21. DOI: https://doi.org/10.15420/ecr.2019.21 Correspondence: Massimo Volpe, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, Sant’Andrea Hospital, Via di Grottarossa 1035-1039, 00198 Rome, Italy. E: massimo.volpe@uniroma1.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Cardiovascular and neoplastic diseases are currently the main causes of mortality and morbidity in developed nations.1 These diseases often coexist in the same individual, worsening general condition, complicating therapeutic management and – from a different perspective – raising the issue of possible shared pathophysiological pathways between cardiovascular disease (CVD) and cancer. Many of the known risk factors for the development of CVD also increase the risk of cancer.2,3 In this complex setting, the debate about the oncogenic potential of some classes of cardiovascular drugs has recently come to the fore. In 2017, three important events focused attention on the postulated oncogenic potential of some antihypertensive drugs. First, news about the US Food and Drug Administration’s withdrawal of some batches of very popular and widely used antihypertensive drugs, such as losartan, valsartan and irbesartan, due to the presence of potentially carcinogenic byproducts of the pharmaceutical process (N-nitrosodimethylamine, N-nitrosodiethylamine and N-nitroso-N-methyl-4-aminobutyric acid).4 Second, the publication of two Scandinavian trials suggesting that thiazide diuretics may play a role in the development of skin neoplasms;5,6 and third, one trial claiming that angiotensin-converting enzyme (ACE) inhibitors may cause lung cancer. These events generated wide concern among physicians and patients, monopolising the medical pages of newspapers and magazines as well as doctor–patient interactions in offices and hospitals. They are part of a debate born in the first half of the 1900s, enriched over time by data obtained mainly from national registers and cohort studies, and only exceptionally by randomised controlled trials (RCTs) which have evaluated the carcinogenic potential of specific antihypertensive drugs. This disparate data collection has jeopardised the reliability of evidence in this setting. In fact, over time, different dosages and associations of the active principles may have varied and other concomitant risk factors for cancer may have

intervened/disappeared without leaving a trace in the records of observational studies or registers.7 In post hoc analysis, preferential recall can occur and adherence to therapy (which is crucial for chronic therapy) is not usually assessed.8 Furthermore, concomitant or previous therapies that were not recorded may have contributed to the modified risk of cancer.6 In general, observational trials lack randomisation, whereas posthoc meta-analyses of RCTs may include important differences in control populations: normotensive patients, non-pharmacologically treated hypertensives and hypertensive patients treated with different active treatments.9,10 These differences make it very difficult to use the data generated to establish firm conclusions about the risk of cancer in relation to antihypertensive use. In light of recent events, this article provides a critical overview of the evidence supporting the carcinogenic role of diuretics, angiotensin receptor blockers (ARBs) and ACE inhibitors in specific settings. Data for this review were identified by a PubMed search going back to 2000 and by analysing articles mentioned in the references of papers yielded by the search. Search terms concentrated upon the prevalence of cancer and selected antihypertensive drugs (diuretics, ACE inhibitors and ARBs). Representative studies for various drugs and cancer in patients with hypertension were included, giving priority to metaanalyses or studies with larger sample sizes.

Antihypertensive Drugs and Cancer Risk Diuretics Renal Cancer Diuretics are largely used as antihypertensive medications, often in combination with other therapies, therefore it may be difficult to assess

Access at: www.ECRjournal.com

Pharmacotherapy the net adverse effect of a single diuretic. In addition, diuretics have been often investigated as one single class. Nonetheless, thiazides have been investigated more closely since the 1980s.11,12 The potential carcinogenic role of thiazides appears to be supported, at least with regards to kidney cancer, by their toxic and mutagenic effect at the distal tubule level during long exposure to these drugs.13,14 Moreover, the toxic metabolites of thiazides and loop diuretics, namely N-nitroso derivates, have been accused of having tumourigenic actions.15 With regards to renal cancer, available data often come from observational studies or retrospective analyses with incomplete assessment of renal cancer risk factors and different cut-offs or means (self-reported or officebased readings) to diagnose hypertension.16 Despite this, most cohort studies and population studies in humans have shown that diuretics, in a dose-dependent fashion, may contribute to a twofold to fourfold increase in the risk of developing renal cell carcinoma, particularly in women.17,18 Recently, a case control study that failed to find any association between antihypertensive drugs and renal carcinoma overall found a positive association between both diuretic and calcium-channel blocker use and papillary renal carcinoma, even in a limited number of hypertensive people.19 In contrast, no significant association has ever been found between diuretic use and renal cell cancer in normotensive people.20–22 Therefore, whether the presence of hypertension itself might be a risk factor for renal cell carcinoma has long been questioned.18 A recent meta-analysis considering evidence from 85 prospective studies found a positive association between hypertension and kidney cancer.23 This evidence seems to be supported by the fact that many metabolic and neuro-hormonal pathways, such as the renin–angiotensin–aldosterone system (RAS), catecholamines and vasopressin, may play a role in both cancer development and hypertension.24–26 The most recent evidence in this setting comes from a systematic review of 27 observational studies that found an association between diuretic use and the risk of kidney cancer (RR 1.34, 95% CI [1.19–1.51]) that increased with the duration of treatment and was still significant after adjusting for hypertension and smoking.27

Skin Cancer A possible association between diuretic use and skin cancer was hypothesised a long time ago. This suggestion has recently become more important because of the increasing incidence of cutaneous melanoma and non-melanoma skin cancers.28 The main risk factors for skin cancer development are exposure to ultraviolet light, fair skin, light eye and hair colour, the presence and number of common and atypical naevi and a tendency to develop freckles. These factors have not been assessed in most available trials. In addition to this, the time between exposure to diuretics and skin cancer development appears to be too short to be biologically plausible in most studies; therefore, data should be interpreted with caution.7 The association between diuretics, in particular thiazides, and skin cancer is supported by the fact that they are photosensitisers, causing direct damage to DNA and chronic subclinical skin inflammation. However, photosensitivity is also a common reaction to many widely used drugs, such as antibiotics, non-steroidal anti-inflammatory drugs and statins, which are often used in the polypharmacy of hypertensive patients.29,30 Self-reported consumption of diuretics, including thiazides, was associated with an increased risk of basal cell carcinoma (BCC) in a nationwide US population-based cohort study, but other studies have not reported similar results (Table 1).31–33 De Vries et al. observed an

association between bendroflumethiazide and BCC, but this finding was no longer significant after correction for multiple hypothesis testing.34 Information reported on specific diuretics found an increased risk of BCC among users of loop diuretics, especially long-term users.35 A 2008 observational study found an increased risk of squamous cell carcinoma (SCC) and malignant melanoma in users of amiloride alone or in combination with hydrochlorothiazide, and of malignant melanoma in users of sulphonamides and other low-ceiling diuretics (e.g. indapamide).36 In 2015, a subsequent case control study including data from this cohort plus data from population-based databases in northern Denmark during 1991–2010 showed that long-term diuretic use was associated with an increased risk of SCC, driven by potassium-sparing agents alone or in combination with low-ceiling diuretics.37 The recent north European nationwide case control study by Pedersen et al. found a clear dose– response relationship between hydrochlorothiazide use and both BCC and SCC, especially the latter cancer type.5 In this analysis, the use of high cumulative doses of hydrochlorothiazide (>50 g) was associated with a dose-dependent increase in the risk of BCC (OR 1.29, 95% CI [1.23–1.35]) and SCC (OR 3.84, 95% CI [3.68–4.31]). The proportion of skin cancers attributable to hydrochlorothiazide use was 0.6% for BCC and 9.0% for SCC. The risk was higher in women than men and in patients <50 years old. This increased risk was not observed with chlorthalidone or indapamide. The main limit of these north European trials is the lack of information on two major risk factors for BCC and SCC, namely ultraviolet exposure and skin phenotype. A recent meta-analysis of 19 studies from 1993 to 2016 concerning diuretic use and the risk of skin cancer found a non-significant 30% increase in skin cancer risk among thiazide users (standardised RR 1.31, 95% CI [0.93–1.83]), based on 11 RR estimates from six independent studies.38 This meta-analysis excluded trials involving different active arms, normotensive people as controls and those lacking distinction between different diuretics. The latest meta-analysis comprising all available studies examining the risk of developing skin cancer with thiazide use found an association between chronic exposure to thiazides and all skin cancers, particularly between the use of hydrochlorothiazide – alone or in combination – and the risk of developing SCC.39 It must be pointed out that this analysis is based on few and generally heterogeneous observational studies for every type of skin cancer and many of these studies do not consider the interaction between different skin types, sun exposure and family history of skin cancer. Despite this, the association between thiazide diuretics and SCC risk appears to be supported by the epidemiological evidence available to date. With regards to melanoma skin cancer, a recent meta-analysis found a RR of 1.17 (95% CI [1.12–1.24]) for the association between thiazide diuretic use (ever versus never) and melanoma risk based on four independent RR estimates. The heterogeneity of studies was low, but the results were heavily influenced by the Danish study by Pottegård et al. that found an increase in melanomas, specifically nodular and lentigo melanomas, in patients treated with hydrochlorothiazide.6,40,41 Based on recent evidence, the British and Irish Hypertension Society recommended that thiazide-like drugs (e.g. chlorthalidone or indapamide) be preferred over thiazide diuretics (e.g. hydrochlorothiazide or bendroflumethiazide) when starting hypertension treatment but should not be discontinued in patients with well-controlled blood pressure levels.42 Likewise, the European Medicines Agency has stated

EUROPEAN CARDIOLOGY REVIEW

Are Antihypertensives a Risk Factor for Cancer? Table 1: Main Studies Reporting on the Diuretic-associated Risk of Skin Cancer Study

Country

Kaae et al. 201032

Denmark

Ruiter et al. 201034

Cohort study, nationwide registry data

Cancer

Number of Cases

Drug and Definition of Exposure

Relative Risk (95% CI)

Melanoma

90 35,328

Bendroflumethiazide: ever use versus no use

1.3 (1.0–1.6)

Basal cell cancer Squamous cell cancer

5,912

The Netherlands Prospective population-based cohort, general Basal cell cancer practitioners’ medical records or registry, prescriptions of drugs from pharmacies

de Vries et al. Europe 201233

Mc Donald et al. 201430

Type of Study and Source

Schmidt et al. Denmark 201436

Multicentre case-control study, partly self-reported

522

1.0 (1.0–1.1) 1.0 (0.8–1.2)

Thiazides: ever use versus no use

1.00 (0.95–1.05)

High ceiling diuretics: ever use versus no use

1.07 (1.02–1.13)

Thiazide diuretics: ever use versus no use

1.66 (1.16–2.37)

Squamous cell cancer

409

Basal cell cancer

602

Melanoma

360

Nationwide prospective cohort study, self-reported data

Basal cell cancer

2,291

Diuretic: ever use versus no use 1.22 (1.07–1.38)

Population-based case-control study, registry data

Squamous cell cancer

2,282

Potassium-sparing agents: ever 1.40 (1.09–1.80) use versus no use

1.27 (0.92–1.75) 1.22 (0.77–1.93)

Potassium-sparing agents with low-ceiling diuretics: ever use versus no use

2.68 (2.24–3.21)

1.17 (1.11–1.23)

Pottegård et al. 20186

Denmark

Case–control study matched by age and gender (1:10 ratio), nationwide registry data

Melanoma

19,723

Hydrochlorothiazide: ever use versus no use

Pedersen et al. 20185

Denmark

Case–control study, matched by age and gender (1:20 ratio), five nationwide data registers

Squamous cell cancer

8,629

Hydrochlorothiazide: cumulative 3.98 (3.68–4.31) dose (≥50 g versus no use)

Basal cell cancer

71,553

Hydrochlorothiazide: cumulative 1.29 (1.23–1.35) dose (≥50 g versus no use)

that hypertensive patients treated with hydrochlorothiazide should be informed about the risks, limit their exposure to ultraviolet rays and regularly check their skin, but should not stop treatment unless they have a history of non-melanoma or melanoma skin cancer.43

Renin–Angiotensin–Aldosterone System Blockers Until recently ARBs were prescribed for several indications beside hypertension with no major safety concerns, but in the past 2 years the US Food and Drug Administration has issued more than 1,000 communications regarding the withdrawal of batches of drugs containing valsartan, irbesartan and losartan, often in fixed-combination pills, due to the presence of excessive quantities of nitrogen derivatives known to have oncogenic effects.4 These impurities were added during the processing of active principles at specific sites in China and India. However, these measures have contributed to the identification of ARBs as oncogenic themselves. From a pathophysiological point of view, the role of angiotensin and its receptors in the development neoplasms appears to be complex. Many types of cancer express type I angiotensin II receptors, suggesting that angiotensin may play a role in mediating processes such as progression, vascularisation and metastasis; therefore, the use of ACE inhibitors and ARBs could be protective from an oncologic point of view.44–46 The proposed mechanisms mediating the anti-tumour activity of ACE inhibitors and ARBs include, among others, the inhibition of matrix metalloproteases and reduced expression of vascular endothelial growth factor, but the role of the consequent unopposed chronic overstimulation of the type II angiotensin receptors is uncertain, as is the increase in renin levels resulting from the blockade of type I angiotensin II receptors.47–49 On

EUROPEAN CARDIOLOGY REVIEW

the other hand, the increase in angiotensin (I–VII) occurring during ARB treatment might have an anti-angiogenic effect in tumours.50 Whereas most of the evidence on ACE inhibitors and ARBs is neutral on cancer risk, some data have been reported since the beginning of RAS modulation therapy that suggest the risk of cancer cannot be ruled out (Table 2). For instance, results from the Candesartan in Heart Failure Assessment of Reduction on Mortality and Morbidity (CHARM) study first pointed towards the possible link between RAS inhibition and cancer development.51 It reported a significantly increased risk of cancer in patients exposed to candesartan (2.3%) compared with placebo (1.6%). With regards to cancer development and cancer-related mortality, in 2011 Sipahi et al. published a meta-analysis based on the evaluation of studies with ARBs reporting cancer data, suggesting that ARBs were associated with a ‘modest increase’ (1–2% absolute risk) in new cancers, especially lung and prostate cancers, as compared with the control group (7.2% versus 6.0%; RR 1.08, 95% CI [1.01–1.15]).52 This meta-analysis included studies with a follow-up of 1 year, the longest follow-up being 5 years, which seems too short to draw conclusions on cancer development. In addition, there was no unique assessment of cancer diagnosis in the studies, data were lacking about other risk factors (such as previous history of cancer) and there were different comparator agents in the meta-analysis. The results were mainly driven by the Renal Outcomes with Telmisartan, Ramipril, or both, in People at High Vascular Risk (ONTARGET) study, which studied telmisartan in association with ramipril. In the same year, the ARB Trialists collaborators published an analysis of individual data from 15 multicentre

Pharmacotherapy Table 2: Main Results from Studies Reporting on the Angiotensin II Receptor Blocker-associated Risk of Lung Cancer Study

Country

Type of Study and Source

Number of Cases

Drug

Relative Risk (95% CI)

Sipahi et al. 201051

International

Meta-analysis of randomised controlled trials

249

ARB with background ACE inhibitor treatment versus1.32 (1.03–1.69) control groups

317

ARB without background ACE inhibitor treatment versus control groups

1.50 (0.93–2.41)

ARB Trialists Collaboration 201152

International

Meta-analysis of randomised controlled trials

1,132

ARB with/without background ACE inhibitor treatment versus controls treated with ARB or ACE inhibitor or neither

1.01 (0.90–1.14)

Rao et al. 201354

Retrospective case-cohort study in 1:15 ratio, electronic medical record registries

6,923

First-time ARB users versus nonusers

0.74 (0.67–0.83)

Hicks et al. 201856

Population-based cohort study, general practitioners’ records

7,952

ACE inhibitors users versus ARB users

1.14 (1.01–1.29)

ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blockers.

double-blind clinical trials involving more than 130,000 individuals at high cardiovascular risk assigned to telmisartan, irbesartan, valsartan, candesartan or losartan, with or without an ACE inhibitor.53 The study included 75,000 more individuals than the meta-analysis by Sipahi et al. and had different control groups (ACE inhibitor, calcium-channel blocker or placebo). It found no increase in overall or site-specific cancer risk from individual ARBs when compared to control.53 Similarly, a huge meta-analysis of more than 300,000 subjects excluded any association between ACE inhibitors and ARBs and an increased risk of any cancer or cancer-related mortality. However, this study was unable to rule out an increased risk of cancer with the combination of ACE inhibitors and ARBs.54 Subsequently, a US nationwide retrospective observational study relying on an administrative database and involving around 70,000 cases and more than 1 million controls, with a follow-up of around 5 years, excluded any association between lung cancer and ARB therapy.55 On the contrary, ARB use appeared to have a protective effect (HR 0.74 [0.67–0.83], p<0.0001), with a small absolute risk reduction of 0.30 lung cancers per 1,000 person-years in the ARBtreated group. Finally, a recent meta-analysis of 19 RCTs with at least 12 months of followup data reporting on cancer incidence involving about 140,000 patients found no significant differences when comparing an ARB with placebo, an ARB with an ACE inhibitor, an ARB plus partial use of ACE inhibition with placebo plus partial use of ACE inhibition or ARB in combination with an ACE inhibitor.56 Data from the Valsartan in a Japanese population with hypertension and other cardiovascular diseases (Jikei Heart Study) and KYOTO HEART studies included in the meta-analysis by Bangalore et al. had been retracted from publications by this time due to unreliable data and were thus excluded from this analysis. ACE inhibitor users were found to have a 14% greater risk of developing lung cancer than ARB users by a cohort study of more than 900,000 patients who started receiving treatment between 1995 and 2015 and who were followed up for 6.4 years.57 The risk increased with longer duration of use and was significant after 5 years. The authors claimed

Wilkins E, Wilson L, Wickramasinghe K, et al. European Cardiovascular Disease Statistics: 2017 editon. Brussels: European Heart Network, 2017.http://www.ehnheart.org/cvd-statistics/ cvd-statistics-2017.html (accessed 7 April 2020). WHO Regional Office for Europe. Cardiovascular disease. 2019. http://www.euro.who.int/en/health-topics/noncommunicable-

that bradykinin and substance P, whose levels increase during ACE inhibitor therapy, had a supporting role in tumour proliferation. These data have been deeply criticised. Indeed, the authors compared ACE inhibitors to ARBs, which may have a role in cancer promotion/ inhibition. Moreover, smoking status did not appear to change the risk of cancer in the ACE inhibitor group and the authors failed to prove an association between ARB-based therapy and cancer in a subsequent analysis of non-smokers, which is highly difficult to explain. In addition, smoking duration and intensity were not completely assessed in all populations. Moreover, persistent cough is a common side effect of ACE inhibitors, raising the possibility that their observed association with lung cancer could be due to detection bias; patients taking ACE inhibitors may be more likely to undergo diagnostic evaluations, leading to increased detection of preclinical lung cancers. Despite this, in our opinion, hard evidence is still lacking in this setting.

Conclusion The possible carcinogenic roles of drugs, foods and lifestyles has been the focus of much scientific interest over the past 50 years. The possibility that some drugs, which have dramatically modified life expectancy and quality of life by contributing to the control of CVD, may increase the risk of cancer when taken over the long term is unquestionably alarming. For this reason, some recently published data – even if not completely free from limitations – have contributed to discussion in this area. This overview of data on the role of diuretics, ARBs and ACE inhibitors in promoting the development of neoplasms highlights the considerable difficulty of deriving reliable evidence in this setting. Although RCTs are ethically unfeasible, observational studies usually present biases that limit their reliability. For this reason, ‘big data’ need to be collected in a more in-depth manner to produce evidence-based recommendations in the future. At this time, recommendations to interrupt successful antihypertensive therapies with ARBs, ACE inhibitors or diuretics to avoid a generic risk of cancer do not appear to be justified; watchful waiting and paying attention to patients whose cancer risk appears to be increased seems the best strategy.

diseases/cardiovascular-diseases (accessed 7 April 2020). Battistoni A, Mastromarino V, Volpe M. Reducing cardiovascular and cancer risk: how to address global primary prevention in clinical practice. Clin Cardiol 2015;38:387–94. https://doi.org/10.1002/clc.22394; PMID: 25873555. U.S. Food and Drug Administration. FDA Updates and

Press Announcements on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan). 13 November 2019. https://www.fda.gov/drugs/drug-safety-andavailability/fda-updates-and-press-announcementsangiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan (accessed 7 April 2020).

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Are Antihypertensives a Risk Factor for Cancer? 5.

10.

11.

12.

13. 14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

Pedersen SA, Gaist D, Schmidt SAJ, et al. Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide casecontrol study from Denmark. J Am Acad Dermatol 2018;78:673– 81. https://doi.org/10.1016/j.jaad.2017.11.042; PMID: 29217346. Pottegård A, Pedersen SA, Schmidt SAJ, et al. Association of hydrochlorothiazide use and risk of malignant melanoma. JAMA Intern Med 2018;178:1120–2. https://doi.org/10.1001/ jamainternmed.2018.1652; PMID: 29813157. Battistoni A, Tocci G, Presta V, Volpe M. Antihypertensive drugs and the risks of cancer: more fakes than facts. Eur J Prev Cardiol 2019;24. https://doi.org/10.1177/2047487319884823; PMID: 31648551; epub ahead of press. Volpe M, Degli Esposti L, Romeo F, et al. Role of adherence to long-term drug therapy in patients with cardiovascular disease: an Italian intersocietary consensus document. G Ital Cardiol 2014;15:3S–10S. https://doi.org/10.1714/1696.18514; PMID: 25426833. Grossman E, Messerli FH, Goldbourt U. Antihypertensive therapy and the risk of malignancies. Eur Heart J 2001;22:1343– 52. https://doi.org/10.1053/euhj.2001.2729; PMID: 11465967. Battistoni A, Tocci G, Coluccia R, et al. Antihypertensive drugs and the risk of cancer: a critical review of available evidence and perspective. J Hypertens 2020. https://doi.org/10.1097/ HJH.0000000000002379; epub ahead of press. Yu MC, Mack TM, Hanisch R, et al. Cigarette smoking, obesity, diuretic use and coffee consumption as risk factors for renal cell carcinoma. J Natl Cancer Inst 1986;77:351–6. http://doi. org/10.1093/jnci/77.2.351; PMID: 3461197. McLaughlin J, Blot W, Fraumeni J. Diuretics and renal cell cancer. J Natl Cancer Inst 1988;80:378. https://doi.org/10.1093/ jnci/80.5.378; PMID: 3357203. Schottenfield D, Fraumeni J. Cancer Epidemiology and Prevention. New York: Oxford University Press, 2006;497–8. Loffing K, Loffing-Cueni D, Hegyi I, et al. Thiazide treatment of rats provokes apoptosis in distal tubule cells. Kidney Int 1996;50:1180–90. https://doi.org/10.1038/ki.1996.426; PMID: 8887276. Gold B, Mirvish SS. N-Nitroso derivatives of hydrochlorothiazide, niridazole, and tolbutamide. Toxicol Appl Pharmacol 1977;40:131–6. https://doi.org/10.1016/0041008x(77)90124-7; PMID: 867427. Corrao G, Scotti L, Bagnardi V, et al. Hypertension, antihypertensive therapy and renal-cell cancer: a metaanalysis. Curr Drug Saf 2007;2:125–33. https://doi. org/10.2174/157488607780598296; PMID: 18690958. Colt JS, Schwartz K, Graubard BI, et al. Hypertension and risk of renal cell carcinoma among white and black Americans. Epidemiology 2011;22:797–804. https://doi.org/10.1097/ EDE.0b013e318230072; PMID: 21881515. Flaherty KT, Fuchs CS, Colditz GA, et al. A prospective study of body mass index, hypertension, and smoking and the risk of renal cell carcinoma (United States). Cancer Causes Control 2005;16:1099–106. https://doi.org/10.1007/s10552-005-0349-8; PMID: 16184476. Colt JS, Hofmann JN, Schwartz K, et al. Antihypertensive medication use and risk of renal cell carcinoma. Cancer Causes Control 2017;28:289–97. https://doi.org/10.1007/s10552-0170857-3; PMID: 28224412. McLaughlin JK, Chow WH, Mandel JS, et al. International renalcell cancer study. VIII. Role of diuretics, other anti-hypertensive medications and hypertension. Int J Cancer 1995;63:216–21. https://doi.org/10.1002/ijc.2910630212; PMID: 7591207. Weinmann S, Glass AG, Weiss NS, et al. Use of diuretics and other antihypertensive medications in relation to the risk of renal cell cancer. Am J Epidemiol 1994;140:792–804. https://doi. org/10.1093/oxfordjournals.aje.a117328; PMID: 7977290. Yuan JM, Castelao JE, Gago-Dominguez M, et al. Hypertension, obesity and their medications in relation to renal cell carcinoma. Br J Cancer 1998;77:1508–13. https://doi. org/10.1038/bjc.1998.248; PMID: 9652770. Seretis A, Cividini S, Markozannes G, et al. Association between blood pressure and risk of cancer development: a systematic review and meta-analysis of observational studies. Sci Rep 2019;9:8565. https://doi.org/10.1038/s41598-019-

EUROPEAN CARDIOLOGY REVIEW

45014-4; PMID: 31189941. 24. Meyer P. Increased intracellular calcium: from hypertension to cancer. J Hypertens Suppl 1987;5:S3–4. https://doi. org/10.1097/00004872-198712004-00002; PMID: 2831321. 25. Hamet P. Cancer and hypertension. An unresolved issue. Hypertension 1996;28:321–4. https://doi.org/10.1161/01. hyp.28.3.321; PMID: 8794810. 26. Gago-Dominguez M, Castelao JE, Yuan JM, et al. Lipid peroxidation: a novel and unifying concept of the etiology of renal cell carcinoma (United States). Cancer Causes Control 2002;13:287–93. https://doi.org/10.1023/a:1015044518505; PMID: 12020111. 27. Xie Y, Xu P, Wang M, et al. Antihypertensive medications are associated with the risk of kidney and bladder cancer: a systematic review and meta-analysis. Aging (Albany NY) 2020;12:1545–62. https://doi:10.18632/aging.102699; PMID: 31968309. 28. Guy GP Jr, Machlin SR, Ekwueme DU, et al. Prevalence and costs of skin cancer treatment in the U.S., 2002–2006 and 2007–2011. Am J Prev Med 2015;48:183–7. https://doi. org/10.1016/j.amepre.2014.08.036; PMID: 25442229. 29. Photosensitizing medication list. In: Tanning Fact Book 2008/2009. Looking Fit, 2008. http://newsletters.vitiligosupport. org/archive/fall2012/medication.pdf (accessed 7 April 2020). 30. Baccino D, Merlo G, Cozzani E, et al. Cutaneous effects of antihypertensive drugs. G Ital Dermatol Venereol. 2019. https:// doi.org/10.23736/S0392-0488.19.06360-0; PMID: 31195782; epub ahead of press. 31. McDonald E, Freedman DM, Alexander BH, et al. Prescription diuretic use and risk of basal cell carcinoma in the nationwide U.S. radiologic technologists’ cohort. Cancer Epidemiol Biomarkers Prev 2014;23:1539–45. https://doi.org/10.1158/10559965.EPI-14-0251; PMID: 24812037. 32. Robinson SN, Zens MS, Perry AE, et al. Photosensitizing agents and the risk of non-melanoma skin cancer: a population-based case-control study. J Invest Dermatol 2013;133:1950–5. https:// doi.org/10.1038/jid.2013.33; PMID: 23344461. 33. Kaae J, Boyd HA, Hansen AV, et al. Photosensitizing medication use and risk of skin cancer. Cancer Epidemiol Biomarkers Prev 2010;19:2942–9. https://doi.org/10.1158/1055-9965.EPI-100652; PMID: 20861398. 34. de Vries E, Trakatelli M, Kalabalikis D, et al. Known and potential new risk factors for skin cancer in European populations: a multicenter case-control study. Br J Dermatol 2012;167(Suppl 2):1–13. https://doi.org/10.1111/ j.1365-2133.2012.11081.x; PMID: 22881582. 35. Ruiter R, Visser LE, Eijgelsheim M, et al. High-ceiling diuretics are associated with an increased risk of basal cell carcinoma in a population-based follow-up study. Eur J Cancer 2010;46:2467–72. https://doi.org/10.1016/j.ejca.2010.04.024; PMID: 20605443. 36. Jensen A, Thomsen HF, Engebjerg MC, et al. Use of photosensitizing diuretics and risk of skin cancer: a population-based case-control study. Br J Cancer 2008;99:1522–8. https://doi.org/10.1038/sj.bjc.6604686; PMID: 18813314. 37. Schmidt SA, Schmidt M, Mehnert F, et al. Use of antihypertensive drugs and risk of skin cancer. J Eur Acad Dermatol Venereol 2015;29:1545–54. https://doi.org/10.1111/ jdv.12921; PMID: 25640031. 38. Gandini S, Palli D, Spadola G, et al. Anti-hypertensive drugs and skin cancer risk: a review of the literature and meta-analysis. Crit Rev Oncol Hematol 2018;122:1–9. https://doi.org/10.1016/j. critrevonc.2017.12.003; PMID: 29458778. 39. Shin D, Lee ES, Kim J, et al. Association between the use of thiazide diuretics and the risk of skin cancers: a meta-analysis of observational studies. J Clin Med Res 2019;11:247–55. https://doi.org/10.14740/jocmr3744; PMID: 30937114. 40. Kreutz R, Algharably EAH, Douros A. Reviewing the effects of thiazide and thiazide-like diuretics as photosensitizing drugs on the risk of skin cancer. J Hypertens 2019;37:1950–8. https:// doi.org/10.1097/HJH.0000000000002136; PMID: 31145177. 41. Bendinelli B, Masala G, Garamella G, et al. Do thiazide diuretics increase the risk of skin cancer? A critical review of the

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

scientific evidence and updated meta-analysis. Curr Cardiol Rep 2019;21:92. https://doi.org/10.1007/s11886-019-1183-z; PMID: 31352643. Faconti L, Ferro A, Webb AJ, et al. Hydrochlorothiazide and the risk of skin cancer. A scientific statement of the British and Irish Hypertension Society. J Hum Hypertens 2019;33:257–8. https://doi.org/10.1038/s41371-019-0190-2; PMID: 30842544. European Medicines Agency. Pharmacovigilance Risk Assessment Committee (PRAC): Minutes of the meeting on 03-06 September 2018. Brussels: EMA, 2018. https://www.ema.europa.eu/en/ events/pharmacovigilance-risk-assessment-committee-prac-36-september-2018 (accessed 7 April 2020). Arrieta O, Pineda-Olvera B, Guevara-Salazar P, et al. Expression of AT1 and AT2 angiotensin receptors in astrocytomas is associated with poor prognosis. Br J Cancer 2008;99:160–6. https://doi.org/10.1038/sj.bjc.6604431; PMID: 18594540. Lindberg H, Nielsen D, Jensen BV, et al. Angiotensin converting enzyme inhibitors for cancer treatment? Acta Oncol 2004;43:142–52. https://doi.org/10.1080/02841860310022346; PMID: 15163162. Lonati C, Morganti A. Are the antagonists of the reninangiotensin system also anticancer agents? High Blood Press Cardiovasc Prev 2015;22:99–102. https://doi.org/10.1007/ s40292-014-0059-y; PMID: 24916368. Volpe M, Azizi M, Danser AH, et al. Twisting arms to angiotensin receptor blockers/antagonists: the turn of cancer. Eur Heart J 2011;32:19–22. https://doi.org/10.1093/eurheartj/ ehq382; PMID: 20965885. Hu LD, Zou HF, Zhan SX, et al. EVL (Ena/VASP-like) expression is up-regulated in human breast cancer and its relative expression level is correlated with clinical stages. Oncol Rep 2008;19:1015–20. https://doi.org/10.3892/or.19.4.1015; PMID: 18357390. Cruciat CM, Ohkawara B, Acebron SP, et al. Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science 2010;327:459–63. https://doi.org/10.1126/science.1179802; PMID: 20093472. Soto-Pantoja DR, Menon J, Gallagher PE, et al. Angiotensin-(1-7) inhibits tumor angiogenesis in human lung cancer xenografts with a reduction in vascular endothelial growth factor. Mol Cancer Ther 2009;8:1676–83. https://doi. org/10.1158/1535-7163.MCT-09-0161; PMID: 19509262. McMurray J, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting enzyme inhibitors: the CHARM-Added Trial. Lancet 2003;362:767–71. https://doi.org/10.1016/S01406736(03)14283-3; PMID: 13678869. Sipahi I, Debanne SM, Rowland DY, et al. Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol 2010;11:627–36. https://doi. org/10.1016/S1470-2045(10)70106-6; PMID: 20542468. ARB Trialists Collaboration. Effects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancers in 15 trials enrolling 138,769 individuals. J Hypertens 2011;29:623–35. https://doi.org/10.1097/HJH.0b013e328344a7de; PMID: 21358417. Bangalore S, Kumar S, Kjeldsen SE, et al. Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324,168 participants from randomised trials. Lancet Oncol 2011;12:65–82. https://doi.org/10.1016/ S1470-2045(10)70260-6; PMID: 21123111. Rao GA, Mann JR, Shoaibi A, et al. Angiotensin receptor blockers: are they related to lung cancer? J Hypertens 2013;31:1669–75. https://doi.org/10.1097/ HJH.0b013e3283621ea3; PMID: 23822929. Zhao YT, Li PY, Zhang JQ, et al. Angiotensin II receptor blockers and cancer risk: a meta-analysis of randomized controlled trials. Medicine (Baltimore) 2016;95:e3600. https://doi. org/10.1097/MD.0000000000003600; PMID: 27149494. Hicks BM, Filion KB, Yin H, et al. Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study. BMJ 2018;363:k4209. https://doi.org/10.1136/bmj. k4209; PMID: 30355745.

Heart Failure

Contemporary Management of Secondary Mitral Regurgitation Kashish Goel, Colin M Barker and JoAnn Lindenfeld Vanderbilt Heart and Vascular Institute, Vanderbilt University School of Medicine, Nashville, TN, US

Abstract Secondary mitral regurgitation (SMR) is a common occurrence in patients with heart failure with reduced ejection fraction. Moderate-severe or severe SMR is associated with increased mortality and hospitalisations from heart failure. Medical and cardiac resynchronisation therapies have been the only treatments proven to improve prognosis in this patient population. The Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy (COAPT) and the Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR) RCTs evaluated transcatheter mitral valve repair with MitraClip for treatment of SMR in addition to medical therapy and they had divergent results. The COAPT trial demonstrated that a reduction in SMR with MitraClip resulted in reduced mortality and heart failure hospitalisations along with improved symptoms and quality of life in appropriately selected patients. The MITRA-FR trial did not show any benefit from using MitraClip for patients with SMR. This article summarises the differences in these two trials and suggests a contemporary approach to the management of SMR.

Keywords Heart failure, secondary mitral regurgitation, mitral regurgitation, functional mitral regurgitation, MitraClip, COAPT, MITRA-FR, randomised controlled trials Disclosure: CMB is on the advisory board of Medtronic and Boston Scientific. JL has been a consultant for Abbott, Edwards Lifesciences, Relypsa, BoehringerIngelheim, CVRx, Impulse Dynamics, Novartis and V-Wave, and has received grants from AstraZeneca. KG has no conflicts of interest to declare. Received: 2 July 2019 Accepted: 20 January 2020 Citation: European Cardiology Review 2020;15:e22. DOI: https://doi.org/10.15420/ecr.2019.08 Correspondence: JoAnn Lindenfeld, Vanderbilt Heart and Vascular Institute, 1215 21st Ave South, South Tower, 5209, Nashville, TN, US. E: joann.lindenfeld@vumc.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Heart failure (HF) is a growing epidemic, with an estimated 6.2 million adults (≥20 years) affected between 2013 and 2016 in the US.1 The prevalence is increasing and is expected to reach 8 million by 2030.1 Mitral regurgitation (MR) is common in HF patients, especially in those with ischaemia, left ventricular (LV) dysfunction or dilated cardiomyopathy. MR in the absence of structural abnormalities of the mitral valve complex is called functional or secondary MR (SMR) as the problem lies with the ventricle. SMR is the most common form of MR and in 2011 its prevalence was reported to be 16,250 per 1 million in the US population – a total of 5.2 million people.2 It creates a vicious cycle of worsening HF and SMR – volume overload and dilated left ventricle (from HF) results in a dilated mitral annulus and tethered mitral leaflets (severe SMR), which in turn causes more HF. This cycle can be interrupted in several ways: • • • •

Medical therapy. Transcatheter mitral valve repair with MitraClip (Abbott). Heart transplantation or LV assist device (LVAD). Surgical intervention.

In a meta-analysis of 53 studies and 45,900 patients, the presence of SMR was associated with an increased risk of cardiac mortality, HF, hospitalisations, transplant or death.3 In this article, we discuss the aetiology, diagnosis and management of SMR in chronic HF.

Access at: www.ECRjournal.com

Aetiology of Secondary Mitral Regurgitation There can be multiple aetiologies of SMR in HF. They are usually related to the aetiology of HF, thus establishing HF as the primary basis of the disease. The aetiology of SMR includes: • Tethered leaflet(s) due to ischaemic cardiomyopathy: MI and ischaemic cardiomyopathy can lead to regional wall motion abnormalities, most commonly resulting in posterior leaflet tethering and anterior leaflet override. • Dilated annulus secondary to severe LV dysfunction and long-term LV ischaemic cardiomyopathy causing non-coaptation of mitral leaflets. • Dilated annulus from dilated non-ischaemic cardiomyopathy with a similar mechanism as the previous aetiology. • Papillary muscle dysfunction related to acute or chronic ischaemia secondary to coronary artery disease. • Dilated left atrium where severe enlargement of the left atrium can result in a dilated mitral annulus and SMR.

Diagnosis of Secondary Mitral Regurgitation The initial diagnosis of MR may be based on a physical examination. However, the systolic murmur can be low-pitched and may be missed in cases of SMR. Echocardiography is the gold standard for the diagnosis of MR. It also helps to quantify the degree of MR based on established criteria. According to the American Society of Echocardiography, severe MR is consistent with: vena contracta

MitraClip in Heart Failure width ≥0.7 cm; effective regurgitant orifice area (EROA) ≥0.4 cm2; regurgitant volume (RVol) ≥60 ml; and regurgitant fraction (RF) ≥50%.4 The severity of MR is classified in grades as mild (1+), moderate (2+), moderate-severe (3+) or severe (4+). Moderate-severe or 3+ MR is defined by an EROA of 0.30–0.39 cm2, RVol of 45–59 ml and RF 40–49%. The measurement of these parameters is difficult and requires experience and time. It can also be limited by measurement errors related to the patient’s body size and build. If there is discrepancy between the echocardiographic results and the patient’s presentation and physical exam, other modalities such as transoesophageal echocardiogram, cardiac MRI or left ventriculography can be used to determine SMR severity.

Management of Secondary Mitral Regurgitation Medical therapy Medical therapy is the mainstay of treatment in patients with HF with reduced ejection fraction (HFrEF) including those with SMR. In a recent study of 163 consecutive patients with HFrEF (left ventricular ejection fraction [LVEF] <40%) and grade 3–4+ SMR who received maximally tolerated guideline-directed medical therapy (GDMT), SMR was assessed at baseline and after a median follow-up period of 50 months. Of the 31% (n=50) of the total group who had severe SMR at baseline, 38% improved to non-severe SMR (≤2+), while 18% of the non-severe participants progressed to severe SMR. Severe SMR, whether it was sustained or developed from non-severe SMR, was the most important independent prognostic determinant of major adverse cardiac events (defined as a composite of all-cause death and the need for heart transplantation or hospitalisation for HF and/or malignant arrhythmias), with an adjusted OR 2.5 (95% CI [1.5–4.3], major adverse cardiac events 83% versus 43%).5 In a subanalysis of the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional MR (COAPT) trial involving the 614 participants who presented with 3+ or 4+ MR at the start of the study, a reduction in SMR to <2+ was seen in 34% of those who were given GDMT.6 According to the American Heart Association (AHA)/American College of Cardiology (ACC) valve guidelines, GDMT is the first-line therapy for HFrEF and SMR (Figure 1) and the only Class I indication for treatment of SMR.7 GDMT includes:

Surgical Intervention Surgical intervention for SMR has been tested in randomised controlled trials (RCTs) by the Cardiothoracic Surgical Trials Network (CTSN). The first CTSN trial compared mitral valve repair versus replacement in 251 patients with severe ischaemic SMR. The investigators reported that mitral valve repair was associated with a significantly higher rate of recurrent moderate or severe MR (58%) as compared with mitral valve replacement (3.8%) at 2 years, resulting in more HF and cardiovascular hospitalisations. The LV end-systolic volume index (LVESVI) or LVEF were not significantly different during follow-up. Similarly, there was no significant difference in rates of all-cause mortality and major adverse cardiac or cerebrovascular events (MACCE) between repair and replacement groups.9 The second CTSN trial compared coronary artery bypass surgery (CABG) alone with CABG plus mitral valve repair in 301 patients with coronary artery disease and moderate SMR. The LVESVI and LVEF were similar in the two groups at 2-year follow-up. Moderate or severe MR was significantly higher in the CABG alone group (32.3%) compared with CABG plus mitral repair (11.2%). All-cause mortality, MACCE or rates of readmission and cardiovascular readmission were similar between the groups. The combined group had a higher rate of early neurological events, probably related to longer cross-clamp times and supraventricular arrhythmias.10 The AHA/ACC valve guidelines give a Class IIb indication for mitral valve surgery in patients with isolated severely symptomatic moderate-severe or severe SMR.11 However, none of these trials compared cardiac surgery to GDMT and these trials did not involve optimisation of medical therapy by HF specialists. Therefore, the role of cardiac surgery in isolated SMR remains uncertain. In patients undergoing CABG or another cardiac surgery, mitral valve surgery is considered reasonable for SMR (US guidelines – Class IIa; European guidelines – Class I [LVEF >30%] and Class IIa [LVEF ≤30%]).11,12

Transcatheter Mitral Valve Repair with MitraClip Transcatheter edge-to-edge repair of the mitral valve with MitraClip has emerged as a catheter-based intervention for the treatment of SMR. This was recently evaluated in two clinical trials, Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR) and COAPT, with different results.

MITRA-FR Trial • beta-blockers to reduce risk of HF hospitalisations and mortality; • angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) to reduce risk of HF hospitalisations and mortality; • angiotensin-receptor-neprilysin inhibitors (ARNI) to replace ACEI or ARB to reduce risk of HF hospitalisations and mortality; • mineralocorticoid receptor antagonists for mortality reduction; • hydralazine-nitrates in African-Americans for mortality reduction; • ivabradine to reduce risk of HF hospitalisations; and • diuretics to reduce congestion. In addition to pharmacological management, cardiac resynchronisation therapy (CRT) should be considered in patients with New York Heart Association (NYHA) Class II–IV HF, LVEF ≤35%, normal sinus rhythm and left bundle branch block with QRS >150 ms. In these patients, CRT can also facilitate LV reverse remodelling and reduce associated SMR.8 Early involvement of HF teams is essential for quick optimisation of therapy in patients with SMR and HF. If medical therapy fails, other interventions can be considered depending on the patient’s condition.

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The MITRA-FR trial was a multicentre, randomised, open-label clinical trial of transcatheter mitral valve repair with MitraClip versus medical therapy in symptomatic patients with SMR conducted in France.13 Key inclusion criteria were: severe MR defined as an EROA >20 mm2 or RVol >30 ml/beat; ejection fraction (EF) 15–40%, at least one HF hospitalisation in the last year and patients were ineligible for surgery. Of the 452 screened patients, 304 patients were randomised 1:1 to MitraClip versus medical therapy. The mean age of the participants was 70 years, 60% had ischaemic cardiomyopathy, two-thirds had NYHA III–IV HF at baseline. The mean LVEF was 33%, mean EROA was 0.31 cm2, mean LV end-diastolic volume (LVEDV) index was 135 ml/m2 and mean regurgitant volume was 45 ml. Medical therapy was optimised by the local investigators. The majority of the patients were on loop diuretics, beta-blockers and ACEI/ARB/ ARNI. CRT was present in 30% of the patients in the MitraClip arm compared with 23% of the control arm. Of the 152 patients in the MitraClip arm, 14 patients did not undergo MitraClip implantation. The reasons for this included: operator unable to grasp the mitral valve

Heart Failure Figure 1: Guideline-directed Medical Therapy in Heart Failure with Reduced Ejection Fraction

Step 1 Establish diagnosis of HFrEF, assess volume, initiate GDMT

HFrEF NYHA class I–IV (Stage C)

Step 2 Consider the following patient scenarios

Step 3 Implement indicated GDMT. Choices are not mutually exclusive and no order is inferred

NYHA class II–IV, provided established CrCI >30 ml/min and K+<5 mEq/l

Aldosterone antagonist (COR I)

NYHA class II–III HF Adequate BP on ACEI or ARB; no contraindications to ARB or sacubitril

Discontinue ACEI or ARB, initiate ARNI (COR I)

Step 4 Reassess symptoms

Step 5 Consider additional therapy

Palliative care† (COR 1)

Transplant (COR 1) NYHA class III–IV in black patients ACEI or ARB AND GDMT beta-blocker; diuretics as needed (COR I)

Hydral-nitrates*,†

NYHA class II–III, LVEF ≤35%; (caveat >1 year survival, >40 days post MI)

ICD† (COR I)

NYHA class II–IV, LVEF ≤35%; NSR and QRS ≥150 ms with LBBB pattern

CRT or CRT-D† (COR I)

NYHA class II–III, NSR, heart rate ≥70 BPMon maximally tolerated dose beta-blocker

Ivabradine (COR IIa)

Refractory NYHA class III–IV (Stage D)

Symptoms improved

LVAD† (COR IIa)

Investigational studies‡

Continue GDMT with serial reassessment and optimised dosing/adherence *Hydral-nitrates box: The combination of ISDN/HYD with ARNI has not been robustly tested. BP response should be carefully monitored. †See Yancy et al.19 ‡Participation in investigational studies is also appropriate for stage C, NYHA class II and III HF. ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; BP = blood pressure; COR = Class of recommendation; CrCl = creatinine clearance; GDMT = guideline-directed medical therapy; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; LBBB = left bundle-branch block; LVAD = left ventriclular assist device; LVEF = left ventricle ejection fraction; NSR = normal sinus rhythm; NYHA = New York Heart Association. Source: Yancy et al. 2017.7 Adapted with permission from the American College of Cardiology Foundation, the American Heart Association and the Heart Failure Society of America.

leaflets (n=3), cardiac tamponade (n=2), cardiogenic shock (n=1), and ‘not attempted’ due to other reasons (n=8). Technical success was achieved in 96% of the patients with MitraClip implantation. At discharge, 91.9% of these patients had MR grade <2+. The primary endpoint of all-cause mortality or unplanned HF hospitalisation was similar in the MitraClip (54.6%) and control arms (51.3%; OR 1.16; 95% CI [0.73–1.84]). The results were similar in most of the major sub-groups such as LVEF <30% or >30%, EROA of <0.3 cm2, 0.3–0.4 cm2 or >0.4 cm2. While the group with an EROA >0.4 cm2 did not demonstrate a statistically significant benefit, the hazard ratio was 0.5 in favour of the MitraClip group, albeit with wide confidence intervals due to the small number of participants in that subgroup. All-cause mortality (24.3% versus 22.4%) and HF hospitalisation (48.7% versus 47.4%) were also similar in the device versus control arm, respectively. In the patients with available echo data during follow-up (n=89), there were no significant changes in end-diastolic volume, end-diastolic diameter, end-systolic volume, end-systolic diameter or LVEF. Recently published 2-year data showed similar results with no difference in allcause mortality (33.9% versus 35%), cardiovascular death (31.2%

versus 32.1%), unplanned HF hospitalisation (58.7% versus 63.5%) or the combined endpoint of all-cause mortality and HF hospitalisation (64.2% versus 68.6%). Additional follow-up to 2 years was available in all patients who were still alive and shows the consistency of previously published 1-year findings. Of note, the rate of first HF hospitalisation was lower in the MitraClip arm between 1 and 2 years although this was not statistically significant.14 In summary, the authors conducted an RCT of MitraClip versus medical therapy in a group of patients with severe HF, large and dilated ventricles and less than severe MR (defined according to current guidelines). MitraClip did not affect survival or HF hospitalisations at 1 or 2 years in patients who met inclusion criteria of MITRA-FR trial.

COAPT The COAPT trial was a multicentre RCT in the US that randomised patients with symptomatic moderate–severe or severe MR to MitraClip and GDMT versus GDMT only.15 The trial randomised 614 patients over a period of 8 years and included 302 patients in the MitraClip arm and 312 patients in the GDMT arm. This final number of randomised patients (n=614) was increased from the initial target of

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MitraClip in Heart Failure Figure 2: Impact of MitraClip on Heart Failure Hospitalisations and All-cause Mortality in COAPT Trial All hospitalisations for HF 283 in 151 patients

MitraClip + GDMT

100

MitraClip + GDMT

GDMT alone

250

GDMT alone 80

200

160 in 92 patients

150

100

All-cause mortality (%)

Cumulative HF hospitalisations (n)

300

All-cause mortality

60 HR 0.62; 95% CI [0.46–0.82] p=0.0007; NNT 5.9 [3.9–11.7]

46.1%

40 29.1% 20

HR 0.53; 95% CI [0.40–0.70] p=0.000006; NNT 3.1 [1.9–7.9]

0 0

Time after randomisation (months)

GDMT = guideline-directed medical therapy; HF = heart failure; NNT = number needed to treat. Source: Stone et al. 2018.15 Adapted with permission from Massachusetts Medical Society.

420 patients due to a higher than expected mortality in both arms. Key inclusion criteria of this trial were: moderate–severe (3+) or severe (4+) MR confirmed by an echocardiography core laboratory, EF 20–50%, LV end-systolic dimension ≤70 mm, at least one HF hospitalisation in the last year and/or elevated B-type natriuretic peptide (BNP) >300 pg/ml adjusted for BMI, and not a candidate for mitral valve surgery at the enrolling centre. Patients with ACC/AHA stage D HF, haemodynamic instability requiring inotropic or mechanical circulatory support, evidence of right-sided congestive HF with moderate/severe right ventricular dysfunction and pulmonary artery systolic pressure >70 mmHg were excluded. The mean age of participants was 72 years, 64% were men and 61% had ischaemic cardiomyopathy. Mean values for echocardiographic data were 101 ml/m2 for LVEDV index, 31% for LVEF, 6.2 cm for LVESD and 0.41 cm2 for EROA. The surgical risk was not high in one-third of the patients. The Society of Thoracic Surgeons (STS) score for the risk of death within 30 days after mitral-valve replacement was 7.8% in MitraClip arm versus 8.5% in GDMT arm. NYHA class II HF was present in 39% of the patients and NYHA class III was present in 52% of the patients. The percentage of patients on diuretics, ACEI, ARB or ARNI, and beta-blockers was similar to the MITRA-FR trial, however exact dosages were not available for comparison. MitraClip was not attempted in six patients. Of the 293 undergoing MitraClip, technical success was achieved in 98% of the patients. At discharge, 82% had <1+ MR and 12.7% has ≤2+ MR. The MR grade was ≤2+ in 92.7% patients at 30 days, 93.8% at 6 months, 94.8% at 1 year and 99.1% at 2 years. The primary endpoint of all HF hospitalisations at 2 years was significantly reduced with MitraClip (35.8%) compared with GDMT alone (67.9%; HR 0.53; 95% CI [0.40–0.70]), translating into a number needed to treat (NNT) of 3.1. (Figure 2). All-cause mortality was also significantly reduced at 2 years with MitraClip versus GDMT (29.1% versus 46.1%; HR 0.63; CI 95% [0.46–0.82] – NNT 5.9). The results were similar in all the pre-specified subgroups based on age, sex, LVEF, LVEDV and surgical risk. The incidence of LVAD or heart transplant was significantly lower in the device arm compared with GDMT alone (4.4%

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versus 9.5%). All other secondary endpoints such as MR grade reduction, quality of life and NYHA class were significantly lower in the MitraClip group. The mean LVEDV increased by 17.1 ml in the control arm compared with a reduction of 5.1 ml in patients receiving the MitraClip (p<0.001). In summary, this large randomised trial reported that MitraClip reduced the rate of HF hospitalisations and all-cause mortality and improved 6-minute walk distance and quality of life in patients with moderate-severe or severe SMR who were carefully screened to determine that they were taking maximally tolerated GDMT. A recent sub-analysis of the COAPT data showed that reduction of MR to ≤2+ by either MitraClip plus GDMT or GDMT alone was associated with a significant reduction in risk of HF hospitalisation or all-cause mortality compared with MR ≥3+ (73.5%). There was no significant difference in this combined outcome between 0/1 (38.6%) and 2+ (49.8%) MR groups. At 30 days, 92.7% of the patients in the MitraClip arm had ≤2+ MR compared with 34.3% patients in the GDMT alone arm. In the MitraClip arm, the reduction in MR grade was stable at 2 years follow-up but in the GDMT alone group with ≤2+ MR at 30 days, an increase in degree of MR to ≥2+ was noted in 30% at 1 year and 66.7% at 2 years, emphasising the importance of close follow-up, early recognition and early treatment with MitraClip in patients who initially get better with GDMT alone.6

Consolidation of Data MITRA-FR and COAPT trials randomised patients with SMR and HF to transcatheter mitral valve repair with MitraClip or GDMT alone. However, the results of these two trials are completely different. This has created vigorous discussion and speculation about the role of MitraClip in SMR. Explanations for the differences in the results of these trials include the following considerations.

Baseline Characteristics Size of the Left Ventricle The left ventricle was significantly more dilated at baseline in the MITRA-FR trial (average LVEDV index 135 ml/m2) compared with the COAPT trial (average LVEDV index 101 ml/m2). These trials do not

Heart Failure Figure 3: Contemporary Management of Secondary Mitral Regurgitation

Figure 4: Echocardiographic Criteria for Diagnosis of Secondary Mitral Regurgitation

Symptomatic secondary MR (moderate-severe/severe/3+)

Secondary MR, severity 3+ or 4+ (graded by 1 of 3 criteria)

Optimisation of heart failure therapy (medications/CRT)

Medical management

Tier 1 EROA ≥0.3 cm2 or PV systolic

<Moderate MR Repeat TTE

Tier 3 EROA not measured or <0.2 cm2

Tier 2 EROA 0.2 cm2 <0.3 cm2 With any 1 of the following: • RV ≥45 ml/beat • RF ≥40% • VC width ≥0.5 cm

With at least 2 of the following: • RV ≥45 ml/beat • RF ≥40% • VC width ≥0.5 cm • PISA radius >0.9 cm But CW Doppler of MR jet not done • Large ≥6 cm holosystolic jet wrapping around LA • Peak E velocity ≥150 cm/s

Moderate-severe/severe MR

• Anatomically suitable leaflets • LVEF 20–50% • LVIDs <70 mm

• TMVR† • MVR • LVAD/Tx

MitraClip* *Food and Drug Administration approved † In clinical trials. CRT = cardiac resynchronisation therapy; LVAD/Tx = left ventricular assist device/heart transplant; LVEF = left ventricle ejection fraction; LVIDs = left ventricle internal diameter (systolic); MR = mitral regurgitation; MVR = mitral valve replacement; TMVR = transcatheter mitral valve replacement; TTE = transthoracic echocardiogram.

provide a specific cut-off for clinical use. The impact of percutaneous mitral valve repair with MitraClip in patients with extremely large left ventricles and severe MR is unclear and needs further assessment. Based on the available data, using the COAPT criteria of LVESD <70 mm and EF >20% can be used as a starting point until more data is available.

Grade of Mitral Regurgitation Prior to MitraClip Placement The mean EROA was 0.31 cm2 in the MITRA-FR trial compared with 0.41 cm2 in the COAPT trial. It can be postulated from the results of these trials that patients with a lower degree of MR may not benefit from this therapy as the change from pre-procedure to post-procedure will be less. In the COAPT trial, 255 patients were ineligible after initial screening because echocardiography criteria were not met which highlights the rigorous criteria for the trial.

The Hypothesis of More Benefit in ‘Disproportionate Versus Proportionate’ SMR A widely discussed hypothesis that combines LV dysfunction as estimated by the LVEDV and the severity of the SMR using the EROA was proposed shortly after the publication of the two trials. The idea is that at any given LVEF and RV, SMR that is more severe than explained by the LV dysfunction is ‘disproportionate’ and is likely to respond to MitraClip therapy while proportionate SMR is not.16

*Percentage of patients in each tier in the COAPT trial: Tier 1 n=570 (85.7%); Tier 2 n=70 (10.5%); Tier 3 n=25 (3.8%) CW = continuous wave; EROA = effective regurgitant orifice area; MR = mitral regurgitation; PISA: Proximal isovelocity surface area; PV = pulmonary vein; RF = regurgitant fraction; RV = regurgitant volume; VC = vena contracta. Source: Asch et al. 2019.17 Adapted with permission from Elsevier.

Procedural Characteristics Procedural Complications Procedural complications, including device implant failure, transfusion or vascular complication requiring surgery, atrial septal defect, cardiogenic shock, thromboembolism/stroke, tamponade or urgent surgery were reported in 14.6% of the patients in MITRA-FR. Devicerelated complications including thromboembolism, tamponade, vascular surgery, or urgent conversion to surgery occurred in 6.5% of patients. In COAPT, device-related complications were defined as any occurrence of single-leaflet device attachment, embolisation of the device, endocarditis that led to surgery, mitral stenosis (as confirmed by the echocardiographic core laboratory) that led to mitral valve surgery, implantation of a LV assist device, heart transplantation, or any other device-related event that led to non-elective cardiovascular surgery occurred in 3.4%.

Effectiveness of Mitral Regurgitation Reduction Post-procedure ≥3+ MR was present in 9% of the MITRA-FR patients versus 5% of the COAPT patients. At 1 year, this was 17% versus 5%, respectively. Residual MR ≥3+ is independently associated with increased mortality and HF hospitalisations, and the consistent results in COAPT may explain better outcomes.

Post-procedural Characteristics Consistency of Mitral Regurgitation Reduction As stated above, reduced prevalence of 3+ MR in the MitraClip arm during follow-up in the COAPT trial may explain better long-term outcomes.

Optimisation of Medical Therapy The percentage of patients on GDMT was high and very similar in both the trials, however the exact dosages were not available. In the COAPT trial, two HF specialists shared the role of primary investigator and an HF expert was involved at each enrolling site for optimisation of medical therapy.15 On the other hand, local team members were asked to optimise HF as per ‘real world’ practice in the MITRA-FR trial.13 As optimised GDMT has a significant impact on mortality and hospitalisations, optimisation of GDMT before the procedure may have affected the results.

Close Follow-up with Heart Failure Close follow-up with the HF team may have helped with further uptitration of GDMT in the COAPT trial. Further substudies from the COAPT trial will help answer this question.

Management of Secondary Mitral Regurgitation in the Contemporary Era SMR is a growing problem and results in increased morbidity and mortality. Early recognition and treatment are the key elements in its

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MitraClip in Heart Failure Figure 5: Reduction in All-cause Mortality with Current Therapies for Heart Failure

% Decrease in mortality

ACEI or ARB

Sacubitril/ Betavalsartan blockers

Mineralocortid receptor Hydralazine antagonists isordil

ICD

CRT

MitraClip

determine the need for treatment as these are recorded at rest and may be higher with exercise. • Consultation with an interventional/structural cardiologist to determine the candidacy for MitraClip. • Optimisation with IV diuretics before and after the MitraClip. • Continued follow-up with an HF specialist for management of HF.

10%

20% 30% 40%

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CRT = cardiac resynchronisation therapy.

Although there were only modest increases in GDMT in the MitraClip group compared with GDMT alone in COAPT due to the protocol instructions, it is quite likely that many patients who undergo transcatheter mitral valve repair with MitraClip will be able to tolerate higher doses of GDMT that were not previously tolerated. This would parallel the situation following CRT where the ability to up-titrate GDMT has been associated with significantly improved outcomes.18

Conclusion management. The following steps may help optimise the management of these patients (Figure 3): • Meticulous assessment of the mitral valve in patients with HFrEF with both quantitative and qualitative assessment of MR. All echocardiograms should report the LVEDV, EROA, RVol and RF, which will help the general cardiologist recognise the need for treatment. The echocardiographic algorithm reported by Asch et al. at the 2019 ACC meeting is likely to become the standard for assessment (Figure 4).17 • Involvement of HF team or specialists early in the care of these patients. Optimisation of medical therapy including the need for CRT is important, ideally on an outpatient basis with close follow-up. • Right and left heart catheterisation to assess the filling pressures after medical optimisation. However, filling pressures should not

Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics – 2019 update: a report from the American Heart Association. Circulation 2019;139:e56–528. https://doi. org/10.1161/CIR.0000000000000659; PMID: 30700139. de Marchena E, Badiye A, Robalino G, et al. Respective prevalence of the different carpentier classes of mitral regurgitation: a stepping stone for future therapeutic research and development. J Card Surg 2011;26:385–92. https://doi.org/10.1111/j.1540-8191.2011.01274.x; PMID: 21793928. Sannino A, Smith RL, Schiattarella GG, et al. Survival and cardiovascular outcomes of patients with secondary mitral regurgitation: a systematic review and meta-analysis. JAMA Cardiol 2017;2:1130–9. https://doi.org/10.1001/ jamacardio.2017.2976; PMID: 28877291. Zoghbi WA, Adams D, Bonow RO, et al. Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr 2017;30:303–71. https://doi. org/10.1016/j.echo.2017.01.007; PMID: 28314623. Nasser R, Van Assche L, Vorlat A, et al. Evolution of functional mitral regurgitation and prognosis in medically managed heart failure patients with reduced ejection fraction. JACC Heart Fail 2017;5:652–9. https://doi.org/10.1016/j. jchf.2017.06.015; PMID: 28859754. Kar S, Mack MJ, Lindenfeld JA, et al. Relationship between residual mitral regurgitation and clinical and functional outcomes in the COAPT trial. Presented at EuroPCR, 21 May 2019, Paris, France. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the

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10.

11.

12.

13.

Transcatheter mitral valve repair with MitraClip is the new gold standard for treatment of SMR. Based on the COAPT trial data, the relative reduction in all-cause mortality with MitraClip is the highest of all the available therapies including medications or CRT as shown in Figure 5. It has proven that correction of SMR in HFrEF with MitraClip reduces mortality, reduces HF hospitalisations and improves quality of life, NHYA class and 6-minute walk distance. Patient selection is the key to identify those who will benefit the most from this therapy. Patients with large dilated left ventricles, ≤3+ MR, severe irreversible pulmonary hypertension, severe right ventricular dysfunction, or those on inotropic support may not benefit. It is important to remember that 29% of the patients in the MitraClip arm in COAPT had died by the 2-year follow-up, emphasising the high mortality associated with SMR. Therefore, we need to identify the factors that can help in early diagnosis and treatment and continue to enhance GDMT as allowed following the procedure.

management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2017;70:776–803. https://doi. org/10.1016/j.jacc.2017.04.025; PMID: 28461007. van Bommel RJ, Marsan NA, Delgado V, et al. Cardiac resynchronization therapy as a therapeutic option in patients with moderate-severe functional mitral regurgitation and high operative risk. Circulation 2011;124:912–9. https:// doi.org/10.1161/CIRCULATIONAHA.110.009803; PMID: 21810666. Goldstein D, Moskowitz AJ, Gelijns AC, et al. Two-year outcomes of surgical treatment of severe ischemic mitral regurgitation. N Engl J Med 2016;374:344–53. https://doi. org/10.1056/NEJMoa1512913; PMID: 26550689. Michler RE, Smith PK, Parides MK, et al. Two-year outcomes of surgical treatment of moderate ischemic mitral regurgitation. N Engl J Med 2016;374:1932–41. https://doi. org/10.1056/NEJMoa1602003; PMID: 27040451. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2438– 88. https://doi.org/10.1016/j.jacc.2014.02.537; PMID: 24603192. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739–91. https://doi.org/10.1093/eurheartj/ehx391; PMID: 28886619. Obadia JF, Messika-Zeitoun D, Leurent G, et al. Percutaneous repair or medical treatment for secondary mitral

regurgitation. N Engl J Med 2018;379:2297–306. https://doi. org/10.1056/NEJMoa1805374; PMID: 30145927. 14. Iung B, Armoiry X, Vahanian A, et al. Percutaneous repair or medical treatment for secondary mitral regurgitation: outcomes at 2 years. Eur J Heart Fail 2019;21:1619–27. https:// doi.org/10.1002/ejhf.1616; PMID: 31476260. 15. Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med 2018;379:2307–18. https://doi.org/10.1056/NEJMoa1806640; PMID: 30280640. 16. Grayburn PA, Sannino A, Packer M. Proportionate and disproportionate functional mitral regurgitation: a new conceptual framework that reconciles the results of the MITRA-FR and COAPT Trials. JACC Cardiovasc Imaging 2019;12:353–62. https://doi.org/10.1016/j.jcmg.2018.11.006; PMID: 30553663. 17. Asch FM, Grayburn PA, Siegel RJ, et al. Mitral regurgitation after MitraClip implantation in patients with heart failure and secondary mitral regurgitation: echocardiographic outcomes from the COAPT trial. Presented at American College of Cardiology 2019, New Orleans, LA, 16–18 March 2019. Abstract 404-11. 18. Martens P, Verbrugge FH, Nijst P, et al. Feasibility and association of neurohumoral blocker up-titration after cardiac resynchronization therapy. J Card Fail 2017;23:597–605. https:// doi.org/10.1016/j.cardfail.2017.03.001; PMID: 28284756. 19. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;128:e240–327. https://doi.org/10.1016/j. jacc.2013.05.019; PMID: 23747642.

COVID-19

Ethical Issues in Decision-making Regarding the Elderly Affected by Coronavirus Disease 2019: An Expert Opinion David Martínez-Sellés,1 Helena Martínez-Sellés2 and Manuel Martinez-Sellés2,3 1. School of Medicine, Autonomous University of Barcelona, Barcelona, Spain; 2. School of Medicine, Complutense University of Madrid, Madrid, Spain; 3. Cardiology Department, Gregorio Marañón University Hospital, CIBERCV, European University of Madrid, Madrid, Spain

Abstract The coronavirus disease 2019 (COVID-19) pandemic is resulting in ethical decisions regarding resource allocation. Prioritisation reflects established practices that regulate the distribution of finite resources when demand exceeds supply. However, discrimination based on sex, race or age has no role in prioritisation unless clearly justified. The risk posed by COVID-19 is higher for elderly people than for younger people, so older adults should be prioritised in preventive measures. In the case of people who already have COVID-19, healthcare professionals might prioritise those most likely to survive. Making decisions based on chronological age alone is not justified; in addition to age, other aspects that determine theoretical life expectancy must be taken into account. Individualised correct prioritisation in the allocation of scarce resources is essential to good clinical practice.

Keywords COVID-19, ethics, elderly, prioritisation, resources, age, life expectancy Disclosure: The authors have no conflicts of interest to declare. Received: 24 April 2020 Accepted: 27 April 2020 Citation: European Cardiology Review 2020;15:e48. DOI: https://doi.org/10.15420/ecr.2020.14 Correspondence: Manuel Martinez-Sellés, Servicio de Cardiología, Hospital Gregorio Marañón, Doctor Esquerdo 46, 28007 Madrid, Spain. E: mmselles@secardiologia.es Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Nearly every country is now affected by the coronavirus disease 2019 (COVID-19) pandemic. The disease is spreading rapidly and is taxing the global healthcare system, particularly intensive care units (ICUs). Physicians are faced with ethical decisions regarding the allocation of these precious resources, especially ventilators. Although only a few of those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) require admission to intensive care, the burden on healthcare systems is unprecedented. This article focuses on ethical issues in decision-making regarding COVID-19, particularly in the elderly. Madrid has been one of the cities with the higher number of COVID-19 cases and casualties so far. We have suffered from limited resources and lived with these ethical issues on a daily basis. Also, Spain is experiencing population ageing at a rate that is unprecedented in Europe and COVID-19 infection is particularly severe in the elderly.1,2

Prioritisation Prioritisation for the allocation of scarce resources is not confined to the COVID-19 outbreak. Transplant organs are examples of scarce resources where prioritisation criteria for allocation are common and physicians have to make a case-by-case evaluation in order to establish which patient receives the organ. Prioritisation reflects established practices that regulate the distribution of finite resources when demand happens to exceed supply. Discrimination based on sex, race or age has no role in prioritisation unless clearly

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justified, for example sex mismatch might influence the outcome of a heart transplant.3,4 Prioritisation does not mean that one life is more valuable than another, as all lives are equally valuable. When resources are insufficient to save all those in need, prioritisation means allocating the available assets in the most effective way. This method allows priority treatment of patients more likely to benefit from the scarce resource. Prioritisation should be as objective as possible but also flexible to changes in clinical situation. Transparent mechanisms to determine which patients will receive a specific resource are desirable and should be explained to patients who finally receive an organ, to those who are denied and to the public.

Ageism Ageism encompasses stereotyping, prejudice and discrimination against people on the basis of their age. Ageism is widespread and an insidious practice that has harmful effects on the health of older adults. A recent systematic review showed that the significant adverse relationship between ageism and health is even more consistent than the relationships found in systematic reviews of the effects of racism on health.5 Moreover, European doctors worry about the care they will receive when they are old, with 80% of healthcare professionals anxious about how they would be treated, suggesting they realise that ageism is very common.6 Paradoxically, increasing numbers of elderly people are remaining healthy and some of them have important

Ethical Issues: Elderly Affected by COVID-19 Figure 1: Queen Elizabeth II and Pope Francis

Queen Elizabeth II, aged 94, and Pope Frances, aged 83. Would they receive optimal management if they had severe COVID-19? Sources: Cubankite/Shutterstock.com and AM113/ Shutterstock.com.

international responsibilities. For instance, Pope Francis is now 83 years old and Queen Elizabeth II is 94 (Figure 1).

Table 1. Therapeutic Planning Checklist for Elderly Patients Admitted to Hospital due to COVID-19

COVID-19 and the Elderly

• Discuss the full therapeutic plan with the patient (and family members)

The risk posed by COVID-19 is higher for elderly people than for younger people.2 For this reason, medical and political authorities should offer older adults strict preventive measures to minimise the risk of exposure and infection. In the event that an effective vaccine for SARS-CoV-2 is developed, priority should be given to vaccination of the elderly, with the aim of maximising the number of lives saved. This is also true for other preventive measures, such as possible preor post-exposure prophylaxis.7 In the case of people with COVID-19, the situation is different. When allocating resources in these scenarios, healthcare professionals might prioritise those most likely to survive over those with remote chances of survival. Making a decision based on chronological age is not justified. In addition to age, other aspects that determine theoretical life expectancy must be taken into account. Biological age and the use of frailty scales and comprehensive geriatric assessment are essential for this purpose. The recent statement of the Executive Board of the European Geriatric Medicine Society insists that advanced age alone should not be a criterion for excluding patients from specialised hospital units.8 If an elderly patient is dismissed from a specialised hospital unit for any reason, access to medical attention, symptomatic treatment and palliative care must be ensured. This last point is essential, as palliative care is frequently suboptimal in elderly patients with other conditions, such as heart failure, and this is probably the case in COVID-19.2,9,10

Therapeutic Adaptation after COVID-19 Admission In patients with advanced age who are admitted to hospital due to a severe SARS-CoV-2 infection, it is very important to establish a therapeutic adaptation plan from the time of admission. This plan should be clearly documented in the clinical history, making it clear whether or not the patient is a candidate for mechanical ventilation and, in case of their condition worsening, when to propose the

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• Ask about advance directives • Identify any next of kin who might be involved in end-of-life decisions • Obtain relatives’ contact information (the more the better) • Include the therapeutic plan clearly in the clinical history • Assess and record whether or not the patient is a candidate for mechanical ventilation • Assess and record whether or not the patient is a candidate for cardiopulmonary resuscitation • Discuss the possibility of future withdrawal of life-sustaining therapies • Ask about religion/spiritual preferences

withdrawal of life-sustaining therapies (Table 1). Decisions that maximise survival to hospital discharge, the number of years of life saved and the possibility of living each of the stages of life can be prioritised. In this regard, patients with minimal expected benefit should not be admitted to ICU and the admission of patients with a life expectancy <1–2 years should be carefully evaluated. This applies to patients of all ages. A utilitarian mentality should be applied, which should prevent prejudice against the elderly. For example, a frail elderly patient might have a low chance of surviving the prolonged intubation required to recover from COVID-19 pneumonia, but this is also the case for young patients with severe comorbidities.11

The Madrid Experience During the peak of the outbreak, more than two-thirds of beds in most hospitals in Madrid were occupied by patients with COVID-19. Figure 2 depicts the official numbers of patients admitted to hospital, admitted to ICUs, who died and who recovered in Spain between midMarch and the middle of April.12 Non-invasive ventilation was attempted frequently, even using improvised alternative strategies like the modified Easybreath diving mask to administer continuous positive airway pressure therapy. Invasive ventilation was often

COVID-19 Figure 2: Official Daily Evolution of the Number of Patients Admitted to Hospital, Admitted to Intensive Care Units, who Died and who Recovered in Spain

therapies have been shown to be effective.15 Moreover, some of these drugs have frequent and potentially life-threatening side-effects, particularly in the elderly. Most are known to prolong the QT interval and can have a proarrhythmic effect.16

Confinement: Pros and Cons

Source: Ministerio de Sanidad et al. 2020.12

Figure 3: Confinement – the Stay-at-home Policy – has Positive and Negative Effects in Individuals of Advanced Age

Cons

Physical and psychological effect s Economic consequences

Pros

Reduce infection risk Win time

Wait for vaccine

necessary and, in spite of tremendous efforts by the hospitals (for example Gregorio Marañón University Hospital opened ICUs in operating rooms and in the library), there were not enough ICU beds for all the critically ill patients who needed them. The limited availability of ventilation support was even more problematic due to the prolonged intubation – often more than 3 weeks – that many of these patients required. The news that prioritisation criteria were being applied in Spanish hospitals sparked widespread controversy and triggered a debate about the right of every individual, particularly the elderly, to access specialised healthcare.13

Use of Off-label Therapies Effective therapies for this novel coronavirus are needed urgently and several clinical trials are now underway.14 Meanwhile, the use of use of off-label therapies based on in vitro data and early clinical experience with COVID-19 has increased dramatically; examples include remdesivir, lopinavir, ritonavir, interferon, chloroquine, hydroxychloroquine, azithromycin, tocilizumab, steroids and cyclosporine. To date, no

Confinement is an effective way to decrease SARS-CoV-2 transmission and is a way to win time until effective therapies are developed and/or an effective and safe vaccine is available. However, the stay-at-home policy has negative effects in those with advanced age (Figure 3). The psychological risk of confinement is particularly high among vulnerable populations, such as those in a situation of dependence or that live alone. The negative consequences are multifaceted, with physical, mental and social aspects. Staying at home for long periods of time facilitates sedentary behaviours and might worsen previous frailty or pre-frail conditions. At the time of writing this article, our parents/ grandparents (aged 82 and 78) have not left their home for 2 months. We are certainly concerned about their situation. Moreover, confinement is extremely negative for the economy and the elderly might end up suffering the consequences of a severe economic depression. Finally, the legal situation varies a lot from country to country. New laws have created legal frameworks that frequently restrict or prohibit the movement of people and vehicles. Some countries have severe penalties for those who do not comply with the new rules.

Family and Mourning The COVID-19 pandemic has isolated the elderly not only at home but also in hospitals. Visits are usually not permitted. Several patients of advanced age with severe infection have died alone in the hospital or in nursing homes. The suffering of the family does not end there, as containment measures also apply in the context of mourning, which adds trauma to that of death itself. Corpses are considered potentially infectious, so are deposited as soon as possible in a body bag that will never be reopened. During the peak of the outbreak in Madrid, we had so many deaths that an ice rink had to be used as a provisional morgue. It was frequently impossible for families to see their deceased loved ones one last time. The rules of social distancing put in place by the health authorities applies also at funerals. Services must be limited to close family members only (with a maximum of three people), usually with video recording and streaming for those who wish to attend the funeral from a distance. Finally, the vast majority of older people in Spain are Catholic. The fact that public masses have been cancelled makes the situation even more difficult for families.

Conclusion COVID-19 in elderly patients raises some ethical issues; however, most of these issues are similar to ethical problems in other conditions, such as heart failure.17–19 The correct prioritisation for the allocation of scarce resources should be based on various factors relating to the individual. Chronological age should not be the only factor that influences the decision-making process. This is essential to good clinical practice.

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Ethical Issues: Elderly Affected by COVID-19 1.

Foreman KJ, Marquez N, Dolgert A, et al. Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016–40 for 195 countries and territories. Lancet 2018;392:2052–90. https://doi.org/10.1016/S01406736(18)31694-5; PMID: 30340847. Bonanad C, García-Blas S, Tarazona-Santabalbina FJ, et al. Coronavirus: the geriatric emergency of 2020. Joint document of the Geriatric Cardiology Section of the Spanish Society of Cardiology and the Spanish Society of Geriatrics and Gerontology. Rev Esp Cardiol 2020 [in Spanish]. https://doi. org/10.1016/j.recesp.2020.03.027; PMID: 32292226; epub ahead of press. Ayesta A, Urrútia G, Madrid E, et al. Sex-mismatch influence on survival after heart transplantation: a systematic review and meta-analysis of observational studies. Clin Transplant 2019;33:e13737. https://doi.org/10.1111/ctr.13737; PMID: 31630456. Martinez-Selles M, Almenar L, Paniagua-Martin MJ, et al. Donor/recipient sex mismatch and survival after heart transplantation: only an issue in male recipients? An analysis of the Spanish Heart Transplantation Registry. Transpl Int 2015;28:305–13. https://doi.org/10.1111/tri.12488; PMID: 25399778. Chang ES, Kannoth S, Levy S, et al. Global reach of ageism on older persons’ health: a systematic review. PLoS One 2020;15:e0220857. https://doi.org/10.1371/journal. pone.0220857; PMID: 31940338. Torjesen I. European doctors worry about the care they will

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10.

11.

12.

13.

receive when they are old. BMJ 2012;344:e77. https://doi. org/10.1136/bmj.e77; PMID: 22228700. Emanuel EJ, Persad G, Upshur R, et al. Fair allocation of scarce medical resources in the time of COVID-19. N Engl J Med 2020. https://doi.org/10.1056/NEJMsb2005114; PMID: 32202722; epub ahead of press. European Geriatric Medicine. Statement of the EuGMS Executive Board on the COVID-19 epidemic. 2020. www.eugms.org/news/read/article/489.html (accessed 5 May 2020). García Pinilla JM, Díez-Villanueva P, Bover Freire R, et al. Consensus document and recommendations on palliative care in heart failure of the Heart Failure and Geriatric Cardiology Working Groups of the Spanish Society of Cardiology. Rev Esp Cardiol 2020;73:69–77. https://doi.org/10.1016/j. recesp.2019.06.024; PMID: 31761573. Sobanski PZ, Alt-Epping B, Currow DC, et al. Palliative care for people living with heart failure: European Association for Palliative Care Task Force expert position statement. Cardiovasc Res 2020;116:12–27. https://doi.org/10.1093/cvr/ cvz200; PMID: 31386104. Rosenbaum L. Facing Covid-19 in Italy – ethics, logistics, and therapeutics on the epidemic’s front line. N Engl J Med 2020. https://doi.org/10.1056/NEJMp2005492; PMID: 32187459; epub ahead of press. Ministerio de Sanidad. Daily evolution of COVID-19 in Spain. 2020. https://covid19.isciii.es/resources/CURVASTATUS.png (accessed 5 May 2020). Grupo de Trabajo de Bioética de la Sociedad Española

14.

15.

16.

17.

18.

19.

de Medicina Intensiva, Crítica y Unidades Coronarias (SEMICYUC). Recomendaciones éticas para la toma de decisiones en la situación excepcional de crisis por pandemia COVID-19 en las unidades de cuidados intensivos. 2020. https://semicyuc.org/wp-content/ uploads/2020/03/%C3%89tica_SEMICYUC-COVID-19.pdf (accessed 5 May 2020). Alpern JD, Gertner E. Off-label therapies for COVID-19. Are we all in this together? Clin Pharmacol Ther 2020. https://doi. org/10.1002/cpt.1862; PMID: 32311763; epub ahead of press. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. JAMA 2020. https://doi.org/10.1001/ jama.2020.6019; PMID: 32282022; epub ahead of press. Kochi AN, Tagliari AP, Forleo GB, et al. Cardiac and arrhythmic complications in patients with COVID-19. J Cardiovasc Electrophysiol 2020. https://doi.org/10.1111/jce.14479; PMID: 32270559; epub ahead of press. Charlier P. Covid-19 and some ethical issues in France. Ethics Med Public Health 2020:100510 [in French]. https://doi. org/10.1016/j.jemep.2020.100510; PMID: 32292810; epub ahead of press. Mannelli C. Whose life to save? Scarce resources allocation in the COVID-19 outbreak. J Med Ethics 2020. https://doi. org/10.1136/medethics-2020-106227; PMID: 32277018; epub ahead of press. Martínez-Sélles M, Díez Villanueva P, Smeding R, et al. Reflections on ethical issues in palliative care for patients with heart failure. European Journal of Palliative Care 2017;24:18–22.

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Contents

Dilated Cardiomyopathy Risk in Patients with Coronavirus Disease 2019: How to Identify and Characterise it Early? Maki Komiyama, Koji Hasegawa and Akira Matsumori DOI: https://doi.org/10.15420/ecr.2020.17

Contemporary Cardiac MRI in Chronic Coronary Artery Disease Michalis Kolentinis, Melanie Le, Eike Nagel and Valentina O Puntmann DOI: https://doi.org/10.15420/ecr.2019.17

Coronavirus Disease 2019 Myocarditis: Insights into Pathophysiology and Management Mahmoud Abdelnabi, Nouran Eshak, Yehia Saleh and Abdallah Almaghraby DOI: https://doi.org/10.15420/ecr.2020.16

Myocardial and Microvascular Injury Due to Coronavirus Disease 2019

Rocco A Montone, Giulia Iannaccone, Maria Chiara Meucci, Filippo Gurgoglione and Giampaolo Niccoli DOI: https://doi.org/10.15420/ecr.2020.22

Using Pharmacogenetic Testing to Tailor Warfarin Therapy: The Singapore Experience and What the Future Holds Grace Shu-wen Chang and Doreen Su-Yin Tan DOI: https://doi.org/10.15420/ecr.2019.12

Smoking and Angiotensin-converting Enzyme Inhibitor/Angiotensin Receptor Blocker Cessation to Limit Coronavirus Disease 2019 Marco Rossato and Angelo Di Vincenzo

DOI: https:/doi.org/10.15420/ecr.2020.20

Response to the Comment ‘Smoking and Angiotensin-converting Enzyme Inhibitor/Angiotensin Receptor Blocker Cessation to Limit Coronavirus Disease 2019 Maki Komiyama and Koji Hasegawa

DOI: https://doi.org/10.15420/ecr.2020.25

Assessing Atherosclerotic Cardiovascular Disease Risk with Advanced Lipid Testing: State of the Science Charles Amir German and Michael David Shapiro DOI: https://doi.org/10.15420/ecr.2019.18

Coronavirus Disease 2019 and Catheterisation Laboratory Considerations: “Looking for Essentials”

Syed Haseeb Raza Naqvi, Madiha Fatima, Fady Gerges, Sara Moscatelli, Tugba Kemaloglu Oz, Irina Kotlar, Nigar Babazade, Arash Hashemi and Abdallah Mostafa Almaghraby DOI: https://doi.org/10.15420/ecr.2020.29

Anticoagulant Therapy for Patients with Coronavirus Disease 2019: Urgent Need for Enhanced Awareness Maki Komiyama and Koji Hasegawa

DOI: https://doi.org/10.15420/ecr.2020.24

Treatment of Coronavirus Disease 2019: Shooting in the Dark Juan Tamargo

DOI: https://doi.org/10.15420/ecr.2020.21

The Role of Nocturnal Blood Pressure and Sleep Quality in Hypertension Management Francesco P Cappuccio

DOI: https://doi.org/10.15420/ecr.2020.13

The Impact of Ethnicity on Cardiac Adaptation Uchenna Ozo and Sanjay Sharma

DOI: https://doi.org/10.15420/ecr.2020.01

The Coronavirus Disease 2019 Outbreak Highlights the Importance of Sex-sensitive Medicine Angela HEM Maas and Sabine Oertelt-Prigione DOI: https://doi.org/10.15420/ecr.2020.28

What is the Real Message of the ISCHEMIA Trial from a Clinician’s Perspective? Islam Y Elgendy and Carl J Pepine

DOI: https://doi.org/10.15420/ecr.2020.27

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COVID-19

Dilated Cardiomyopathy Risk in Patients with Coronavirus Disease 2019: How to Identify and Characterise it Early? Maki Komiyama, Koji Hasegawa and Akira Matsumori Division of Translational Research, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

Abstract Multiple lines of evidence have shown that elevated blood troponin is strongly associated with poor prognosis in patients with the novel coronavirus disease 2019 (COVID-19). Possible mechanisms of myocardial injury in COVID-19 include ischaemia due to circulatory and respiratory failure, epicardial or intramyocardial small coronary artery thrombotic obstruction due to increased coagulability, and myocarditis caused by systemic inflammation or direct binding of the virus to its receptor, angiotensin-converting enzyme-2 (ACE2), which is abundantly expressed in the heart. It is postulated that persistent immune activation upon viral infection increases the risk of developing dilated cardiomyopathy in COVID-19 patients.

Keywords COVID-19, SARS-CoV-2, myocardial injury, troponin, myocarditis, cardiomyopathy, heart failure Disclosure: The authors have no conflicts of interest to declare. Received: 6 May 2020 Accepted: 6 May 2020 Citation: European Cardiology Review 2020;15:e49. DOI: https://doi.org/10.15420/ecr.2020.17 Correspondence: Koji Hasegawa, Division of Translational Research, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555, Japan. E: koj@kuhp.kyoto-u.ac.jp Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

The novel coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a public health emergency of international concern.1 The pandemic is ongoing, and the world is faced with the urgent task of minimising the mortality associated with COVID-19. Besides advanced age, risk factors for escalation of COVID-19 severity include underlying comorbidities, such as cardiovascular disease, diabetes, malignant neoplasm and chronic respiratory disease.2,3 Limited information is available on cardiac complications that can lead to fatal outcomes in patients with COVID-19. However, an increasing number of reports have shown that direct and indirect effects of SARS-CoV-2 on the heart are extremely important as prognostic determinants of COVID-19.5–7 Angiotensin-converting enzyme-2 (ACE2) is a membrane-associated aminopeptidase that inhibits the activation of the renin–angiotensin system and prevents the development of heart failure (HF), hypertension and diabetes.4 Moreover, ACE2 serves as a functional receptor for SARS-CoV-2, and COVID-19 is triggered by binding of the SARS-CoV-2 spike protein to ACE2. In addition to well-known mucosal epithelial cells in the respiratory tract and alveolar type II epithelial cells, ACE2 is highly expressed on the myocardium and vascular endothelium. Therefore, after entering the body, SARS-CoV-2 can damage the heart and vasculature as well as causing pneumonia. An increase in blood troponin levels (troponin I or troponin T) is an indicator of myocardial damage, and blood troponin measurements are widely used for the diagnosis of acute coronary syndrome (ACS). Several studies have documented a strong association between

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COVID-19 progression and elevated blood troponin.5–7 In hospitalised patients with COVID-19, mortality in the elevated blood troponin group was 51.2–59.6%, a range markedly higher than the 4.5–8.9% in the normal blood troponin group.5,6 The incidence of lethal arrhythmia increases during follow up in patients with COVID-19 and elevated blood troponin;3 therefore, patients with COVID-19 and elevated blood troponin should be provided with cardiac function/arrhythmia monitoring (ECG and N-terminal pro-brain natriuretic peptide measurement) during management, and it is important to appropriately triage such patients and design treatment strategies to address specific cardiac conditions. Patients with cardiovascular disease tend to have higher blood troponin levels than those without such disease. Moreover, even in patients without underlying cardiovascular disease, those with elevated blood troponin have a poor prognosis; therefore, an elevation in blood troponin may be a prognostic determinant in hospitalised patients with COVID-19. Further, elevated blood troponin T is associated with the use of ACE inhibitors/angiotensin II receptor blockers (ACEIs/ARBs; elevated troponin group, 21.1% versus normal troponin group, 5.9%; p=0.002).5 This association may be attributed to the high number of patients with HF or high blood pressure in the elevated troponin group, and the current data cannot be regarded as evidence for an association between ACEI/ARB use and fatal outcome in patients with COVID-19. ACEIs and ARBs, however, have been shown to have beneficial effects on experimental myocarditis.8,9 Nevertheless, the possibility that ACEIs/ ARBs increase the sensitivity to SARS-CoV-2 cannot be ruled out. Given that HF itself is a risk factor for severe COVID-19, careful follow-up for

Dilated Cardiomyopathy Risk and COVID-19 COVID-19 is warranted for patients with HF undergoing treatment with any ACEI/ARB. Information about the mechanism by which SARS-CoV-2 infection causes elevation in blood troponin levels, thereby indicating myocardial damage, remains unknown. Although various mechanisms can be postulated, the possible mechanisms are: • Ischaemia resulting from decreased myocardial oxygen supply because of respiratory failure/hypoxemia due to pneumonia and circulation insufficiency due to shock/low blood pressure. • Myocardial damage caused by the cytokine storm induced by the strong release of inflammatory cytokines and chemokines.10,11 • ACS due to the destabilisation/rupture of the atherosclerotic plaque or coronary spasm caused by the spread of inflammation to the coronary artery. • Obstruction of the myocardial small coronary arteries due to inflammation-induced enhancement of coagulation activity. • Cardiomyocyte damage/viral myocarditis caused by the direct binding of SARS-CoV-2 to cardiomyocytes. Regarding ACS, 18 patients with COVID-19 were found to have ST elevation on ECG.12 Nine of these patients were given coronary artery angiography; coronary obstruction was detected in six patients; the remaining three patients were considered to have non-coronaryobstructive myocardial damage. Of the nine patients who did not undergo angiography of the coronary artery, two were diagnosed with MI due to epicardial coronary artery obstruction based on ECG and echocardiography. The remaining seven patients were diagnosed with non-coronary artery-related myocardial injury. Overall, more than half of the patients with COVID-19 and ST elevation on ECG had noncoronary artery-related myocardial injury, and fewer than half of them had MI due to coronary artery thrombus. Thus, myocardial injury

WHO. Coronavirus disease (COVID-19) pandemic. https://www. who.int/emergencies/diseases/novel-coronavirus-2019 (accessed 9 May 2020). Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020;323:1239–42. https://doi.org/10.1001/jama.2020.2648; PMID: 32091533. European Centre for Disease Prevention and Control. Information on COVID-19 for specific groups: the elderly, patients with chronic diseases, people with immunocompromising condition and pregnant women. https://www.ecdc.europa.eu/en/news-events/informationcovid-19-specific-groups-elderly-patients-chronic-diseasespeople (accessed 9 May 2020). Lukassen S, Chua RL, Trefzer T, et al. SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. EMBO J 2020. https://doi. org/10.15252/embj.20105114; PMID: 32246845; epub ahead of press. Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID19). JAMA Cardiol 2020. https://doi.org/10.1001/ jamacardio.2020.1017; PMID: 32219356; epub ahead of press. Shi S, Qin M, Shen B, et al. Association of cardiac injury

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unrelated to epicardial coronary artery obstruction is frequent in COVID-19 patients. Moreover, elevated D-dimer levels were observed in all 18 patients, suggesting the relevance of the thrombotic occlusion of epicardial or intra-myocardial small coronary arteries as a mechanism of ST elevation. Nevertheless, 13 of these 18 patients died, and myocardial damage appears to be closely associated with poor prognosis regardless of the presence or absence of coronary obstruction. Currently, a high frequency of SARS-CoV-2 infection-induced myocarditis has not been observed. However, acute/fulminant myocarditis has been reported in individuals infected with SARS-CoV and Middle East respiratory syndrome CoV.13 Considering the pathogenic similarities, it can be predicted that SARS-CoV-2 can cause myocardial damage via direct and/or indirect effects.7 Moreover, growing indirect evidence of high ACE2 expression in the heart and elevated troponin in patients with severe COVID-19 suggests that SARS-CoV-2 infection can induce myocarditis.13 Although the aetiology of non-hereditary dilated cardiomyopathy has not yet been elucidated, viral genomes have been detected in myocardial tissue samples from patients diagnosed with dilated cardiomyopathy, even when infiltrating inflammatory cells are undetectable.14 Furthermore, some patients with myocarditis had repeated cycles of recurrence and remission.14–17 It is presumed that upon viral infection, a persistent immune mechanism is activated, leading to a transition to dilated cardiomyopathy.15–17 Moreover, potential persistent infection of the heart cannot be ruled out even after SARS-CoV-2 becomes undetectable on polymerase chain reaction of samples collected from the pharyngeal or nasal mucosa. Therefore, for patients whose blood troponin levels are elevated after SARS-CoV-2 infection, long-term careful monitoring of cardiac function is necessary after recovery. Further, studies should address whether conditions such as dilated cardiomyopathy would develop following COVID-19 even when patients are asymptomatic.

with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol 2020. https://doi.org/10.1001/ jamacardio.2020.0950; PMID: 32211816; epub ahead of press. 7. Bonow RO, Fonarow GC, O’Gara PT, Yancy CW. Association of coronavirus disease 2019 (COVID-19) with myocardial injury and mortality. JAMA Cardiol 2020. https://doi. org/10.1001/jamacardio.2020.1105; PMID: 32219362; epub ahead of press. 8. Suzuki H, Matsumori A, Matoba Y, et al. Enhanced expression of superoxide dismutase messenger RNA in viral myocarditis. An SH-dependent reduction of its expression and myocardial injury. J Clin Invest 1993;91:2727–33. https://doi.org/10.1172/ JCI116513; PMID: 8390488. 9. Tanaka A, Matsumori A, Wang W, Sasayama S. An angiotensin II receptor antagonist reduces myocardial damage in an animal model of myocarditis. Circulation 1994;90:2051–5. https://doi. org/10.1161/01.cir.90.4.2051; PMID: 7923693. 10. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033–4. https://doi.org/10.1016/S01406736(20)30628-0; PMID: 32192578. 11. Yang C, Jin Z. An acute respiratory infection runs into the most common noncommunicable epidemic: COVID-19 and cardiovascular diseases. JAMA Cardiol 2020. https://doi. org/10.1001/jamacardio.2020.0934; PMID: 32211809; epub ahead of press.

12. Bangalore S, Sharma A, Slotwiner A, et al. ST-segment elevation in patients with Covid-19: a case series. N Engl J Med 2020. https://doi.org/10.1056/NEJMc2009020; PMID: 32302081; epub ahead of press. 13. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020;17:259–60. https:// doi.org/10.1038/s41569-020-0360-5; PMID: 32139904. 14. Kühl U, Pauschinger M, Noutsias M, et al. High prevalence of viral genomes and multiple viral infections in the myocardium of adults with “idiopathic” left ventricular dysfunction. Circulation 2005;111:887–93. https://doi.org/10.1161/01. CIR.0000155616.07901.35; PMID: 15699250. 15. Matsumori A. Cardiomyopathies and heart failure. In: Matsumori A (ed). Cardiomyopathies and Heart Failure. Developments in Cardiovascular Medicine, vol 248. Boston, MA: Springer, 2003; 1–15. https://doi.org/10.1007/978-1-4419-92642_1. 16. Kawai C, Matsumori A. Dilated cardiomyopathy update: infectious-immune theory revisited. Heart Fail Rev 2013;18:703– 14. https://doi.org/10.1007/s10741-013-9401-z; PMID: 23892949. 17. Schultheiss HP, Fairweather D, Caforio ALP, et al. Dilated cardiomyopathy. Nat Rev Dis Primers 2019;5:32. https://doi. org/10.1038/s41572-019-0084-1; PMID: 31073128.

Imaging

Contemporary Cardiac MRI in Chronic Coronary Artery Disease Michalis Kolentinis, Melanie Le, Eike Nagel and Valentina O Puntmann Institute of Experimental and Translational Cardiovascular Imaging, German Centre for Cardiovascular Research (DZHK) Centre for Cardiovascular Imaging, Partner Site Rhein-Main, University Hospital Frankfurt, Frankfurt, Germany

Abstract Chronic coronary artery disease remains an unconquered clinical problem, affecting an increasing number of people worldwide. Despite the improved understanding of the disease development, the implementation of the many advances in diagnosis and therapy is lacking. Many clinicians continue to rely on patient’s symptoms and diagnostic methods, which do not enable optimal clinical decisions. For example, echocardiography and invasive coronary catheterisation remain the mainstay investigations for stable angina patients in many places, despite the evidence on their limitations and availability of better diagnostic options. Cardiac MRI is a powerful diagnostic method, supporting robust measurements of crucial markers of cardiac structure and function, myocardial perfusion and scar, as well as providing detailed insight into myocardial tissue. Accurate and informative diagnostic readouts can help with guiding therapy, monitoring disease progress and tailoring the response to treatment. In this article, the authors outline the evidence supporting the state-of-art applications based on cardiovascular magnetic resonance, allowing the clinician optimal use of this insightful diagnostic method in everyday clinical practice.

Keywords Chronic coronary artery disease, cardiac MRI, myocardial perfusion, ischaemia, remodelling Disclosure: The authors have no conflicts of interest to declare. Received: 28 November 2019 Accepted: 17 February 2020 Citation: European Cardiology Review 2020;15:e50. DOI: https://doi.org/10.15420/ecr.2019.17 Correspondence: Valentina Puntmann, Institute for Experimental and Translational Cardiovascular Imaging, DZHK Centre for Cardiovascular Imaging, Goethe University Frankfurt, University Hospital Frankfurt, Theodor-Stern Kai 7, H25B EG, 60590 Frankfurt am Main, Germany. E: vppapers@icloud.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Ischaemic heart disease (IHD) is the leading cause of morbidity and mortality worldwide. Two major pathways of disease development are acute coronary syndrome (ACS) and stable chronic angina.1,2 The success of prevention measures and early treatment pathways in ACS has helped to reduce the heart failure (HF) burden due to post-infarction remodelling and systolic dysfunction. However, accurately identifying patients with stable angina and relevant obstructive coronary artery disease (CAD) remains an on-going clinical challenge. The guidance on effective therapy for prognostic benefit is also continuously refined.3 In patients with chronic IHD, therapeutic strategies include medical management – which is a combination of risk-factor modification – or revascularisation in the presence of persistent symptoms and evidence of significant ischaemia.4 The need for revascularisation continues to be guided by way of pre-test probability (PTP) for CAD as a gatekeeper to the next diagnostic step and to evaluate the presence of relevant myocardial ischaemia. If the PTP is high, an invasive strategy accompanied by measurement of fractional flow reserve (FFR) is advised.5,6 In the more prevalent group who have intermediate PTP, a non-invasive diagnostic test is first used. Then, if significant ischaemia is proven, the patient proceeds to coronary angiography and revascularisation of the target vessel. Patients with low PTP are deemed to not have any relevant ischaemia at all and other options of cardiovascular diseases are not routinely considered.

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In the intermediate PTP group, a plethora of reasonably accurate noninvasive diagnostic tests exists. These include stress echocardiography, cardiac magnetic resonance (CMR) and nuclear imaging methods, single-photon emission CT (SPECT) and PET.2 Among these, the overall body of evidence – including validation, comparative diagnostic accuracy and, more recently the clinical effectiveness of directlyguided revascularisation – distinguishes CMR among the available imaging options.7 In addition to the many practical advantages, which include the absence of ionising radiation, non-invasiveness and accurate and reproducible measurements, it is the unique ability of ischaemia imaging and tissue characterisation that further separates this diagnostic approach. The three imaging readouts, myocardial perfusion, late gadolinium enhancement (LGE) and myocardial T1 mapping techniques, together allow a comprehensive assessment with diagnostic and prognostic relevance.8–11 In this article, we summarise the evidence behind these imaging readouts and outline the ways of supporting an informed individual approach to treatment of patients with stable chronic CAD.

Ischaemia Detection and Quantification The primary utility of angiographical assessment of the severity and extent of epicardial coronary artery stenosis in stable CAD is based on historical evidence that significant (>70% lumen reduction) triple vessel disease and/or left main CAD lead to poor outcomes if left untreated.4 The many limitations regarding the visual or quantitative assessment of coronary artery anatomy, rather than haemodynamic significance, have

Contemporary Cardiac MRI in CAD been well covered elsewhere.6,12–14 The results of the Clinical Outcomes Utilizing Revascularization And Aggressive Drug Evaluation (COURAGE) trial indicated that revascularisation did not reduce the risk of major cardiovascular and cerebral adverse events (MACCE) in stable patients.15 The Fractional Flow Reserve Versus Angiography For Multivessel Evaluation (FAME) trials highlighted the need for an objective measurement of the significance of high-grade stenoses in terms of their functional relevance prior to intervention.6,16 While the superiority of an FFR-supported strategy in determination of haemodynamic significance corroborated the notion of previous observational imaging studies, it also opened up further unresolved questions for various non-invasive options of detection and quantification of myocardial ischaemia: which patients, which method and with what aim.16,17 The choice of imaging approaches in guidelines – stress echo, SPECT, PET and perfusion CMR – remains guided primarily by the local availability of technique and expertise.2 Numerous studies have assessed their comparative diagnostic performance against clinical gold standards, angiographically determined luminal coronary stenosis and FFR, reporting good diagnostic accuracy for significant obstructive CAD (Figure 1). NB: data for stress-echo versus FFR are not available, and there are limited data for SPECT versus FFR. The comprehensive body of evidence for CMR further strengthens its position, along with the available comparative data with SPECT, which reveals the superior diagnostic performance of CMR.17–19 This is also supported by data from meta-analyses.20,21 Furthermore, CMR can be distinguished from nuclear imaging methods in several practical ways, including the absence of exposure to ionising radiation and accurate multiparametric assessment (cardiac function, structure, flows and both scar and ischaemia imaging). Shorter acquisition and post-processing times have cut the time and the costs of investigation and there is a much wider availability compared with PET. Although currently less used in favour of the simpler and safer vasodilatory test of myocardial perfusion, high dose dobutamine CMR yields an even higher diagnostic accuracy. CMR is also the only technique offering insight into comparative performance against dobutamine stress echocardiography.22 This prevailing data on the superiority of CMR (and PET) has now also been adopted in the European Society of Cardiology guidelines.2

Perfusion Techniques Perfusion CMR imaging uses dynamic image acquisition of contrast agent wash-in into the myocardium using saturation-prepulse prepared T1 weighted gradient echo sequence. Saturation prepulse helps to blacken the background signal, allowing visualisation of the contrast-agent-induced brightness while washing into the myocardial muscle. A vasodilator substance – adenosine or the more specific A2A receptor agonist regadenoson – is typically used to stimulate blood flow through the myocardium. Although these medications are relatively safe, adenosine infusion is often accompanied with considerable chest discomfort. These adverse effects are much milder with regadenoson, which is injected as a slow bolus mandating only one IV line. This allows much more amenable proceedings and an overall better image quality. During subsequent administration of gadolinium contrast agent, typically three short-axis images per cardiac cycle are obtained continuously and consecutively for about 60 heart beats to acquire

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Figure 1: Clinical Likelihood of Diagnostic Modalities to Rule In or Rule Out Significant Coronary Artery Disease Test results

50%

100%

+ ICA

–

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+ –

+ PET

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+ Stress CMR

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Clinical Likelihood range where test can rule-in CAD (Post-test probability will rise above 85%) Clinical Likelihood range where test can rule-out CAD (Post-test probability will rise above 15%) Ranges of likelihood of CAD for each functional diagnostic test to rule in (red) and rule out (green) when the reference standard is (A) anatomical assessment using invasive coronary angiography and (B) functional assessment using FFR. Values are shown as SD ± 95% CI. CAD = coronary artery disease; CMR = cardiac magnetic resonance; CTA = CT angiography; FFR = fractional flow reserve; ICA = invasive coronary angiography; SPECT = single-photon emission CT. Source: Knuuti et al. 2020.56 Reproduced with permission from Oxford University Press.

the myocardial wash-in and wash-out (e.g. gadobutrol dose 0.05–0.1 mmol/kg bodyweight).7,23,24 In routine clinical practice, visual assessment is the mainstay approach to recognition of relevant hypoperfusion. Normal myocardium exhibits a characteristic homogenous distribution of rapid contrast uptake. The typical contrast agent wash-in begins at the epicardium of the left anterior descending coronary artery and then proceeds rapidly towards the endocardium as well as the right coronary artery territory. Perfusion defects are recognised as areas of visually perceived low signal indicating reduced contrast uptake (i.e. hypoperfusion), which follow a typical segmental distribution of an epicardial coronary vessel and persist for four or more consecutive cardiac cycles (Figure 2). Areas of hypoperfusion are compared against the LGE images. Where there is post-infarction scar, careful assessment is made to identify peri-infarct ischaemia. Quantitative approaches to myocardial blood flow and flow reserve assessment continue to be an active research area and have been well covered elsewhere.25 They may be particularly useful in assessment of intermediate stenoses given the on-going lack of clarity in defining its presence, as there is considerable discrepancy between the FFR and angiography, as well as an overall absence of outcome data on their prognostic relevance.17

Imaging Figure 2: Perfusion in Four Consecutive Cardiac Cycles A

Perfusion in four consecutive cardiac cycles in three short axis slices in the base (A) mid (B) and apical left ventricular segments (C). Panel D shows late gadolinium enhancement pictures in the same segments. There is significant ischaemia in the inferior and inferolateral wall. Note that perfusion defects exceed the gadolinium enhancement area.

Perfusion Cardiovascular Magnetic Resonance as a Tool to Guide Therapy Functional proof of ischaemia remains the major criterion for prognostically relevant CAD.3,26 Furthermore, the extent of ischaemia (in addition to the presence of postinfarction scar and native T1 of noninfracted myocardium) is directly related to the number of subsequent CAD events. Primarily based on SPECT studies, the yearly CAD event rates generally range from approximately 1% for normal stress imaging findings to as high as 10% for severely abnormal studies. Several observational studies have also shown that the degree of relative risk reduction with treatment is related to the amount of ischaemia observed on non-invasive imaging.3,26 Yet the exact definition of ischaemic burden and thresholds for initiating revascularisation remains a subject of considerable debate, in part because of the difficulty in translating the proof and severity of ischaemia into comparable categories across other imaging modalities.3 Observational evidence indicates that medical therapy alone may be associated with a reduced risk of death compared with revascularisation for patients with less extensive and severe ischaemia (i.e. <10% of the myocardium). Conversely, patients with ≥10% ischaemic myocardium demonstrated a reduced risk of CAD and all-cause death with coronary revascularisation compared with medical therapy.26 Thus, the current practice guidelines support the requirement of moderate–severe ischaemia before elective revascularisation, whereby a threshold of ≥10% ischaemic myocardium provides a benchmark from which to define treatment effectiveness.26–28 Thresholds for relevant ischaemia using perfusion CMR follow this concept, with slight modification reflecting its technical advantages. 29,30 For example, the spatial resolution techniques of SPECT (10 mm × 10 mm

in-plane spatial resolution) only to detect transmural hypoperfusion, which can be recorded using a standard American Heart Association 16-segment model, meaning that relevant ischaemia will be defined as the presence of two adjacent hypoperfused segments. In contrast, higher spatial resolution of CMR allows recording of even smaller myocardial areas of hypoperfusion (with standard sequences of 3 mm × 3 mm in-plane resolution, with some advanced techniques perhaps also achieving 1 mm × 1 mm). Consequently, in CMR a 32-segment model is used, with division of each segment into endocardial and epicardial subsegments, also accounting for physiological distribution of contrast agent wash-in from epicardium into endocardium. In CMR, four or more affected subsegments are required to indicate relevant myocardial ischaemia (Figure 3). New data suggest that a further subdivision of segments may foster an even better diagnostic performance.31 The recently published MR Perfusion Imaging To Guide Management Of Patients With Stable Coronary Artery Disease (MR-INFORM) study is an international, multicentre, randomised controlled clinical effectiveness trial that has clarified several aspects of the therapeutic conundrum in patients with medium to high PTP for CAD.7 It investigated the ability of perfusion CMR to directly guide revascularisation compared with the standard of care based on FFR measurement. In the MRI-guided group, a positive CMR perfusion finding followed the above-mentioned definition, which was expanded for ease of interpretation to either two or more neighbouring segments, two adjacent slices, or a single transmural segment (approximately 6% of the myocardium). In the FFR arm, a measurement of ≤0.80 was defined as positive for relevant ischaemia in the target vessel. Revascularisation was recommended for patients in the CMR group with ischaemia in at least 6% of the myocardium or in the FFR group with an FFR of ≤0.8. Patients with a positive index test underwent revascularisation and all patients received guideline-directed medical therapy. The trial was designed to assess non-inferiority of the non-invasive ischaemic test to FFR in terms of 1-year outcome, defined by the composite primary outcome of death, nonfatal MI, or target-vessel revascularisation. The most important result was the non-significant difference between approaches in guiding treatment in terms of major adverse events (p=0.21). CMR was associated with a lower incidence of coronary revascularisation than FFR (36% versus 44.2%; p<0.01), which led to a considerable reduction in unnecessary invasive angiography to 51% of patients owing to having negative CMR test. These findings support perfusion CMR as the first-line approach in identifying patients who would benefit from treatment by revascularisation.

Chronic Coronary Artery Disease: Interstitial Myocardial Remodelling Diffuse interstitial myocardial fibrosis is the histological hallmark of myocardial remodelling, including in patients with CAD.32,33 Chronic neurohormonal stimulation and changes in gene expression promote the extracellular matrix remodelling processes in noninfarcted segments, eventually leading to accumulation of diffuse fibrosis.34 Although adaptive at first, this process becomes maladaptive, eventually leading to HF and poor prognosis.35–46 The considerable success of anti-remodelling therapies indicates that – despite the often late diagnosis – there is considerable potential for improvement prior to definitive or irreversible ventricular systolic dysfunction and abnormal remodelling with increased ventricular volumes and stiffness.32 Traditionally, low left ventricular ejection fraction (LVEF) has been the marker of poor outcome in post-MI patients, with LVEF ≤35% denoting high-risk and used as a surrogate

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Contemporary Cardiac MRI in CAD Figure 3: Non-infarcted Myocardium and its Relation to Clinical Outcome in Patients with Coronary Artery Disease

Improved management of CAD

LVEF dominates outcome

SCAR dominates outcome Native T1 dominates outcome

CAD = coronary artery disease; LVEF = left ventricular ejection fraction. Source: Puntmann et al. 2018.9 Reproduced with permission from Elsevier.

for a more aggressive management.1 The extent of scar is also a strong predictor for adverse outcome.38,43â&#x20AC;&#x201C;46 In modern populations of CVD patients receiving revascularisation therapies and strong prevention measures, the residual infarct size is relatively small and cardiac function is frequently preserved. With an overall reduced importance of the two traditional parameters, LVEF and LGE, the focus has shifted onto the non-infarcted myocardium. Studies have shown that T1 mapping indices, expressed by native T1 and extracellular volume and measured in the non-infarcted myocardium, increase in response to accumulation of diffuse myocardial fibrosis (Figure 3).38â&#x20AC;&#x201C;41 These measures generally reflect the presence of the diffuse pathological processes that underlie myocardial remodelling, including inflammation, infiltration or fibrosis.41,42 Recent studies have demonstrated that T1 mapping measures are predictive of adverse outcome.9,47,48 A single multicentre study in patients with chronic CAD revealed that native T1, the gadolinium-contrast free measure of non-infarcted myocardium was the strongest independent predictor of survival and major cardiocerebrovascular events.9 Moreover, with rising native T1 values, the likelihood of events was significantly increased. Patients with values in the upper tertile had 6.2-times greater likelihood of allcause mortality and 4.5-times for MACCE, compared with those with native T1 within the normal range (Figure 4). However, the presence of LGE remained an important predictor of outcome only in those patients with considerably large scars and functional impairment. The findings of this study are important for several reasons. Firstly, they are a testament to the importance of a direct measure of myocardial pathology, exposing the limitations of population-

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based risk scores that rely on indirect indicators such as cardiovascular risk factors. Native T1 reflects the presence and severity of myocardial changes and pathological myocardial remodelling, directly relating to the intrinsic myocardial disease such as the presence of myocardial oedema, inflammation, diffuse fibrosis and infiltration. 49,51 These intrinsic disease mechanisms are, on one hand, pathophysiologically different and separate from the ischaemic injury as a result of MI, and on the other hand, central to prognosis in a prevalently scar-free CAD population. Secondly, native T1 is a quantitative biomarker; thus unsurprisingly, the prognosis is proportionally related to disease severity. As a sensitive measure of pathological myocardial remodelling, native T1 may reflect a modifiable substrate and act as a potential therapeutic target, providing means of risk modification and improved prognosis. Sustained monitoring of native T1 levels may allow for an individual optimisation of treatment, possibly ahead of the symptom manifestation and development of phenotypically expressed, often an irreversible disease. Technical diversity in a field littered with various T1 mapping methodologies underlies the fact that the findings of the various studies are not transferable owing to the different choices of T1 mapping sequences used. 38,50 However, CMR with T1 mapping provides an important refinement of the current concept of risk assessment and may help to overcome an important gap in clinical management and discovery of therapies. 51

Cardiovascular Magnetic Resonance and Health Socioeconomics The cardiology practice guidelines set out the role of cardiac MRI as a part of clinical routine practice more firmly than ever before. Admittedly,

Imaging Figure 4: Kaplan-Meier Curves for Native T1 Values and All-cause Mortality A

LGE absent

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Native T1 2SD Chi2 0.62 (p=0.43)

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Native T1 values by SD of remote myocardium. LGE = late gadolinium enhancement; LVEF = left ventricular ejection fraction. Source: Puntmann et al. 2018.9 Reproduced with permission from Elsevier.

the phrasing remains cautious: ‘a promising’ diagnostic tool with a ‘great potential’ to illuminate the underlying aetiology of heart disease. This rather reserved status of cardiac MRI continues to reflect an overall poor availability of CMR in routine practice and there are several aspects responsible for this. Firstly, there is an on-going lack of scanner access, skill and expertise, in part a result of the perpetuating cardiology and radiology conflict over equipment sharing. Although there are international and allinclusive CMR accreditation schemes, in most countries these are neither recognised nor integrated into traditional cardiology curriculum. Ironically, the absence of formal expertise remains the main argument of the national healthcare providers, precluding the rollout of the reimbursement in clinical practice.

Finally, as imaging requires no regulatory evidence of clinical effectiveness in delivery of medical care (such as guiding treatment to change outcome), use is guided by a market of existing reimbursement schemes rather than a recognised clinical need. This also explains the persistent use of methods that are entitled to reimbursement despite recognised significant disadvantages and inferior evidence – such as nuclear medicine methods – and are simply underpowered to deliver the insights to a complex pathophysiology, for example, serial echocardiography, cardiac CT or invasive catheterisation.53–55 A move towards evidence-based use of imaging techniques in guiding treatment and improve outcome by way of regulation is pertinent to improve the current state of the art and stove off the rising HF epidemic, fuelled by the currently inadequate approaches.

Conclusion Secondly, there is an overwhelming perception that the clinical market is not only saturated with MRI-based imaging, but that it is at risk of ‘overuse’, as overall morbidity and mortality has not been reduced despite a considerable increase in imaging over the last two decades. The caveat of this misconception is exposed by an organbased breakdown of scanner utilisation, revealing that over 70% of MR scanner time worldwide goes to brain, spine and extremities, whereby cardiac MR imaging amounts to a mere 1%.52 Clearly, this deployment is illogically disproportionate to the magnitude of a problem created by heart disease, the major contributor to morbidity and mortality worldwide.

The accurate diagnosis of underlying pathophysiology is paramount to safeguard good prognosis and the patient’s quality of life. Of the available diagnostic tools, CMR is distinguished by the overall body of evidence, ranging from validation, comparative diagnostic accuracy studies and, more recently, of clinical effectiveness of the direct guidance of revascularisation, showing that CMR is safe, delivering measurements that are accurate and highly reproducible, as well as provide valuable prognostic information. In addition to coronary artery disease and its complications, it is also able to elucidate the many non-ischaemic causes of symptoms in patients with relatively low pre-test probability for CAD.51 In survivors of acute MI, CMR can

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Contemporary Cardiac MRI in CAD show the extent of salvages myocardium and, thus, the efficacy of treatment.52 This capacity renders CMR an invaluable modality for assessing the potential future advancements in treatment. Finally, CMR can illustrate the extent and severity of left ventricular remodelling following an MI, providing useful information for the management and prognosis of patients with ischaemic heart disease. This includes the transmurality of the scar, the degree of left

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Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891–975. https://doi.org/10.1002/ejhf.592; PMID: 27207191. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. https://doi.org/10.1093/eurheartj/ ehz425; PMID:31504439. Shaw LJ, Berman DS, Picard MH. Comparative definitions for moderate-severe ischaemia in stress nuclear, echocardiography, and magnetic resonance imaging. JACC Cardiovasc Imaging 2014;7:593–604. https://doi.org/10.1016/j. jcmg.2013.10.021; PMID: 24925328. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1714/3203.31801; PMID: 31379378. Pijls NHJ, van Schaardenburgh P, Manoharan G. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol 2007;49:2105–11. https://doi.org/10.1016/j.jacc.2007.01.087; PMID: 17531660. Tonino PA, De Bruyne B, Pijls NH. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213–24. https://doi.org/ 10.1056/NEJMoa0807611; PMID: 19144937. Nagel E, Greenwood JP, McCann GP. Magnetic resonance perfusion or fractional flow reserve in coronary disease. N Engl J Med 2019;380:2418–28. https://doi.org/10.1056/ NEJMoa1716734; PMID:31216398. Puntmann VO, Valbuena S, Hinojar R, et al. Society for Cardiovascular Magnetic Resonance (SCMR) expert consensus for CMR imaging endpoints in clinical research: part I – analytical validation and clinical qualification. J Cardiovasc Magn Reson 2018;20:67. https://doi.org/10.1186/s12968-018-0484-5; PMID: 30231886. Puntmann VO, Carr-White G, Jabbour A. Native T1 and ECV of noninfarcted myocardium and outcome in patients with coronary artery disease. J Am Coll Cardiol 2018;71:766–78. https://doi.org/10.1016/j.jacc.2017.12.020; PMID: 29447739. Kwong RY, Chan AK, Brown KA, et al. Impact of unrecognized myocardial scar detected by cardiac magnetic resonance imaging on event-free survival in patients presenting with signs or symptoms of coronary artery disease. Circulation 2006;113:2733–43. https://doi.org/0.1161/ CIRCULATIONAHA.105.570648; PMID: 16754804. Klem I, Shah DJ, White RD, et al. Prognostic value of routine cardiac magnetic resonance assessment of left ventricular ejection fraction and myocardial damage: an international, multicenter study. Circ Cardiovasc Imaging 2011;4:610–9. https://doi.org/10.1161/CIRCIMAGING.111.964965; PMID: 21911738. Tebaldi M, Biscaglia S, Fineschi M, et al. Evolving routine standards in invasive hemodynamic assessment of coronary stenosis: the nationwide Italian SICI-GISE cross-sectional ERIS study. JACC Cardiovasc Interv 2018;11:1482–91. https://doi. org/10.1016/j.jcin.2018.04.037; PMID: 29803695. Zhang H, Mu L, Hu S, et al. Comparison of physician visual assessment with quantitative coronary angiography in assessment of stenosis severity in China. JAMA Intern Med 2018;178:239–47. https://doi.org/10.1001/ jamainternmed.2017.7821; PMID: 29340571. Grundeken MJ, Collet C, Ishibashi Y, et al. Visual estimation versus different quantitative coronary angiography methods to assess lesion severity in bifurcation lesions. Catheter Cardiovasc Interv 2018;91:1263–70. https://doi.org/10.1002/ ccd.27243; PMID: 28836339. Boden WE, O’Rourke RA, Teo KK. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–16. https://doi.org/0.1056/NEJMoa070829; PMID: 17387127. Fearon WF, Nishi T, De Bruyne B, et al. Clinical outcomes and cost-effectiveness of fractional flow reserve-guided percutaneous coronary intervention in patients with stable coronary artery disease: Three-year follow-up of the FAME 2 trial (Fractional flow reserve versus Angiography for Multivessel Evaluation). Circulation 2018;137:480–7. https://doi. org/10.1161/CIRCULATIONAHA.117.031907; PMID: 29097450.

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ventricular dilatation, left ventricular ejection fraction and the extent of remote myocardial adverse remodelling. Despite being a powerful tool, the huge methodological diversity and lack of standardisation of CMR sequences and techniques poses an ongoing problem and a limitation to translation of scientific results into everyday practice, hindering collaboration among CMR centres and the understanding of disease pathophysiology.

17. Knuuti J, Ballo H, Juarez-Orozco LE, et al. The performance of non-invasive tests to rule-in and rule-out significant coronary artery stenosis in patients with stable angina: a meta-analysis focused on post-test disease probability. Eur Heart J 2018;39:3322–30. https://doi.org/10.1093/eurheartj/ehy267; PMID: 29850808. 18. Schwitter J, Wacker CM, van Rossum AC. MR-IMPACT: comparison of perfusion-cardiac magnetic resonance with single-photon emission computed tomography for the detection of coronary artery disease in a multicentre, multivendor, randomized trial. Eur Heart J 2008;29:480–9. https://doi.org/10.1093/eurheartj/ehm617; PMID: 18208849. 19. Greenwood JP, Maredia N, Younger JF. Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial. Lancet 2012;379:453–60. https://doi. org/10.1016/S0140-6736(11)61335-4; PMID: 22196944. 20. Jaarsma C, Leiner T, Bekkers SC. Diagnostic performance of noninvasive myocardial perfusion imaging using single-photon emission computed tomography, cardiac magnetic resonance, and positron emission tomography imaging for the detection of obstructive coronary artery disease: a meta-analysis. J Am Coll Cardiol 2012;59:1719–28. https://doi.org/10.1016/j. jacc.2011.12.040; PMID: 22554604. 21. Takx RAP, Blomberg BA, El Aidi H. Diagnostic accuracy of stress myocardial perfusion imaging compared to invasive coronary angiography with fractional flow reserve metaanalysis. Circ Cardiovasc Imaging 2015;8:e002666. https://doi. org/10.1161/CIRCIMAGING.114.002666; PMID: 25596143. 22. Nagel E, Lehmkuhl HB, Bocksch W, et al. Noninvasive diagnosis of ischaemia-induced wall motion abnormalities with the use of high-dose dobutamine stress MRI: comparison with dobutamine stress echocardiography. Circulation 1999;99:763–70. https://doi.org/0.1161/01.cir.99.6.763; PMID: 9989961. 23. D’Angelo T, Grigoratos C, Mazziotti S, et al. High-throughput gadobutrol-enhanced CMR: a time and dose optimization study. J Cardiovasc Magn Reson 2017;19:83. https://doi. org/10.1186/s12968-017-0400-4; PMID: 29110679. 24. ClinicalTrials.gov. Gadobutrol/gadavist-enhanced cardiac magnetic resonance imaging (CMRI) to detect coronary artery disease (CAD) (GadaCAD 1). https://clinicaltrials.gov/ct2/show/ NCT01890421 (accessed 8 March 2020). 25. Morton G, Chiribiri A, Ishida M, et al. Quantification of absolute myocardial perfusion in patients with coronary artery disease: comparison between cardiovascular magnetic resonance and positron emission tomography. J Am Coll Cardiol 2012;60:1546–55. https://doi.org/10.1016/j.jacc.2012.05.052; PMID: 22999722. 26. Hachamovitch R, Rozanski A, Shaw LJ. Impact of ischaemia and scar on the therapeutic benefit derived from myocardial revascularization vs. medical therapy among patients undergoing stress-rest myocardial perfusion scintigraphy. Eur Heart J 2011;32:1012–24. https://doi.org/10.1093/eurheartj/ ehq500; PMID: 22258084. 27. Hachamovitch R, Hayes SW, Friedman JD. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 2003;107:2900–7. https://doi.org/10.1161/01. CIR.0000072790.23090.41; PMID: 12771008. 28. Hachamovitch R, Rozanski A, Hayes SW. Predicting therapeutic benefit from myocardial revascularization procedures: are measurements of both resting left ventricular ejection fraction and stress-induced myocardial ischaemia necessary? J Nucl Cardiol 2006;13:768–78. https://doi.org/10.1016/j. nuclcard.2006.08.017; PMID: 17174808. 29. Jahnke C, Nagel E, Gebker R, et al. Prognostic value of cardiac magnetic resonance stress tests: adenosine stress perfusion and dobutamine stress wall motion imaging. Circulation 2007 Apr;115:1769–76. https://doi.org/10.1161/ CIRCULATIONAHA.106.652016; PMID: 17353441. 30. Kelle S, Chiribiri A, Vierecke J, et al. Long-term prognostic value of dobutamine stress CMR. JACC Cardiovasc Imaging 2011;4:161–72. https://doi.org/10.1016/j.jcmg.2010.11.012; PMID: 21329901. 31. Le M, Zarinabad N, D’Angelo T, et al. Sub-segmental quantification of single (stress)-pass perfusion CMR improves the diagnostic accuracy for detection of obstructive coronary artery disease. J Cardiovasc Magn Reson 2020;22:14. https://doi. org/10.1186/s12968-020-0600-1; PMID: 32028980.

32. Weber KT, Sun Y, Bhattacharya SK, et al. Myofibroblastmediated mechanisms of pathological remodelling of the heart. Nat Rev Cardiol 2013;10:15–26. https://doi.org/10.1038/ nrcardio.2012; PMID: 23207731. 33. Hill JA, Olson EN. Cardiac plasticity. N Engl J Med 2008;358:1370–80. https://doi.org/10.1056/NEJMra072139; PMID: 18367740. 34. Creemers EE, Pinto YM. Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart. Cardiovasc Res 2011;89:265–72. https://doi.org/10.1093/cvr/cvq308; PMID: 20880837. 35. Cohn JN. New therapeutic strategies for heart failure: left ventricular remodeling as a target. J Card Fail 2004;10(Suppl 6):S200–1. https://doi.org/10.1016/j.cardfail.2004.09.007; PMID: 15803550. 36. Likoff MJ, Chandler SL, Kay HR. Clinical determinants of mortality in chronic congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy. Am J Cardiol 1987;59:634–8. https://doi.org/10.1016/0002-9149(87)91183-0; PMID: 2825904. 37. St John Sutton M, Pfeffer MA, Moye L. Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial. Circulation 1997;96:3294–9. https:// doi.org/10.1161/01.cir.96.10.3294; PMID: 9396419. 38. Puntmann VO, Peker E, Chandrashekhar Y, Nagel E. T1 mapping in characterizing myocardial disease: a comprehensive review. Circ Res 2016;119:277–99. https://doi. org/10.1161/CIRCRESAHA.116.307974; PMID: 27390332. 39. Chan W, Duffy SJ, White DA. Acute left ventricular remodeling following myocardial infarction: coupling of regional healing with remote extracellular matrix expansion. JACC Cardiovasc Imaging 2012;5:884–93. https://doi.org/10.1016/j. jcmg.2012.03.015; PMID: 22974800. 40. Kali A, Choi EY, Sharif B. Native T1 mapping by 3-T CMR imaging for characterization of chronic myocardial infarctions. JACC Cardiovasc Imaging 2015;8:1019–30. https://doi. org/10.1016/j.jcmg.2015.04.018; PMID: 26298071. 41. Child N, Suna G, Dabir D, et al. Comparison of MOLLI, shMOLLLI, and SASHA in discrimination between health and disease and relationship with histologically derived collagen volume fraction. Eur Heart J Cardiovasc Imaging 2018;19:768–76. https://doi.org/10.1093/ehjci/jex309; PMID: 29237044. 42. Winau L, Hinojar Baydes R, Braner A, et al. High-sensitive troponin is associated with subclinical imaging biosignature of inflammatory cardiovascular involvement in systemic lupus erythematosus. Ann Rheum Dis 2018;77:1590–8. https://doi. org/10.1136/annrheumdis-2018-213661; PMID: 30077990. 43. Kwon DH, Halley CM, Carrigan TP, et al. Extent of left ventricular scar predicts outcomes in ischemic cardiomyopathy patients with significantly reduced systolic function: A delayed hyperenhancement cardiac magnetic resonance study. JACC Cardiovasc Imaging 2009;2:34–44. https:// doi.org/10.1016/j.jcmg.2008.09.010; PMID: 19356530. 44. Gerber BL, Rousseau MF, Ahn SA, et al. Prognostic value of myocardial viability by delayed-enhanced magnetic resonance in patients with coronary artery disease and low ejection fraction: Impact of revascularization therapy. J Am Coll Cardiol 2012;59:825–35. https://doi.org/10.1016/j.jacc.2011.09.073; PMID: 22361403. 45. El Aidi H, Adams A, Moons KGM, et al. Cardiac magnetic resonance imaging findings and the risk of cardiovascular events in patients with recent myocardial infarction or suspected or known coronary artery disease: a systematic review of prognostic studies. J Am Coll Cardiol 2014;63:1031–45. https://doi.org/10.1016/j.jacc.2013.11.048; PMID: 24486280. 46. Kelle S, Roes SD, Klein C, et al. Prognostic value of myocardial infarct size and contractile reserve using magnetic resonance imaging. J Am Coll Cardiol 2009;54:1770–7. https://doi. org/10.1016/j.jacc.2009.07.027; PMID: 19874990. 47. Wong TC, Piehler K, Meier CG, et al. Association between extracellular matrix expansion quantified by cardiovascular magnetic resonance and short-term mortality. Circulation 2012;126:1206–16. https://doi.org/10.1161/ CIRCULATIONAHA.111.089409; PMID: 22851543. 48. Puntmann VO, Carr-White G, Jabbour A, et al. T1-mapping and outcome in nonischemic cardiomyopathy: All-cause mortality and heart failure. JACC Cardiovasc Imaging 2016;9:40–50. https:// doi.org/10.1016/j.jcmg.2015.12.001; PMID: 26762873. 49. Arcari L, Hinojar R, Engel J, et al. Native T1 and T2 provide

distinctive signatures in hypertrophic cardiac conditions – comparison of uremic, hypertensive and hypertrophic cardiomyopathy. Int J Cardiol 2020;306:102–8. https://doi. org/10.1016/j.ijcard.2020.03.002; PMID: 32169347. 50. Robinson AA, Chow K, Salerno M. Myocardial T1 and ECV measurement: Underlying concepts and technical considerations. JACC Cardiovasc Imaging 2019;12:2332–44. https://doi.org/10.1016/j.jcmg.2019.06.031; PMID: 31542529 51. Haslbauer JD, Lindner S, Valbuena-Lopez S, et al. CMR imaging biosignature of cardiac involvement due to cancer-related treatment by T1 and T2 mapping. Int J Cardiol 2019;275:179–86. https://doi.org/10.1016/j.ijcard.2018.10.023; PMID: 30360992. 52. Puntmann VO. Editorial. Magnetom Flash SCMR 2020 Edition. Siemens Healthineers 2020;76:4–8. https://static.healthcare.

siemens.com/siemens_hwem-hwem_ssxa_websites-contextroot/wcm/idc/groups/public/@global/@imaging/@mri/ documents/download/mda5/ntqy/~edisp/siemenshealthineers-magnetom-world-puntmann_editorial-07014529. pdf (accessed 18 March 2020). 53. Campbell F, Thokala P, Uttley LC, et al. Systematic review and modelling of the cost-effectiveness of cardiac magnetic resonance imaging compared with current existing testing pathways in ischaemic cardiomyopathy. Health Technol Assess 2014;18:1–120. https://doi.org/10.3310/hta18590; PMID: 25265259. 54. Walker S, Girardin F, McKenna C, et al. Cost-effectiveness of cardiovascular magnetic resonance in the diagnosis of coronary heart disease: an economic evaluation using

data from the CE-MARC study. Heart 2013;99:873–81. https://doi.org/10.1136/heartjnl-2013-303624; PMID: 23591668. 55. Boldt J, Leber A, Bonaventura K, et al. Cost-effectiveness of cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary artery disease in Germany. J Cardiovasc Magn Reson 2013;15:30. https://doi.org/10.1186/1532-429X-15-30; PMID: 23574690. 56. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes: the Task Force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC). Eur Heart J 2020;41:407–77. https://doi.org/10.1093/ eurheartj/ehz425; PMID: 31504439.

COVID-19

Coronavirus Disease 2019 Myocarditis: Insights into Pathophysiology and Management Mahmoud Abdelnabi,1 Nouran Eshak,2,3 Yehia Saleh4,5 and Abdallah Almaghraby4 1. Cardiology and Angiology Unit, Department of Clinical and Experimental Internal Medicine, Medical Research Institute, Alexandria University, Alexandria, Egypt; 2. Rheumatology Unit, Department of Internal Medicine, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 3. Department of Internal Medicine, Texas Tech University, Health Science Center, Lubbock, TX, US; 4. Department of Cardiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 5. Department of Internal Medicine, Michigan State University, East Lansing, MI, US

Abstract The world is dealing with a global pandemic of severe acute respiratory coronavirus 2 (SARS-CoV-2). Coronavirus disease 2019 (COVID-19), which is the illness caused by SARS-CoV-2, is overwhelming healthcare systems around the world. Although the main clinical manifestations of COVID-19 are respiratory symptoms, several reports have noted myocarditis, cardiomyopathy, arrhythmias and cardiac arrests as COVID-19 complications. Here, the authors highlight the current understanding of the pathophysiology of myocarditis related to COVID-19 and its management.

Keywords COVID-19, myocarditis, cytokine storm, immunomodulation Disclosure: The authors have no conflict of interest to declare. Received: 1 May 2020 Accepted: 22 May 2020 Citation: European Cardiology Review 2020;15:e51. DOI: https://doi.org/10.15420/ecr.2020.16 Correspondence: Mahmoud Hassan Abdelnabi, Cardiology and Angiology Unit, Department of Clinical and Experimental Internal Medicine, Medical Research Institute, University of Alexandria, 165 El-Horeya Rd, Al Ibrahimeyah Qebli WA Al Hadrah Bahri, Qism Bab Sharqi, Alexandria Governorate, Egypt 21561. E: mahmoud.hassan.abdelnabi@outlook.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Pathophysiology of COVID-19-related Cardiac Injury Acute myocarditis is a potentially life-threatening disease, which is most commonly caused by a viral infection. Among the viruses, the most cited are enteroviruses (especially coxsackievirus), adenovirus and parvovirus B19 and, rarely, coronavirus. Recently, coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), was declared by the WHO to be a pandemic. There has been an upsurge in patients presenting with COVID-induced myocarditis globally. Although the pathophysiology of acute myocarditis of SARS-CoV-2 is not fully understood, several mechanisms have been proposed. Some studies have suggested cytokine release syndrome is the core pathophysiology of SARS-CoV-2 fulminant myocarditis. Chen et al. reported that patients who are infected with SARS-CoV-2 had high levels of interleukin-1 (IL-1) beta, IL-6, interferon (IFN) gamma, IFN inducible protein-10 (IP-10) and monocyte chemoattractant protein-1 (MCP-1), which probably led to massive activation of T-helper-1 cell response.1 Higher granulocyte colony-stimulating factor, IP-10, MCP-1, macrophage inflammatory protein-1A and tumour necrosis factor alpha have also been reported, suggesting that the cytokine storm might affect disease severity.1 Another mechanism, proposed by Zheng et al., was that it might be related to angiotensin-converting enzyme 2 (ACE2); this is widely

ÂŠ RADCLIFFE CARDIOLOGY 2020

expressed not only in the lungs but also in the cardiovascular system, so ACE2-related signalling pathways might also have a role in heartÂ injury.2 ACE2 is a membrane-bound aminopeptidase that has been identified as a functional receptor for coronaviruses. SARS-CoV-2 infection is triggered by the spike protein of the virus binding to ACE2, which is highly expressed in the heart and lungs resulting in ARDS and fulminant myocarditis. This hypothesis has generated a lot of anxiety among patients on ACE-inhibitors or angiotensin-receptor blockers. Moreover, in a less-adopted hypothesis, several authors have speculated that SARS-CoV-2-induced severe acute respiratory distress syndrome (ARDS) results in intractable hypoxaemia leading to myocardial cell damage.2

Management of COVID-19 Myocarditis The prevalence of COVID-19-induced myocarditis varies between reports, and is involved in up to 7% of COVID-related deaths.3 Screening for myocardial injury in patients admitted to the hospital with COVID-19 is advisable, given that the diagnosis will change the management, especially regarding fluid administration. Siripanthong et al. recommended a baseline ECG, and assessing troponin and B-type natriuretic peptide levels on hospital admissions. If myocarditis is suspected, an echocardiogram should be done because it is more accessible than other imaging modalities; moreover,

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COVID-19 point-of-care ultrasound is often readily available. Although cardiac magnetic resonance would provide more information than an echocardiogram, its use is limited because of prolonged acquisition time, the need for breath-holding and, given that COVID-19 is highly contagious, the requirement for deep cleaning after use.4 If myocarditis is still suspected and cardiac magnetic resonance cannot be performed, ECG-gated CT with contrast would be a reasonable option. Since many COVID-19 patients will undergo a chest CT at some point, adding the cardiac component to the CT is a feasible technique to use to obtain valuable information. If none of these modalities provide the information needed, an endomyocardial biopsy would be warranted. The current European Society of Cardiology (ESC) position statement recommends treating patients with acute myocarditis complicated by cardiogenic shock with inotropes and/or vasopressors and mechanical ventilation.5 Additionally, in patients requiring longer-term support, extracorporeal membrane oxygenation (ECMO) and ventricular assist devices should be used. Generally, glucocorticoid and immunoglobulin therapy are discouraged in acute myocarditis. In a systematic review, Chen et al. reported that corticosteroids did not reduce mortality.6 Moreover, a systematic review of IV immunoglobulins as acute myocarditis therapy showed insufficient evidence to support their routine use.7 Partly because of

Chen C, Zhou Y, Wang DW. SARS-CoV-2: a potential novel etiology of fulminant myocarditis. Herz 2020;45:230–2. https:// doi.org/10.1007/s00059-020-04909-z; PMID: 32140732. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020;17:259–60. https:// doi.org/10.1038/s41569-020-0360-5; PMID: 32139904. Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020;46:846–8. https:// doi.org/10.1007/s00134-020-05991-x; PMID: 32125452. Siripanthong B, Nazarian S, Muser D, et al. Recognizing COVID-19-related myocarditis: the possible pathophysiology and proposed guideline for diagnosis and management. Heart Rhythm 2020. https://doi.org/10.1016/j.

these data, the ESC recommends that immunosuppression should be started only after ruling out an active infection.5 Interestingly, three case reports have noted successful management of COVID-19 fulminant myocarditis using mainly immune-modulators and supportive measures. Zeng et al. reported the successful treatment of a patient with COVID-19 presenting with fulminant myocarditis, ARDS and multiple organ dysfunction syndrome using ventilatory support, high-flow oxygen, lopinavir-ritonavir antiviral therapy, interferon alpha1b, methylprednisolone, immunoglobulin and ECMO with gradual improvement of left ventricular ejection fraction (LVEF).8 Hu et al. described successful management of fulminant myocarditis using methylprednisolone, immunoglobulin, inotropes and diuretics with gradual improvement of LVEF and cardiac biomarkers over several weeks.9 Inciardi et al. described a case of peri-myocarditis as the sole manifestation of COVID-19, without interstitial pneumonia, with gradual improvement of symptoms and LVEF using hydroxychloroquine, lopinavir/ritonavir, methylprednisolone, inotropic support and diuresis.10

Conclusion In general, the use of corticosteroids and IV immunoglobulins are not supported by the guidelines for the management of acute myocarditis. However, in the very few patients who have been diagnosed with COVID myocarditis, management with immunomodulators showed positive results. This suggests that the core pathophysiologic process of COVID-19-related cardiac injury is linked to a cytokine storm.

hrthm.2020.05.001; PMID: 32387246; epub ahead of press. Caforio AL, Pankuweit S, Arbustini E, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013;34:2636–48. https://doi.org/10.1093/ eurheartj/eht210; PMID: 23824828. Chen HS, Wang W, Wu SN, Liu JP. Corticosteroids for viral myocarditis. Cochrane Database Syst Rev 2013;(10):CD004471. https://doi.org/10.1002/14651858.CD004471.pub3; PMID: 24136037. Robinson JL, Hartling L, Crumley E, et al. A systematic review of intravenous gamma globulin for therapy of acute myocarditis. BMC Cardiovasc Disord 2005;5:12. https://doi.

org/10.1186/1471-2261-5-12; PMID: 15932639. Zeng JH, Liu YX, Yuan J, et al. First case of COVID-19 complicated with fulminant myocarditis: a case report and insights. Infection 2020. https://doi.org/10.1007/s15010-02001424-5; PMID: 32277408; epub ahead of press. 9. Hu H, Ma F, Wei X, Fang Y. Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin. Eur Heart J 202. https://doi.org/10.1093/eurheartj/ehaa190; PMID: 32176300; epub ahead of press. 10. Inciardi RM, Lupi L, Zaccone G, et al. Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020. https://doi.org/10.1001/jamacardio.2020.1096; PMID: 32219357; epub ahead of press. 8.

EUROPEAN CARDIOLOGY REVIEW

COVID-19

Myocardial and Microvascular Injury Due to Coronavirus Disease 2019 Rocco A Montone,1 Giulia Iannaccone,2 Maria Chiara Meucci,2 Filippo Gurgoglione2 and Giampaolo Niccoli1,2 1. Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy; 2. Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy

Abstract Over the past few months, health systems worldwide have been put to the test with the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Even though the leading clinical manifestations of the SARSCoV-2 infection involve the respiratory tract, there is a non-negligible risk of systemic involvement leading to the onset of multi-organ failure with fatal consequences. Since the onset of COVID-19, patients with underlying cardiovascular disease have been at increased risk of poor clinical outcomes with higher death rates. Moreover, the occurrence of new-onset cardiac complications is not uncommon among patients hospitalised for COVID-19. Of importance, a significant portion of COVID-19 patients present with myocardial injury. Herein, the authors discuss the mechanisms leading to myocardial and microvascular injury in SARS-CoV-2 infection and their clinical implications.

Keywords COVID-19, microvascular dysfunction, microvascular injury, MI, myocardial injury Disclosure: The authors have no conflicts of interest to declare. Received: 18 May 2020 Accepted: 30 May 2020 Citation: European Cardiology Review 2020;15:e52. DOI: https://doi.org/10.15420/ecr.2020.22 Correspondence: Niccoli Giampaolo, Institute of Cardiology, Catholic University of the Sacred Heart, Largo F Vito 1, Rome 00168, Italy. E: gniccoli73@hotmail.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

In December 2019, several cases of interstitial pneumonia of unknown origin were detected in Wuhan, China, and on 9 January 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the causative agent of coronavirus disease 2019 (COVID-19). Within a few weeks, the contagion spread through China and South Korea, and the outbreak rapidly extended worldwide due to asymptomatic cases and modern travel. Finally, on 11 March 2020, the WHO declared the coronavirus outbreak a pandemic.

respiratory and non-respiratory consequences of the disease.2 The proinflammatory milieu may contribute to microvascular dysfunction and diffuse intravascular coagulation.3

Over the past few months, health systems worldwide have been put to the test with the uncontrolled diffusion of a completely new disease with different levels of severity, and frequently, poor prognosis. Even though the leading clinical manifestations of SARS-CoV-2 infection involve the respiratory tract, with a risk of worsening dyspnoea, oxygen blood desaturation and frequent need for orotracheal intubation, the involvement of other organs and systems, such as the cardiovascular system and the gastrointestinal tract, can lead to multiorgan failure with fatal consequences.

Herein, we discuss the direct and indirect mechanisms leading to myocardial and microvascular injury in SARS-CoV-2 infection (Figure 1) and the implications of the COVID-19 pandemic for patients and clinicians in terms of CVD management and treatment.

The mechanisms underlying the pathophysiology of COVID-19 and its systemic manifestations are not well understood. The SARS-CoV-2 host cell receptor, the angiotensin-converting enzyme 2 (ACE-2), is widely expressed in several organs, including the lung, heart, endothelial cells, kidney and intestine, thus explaining the detection of viral particles in cardiac pericytes and urinary and faecal samples.1 Of importance, host immune system dysregulation, which is a consequence of viral infection, has recently been found to be important in determining exaggerated cytokine release and inflammasome activation, which are

ÂŠ RADCLIFFE CARDIOLOGY 2020

The cardiovascular system is often involved in SARS-CoV-2 infection, and patients with underlying cardiovascular disease (CVD) or with new onset cardiovascular complications need prompt diagnosis and treatment, as their prognosis is usually poorer (Table 1).

Pathogenic Mechanisms Underlying Myocardial and Microvascular Injury Patients with COVID-19 can develop cardiovascular complications, such as heart failure, myocarditis, pericarditis, vasculitis and cardiac arrhythmias. Moreover, between 8% and 28% of patients with COVID-19 will manifest troponin release early in the course of the disease, reflecting the occurrence of a myocardial cardiac injury.4 Of note, the presence of troponin elevation, or its dynamic increase during hospitalisation, confers up to a fivefold risk of requiring ventilation; increases in arrhythmias, such as VF and ventricular tachycardia; and a fivefold risk of mortality. In their study, Shi et al. showed that, among 671 SARS-CoV-2-positive patients, those who died (n=62) were more likely to have myocardial injury (75.8% versus 9.7%; p<0.001) than those who survived, thus suggesting that markers of myocardial

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COVID-19 Table 1: Studies Comparing Clinical Characteristics and Outcomes of Patients with or without Myocardial Injury Shi at al.4 (n=416)

Shi et al.5 (n=647)

Myocardial Without p-value Myocardial Injury (n=82), Myocardial Injury n (%) Injury (n=334), (n=106), n (%) n (%)

Guo et al.9 (n=187)

Without p-value Myocardial Myocardial Injury (n=52), Injury (n=565), n (%) n (%)

Without p-value Myocardial Injury (n=135), n (%)

Baseline Characteristics Age (years), mean

<0.001

Hypertension

49 (59.8)

78 (23.4)

<0.001

63 (59.4)

136 (24.1)

Diabetes

20 (24.4)

40 (12)

0.008

25 (23.6)

72 (12.7)

Coronary heart disease

24 (29.3)

20 (6)

<0.001

29 (27.4)

Chronic heart failure

12 (14.6)

5 (1.5)

<0.001

Cerebrovascular 13 (15.9) disease

9 (2.7)

Chronic obstructive pulmonary disease

6 (7.3)

<0.001

33 (63.5)

28 (20.7)

<0.001

0.006

16 (30.8)

12 (8.9)

<0.001

31 (5.5)

<0.001

17 (32.7)

4 (3)

<0.001

13 (12.3)

9 (1.6)

<0.001

–

<0.001

11 (10.4)

11 (1.9)

<0.001

–

6 (1.8)

0.02

10 (9.49

13 (2.3)

0.001

4 (7.7)

0 (0)

0.001

Laboratory Findings Troponin I, mean

0.19 µg/l

<0.006 µg/l

<0.001

0.159 ng/ml

<0.006 ng/ml

<0.001

–

NT-proBNP (pg/ml), mean

1689

139

<0.001

1346

113

<0.001

–

Leukocytes/ µl, mean

9400

5500

<0.001

9000

5300

<0.001

–

C-reactive protein (mg/dl), mean

10.2

3.7

<0.001

<0.0001

–

Clinical Outcomes Acute respiratory distress syndrome

48 (58.5)

49 (14.7)

<0.001

–

30 (57.7)

16 (11.9)

<0.001

Acute kidney injury

7 (8.5)

1 (0.3)

<0.001

–

14 (36.8)

4 (4.7)

<0.001

Invasive mechanical ventilation

18 (22)

14 (4.2)

<0.001

–

31 (59.6)

14 (10.4)

<0.001

Deaths

42 (51.2)

15 (4.5)

<0.001

–

31 (59.6)

12 (8.9)

<0.001

necrosis may be useful in predicting the risk of in-hospital death.5 Of importance, the area under the receiver operating characteristic curve of initial cardiac troponin I for predicting in-hospital mortality was 0.92 (95% CI [0.87–0.96], sensitivity: 0.86, specificity: 0.86, p<0.001), and in the multivariable logistic regression, older age, comorbidities (e.g. hypertension, coronary heart disease, chronic renal failure and chronic obstructive pulmonary disease), and a high level of C-reactive protein were predictors of myocardial injury. Myocardial injury could be due to different pathogenic mechanisms (ischaemic or non-ischaemic), and thus have different clinical consequences.4 In particular, cardiac ischaemia can arise from an imbalance between oxygen supply and demand, a type 2 MI, a situation that can prevail in acute infections, particularly those that affect the lungs, such as COVID-19. As with other pneumonias, cardiac troponins are often increased in COVID-19 as a result of pre-existing CVD and/or the acute stress related to the viral infection, thereby mild elevations in

patients without signs or symptoms of heart involvement nor ECG changes do not require further investigation. However, cardiac biomarker levels correlate with disease severity and prognosis, so attention should be paid to increments that are two to three times the upper limit, which could be associated with typical angina and/or newonset ECG abnormalities as possible markers of cardiac ischaemic or non-ischaemic damage.6 Type 2 MI is typically related to imbalanced myocardial oxygen demand and supply, and several different mechanisms could lead to this complication in COVID-19 patients. For example, the hypotension determined by the septic state and the blood hypoxemia as a consequence of respiratory function impairment could reduce oxygen supply to the heart, thus leading to acute myocardial injury, particularly in patients with underlying chronic coronary syndrome.7 Moreover, increased myocardial oxygen demand could be a consequence of sustained/repetitive cardiac arrhythmias, which has been reported in 16.7% of all hospitalised COVID-19 patients and in 44.4% of patients requiring intensive care admission to date.8

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Myocardial and Microvascular Injury Due to COVID-19 Figure 1: Mechanisms Underlying the Occurrence of Myocardial and Microvascular Injury in COVID-19 Patients

SARS-CoV-2

Respiratory failure

Plaque instability, thrombotic occlusion

Type 1 AMI

Proinflammatory milieu

Hypoxia, hypotension, arrhythmias Type 2 AMI

Hypercoagulable state

Acute microvascular dysfunction Takotsubo syndrome

Direct pericytes and endothelial injury

Viral-mediated cardiomyocyte lysis, immune activation Myocarditis

O2 AMI = acute MI; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

However, some patients could present with a type 1 MI due to preexisting coronary plaques (often present in older patients with hypertension and/or multiple comorbidities; the majority of patients admitted to hospital for COVID-19) that become unstable because of inflammatory activation due to SARS-CoV-2. The proinflammatory milieu determined by viral activity can cause a destabilisation of coronary artery plaques.9 Moreover, the procoagulatory state favours coronary artery thrombotic occlusion.3 Microvascular dysfunction is another mechanism responsible for myocardial injury in SARS-CoV-2-positive patients. Microvascular impairment in these patients can be a consequence of the exaggerated systemic inflammatory response and the relied endothelial dysfunction found to be responsible for microthrombi formation. In addition, a direct action of SARS-CoV-2 on microvessels has been suggested, as the cellular host receptor ACE-2 is also expressed on the surface of endothelial cells.10 In their study, Chen et al. demonstrated that heart pericytes have a high expression of ACE-2, thus endorsing the hypothesis that pericyte injury due to virus infection could result in capillary endothelial cell dysfunction and microvascular impairment.1 It is also well known that acute coronary microvascular dysfunction can contribute to the onset of takotsubo syndrome (TTS).11,12 At present, a few cases of TTS have been registered among COVID-19 patients; therefore, the prevalence and the prognostic impact of this syndrome in this particular patient population is still unknown.13 At the opposite end of the spectrum, myocardial injury could be a consequence of myocardial involvement in inflammatory processes leading to myocarditis. Of note, in a case series of 150 patients with COVID-19, in which 68 deaths were reported, 7% were attributed to myocarditis with circulatory failure.14 The degeneration of cardiomyocytes and inflammatory infiltrates in the myocardial interstitium have been described together with vascular disepithelisation, vasculitis and

EUROPEAN CARDIOLOGY REVIEW

microthrombi formation. However, SARS-CoV-2 has still not been isolated in the myocardium, thus experts are unable to determine whether myocarditis in COVID-19 patients is only an epiphenomenon of the infection-related systemic inflammatory response or if it could also be the direct consequence of local viral activity.15

Clinical Implications Severe respiratory distress is usually considered as a leading cause of SARS-CoV-2-induced death. Other complications are also associated with increased risk of in-hospital death. Although information on cardiac complications is limited among COVID-19 patients, cardiac impairment has been demonstrated as a direct or underlying cause of death in 27% of pneumonia-associated deaths. Even after adjustment for baseline risk, cardiac complications are associated with a 60% increase in pneumonia-associated short-term mortality.16,17 The occurrence of myocardial injury in particular has been shown to be associated with higher mortality among COVID-19 patients.9 A highly fatal possible consequence of myocardial injury due to SARSCoV-2 is the development of cardiogenic shock (CS), defined as clinical and biochemical evidence of peripheral hypoperfusion. In COVID-19 patients in the intensive care unit, CS of undetermined aetiology occurs in up to 12% of cases, and the management of this ominous complication is critically time dependent and requires multidisciplinary expertise.18 Possible causes leading to CS in these patients are ST-elevation MI (STEMI), myocarditis, stress cardiomyopathy, and acute heart failure as a consequence of respiratory and renal impairment; however, sepsis should also be considered as a possible or mixed aetiology. In this patient population, the potential beneficial and harmful effects of mechanical circulatory support (MCS) should be properly weighted to consider the procoagulatory state characteristic of COVID-19 and the need for specific treatments for lung injury, including the prone position. In critical cases, when MCS is undeferrable, venoarterial extracorporeal membrane oxygenation (VA-ECMO) is the strategy of choice, as it

COVID-19 guarantees both lung and cardiac function support. Impella and intraaortic balloon pump can be useful for left ventricular overdistention management in patients receiving VA-ECMO, and the latter should be considered as an alternative option in patients presenting with STEMIrelated mechanical complications if other MCS are not available.18 Clinicians should be aware that there are multiple pathogenic mechanisms underlying myocardial injury and a differential diagnosis is not easy. In a recent study, Stefanini et al. demonstrated that in approximately 40% of SARS-CoV-2-positive patients undergoing urgent coronary angiography for suspected ST-STEMI a culprit lesion was not detected, and other mechanisms should be investigated (i.e. type 2 MI, TTS and myocarditis).19 In particular, if myocarditis is suspected, cardiac magnetic resonance might be considered for further diagnostic assessment, whereas endomyocardial biopsy is not recommended. However, there are no clear guidelines for SARS-CoV-2-related myocarditis treatment, but anti-inflammatory drugs have proved beneficial when associated with supportive therapies.6 The management of COVID-19 patients presenting with acute coronary syndrome has been matter of debate in recent months. The latest European Society of Cardiology (ESC) guidance for the management of cardiac complications related to COVID-19 suggests that, in case of STEMI, timely primary percutaneous intervention should be performed as stated by current ESC guidelines, irrespective of SARS-CoV-2

Chen L, Li X, Chen M, et al. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res 2020;116:1097–100. https://doi.org/10.1093/cvr/cvaa078; PMID: 32227090. Tay MZ, Poh CM, Rénia L, et al. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol 2020;20:363–74. https://doi.org/10.1038/s41577-020-0311-8; PMID: 32346093. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol 2020;75:2950–73. https://doi.org/10.1016/j. jacc.2020.04.031; PMID: 32311448. Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol 2020;395:497–506. https://doi.org/10.1001/ jamacardio.2020.0950; PMID: 32211816. Shi S, Qin M, Cai Y, et al. Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019. Eur Heart J 2020;41:2070–9. https:// doi.org/10.1093/eurheartj/ehaa408; PMID: 32391877. European Society of Cardiology. ESC guidance for the diagnosis and management of CV disease during the COVID19 pandemic. ESC; 10 June 2020. https://www.escardio.org/ Education/COVID-19-and-Cardiology/ESC-COVID-19-Guidance (accessed 11 June 2020). Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan,

10.

11.

12.

13.

14.

infection, and in the absence of virological testing results available at the time of the procedure, every patient should be considered as positive. Immediate complete revascularisation when non-culprit lesions susceptible of treatment are present should be considered if appropriate to avoid staged procedures and to reduce hospital stay.18 Fibrinolysis remains the strategy of choice when percutaneous intervention is not feasible within 12 hours of symptom onset. In case of non-ST-STEMI, the treatment strategy should be based on risk stratification. In very high-risk cases, immediate invasive strategy should be performed; in high-risk cases, SARS-CoV-2 testing should be delayed if possible; and in intermediate/low-risk cases, differential diagnoses and non-invasive strategies, such as coronary computed tomography angiography, should be prioritised and appropriate followup should be planned.18 Finally, in order to reduce the occurrence of myocardial injury among COVID-19 patients, the use of medications improving microcirculation has been recently suggested. This strategy could be particularly relevant for vulnerable patients with risk factors for pre-existing endothelial dysfunction (i.e. male sex, smoking, hypertension, diabetes, obesity and established CVD).20 In conclusion, the occurrence of myocardial injury in COVID-19 patients is a frequent and prognostically relevant complication. Clinicians should be aware that multiple mechanisms could explain this phenomenon, and clinical management may differ according to the underlying mechanism.

China. JAMA Intern Med 2020. https://doi.org/10.1001/ jamainternmed.2020.0994; PMID: 32167524; epub ahead of press. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061–9. https:// doi.org/10.1001/jama.2020.1585; PMID: 32031570. Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019. JAMA Cardiol 2020. https://doi.org/10.1001/jamacardio.2020.1017; PMID: 32219356; epub ahead of press. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020;395:1417– 8. https://doi.org/10.1016/S0140-6736(20)30937-5; PMID: 32325026. Crea F, Montone RA, Niccoli G. Myocardial infarction with nonobstructive coronary arteries: dealing with pears and apples. Eur Heart J 2020;41:879–81. https://doi.org/10.1093/eurheartj/ ehz561; PMID: 31377808. Montone RA, Galiuto L, Meucci MC, et al. Coronary slow flow is associated with a worse clinical outcome in patients with takotsubo syndrome. Heart 2020;106:923–30. https://doi. org/10.1136/heartjnl-2019-315909; PMID: 31924712. Minhas AS, Scheel P, Garibaldi B, et al. Takotsubo syndrome in the setting of COVID-19 infection. JACC Case Rep 2020. https:// doi.org/10.1016/j.jaccas.2020.04.023; PMID: 32363351; epub ahead of press. Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020;46:846–8.

https://doi.org/10.1007/s00134-020-05991-x; PMID: 32125452. 15. Chen C, Zhou Y, Wang DW. SARS-CoV-2: a potential novel etiology of fulminant myocarditis. Herz 2020;45:230–2. https:// doi.org/10.1007/s00059-020-04909-z; PMID: 32140732. 16. Corrales-Medina VF, Musher DM, Wells GA, et al. Cardiac complications in patients with community-acquired pneumonia: incidence, timing, risk factors, and association with short-term mortality. Circulation 2012;125:773–81. https:// doi.org/10.1161/CIRCULATIONAHA.111.040766; PMID: 22219349. 17. Mortensen EM, Coley CM, Singer DE, et al. Causes of death for patients with community-acquired pneumonia: results from the Pneumonia Patient Outcomes Research Team cohort study. Arch Intern Med 2002;162:1059–64. https://doi. org/10.1001/archinte.162.9.1059; PMID: 11996618. 18. Chieffo A, Stefanini GG, Price S, et al. EAPCI position statement on invasive management of acute coronary syndromes during the COVID-19 pandemic. EuroIntervention 2020. https://doi. org/10.4244/EIJY20M05_01; PMID: 32404302; epub ahead of press. 19. Stefanini GG, Montorfano M, Trabattoni D, et al. ST-elevation myocardial infarction in patients with COVID-19: clinical and angiographic outcomes. Circulation 2020. https://doi.org/ 10.1161/CIRCULATIONAHA.120.047525; PMID: 32352306; epub ahead of press. 20. Kuster GM, Pfister O, Burkard T, et al. SARS-CoV2: should inhibitors of the renin–angiotensin system be withdrawn in patients with COVID-19? Eur Heart J 2020;41:1801–3. https:// doi.org/10.1093/eurheartj/ehaa235; PMID: 32196087.

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Platelets and the Coagulation System

Using Pharmacogenetic Testing to Tailor Warfarin Therapy: The Singapore Experience and What the Future Holds Grace Shu-wen Chang and Doreen Su-Yin Tan Department of Pharmacy, Khoo Teck Puat Hospital, Yishun Health, Singapore

Abstract Genetic polymorphisms significantly affect individual responses to warfarin, contributing to unpredictability and challenges in managing anticoagulation. Although numerous studies have demonstrated that pharmacogenetic testing improves anticoagulation-related outcomes in the Caucasian population, its effect in the Asian population has not been well studied. This article discusses controversies surrounding tailoring warfarin therapy using pharmacogenetic testing and its role in clinical practice, with a focus on the Asian context. Using the Singapore experience as an example, the authors propose how pharmacogenetic testing can be a means to reduce dose titrations in select patient populations, and how it may be positioned as an enabler to reduce healthcare resources needed for anticoagulation management.

Keywords Warfarin, direct-acting oral anticoagulants, VKORC1 gene testing, CYP2C9 gene testing, Asian, anticoagulation, personalised medicine Disclosure: The authors have no conflicts of interest to declare. Received: 9 August 2019 Accepted: 3 April 2020 Citation: European Cardiology Review 2020;15:e53. DOI: https://doi.org/10.15420/ecr.2019.12 Correspondence: Grace Shu-wen Chang, Department of Pharmacy, Khoo Teck Puat Hospital, 90 Yishun Central, Singapore 768828. E: chang.grace.sw@ktph.com.sg Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Warfarin is a widely used anticoagulant for the prevention and treatment of thromboembolic disorders. It is well known that there is considerable inter-individual variability in warfarin dose requirements. Furthermore, because warfarin has a narrow therapeutic window, there is a risk of serious sequelae, such as thromboembolism or bleeding, if international normalised ratio (INR) levels fall into the sub- or supratherapeutic range, respectively. Dosing is highly individualised and is affected by various factors, including age, ethnicity, concomitant drugs used, nutritional status and acute and chronic disease states, among others. Maintenance doses in patients have been observed to range from as little as 1 to >10 mg/day. This leads to significant delays in achieving INR within the therapeutic range, especially when prescribers are inexperienced with warfarin titration. Genetic polymorphisms are important factors affecting an individual’s dose requirements for warfarin. Genetic variants of the vitamin K epoxide reductase complex subunit 1 (VKORC1) gene, which encodes the target enzyme of warfarin, the cytochrome P450 family 2 subfamily C member 9 (CYP2C9) gene, which is the main enzyme involved in warfarin metabolism and the cytochrome P450 family 4 subfamily F member 2 (CYP4F2) gene, as well as other non-genetic factors, such as age, smoking status, concomitant drugs and comorbid conditions, account for approximately 50% of the variability in warfarin dose requirements, and up to 60% in Singapore.1,2 Patients who have the VKORC1 –1639 G>A variant are more sensitive to warfarin, and those who carry the decreased function alleles CYP2C9*2 and CYP2C9*3 have reduced dose requirements due to impaired metabolism.

The effects of genotype on warfarin dose are well recognised, as evidenced by drug labels such as those of the Food and Drug Administration and the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for pharmacogenetics (PGx)-guided warfarin dosing.1 The CPIC guidelines strongly recommend a PGxguided approach in patients of non-African ancestry, although there is a difference in the spread of genetic variants between Caucasians and Asian populations (Table 1) that makes these recommendations challenging to contextualise.1 In general, Asians are under-represented in validated models used in clinical trials, making it difficult to routinely apply the recommendations in Asia.3 When faced with heterogeneous patient populations in our practice, which includes Asian patients, how should we be tackling these differences and can genotyping help? What is the current evidence for and against warfarin genotyping, and how should it be positioned based on what we know? This article briefly reviews the current evidence surrounding genotype-guided dosing and discusses the role of genotyping in an Asian context, such as Singapore. In addition, we share our experience of implementing genotype-guided warfarin dosing and our opinion on its usefulness in the real-world setting.

Key Trials for Genotype-guided Dosing Although the latest disease-specific major society guidelines mention the effect of genotype on warfarin dose, they do not recommend routine testing. In 2013, two important studies were published. The first of these studies was the European Pharmacogenetics of Anticoagulation Therapy (EU-PACT) trial, considered a ‘positive’ study,

Access at: www.ECRjournal.com

Platelets and the Coagulation System Table 1: Reported Prevalence of Minor Allele Frequencies by Ancestry Variant

Prevalence of minor allele frequency (%) European

African–American

Asian

VKORC1 –1639A

CYP2C9*2

3–4

CYP2C9*3

1–3

6–8

CYP4F2 –433Met

40–42

CYP2C9 = cytochrome P450 family 2 subfamily C member 9; CYP4F2 = cytochrome P450 family 4 subfamily F member 2; VKORC1 = vitamin K epoxide reductase complex subunit 1. Source: Johnson et al.10 Adapted with permission from the American Society for Pharmacology and Experimental Therapeutics (ASPET).

which compared PGx-guided dosing versus fixed dosing in a homogeneous European population (n=445).4 At 12 weeks, the primary outcome of the percentage of time in the therapeutic range (%TTR), as well as the secondary endpoints of INR ≥4 and time to attain stable dosing, were better in the PGx-guided dosing than the comparator arm.4 The second study was the Clarification of Optimal Anticoagulation Through Genetics (COAG) trial, comparatively thought of as the ‘negative’ study, which was performed in an ethnically diverse North American population (n=1,015).5 The COAG trial compared PGx-guided dosing versus a clinical algorithm that took into consideration age, body size, interacting drugs and other factors. The results of COAG showed no difference in time to stable dose, %TTR or a reduction in the number of episodes with out-of-range INR values or bleeding.5 The absence of recommendations regarding the routine use of PGx-guided warfarin dosing is likely due to the conflicting findings from these two clinical trials.

are three main ethnic groups in Singapore, namely Chinese (~74% of the population), Malay (13%) and Indian (9%), with a small proportion of Caucasian and other ethnicities (3%).7 Clear interethnic genotypic differences have been reported for the Singaporean population.8 Specifically, Chinese and Malays have lower warfarin requirements, reflective of the typical ‘Asian’ profile, whereas Indians require higher maintenance doses, more closely resembling the ‘Caucasian’ profile. Local Singaporean data regarding PGx-guided warfarin dosing appears reassuring. Locally developed dosing algorithms incorporating VKORC1 and CYP2C9 status predicted up to 60.2% and 73.4% of variability in dose requirements among Chinese patients and the population as a whole, respectively.2,9 In 2018, the results of an open-label randomised trial consisting of 322 patients and testing the utility of the algorithm of Tham et al.2 were published.6 In that study, the PGx-guided approach significantly reduced the number of dose titrations within the first 2 weeks (1.77 versus 2.93; p<0.001 for both non-inferiority and superiority) and the number of dose adjustments required over a 90-day follow-up period (4.51 versus 6.06; p=0.001) compared with a traditional dosing approach. Both approaches had similar efficacy (%TTR at 3 months 60.0% versus 57.1%; p=0.29) and comparable rates of bleeding events.6 These results suggest that dose titrations could potentially be reduced by approximately 30%, translating into reductions in hospital length of stay and the number of outpatient appointments.

Determining the Best Algorithm for Genotype-guided Dosing

Genotype-guided Dosing in Singapore

With numerous algorithms available in the literature, how does one decide on the best algorithm for patients? We aimed to answer this question by performing a correlation study using two different algorithms to predict maintenance dose. All-comers newly initiated on warfarin for indications requiring therapy for a minimum of 3 months and those who had never been on a stable dose of warfarin before were included in the study. Predicted doses were calculated for each patient using two algorithms, namely the validated Gage algorithm used in the COAG trial5 and the locally developed algorithm by Tham et al.2 The predicted doses were then compared to the actual maintenance dose for each patient. The results showed that the mean prediction error, calculated by the mean difference between the predicted and actual stable doses, was 0.4 ± 1.3 mg/day with the Gage algorithm and 0.1 ± 1.3 mg/day with the Tham algorithm (Chang et al., unpublished data, 2015). The doses predicted by the two algorithms had moderately strong correlations with the actual stable dose (R2=0.69 and 0.68 for the Gage and Tham algorithms, respectively). The doses predicted by both algorithms were strongly correlated with each other (R2=0.95). Compared with a cohort of 81 patients who received standard dosing, our PGx-guided dosing arm trended towards achieving a stable dose more quickly (16.0 versus 18.5 days; p=0.49) with a commendable 90-day %TTR of 71.1%. There were no bleeding or thromboembolic events in either group. The mean daily dose of warfarin in patients who achieved a stable dose according to ethnicity was 2.9 ± 1.1 mg/day for Chinese, 3.5 ± 1.6 mg/day for Malays and 5.9 ± 3.1 mg/day for Indians; which mirror our observations in practice and further confirm the ‘heterogeneity’ of our population. In addition, the data confirmed the spread of genotypic variants in Singapore (Table 2). Based on these results, we concluded that either algorithm can be used for PGx-guided dosing, particularly the Gage algorithm, which can be accessed at WarfarinDosing.org.

We are fortunate to have data available regarding PGx-guided warfarin dosing in Singapore.6 Singaporeans are heterogeneous in genetic make-up, as seen in the genotype differences observed thus far. There

To summarise local findings, genotyping appears to be safe and efficacious and can reduce the number of dose titrations. Unlike in the

These two large trials, with essentially the same study design but performed in different geographical locations and yielding different results, illustrate the complexities in interpreting studies on PGxguided dosing. Plausible explanations for the discordant findings lay in the different dosing strategies for the comparator arms, as well as in the ethnic make-up of the study populations. In terms of dosing strategies, the comparator arm in COAG used a clinical algorithm, whereas the EU-PACT trial used an algorithm with fixed doses. The clinical algorithm would be expected to perform better because it accounts for various factors affecting anticoagulation, unlike the fixeddose approach, which is actually more pragmatic and reflective of actual practice. In terms of ethnic make-up, the COAG trial included a heterogeneous population comprising 30% African–Americans, whereas EU-PACT was performed on a homogeneous European population. African–Americans carry additional variants of CYP2C9*5, CYP2C9*6, CYP2C9*8 and CYP2C9*11, and the lack of inclusion of these variants in COAG was a possible factor in reducing the accuracy of the predicted dose. Because the results from COAG suggested harm in the African–American subgroup, CPIC discourages PGx-guided dosing for African–Americans if testing for the additional variants is not available. In conclusion, the results of these trials indicate that a good understanding of the factors contributing to the accuracy of predicted doses is instrumental in determining how useful a genotype-guided dosing strategy will be.

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The Singapore Experience and What the Future Holds COAG study, even though our study population appeared heterogeneous, we managed to demonstrate good anticoagulation control with a %TTR of >70%. This is likely because our local patients did not have rare alleles like CYP2C9*5, CYP2C9*6, CYP2C9*8 and CYP2C9*11, which was the issue with the subgroup in COAG.5

Which Populations Would Benefit from Genotype-guided Dosing? Below, we discuss which patient populations would likely benefit from genotyping. In terms of positioning, we believe genotyping is best used locally as an enabler to reduce healthcare resources needed for anticoagulation management. Two possible scenarios are discussed below: MI patients with left ventricular (LV) thrombi, in whom warfarin is used exclusively; and cases in which there is the possibility of significant drug–drug interactions with warfarin.

Patient Groups in Whom Warfarin is Used Exclusively There are insufficient data for the use of direct oral anticoagulants (DOACs) in patients with MI who have LV thrombi, and so warfarin is used exclusively in this patient group. Most of these patients are young males with no significant past medical history and are otherwise fit for discharge after coronary revascularisation. Instead, they remain hospitalised for periods up to 1 week purely for warfarin titration, with no other active medical issues other than receiving subcutaneous enoxaparin and waiting for their INR to rise. With PGx-guided estimation of the maintenance dose, loading doses can be administered with greater confidence, and patients can be discharged early with enoxaparin to self-administer and a same-week outpatient appointment to return for INR monitoring. This strategy expedites the freeing-up of precious hospital beds and allows patients to return to their family and work commitments sooner. At our institution (Khoo Teck Puat Hospital), approximately eight patients newly start warfarin each month (close to 100 patients per year) for LV thrombus after MI. Bearing in mind Khoo Teck Puat Hospital is the smallest restructured hospital in Singapore by bed size, and adding up the numbers from all other institutions, we estimate that warfarin genotyping may benefit close to 1,000 patients per year in Singapore.

Drug–Drug Interactions with Warfarin Another scenario in which genotyping could be positioned is when there are significant drug–drug interactions with warfarin. Patients on concomitant antiretroviral, antituberculosis and antiepileptic treatments receive warfarin exclusively because concomitant DOAC use is contraindicated and poorly studied. Warfarin dose fluctuations are even more unpredictable in these patients, with the only solution being to monitor and order blood draws even more frequently than usual. We suggest that genotyping be used to first derive a predicted maintenance dose in the absence of the drug interaction and then to adjust the predicted dose up or down based on the nature of the interaction. This reduces unpredictability in the initiation phase and reduces the number of titrations, translating to fewer outpatient visits. A reduction in the number of appointments and blood draws would be especially appreciated by the patients, because they are likely to be already laden with multiple specialist appointments for their various medical conditions. Although this scenario is less common

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Table 2: Genotypic Variants and Warfarin Maintenance Dose According to Ethnicity in the Singapore Population Chinese Malay (n=59) (n=41)

Indian (n=9)

VKORC1 –1639A

CYP2C9*2

CYP2C9*3

Mean ± SD warfarin maintenance dose (mg/day)

2.9 ± 1.1

3.5 ± 1.6

5.9 ± 3.1

Variant frequency (%):

CYP2C9 = cytochrome P450 family 2 subfamily C member 9; VKORC1 = vitamin K epoxide reductase complex subunit 1. Data taken from the unpublished WARFGEN study.

than the one described above, as we move towards patient-centred care we believe that the time and effort saved would be significant for each individual patient. With regard to the specific populations highlighted above, we are further exploring the comparisons in a larger cohort as part of the iRight4Me program at our institution because of the large burden of LV thrombus observed. We look forward to sharing our results and experiences in subsequent publications.

Cost-effectiveness of Genotype-guided Dosing Concerns about genotyping involve the question of cost-effectiveness; this has not been formally studied in Singapore. However, with advances in technology, the cost of genotyping can now be comparable to that of routine investigations. In Singapore, a patient’s out-of-pocket cost for genotyping is approximately US$75 (SG$100). In comparison, one outpatient-based visit, comprising an Anticoagulation Clinic consult and a blood draw to monitor INR, costs approximately US$50 (SG$70) with opportunity costs of half a day off work or time away from daily commitments. One hospital bed day saved to monitor INR would translate to cost savings of approximately US$850 (SG$1,200) for the institution and US$150 (SG$200) out-of-pocket costs for the patient after implementation of government subsidies. Extrapolating the findings of Syn et al., who found that 30% of dose titrations could be saved with genotyping-guided dosing, warfarin genotyping, which only needs to be performed once in each patient’s life, would more than pay for itself if positioned for the working individual or that caregiver who has to accompany an elderly patient to clinic appointments.6

Conclusion Based on our experience in Singapore, despite a heterogeneous population the genotype-guided predicted and actual maintenance doses were moderately correlated (R2≈0.7). With the advent of DOACs, most patients will receive DOACs, but a subgroup will still require warfarin for LV thrombi, multimorbidity or renal impairment. It would be acceptable to implement warfarin genotyping as a means of saving costs through avoided appointments and reduced hospital length of stay. Finally, there is a lack of evidence for genotyping in the multimorbid population, and future studies should investigate genotype-guided warfarin dosing in the aforementioned special populations. We look forward to sharing our experience in these populations from the iRight4me program at our institution.

Platelets and the Coagulation System 1.

Johnson JA, Caudle KE, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for pharmacogenetics-guided warfarin dosing: 2017 update. Clin Pharmacol Ther 2017;102:397–404. https://doi. org/10.1002/cpt.668; PMID: 28198005. Tham LS, Goh BC, Nafziger A, et al. A warfarin-dosing model in Asians that uses single-nucleotide polymorphisms in vitamin K epoxide reductase complex and cytochrome P450 2C9. Clin Pharmacol Ther 2006;80:346–55. https://doi.org/10.1016/j. clpt.2006.06.009; PMID: 17015052. Gage BF, Eby C, Johnson JA, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther 2008;84:326–31. https://doi.org/10.1038/ clpt.2008.10; PMID: 18305455. Pirmohamed M, Burnside G, Eriksson N, et al. A randomized

trial of genotype-guided dosing of warfarin. N Engl J Med 2013;369:2294–303. https://doi.org/10.1056/NEJMoa1311386; PMID: 24251363. Kimmel SE, French B, Kasner SE, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med 2013;369:2283–93. https://doi.org/10.1056/NEJMoa1310669; PMID: 24251361. Syn NL, Wong AL, Lee SC, et al. Genotype-guided versus traditional clinical dosing of warfarin in patients of Asian ancestry: a randomized controlled trial. BMC Med 2018;16:104. https://doi.org/10.1186/s12916-018-1093-8; PMID: 29986700. Department of Statistics Singapore. Population Trends 2018. Singapore: Department of Statistics Singapore; 2018. https:// www.singstat.gov.sg/-/media/files/publications/population/

population2018.pdf (accessed 21 June 2020). Lee SC, Ng SS, Oldenburg J, et al. Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population. Clin Pharmacol Ther 2006;79:197–205. https://doi.org/10.1016/j.clpt.2005.11.006; PMID: 16513444. 9. Sandanaraj E, Lal S, Cheung YB, et al. VKORC1 diplotypederived dosing model to explain variability in warfarin dose requirements in Asian patients. Drug Metab Pharmacokinet 2009;24:365–75. https://doi.org/10.2133/dmpk.24.365; PMID: 19745563. 10. Johnson JA, Cavallari LH. Pharmacogenetics and cardiovascular disease – implications for personalized medicine. Pharmacol Rev 2013;65:987–1009. https://doi. org/10.1124/pr.112.007252; PMID: 23686351.

EUROPEAN CARDIOLOGY REVIEW

Letter to the Editor

Smoking and Angiotensin-converting Enzyme Inhibitor/Angiotensin Receptor Blocker Cessation to Limit Coronavirus Disease 2019 Marco Rossato and Angelo Di Vincenzo Clinica Medica 3, Department of Medicine – DIMED, University Hospital of Padova, Italy

Keywords Coronavirus disease 2019, COVID-19, SARS-CoV-2, cigarette smoking, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers Disclosure: The authors have no conflicts of interest to declare. Received: 8 May 2020 Accepted: 20 May 2020 Citation: European Cardiology Review 2020;15:e54. DOI: https:/doi.org/10.15420/ecr.2020.20 Correspondence: Marco Rossato, Department of Medicine, Clinica Medica 3, University Hospital of Padova, Via Giustiniani, 2, 35128 Padova, Italy. E: marco.rossato@unipd.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

We read with interest the paper by Komiyama and Hasegawa on the need for smoking cessation as a public health measure to limit the coronavirus disease 2019 (COVID-19) pandemic.1 It seems obvious to reiterate that smoking cessation is advisable to reduce many other severe conditions, such as chronic lung and cardiovascular diseases and some types of cancer, which are leading causes of morbidity and mortality. Cigarette smoking kills more than 8 million people each year worldwide, with more than 7 million of those deaths being the result of direct tobacco use and around 1 million occurring in non-smokers exposed to second-hand smoke.2 Aside from this, regarding the COVID-19 pandemic, the authors state that published data appear to indicate an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, morbidity and mortality in smokers due to the possible effect of smoking in overexpressing angiotensin-converting enzyme 2 (ACE2). This protein is found in various tissues, mainly in the lungs, gastrointestinal tract and testes, which SARS-CoV-2 uses to enter the host cell, so this possibly increases the risk of infection.3 However, published data at the time the authors’ paper was submitted to European Cardiology Review (7 April 2020), coming mainly from China, indicated the opposite, noting that current smokers are strongly under-represented among patients hospitalised for COVID-19.4,5 A recent analysis covering 8,910 patients hospitalised for COVID-19 in Asia, Europe and the US showed that only 5.5% were current smokers and 94.5% were former or non-smokers and, among non-survivors, the percentage of current smokers was lower than that of former smokers.6 In a recent published paper, we reported that among 132 patients hospitalised at the University Hospital of Padova for COVID-19 pneumonia, none were current smokers, 84.8% were former smokers and 15.2% had never smoked.7 Nonetheless, we are far from hypothesising that cigarette smoking has a ‘protective’ role regarding susceptibility to SARS-CoV-2 infection or COVID-19 complications.

We are also aware that any public health policy perspective cannot be left only to science. If scientific evidence shows that smoking is protective against COVID-19, we absolutely cannot suggest people smoke to avoid SARS-CoV-2 infection. Researchers have to gain more insight into the pathogenesis of SARS-CoV-2 to discover any possible biological mechanism related to the low prevalence of smokers among COVID-19 patients, considering for example the role of ACE2 expression that has been shown to be downregulated by cigarette smoking at least in experimental animals.8 Furthermore, Komiyama and Hasegawa state that ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs) increase the expression of ACE2, the putative receptor that SARS-CoV-2 uses to enter the host cell.1 To this regard, they report that many scientific societies, including the European Society of Cardiology (ESC), have issued alerts suggesting patients discontinue ACEis and ARBs and switch to calcium antagonists. This is not correct. In its recent position statement, the ESC Council on Hypertension has expressed concern over any speculation about the safety of ACEi or ARB treatment in relation to COVID-19, since this does not have any scientific basis or evidence to be supported at yet. In that statement, patients are recommended to continue their usual antihypertensive therapy because of a lack of any clinical or scientific evidence to suggest that treatment with ACEis or ARBs should be discontinued to prevent SARS-CoV-2 infection or reduce COVID-19 severity.9 Many other highly reputable scientific societies, including the American Heart Association, the American College of Cardiology and the Heart Failure Society of America, have issued similar recommendations.10 Recent data published after the Komiyama and Hasegawa paper did not provide evidence that patients treated with ACEis and ARBs were at a higher risk for COVID-19.1,6 Those treated with ACEis had a better chance of survival to hospital discharge and there was no

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Letter to the Editor such association for ARBs. However, these results should be considered with caution since they were not derived from a randomised controlled study.6

2. 3.

Komiyama M, Hasegawa K. Smoking cessation as a public health measure to limit the coronavirus disease 2019 pandemic. Eur Cardiol 2020;15:e16. https://doi.org/10.15420/ ecr.2020.11; PMID: 32373189. WHO. Tobacco. Key facts. 2019. https://www.who.int/newsroom/fact-sheets/detail/tobacco (accessed 27 May 2020). Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271–80.e8. https://doi.org/10.1016/j.cell.2020.02.052; PMID: 32142651. Lippi G, Henry BM. Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19). Eur J Intern Med 2020;75:107–8. https://doi.org/10.1016/j.ejim.2020.03.014; PMID: 32192856.

In conclusion, Komiyama and Hasegawa’s suggestions do not seem to fit adequately with what is currently known from the literature.1 Nonetheless, the advice to stop smoking must be followed anyway.

Miyara M, Tubach F, Pourcher V, et al. Low rate of daily active tobacco smoking in patients with symptomatic COVID-19. Qeios 2020. https://doi.org/10.32388/WPP19W.4; preprint. Mancia G, Rea F, Ludergnani M, et al. Renin–angiotensin– aldosterone system blockers and the risk of Covid-19. N Engl J Med 2020;382:2431–40. https://doi.org/10.1056/ NEJMoa2006923; PMID: 32356627. Rossato M, Russo L, Mazzocut S, et al. Current smoking is not associated with COVID-19. Eur Respir J 2020;55:2001290. https://doi.org/10.1183/13993003.01290-2020; PMID: 32350106. Oakes JM, Fuchs RM, Gardner JD, et al. Nicotine and the reninangiotensin system. Am J Physiol Regul Integr Comp Physiol

2018;315:R895–906. https://doi.org/10.1152/ ajpregu.00099.2018. PMID: 30088946. European Society of Cardiology. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers. 2020. https://www.escardio.org/Councils/ Council-on-Hypertension-(CHT)/News/position-statement-ofthe-esc-council-on-hypertension-on-ace-inhibitors-and-ang (accessed 27 May 2020). 10. American College of Cardiology. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. 2020. https://www.acc.org/latest-in-cardiology/ articles/2020/03/17/08/59/hfsa-acc-aha-statement-addressesconcerns-re-using-RAAS-antagonists-in-COVID-19 (accessed 27 May 2020). 9.

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COVID-19

Response to the Comment ‘Smoking and Angiotensin-converting Enzyme Inhibitor/Angiotensin Receptor Blocker Cessation to Limit Coronavirus Disease 2019’ Maki Komiyama and Koji Hasegawa National Hospital Organization Kyoto Medical Center, Kyoto, Japan

Keywords Current smoking, former smoking, COVID-19 Received: 25 May 2020 Accepted: 8 June 2020 Citation: European Cardiology Review 2020;15:e55. DOI: https://doi.org/10.15420/ecr.2020.25 Correspondence: Koji Hasegawa, Division of Translational Research, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihatacho Fukakusa, Fushimi-ku, Kyoto 612-8555, Japan. E: koj@kuhp.kyoto-u.ac.jp Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Thank you very much for your interesting and important comments on our review that discussed smoking cessation to limit the coronavirus disease 2019 (COVID-19) pandemic.1,2 As you pointed out, the reported number of hospitalised COVID-19 patients who are current or former smokers is small.3,4 One reason for this small number of smokers is that an unknown history of smoking may be treated as a non-smoking history. Most emergency or sub-emergency COVID-19 patients are admitted to hospital as new patients. Because medical workers face difficulty in managing these patients, smoking history is often insufficiently assessed in the real-world clinical setting. Another reason for the small number of hospitalised COVID-19 patients who are current smokers is that older age is associated with a reduced prevalence of current smoking and an increased prevalence of former smoking. As you reported, former smokers constitute a major category of hospitalised COVID-19 patients.5 Furthermore, former smokers, as a result of a long history of smoking, have comorbidities, such as cardiovascular disease, chronic obstructive pulmonary disease, diabetes and cancer. In fact, the report cited in our

Rossato M, Di Vincenzo A. Smoking and angiotensinconverting enzyme inhibitor/angiotensin receptor blocker cessation to limit coronavirus disease 2019. Eur Cardiol 2020;15:e54. https://doi.org/10.15420/ecr.2020.20. Komiyama M, Hasegawa K. Smoking cessation as a public health measure to limit the coronavirus disease 2019 pandemic. Eur Cardiol 2020;15:e16. https://doi.org/10.15420/ ecr.2020.11; PMID: 32373189. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708–20. https:// doi.org/10.1056/NEJMoa2002032; PMID: 32109013. CDC COVID-19 Response Team. Preliminary estimates of the

review states that the proportion of patients with progression to severe COVID-19 status was the highest in former smokers, followed by current smokers, whereas the proportion was low in non-smokers.3 However, a systematic literature review and meta-analysis has demonstrated that current smoking is associated with a greater risk of critical or mortal COVID-19 status.6 Therefore, smoking cessation is an important measure to limit the severity of COVID-19. There may be multiple mechanisms underlying the association of smoking with disease progression. Angiotensin-converting enzyme (ACE) 2 appears to play a protective role against pneumonia. At the beginning of the pandemic, concerns were raised that ACE inhibitors could predispose individuals to severe COVID-19. However, recent evidence has shown that ACE inhibitors and angiotensin receptor blockers do not increase the risk of severe COVID-19.7 This is in agreement with international guideline recommendations that these medications should not be withdrawn in patients currently taking them and that there is no contraindication at present for the use of ACE inhibitors/angiotensin receptor blockers in patients with COVID-19.8

prevalence of selected underlying health conditions among patients with coronavirus disease 2019 – United States, February 12–March 28, 2020. MMWR Morb Mortal Wkly Rep 2020;69:382–6. https://doi.org/10.15585/mmwr.mm6913e2; PMID: 32240123. Rossato M, Russo L, Mazzocut S, et al. Current smoking is not associated with COVID-19. Eur Respir J 2020;55:2001290. https://doi.org/10.1183/13993003.01290-2020; PMID: 32350106. Zheng Z, Peng F, Xu B, et al. Risk factors of critical & mortal COVID-19 cases: a systematic literature review and metaanalysis. J Infect 2020. https://doi.org/10.1016/j.

jinf.2020.04.021; PMID: 32335169; epub ahead of press. Abajo FJ, Rodriguez-Martin S, Lerma V, et al. Use of reninangiotensin-aldosterone system inhibitors and risk of COVID19 requiring admission to hospital: a case-population study. Lancet 2000;395:1705–14. https://doi.org/10.1016/S01406736(20)31030-8; PMID: 32416785. Position Statement of the ESC Council on hypertension on ACE-inhibitors and angiotensin receptor blockers. 2020. https://www.escardio.org/Councils/Council-on-Hypertension(CHT)/News/position-statement-of-the-esc-council-onhypertension-on-ace-inhibitors-and-ang (accessed 19 June 2020).

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Dyslipidaemia

Assessing Atherosclerotic Cardiovascular Disease Risk with Advanced Lipid Testing: State of the Science Charles Amir German and Michael David Shapiro Division of Cardiovascular Disease, Center for Preventive Cardiology, Wake Forest Baptist Medical Center, Winston-Salem, NC, US

Abstract Cardiovascular disease is the number one cause of death and disability worldwide. While substantial gains have been made in reducing cardiovascular mortality, future projections suggest that we have reached a nadir and may be at an inflection point, given the rising tide of obesity and diabetes. Evaluation and management of plasma lipids is central to the prevention of atherosclerotic cardiovascular disease. Although the standard lipid panel represents a well-established platform to assess risk, this test alone can be insufficient and/or misleading. Advances in our understanding of atherosclerosis have led to the development of lipid-based biomarkers that help to discriminate the risk of cardiovascular disease when it is unclear. While these biomarkers provide novel information, their implementation into clinical medicine remains difficult given discrepancies in the literature, lack of assay standardisation, poor accessibility and high cost. However, additional measures of atherogenic lipoproteins or their surrogates may offer insight beyond the standard lipid panel, providing a more precise assessment of risk and more accurate assessment of lipid-lowering therapy.

Keywords Lipids, cholesterol, prevention, cardiovascular disease, lipoprotein Disclosure: MDS receives compensation for advisory activities from Regeneron and consulting for Amarin. CAG has no conflicts of interest to declare. Received: 30 November 2019 Accepted: 17 February 2020 Citation: European Cardiology Review 2020;15:e56. DOI: https://doi.org/10.15420/ecr.2019.18 Correspondence: Michael D Shapiro, Center for Prevention of Cardiovascular Disease, Wake Forest Baptist Medical Center, 1 Medical Center Blvd, Winston-Salem, NC 27157, US. E: mdshapir@wakehealth.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Cardiovascular disease (CVD) is the leading cause of mortality in the world, accounting for 17.9 million deaths per year and 31% of deaths worldwide.1 In addition to the toll on human life, the healthcare cost of CVD continues to grow, with estimates of up to US$1.1 trillion by 2035.1 Given the significant public health burden of disease as well as the cost of healthcare, we must shift our focus from downstream treatment to upstream prevention of CVD. Guidelines on the prevention of CVD in clinical practice recommend the assessment of total CVD risk. Many risk assessment tools have been developed and validated, including the Systematic Coronary Risk Estimation (SCORE) system and Pooled Cohort Equations (PCE), which represent the gold standard in Europe and the US respectively.2,3 These tools incorporate age and gender, among other factors, to calculate an estimated risk of CVD over time. However, these risk assessment tools have inherent limitations, with several studies demonstrating over- or under-estimation of risk in certain populations, highlighting their imprecision.4â&#x20AC;&#x201C;8 Total cholesterol, high-density lipoprotein (HDL) cholesterol (HDL-C) and low-density lipoprotein (LDL) cholesterol (LDL-C) are important parameters in determining CVD risk, though the standard lipid profile alone does not reliably capture all lipid-related atherosclerotic risk in an individual patient. Several other lipid and lipoprotein assays have been developed with the goal of guiding lipid-modifying

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therapies, to improve risk assessment and prevent incident or recurrent CVD. A fundamental understanding of terminology and basic lipoprotein physiology must be established in order to appropriately identify and implement these biomarkers of CVD risk (Tables 1 and 2). This article addresses the current state of the science regarding advanced lipid testing and its implications for clinical care.

Non-high-density Lipoprotein Cholesterol Non-HDL-C represents the cholesterol contained in all lipoproteins except HDL-C and it can be calculated from the standard lipid panel by subtracting HDL-C from total cholesterol. It represents the cholesterol content present in all atherogenic lipoproteins and serves as a better surrogate for the overall atherogenic burden than LDL-C alone, making it a useful marker in the assessment of CVD risk.9 As non-HDL-C serves as a surrogate for the entire spectrum of atherogenic lipoproteins, estimation of lipoprotein-related atherosclerotic risk may be more accurate than simply using LDL-C.10 Moreover, non-HDL-C offers several additional advantages over LDL-C in assessing risk. For example, non-HDL-C is easily calculated from the standard lipid profile and incurs no added cost. It can be measured in the non-fasting state, making it easier to attain for the patient and the healthcare provider, although some guidelines suggest non-fasting lipid

ÂŠ RADCLIFFE CARDIOLOGY 2020

Advanced Lipid Testing Table 1: Definitions of Lipids, Lipoproteins and Apolipoproteins Lipids

Broad grouping of molecules including fatty acids, monoglycerides, diglycerides and triglycerides, phospholipids, sphingolipids, sterols (including cholesterol), terpenes, fat-soluble vitamins, prenols and eicosanoids

Lipoprotein

A macromoelcular complex that is soluble in plasma and contains an internal core of lipids. It consists of esterified and unesterified cholesterol, triglycerides, phospholipids and apolipoproteins

Apolipoprotein

The protein constituent of lipoproteins. Apolipoproteins play a role in assembly and secretion of lipoproteins, provide structural integrity, activate or inhibit enzymes and act as ligands for specific receptors, mitigating uptake of particles or lipid components

Table 2: Plasma Lipoprotein Classes Lipoprotein

Origin

Size (nm)

Density (g/ml)

Predominant Lipids

Major Apoliproprotein

Chylomicron

Intestine

75–1,200

<0.930

Triglycerides

apoB48

Chylomicron Remnant

Chylomicron metabolism

30–80

0.930–1.006

Triglycerides Cholesterol

apoB48

VLDL

Liver

40–50

0.930–1.006

Triglycerides

apoB100

IDL

VLDL

25–35

1.006–1.019

Triglycerides Cholesterol

apoB100

LDL

IDL

18–25

1.019–1.063

Cholesterol

apoB100

HDL

Liver, intestine

5–12

1.063–1.210

Cholesterol Phospholipids

apoA-I

Lp(a)

Liver

20–30

1.055–1.085

Cholesterol

apo(a)

apoB100 = apolipoprotein B100; apoB48 = apolipoprotein B48; apoA–I = apolipoprotein A–I; apo(a) = apolipoprotein(a); HDL = high-density lipoprotein; IDL = intermediate-density lipoprotein; VLDL = very low-density lipoprotein.

values are also acceptable.11 Non-HDL-C levels help to identify a subset of patients with residual CVD risk despite having controlled LDL-C, particularly in those with metabolic syndrome and/or diabetes.12,13

single copy of apoB. Thus, apoB represents a better proxy of total atherogenic lipoprotein particle concentration than the lipid fractions measured in the standard lipid panel.

Several key organisations provide formal guidance regarding the clinical use of non-HDL-C. The 2019 European Society of Cardiology/ European Atherosclerosis Society (ESC/EAS) guideline recommends using non-HDL-C as part of routine lipid analysis for risk evaluation in patients with diabetes or elevated triglycerides and in patients with very low LDL-C levels. They propose non-HDL-C targets of <2.2 mmol/l (<85 mg/dl), <2.6 mmol/l (<100 mg/dl), and <3.3 mmol/l (130 mg/dl) for people at very high, high and moderate risk, respectively.11 These targets are also referenced in a consensus statement released from the EAS and the European Federation of Clinical Chemistry and Laboratory Medicine (EAS/EFLM) as secondary treatment goals.14 The National Lipid Association (NLA) states that non-HDL-C outperforms LDL-C in the prediction of CVD, and thus advocates for its inclusion when reporting standard lipid laboratory values in a patient’s medical record.15 The 2018 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guideline also mentions non-HDL-C in several capacities. According to the ACC/AHA guideline, non-HDL-C can be used to define primary hypercholesterolaemia (non-HDL-C 4.9–5.7 mmol/l; 190–219 mg/dl) as a risk-enhancing factor and may facilitate decisions regarding initiation of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (non-HDL-C ≥2.6 mmol/l) (≥100 mg/dl) in those with established atherosclerotic CVD.16

To be clear, while both apoB and non-HDL-C are useful biomarkers for risk assessment, they quantify different parameters. ApoB represents the concentration of atherogenic particles in the plasma, whereas nonHDL-C represents the concentration of cholesterol trafficked by atherogenic lipoproteins in the plasma. However, non-HDL-C and apoB are highly correlated and both perform better than LDL-C when assessing risk of atherosclerotic CVD.17–19 While some studies have found apoB to be a superior biomarker of atherosclerotic CVD risk compared with LDL-C or non-HDL-C, others report similar risk prediction compared withnon-HDL-C.20,21 Measurement of apoB can be accomplished either directly or indirectly by vertical auto profile, nuclear magnetic resonance (NMR) or immunoassay.22 While all three methods are considered comparable by international standards, there is substantial variability in apoB measurement among these tests, with apoB levels found to be highest when measured by immunoassay, lower by NMR and lowest by vertical auto profile.22–24

Apolipoprotein B Apolipoprotein B (ApoB) is a large surface protein present on atherogenic lipoproteins and serves as a macromolecular scaffold to provide structural integrity. It also serves as a ligand for the LDL receptor, which facilitates its clearance from the plasma. There are two major isoforms of apoB: apoB48, found on intestinally derived lipoproteins (chylomicrons and their remnants) and apoB100, found on hepatically derived lipoproteins – very LDL, intermediate-density lipoprotein, LDL and lipoprotein (a) (Lp[a]). Each of these atherogenic particles harbours a

EUROPEAN CARDIOLOGY REVIEW

The 2019 ESC/EAS guideline states that measurement of apoB should be performed as part of routine CVD risk evaluation in patients with diabetes or elevated triglycerides and in patients with very low LDL-C levels. ApoB is the preferred biomarker to guide cardiovascular risk management with on-treatment target levels of <1.2 µmol/l (<65 mg/dl), <1.6 µmol/l (<80 mg/dl) and <1.9 µmol/l (<100 mg/dl) in people considered very high, high, and moderate risk, respectively.11 The EAS/EFLM consensus statement mentions the measurement of apoB can be useful in those with a moderate estimated risk and additional metabolic risk factors.14 The NLA endorses measurement of apoB to guide risk assessment and to adjudicate the efficacy of lipidlowering therapy in those at intermediate risk, in those with a strong family history of premature CVD, or in those with recurrent atherosclerotic events.25 The NLA also states that apoB measurement may inform the need to intensify lipid-lowering therapy, especially

Dyslipidaemia Figure 1: Low-density Lipoprotein Cholesterol and Lipoprotein(a) LDL-C

There is no mention of LDL-P measurement in the 2019 ESC/EAS guideline or 2018 ACC/AHA guideline when assessing CVD risk. The NLA states that clinicians can consider measuring LDL-P as an alternative to apoB.40

Lp(a)

Lipoprotein(a) apo(B)

apo(B)

apo(a) apo(a) = apolipoprotein(a); apo(B) = apolipoprotein B; LDL-C = low-density lipoprotein-C; Lp(a) = lipoprotein a. Source: Anfinsen et al. 1994.88 Adapted with permission from Elsevier.

when apoB levels remain high despite attainment of LDL-C goals. The 2018 ACC/AHA cholesterol guideline mentions that apoB levels may be useful in identifying whether hypertriglyceridaemia is associated with increased atherosclerotic risk. There is considerable evidence that CVD risk is higher in those with hypertriglyceridemia and high apoB versus those with hypertriglyceridaemia and normal apoB levels.26–28 Therefore, when triglycerides exceed 200 mg/dl, apoB can be considered a risk-enhancing factor when its levels exceed 2.5 µmol/l (130 mg/dl).16

Low-density Lipoprotein Particle Number LDL particle (LDL-P) number represents an alternative to LDL-C as a marker of CVD risk. While LDL-P represents the concentration in nanomoles of LDL particles per litre of plasma volume, LDL-C represents the cholesterol mass in milligrams found in LDL particles in a decilitre of plasma. Though related, the amount of cholesterol carried by LDL particles differs in and across individuals, with significant variability observed in numerous studies.29,30 The heterogeneity in cholesterol cargo among LDL particles leads to frequent discordance between concentrations of LDL-C and LDL-P. This observation is particularly evident in patients with low HDL-C, hypertriglyceridaemia, metabolic syndrome and diabetes.31–34 A study by Cromwell et al. was conducted to determine which of several measurements of LDL-related risk was most strongly related to incident CVD, and found that LDL-P was a more sensitive indicator of low CVD risk compared with LDL-C and non-HDL-C.35 Another study using data from the Multi-Ethnic Study of Atherosclerosis found that LDL-P was more closely associated with incident subclinical atherosclerosis compared with non-HDL-C.36 About 90% of apoB is carried on LDL in the fasting state.37 Thus, comparisons between LDL-P and apoB have been made to determine if discordance exists between these two closely correlated parameters. A meta-analysis of 25 clinical trials compared the performance of LDL-P and apoB to predict CVD events.38 The American Association for Clinical Chemistry Lipoproteins and Vascular Diseases Division Working Group on Best Practices found a strong association between apoB and LDL-P concentration with CVD events and concluded that both markers were largely comparable in their association with outcomes. A commentary by Master et al. echoed these findings, stating that either LDL-P concentration or apoB may be better predictors of CVD risk than the classic measurement of LDL-C. Thus, either marker can be incorporated into clinical practice when making decisions regarding initiation or intensification of lipid-lowering therapy.39

Lp(a) consists of a molecule of apolipoprotein(a) – apo(a) – a nonfunctional mimic of plasminogen, covalently bound to apoB on an LDL-like particle (Figure 1).41 Significant heterogeneity between apo(a) isoforms confers heterogeneity in Lp(a) particles. Plasma concentration of Lp(a) is >90% genetically determined in an autosomal co-dominant fashion, with adult levels achieved by about 5 years of age.42 Additionally, Lp(a) levels remain stable throughout life regardless of lifestyle. Interestingly, there is a strong established link between Lp(a) and calcific aortic valve stenosis (CAVS) though the mechanism remains unclear.43,44 High-quality evidence supports the relationship between Lp(a) and important CVD-related outcomes. Several observational studies, large scale meta-analyses, Mendelian randomisation analyses and genome-wide association studies suggest a likely causal relationship between circulating Lp(a) and MI, peripheral arterial disease, ischaemic stroke, heart failure, CAVS, cardiovascular mortality and all-cause mortality.45–48 Additionally, Lp(a) demonstrates an incremental predictive value that is additive to other traditional risk factors for CVD independent of LDL-C, non-HDL-C and other CVD risk factors.41,46,47 Unfortunately, methodologies of Lp(a) measurement are not standardised. Assays report results in either mass (mg/dl) or concentration (nmol/l) and direct conversion between the two units is not possible due to the variability among different apo(a) isoforms. Therefore, isoformindependent assays are necessary to avoid erroneous estimation of Lp(a) levels. The absence of evidence-based Lp(a) cut points in different risk groups, ethnic populations and comorbidities also limits its use on a large scale. The 2019 ESC/EAS guideline suggests measurement of Lp(a) at least once in each individual’s lifetime to identify people with high levels, signifying a very high lifetime risk of CVD. People with very high Lp(a) can have a lifetime risk of atherosclerotic CVD equivalent to the lifetime risk of CVD observed in people with heterozygous familial hypercholesterolaemia, highlighting the need for early recognition and aggressive management.11,49 The authors of this guideline also recommend consideration of Lp(a) measurement in people with a moderate to high 10-year risk of atherosclerotic CVD. Similarly, the EAS/ EFLM consensus statement mentions Lp(a) can be measured to help refine CVD risk and/or characterise dyslipidaemia when unclear.14 The NLA states it is reasonable to measure Lp(a) to assess atherosclerotic CVD risk in patients with a strong family history of premature CVD or recurrent cardiovascular events. However, they give a weaker recommendation for its use to aid in clinical decision making, stating it can be ‘considered for selected patients’.25 The 2018 AHA/ACC cholesterol guideline considers a Lp(a) ≥125 nmol/l (≥50 mg/dl) as a risk-enhancing factor, and its measurement can be considered in patients with a strong family history of premature CVD or personal history of CVD not explained by other traditional risk factors.16 Moreover, Lp(a) measurement should be considered in people with familial hypercholesterolaemia, given evidence that this condition and Lp(a) are synergistic in predicting early onset CVD and its severity.50

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Advanced Lipid Testing Several classes of therapeutics demonstrate the ability to lower Lp(a), including PCSK9 inhibitors, niacin, mipomersen, lomitapide, cholesterol ester transfer protein inhibitors and oestrogen, though clinical implications remain unclear.41,51–53 A novel antisense oligonucleotide that effectively reduces translation of APOA1 mRNA (APOA1 mRNA undergoes translation to become apolipoprotein A-I [apoA-I] protein) and plasma Lp(a) by about 80% is currently under development. Lipoprotein apheresis is an effective method for lowering plasma Lp(a) and remains an option in patients with progressive CVD despite optimal control of all other risk factors. Apheresis sessions are usually performed once every 2 weeks with sessions lasting 1.5–4 hours. In general, Lp(a) levels decrease acutely by 60–75% with each apheresis session, dependent upon baseline Lp(a) concentration and apheresis interval.54–56

However, a direct mechanistic relationship between HDL-P and CVD has not been fully elucidated. Several studies have compared the ability of HDL-P and HDL-C to predict CVD events, with the majority demonstrating that HDL-P performs as well or better than HDL-C.70,73–78 Notably, the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) found that HDL-C did not predict CVD after adjusting for HDL-P, while HDL-P remained significantly and inversely associated with CVD after adjusting for HDL-C.75,76,79 Furthermore, several studies assessing HDL particle size report that patients with CVD tend to have more small compared with large HDL particles, with larger particles mediating atheroprotection.80–82 Conversely, other studies have shown the opposite.83 Such discrepancies in the data have made interpretation difficult.

Apolipoprotein A-I ApoA-I is the major protein constituent on HDL and plays a central role in reverse cholesterol transport by stabilising the HDL particle, interacting with the ATP-binding cassette transporter I, activating lecithin cholesterol acyl transferase and acting as a ligand for the hepatic scavenger receptor.57–59 Levels of apoA-I are strongly correlated with HDL-C, with evidence suggesting apoA-I gene expression may be

Currently, there are no guidelines that recommend the use of HDL-P to assess CVD risk. The NLA does not recommend measuring HDL-P and discourages using HDL-C as a target for lipid pharmacotherapy.40

High-density Lipoprotein Subfractions NMR technology and ultracentrifugation enable scientists and

responsible for determining plasma HDL concentrations via changes in clearance rate.60,61 However, the stoichiometry of apoA-I differs from apoB in that more than one molecule of apoA-I can be present on an individual HDL particle. As such, apoA-I cannot serve as a reliable proxy for HDL particle concentration compared with apoB which can serve as an excellent surrogate of atherogenic particle concentration.

researchers to further classify HDL-P into subfractions, HDL2 (large, buoyant HDL) and HDL3 (small, dense, protein-rich HDL). While there does seem to be an association between HDL subfractions and CVD, many studies are conflicting due to differences in study design, patient population, adjustment of confounders, the technique used for HDL subfractionation and the different studied outcomes.84

The Bogalusa Heart Study played a pivotal role in establishing the link between apoA-I and CVD by demonstrating that children of parents with a history of CVD had low apoA-I levels.62 Other studies went on to strengthen this association by establishing that baseline levels of HDL-C and apoA-I can predict MI independent of other coronary risk factors (including lipids) and are associated with an increased risk of total and cardiovascular mortality.63,64 However, when accounting for apoA-I independent from HDL-C, this biomarker seems to lose its predictive ability for CVD events.65,66 Some experts believe that the ratio of apoB/ apoA-I (or atherogenic particles/anti-atherogenic particles) has significant value in predicting CVD risk, though results from the literature are inconsistent. For example, data from the Apolipoprotein-Related Mortality Risk (AMORIS) trial demonstrated that apoB/apoA-I was superior to total cholesterol/HDL-C ratio in predicting CVD events, while data from the Framingham Offspring Study demonstrated that these two ratios were comparable in their ability to predict CVD events.67,68 Neither the 2019 ESC/EAS guideline, 2018 AHA/ACC, guideline, nor the NLA provide guidance on the clinical use of apoA-I in assessing CVD risk.

A review of the literature by Superko et al. was conducted to better understand the clinical utility of HDL subfractions. Eighty studies were evaluated to assess the ability of HDL2 and HDL3 to predict CVD and found that neither HDL subfraction consistently improved identification of individuals at risk.85 Of the eight prospective studies evaluated, four demonstrated an association between both subfractions, three demonstrated an association with HDL3 alone and one demonstrated an association with HDL2 alone. In an attempt to harmonise the conflicting data on HDL subfractions, a consensus statement by Rosenson et al. proposed a new classification of HDL based on the various fractionating methods.86 Five distinct subfractions were proposed – very large, large, medium, small, and very small – based predominantly on size and density.87 However, given conflicting data, cost and difficulty in measurement, HDL subfraction measurement is not recommended for clinical CVD risk assessment. The ESC/EAS, ACC/ AHA and NLA do not support the measurement of HDL subfractions.

Conclusion

HDL particles are heterogeneous in composition, structure, metabolism and function, leading to differential effects on atherosclerosis.69 Akin to alternative measurements of LDL, HDL particle measurement represents the concentration of HDL particles within a given volume of plasma, whereas HDL-C represents the mass of cholesterol carried by

Advanced lipid testing encompasses a wide range of diagnostic laboratory tests as illustrated in this article. Selective use of lipid and lipoprotein biomarkers enhance prediction of CVD risk in patients whose risk is difficult to discern and helps the assessment of the efficacy of lipid-lowering therapy. Further studies are warranted to better understand the usefulness of these risk biomarkers. Additionally, variability of assay methodology and reporting also serve as a barrier

HDL particles in a given volume of plasma. Both HDL particle number (HDL-P) and HDL-C are independently associated with CVD risk.70 Measurement of HDL-P is accomplished by NMR or ion mobility analysis, with most studies using NMR. In general, HDL particles are thought to enhance vascular health by promoting cholesterol efflux, endothelial integrity, antiplatelet activity and anticoagulation.71,72

for widespread clinical implementation. As of now, the most promising markers are non-HDL-C, apoB, and Lp(a) based on the quality and consistency of the literature. When used in the appropriate context, they can provide incremental prognostic information, enhance shared decision-making and inform therapeutic decisions to improve cardiovascular health.

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Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics – 2019 update: a report from the American Heart Association. Circulation 2019;139:e56–528. https://doi. org/10.1161/CIR.0000000000000659; PMID: 30700139. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889–934. https://doi.org/10.1016/j.jacc.2013.11.002. PMID: 24239923. Conroy RM, Pyorala K, Fitzgerald AP, et al. Estimation of tenyear risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003;24:987–1003. https://doi.org/10.1016/ S0195-668X(03)00114-3; PMID: 12788299. Rana JS, Tabada GH, Solomon MD, et al. Accuracy of the atherosclerotic cardiovascular risk equation in a large contemporary, multiethnic population. J Am Coll Cardiol 2016;67:2118–30 https://doi.org/10.1016/j.jacc.2016.02.055; PMID: 27151343. DeFilippis AP, Young R, Blaha MJ. Calibration and discrimination among multiple cardiovascular risk scores in a modern multiethnic cohort. Ann Intern Med 2015;163:68–9. https://doi. org/10.7326/L15-5105-2; PMID: 26148287. DeFilippis AP, Young R, McEvoy JW, et al. Risk score overestimation: the impact of individual cardiovascular risk factors and preventive therapies on the performance of the American Heart Association–American College of CardiologyAtherosclerotic Cardiovascular Disease risk score in a modern multi-ethnic cohort. Eur Heart J 2017;38:598–608. https://doi. org/10.1093/eurheartj/ehw301; PMID: 27436865. Muntner P, Colantonio LD, Cushman M, et al. Validation of the atherosclerotic cardiovascular disease pooled cohort risk equations. JAMA 2014;311:1406–15. https://doi.org/10.1001/ jama.2014.2630; PMID: 24682252. Jorstad HT, Colkesen EB, Boekholdt SM, et al. Estimated 10-year cardiovascular mortality seriously underestimates overall cardiovascular risk. Heart 2016;102:63–8. https://doi. org/10.1136/heartjnl-2015-307668; PMID: 26261158. Cui Y, Blumenthal RS, Flaws JA, et al. Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality. Arch Intern Med 2001;161:1413–9. https://doi. org/10.1001/archinte.161.11.1413; PMID: 11386890. Virani SS. Non-HDL cholesterol as a metric of good quality of care: opportunities and challenges. Tex Heart Inst J 2011;38:160–2. PMID: 21494527. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2019;41:111–88. https://doi.org/10.1093/eurheartj/ehz455; PMID: 31504418. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499–502. https://doi.org/10.1093/clinchem/18.6.499; PMID: 4337382. Sattar N, Williams K, Sniderman AD, et al. Comparison of the associations of apolipoprotein B and non-high-density lipoprotein cholesterol with other cardiovascular risk factors in patients with the metabolic syndrome in the Insulin Resistance Atherosclerosis Study. Circulation 2004;110:2687– 93. https://doi.org/10.1161/01.CIR.0000145660.60487.94; PMID: 15492304. Langlois MR, Nordestgaard BG, Langsted A, et al. Quantifying atherogenic lipoproteins for lipid-lowering strategies: consensus-based recommendations from EAS and EFLM. Clin Chem Lab Med 2019;58:496–517. https://doi.org/10.1515/cclm2019-1253; PMID: 31855562. Blaha MJ, Blumenthal RS, Brinton EA, et al. The importance of non-HDL cholesterol reporting in lipid management. J Clin Lipidol 2008;2:267–73. https://doi.org/10.1016/j. jacl.2008.06.013; PMID: 21291742. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/ AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. Circulation 2018:139:e1082–143. https://doi.org/10.1161/ CIR.0000000000000625; PMID: 30586774. Grundy SM, Vega GL, Tomassini JE, et al. Correlation of nonhigh-density lipoprotein cholesterol and low-density lipoprotein cholesterol with apolipoprotein B during simvastatin + fenofibrate therapy in patients with combined hyperlipidemia (a subanalysis of the SAFARI trial). Am J Cardiol 2009;104:548–53. https://doi.org/10.1016/j.amjcard. 2009.04.018; PMID: 19660610. Lavie CJ, Milani RV, O’Keefe JH. To B or not to B: is non-highdensity lipoprotein cholesterol an adequate surrogate for apolipoprotein B? Mayo Clin Proc 2010;85:446–50. https://doi. org/10.4065/mcp.2010.0058; PMID: 20435838. Hermans MP, Sacks FM, Ahn SA, et al. Non-HDL-cholesterol as valid surrogate to apolipoprotein B100 measurement in diabetes: discriminant ratio and unbiased equivalence. Cardiovasc Diabetol 2011;10:20. https://doi.org/10.1186/14752840-10-20; PMID: 21356116. Sniderman AD, Williams K, Contois JH, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes 2011;4:337– 45. https://doi.org/10.1161/CIRCOUTCOMES.110.959247; PMID: 21487090. Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993–2000. https://doi.org/10.1001/jama.2009.1619; PMID: 19903920. Chandra A, Rohatgi A. The role of advanced lipid testing in the prediction of cardiovascular disease. Curr Atheroscler Rep 2014;16:394. https://doi.org/10.1007/s11883-013-0394-9; PMID: 24445969. Albers JJ, Marcovina SM, Kennedy H. International Federation of Clinical Chemistry standardization project for measurements of apolipoproteins A-I and B. II. Evaluation and selection of candidate reference materials. Clin Chem 1992;38:658–62. https://doi.org/10.1093/clinchem/38.5.658; PMID: 1582016. Grundy SM, Vega GL, Tomassini JE, et al. Comparisons of apolipoprotein B levels estimated by immunoassay, nuclear magnetic resonance, vertical auto profile, and non-highdensity lipoprotein cholesterol in subjects with hypertriglyceridemia (SAFARI Trial). Am J Cardiol 2011;108:40–6. https://doi.org/10.1016/j.amjcard.2011.03.003; PMID: 21565322. Davidson MH, Ballantyne CM, Jacobson TA, et al. Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists. J Clin Lipidol 2011;5:338–67. https://doi.org/10.1016/j.jacl.2011.07.005; PMID: 21981835. Barbir M, Wile D, Trayner I, et al. High prevalence of hypertriglyceridaemia and apolipoprotein abnormalities in coronary artery disease. Br Heart J 1988;60:397–403. https:// doi.org/10.1136/hrt.60.5.397; PMID: 3203033. Brunzell JD, Schrott HG, Motulsky AG, et al. Myocardial infarction in the familial forms of hypertriglyceridemia. Metabolism 1976;25:313–20. https://doi.org/10.1016/00260495(76)90089-5; PMID: 1250165. Sniderman AD, Tremblay A, De Graaf J, et al. Phenotypes of hypertriglyceridemia caused by excess very-low-density lipoprotein. J Clin Lipidol 2012;6:427–33. https://doi. org/10.1016/j.jacl.2012.04.081; PMID: 23009778. Otvos JD, Jeyarajah EJ, Cromwell WC. Measurement issues related to lipoprotein heterogeneity. Am J Cardiol 2002;90:22i– 9i. https://doi.org/10.1016/S0002-9149(02)02632-2; PMID: 12419478. Sniderman AD, Furberg CD, Keech A, et al. Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment. Lancet 2003;361:777–80. https://doi. org/10.1016/S0140-6736(03)12663-3; PMID: 12620753. Sniderman AD, Scantlebury T, Cianflone K. Hypertriglyceridemic hyperapob: the unappreciated atherogenic dyslipoproteinemia in type 2 diabetes mellitus. Ann Intern Med 2001;135:447–59. https://doi.org/10.7326/0003-4819-135-6-200109180-00014; PMID: 11560458. Krauss RM, Siri PW. Metabolic abnormalities: triglyceride and low-density lipoprotein. Endocrinol Metab Clin North Am 2004;33:405–15. https://doi.org/10.1016/j.ecl.2004.03.016; PMID: 15158526. Genest J, Jr, Bard JM, Fruchart JC, et al. Familial hypoalphalipoproteinemia in premature coronary artery disease. Arterioscler Thromb 1993;13:1728–37. https://doi. org/10.1161/01.ATV.13.12.1728; PMID: 8241092. Sniderman AD, Dagenais GR, Cantin B, et al. High apolipoprotein B with low high-density lipoprotein cholesterol and normal plasma triglycerides and cholesterol. Am J Cardiol 2001;87:792–3,A8. PMID: 11249908; https://doi.org/10.1016/ S0002-9149(00)01508-3. Cromwell WC, Otvos JD, Keyes MJ, et al. LDL particle number and risk of future cardiovascular disease in the Framingham offspring study – implications for LDL management. J Clin Lipidol 2007;1:583–92. https://doi.org/10.1016/j. jacl.2007.10.001; PMID: 19657464. Degoma EM, Davis MD, Dunbar RL, et al. Discordance between non-HDL-cholesterol and LDL-particle measurements: results from the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 2013;229:517–23. https://doi.org/10.1016/j.atherosclerosis. 2013.03.012; PMID: 23591415. Sniderman AD, Marcovina SM. Apolipoprotein A1 and B. Clin Lab Med 2006;26:733–50. https://doi.org/10.1016/j. cll.2006.07.007; PMID: 17110237. Cole TG, Contois JH, Csako G, et al. Association of apolipoprotein B and nuclear magnetic resonance spectroscopy-derived LDL particle number with outcomes in 25 clinical studies: assessment by the AACC Lipoprotein and Vascular Diseases Division Working Group on Best Practices. Clin Chem 2013;59:752–70. https://doi.org/10.1373/ clinchem.2012.196733; PMID: 23386699. Master SR, Rader DJ. Beyond LDL cholesterol in assessing cardiovascular risk: apo B or LDL-P? Clin Chem 2013;59:723–5. https://doi.org/10.1373/clinchem.2013.203208; PMID: 23487171. Jacobson TA, Ito MK, Maki KC, et al. National lipid association recommendations for patient-centered management of dyslipidemia: part 1 – full report. J Clin Lipidol 2015;9:129–69.

https://doi.org/10.1016/j.jacl.2015.02.003; PMID: 25911072. 41. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844–53. https://doi.org/10.1093/eurheartj/ehq386; PMID: 20965889. 42. Boerwinkle E, Leffert CC, Lin J, et al. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J Clin Invest 1992;90:52–60. https://doi.org/10.1172/JCI115855; PMID: 1386087. 43. Thanassoulis G, Campbell CY, Owens DS, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 2013;368:503–12. https://doi.org/10.1056/ NEJMoa1109034; PMID: 23388002. 44. Chen HY, Dufresne L, Burr H, et al. Association of LPA variants with aortic stenosis: a large-scale study using diagnostic and procedural codes from electronic health records. JAMA Cardiol 2018;3:18–23. https://doi.org/10.1001/jamacardio.2017.4266; PMID: 29128868. 45. Erqou S, Thompson A, Di Angelantonio E, et al. Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J Am Coll Cardiol 2010;55:2160–7. https://doi.org/10.1016/j. jacc.2009.10.080; PMID: 20447543. 46. Emerging Risk Factors Collaboration. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009;302:412–23. https://doi. org/10.1001/jama.2009.1063; PMID: 19622820. 47. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation 2000;102:1082–5. https://doi.org/10.1161/01.CIR.102.10.1082; PMID: 10973834. 48. Craig WY, Neveux LM, Palomaki GE, et al. Lipoprotein(a) as a risk factor for ischemic heart disease: metaanalysis of prospective studies. Clin Chem 1998;44:2301–6. https://doi. org/10.1093/clinchem/44.11.2301; PMID: 9799757. 49. Burgess S, Ference BA, Staley JR, et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol 2018;3:619–27. https://doi.org/10.1001/ jamacardio.2018.1470; PMID: 29926099. 50. Li S, Wu NQ, Zhu CG, et al. Significance of lipoprotein(a) levels in familial hypercholesterolemia and coronary artery disease. Atherosclerosis 2017;260:67–74. https://doi.org/10.1016/j. atherosclerosis.2017.03.021; PMID: 28351002. 51. Tsimikas S, Hall JL. Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: a rationale for increased efforts to understand its pathophysiology and develop targeted therapies. J Am Coll Cardiol 2012;60:716–21. https:// doi.org/10.1016/j.jacc.2012.04.038; PMID: 22898069. 52. Norata GD, Ballantyne CM, Catapano AL. New therapeutic principles in dyslipidaemia: focus on LDL and Lp(a) lowering drugs. Eur Heart J 2013;34:1783–9. https://doi.org/10.1093/ eurheartj/eht088; PMID: 23509227. 53. Bays HE, Jones PH, Orringer CE, et al. National Lipid Association annual summary of clinical lipidology 2016. J Clin Lipidol 2016;10(1 Suppl):S1–43. https://doi.org/10.1016/j. jacl.2015.08.002; PMID: 26891998. 54. Waldmann E, Parhofer KG. Lipoprotein apheresis to treat elevated lipoprotein (a). J Lipid Res 2016;57:1751–7. https://doi. org/10.1194/jlr.R056549; PMID: 26889050. 55. Thompson GR, Maher VM, Matthews S, et al. Familial hypercholesterolaemia regression study: a randomised trial of low-density-lipoprotein apheresis. Lancet 1995;345:811–6. https://doi.org/10.1016/S0140-6736(95)92961-4; PMID: 7898227. 56. Leebmann J, Roeseler E, Julius U, et al. Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study. Circulation 2013;128:2567–76. https://doi.org/10.1161/ CIRCULATIONAHA.113.002432; PMID: 24056686. 57. Lee JY, Parks JS. ATP-binding cassette transporter AI and its role in HDL formation. Curr Opin Lipidol 2005;16:19–25. https://doi.org/10.1097/00041433-200502000-00005; PMID: 15650559. 58. Fielding CJ, Shore VG, Fielding PE. A protein cofactor of lecithin: cholesterol acyltransferase. Biochem Biophys Res Commun 1972;46:1493–8. https://doi.org/10.1016/0006291X(72)90776-0; PMID: 4335615. 59. Acton S, Rigotti A, Landschulz KT, et al. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 1996;271:518–20. https://doi.org/10.1126/ science.271.5248.518; PMID: 8560269. 60. Srivastava RA, Srivastava N. High density lipoprotein, apolipoprotein A-I, and coronary artery disease. Mol Cell Biochem 2000;209:131–44. https://doi.org/10.1023/ A:1007111830472; PMID: 10942211. 61. Reyes-Soffer G, Millar JS, Ngai C, et al. Cholesteryl ester transfer protein inhibition with anacetrapib decreases fractional clearance rates of high-density lipoprotein apolipoprotein a-i and plasma cholesteryl ester transfer protein. Arterioscler Thromb Vasc Biol 2016;36:994–1002. https:// doi.org/10.1161/ATVBAHA.115.306680; PMID: 26966279. 62. Freedman DS, Srinivasan SR, Shear CL, et al. The relation of apolipoproteins A-I and B in children to parental myocardial

EUROPEAN CARDIOLOGY REVIEW

Advanced Lipid Testing

63.

64.

65.

66.

67.

68.

69.

70.

71.

infarction. N Engl J Med 1986;315:721–6. https://doi. org/10.1056/NEJM198609183151202; PMID: 3092050. Bolibar I, von Eckardstein A, Assmann G, et al. Shortterm prognostic value of lipid measurements in patients with angina pectoris. Thromb Haemost 2000;84:955–60. https:// doi.org/10.1055/s-0037-1614155; PMID: 11154140. Lundstam U, Herlitz J, Karlsson T, et al. Serum lipids, lipoprotein(a) level, and apolipoprotein(a) isoforms as prognostic markers in patients with coronary heart disease. J Intern Med 2002;251:111–8. https://doi.org/10.1046/ j.1365-2796.2002.00937.x; PMID: 11905586. Stampfer MJ, Sacks FM, Salvini S, et al. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med 1991;325:373–81. https://doi.org/10.1056/NEJM199108083250601; PMID: 2062328. Sharrett AR, Ballantyne CM, Coady SA, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 2001;104:1108–13. https://doi. org/10.1161/hc3501.095214; PMID: 11535564. Walldius G, Jungner I, Holme I, et al. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 2001;358:2026–33. https://doi.org/10.1016/S01406736(01)07098-2; PMID: 11755609. Ingelsson E, Schaefer EJ, Contois JH, et al. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA 2007;298:776–85. http://doi. org/10.1001/jama298.7.776; PMID: 17699011. Camont L, Chapman MJ, Kontush A. Biological activities of HDL subpopulations and their relevance to cardiovascular disease. Trends Mol Med 2011;17:594–603. https://doi.org/10.1016/j. molmed.2011.05.013; PMID: 21839683. El Harchaoui K, Arsenault BJ, Franssen R, et al. High-density lipoprotein particle size and concentration and coronary risk. Ann Intern Med 2009;150:84–93. https://doi.org/10.7326/00034819-150-2-200901200-00006; PMID: 19153411. Barter P. HDL-C: role as a risk modifier. Atheroscler Suppl 2011;12:267–70. https://doi.org/10.1016/S1567-5688(11)708856; PMID: 22152280.

EUROPEAN CARDIOLOGY REVIEW

72. Natarajan P, Ray KK, Cannon CP. High-density lipoprotein and coronary heart disease: current and future therapies. J Am Coll Cardiol 2010;55:1283–99. https://doi.org/10.1016/j. jacc.2010.01.008; PMID: 20338488. 73. Otvos JD, Collins D, Freedman DS, et al. Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation 2006;113:1556–63. https://doi.org/10.1161/CIRCULATIONAHA.105.565135; PMID: 16534013. 74. Parish S, Offer A, Clarke R, et al. Lipids and lipoproteins and risk of different vascular events in the MRC/BHF Heart Protection Study. Circulation 2012;125:2469–78. https://doi. org/10.1161/CIRCULATIONAHA.111.073684; PMID: 22539783. 75. Mackey RH, Greenland P, Goff DC Jr, et al. High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2012;60:508–16. https://doi.org/10.1016/j.jacc.2012.03.060; PMID: 22796256. 76. Mora S, Glynn RJ, Ridker PM. High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy. Circulation 2013;128:1189–97. https://doi.org/10.1161/CIRCULATIONAHA.113.002671; PMID: 24002795. 77. Kuller LH, Grandits G, Cohen JD, et al. Lipoprotein particles, insulin, adiponectin, C-reactive protein and risk of coronary heart disease among men with metabolic syndrome. Atherosclerosis 2007;195:122–8. https://doi.org/10.1016/j. atherosclerosis.2006.09.001; PMID: 17011566. 78. Musunuru K, Orho-Melander M, Caulfield MP, et al. Ion mobility analysis of lipoprotein subfractions identifies three independent axes of cardiovascular risk. Arterioscler Thromb Vasc Biol 2009;29:1975–80. https://doi.org/10.1161/ ATVBAHA.109.190405; PMID: 19729614. 79. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–207. https://doi. org/10.1056/NEJMoa0807646; PMID: 18997196. 80. Watanabe H, Soderlund S, Soro-Paavonen A, et al. Decreased high-density lipoprotein (HDL) particle size, prebeta-, and large

81.

82.

83.

84.

85.

86.

87.

88.

HDL subspecies concentration in Finnish low-HDL families: relationship with intima-media thickness. Arterioscler Thromb Vasc Biol 2006;26:897–902. https://doi.org/10.1161/01. ATV.0000209577.04246.c0; PMID: 16469947. Cheung MC, Brown BG, Wolf AC, et al. Altered particle size distribution of apolipoprotein A-I-containing lipoproteins in subjects with coronary artery disease. J Lipid Res 1991;32:383– 94. PMID: 1906084. Johansson J, Carlson LA, Landou C, et al. High density lipoproteins and coronary atherosclerosis. A strong inverse relation with the largest particles is confined to normotriglyceridemic patients. Arterioscler Thromb 1991;11:174–82. https://doi.org/10.1161/01.ATV.11.1.174; PMID: 1987996. Syvanne M, Nieminen MS, Frick MH, et al. Associations between lipoproteins and the progression of coronary and vein-graft atherosclerosis in a controlled trial with gemfibrozil in men with low baseline levels of HDL cholesterol. Circulation 1998;98:1993–9. https://doi.org/10.1161/01.CIR.98.19.1993; PMID: 9808595. Martin SS, Jones SR, Toth PP. High-density lipoprotein subfractions: current views and clinical practice applications. Trends Endocrinol Metab 2014;25:329–36. https://doi. org/10.1016/j.tem.2014.05.005; PMID: 24931711. Superko HR, Pendyala L, Williams PT, et al. High-density lipoprotein subclasses and their relationship to cardiovascular disease. J Clin Lipidol 2012;6:496–523. https://doi.org/10.1016/j. jacl.2012.03.001; PMID: 23312047. Rosenson RS, Brewer HB Jr, Chapman MJ, et al. HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events. Clin Chem 2011;57:392– 410. https://doi.org/10.1373/clinchem.2010.155333; PMID: 21266551. Akinkuolie AO, Paynter NP, Padmanabhan L, et al. High-density lipoprotein particle subclass heterogeneity and incident coronary heart disease. Circ Cardiovasc Qual Outcomes 2014;7:55–63. https://doi.org/10.1161/CIRCOUTCOMES. 113.000675; PMID: 24248942. Apolipoprotein B and low-density lipoprotein structure: implications for biosynthesis of triglyceride-rich lipoproteins. In: Anfinsen CB, Edsall JT, Richards FM. Advances in Protein Chemistry. New York: Elsevier, 1995;205–48.

COVID-19

Coronavirus Disease 2019 and Catheterisation Laboratory Considerations: “Looking for Essentials” Syed Haseeb Raza Naqvi,1 Madiha Fatima,1 Fady Gerges,2 Sara Moscatelli,3 Tugba Kemaloglu Oz,4 Irina Kotlar,5 Nigar Babazade,6 Arash Hashemi7 and Abdallah Mostafa Almaghraby8 1. Cardiology Department, National Institute of Cardiovascular Diseases, Sindh, Pakistan; 2. Cardiovascular Sciences Department, NMC Speciality Hospital, Al Ain, United Arab Emirates; 3. Clinic of Cardiovascular Diseases, University of Genoa, Genoa, Italy; 4. Cardiology Department, Istinye University, Istanbul, Turkey; 5. Cardiology Department, University Clinic of Cardiology, Skopje, North Macedonia; 6. Cardiology Department, Baku Health Clinic, Baku, Azerbaijan; 7. Cardiology Department, Erfan General Hospital, Tehran, Iran; 8. Cardiology Department, University of Alexandria, Alexandria, Egypt

Abstract The current coronavirus disease 2019 (COVID-19) outbreak is a significant health crisis that impacts every healthcare system worldwide, and has led to a dramatic change in dealing with different diseases during the pandemic. Interventional cardiologists are frontline workers who deal with many cardiovascular emergencies, either in patients with proven COVID-19 or in suspected cases. Many heart associations worldwide are currently setting appropriate recommendations for the management of emergency cardiac interventions. In this expert opinion, the authors highlight the essential requirements in the cardiac catheterisation laboratory during the COVID-19 pandemic.

Keywords Cardiopulmonary resuscitation, catheterisation laboratory, coronavirus disease 2019, coronary CT angiography, fibrinolytic therapy, Global Registry of Acute Coronary Events, severe acute respiratory syndrome coronavirus 2, ST-segment elevation MI, acute coronary syndrome Disclosure: The authors have no conflicts of interest to declare. Received: 1 June 2020 Accepted: 24 June 2020 Citation: European Cardiology Review 2020;15:e57. DOI: https://doi.org/10.15420/ecr.2020.29 Correspondence: Abdallah Almaghraby, Department of Cardiology, Faculty of Medicine, University of Alexandria, Khartoum Square, 21524 Alexandria, Egypt. E: dr.maghraby@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

The current coronavirus disease 2019 (COVID-19) outbreak is more than a health crisis, and its impact on the management of other diseases of various specialties is one of the greatest challenges facing healthcare professionals. Health associations worldwide are now recommending dealing with emergencies only, utilising telemedicine and providing ambulatory facilities, where available, for non-emergency conditions to control the pandemic. Interventional cardiologists are frontline workers who deal with many cardiovascular emergencies among suspected or confirmed COVID-19 patients. They are not only responsible for ensuring adequate protection against the infection, but also for the efficient utilisation of resources when considering non-emergency procedures. Many recognised international heart associations, including the American Heart Association and European Society of Cardiology (ESC), are currently setting appropriate recommendations for the management of emergency cardiac interventions (Table 1).1–3 Elective cases can be easily postponed to later dates after weighing risks versus benefits to avoid the exposure of patients to the hospital environment, where COVID-19 may be more prevalent, and to minimise exposure to healthcare workers and to preserve hospital bed capacity and other resources. Examples include percutaneous intervention for

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stable ischaemic heart disease, peripheral arterial disease procedures, atrial septal defect closure or left atrial appendage closure.1,4 During the COVID-19 pandemic, primary percutaneous coronary intervention (PCI) remains the standard of care for ST-segment elevation MI (STEMI) patients at PCI-capable hospitals when it can be provided in a timely fashion, with an expert team outfitted with personal protective equipment (PPE) in a dedicated catheterisation laboratory (cath lab). A fibrinolysis-based strategy may be used at non-PCI-capable referral hospitals or in certain situations where primary PCI cannot be executed or is not deemed to be the best option.2 In certain circumstances, a more detailed and confirmatory evaluation in the emergency department (ED) might be required prior to transfer to the cath lab. Thus, during the COVID-19 pandemic, there may be longer door-to-balloon (D2B) times. D2B times should still be tracked; however, patient and/or system-related delays are considered appropriate reasons for delay.2 Every patient who needs cardiac catheterisation must be screened at presentation.5 The WHO provides guidance for the risk stratification of patients at low to high risk of infection of COVID-19.6 Together with relevant history and examination, this can aid in taking appropriate

COVID-19 and Cath Lab Considerations Table 1: American College of Cardiology/Society of Cardiovascular Angiography and Intervention and European Society of Cardiology Recommendations for Acute MI ACC/SCAI

ESC

STEMI (PCI-capable hospitals) Definite STEMI

PPCI

Possible STEMI

Additional noninvasive evaluation in the ED

Futile prognosis

Case-by-case discussion

PPCI

STEMI (non-PCI-capable hospitals) First medical contact to reperfusion should be >120 min

Pharmaco-invasive

First medical contact to reperfusion should be <120 min

PPCI

Cardiogenic shock and/or out-of-hospital cardiac arrest STEMI

PPCI

NSTEMI

No routine PCI

PPCI

NSTE-ACS COVID-19-positive

Medical treatment*

Transfer to COVID-19-equipped hospital

Possibility of COVID-19

Early invasive

If not high risk, test first

COVID-19-negative

Early invasive

Manage as guidelines

*Only taken for urgent coronary angiography and possible PCI in the presence of high-risk clinical features. ACC = American College of Cardiology; COVID-19 = coronavirus disease 2019; ED = emergency department; ESC = European Society of Cardiology; NSTE-ACS = non-ST-elevation acute coronary syndrome; NSTEMI = non-ST-elevation MI; PCI = percutaneous coronary intervention; PPCI = primary percutaneous coronary intervention; SCAI = Society of Cardiovascular Angiography and Intervention; STEMI = ST-elevation MI.

protective measures when dealing with patients with, or at risk of COVID-19. Healthcare professionals must be provided with personal PPE, including respirators, a fluid-impermeable gown, head cover, gloves, splash goggles and shoe covers, whereas patients should wear a surgical mask from ED until intervention completion, or even until the discharge.7

strategy. However, the time of the invasive strategy may be greater than 24 hours and depends on the timing of the test results. If feasible, a dedicated area to manage these patients while waiting for test results should be arranged in the ED. In the case of a positive COVID-19 test, patients should be transferred, for invasive management, to a hospital equipped to manage COVID-19-positive patients.3

Confirmed or suspected COVID-19 patients requiring intubation should be intubated prior to arrival at the cath lab, and the threshold for intubation may need to be lowered to avoid emergency intubation in the cath lab leading to aerosolisation of respiratory secretions.1

It is best to dedicate one cath lab for COVID-19 patients.11 The cath lab must be fully equipped and the healthcare professionals should have proper PPE inside the lab, avoiding unnecessary entry and exit during the procedure.12

Radial access is the preferred approach over femoral access, because it keeps the primary operator at a greater distance from the patientâ&#x20AC;&#x2122;s face, reducing the possibility of aerosol transmission, and takes less time.8

It is strongly recommended that procedures for donning and doffing of PPE are followed.7,12 It is important to minimise the number of in-lab healthcare professionals and to ensure that all doors are closed; for communication outside the lab, a microphone system should be used. Maintaining physical distance during the procedure as much as possible is also an important consideration.11 In cases where a patient requires resuscitation while in the cath lab, automatic chest compression devices are recommended.11 If unavailable, hands-only cardiopulmonary resuscitation (CPR) has been shown to be as effective as conventional CPR in many cases.13

For non-ST segment elevation acute coronary syndrome (NSTE-ACS), the treatment strategy must be tailored according to Global Registry of Acute Coronary Events (GRACE) scoring, as well as to the risk of being infected with COVID-19. Chest CT and swab tests should be immediately performed for suspected cases, and if necessary, coronary CT angiography (CCTA) done at the same time. Strict isolation should be started immediately for all ACS patients. If results are negative for COVID-19, then the patient can be transferred to the coronary care unit.9 According to the ESC guidelines for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic, the management and treatment pathways for NSTE-ACS are categorised according to the risks to every patient.3 Patients with troponin elevation and no acute clinical signs of instability (i.e. ECG changes or recurrence of pain) could be managed with a primarily conservative approach. Non-invasive imaging using CCTA might speed-up risk stratification and avoid an invasive approach, allowing early discharge.10 For patients at high risk, the medical strategy is aimed at stabilisation and planning an early (<24Â hours) invasive

EUROPEAN CARDIOLOGY REVIEW

For suspected or confirmed COVID-19 STEMI patients, there are two options: fibrinolytic therapy or primary angioplasty. Fibrinolysis is favored in China for their local conditions and because of the risk of staff contamination. In China, experts dealing with the COVID-19 pandemic recommend fibrinolytic therapy over PPCI for STEMI and especially for stable patients, as lytic therapy is less resource-intensive for the system overall.14,15 The same is not true in Europe, where the superiority of PPCI over thrombolysis is well-established and where efficient networks between the hub and spoke centers are active.16 As soon as the procedure is completed, the patient should be transferred to a dedicated isolation area. If no anteroom is available, the doffing of PPE must be done inside the lab, with the exception of the facial respirator, which should be removed outside of the lab. After

COVID-19 waste disposal according to protocols, the lab should be closed for an hour before thorough cleaning to reduce the possibility of aerosol transmission. Cleaners must be fully equipped with PPE. All disposable material should be safely discarded. Surfaces can be disinfected by using sodium hypochlorite at a concentration of 1,000 parts per million, leaving it in contact with the surface for 5 minutes.7 It is preferable that medical staff, cardiology advance trainees and fellows, consultants, nursing staff, radiographers and cardiac technologists form teams that can work on a rotating basis in shifts, secluding ones from frontline care who are immunocompromised, have a chronic illness or are aged >65 years with comorbidities.11 Considering the care pathway for STEMI at referral hospitals (non-PCI centres), the decision to proceed with an initial fibrinolysis or a direct transfer to a PCI centre is multifactorial and will likely vary in different regions. The treatment decision also depends on whether the patient is COVID-19 positive or suspected of having COVD-19, and should be made between the referring hospital physician and PCI centre physician. Upon transfer of a patient with a STEMI from a referral hospital to a PCI centre, the patient should be re-evaluated for COVID-19 status and STEMI diagnosis. The patient can then be taken for primary PCI, pharmaco-invasive PCI or rescue PCI, as indicated.2 Once primary PCI is performed on the infarct related artery, if clinically safe and indicated, any high-grade disease in a non-infarct related artery should also be treated during the index procedure to minimise further exposure of the cath lab staff during a staged procedure. Primary PCI is superior for establishing normal thrombolysis in MI grade 3 coronary flow compared to an initial fibrinolysis strategy, and has a significantly lower risk of fatal and non-fatal bleeding complications.17 Furthermore, after a fibrinolysis-based strategy, just over 50% of patients are reperfused, resulting in a high proportion of patients requiring rescue PCI.17 This can result in prolonged intensive care unit (ICU) hospitalisation, with exposure to multiple healthcare

Welt FGP, Shah PB, Aronow HD, et al. Catheterization laboratory considerations during the coronavirus (COVID-19) pandemic: from the ACC’s Interventional Council and SCAI. J Am Coll Cardiol 2020;75:2372–5. https://doi.org/10.1016/j. jacc.2020.03.021; PMID: 32199938. Mahmud E, Dauerman HL, Welt FG, et al. Management of acute myocardial infarction during the COVID-19 pandemic. J Am Coll Cardiol 2020. https://doi.org/10.1016/j.jacc.2020.04.039; PMID: 32330544; epub ahead of press. European Society for Cardiology. ESC guidance for the diagnosis and management of CV disease during the COVID-19 pandemic. 10 June 2020. https://www.escardio.org/Education/COVID-19and-Cardiology/ESC-COVID-19-Guidance (accessed 10 June 2020). Lakkireddy DR, Chung MK, Gopinathannair R, et al. Guidance for cardiac electrophysiology during the coronavirus (COVID19) pandemic from the Heart Rhythm Society COVID-19 Task Force; Electrophysiology Section of the American College of Cardiology; and the Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology, American Heart Association. Heart Rhythm 2020. https://doi.org/10.1016/j. hrthm.2020.03.028; PMID: 32247013; epub ahead of press. Cascella M, Rajnik M, Cuomo A, et al. Features, evaluation and treatment coronavirus (COVID-19). Treasure Island, FL: StatPearls Publishing, 2020. https://www.ncbi.nlm.nih.gov/ books/NBK554776/ (accessed 2 July 2020). WHO. Global surveillance for COVID-19 disease caused by human infection with the 2019 novel coronavirus. Interim guidance. Geneva: WHO, 27 February 2020. Romaguera R, Cruz-González I, Ojeda S, et al. Consensus document of the Interventional Cardiology and Heart Rhythm Associations of the Spanish Society of Cardiology on the management of invasive cardiac procedure rooms during the COVID-19 coronavirus outbreak. REC Interv Cardiol 2020;2:106– 11. https://doi.org/10.24875/RECICE.M20000116.

10.

11.

12.

13.

providers, limiting access to ICU beds for COVID-19 patients. In addition, some of these patients may have a ‘STEMI mimicker’, such as focal myocarditis or stress cardiomyopathy known to be associated with COVID-19.18,19 Fibrinolysis of these patients would provide no benefit to the patient, but still incur bleeding risk and eventual invasive diagnostic catheterisation given that the ST-elevation is unlikely to resolve. Ideally, a dedicated cath lab should be located in a COVID-19 area of the hospital, but this might not always be possible. In the latter case, a temporary COVID-19 lab and procedure with a protected team needs to be set up for each patient; this might require a longer time. If the cath lab is not ready, we suggest that patients wait in the ambulance, rather than in the pre-operating room.20 Finally, the safe reintroduction of cardiovascular interventional procedures during the COVID-19 pandemic can be achieved according to response level. Primary PCI should be introduced for most STEMI patients, and selective pharmaco-invasive therapy as per regional practice. If a patient has COVID-19 or there is a moderateto-high probability of a patient being COVID-19 positive, consider alternative investigations (transthoracic echo and/or CCTA) prior to cath lab activation or pharmaco-invasive therapy. In high-risk ACS (non-STEMI/unstable angina), an invasive strategy is the treatment of choice, particularly when there are refractory symptoms, haemodynamic instability, significant left ventricular dysfunction, suspected left main or significant proximal epicardial disease and a GRACE risk score >140.21 The COVID-19 pandemic has had a global impact on the way in which healthcare systems operate. Frontline healthcare professionals put themselves at risk when treating patients. Excellent leadership, proper cath lab preparation, teamwork, mutual trust, regular updates, feedback and communication between multidisciplinary departments are essential during the pandemic.

Daralammouri Y, Azamtta M, Hamayel H, et al. Recommendations for safe and effective practice of interventional cardiology during COVID-19 pandemic: expert opinion from Jordan and Palestine. Palestinian Medical and Pharmaceutical Journal 2020;5:65–73. Jing ZC, Zhu HD, Yan XW, et al. Recommendations from the Peking Union Medical College Hospital for the management of acute myocardial infarction during the COVID-19 outbreak. Eur Heart J 2020;41:1791–4. https://doi.org/10.1093/eurheartj/ ehaa258; PMID: 32232396. Stefanini GG, Azzolini E, Condorelli G. Critical organizational issues for cardiologists in the COVID-19 outbreak: a frontline experience from Milan, Italy. Circulation 2020;141:1597–9. https://doi.org/10.1161/CIRCULATIONAHA.120.047070; PMID: 32207994. Lo STH, Yong AS, Sinhal A, et al. Consensus guidelines for interventional cardiology services delivery during COVID-19 pandemic in Australia and New Zealand. Heart Lung Circ 2020;29:e69–77. https://doi.org/10.1016/j.hlc.2020.04.002; PMID: 32471696. Tarantini G, Fraccaro C, Chieffo A, et al. Italian Society of Interventional Cardiology (GISE) position paper for cath labspecific preparedness recommendations for healthcare providers in case of suspected, probable or confirmed cases of COVID-19. Catheter Cardiovasc Interv 2020; https://doi. org/10.1002/ccd.28888; PMID: 32223063; epub ahead of press. Edelson DP, Sasson C, Chan PS, et al. Interim guidance for basic and advanced life support in adults, children, and neonates with suspected or confirmed COVID-19: from the Emergency Cardiovascular Care Committee and Get With The Guidelines-Resuscitation Adult and Pediatric Task Forces of the American Heart Association. Circulation 2020;141:e933–43. https://doi.org/10.1161/CIRCULATIONAHA.120.047463; PMID: 32270695.

14. Zeng J, Huang J, Pan L. How to balance acute myocardial infarction and COVID-19: the protocols from Sichuan Provincial People’s Hospital. Intensive Care Med 2020;46:1111– 3. https://doi.org/10.1007/s00134-020-05993-9; PMID: 32162032. 15. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061–9. https:// doi.org/10.1001/jama.2020.1585; PMID: 32031570. 16. Ratcliffe AT, Pepper C. Thrombolysis of primary angioplasty? Reperfusion therapy for myocardial infarction in UK. Postgrad Med J 2008;84:73–7. https://doi.org/10.1136/pgmj.2007.060921; PMID: 18322126. 17. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78-e140. https:// doi.org/10.1016/j.jacc.2012.11.019; PMID: 23256914. 18. Madjid M, Safavi-Naeini P, Solomon SD, et al. Potential effects of coronaviruses on the cardiovascular system: a review. JAMA Cardiol 2020. https://doi.org/10.1001/jamacardio.2020.1286; PMID: 32219363; epub ahead of press. 19. Fried JA, Ramasubbu K, Bhatt R, et al. The variety of cardiovascular manifestations of COVID-19. Circulation 2020;141:1930-1936. https://doi.org/10.1161/ CIRCULATIONAHA.120.047164; PMID: 32243205. 20. Campo G, Rapezzi C, Tavazzi L, et al. Priorities for cath labs in the COVID-19 tsunami. Eur Heart J 2020;41:1784-1785. https:// doi.org/10.1093/eurheartj/ehaa308; PMID: 32286606. 21. Wood DA, Mahmud E, Thourani VH, et al. Safe reintroduction of cardiovascular services during the COVID-19 pandemic: guidance from North American societies. Ann Thorac Surg 2020;110:733–40. https://doi.org/10.1016/j.athoracsur.2020. 04.017; PMID: 32380058.

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COVID-19

Anticoagulant Therapy for Patients with Coronavirus Disease 2019: Urgent Need for Enhanced Awareness Maki Komiyama and Koji Hasegawa Division of Translational Research, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

Abstract Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic. SARS-CoV-2 binds to the angiotensin-converting enzyme 2 receptor, which is abundantly expressed in vascular endothelial cells and damages these cells. Besides pneumonia-induced respiratory failure, thrombotic cardiovascular complications are increasingly emerging as a major COVID-19 symptom. Multiple retrospective studies have strongly suggested that anticoagulant therapy improves the prognosis of people with COVID-19. However, validation of the safety and effectiveness of anticoagulant therapy for COVID-19 and greater awareness of this clinical therapeutic option are urgently needed.

Keywords COVID-19, SARS-CoV-2, thrombosis, anticoagulant Disclosure: The authors have no conflicts of interest to declare. Received: 25 May 2020 Accepted: 19 June 2020 Citation: European Cardiology Review 2020;15:e58. DOI: https://doi.org/10.15420/ecr.2020.24 Correspondence: Koji Hasegawa, Division of Translational Research, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612â&#x20AC;&#x201C;8555, Japan. E: koj@kuhp.kyoto-u.ac.jp Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has generated a pandemic that has heavily affected the global population, with more than 5.2 million infected and more than 337,000 deaths worldwide recorded between the end of 2019 and 24 May 2020.1 In the absence of vaccines or specific targeted treatments, strategies to reduce the COVID-19 mortality rate have gained importance as a global need. However, the exact mechanisms underlying the disease progression of COVID-19 remain unknown. Worldwide, thrombotic findings, ranging from benign pedal skin lesions (known as COVID toe) to cerebral infarctions in asymptomatic to mildly ill young patients have been reported as manifestations of the disease. In addition to the pneumoniainduced respiratory failure, thrombotic cardiovascular complications are increasingly gaining importance as a major COVID-19 presentation.2 This risk of thrombosis, if unaddressed, can cause severe damage even in patients with mild symptoms of pneumonia.

COVID-19 Hypercoagulability Viral infections are associated with an increased risk of thrombosis. Coagulopathy was reported as a disease manifestation in the Spanish influenza pandemic of 1918, which killed about 50 million people worldwide. A case of SARS-related macrovascular complication of stroke was reported in Singapore during the SARS-CoV outbreak of 2004.3 Moreover, thrombosis is a common feature of viral infections, such as AIDS, dengue fever and Ebola virus disease. Among critically ill patients, the incidence of pulmonary thrombosis has been reported to be as high as 30% in COVID-19 patients, compared with 1.3% among non-COVID-19 patients.4 A study in the Netherlands of 184 critically ill

ÂŠ RADCLIFFE CARDIOLOGY 2020

patients in intensive care (ICU) found that COVID-19-associated thrombotic complications occurred in 31% of their participants.5 An analysis of contrast-enhanced CT findings in a case series of ICU patients showed the presence of pulmonary artery thrombosis in 20.6% of 107 patients admitted to ICU with COVID-19, compared with 7.5% of 40 influenza patients admitted during the previous year.6 Anticoagulant therapy was administered in more than 90% of COVID-19 patients with thrombosis in this study and it appears that COVID-19 induces a greater hypercoagulability than other infections.

Pathogenesis of COVID-19-associated Thrombosis The pathogenesis underlying the more hypercoagulable state in COVID-19 compared with other infections needs to be ascertained. SARS-CoV-2 infection induces the production of cytokines, such as interferons and interleukins, resulting in a systemic inflammatory reaction, which eventually causes the so-called cytokine storm.7,8 Higher cytokine concentrations can lead to systemic thrombus formation, with consequent pulmonary artery thrombosis, cerebral infarction, MI and lower limb arterial thrombosis. In addition to this typical inflammatory mechanism, direct injuries to the vascular endothelium by SARS-CoV-2 appear to be involved in COVID-19 thrombogenesis.9 Large amounts of angiotensin-converting enzyme 2 (ACE2), which mediates function of the ACE receptor as a SARS-CoV-2 receptor, are found in mucosal epithelial cells in the respiratory tract and in pulmonary alveolar tissue. Furthermore, ACE2 is expressed in other organs, such as the heart, kidneys and intestinal tract, as well as in high concentrations in vascular endothelial cells.10

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COVID-19 In the initial stage of infection, SARS-CoV-2 uses ACE2 to enter vascular endothelial cells, thereby injuring the vascular endothelium, which has antithrombogenic properties. Then, platelet adhesion/aggregation and tissue factor release induce thrombus formation mainly in the microvasculature.9,11 Even in the absence of severe pneumonia or a cytokine storm, endovascular inflammation through the direct action of SARS-CoV-2 produces a hypercoagulable state, with consequent thrombosis at various sites.

survival in patients who did not.19 Among 395 critically ill patients managed with mechanical ventilation, the in-hospital mortality was 29.1% for those who did receive anticoagulation therapy and 62.7% for those who did not. No significant difference was observed in the incidence of haemorrhagic complications (3.0% and 1.9% in the groups with and without anticoagulation therapy, respectively).

After the initiation of the thrombotic process begins, a self-sustaining chain reaction ensues whereby a thrombus stimulates the formation of other thrombi, with a resultant rapid increase in systemic thrombosis and the severity of the patient’s condition. A close correlation has been observed between blood levels of D-dimer, a fibrin degradation product, and COVID-19 disease severity.11 D-dimer levels are markedly elevated in patients with severe COVID-19, despite no marked prolongation in prothrombin time or thrombocytopenia. These findings suggest that disseminated intravascular coagulation alone does not fully explain thrombosis in severe cases.11

In general, treatment with low-molecular-weight heparin is associated with a better prognosis in patients with a sepsis-induced coagulopathy score of ≥4 points.20 However, the prothrombotic tendency in COVID-19 may be stronger than with other infections. The ISTH interim guidance proposes the use of anticoagulation therapy for a wide range of patients, recommending prophylactic administration of low-molecularweight heparin for hospitalised COVID-19 patients with markedly elevated D-dimer levels or high fibrinogen levels.17 Most hospitalised patients will meet these criteria. However, the decision to hospitalise patients with COVID-19 cannot be based exclusively on the D-dimer level, considering that a multiparametric evaluation is necessary, especially in elderly patients.21

The risk of sudden death in patients with COVID-19 is linked to direct cardiac injury and myocarditis, with arrhythmic complications observed in 16.7% of 138 patients with COVID-19 seen in Wuhan, China, in January 2020.12 Sudden death in COVID-19 patients may as well be attributable to MI or pulmonary infarction due to generalised thrombosis. Cerebral infarction in young patients without risk factors of arteriosclerosis are attributed to thrombosis due to SARS-CoV-2-induced endovascular injuries.13,14 Risk factors for higher severity of COVID-19 include advanced age, cardiovascular disease, hypertension, diabetes, smoking, chronic respiratory disease and malignant tumours.15,16 These factors are associated with endovascular dysfunction and increased coagulability and, therefore, the hypercoagulability may be a mechanism that contributes to the adverse outcomes of COVID-19.

Antiplatelet agents are usually administered for patients with atherosclerotic cerebral infarction or MI, although anticoagulants may represent a mechanistically preferable choice over antiplatelet agents for COVID-19 patients. If the patient’s general condition is favourable, then non-vitamin K antagonist oral anticoagulants (NOACs) may be an option. However, cautious use is advisable as blood levels may increase when NOAC is administered in combination with various antiviral agents. NOACs can present side-effects caused by the extensive interactions with the drugs currently in use for the therapy of patients with COVID-19, whereas low-molecular-weight heparins do not exhibit significant interactions; thus, the latter is currently the first choice drug to prevent thromboembolic phenomena in these patients.12

Treatment of COVID-19-associated Hypercoagulability

Investigating the anti-inflammatory role of low-molecular-weight heparin, as well as its supposed antiviral role, seems appropriate, considering that heparin sulphate may bind to SARS-CoV-2 spike protein to block viral attachment or entry.22 The risk of deep vein thrombosis in Chinese patients is generally one-quarter to one-third of that of white patients, whereas the risk in African-Americans is markedly higher than in white people.23,24 Therefore, ethnicity needs to be considered when determining anticoagulative strategies for COVID-19 patients. As pulmonary artery thrombosis is frequently observed even in patients undergoing anticoagulation therapy, anticoagulants need to be administered in sufficient amounts.

Coagulative and fibrinolytic abnormalities are closely involved in the COVID-19 pathogenesis and have a big effect on prognosis. Therefore, the International Society on Thrombosis and Haemostasis (ISTH) issued an interim guidance recommending the measurement of D-dimer, fibrinogen, prothrombin time and platelet count in all COVID-19 patients.17 The onset of coagulopathy in COVID-19 patients is one of the most important signs of poor prognosis. As marked D-dimer elevation is a predictor of mortality, hospitalisation should be considered for patients with high D-dimer levels. For the treatment for COVID-19associated hypercoagulability, the administration of anticoagulants has been reported to potentially improve prognosis according to findings from a retrospective study.18 A single-centre observational study including 2,773 COVID-19 patients at Mount Sinai Hospital in the US has reported that of 786 patients who received anticoagulation therapy, in-hospital mortality was 22.5%, with a median survival of 21 days, compared with 22.8% and 14 days median

WHO. Coronavirus disease (COVID-19) outbreak. 2020 https:// www.who.int/emergencies/diseases/novel-coronavirus-2019 (accessed 1 July 2020). Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol 2020;75:2950–73. https://doi.org/10.1016/j. jacc.2020.04.031; PMID: 32311448. Umapathi T, Kor AC, Venketasubramanian N, et al. Large artery

Awareness of the importance of anticoagulation therapy is currently low and anticoagulation therapy is not generally administered to COVID-19 patients due to fears of haemorrhage as a side-effect. Anticoagulation therapy may potentially result in a marked improvement of prognosis in COVID-19 patients. Therefore, efforts to rapidly increase awareness and fully establish the validity of the ISTH interim guidance are required.

ischaemic stroke in severe acute respiratory syndrome (SARS). J Neurol 2004;251:1227–31. https://doi.org/10.1007/s00415004-0519-8; PMID: 15503102. Gale J. Coronavirus causes damaging blood clots from brain to toes. Bloomberg 5 May 2020. https://www. bloomberg.com/news/articles/2020-05-04/coronaviruscauses-blood-clots-harming-organs-from-brain-to-toes (accessed 1 July 2020). Klok FA, Kruip MJHA, van der Meer NJM, et al.

Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020;191:145–7. https://doi.org/10.1016/j.thromres.2020.04.013; PMID: 32291094. Poissy J, Goutay J, Caplan M, et al. Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence. Circulation 2020;142:184–6. https://doi.org/10.1161/ CIRCULATIONAHA.120.047430; PMID: 3233008. Soy M, Keser G, Atagündüz P, et al. Cytokine storm in

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Anticoagulant Therapy in COVID-19 Patients

10.

11.

12.

13.

COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol 2020;39:2085–94. https://doi.org/10.1007/s10067-020-05190-5; PMID: 32474885. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033–4. https://doi.org/10.1016/S01406736(20)30628-0; PMID: 32192578. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020;395:1417–8. https://doi.org/10.1016/S0140-6736(20)30937-5; PMID: 32325026. Lukassen S, Chua RL, Trefzer T, et al. SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. EMBO J 2020;39:e105114. https://doi. org/10.15252/embj.20105114; PMID: 32246845. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18:844–7. https://doi.org/10.1111/jth.14768; PMID: 32073213. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA 2020;323:1061–9. https://doi.org/ 10.1001/jama.2020.1585; PMID: 32031570. Oxley TJ, Mocco J, Majidi S, et al. Large-vessel stroke as a presenting feature of COVID-19 in the young. N Engl J Med

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14.

15.

16.

17.

18.

19.

2020;382:e60. https://doi.org/10.1056/NEJMc2009787; PMID: 32343504. Fogarty H, Townsend L, Ni Cheallaigh C, et al. COVID-19 coagulopathy in Caucasian patients. Br J Haematol 2020;189:1044–9. https://doi.org/10.1111/bjh.16749; PMID: 32330308. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020;323:1239–42. https://doi.org/10.1001/jama.2020.2648; PMID: 32091533. Komiyama M, Hasegawa K. Smoking cessation as a public health measure to limit the coronavirus disease 2019 pandemic. Eur Cardiol 2020;15:e16. https://doi.org/10.15420/ ecr.2020.11; PMID: 32373189. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 2020;18:1023–6. https://doi.org/10.1111/ jth.14810; PMID: 32338827. Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020;18:1094–9. https://doi.org/10.1111/jth.14817; PMID: 32220112. Paranjpe I, Fuster V, Lala A, et al. Association of treatment

20.

21.

22.

23.

24.

dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol 2020;76:122–4. https://doi.org/10.1016/j.jacc.2020.05.001; PMID: 32387623. Iba T, Nisio MD, Levy JH, et al. New criteria for sepsis‐induced coagulopathy (SIC) following the revised sepsis definition: a retrospective analysis of a nationwide survey. BMJ Open 2017;7:e017046. https://doi.org/10.1136/ bmjopen-2017-017046; PMID: 28963294. Boccardi V, Ruggiero C, Mecocci P. COVID-19: a geriatric emergency. Geriatrics (Basel) 2020;5:e24. https://doi. org/10.3390/geriatrics5020024; PMID: 32357575. Liu J, Li J, Arnold K, et al. Using heparin molecules to manage COVID-2019. Res Pract Thromb Haemost 2020;4:518–23. https:// doi.org/10.1002/rth2.12353; PMID: 32542212. Huang D, Wong E, Zuo ML, et al. Risk of venous thromboembolism in Chinese pregnant women: Hong Kong venous thromboembolism study. Blood Res 2019;54:175–80. https://doi.org/10.5045/br.2019.54.3.175; PMID: 31730677. Liao S, Woulfe T, Hyder S, et al. Incidence of venous thromboembolism in different ethnic groups: a regional direct comparison study. J Thromb Haemost 2014;12:214–9. https://doi.org/10.1111/jth.12464; PMID: 24283769.

COVID-19

Treatment of Coronavirus Disease 2019: Shooting in the Dark Juan Tamargo Department of Pharmacology, School of Medicine, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón, CIBERCV, Madrid, Spain

Abstract The identification of effective interventions against the coronavirus disease 2019 (COVID-19) pandemic has become a health priority. The rational treatment of a disease is based on the knowledge of its pathophysiology, the identification of a therapeutic target and the confirmation of the efficacy and safety of the selected therapeutic intervention in randomised controlled trials. However, we are facing the COVID-19 pandemic without a clear understanding of the pathophysiology of the disease. As we are fighting against a viral infection, drugs previously developed or approved to treat other viral infections or that exhibit a broad-spectrum antiviral activity, anti-inflammatory drugs and drugs against cytokine storm are currently being tested. Unfortunately, the efficacy and safety of these medications remain uncertain, and some may increase the risk of cardiovascular complications in patients with COVID-19. Thus, at the present time, due to the lack of solid scientific data to support a therapeutic strategy, we truly are shooting in the dark with the treatment of COVID-19. We must wait for the results of ongoing randomised, controlled studies before the widespread adoption of these drugs. In the meantime, investigational anti-COVID-19 drugs should be used in hospitals or as part of clinical trials.

Keywords COVID-19, SARS-CoV-2, coronavirus, pandemic, pharmacology Disclosure: This work was supported by grants from the Institute of Health Carlos III (PI16/00398 and CB16/11/00303). Received: 14 May 2020 Accepted: 14 May 2020 Citation: European Cardiology Review 2020;15:e59. DOI: https://doi.org/10.15420/ecr.2020.21 Correspondence: Juan Tamargo, Department of Pharmacology, School of Medicine, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón, CIBERCV, 28040 Madrid, Spain. E: jtamargo@med.ucm.es Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

“ When the cause of the sickness is unknown, only a miracle can cure it.” Don Quixote, Miguel de Cervantes, 1605. The coronavirus 2019 (COVID-19) pandemic was caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARSCoV-2).1,2 COVID-19 rapidly spread from China to most countries around the world, and on 11 March 2020 the WHO declared a global pandemic. The COVID-19 pandemic has already had a major negative impact on global health systems and the economy.3 From a pharmacological point of view, the rational treatment of a disease is based on the knowledge of its pathophysiology, the identification of a therapeutic target and trial confirmation of the effectiveness of the intervention. Indeed, under normal circumstances, well-designed randomised controlled trials (RCTs) are key to confirm that a pharmacological intervention directed at a selected target is effective and safe. However, these are not normal times and we find ourselves facing a pandemic caused by a virus of which we know very little, and for which there is no clear understanding of the pathogenesis or pathophysiology of the diseases triggered by COVID-19. Moreover, little is known regarding the short- and long-term clinical consequences of the disease and why different individuals respond so differently to the aggression of the virus. Without specific effective therapies for COVID-19 we are facing a very large death toll and the collapse of many health services worldwide. As a result of the severity of the problem, in the past few months numerous drugs have been proposed that might be effective in the treatment of

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COVID-19 (Table 1). However, due to the lack of true scientific data to support a therapeutic strategy for COVID-19, it has become apparent that we truly are shooting in the dark. This article aims to convey my reflections on the current situation from a clinical pharmacologist’s viewpoint. Several issues have attracted my attention since the initial reports emerged from China at the time of rapid death progression in that country.

The Ibuprofen Story On 14 March 2020 the French Health Minister, Olivier Véran, claimed on Twitter that anti-inflammatory drugs such as ibuprofen or cortisone could be an aggravating factor in people with COVID-19.4 A few days later, on 18 March, the WHO recommended using paracetamol instead of ibuprofen. On 19 March, the WHO updated its advice on the official Twitter account: “Based on currently available information, WHO does not recommend against the use of ibuprofen”.5 Finally, on 14 April, the Commission on Human Medicines Expert Working Group on COVID-19 concluded that there is currently insufficient evidence to link ibuprofen or other non-steroidal anti-inflammatory drugs, with a susceptibility to contracting COVID-19 or the worsening of its symptoms.6

Use of Renin-Angiotensin-Aldosterone System Inhibitors in COVID-19 Patients The angiotensin-converting enzyme 2 (ACE2) is the receptor responsible for SARS-CoV entry into cells, and because ACE2 expression increases in patients treated with ACE inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), it was hypothesised in a letter published in

Treatment of COVID-19 Table 1: Drugs Under Development for the Treatment of COVID-19 Family

Drugs

Antibiotics

Azithromycin plus chloroquine

Antifibrotic drugs

Defibrotide, pirfenidone

Antihelminthic drugs

Ivermectin, niclosamide, nitazoxanide

Anti-inflammatory drugs

Glucocorticoids, NSAIDs

Antimalarial drugs

Chloroquine, hydrochloroquine

Antiviral drugs

Anti-influenza compounds: baloxavir, DAS181,† favipiravir,† laninamivir,† oseltamivir, peramivir, rintatolimod, zanamivir HIV protease inhibitors: ASC09/ritonavir, darunavir/cobicistat, lopinavir/ritonavir Other antivirals: Azvudine,† galidesivir,† merimepodib,† remdesivir,† ribavirin, umifenovir

Cytokine therapy (inhibit cytokine storm)

IL-6 inhibitors: sarilumab, tozilizumab Interferons Monoclonal antibodies: bevacizumab, camrelizumab,† eculizumab, emapalumab, IFX-1,† leronlimab†

Immunosuppressants

Bariticinib, fingolimod

Neurokinin 1 receptor antagonists

Tradipitant†

Pathway-targeted therapies

Ruxolitinib

Recombinant fusion proteins

CD24Fc†

Experimental drugs. Ongoing trials with these and other drugs in patients with coronavirus disease 2019 (COVID-19) can be consulted on ClinicalTrials.gov (https://clinicaltrials.gov), National Institutes of Health COVID-19 page (https://www.nih.gov/health-information/coronavirus) and Chinese Clinical Trials (http://www.chictr.org.cn/enindex.aspx). IL = interleukin; NSAID = non-steroidal anti-inflammatory drug. †

The Lancet Respiratory Medicine that patients treated with agents capable of increasing ACE2 availability/density such as ACEIs, ARBs, and ibuprofen could be at higher risk of developing severe and fatal COVID-19 infection.7–9 Furthermore, the authors added that ACEIs can modify the adaptive immune response and suggested that long-term use of ACEIs might suppress the adaptive immune response in individuals affected by COVID-19. The article caused great consternation among patients and physicians alike. Although it was somewhat ‘reasonable’ on theoretical grounds, there is no clinical or scientific evidence to indicate that treatment with these important medications should be abandoned or discontinued in patients affected by SARSCoV-2 infection.10,11 The above examples are of concern, given that they led to confusing and contradictory recommendations, created uncertainty among prescribers and increased mistrust in medical decisions among the general public. They may also fuel the proliferation of false information or imaginative uses for medications or substances that may not only be ineffective but also extremely dangerous and life-threatening. As expected, scientists all over the world are assessing whether drugs that inhibit SARS-CoV-2 in vitro (even when their effects in vivo may remain uncertain), agents with broad-spectrum antiviral actions, previously developed and approved for the treatment of other viral infections (particularly RNA viruses, i.e. influenza and HIV) or drugs approved for other clinical indications that exhibit potent broad-spectrum antiviral effects (i.e. chloroquine, hydrochloroquine, ivermectin) might also be effective against SARS-CoV-2 (Table 1). Azithromycin was also tested in this context because its early use is known to reduce the likelihood of recurrent severe episodes of lower respiratory tract illness.12 The race to find an effective medication is progressing at high speed, but the risk is that the quality of the research could be compromised by the anxiety driving some of the research projects. Severe pneumonia caused by human coronavirus is often associated with massive inflammatory cell infiltration, increased plasma concentration of inflammatory cytokines/chemokines and multiorgan failure, resulting in acute lung injury and acute respiratory distress

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syndrome.13,14 Indeed, high virus titres and deregulated cytokine/ chemokine responses cause a cytokine storm, which results in high morbidity and mortality due to immunopathology.1,14,15 Furthermore, a recent meta-analysis found that measurement of circulating interleukin-6 (IL-6) may predict disease progression in COVID-19 patients.16 This suggests that besides controlling viral load, novel strategies directed at attenuating the cytokine storm (e.g. IL-6 receptor antagonists, immunosuppressants, interferons, fingolimod) may possibly improve clinical outcome, although these medications can increase the risk of secondary infection. Table 2 summarises the mechanisms of action, the main adverse effects and potential interactions with other cardiovascular drugs, of drugs currently under clinical investigation for the treatment of COVID-19.

Some Pharmacological Reflections COVID-19 is a new pandemic and to date, no specific drug (or vaccine) has been found to be effective. Therefore, there is no solid evidence at this point in time that allows treating physicians to use COVID-19specific treatments, thus management should include the prompt implementation of proven infection prevention and control measures and supportive care, ranging from symptomatic outpatient management to full intensive care support.17 At the onset of the COVID-19 outbreak and in view of the lack of specific treatment for this new coronavirus, SARS-CoV-2, antiviral screening programs identified many antiviral agents that showed in vitro activity against SARS-CoV-2. These drugs are presently being tested in ongoing clinical trials. Several issues have emerged in relation to the strategies that are currently being implemented. The first is whether the antiviral effects reported in vitro could also be achieved in vivo. Sometimes the concentrations at which these agents inhibit SARS-CoV in vitro are much higher (‘supratherapeutic’) than the therapeutic plasma levels reached at the recommended doses. Thus, it is possible that plasma levels with meaningful activity against SARS-CoV in vitro would not be achieved in vivo without potentially adverse effects. This may be the case for ivermectin and

COVID-19 Table 2: Main Pharmacological Characteristics of Some Proposed Drugs for Treating COVID-19 Drug

Target

Adverse Effects

Drug Interactions/Cautions

Baricitinib

Reversible inhibitor of JAK1 and 2

Hyperlipidaemia, deep vein thrombosis, pulmonary embolism, ALT/AST elevations

Avoid in pregnancy

Bevacizumab

Inhibits the binding of VEGF to its receptors VEGFR-1 and VEGFR-2

Hypertension, venous thromboembolism, Avoid in pregnancy deep vein thrombosis, congestive heart failure, supraventricular tachycardia, pulmonary embolism

Camostat mesylate

Inhibits transmembrane serine protease TMPRSS2

Not published

CD24Fc

CD24 extracellular domain-IgG1 Fc domain recombinant fusion protein

Not published

Chloroquine(CQ)/ hydroxychloroquine (HCQ)

Interfere with ACE2 receptor glycosylation; block virus infection by increasing the endosomal pH required for virus/cell fusion; reduce the production of proinflammatory cytokines. Inhibit SARS-CoV-2 in vitro (HCQ > CQ)

Inhibit Na+, L-type Ca2+ and several cardiac K+ channels Hypotension, hypoglycaemia, ECG changes (inversion or depression of the T-wave, QT, PR and/or QRS prolongation), conduction disorders (AV block, bundle branch block), torsade de pointes, ventricular tachycardia, ventricular fibrillation. Cardiomyopathy, which may result in cardiac failure and in some cases a fatal outcome

Inhibit CYP2D6, increasing the exposure of carvedilol, digoxin, metoprolol, propranolol; decrease effectiveness of prodrugs reliant on CYP2D6 for activation (codeine, tramadol). Avoid in patients treated with QT-prolonging drugs or with electrolyte abnormalities. Concomitant use with amiodarone contraindicated. CQ/HCQ are recommended for COVID-19 infection when prescribed in the hospital or as part of a clinical trial. May be used in pregnancy

No evidence of the efficacy of this combination

These drugs prolong the QT interval and their combination is contraindicated

Oedema, electrolyte abnormalities, hypertension, risk of secondary infection

Reduce the dose of warfarin and monitor the INR

HCQ + azithromycin Corticosteroids

Anti-inflammatory and immunosuppressive drugs

Darunavir/cobicistat HIV protease inhibitor/CYP3A4 inhibitor. Darunavir is not active against SARS-CoV-2

Dyslipidaemia, hepatotoxicity (AST/ALT elevations, Both inhibited CYP3A and CYP2D6. Avoid jaundice), severe skin reactions coadministration with amiodarone, dabigatran, dronedarone, ivabradine, lovastatin, quinidine, PDE5 inhibitors, ranolazine, simvastatin, ticagrelor. Avoid during pregnancy

DAS181†

Sialidase catalytic domain/amphiregulin glycosaminoglycan binding sequence fusion protein

Unknown

Eculizumab (NCT04288713)

Humanised mAb that specifically binds to the complement protein C5 preventing the generation of the terminal complement complex C5b-9

Muscle and back pain, headache, nasopharyngitis, Caution with any systemic infections hypertension. Increases the risk of fatal meningococcal infections

Emapalumab

Human mAb that binds to and neutralises IFN-gamma

Hypertension, hypokalaemia, tachycardia, oedema Increases the risk of serious infections. Emapalumab may normalise CYP450 activities and reduce the efficacy of drugs that are CYP450 substrates

Favipiravir (investigational)

Inhibits RNA polymerase. No effect against SARS-CoV-2 in vitro

No significant differences were observed in the severe or severe and moderate (combined) arms Hyperuricemia, AST/ALT elevations, neutropenia

Contraindicated during pregnancy and breastfeeding

Fingolimod

Sphingosine 1-phosphate receptor modulator

Hypertension, bradycardia, AV block, ALT/AST elevations

Contraindicated in patients with: recent (>6 months) MI, unstable angina, stroke/ transient ischemic attacks, NYHA Class III/ IV heart failure; cardiac arrhythmias treated with Class Ia or III anti-arrhythmic drugs; second- or third-degree AV block, or sick-sinus syndrome without a pacemaker; baseline QTc interval ≥500 ms. Avoid with bradycardic agents (Class Ia, III and IV anti-arrhythmics, ivabradine, digoxin)

IFX-1

Anti-human complement factor C5a mAb

Unknown

IFN-alpha and IFN-beta

Activate cytoplasmic enzymes affecting viral mRNA translation and protein synthesis

Hypertension, palpitations, tachycardia

Not recommended to treat SARS-CoV-2

Unknown

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Treatment of COVID-19 Table 2: Cont. Drug

Target

Adverse Effects

Ivermectin

Inhibits replication of SARS-CoV-2 in vitro

Hypotension, oedema, tachycardia, ALT/AST increases.

Drug Interactions/Cautions

Leronlimab (experimental)

Humanized mAb against CC chemokine receptor 5 (CCR5)

Unknown

Lopinavir/ritonavir (±IFN-beta)

Inhibits the enzyme 3-CL protease crucial in processing the viral RNA. Lopinavir inhibits SARS-CoV-2 replication in vitro

There is no strong evidence to recommend the use of lopinavir/ritonavir for COVID-19 Hypertension, AV block, QTc prolongation, high-degree AV block, PR and QT prolongation, torsades de pointes. Elevated ALT/AST, hepatoxicity, hyperlipidaemia, new-onset diabetes, pancreatitis

They are potent inhibitors of CYP3A4 and should not be administered with CYP3A4 substrates: amiodarone, apixaban, atorvastatin, bosentan, calcium channel blockers, clarithromycin, cyclosporin, dronedarone, digoxin, edoxaban, flecainide, lovastatin, PDE5 inhibitors, propafenone, ranolazine, riociguat, rosuvastatin, simvastatin, tacrolimus, ticagrelor, warfarin. Decrease the exposure to clopidogrel and prasugrel. Avoid QT-prolonging drugs. Can be used in pregnancy

Merimepodib

Inosine-5’-monophosphate dehydrogenase inhibitor. Inhibits SARS-CoV-2 replication

Unknown

Niclosamide

Prevents viral entry by altering endosomal pH and prevents viral replication

No longer approved for use in the US as an antihelminthic drug

Nitazoxanide

Increases phosphorylated factor 2-alpha required for protein synthesis

Adverse effects are rare

Unknown

NSAIDs

Anti-inflammatory drugs

Oseltamivir

Inhibits influenza A and B neuraminidases. No apparent effect against SARS-CoV-2 in vitro

ALT/AST elevations, hepatotoxicity, angioneurotic oedema

Acetaminophen is recommended No role in the management of COVID-19 once influenza has been excluded

Pirfenidone

Inhibits the release of pro-inflammatory cytokines (TNF-alpha, IL-1beta)

Hot flush, ALT/AST elevations

Unknown

Remdesivir†

Inhibits RNA polymerase to stop viral replication. Antiviral activity against SARSCoV-2

Approved by the FDA (emergency use authorisation) and EMA (conditional marketing authorisation). Infusion-related reaction (hypotension, nausea, vomiting, sweating and shivering), ALT/AST elevations, renal impairement, multiorgan failure

Not reported

Rintatolimod†

TLR3 agonist

Unknown

Ribavirin

Inhibits viral RNA-dependent RNA polymerase. Palpitations, tachycardia, hypotension, No antiviral effect against SARS-CoV-2 in vitro hypertriglyceridemia, hyperuricemia, ALT/AST elevations. Haemolytic anaemia, which may result in worsening of cardiac disease and lead to MI

Inconclusive results in the treatment of SARS. Contraindicated if pre-existing cardiac disease, including unstable or uncontrolled cardiac disease, during pregnancy and breastfeeding

Ruxolitinib

JAK1 and JAK2 inhibitor

Hypertension, increases in ALT/AST and lipid parameters, infections

Strong CYP3A4 inhibitors increase ruxolitinib exposure: reduce the dose by 50%. Ruxolitinib increases the exposure to dabigatran etexilate, cyclosporin, rosuvastatin and digoxin

Sarilumab

Human mAb that specifically binds to IL-6 receptors

Hyperlipidaemia, upper respiratory tract infection, ALT/AST elevations

Increases the expression/activity of CYP450 enzymes (1A2, 2B6, 2C9, 2C19, 2D6 and 3A4) decreasing the plasma levels of drugs that are substrates of these enzymes

Tocilizumab

Recombinant humanised anti-human IL-6 receptor mAb

Hypertension, upper respiratory tract infections, hyperlipidaemia, ALT/AST elevations, hepatoxicity, gastrointestinal perforations. Increased severe and sometimes fatal infections. Serious allergic reactions, including death

Increases the expression/activity of CYP450 enzymes (1A2, 2B6, 2C9, 2C19, 2D6 and 3A4), decreasing the plasma levels of drugs that are substrates of these enzymes. Caution in patients with neutropenia or thrombocytopenia. May cause foetal harm

Tradipitant

Neurokinin-1 receptor antagonist

Unknown

Umifenovir

S protein/ACE2 membrane fusion inhibitor that prevents viral entry to the target cell

GI upset, ALT/AST elevations, allergic reactions

Caution with potent CYP3A4 inhibitors/ inducers

Experimental drugs. 3-CL = 3-chymotrypsin-like; ACE2 = angiotensin-converting enzyme 2; ALT/AST = alanine/aspartate aminotransferase; AV = atrioventricular; CYP = cytochrome P450; FDA = Food and Drug Administration; GI = gastrointestinal; IFN = interferon; IL = interleukin; INR, international normalised ratio; JAK = Janus-associated kinase; mAb = monoclonal antibody; NYHA = New York Heart Association; PDE5 = phosphodiesterase type 5; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TLR = Toll-like receptors; TMPRSS2 = transmembrane protease, serine 2; TNF = tumour necrosis factor; VEGF = vascular endothelial growth factor. †

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COVID-19 ribavirin. 18 Furthermore, several drugs under development or already approved for other indications, exhibiting a broad-spectrum antiviral activity, are now being tested in COVID-19 patients even when their efficacy and safety in in vivo models or in patients is uncertain. Some antivirals (favipiravir, baloxavir) show no activity against SARS-CoV-2 in vitro at concentrations under 100 μmol/l, but they are, however, being tested in ongoing trials.19 It would not be surprising if the results were disappointing. The second is how the pharmacokinetic properties of many of the currently investigated drugs, which were studied in healthy volunteers or in patients affected with the disease for which the drug was initially approved, behave in COVID-19 patients. In the rush to find a treatment, several ongoing trials are being conducted with drugs that were developed but not approved as yet, or were approved to treat other non-COVID-19 diseases (repurposed agents). However, the half maximum effective concentrations and the recommended doses of these drugs against different viruses are quite different and are based on the particular type of infectious disease. Therefore, the question is how will the most effective and safer dose be calculated in patients with COVID-19? In fact, doses of a given drug may differ in different trials. For example, the dose of chloroquine used to treat COVID-19 varies from 500 mg orally twice daily for 5–10 days to a loading dose of 400 mg twice daily for 1 day followed by 200 mg twice daily for 4 days.20–22 Thus, studies are needed to determine the optimal dose range for the drugs used in the treatment of COVID-19 patients. We must keep in mind that patients with COVID-19 and pre-existing cardiovascular disease have an increased risk of developing severe symptoms and death, and COVID-19 itself is associated with several cardiovascular complications, including acute myocardial injury, myocarditis, arrhythmias and venous thromboembolism.8,23 Some drugs tested in ongoing trials produce serious cardiovascular and noncardiovascular adverse effects (hepatotoxicity, neutropenia and increased risk of infection), which clearly represents a clinical challenge (Table 2). It is also recommended to avoid the coadministration of drugs that prolong the QT interval (azithromycin with chloroquine/ hydroxychloroquine) and to prescribe chloroquine/hydroxychloroquine, which can produce serious cardiovascular events, only in-hospital or as part of a clinical trial, in patients with COVID-19. Although corticosteroids were not initially recommended for COVID-19 patients because of the lack of proven benefit and potential harm with these drugs, the RECOVERY Collaborative Group has very recently shown that in hospitalised patients with COVID-19, the use of dexamethasone for up to 10 days resulted in lower 28-day mortality than usual care among those who were receiving either invasive mechanical ventilation or oxygen alone at randomisation.24 Interestingly, the safety profile of drugs not already approved by the Food and Drug Administration (FDA) or the European Medicines Agency is based on limited published evidence, so that their safety profile remains uncertain and we must await the results of ongoing prospective, randomised, controlled studies before the widespread adoption of these drugs.25 Additionally, some drugs (HIV protease inhibitors, IL-6 receptor antagonists) inhibit or induce the activity of some cytochrome P450 3A4 enzymes and

increase or decrease, respectively, the exposure of multiple drugs that are substrates of such isoforms (Table 2). Therefore, investigational antiCOVID-19 therapeutics should be used only in approved, RCTs. Almost on a daily basis, case reports, observational or small retrospective, non-randomised studies are published in major journals and non peer-reviewed journals. Albeit describing interesting cases and findings, many of these articles suffer from serious methodological problems, including lack of blinding, small sample size (<50 patients per group) and marked variations in the inclusion/exclusion criteria, presence of background therapy and varied treatment regimens (different doses, different duration of therapy and different routes of administration), which makes it difficult to ascertain the true treatment effect. Furthermore, the effects of current treatments on quality of life and drug safety are underreported. This variability can explain why even studies performed in the same country with the combination of hydroxychloroquine and azithromycin may lead to contradictory results. 26,27 Additionally, the non-standardised collection of clinical data limits the conclusions from retrospective analysis. As an example, one trial recruiting 21 patients concluded that 91% of patients were discharged on average 13.5 days after the treatment with tocilizumab (400 mg IV), with most patients receiving only one dose; however, the lack of a comparator group limits the interpretation of these results.28 Furthermore, sometimes the preliminary exciting results of one study are not confirmed in other trials. This may indeed be the case of remdesivir. In 53 patients hospitalised for severe COVID-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 68% of patients.29 These promising results led to a Phase III trial in China. Surprisingly, on 23 April 2020, the WHO reported the preliminary results of a Phase III Chinese trial but this report was quickly withdrawn, suggesting that remdesivir did not have beneficial effects in COVID-19 patients or that it was not able reduce the virus in the bloodstream. Interestingly, the researchers responsible for the study indicated that they had not approved its posting. This is a good example of how rushing to obtain results can lead to speculation and unhelpful rumours about the effectiveness of drugs. Nevertheless, on 1 May 2020, the FDA issued an Emergency Use Authorisation for emergency use of remdesivir for the treatment of hospitalised COVID-19 patients.30 Ongoing clinical trials will define which patients will best benefit from remdesivir treatment.

Conclusion COVID-19 is a new pandemic and, to date, no specific drug has been found to be effective. The identification of effective interventions against COVID-19 (including vaccines) has become a public health priority. Scientists and physicians are facing the challenge to better understand the characteristics of this new virus and the pathophysiology of the disease that it causes, in order to identify possible therapeutic targets and effective therapeutic drugs and vaccines. Despite these efforts, at the present time, we are still shooting in the dark for the reasons mentioned here. Adequately powered randomised clinical trials are needed to establish the efficacy and safety of therapeutic agents prior to the widespread adoption of these therapies. Attempts should be made to develop suitable treatment protocols and to standardise datasets that could facilitate meaningful analysis of treatment effects and clinical outcomes.

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Treatment of COVID-19 1.

Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497–506. https://doi.org/10.1016/S01406736(20)30183-5;PMID: 31986264. 2. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727–33. https://doi.org/10.1056/ NEJMoa2001017;PMID: 31978945. 3. WHO. Coronavirus disease (COVID-2019) situation reports. 2020. https://www.who.int/emergencies/diseases/ novel-coronavirus-2019/situation-reports (accessed 28 April 2020). 4. Véran O. Twitter. 14 March 2020. https://twitter.com/ olivierveran/status/1238776545398923264 (accessed 22 May 2020). 5. Updated: WHO Now Doesn’t Recommend Avoiding Ibuprofen For COVID-19 Symptoms. https://www.sciencealert.com/whorecommends-to-avoid-taking-ibuprofen-for-covid-19symptoms (accessed 28 May 2020). 6. Medicines and Healthcare products Regulatory Agency and Commission on Human Medicines. Commission on Human Medicines advice on ibuprofen and coronavirus (COVID-19). London: MHRA/CHM, 2020. https://www.gov.uk/government/ news/commission-on-human-medicines-advice-on-ibuprofenand-coronavirus-covid-19 (accessed 28 April 2020). 7. Li XC, Zhang J, Zhuo JL. The vasoprotective axes of the reninangiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res 2017;125:21–38. https://doi. org/10.1016/j.phrs.2017.06.005;PMID: 28619367. 8. Zheng YY, Ma YT, Zhang JY, et al. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020;17:259–60. https:// doi.org/10.1038/s41569-020-0360-5;PMID: 32139904. 9. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?. Lancet Respir Med 2020;8:e21. https://doi. org/10.1016/S2213-2600(20)30116-8;PMID: 32171062. 10. Danser AHJ, Epstein M, Batlle D. Renin-angiotensin system blockers and the COVID-19 pandemic: at present there is no evidence to abandon renin-angiotensin system blockers. Hypertension 2020;75:1382–5. https://doi.org/10.1161/ HYPERTENSIONAHA.120.15082;PMID: 32208987. 11. European Society for Cardiology. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers. 13 March 2020. https://www.

EUROPEAN CARDIOLOGY REVIEW

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

escardio.org/Councils/Council-on-Hypertension-(CHT)/News/ position-statement-of-the-esc-council-on-hypertension-onace-inhibitors-and-ang (accessed 18 March 2020). Bacharier LB, Guilbert TW, Mauger DT, et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial. JAMA 2015;314:2034–44. https://doi.org/10.1001/ jama.2015.13896;PMID: 26575060. Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Front Immunol 2019;10:119. https://doi.org/10.3389/ fimmu.2019.00119;PMID: 30774631. Chen X, Zhao B, Qu Y, et al. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. Clin Infect Dis 2020. https://doi.org/10.1093/cid/ ciaa449;PMID: 32301997; epub ahead of press. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017;39:529–39. https://doi.org/10.1007/s00281-017-0629-x; PMID: 28466096. Ulhaq ZS, Soraya GV. Interleukin-6 as a potential biomarker of COVID-19 progression. Med Mal Infect 2020;50:382–3. https:// doi.org/10.1016/j.medmal.2020.04.002;PMID: 32259560. WHO. Clinical management of severe acute respiratory infection when COVID-19 is suspected. 2020. https://www. who.int/publications-detail/clinical-management-of-severeacute-respiratory-infection-when-novel-coronavirus-(ncov)infection-is-suspected (accessed 28 April 2020). Momekov G, Momekova D. Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view. MedRxiv 17 April 2020. https://doi.org/10.1101/2020.04.11.20061804 (accessed 22 May 2020). Choy KT, Wong AYL, Kaewpreedee P, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res 2020;178:104786. https://doi. org/10.1016/j.antiviral.2020.104786;PMID: 32251767. Colson P, Rolain JM, Lagier JC, et al. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents 2020;55:105932. https://doi. org/10.1016/j.ijantimicag.2020.105932;PMID: 32145363. Office of the National Health and Health Commission Office of the State Administration of Traditional Chinese Medicine. New

22.

23.

24.

25.

26.

27.

28.

29.

30.

coronavirus pneumonia diagnosis and treatment program (trial version 7) [in Chinese]. 2020. http://www.gov.cn/ zhengce/zhengceku/2020-03/04/content_5486705.htm (accessed 22 May 2020). Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020. https://doi. org/10.1093/cid/ciaa237;PMID: 32150618; epub ahead of press. Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. J Am Coll Cardiol 2020;75:2352–71. https://doi.org/10.1016/j. jacc.2020.03.031;PMID: 32201335. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with Covid-19 preliminary report. N Engl J Med 2020. https://doi.org/10.1056/ NEJMoa2021436; PMID: 32678530; epub ahead of press. Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. MedRxiv 23 April 2020. https://doi.org/10.1101/2020.04.16.20065920 (accessed 22 May 2020). Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an openlabel non-randomized clinical trial. Int J Antimicrob Agents 2020. https://doi.org/10.1016/j.ijantimicag.2020.105949; PMID: 32205204; epub ahead of press. Molina JM, Delaugerre C, Le Goff J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect 2020;50:384. https://doi. org/10.1016/j.medmal.2020.03.006;PMID: 32240719. Xu, X, Han M, Li T, et al. Effective treatment of severe COVID19 patients with tocilizumab. 2020. http://chinaxiv.org/ abs/202003.00026 (accessed 22 May 2020). Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med 2020. https://doi.org/10.1056/NEJMoa2007016; PMID: 32275812; epub ahead of press. Food and Drug Administration. Emergency use authorization for emergency use of remdesivir for the treatment of hospitalized 2019 coronavirus disease (COVID-19) patients. 1 May 2020. https://www.fda.gov/media/137564/download (accessed 22 May 2020).

Hypertension

The Role of Nocturnal Blood Pressure and Sleep Quality in Hypertension Management Francesco P Cappuccio1,2 1. ESH Centre of Excellence in Hypertension and Cardio-metabolic Research, University of Warwick Medical School, Coventry, UK; 2. University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK

Abstract The accurate measurement, prediction and treatment of high blood pressure (BP) are essential to the management of hypertension and the prevention of its associated cardiovascular (CV) risks. However, even if BP is optimally controlled during the day, nocturnal high blood pressure may still increase the risk of CV events. The pattern of circadian rhythm of BP can be evaluated by ambulatory BP monitoring (ABPM). Nighttime ABPM is more closely associated with fatal and nonfatal CV events than daytime ambulatory BP. However, the use of ABPM is limited by low availability and the fact that it can cause sleep disturbance, therefore may not provide realistic nocturnal measurements. Home blood pressure monitoring (HBPM) offers an inexpensive alternative to ABPM, is preferred by patients and provides a more realistic assessment of BP during an individual’s daily life. However, until recently, HBPM did not offer the possibility to measure nocturnal (sleep time) BP. The development and validation of new BP devices, such as the NightView (OMRON Healthcare, HEM9601T-E3) HBPM device, could overcome these limitations, offering the possibility of daytime and night-time BP measurements with minimal sleep disturbance.

Keywords Ambulatory blood pressure monitoring, cardiovascular disease, home blood pressure monitoring, hypertension, nocturnal blood pressure monitoring Disclosure: FPC has received fees and refund of expenses from OMRON Healthcare Europe and Asia for educational involvement in the development and delivery of the OMRON Academy Programme. Received: 21 April 2020 Accepted: 5 June 2020 Citation: European Cardiology Review 2020;15:e60. DOI: https://doi.org/10.15420/ecr.2020.13 Correspondence: Francesco P Cappuccio, WMS – Mental Health and Wellbeing, University of Warwick, Gibbet Hill Rd, Coventry CV4 7AL, UK. E: F.P.Cappuccio@warwick.ac.uk Support: The publication of this manuscript was supported by OMRON Healthcare Europe B.V. Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Hypertension is a major independent risk factor for cardiovascular (CV) diseases, including cardiac death, coronary heart disease, heart failure, stroke and chronic kidney disease. Therefore, early diagnosis, prevention and optimal management of hypertension is essential.1 Hypertension poses a growing public health burden: the number of adults with elevated blood pressure (BP) increased from 594 million in 1975 to 1.13 billion in 2015, and it is estimated that the number of people with hypertension will be close to 1.5 billion by 2025.2,3 During the past decades, BP measurement has evolved from manual measuring to fully automatic monitoring; ambulatory BP monitoring (ABPM) was first described in 1964.4 Since then, the importance of nocturnal BP has been recognised.5 This article aims to understand the clinical significance, therapeutic implications and optimal measurement of nocturnal hypertension.

on the circadian pattern, causing much of the observed day-night pattern in BP.6 In general, BP starts declining from late evening onwards, reaches a nadir around midnight and rises just after awakening in the morning (Figure 1).7,8 People are defined as dippers if their nocturnal BP falls by >10 % of the daytime average BP value; however, dipping status varies from day to day and the classification of patients into dippers and non-dippers is not reproducible over time.1,5,9 Non-dipping status is associated with sleep disturbance, obstructive sleep apnoea (OSA), obesity, high salt intake in salt-sensitive people, orthostatic hypotension, autonomic dysfunction, chronic kidney disease, diabetic neuropathy and older age.10–16

Nocturnal Hypertension

In recent years, it has been recognised that nocturnal BP is, in general, a better predictor of the risk of fatal and nonfatal CV events (stroke, MI and CV death) and organ damage than daytime BP in hypertensive and renal transplant patients.10,15–19

BP variation over 24 hours normally follows a pattern, with a peak in the early morning hours and a decrease at night, known as dipping. This variation is the result of an endogenous circadian rhythm, which exerts its peak at around 9 pm, and behavioural effects that are superimposed

Night-to-day ratio is also a significant predictor of CV events, and patients defined as non-dippers have an increased CV risk.15 A nondipping BP pattern has been shown to be predictive of a range of CV

Access at: www.ECRjournal.com

Nocturnal Blood Pressure and Sleep Quality in Hypertension Management events, including total CV death, sudden death, nonfatal CV events and nonfatal stroke, in people with and without carotid atherosclerosis.20 In patients with heart failure with preserved ejection fraction, a nondipping pattern was found to be an independent risk factor for future CV events, including recurrence of hospitalisation for heart failure and cognitive dysfunction.21,22 People who experience a night-time BP decrease of ≥20% are termed extreme dippers; this may be associated with an increased risk of ischaemic stroke and silent cerebral diseases.23 An exaggerated morning surge in BP is also associated with an increased risk of stroke.24 Therefore, nocturnal hypertension has become an important therapeutic target for the prevention of CV events in patients with hypertension.

Obstructive Sleep Apnoea in Patients with Hypertension OSA is a sleep disorder characterised by frequent episodes of partial or complete collapse of the upper airway during sleep.25 A large body of evidence supports the association of OSA with hypertension, CV disease and disorders of glucose metabolism.26,27 The relationship between OSA and hypertension is bidirectional: not only does OSA predispose patients to develop hypertension, but there is also a greater incidence of OSA in hypertensive patients.28–30 Hypertension in patients with OSA is predominantly nocturnal, and non-dipping BP is common in patients with OSA.14,31–33 The average peak and the maximal nocturnal BP values may be related to the nocturnal BP surge triggered by the apnoea or hypopnea episodes of OSA.34 The prompt diagnosis and treatment of OSA are essential to the management of hypertensive patients, since OSA is a common cause of resistant hypertension.35 Furthermore, the constant sleep fragmentation associated with OSA and related conditions, such as OSA–hypopnoea syndrome is associated with disrupted and short sleep, excessive daytime sleepiness, fatigue, headaches and high rates of morbidity and mortality.36 Poor quality and quantity of sleep has a substantial negative impact on CV health and all-cause mortality, type 2 diabetes, hypertension, respiratory disorders and obesity at all ages.34–38 Importantly, OSA can be treated; continuous positive airway pressure (CPAP), the first-line therapy for moderate to severe OSA syndrome, reduces the 24-hour mean BP by approximately 2 mmHg.39 Active or supportive measures to increase quality or quantity of sleep may also be beneficial to patients with OSA–hypopnoea syndrome.39

Challenges of Diagnosing Obstructive Sleep Apnoea and Related Hypertension OSA and nocturnal hypertension are often not recognised, or masked.40 Unlike white coat hypertension, in which BP is elevated in clinical settings but normal at other times, people with masked hypertension have normal BP in the office, but elevated BP at other times.1 Masked hypertension has been reported in approximately 15% of patients with a normal BP in the office. It is associated with dyslipidaemia, increases in arterial stiffness, raised plasma B-type natriuretic peptide level and urinary albumin:excretion ratio, increased risk of developing diabetes, and sustained hypertension and CV disease.1,41,42 Masked nocturnal hypertension has been associated with markers of CV risk, even in hypertensive patients with well-controlled self-measured home BP.43–45 Therefore, it is important that a uniform, reproducible method for the measurement of nocturnal BP is established. Nocturnal BP is generally considered the average of BP readings recorded during the period most likely coinciding with sleep time.46 Night-time is usually set a priori

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Figure 1: Components of Nocturnal Hypertension

Blood pressure

Morning surge

Night-time surge

Cold Exercise Worksite stress Smoking Alcohol (dinner) Insomnia Sleep apnoea

OSA Arousal REM sleep Nocturia

Riser Night-time dipping Salt Salt sensitivity CKD CHF Diabetes Structural vascular disease Insomnia

Non-dipper Dipper Extreme dipper

Basal BP

Arising

Night-time (sleep)

Morning

CHF = chronic heart failure; CKD = chronic kidney disease; OSA = obstructive sleep apnoea; REM = rapid eye movement. Source: Kario et al. 2018.8 Reproduced with permission from Wolters Kluwer Health.

Table 1: Definitions of Hypertension According to Office, Ambulatory and Home Blood Pressure Levels Category

SBP (mmHg)

DBP (mmHg)

Office BP*

≥140

and/or

≥90

Ambulatory BP

Daytime (or awake) mean

≥135

and/or

≥85

Night-time (or asleep) mean

≥120

and/or

≥70

24 h mean

≥130

and/or

≥80

Home BP mean

≥135

and/or

≥85

*Refers to conventional office BP rather than unattended office BP. BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure. Source: Williams et al. 2018.1 Reproduced with permission from Oxford University Press.

(e.g. from 10 pm to 6 am), without considering variations in sleeping times between patients and individual patient fluctuations. Furthermore, the current methods are unable to differentiate between time in bed and time asleep. Issues such as differing methods for monitoring nocturnal BP, different definitions of nocturnal time, diagnostic thresholds and opinions of whether to control abnormal nocturnal BP, have hindered progress in the appropriate management of patients with hypertension.47 Ambulatory BP monitoring (ABPM) has historically been the gold standard for measuring nocturnal BP. It provides the average of BP readings over a defined period, usually 24 hours. The device is programmed to record BP at 15–30 minute intervals (often 60 minute intervals at night), and calculates average BP values for daytime, nighttime and over 24 hours.1,48 According to the latest European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) guidelines, the thresholds for diagnosis of hypertension based on ABPM are ≥130/80 mmHg over 24 hours, ≥135/85 mmHg in the daytime and ≥120/70 mmHg at night (Table 1).1 The night-time BP is calculated as the average of night-time measurements, which is typically set between 10 pm and 6 am, so that average readings often do not reflect BP at the time of sleep. It is well established that ABPM is more sensitive than office BP in predicting CV events.1,49 The use of ABPM also enables the diagnosis of white coat and masked hypertension.1

Hypertension Table 2: Comparison of Ambulatory Blood Pressure Monitoring and Home Blood Pressure Monitoring ABPM

HBPM

Advantages • Ability to identify white coat and masked hypertension

• Substantial information from a single • Inexpensive and widely available measurement session, including • Tend to be preferred by patients over short-term BP variability ABPM • Particularly useful for patients with OSA • Can be used over long periods to assess day-to-day variability Disadvantages • Relatively expensive

Disadvantages • Potential for measurement error

• Can be cumbersome and often uncomfortable

• Limited data available on nocturnal BP monitoring

• Can cause sleep disturbance, resulting in an inaccurate measured nocturnal BP value ABPM = ambulatory blood pressure monitoring; BP = blood pressure; HBPM = home blood pressure monitoring; OSA = obstructive sleep apnoea.

Despite the advantages of ABPM, its availability is limited, and the devices are relatively expensive.48,50 As a result, not every patient with hypertension will have ABPM measurements and nocturnal hypertension can remain undetected. Furthermore, ABPM devices are cumbersome and often uncomfortable, and can cause sleep disturbance because of the device cuff inflation and frequency of measurements, resulting in a measured nocturnal BP value that is different from the true BP when the patient has an undisturbed sleep.51 A prospective study found that nighttime BP rises and loses its prognostic significance in the patients who perceive a sleep deprivation by at least 2 hours during overnight monitoring.52 Finally, the definitions of masked and white-coat uncontrolled hypertension defined with ABPM show poor reproducibility over time, reducing its long-term prognostic value.53 Therefore, there are several reasons to believe that there are still unmet needs for obtaining high-quality BP values during sleep.

The Role of Home Blood Pressure Monitoring in the Diagnosis and Treatment of Hypertension The use of home BP monitoring (HBPM) is widespread, well accepted and is relatively inexpensive compared with ABPM.1 A comparison of the advantages and disadvantages of the two techniques is given in Table 2. Patient preference might influence adherence to BP-lowering medication. A 2014 study of 119 patients found that patients with hypertension prefer HBPM to ABPM.54 This is an important finding and warrants further investigation. Early studies suggested that the use of HBPM could improve adherence and the level of BP control to target.55 A recent trial confirmed that the use of connected HBPM devices improves the percentage of patients that achieve target values and the time in which the target is reached.56 Therefore, home BP monitoring has become widely recommended for the management of hypertension, as it enables the collection of more data away from the office setting and in a patient’s normal environment.1 The ESC/ESH guidelines state that the lack of nocturnal readings in HBPM is a disadvantage, and that home nocturnal BP monitoring is not available.1 However, recent technological advances in self-monitoring devices have facilitated the development of several kinds of home measurement devices for nocturnal BP, and a number of studies have shown that

nocturnal HBPM is both feasible and effective.8,57–65 The first data on nocturnal BP measurement were obtained in 2001, when a Japanese research group examined the impact of a single nocturnal BP measurement on sleep quality.63 The same research group later found that the reproducibility of a single nocturnal BP measurement as assessed using an HBPM device was not good.61 Subsequently, HBPM devices have produced data that correlate more closely with ABPM measurements.64 A number of nocturnal HBPM devices have been validated. These include two oscillometric upper-arm cuff home BP monitors (Omron HEM-747IC-N; OMRON Healthcare and the HEM-5001; Medinote, Omron Healthcare).66,67At present, no comparative studies have been performed for these devices. In order to fully assess the benefits of nocturnal HBPM, studies are needed to assess its reproducibility within subjects and the prognostic ability. In a pilot study, 39 patients with OSA underwent polysomnography, clinic BP measurements, and HBPM using a device that allowed daytime (3 days, two duplicate readings per day) and automated night-time BP measurement (3 nights, three readings per night).65 HBPM showed a stronger correlation than ABPM to the severity of OSA.60 Another study (n=30) evaluating nocturnal BP of treatment-naive individuals using an HBPM device found that night-time BP measurements were significantly lower in subjects without left ventricular hypertrophy (LVH) compared with those with LVH, while daytime readings were not significantly different between the two groups.62 A recent meta-analysis found that the nocturnal HBPM and ABPM measurements provided similar values (HBPM readings were 1.4 mmHg higher for systolic and 0.2 mmHg lower for diastolic values) compared with ABPM measurements, and both were similarly associated with measures of target organ damage (left ventricular mass index).58

The NightView HBPM Device To date, all studies on nocturnal HBPM have been small. Practical issues need to be addressed, including the optimal number of nocturnal BP readings needed to obtain clinically meaningful information. The most accurate assessment of nocturnal BP would require frequent measurements during sleep, but this may cause sleep interruption and would be expensive for individuals with the current method of ABPM. On the other hand, HBPM with cheaper and validated available devices is not suitable for night-time BP measurements because these need patients to initiate the readings. Therefore, a reasonable compromise is needed. Available data suggest that HBPM may prove to be more feasible, affordable and widely available for routine continued clinical assessment of nocturnal BP, but a standardised validated method for the measurement of nocturnal BP is needed. NightView (OMRON Healthcare, HEM9601T-E3) is a connected wrist type HBPM device for use in adults with wrist circumference ranging from 13.5 cm to 21.5 cm (Figure 2). In addition to normal daytime measurements, it also automatically takes BP measurements during sleep. The NightView nocturnal mode is selected when the patient goes to bed and automatically takes three measurements whether the user is asleep or awake at the time of measurement: 4 hours after going to bed, at 2 am and 4 am. These measurements are silent and do not cause sleep disturbance. If a nocturnal measurement fails because of an error such as movement error, the monitor will try to take another measurement a minute later (it tries only once). The device is connected via Bluetooth and data management is done via the Omron Connect app. NightView has been clinically validated in

EUROPEAN CARDIOLOGY REVIEW

Nocturnal Blood Pressure and Sleep Quality in Hypertension Management sitting and in supine position (with palm placed sideways, upwards and downwards), according to the ANSI/AAMI/ISO81060-2:201 protocol and has passed all criteria.68,69 A comparison with ABPM in 85 subjects found similar results in office and out of office.68,69 This improved possibility to detect masked nocturnal hypertension will allow optimisation of BP-lowering medication, with the ultimate goal of optimising the achievement of BP target values and reduce CV events.

Figure 2: The NightView Blood Pressure Monitor

Treatment of Nocturnal Hypertension The impact of controlling night-time BP is potentially greater in people with hypertension who are taking medication than in those who are not taking medication, because the BP-lowering effect of a once-daily BP drug may not persist for 24 hours even in patients with well-controlled daytime BP.8 Therefore, it has been suggested that taking BP-lowering medication at night may be more effective than in the morning. The Ambulatory Blood Pressure Monitoring and Cardiovascular Events (MAPEC) study, which included 2,156 hypertensive adults with a median follow-up of 5.6 years, found that the administration of at least one BPlowering medication at bedtime was more effective than morning dosing, both in terms of lowering nocturnal BP and restoring the expected variability in BP, and for reducing CV events and total mortality.70 Recently, the Hygia Chronotherapy Trial in Spain involved 19,084 patients in the primary care setting.71 The trial was designed to compare treatment with BP-lowering medications at bedtime with usual upon awakening hypertension therapy in terms of CV risk reduction. The results have sparked much interest and debate, since they suggest that patients who took medication at bedtime, compared with upon awakening, had more than half the rate of CV events during the mean 6.3 year follow-up, attributable only to a 3.3/1.6 mmHg greater fall in night-time BP and no difference in daytime BP.71 However, the study has a number of important limitations. The two groups differed significantly: there were more patients with previous CV events and more patients taking diuretics and beta-blockers in the awakening medication group than in the group receiving bedtime medication.72 The prevalence of side-effects and non-adherence was unexpectedly similar between groups, and the relative risk reduction recorded was unexpectedly high for the reported small differences in BP recorded at night.73 Doubts concerning ethics, randomisation and plausibility have led to questioning the credibility of the results.73,74 Further well-designed randomised controlled trials are needed to provide evidence that treating nocturnal BP is beneficial.

Reproduced with permission from OMRON.

treatment of hypertension and OSA to help address the increasing CV morbidity and mortality due to the frequent co-morbidity. A recent review found that certain antihypertensive medications are more effective than others in regulation of nocturnal BP, but that the timing of drug administration is key to the reduction of night-time BP. However, the authors concluded that further studies are needed.75,76

Conclusion

Night-time ABPM may interfere with sleep quality because of the intrusive cuff inflation and the frequency of measurements, often resulting in disturbed sleep and inaccurate nocturnal BP measurements. The use of nocturnal HBPM is potentially a reliable, cheaper and practical alternative to ABPM for the repeated measurement of BP during sleep. The use of HBPM devices is widespread, well accepted by users and is relatively inexpensive, it may prove to be more feasible and widely available for routine clinical assessment of nocturnal BP, reducing primary care consultations and healthcare costs. Preliminary data suggest that nocturnal HBPM is feasible and provides prognostic information similar to that of ABPM. The NightView HBPM device offers the possibility of daytime and night-time BP measurements with minimal sleep disturbance.

Nocturnal hypertension, as assessed by ABPM, is a stronger predictor of CV events than daytime hypertension, suggesting that monitoring nocturnal BP is an important method of stratifying CV risk due to high BP, although the additional CV benefits of lowering night-time BP is still debated. Furthermore, there is a need for the prompt diagnosis and

Further data are needed on the prognostic significance of nocturnal BP measured by HBPM in terms of CV outcomes, optimal schedules for measurement, and the value of administering BP medications at different time of the day.

Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018;39:3021–104. https://doi.org/10.1093/eurheartj/ ehy339; PMID: 30165516. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19.1 million participants. Lancet 2017;389:37–55. https://doi.org/10.1016/s0140-6736(16)31919-5; PMID: 27863813. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet 2005;365:217–23. https://doi.org/10.1016/s0140-

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6736(05)17741-1; PMID: 15652604. Kain HK, Hinman AT, Sokolow M. Arterial blood pressure measurements with a portable recorder in hypertensive patients. I. Variability and correlation with “casual” pressures. Circulation 1964;30:882–92. https://doi.org/10.1161/01. CIR.30.6.882; PMID: 14246333. O’Brien E, Sheridan J, O’Malley K, Dippers and non-dippers. Lancet 1988;2:397. https://doi.org/10.1016/s01406736(88)92867-x; PMID: 2899801. Shea SA, Hilton MF, Hu K, et al. Existence of an endogenous circadian blood pressure rhythm in humans that peaks in the evening. Circ Res 2011;108:980–4. https://doi.org/10.1161/ CIRCRESAHA.110.233668; PMID: 21474818.

Pickering TG. The clinical significance of diurnal blood pressure variations. Dippers and nondippers. Circulation 1990;81:700–2. https://doi.org/10.1161/01.CIR.81.2.700; PMID: 2137050. 8. Kario K. Nocturnal hypertension: new technology and evidence. Hypertension 2018;71:997–1009. https://doi. org/10.1161/hypertensionaha.118.10971; PMID: 29712746. 9. Omboni S, Parati G, Palatini P, et al. Reproducibility and clinical value of nocturnal hypotension: prospective evidence from the SAMPLE study. J Hypertens 1998;16:733–8. https://doi. org/10.1097/00004872-199816060-00003; PMID: 9663912. 10. Ohkubo T, Hozawa A, Yamaguchi J, et al. Prognostic significance of the nocturnal decline in blood pressure in individuals with and without high 24-h blood pressure: the

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11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

Ohasama study. J Hypertens 2002;20:2183–9. https://doi. org/10.1097/00004872-200211000-00017; PMID: 12409956. de la Sierra A, Redon J, Banegas JR, et al. Prevalence and factors associated with circadian blood pressure patterns in hypertensive patients. Hypertension 2009;53:466–72. https:// doi.org/10.1161/hypertensionaha.108.124008; PMID: 19171788. de la Sierra A, Gorostidi M, Banegas JR, et al. Nocturnal hypertension or nondipping: which is better associated with the cardiovascular risk profile? Am J Hypertens 2014;27:680–7. https://doi.org/10.1093/ajh/hpt175; PMID: 24061070. Crinion SJ, Ryan S, Kleinerova J, et al. Nondipping nocturnal blood pressure predicts sleep apnea in patients with hypertension. J Clin Sleep Med 2019;15:957–63. https://doi. org/10.5664/jcsm.7870; PMID: 31383232. Fagard RH, Celis H, Thijs L, et al. Daytime and nighttime blood pressure as predictors of death and cause-specific cardiovascular events in hypertension. Hypertension 2008;51:55–61. https://doi.org/10.1161/ hypertensionaha.107.100727; PMID: 18039980. Salles GF, Reboldi G, Fagard RH, et al. Prognostic effect of the nocturnal blood pressure fall in hypertensive patients: the Ambulatory Blood Pressure Collaboration in Patients With Hypertension (ABC-H) meta-analysis. Hypertension 2016;67:693–700. https://doi.org/10.1161/ hypertensionaha.115.06981; PMID: 26902495. Fagard RH, Thijs L, Staessen JA, et al. Night-day blood pressure ratio and dipping pattern as predictors of death and cardiovascular events in hypertension. J Hum Hypertens 2009;23:645–53. https://doi.org/10.1038/jhh.2009.9; PMID: 19225527. Boggia J, Li Y, Thijs L, et al. Prognostic accuracy of day versus night ambulatory blood pressure: a cohort study. Lancet 2007;370:1219–29. https://doi.org/10.1016/s01406736(07)61538-4; PMID: 17920917. Hansen TW, Li Y, Boggia J, et al. Predictive role of the nighttime blood pressure. Hypertension 2011;57:3–10. https://doi. org/10.1161/hypertensionaha.109.133900; PMID: 21079049. Kario K, Pickering TG, Matsuo T, et al. Stroke prognosis and abnormal nocturnal blood pressure falls in older hypertensives. Hypertension 2001;38:852–7. https://doi. org/10.1161/hy1001.092640; PMID: 11641298. Kario K, Pickering TG, Umeda Y, et al. Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: a prospective study. Circulation 2003;107:1401–6. https://doi.org/10.1161/01. cir.0000056521.67546.aa; PMID: 12642361. Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008;5:136–43. https://doi. org/10.1513/pats.200709-155MG; PMID: 18250205. Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–84. https://doi. org/10.1056/nejm200005113421901; PMID: 10805822. Peker Y, Carlson J, Hedner J. Increased incidence of coronary artery disease in sleep apnoea: a long-term follow-up. Eur Respir J 2006;28:596–602;10.1183/09031936.06.00107805; PMID: 16641120. Punjabi NM, Polotsky VY. Disorders of glucose metabolism in sleep apnea. J Appl Physiol (1985) 2005;99:1998–2007. https:// doi.org/10.1152/japplphysiol.00695.2005; PMID: 16227461. Ahmad M, Makati D, Akbar S. Review of and updates on hypertension in obstructive sleep apnea. Int J Hypertens 2017;2017:1848375. https://doi.org/10.1155/2017/1848375; PMID: 29147581. Lavie P, Herer P, Hoffstein V. Obstructive sleep apnoea syndrome as a risk factor for hypertension: population study. BMJ 2000;320:479–82. https://doi.org/10.1136/ bmj.320.7233.479; PMID: 10678860. Nieto FJ, Young TB, Lind BK, et al. Association of sleepdisordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 2000;283:1829–36. https://doi.org/10.1001/jama.283.14.1829; PMID: 10770144. Loredo JS, Ancoli-Israel S, Dimsdale JE. Sleep quality and blood pressure dipping in obstructive sleep apnea. Am J Hypertens 2001;14:887–92. https://doi.org/10.1016/s0895-7061(01)021434; PMID: 11587154. Marrone O, Bonsignore MR, Blood-pressure variability in patients with obstructive sleep apnea: current perspectives. Nat Sci Sleep 2018;10:229–42. https://doi.org/10.2147/nss. S148543; PMID: 30174467. Marin JM, Agusti A, Villar I, et al. Association between treated and untreated obstructive sleep apnea and risk of hypertension. JAMA 2012;307:2169–76. https://doi. org/10.1001/jama.2012.3418; PMID: 22618924. Baguet JP, Hammer L, Levy P, et al. Night-time and diastolic hypertension are common and underestimated conditions in newly diagnosed apnoeic patients. J Hypertens 2005;23:521–7. https://doi.org/10.1097/01.hjh.0000160207.58781.4e; PMID: 15716692. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research,

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

Circulation 2008;117:e510–26. https://doi.org/10.1161/ circulationaha.108.189141; PMID: 18574054. Marin JM, Carrizo SJ, Vicente E, et al. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046–53. https://doi.org/10.1016/s0140-6736(05)71141-7; PMID: 15781100. Cappuccio FP, Cooper D, D’Elia L, et al. Sleep duration predicts cardiovascular outcomes: a systematic review and metaanalysis of prospective studies. Eur Heart J 2011;32:1484–92. https://doi.org/10.1093/eurheartj/ehr007; PMID: 21300732. Cappuccio FP, D’Elia L, Strazzullo P, et al. Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies. Sleep 2010;33:585–92. https://doi. org/10.1093/sleep/33.5.585; PMID: 20469800. Cappuccio FP, D’Elia L, Strazzullo P, et al. Quantity and quality of sleep and incidence of type 2 diabetes: a systematic review and meta-analysis. Diabetes Care 2010;33:414–20. https://doi. org/10.2337/dc09-1124; PMID: 19910503. Gangwisch JE, Heymsfield SB, Boden-Albala B, et al. Short sleep duration as a risk factor for hypertension: analyses of the first National Health and Nutrition Examination Survey. Hypertension 2006;47:833–9. https://doi.org/10.1161/01. HYP.0000217362.34748.e0; PMID: 16585410. Cappuccio FP, Stranges S, Kandala NB, et al. Gender-specific associations of short sleep duration with prevalent and incident hypertension: the Whitehall II Study. Hypertension 2007;50:693–700. https://doi.org/10.1161/ hypertensionaha.107.095471; PMID: 17785629. Bliwise DL. Sleep-related respiratory disturbances. J Gerontol 1984;39:255. https://doi.org/10.1093/geronj/39.2.255; PMID: 6699385. Cappuccio FP, Taggart FM, Kandala NB, et al. Meta-analysis of short sleep duration and obesity in children and adults. Sleep 2008;31:619–26. https://doi.org/10.1093/sleep/31.5.619; PMID: 18517032. Miller MA, Kruisbrink M, Wallace J, et al. Sleep duration and incidence of obesity in infants, children, and adolescents: a systematic review and meta-analysis of prospective studies. Sleep 2018;41:zsy018. https://doi.org/10.1093/sleep/zsy018; PMID: 29401314. Haentjens P, Van Meerhaeghe A, Moscariello A, et al. The impact of continuous positive airway pressure on blood pressure in patients with obstructive sleep apnea syndrome: evidence from a meta-analysis of placebo-controlled randomized trials. Arch Intern Med 2007;167:757–64. https://doi. org/10.1001/archinte.167.8.757; PMID: 17452537. Randerath W, Bassetti CL, Bonsignore MR, et al. Challenges and perspectives in obstructive sleep apnoea. Eur Respir J 2018;52:1702616. https://doi.org/10.1183/13993003.026162017; PMID: 29853491. Bobrie G, Clerson P, Menard J, et al. Masked hypertension: a systematic review. J Hypertens 2008;26:1715–25. https://doi. org/10.1097/HJH.0b013e3282fbcedf; PMID: 18698202. Mancia G, Facchetti R, Bombelli M, et al. Long-term risk of mortality associated with selective and combined elevation in office, home, and ambulatory blood pressure. Hypertension 2006;47:846–53. https://doi.org/10.1161/01. HYP.0000215363.69793.bb; PMID: 16567588. Hoshide S, Ishikawa J, Eguchi K, et al. Masked nocturnal hypertension and target organ damage in hypertensives with well-controlled self-measured home blood pressure. Hypertens Res 2007;30:143–9. https://doi.org/10.1291/hypres.30.143; PMID: 17460384. Wijkman M, Lanne T, Engvall J, et al. Masked nocturnal hypertension – a novel marker of risk in type 2 diabetes. Diabetologia 2009;52:1258–64. https://doi.org/10.1007/s00125009-1369-9; PMID: 19396423. O’Flynn AM, Madden JM, Russell AJ, et al. Isolated nocturnal hypertension and subclinical target organ damage: a systematic review of the literature. Hypertens Res 2015;38:570– 5. https://doi.org/10.1038/hr.2015.43; PMID: 25832917. Waeber B, Mourad JJ, O’Brien E, Nighttime blood pressure: a target for therapy? Curr Hypertens Rep 2010;12:474–9. https:// doi.org/10.1007/s11906-010-0152-0; PMID: 20862569. Xu T, Zhang YQ, Tan XR, The dilemma of nocturnal blood pressure. J Clin Hypertens (Greenwich) 2012;14:787–91. https:// doi.org/10.1111/jch.12003; PMID: 23126351. Pickering TG, Shimbo D, Haas D. Ambulatory blood-pressure monitoring. N Engl J Med 2006;354:2368–74. https://doi. org/10.1056/NEJMra060433; PMID: 16738273. Piper MA, Evans CV, Burda BU, et al. Diagnostic and predictive accuracy of blood pressure screening methods with consideration of rescreening intervals: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2015;162:192–204. https://doi.org/10.7326/m14-1539; PMID: 25531400. Mancia G, Facchetti R, Cuspidi C et al. Limited reproducibility of MUCH and WUCH: evidence from the ELSA study. Eur Heart J 2020;41:1565–71. https://doi.org/10.1093/eurheartj/ehz651; PMID: 31539054. Dadlani A, Madan K, Sawhney JPS. Ambulatory blood pressure monitoring in clinical practice. Indian Heart J 2019;71:91–7. https://doi.org/10.1016/j.ihj.2018.11.015; PMID: 31000190.

55. Davies RJ, Jenkins NE, Stradling JR. Effect of measuring ambulatory blood pressure on sleep and on blood pressure during sleep. BMJ 1994;308:820–3. https://doi.org/10.1136/ bmj.308.6932.820; PMID: 8167489. 56. Verdecchia P, Angeli F, Borgioni C, et al. Ambulatory blood pressure and cardiovascular outcome in relation to perceived sleep deprivation. Hypertension 2007;49:777–83. https://doi. org/10.1161/01.Hyp.0000258215.26755.20; PMID: 17261645. 57. Nasothimiou EG, Karpettas N, Dafni MG, Stergiou GS. Patients’ preference for ambulatory versus home blood pressure monitoring. J Hum Hypertens 2014;28:224–9. https://doi. org/10.1038/jhh.2013.104; PMID: 24152822. 58. Cappuccio FP, Kerry SM, Forbes L, Donald A. Blood pressure control by home monitoring: meta-analysis of randomised trials. BMJ 2004;329:145. https://doi.org/10.1136/ bmj.38121.684410.AE; PMID: 15194600. 59. McManus RJ, Mant J, Franssen M, et al. Efficacy of selfmonitored blood pressure, with or without telemonitoring, for titration of antihypertensive medication (TASMINH4): an unmasked randomised controlled trial. Lancet 2018;391:94959. https://doi.org/10.1016/s0140-6736(18)30309-x; PMID: 29499873. 60. Asayama K, Fujiwara T, Hoshide S, et al. Nocturnal blood pressure measured by home devices: evidence and perspective for clinical application. J Hypertens 2019;37:905–16. https://doi.org/10.1097/hjh.0000000000001987; PMID: 30394982. 61. Kollias A, Ntineri A, Stergiou GS. Association of night-time home blood pressure with night-time ambulatory blood pressure and target-organ damage: a systematic review and meta-analysis. J Hypertens 2017;35:442–52. https://doi. org/10.1097/hjh.0000000000001189; PMID: 27930440. 62. Andreadis EA, Agaliotis G, Kollias A, et al. Night-time home versus ambulatory blood pressure in determining target organ damage. J Hypertens 2016;34:438–44. https://doi.org/10.1097/ hjh.0000000000000815; PMID: 26727487. 63. Stergiou GS, Triantafyllidou E, Cholidou K, et al. Asleep home blood pressure monitoring in obstructive sleep apnea: a pilot study. Blood Press Monit 2013;18:21–6. https://doi.org/10.1097/ MBP.0b013e32835d3608; PMID: 23263537. 64. Hosohata K, Kikuya M, Ohkubo T, et al. Reproducibility of nocturnal blood pressure assessed by self-measurement of blood pressure at home. Hypertens Res 2007;30:707–12. https:// doi.org/10.1291/hypres.30.707; PMID: 17917318. 65. Pai AU, Chakrapani M, Bhaskaran U, et al. Study of homemonitored night blood pressure and its correlation with left ventricular hypertrophy in treatment-naive hypertensive patients. Singapore Med J 2012;53:95–8. PMID: 22337182. 66. Chonan K, Kikuya M, Araki T, et al. Device for the selfmeasurement of blood pressure that can monitor blood pressure during sleep. Blood Press Monit 2001;6:203–5. https://doi.org/10.1097/00126097-200108000-00008; PMID: 11805470. 67. Ushio H, Ishigami T, Araki N, et al. Utility and feasibility of a new programmable home blood pressure monitoring device for the assessment of nighttime blood pressure. Clin Exp Nephrol 2009;13:480–5. https://doi.org/10.1007/s10157-0090192-4; PMID: 19449180. 68. Kuwabara M, Harada K, Hishiki Y, et al. Validation of a wrist‐ type home nocturnal blood pressure monitor in the sitting and supine position according to the ANSI/AAMI/ISO81060‐2:2013 guidelines: Omron HEM9601T. J Clin. Hypertens (Greenwich) 2020;22:970–8. https://doi/org/10.1111/jch.13864; PMID: 32447831. 69. Heo R, Shin J. Wrist devices with both accuracy and feasibility, new option to measure nocturnal blood pressure? J Clin Hypertens (Greenwich) 2020;22:979–80. https://doi.org/10.1111/ jch.13862; PMID: 32282114. 70. Hermida RC, Ayala DE, Mojon A, et al. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study, Chronobiol Int 2010;27:1629–51. https:// doi.org/10.3109/07420528.2010.510230; PMID: 20854139. 71. Hermida Hermida RC, Crespo JJ, Domínguez-Sardina M, et al. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. Eur Heart J 2019. https://doi.org/10.1093/eurheartj/ehz754; PMID: 31641769; epub ahead of press. 72. Sen S, Kaskal M, Üresin Y. Chrono-pharmacological effects of antihypertensive drugs. Eur Heart J 2020;41:1601. https://doi. org/10.1093/eurheartj/ehaa213; PMID: 32298408. 73. Guthrie G, Poulter N, Macdonald T, et al. Chronotherapy in hypertension: the devil is in the details. Eur Heart J 2020;41:1606–7. https://doi.org/10.1093/eurheartj/ehaa265; PMID: 32306034. 74. Lüscher TF. The Hygia trial: discussions about surprising results. Eur Heart J 2020;41:1600. https://doi.org/10.1093/ eurheartj/ehaa274; PMID: 32306031. 75. Expression of Concern. Relates to: ‘Bedtime Hypertension Treatment Improves Cardiovascular Risk Reduction: Hygia Chronotherapy Trial’. Eur Heart J 2020;41:1600. https://doi. org/10.1093/eurheartj/ehaa339; PMID: 32318736. 76. Tadic M, Cuspidi C, Grassi G, Mancia G. Isolated nocturnal hypertension: what do we know and what can we do? Integr Blood Press Control 2020;13:63–9. https://doi.org/10.2147/IBPC. S223336; PMID: 32368135.

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Expert Opinion

The Impact of Ethnicity on Cardiac Adaptation Uchenna Ozo and Sanjay Sharma St George’s University Hospital, London, UK

Abstract Regular intensive exercise is associated with a plethora of electrical, structural and functional adaptations within the heart to promote a prolonged and sustained increase in cardiac output. Bradycardia, increased cardiac dimensions, enhanced ventricular filling, augmentation of stroke volume and high peak oxygen consumption are recognised features of the athlete’s heart. The type and magnitude of these adaptations to physical exercise are governed by age, sex, ethnicity, sporting discipline and intensity of sport. Some athletes, particularly those of African or Afro-Caribbean (black) origin reveal changes that overlap with diseases implicated in sudden cardiac death. In such instances, erroneous interpretation has potentially serious consequences ranging from unfair disqualification to false reassurance. This article focuses on ethnic variation in the physiological cardiac adaption to exercise.

Keywords Athlete’s heart, black athletes, Asian athletes, east Asian athletes, cardiac adaptation, ethnicity Disclosure: The authors have no conflicts of interest to declare. Received: 21 January 2020 Accepted: 22 May 2020 Citation: European Cardiology Review 2020;15:e61. DOI: https://doi.org/10.15420/ecr.2020.01 Correspondence: Uchenna Ozo, St George’s University Hospitals NHS Foundation Trust, Blackshaw Rd, Tooting, London SW17 0QT, UK. E: uozo@sgul.ac.uk

Athletes may occasionally succumb to sudden cardiac arrest because of a quiescent cardiac abnormality. These catastrophes are rare, affecting between 1 in 17,000 to 1 in 50,000 athletes, depending on the sporting discipline.1,2 Most deaths affect male athletes participating in explosive sports of a start–stop nature, such as basketball and soccer, and occur during or immediately after exercise.1 The visibility afforded by such deaths generates considerable concern in the lay public, because young athletes are considered to represent the healthiest segment of society. Furthermore, there are several acceptable interventions to modify the natural history of these diseases and minimise the risk of sudden cardiac death.2,3 Over the past two decades there has been a growing momentum to provide cardiac evaluations in young athletes competing in the highest echelons of sport.3–6 Concurrently there has been an explosive increase in ethnic diversity in sport. Athletes from around the world now perform at the highest level in a multitude of sports. Therefore, the ethnic component of cardiovascular adaptation to exercise has become increasingly relevant, particularly in pre-participation screening. A thorough knowledge of these differences is highly pertinent for the practicing cardiologist because some athletes, especially black men, reveal electrical repolarisation changes and/or echogenic features, as part of a normal ethnic variant that overlaps with cardiac disease.7,8 This short review will examine ethnic differences in cardiac adaptation to sport. Most data are available in white athletes. There is also a wealth of data in athletes of African or Afro-Caribbean origin. However, smaller studies in athletes from other ethnicities are also included for comparison.

Cardiac Adaptation in White Athletes Participation in regular systematic intensive physical training is accompanied by an alteration in autonomic tone and increase in

cardiac size, both of which have an impact on electrocardiographic and cardiac imaging studies in athletes (Figure 1).7,9 The magnitude of these adaptations, described as the ‘athlete heart’, are governed by several factors including age, sex, ethnicity, type and intensity of sport, and – notably – ethnicity.10

Electrical Adaptation The electrical manifestations of the athlete heart broadly reflect increased vagal tone and a relative increase in cardiac dimensions.7,10,11 Sinus bradycardia, sinus arrhythmia, first degree atrio-ventricular block, large QRS voltages, incomplete right bundle branch block and early repolarisation are common in athletes of all ethnicities (Figure 2).10 In 2010, the European Society of Cardiology (ESC) provided recommendations for investigating athletes following a 12-lead ECG, whereby normal changes were classified as group one and abnormal changes were classified as group two (Table 1).12 These classifications were derived from a white population of >30,000 Italian amateur athletes, with some entering sports competition for the first time. Hence, these recommendations are appropriate for the white population, but did not account for ethnic variations.12

Structural Adaptations Structural data derived from large cohorts of white athletes have shown that athletes reveal a 10–20% increase in left ventricular wall thickness (LVWT) measurements and a 10–15% increase in ventricular cavity size compared with sedentary counterparts.13,14 Female athletes have smaller dimensions compared with male athletes in all ethnicities, but show the same qualitative changes as male athletes when they are compared with relatively sedentary female controls.15–17 LVWT >12 mm is rare in white athletes, although a significant proportion (14%) reveal a LV diameter of >60 mm.14 These features are generally confined to large men competing in endurance sports.14,18 Similar to adult white

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Expert Opinion Table 1: Common and Uncommon ECG Findings in Athletes ECG Changes Related to Exercise

Uncommon ECG Changes Requiring Further Investigation

• Sinus bradycardia

• T wave inversion

• Sinus arrhythmia

• ST segment depression

• Isolated voltage criteria for left ventricular hypertrophy

• Pathological Q waves

• Incomplete right bundle branch block

• Left atrial enlargement

• Early repolarisation

• Right ventricular hypertrophy

• First-degree heart block

• Complete left or right bundle branch block

• Wenckebach phenomenon (second-degree heart block Mobitz type 2)

• Long or short QT interval • Brugada-like early repolarisation • Ventricular arrhythmias

Source: Sharma et al. 2017 3 Reproduced with permission from Elsevier.

Figure 1: Cardiac Adaptation in Athletes

Electrical changes • Sinus bradycardia • Sinus arrhythmia • First degree AV block • Voltage criteria LVH and RVH • Incomplete RBBB

Structural changes • Increased left ventricular wall thickness • Increased left and right ventricle cavity • Bi-atrial enlargement

Functional changes • Increased diastolic filling • Increased augmentation of stroke volume

AV = atrio-ventricular; LVH = left ventricular hypertrophy; RBBB = right bundle branch block; RVH = right ventricular hypertrophy; TWI = T-wave inversion. Source: Sharma et al. 2015.10 Adapted with permission from Oxford University Press.

athletes, male adolescent athletes show a greater LVWT compared to female athletes of similar age. However, the degree of LV cavity increase in adolescent athletes is smaller compared to adult athletes.19 Changes in LV volume are mirrored in the right ventricle.20 A very small proportion of athletes show an aortic root diameter >40 mm.21

Black Athletes Electrical Adaptation Athletes of African and Afro-Caribbean (black) origin have a higher prevalence of voltage criteria for left ventricular hypertrophy (LVH), right ventricular hypertrophy (RVH) and atrial enlargement compared to white athletes. Black athletes also reveal a higher prevalence of repolarisation anomalies affecting the J point, ST segments and T waves.22,23 According to the 2010 ESC recommendations, black athletes are 2.5 times more likely to exhibit an abnormal ECG suggestive of pathology than white athletes (40.4% and 16.2%, respectively).24 These data prompted researchers to refine ECG criteria for ECG interpretation in athletes.25,26

Early Repolarisation Pattern and ST-segment Morphology Early repolarisation (ER), defined as J point elevation ≥0.1 mV in the inferior and/or lateral leads, is more prevalent in black athletes compared to non-black athletes (34% versus 28%, respectively).27 Most black athletes reveal the ER in the lateral lead where the accompanying ascending concave ST-segments (Figure 3). The J point elevation may be >0.2 mV. Among athletes the ER pattern is frequently associated with increased voltage criterion for LVH, LV mass and relative wall thickness (RWT).28

In 2008, Haïssaguerre et al. reported that ER in the inferolateral leads was associated with idiopathic VF. However, few participants were athletes or black.29 Noseworthy et al. investigated 879 college athletes and showed that among athletes of all ethnicities, the ER pattern was more prevalent in male black athletes and – in multivariate analysis – was also associated with increased QRS voltage and slower heart rate, both markers of intensive physical training.30 Athletes frequently demonstrate an upsloping or ascending ST-segment type that is benign. 31,32 One hypothesis proposes that parasympathetic modulation increases regional electrophysiological differences and repolarisation dispersion leading to ST-elevation.33 However, the ER pattern in the inferior, associated with higher J wave amplitudes (≥0.2 mV) and demonstrating horizontal or down sloping ST-segment after the J wave are associated with an increased risk of arrhythmic death in athletes and the general public.29,30,34 ST elevation is more common in black athletes than white athletes.22 Over 60% of black athletes reveal ST-segment elevation compared with 25% of white athletes. The ST-segments show a convex pattern in the anterior leads and a concave pattern in the inferior and lateral leads. Indeed, 40% of black athletes demonstrate convex anterior ST elevation in leads V1–V4.22,35 This pattern can be differentiated from the type 1 Brugada ECG pattern by measuring the amplitude at the J point (STJ) and 80 ms after (ST80). Athletes have ST-segment elevation after the J point whereas the ST-segment comes down after the J point in Brugada syndrome, therefore a STJ/ST80 ratio <1 suggests early repolarisation whereas a ratio >1 characterises a type one Brugada pattern. ST-segment depression is exceedingly rare in athletes irrespective of ethnicity and warrants further investigation to exclude structural cardiac disease.22

Anterior T Wave Inversion Anterior T wave inversion in leads V1–V4 on 12-lead ECG is common in the black population, with a prevalence of 12.7% of athletes and 4.2% in black controls compared with 1.9% in white athletes.22 Moreover, black male endurance athletes have an even higher prevalence of anterior T wave inversion – affecting one in five athletes – and is predicted by maximum LVWT.22 Anterior T wave inversion in black athletes is classically associated with J point elevation and convex ST elevation. T wave inversion is usually asymmetric with a steep downward slope, as illustrated in Figure 4. Detailed investigation of black athletes with anterior T wave inversion preceded by J point and convex ST segment elevation, including imaging studies, exercise stress test and prolonged ECG monitoring,

EUROPEAN CARDIOLOGY REVIEW

Impact of Ethnicity on Cardiac Adaptation Figure 2: 12-Lead ECG Changes in an Athlete

The ECG demonstrates sinus bradycardia, large QRS complexes, a partial right bundle branch block and early repolarisation pattern. These are all features related to exercise.

Figure 3: Early Repolarisation Pattern on 12-lead ECG in a Black Male Athlete

Black arrows demonstrate early repolarisation pattern.

have failed to identify an underlying abnormality.22,36,37 In our experience, anterior T wave inversion resolves within 6 weeks of detraining. Genetic studies using large gene panels to identify pathogenic variants causing cardiomyopathy and ion channel diseases have failed to identify any pathological abnormalities in black athletes with this repolarisation abnormality.38 Based on these observations, anterior T wave inversion preceded by J point and ST-segment elevation is considered a normal ethnic variant.3,22,35 Anterior T wave inversion is also recognised in arrhythmogenic right ventricular cardiomyopathy (ARVC). However, a study involving 80 healthy athletes with T wave inversion and patients with hypertrophic cardiomyopathy (HCM) and ARVC indicated that in contrast with healthy athletes, black individuals, including athletes with ARVC, show J point elevation <0.1 mV and isoelectric or depressed ST-segments preceding the T wave inversion in the anterior leads.39

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Inferior T Wave Inversion A study involving over 900 black athletes and 1,819 white athletes indicates that the prevalence of inferior T wave inversion (leads II, and aVF on 12-lead ECG) in black athletes is four times that of white athletes (6% versus 1.5%).22,40 Although current recommendations support further investigation of athletes with inferior T wave inversion, the precise significance of this repolarisation anomaly in black athletes is uncertain. Our own experience suggests that inferior T wave inversion is also more common in adolescent black athletes and we have yet to detect cardiac pathology in a black athlete with T wave inversion confined solely to the inferior leads.35,41 It is possible that this anomaly may be an ethnic variant but further large-scale studies are warranted.35

Lateral T Wave Inversion Lateral T wave inversion (lead I and aVL, V5 and V6) occurs with a similar prevalence in sedentary and athletic black individuals (3â&#x20AC;&#x201C;4%)

Expert Opinion Figure 4: ECG of Black Athlete Showing Anterior T-wave Inversion with J Point Elevation and Convex ST-segments in Leads V2â&#x20AC;&#x201C;V4

T wave inversion as shown by arrows.

Figure 5: ECG Showing Inferolateral T Wave Inversion in a Black Athlete

The 12-lead ECG demonstrates T wave inversion in leads II, III and aVF, as well as leads V4â&#x20AC;&#x201C;V6.

and is 10 times more common than in white athletes.22 One study also showed that the prevalence of lateral T wave inversion in adolescent black athletes was also considerably higher than in white counterparts (2.4% versus 0.3%) (Figure 5).35 It is unlikely that all black athletes with lateral T wave inversion are destined to develop a cardiomyopathy. However, it is important to note that lateral T wave inversion is also a very common feature in black

individuals with HCM (76.9%). 22 Although the diagnostic yield of cardiomyopathy in black athletes with lateral T wave inversion is considerably less than in white athletes, one study showed that up to 18% of black athletes with lateral T wave inversion have an underlying cardiomyopathy.42 Therefore, all black athletes with lateral T wave inversion should be investigated as comprehensively as white athletes.42

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Impact of Ethnicity on Cardiac Adaptation Structural Changes In general, black athletes undergo a similar process of exercise-related structural cardiac adaptation as white athletes.8 The effect of ethnicity on left or right ventricular cavity size between black and white athletes is minimal, with black athletes demonstrating marginally smaller proximal right ventricular outflow tract and longitudinal dimensions.8,43 Some studies have reported slightly larger left atrium and aortic dimensions compared to white athletes. However, there are a few notable structural differences.8,22 Black athletes generally exhibit a larger body surface area (BSA) and systolic blood pressure (SBP) than white athletes.22 Black male athletes demonstrate an increased LVWT ≥12 mm compared to white male athletes (12.4% versus 1.6%, respectively).22 Maximal LVWT >16 mm is rare in all athletes. One study showed that female black athletes also reveal an increased LVWT compared with white athletes. In this study investigating 240 nationally ranked black female athletes and 200 white female athletes, 3% of black athletes had a LVWT >11 mm compared to none of female athletes. None of the women revealed a LVWT >13 mm.36 Adolescent black athletes demonstrate a 5% increase in mean LVWT compared to white Italian athletes of a similar age (9.7 mm versus 9.2 mm, respectively).37 Concentric LV remodelling or hypertrophy is more prevalent in black male, female and adolescent athletes than their white counterparts.44–46 Haemodynamic responses to exercise have been proposed as a possible mechanism. One study showed that black adolescent athletes exhibit a higher SBP on exercise compared to white athletes.46 Furthermore SBP at peak exercise is a predictor of LV mass. However, ultimately ethnicity was the main determinant of RWT with a significant increases in LV wall thickness and mass suggestive of concentric remodelling.46 Delineating between physiological LVH and pathology is integral as American autopsy data suggest that HCM may go unrecognised in black athletes as the number dying suddenly from HCM is significantly greater than African-Americans diagnosed with HCM in hospital settings.47

and west Africans demonstrated more T wave inversion compared to other black athletes (8.5% and 6.4%, respectively). Absolute wall thickness ≥12 mm was more common among African-American/ Caribbean (9.5%), middle African (5.5%) and west African (4.9%) groups. However, when indexed to body size, LVWT was only significant in the middle and west African groups.44 It is not unexpected that athletes from the west and central Africa have similar patterns of cardiac adaptation. The Bantu expansion of people from west to central Africa explains the cultural and language similarities between these people and presumably their shared ethnicity and genetics.49 A criticism of the study is the lack of genetic testing to determine true genealogy and the effect of mixed heritage. Furthermore, there was no female participation in the trial.50

Studies in Athletes of Other Ethnicities There are a limited number of studies examining cardiovascular adaptation in other ethnicities and almost all have focused on male athletes.

West Asians Electrical Changes Few studies have examined cardiac adaptation to exercise in athletes of west Asia. Wilson et al. assessed 800 male west Asian athletes with 135 controls, 300 black and 120 white athletes against the 2010 ESC recommendations.51 The authors did not find any significant differences in the incidence of abnormal ECGs between west Asian athletes and white athletes (1.6% and 0%, respectively).51 A recent study showed that, as with white athletes, west Asian adolescent athletes 11–18 years old demonstrate a lower prevalence of anterior T wave inversion beyond lead V3 than black adolescent athletes (0.7% v 7.0%), respectively.52 Conversely, Riding et al. found increased abnormal T wave inversion in west Asians compared to white south Europeans in a much smaller sample size. However, this did not correspond with any structural differences on echocardiography.44

Structural Changes

LV hypertrabeculation is more prevalent in black than white athletes (28.8% versus 16.3%; p=0.002), specifically in athletes who participate in dynamic sports. Hypertrabeculation combined with T wave inversion may be suggestive of LV non-compaction. The use of cardiac MRI, exercise stress testing and prolonged ECG monitoring along with clinical assessment after a period of detraining can provide valuable information in differentiating pathology from physiological adaptation.48

Arab athletes demonstrate increased LV mass and wall thickness compared with sedentary controls. However, absolute cardiac structure parameters are significantly smaller than both white and black athletes.53 There is no significant difference between LVWT between Arab and white athletes with a similar percentage demonstrating LVH (0.5% and 0.6%, respectively).53 To our knowledge, there are no studies on west Asian female athletes, making this an area that requires further research.

Impact of Geographical Origins

South and Far East Asian Athletes

The term ‘black athletes’ used throughout the literature encompasses a vastly diverse group of individuals spanning American football players, Brazilian soccer players and Kenyan long-distance runners. Riding et al. attempted to evaluate the role of geographical origin on electrical and structural adaptations in black athletes. In this novel study, they subdivided 1,698 male athletes into north, east, middle and west African, African-American/Caribbean, South American and west Asian groups.44

Studies on South Asian athletes are exceedingly rare. A study of more than 18,000 South East Asian multi-ethnic male conscripts undergoing preparticipation screening for the Singapore armed forces showed a higher prevalence of voltage criterion for LVH in Chinese participants.54 A study of 351 Chinese athletes from the Han population suggested that 4.5% demonstrate an abnormal ECG requiring further evaluation.55 Echocardiography seems to correlate well to previously reported echocardiographic findings in white athletes in both men and women. Only three male athletes (1.76%) revealed a LVWT >12 mm.55

The large diversity in geographical origin directly affected the pattern of cardiac adaptation, with west and middle Africans having significantly more abnormal ECG findings as per the 2017 international recommendations (9.2% and 11.9%, respectively).44 Specifically, middle

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Carre et al. described a study of Japanese professional footballers that showed no difference between ECG abnormalities in Japanese athletes and white athletes. Eccentric LV remodelling was more common in

Expert Opinion Japanese athletes with an enlarged LV cavity when corrected for BSA compared to black and white athletes.56 A study of Japanese ultramarathon runners also suggested that Japanese ethnicity is associated with larger LV end diastolic dimensions however this showed a significant correlation with age and years of exercise in a cohort of athletes with a much higher age range than previous mentioned studies.57,58 More research is required in the Far East Asian populations, particularly for female and adolescent athletes. However, existing evidence suggests that male Far East Asian athletes undergo a similar process of cardiac adaptation to white athletes with similar ECG interpretation.

Pacific Islanders Pacific Islanders are indigenous people from Polynesia, Micronesia and Melanesia. A pilot study suggested that Pacific Islander rugby league players had increased LV mass and RWT when compared to white players as a result of cardiac adaptation.59 A larger study of 2,281 Pacific Islanders that included 716 women (mean age 19.4 ± 6.5) evaluated the differences between Melanesian, Polynesian, white and Métis athletes.60 Melanesians demonstrated significantly more T wave inversion compared to white men (2.6% versus 1.5%). The authors suggest that Melanesians have ECG patterns similar to black athletes. Unfortunately, not all participants with abnormal ECGs could have echocardiography or MRI scans, which may have increased the detection of cardiomyopathies. However, an increased prevalence of rheumatic valve disease (1.5%) was noted to be 3.9-fold higher than that reported in western and Middle East countries.60,61

and maintained sensitivity when reviewed by a sports cardiology expert.62 In adolescent black athletes, the international recommendations outperform the ESC recommendations.63 Both the Seattle criteria and the latest international recommendations account for some repolarisation anomalies and normal ethnic variants in black athletes. However the abnormal ECG rate remains considerably higher than in white athletes.64 In contrast, limited data from other ethnicities suggest that athletes of Asian origin reveal similar ECG patterns to white athletes.54,55 Screening with the international guidelines significantly reduces false positive rates for pathology in white athletes and, therefore, probably in Asian athlete cohorts. Nevertheless the false-positive rate in black athletes remains relatively high, despite the increased specificity (97%) compared to the ESC and Seattle criteria.64,65

Mixed Ethnicity Our experiences and preliminary data on adolescent ‘mixed’ ethnicity footballers, specifically white and African descent, suggest phenotypical similarities with black athletes. Mixed athletes demonstrated significant increases in LVWT and prevalence of T wave inversion compared to white athletes but to a lesser extent than in black athletes.66

Conclusion

Pre-participation Screening

Ethnicity is an important determinant of cardiac adaptation to exercise and should be considered during cardiac evaluation of an athlete. Black athletes from middle and west Africa and the Caribbean appear to develop the most profound electrical and structural changes. An awareness of these ethnic variants will prevent over investigation of healthy athletes and potentially unwarranted exclusion from competitive sports.

The previous (2010) ESC recommendations for ECG interpretation in athletes were associated with a high false-positive rate in black athletes, with two in five requiring further investigation.24 The Seattle and refined 12-lead-ECG criteria maintained the same sensitivity of the ESC recommendations while improving the specificity for black athletes to 18.4% and 11.5% respectively.24 When compared to the Seattle criteria, the 2017 international ECG recommendations further reduced the number of ‘abnormal’ 12-lead ECGs from 3% to 1.6%, false positives

Widespread pre-participation screening practice is fertile ground for research in ethnicity-specific cardiovascular adaptation to intensive exercise and has the potential to fill the gaps in our current body of knowledge. This information combined with long term surveillance of asymptomatic athletes with currently perceived ‘abnormal’ ECG findings will influence future recommendations on screening and expand our understanding of cardiac adaptation.

Harmon KG, Drezner JA, Wilson MG, Sharma S. Incidence of sudden cardiac death in athletes: a state-of-the-art review. Br J Sports Med 2014;48:1185–92. https://doi.org/10.1136/ bjsports-2014-093872; PMID: 24963027. Malhotra A, Dhutia H, Finocchiaro G, et al. Outcomes of cardiac screening in adolescent soccer players. N Engl J Med 2018;379:524–34. https://doi.org/10.1056/NEJMoa1714719; PMID: 30089062. Sharma S, Drezner JA, Baggish A, et al. International recommendations for electrocardiographic interpretation in athletes. J Am Coll Cardiol 2017;69:1057–75. https://doi. org/10.1016/j.jacc.2017.01.015; PMID: 28231933. Drezner JA, Ackerman MJ, Anderson J, et al. Electrocardiographic interpretation in athletes: The “Seattle Criteria.” Br J Sports Med 2013;47:122–4. https://doi. org/10.1136/bjsports-2012-092067; PMID: 23303758. Corrado D, van-Buuren F, Mellwig KP, et al. Cardiovascular pre-participation screening of young competitive athletes for prevention of sudden death: proposal for a common European protocol: Consensus Statement of the Study Group of Sport Cardiology of the Working Group of Cardiac Rehabilitation and. Eur Heart J 2005;26:516–24. https://doi.org/10.1093/eurheartj/ ehi108; PMID: 15689345. Maron BJ, Thompson PD, Ackerman MJ, et al. .Recommendations and considerations related to preparticipation screening for cardiovascular abnormalities in competitive athletes: 2007 update: a scientific statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology Foundation Circulation 2007;115:1643–55. https://

10.

11.

12.

13.

14.

doi.org/10.1161/CIRCULATIONAHA.107.181423; PMID: 17353433. Prakash K, Sharma S. Interpretation of the electrocardiogram in athletes. Can J Cardiol 2016;32:438–51. https://doi. org/10.1016/j.cjca.2015.10.026; PMID: 26860775. Basavarajaiah S, Boraita A, Whyte G, et al. Ethnic differences in left ventricular remodeling in highly-trained athletes: relevance to differentiating physiologic left ventricular hypertrophy from hypertrophic cardiomyopathy. J Am Coll Cardiol 2008;51:2256– 62. https://doi.org/10.1016/j.jacc.2007.12.061; PMID: 18534273. Baggish AL, Wood MJ. Athlete’s heart and cardiovascular care of the athlete: scientific and clinical update. Circulation 2011;123:2723–35. https://doi.org/10.1161/ CIRCULATIONAHA.110.981571; PMID: 21670241. Sharma S, Merghani A, Mont L. Exercise and the heart: the good, the bad, and the ugly. Eur Heart J 2015;36:1445–53. https://doi.org/10.1093/eurheartj/ehv090; PMID: 25839670. Prior DL, La Gerche A. The athlete’s heart. Heart 2012;98:947–55. https://doi.org/10.1136/heartjnl-2011-301329; PMID: 22626903. Corrado D, Pelliccia A, Heidlbuchel H, et al. Recommendations for interpretation of 12-lead electrocardiogram in the athlete. Eur Heart J 2010;31:243–59. https://doi.org/10.1093/eurheartj/ ehp473; PMID: 19933514. Pelliccia A, Maron BJ, Spataro A, et al. The upper limit of physiologic cardiac hypertrophy in highly trained elite athletes. N Engl J Med 1991;324:295–301. https://doi.org/10.1056/ NEJM199101313240504; PMID: 1824720. Pelliccia A, Culasso F, Di Paolo FM, Maron BJ. Physiologic left ventricular cavity dilatation in elite athletes. Ann Intern Med

1999;130:23–31. https://doi.org/10.7326/0003-4819-130-1199901050-00005; PMID: 9890846. 15. Pelliccia A, Adami PE. The female side of the heart: Sex differences in athlete’s heart. JACC Cardiovasc Imaging 2017;10:973–5. https://doi.org/10.1016/j.jcmg.2016.08.010; PMID: 27865720. 16. Pelliccia A, DiPaolo FM. Cardiac remodeling in women athletes and implications for cardiovascular screening. Med Sci Sports Exerc 2005;37:1436–9. https://doi org/10.1249/01. mss.0000174885.08564.6f; PMID: 16118595. 17. Pelà G, Crocamo A, Li Calzi M, et al. Sex-related differences in left ventricular structure in early adolescent non-professional athletes. Eur J Prev Cardiol 2016;23:777–84. https://doi. org/10.1177/2047487315608826; PMID: 26405258. 18. Basavarajaiah S, Wilson M, Whyte G, et al. Prevalence of hypertrophic cardiomyopathy in highly trained athletes. Relevance to pre-participation screening. J Am Coll Cardiol 2008;51:1033–9. https://doi.org/10.1016/j.jacc.2007.10.055; PMID: 18325444. 19. Makan J, Sharma S, Firoozi S, et al. Physiological upper limits of ventricular cavity size in highly trained adolescent athletes. Heart 2005;91:495–9. https://doi.org/10.1136/hrt.2004.035121; PMID: 15772210. 20. Pluim BM, Zwinderman AH, van der Laarse A, et al. The athlete’s heart: a meta-analysis of cardiac structure and function. Circulation 2000;101:336–44. https://doi. org/10.1161/01.CIR.101.3.336; PMID: 10645932. 21. Iskandar A, Thompson PD. A meta-analysis of aortic root size in elite athletes. Circulation 2013;127:791–8. https://doi. org/10.1161/CIRCULATIONAHA.112.000974; PMID: 23322885.

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Impact of Ethnicity on Cardiac Adaptation 22. Papadakis M, Carre F, Kervio G, et al. The prevalence, distribution, and clinical outcomes of electrocardiographic repolarization patterns in male athletes of African/AfroCaribbean origin. Eur Heart J 2011;32:2304–13. https://doi. org/10.1093/eurheartj/ehr140; PMID: 21613263. 23. Magalski A, Maron BJ, Main ML, et al. Relation of race to electrocardiographic patterns in elite American football players. J Am Coll Cardiol 2008;51:2250–5. https://doi. org/10.1016/j.jacc.2008.01.065; PMID: 18534272. 24. Sheikh N, Papadakis M, Ghani S, et al. Comparison of electrocardiographic criteria for the detection of cardiac abnormalities in elite black and white athletes. Circulation 2014;129:1637–49. https://doi.org/10.1161/ CIRCULATIONAHA.113.006179; PMID: 24619464. 25. Drezner JA, Sharma S, Baggish A, et al. International criteria for electrocardiographic interpretation in athletes: consensus statement. Br J Sports Med 2017;51:704–31. https://doi. org/10.1136/bjsports-2016-097331; PMID: 28258178. 26. Riding NR, Sheikh N, Adamuz C, et al. Comparison of three current sets of electrocardiographic interpretation criteria for use in screening athletes. Heart 2015;101:384–90. https://doi. org/10.1136/heartjnl-2014-306437; PMID: 25502812. 27. Junttila MJ, Sager SJ, Freiser M, et al. Inferolateral early repolarization in athletes. J Interv Card Electrophysiol 2011;31:33–8. https://doi.org/10.1007/s10840-010-9528-y; PMID: 21161572. 28. Miragoli M, Goldoni M, Demola P, et al. Left ventricular geometry correlates with early repolarization pattern in adolescent athletes. Scand J Med Sci Sport 2019;29:1727–35. https://doi.org/10.1111/sms.13518; PMID: 31302929. 29. Haïssaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008;358:2016–23. https://doi.org/10.1056/NEJMoa071968; PMID: 18463377. 30. Noseworthy PA, Weiner R, Kim J, et al. Early repolarization pattern in competitive athletes: clinical correlates and the effects of exercise training. Circ Arrhythm Electrophysiol 2011;4:432–40. https://doi.org/10.1161/CIRCEP.111.962852; PMID: 21543642. 31. Tikkanen JT, Anttonen O, Junttila MJ, et al. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009;361:2529–37. https://doi.org/10.1056/ NEJMoa0907589; PMID: 19917913. 32. Quattrini FM, Pelliccia A, Assorgi R, et al. Benign clinical significance of J-wave pattern (early repolarization) in highly trained athletes. Heart Rhythm 2014;11:1974–82. https://doi. org/10.1016/j.hrthm.2014.07.042; PMID: 25092400. 33. Barbosa EC, Bomfim ADS, Benchimol-Barbosa PR, Ginefra P. Ionic mechanisms and vectorial model of early repolarization pattern in the surface electrocardiogram of the athlete. Ann Noninvasive Electrocardiol 2008;13:301–7. https://doi. org/10.1111/j.1542-474X.2008.00235.x; PMID: 18713332. 34. Tikkanen JT, Junttila MJ, Anttonen O, et al. Early repolarization: Electrocardiographic phenotypes associated with favorable long-term outcome. Circulation 2011;123:2666–73. https://doi. org/10.1161/CIRCULATIONAHA.110.014068; PMID: 21632493. 35. Sheikh N, Papadakis M, Carre F, et al. Cardiac adaptation to exercise in adolescent athletes of African ethnicity: an emergent elite athletic population. Br J Sports Med 2013;47:585–92. https://doi.org/10.1136/bjsports-2012-091874; PMID: 23372065. 36. Rawlins J, Carre F, Kervio G, et al. Ethnic differences in physiological cardiac adaptation to intense physical exercise in highly trained female athletes. Circulation 2010;121:1078–85. https://doi.org/10.1161/CIRCULATIONAHA.109.917211; PMID: 20176985. 37. Di Paolo FM, Schmied C, Zerguini YA, et al. The athlete’s heart in adolescent Africans: an electrocardiographic and

EUROPEAN CARDIOLOGY REVIEW

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

echocardiographic study. J Am Coll Cardiol 2012;59:1029–36. https://doi.org/10.1016/j.jacc.2011.12.008; PMID: 22402076. Sheikh N, Papadakis M, Wilson M, et al. Diagnostic yield of genetic testing in young athletes with T-wave inversion. Circulation 2018;138:1184–94. https://doi.org/10.1161/ CIRCULATIONAHA.118.034208; PMID: 29764897. Calore C, Zorzi A, Sheikh N, et al. Electrocardiographic anterior T-wave inversion in athletes of different ethnicities: differential diagnosis between athlete’s heart and cardiomyopathy. Eur Heart J 2016;37:2515–27. https://doi.org/10.1093/eurheartj/ ehv591; PMID: 26578198. Papadakis M, Basavarajaiah S, Rawlins J, et al. Prevalence and significance of T-wave inversions in predominantly Caucasian adolescent athletes. Eur Heart J 2009;30:1728–35. https://doi. org/10.1093/eurheartj/ehp164; PMID: 19429915. Malhotra A, Dhutia H, Yeo TJ, et al. Accuracy of the 2017 international recommendations for clinicians who interpret adolescent athletes’ ECGs: a cohort study of 11 168 British white and black soccer players. Br J Sports Med;54:739–45. https://doi.org/10.1136/bjsports-2017-098528; PMID: 31278087. Sheikh N, Papadakis M, Schnell F, et al. Clinical profile of athletes with hypertrophic cardiomyopathy. Circ Cardiovasc Imaging 2015;8:1–9. https://doi.org/10.1161/ CIRCIMAGING.114.003454; PMID: 26198026. Zaidi A, Ghani S, Sharma R, et al. Physiological right ventricular adaptation in elite athletes of African and Afro-Caribbean origin. Circulation 2013;127:1783–92. https://doi.org/10.1161/ CIRCULATIONAHA.112.000270; PMID: 23538381. Riding NR, Sharma S, McClean G, et al. Impact of geographical origin upon the electrical and structural manifestations of the black athlete’s heart. Eur Heart J 2019;40:50–8. https://doi. org/10.1093/eurheartj/ehy521; PMID: 30169663. Drazner MH, Dries DL, Peshock RM, et al. Left ventricular hypertrophy is more prevalent in blacks than whites in the general population: the Dallas heart study. Hypertension 2005;46:124–9. https://doi.org/10.1161/01. HYP.0000169972.96201.8e; PMID: 15939807. Demola P, Crocamo A, Ceriello L, et al. Hemodynamic and ECG responses to stress test in early adolescent athletes explain ethnicity-related cardiac differences. Int J Cardiol 2019;289:125– 30. https://doi.org/10.1016/j.ijcard.2019.04.084; PMID: 31072636. Maron BJ, Carney KP, Lever HM, et al. Relationship of race to sudden cardiac death in competitive athletes with hypertrophic cardiomyopathy. J Am Coll Cardiol 2003;41:974–80. https://doi.org/10.1016/S0735-1097(02)02976-5; PMID: 12651044. Gati S, Chandra N, Bennett RL, et al. Increased left ventricular trabeculation in highly trained athletes: do we need more stringent criteria for the diagnosis of left ventricular noncompaction in athletes? Heart 2013;99:401–8. https://doi. org/10.1136/heartjnl-2012-303418; PMID: 23393084. Grollemund R, Branford S, Bostoen K, et al. Bantu expansion shows that habitat alters the route and pace of human dispersals. Proc Natl Acad Sci 2015;112:13296–301. https://doi. org/10.1073/pnas.1503793112; PMID: 26371302. Zorzi A, D’Ascenzi F, Corrado D. Black athletes’ hearts. Eur Heart J 2019;40:59–61. https://doi.org/10.1093/eurheartj/ ehy698; PMID: 30445593. Wilson MG, Chatard JC, Carre F, et al. Prevalence of electrocardiographic abnorm alities in West-Asian and African male athletes. Br J Sports Med 2012;46:341–7. https://doi. org/10.1136/bjsm.2010.082743; PMID: 21596717. McClean G, Riding NR, Pieles G, et al. Prevalence and significance of T-wave inversion in Arab and Black paediatric athletes: should anterior T-wave inversion interpretation be governed by biological or chronological age? Eur J Prev Cardiol

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

2019;26:641–52. https://doi.org/10.1177/2047487318811956; PMID: 30426769. Riding NR, Salah O, Sharma S, et al. ECG and morphologic adaptations in Arabic athletes: are the European Society of Cardiology’s recommendations for the interpretation of the 12-lead ECG appropriate for this ethnicity? Br J Sports Med 2014;48:1138–43. https://doi.org/10.1136/ bjsports-2012-091871; PMID: 23564906. Ng CT, Ong HY, Cheok C, et al. Prevalence of electrocardiographic abnormalities in an unselected young male multi-ethnic South-East Asian population undergoing pre-participation cardiovascular screening: results of the Singapore Armed Forces Electrocardiogram and Echocardiogram screening protocol. Europace 2012;14:1018– 24. https://doi.org/10.1093/europace/eur424; PMID: 22308089. Ji P, Ma JZ, Yang D, et al. Cardiovascular pre-participation screening of young competitive athletes for prevention of sudden death in China. J Sci Med Sport 2006;10:227–33. https:// doi.org/10.1016/j.jsams.2006.07.001; PMID: 16914373. Kervio G, Pelliccia A, Nagashima J, et al. Alterations in echocardiographic and electrocardiographic features in Japanese professional soccer players: Comparison to AfricanCaucasian ethnicities. Eur J Prev Cardiol 2013;20:880–8. https:// doi.org/10.1177/2047487312447905; PMID: 22548966. Nagashima J, Musha H, Takada H, Murayama M. New upper limit of physiologic cardiac hypertrophy in Japanese participants in the 100-km ultramarathon. J Am Coll Cardiol 2003;42:1617–23. https://doi.org/10.1016/j.jacc.2003.06.005; PMID: 14607449. Kinoshita N, Katsukawa F, Yamazaki H. Modeling of longitudinal changes in left ventricular dimensions among female adolescent runners. PLoS One 2015;10:e0140573. https://doi. org/10.1371/journal.pone.0140573; PMID: 26469336. Johnson C, Forsythe L, Somauroo J, et al. Cardiac structure and function in elite Native Hawaiian and Pacific Islander rugby football league athletes: an exploratory study. Int J Cardiovasc Imaging 2018;34:725–34. https://doi.org/10.1007/ s10554-017-1285-x; PMID: 29189933. Chatard JC, Espinosa F, Donnadieu R, et al. Pre-participation cardiovascular evaluation in Pacific Island athletes. Int J Cardiol 2019;278:273–79. https://doi.org/10.1016/j.ijcard.2018.11.012; PMID: 30579721. Chatard JC, Mujika I, Goiriena JJ, Carré F. Screening young athletes for prevention of sudden cardiac death: Practical recommendations for sports physicians. Scand J Med Sci Sport 2016;26:362–74. https://doi.org/10.1111/sms.12502; PMID: 26432052. Hyde N, Prutkin JM, Drezner JA. Electrocardiogram interpretation in NCAA athletes: Comparison of the ‘Seattle’ and ‘International’ criteria. J Electrocardiol 2019;56:81–4. https://doi.org/10.1016/j.jelectrocard.2019.07.001; PMID: 31326858. McClean G, Riding NR, Pieles G, et al. Diagnostic accuracy and Bayesian analysis of new international ECG recommendations in paediatric athletes. Heart 2019;105:152–9. https://doi. org/10.1136/heartjnl-2018-313466; PMID: 30228247. Dhutia H, Malhotra A, Finocchiaro G, et al. Impact of the international recommendations for electrocardiographic interpretation on cardiovascular screening in young athletes. J Am Coll Cardiol 2017;70:805–7. https://doi.org/10.1016/j. jacc.2017.06.018; PMID: 28774386. Sharma S. Effects of international electrocardiographic interpretation recommendations on African American athletes. JAMA Cardiol 2018;3:75–6. https://doi.org/10.1001/ jamacardio.2017.4573; PMID: 29214291. Malhotra A, Dhutia H, Rao P, et al. The mixed race heart: not so black and white. Eur Heart J 2017;38(Suppl 1):P3244. https://doi. org/10.1093/eurheartj/ehx504.p3244.

COVID-19

The Coronavirus Disease 2019 Outbreak Highlights the Importance of Sex-sensitive Medicine Angela HEM Maas1 and Sabine Oertelt-Prigione2 1. Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands; 2. Department of Primary and Community Care, Radboud University Medical Center, Nijmegen, the Netherlands

Abstract The novel coronavirus disease 2019 (COVID-19) pandemic has revealed important differences between the sexes in epidemiology, risk factors, clinical course, mortality and socioeconomic dimensions of the disease in all populations worldwide. This has emphasised the need for a better understanding of diversity aspects in healthcare to improve prevention, treatment and long-term consequences. In this article, the authors describe the most relevant knowledge thus far on sex differences regarding COVID-19.

Keywords COVID-19, gender differences, inflammation, SARS-CoV-2, sex differences, coronavirus Disclosure: The authors have no conflicts of interest to declare. Received: 1 June 2020 Accepted: 6 July 2020 Citation: European Cardiology Review 2020;15:e62. DOI: https://doi.org/10.15420/ecr.2020.28 Correspondence: Angela HEM Maas, Radboud University Medical Center, Geert Grooteplein-Zuid 10, Route 616, 6525GA Nijmegen, the Netherlands. E: angela.maas@radboudumc.nl Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

While 2020 is only halfway through, we have already experienced a historical year in global healthcare with a high societal impact. When the first severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) infections were reported in China at the end of 2019, few people realised we would all be affected by a global pandemic several months later. Women are less susceptible than men to many viral infections, such as coxsackievirus B, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome.1–3 This is partially because of a different innate immunity, the influence of steroid hormones and factors related to sex chromosomes.2–4 Testosterone, estradiol and progesterone influence the functioning of immune cells. Several immune-related genes are encoded on the X chromosome and there is some evidence of greater activation of X-linked genes in immune cells from women than men.5 Sex-related differences in gene expression and distribution of angiotensinconverting enzyme 2 (ACE2), which serves as the entry receptor for SARSCoV-2, are also possibly connected to the reported differences in novel coronavirus disease 2019 (COVID-19) between women and men.6 Sex hormones can modulate the expression of ACE2, as can risk factors such as hypertension and obesity. Cardiac injury occurs in more than one in three patients affected by COVID-19, who often have pre-existing heart disease, who present with heterogeneous cardiac manifestations that may also differ between male and female patients.7–9 In addition to sex-linked biological differences, we have learned from the COVID-19 outbreak that lifestyle factors, age, comorbidities and

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environmental factors are crucial modulators of gender-related susceptibility, affecting the course of the disease and mortality. Ethnicity also appears to be an important determinant of outcomes.10–12 People from ethnic minority groups in European countries often live in extended, cohabiting families, which potentially increases the risk of virus transmission. About two-thirds of patients who have died worldwide are men, which needs to be further investigated to better understand the various patient phenotypes and to develop tailored directions for treatment and prevention.13–15 Last but not least, the socioeconomic and cultural roles of women both at work and at home are important in the course of this pandemic and its long-term consequences. Women make up the majority of the workforce at the frontline of the pandemic whereas men are more often in leading positions.16 Women are more likely to be the primary caregivers within a household, increasing the risk of psychosocial stress. The consequences of lockdown situations have already translated into a 30% increase in intimate partner violence and, as women are more likely to have part-time and freelance jobs, their economic situation is seriously at stake.17 This applies even more for women from ethnic minority groups and those living in low-income countries. The decline in finances because of job loss may lead to a deterioration in health in the years ahead. As such, the COVID-19 pandemic may have a higher impact on women than men. The need for equal treatment opportunities for all is of utmost importance towards ending this global pandemic.

Sex in COVID-19 Sex Hormones and Genetic Differences in SARS-CoV2 Infections Several steps of the SARS-CoV-2 virus infection process are susceptible to sex-specific influences. Analogously to the SARS-S virus, the viral haemagglutinin of the SARS-CoV-2 virus employs (ACE2) as the entry receptor.6,18 The viral haemagglutinin is then cleaved by serine protease TMPRSS2 on the host cell to activate the internalisation of the virus.18,19 The ACE2 receptor gene is located on the X chromosome and displays marked heterogeneity of expression across different tissues.20 A recent, as yet unpublished report has described a significant overexpression in testicular tissue, suggesting that the testis could potentially be a reservoir for the virus.21 In addition to these differences in expression, the dynamic interaction of the virus with host tissue needs to be taken into account. During SARS-S infection, ACE2 appears to provides protection from lung injury and the virus itself downregulates its expression.22 It is not yet known whether SARS-CoV-2 directly interferes with ACE2 expression. The role of the TMPRSS2 protease in SARS-CoV-2 needs to be further investigated, but information on other diseases points towards sexspecific differences. For example, TMPRSS2 serine protease appears essential to infection with the influenza virus. Single-nucleotide polymorphisms associated with a higher expression of TMPRSS2 correlate with a higher susceptibility to influenza virus infection in distinct cohorts.23 In TMPRSS knockout mice, female animals infected by H1N1 virus had a significantly attenuated course of infection compared with wild-type mice.24 The impact of hormones on the serine protease has been investigated in the field of oncology and androgens appear to upregulate its expression.25 In addition to androgen susceptibility, a potential role of oestrogens as modulators of TMPRSS2 in prostate cancer has also been postulated.26 The role of these hormonal regulation pathways warrants further investigation, especially in the context of SARS-CoV-2 infection. Given the impact of this mechanism in different respiratory viruses and the previously described sex differences in susceptibility to influenza infection and vaccine response, this appears to be a promising future area of investigation.4

Sex Differences in Cardiac Manifestations of COVID-19 Cardiovascular complications are common in patients with COVID-19, in a range of 20–40% in hospitalised patients’ series.27 Many different complications may occur as direct or indirect effects of the infection. These vary from arrhythmias, heart failure, acute fulminant myocarditis, acute coronary syndromes (ACS; both type I and type II ACS) to (micro-) thromboembolic events. It is estimated that half of patients with serious cardiac problems had pre-existing comorbidities, especially hypertension, diabetes, prior ischaemic heart disease (IHD), pulmonary diseases and cancer. Sex-specific data about patients with COVID-19 are still scarce. A small study of 43 patients from Wuhan showed no differences in age and symptoms between hospitalised men and women.28 However, the clinical course was more severe in men, with a more than two-fold higher mortality; specific cardiac data were not reported. In a review of 28 patients with ST-elevation MI in the Lombardy region in Italy, twothirds were men.29 At coronary angiography, 40% of patients were classified as having an MI with no obstructive coronary artery disease, significantly higher than the

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average. This may be related to the hypotension, hypoxaemia and hypovolaemia that frequently occur in severely affected COVID-19 patients, which may cause this type of ACS. A recent European position statement on invasive management of ACS during the COVID-19 pandemic emphasised that the use of coronary angiography for COVID19-positive patients with elevation in troponin-c should be restricted to those in whom type I ACS is suspected.30 This occurs more often in men than women and its diagnosis may be delayed in people needing longterm ventilation.31 In the Lombardy region, a striking increase in out-of-hospital cardiac arrests of 58% was seen compared to a year earlier, of which more than 77% were related to COVID19 infections.32 There was no mention, however, of the sex of the patients. The diffuse myocardial damage caused by the cytokine storm in the most severe stage of the infection seems to be more detrimental to men than women.27 It is speculated that the adverse impact of obesity on survival in men may be associated with a lower testosterone:estradiol ratio in visceral fat tissue, which may increase the inflammatory reaction to the virus.33 Others studies, however, postulate that sex differences in inflammatory regulation in obesity are not dependent on sex steroids.34 Sex differences in the binding of SARS-CoV-2 to the ACE2 receptor have been identified as an important contributor to the initiation and course of the disease.6,7,27 Women are at an advantage as the ACE2 gene is located on the X chromosome, so they have higher ACE2 levels, which has a protective effect.35 It has been disputed whether the use of angiotensinconverting-enzyme inhibitors or angiotensin II receptor blockers should be discontinued, but there is no evidence so far that they are harmful.35 In contrast, by providing a better control of blood pressure, the dysregulated immune system may be better restored in patients with hypertension.27,35,36 Sex differences regarding potential protective effects of renin–angiotensin–aldosterone system inhibitors in SARS-CoV-2 infections are as yet unknown.37

Sex Differences in Long-term Health Sequelae in COVID19 As this pandemic unfolds and we gather new data, the impact of SARSCoV2 infection on the human body appears more complex than initially described. At the outset, COVID-19 was classified mainly as a respiratory disease. By now, we know that the virus can infect any organ of the human body and that at least four symptom clusters are present: respiratory, musculoskeletal, enteric and mucocutaneous.38,39 In certain groups of patients, symptoms persist for weeks or months, so there is a need for individualised long-term support.40 Patients treated with invasive ventilation could need long-term rehabilitation and may experience irreparable disability. Men make up the greater proportion of this group, and will possibly have extensive, long-term therapy needs.41 Men appear to have better access to cardiovascular rehabilitation overall and a potential need to make services sex-specific has been suggested.42 An important aspect to consider in this context is the potential loss of a stereotypically masculine role in younger patients because of longterm disability. Work ability, expectation and role distribution in households might change, which could foster a more equal distribution of tasks between partners or put additional strain on unequal relationships. Patients should be adequately counselled and potential options to mitigate this impact discussed.

COVID-19 This pandemic has the potential to significantly affect the mental health of the affected population. In addition to previously described sex differences in the incidence of depression or anxiety, unequally distributed mental load and sources of stress during the pandemic and in its aftermath have to be considered.43 In the acute phase of the infection, during quarantine and in the recovery period, care tasks might be unequally allocated in households, particularly burdening women. The economic downturn and the redundancy of specific fields of work will affect women and men differently. Loss of jobs and livelihoods is an additional stressor to the immediate existential fears of infection, illness and mortality. Women make up a larger proportion of the healthcare and essential workers who have to provide services in times of quarantine.44 This could increase strain on already overburdened women, who are having to juggle caring for children and relatives with intensive work schedules and mental stressors. In addition to the effects on mental health, an increased risk for stress-related cardiovascular illness is another possible consequence for the female population.

Experiences with COVID-19 and Sex-specific Medicine After years of campaigning for more attention to the impact of sex on healthcare, COVID-19 has provided the discipline with an unexpected increase in validation. Likely higher mortality rates in men, a receptor encoded on an X-linked gene and sex differences in the immune response seem convincing even to many skeptics.

1. 2.

10.

11.

12.

13.

14.

Woodruff JF. Viral myocarditis. A review. Am J Pathol 1980;101:425–84. PMID: 6254364. Fairweather D, Cooper LT Jr, Blauwet LA. Sex and gender differences in myocarditis and dilated cardiomyopathy. Curr Probl Cardiol 2013;38:7–46. https://doi.org/10.1016/j. cpcardiol.2012.07.003; PMID: 23158412. Klein SL. Sex influences immune responses to viruses, and efficacy of prophylaxis and treatments for viral diseases. Bioessays 2012;34:1050–9. https://doi.org/10.1002/ bies.201200099; PMID: 23012250. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol 2016;16:626–38. https://doi.org/10.1038/ nri.2016.90; PMID:˛27546235. Schurz H, Salie M, Tromp G, et al. The X chromosome and sexspecific effects in infectious disease susceptibility. Hum Genomics 2019;13:2. https://doi.org/10.1186/s40246-0180185-z; PMID: 30621780. La Vignera S, Cannarella R, Condorelli RA, et al. Sex-specific SARS-CoV-2 mortality: among hormone-modulated ACE2 expression, risk of venous thromboembolism and hypovitaminosis D. Int J Mol Sci 2020;21:2948. https://doi. org/10.3390/ijms21082948; PMID: 32331343. Chen L, Li X, Chen M, et al. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res 2020;116:1097–100. https://doi.org/10.1093/cvr/cvaa078; PMID: 32227090. Chen R, Liang W, Jiang M, et al. Risk factors of fatal outcome in hospitalized subjects with coronavirus disease 2019 from a nationwide analysis in China. Chest 2020;158:97–105. https:// doi.org/10.1016/j.chest.2020.04.010; PMID: 32304772. Zhou K, Yang S, Jia P. Towards precision management of cardiovascular patients with COVID-19 to reduce mortality. Prog Cardiovasc Dis 2020. https://doi.org/10.1016/j. pcad.2020.04.012; PMID: 32353374; epub ahead of press. Pareek M, Bangash MN, Pareek N, et al. Ethnicity and COVID19: an urgent public health research priority. Lancet 2020;395:1421–2. https://doi.org/10.1016/S01406736(20)30922-3; PMID: 32330427. Rimmer A. Covid-19: two thirds of healthcare workers who have died were from ethnic minorities. BMJ 2020;369:m1621. https://doi.org/10.1136/bmj.m1621; PMID: 32327412. Haynes N, Cooper LA, Albert M. At the heart of the matter: unmasking and addressing COVID-19’s toll on diverse populations. Circulation 2020;142:105–7. https://doi. org/10.1161/CIRCULATIONAHA.120.048126; PMID: 32364762. Walter LA, McGregor AJ. Sex- and gender-specific observations and implications for COVID-19. West J Emerg Med 2020;21:507– 9. https://doi.org/10.5811/westjem.2020.4.47536; PMID: 32302282. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 2020;323:2052–9. https://doi.org/10.1001/

Nevertheless, reporting of sex-disaggregated data is still not the standard, not even in COVID-19 research. Lack of disaggregated data can severely limit our ability to predict the clinical course of patients and mitigate the wider inequities potentially connected to the disease. It is still unknown if symptoms at presentation differ between women and men and if they respond differently to therapy, including experiencing different side effects. We do not know if people caring for infected patients in their homes need specific protective equipment depending on the age or severity of the patient. We do not know if women and men adhere differently to preventive measures and if they need to be motivated differently. Finally, we do not know if the mental health impact of the pandemic will differ according to sex.

Sex and Gender Medicine Gender medicine gives us guidance and tools to approach these questions and provide answers that can aid the treatment of our patients and possibly prevent infection at the population level. We have the opportunity to witness on a large scale how the investigation of sex differences could help identify disease mechanisms, improve prognosis and aid in identifying therapeutic targets. The COVID-19 pandemic is forcing us to rethink many healthcare processes and consider changes to our practices for the future; we urge that a systematic attention to sex be one of them.

jama.2020.6775; PMID: 32320003. 15. Myers LC, Parodi SM, Escobar GJ, et al. Characteristics of hospitalized adults with COVID-19 in an integrated health care system in California. JAMA 2020;323:2195–8. https://doi. org/10.1001/jama.2020.7202; PMID: 32329797. 16. Gausman J, Langer A. Sex and gender disparities in the COVID19 pandemic. J Womens Health (Larchmt) 2020;29:465–6. https:// doi.org/10.1089/jwh.2020.8472; PMID: 32320331. 17. Un Women. EVAW COVID-19 briefs. https://www.unwomen. org/en/digital-library/publications/2020/04/series-evaw-covid19-briefs (accessed 23 July 2020). 18. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271–80.e8. https://doi.org/10.1016/j.cell.2020.02.052; PMID: 32142651. 19. Matsuyama S, Nagata N, Shirato K, et al. Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2. J Virol 2010;84:12658–64. https://doi.org/10.1128/JVI.01542-10; PMID: 20926566. 20. Tukiainen T, Villani AC, Yen A, et al. Landscape of X chromosome inactivation across human tissues. Nature 2017;550:244–8. https://doi.org/10.1038/nature24265; PMID: 29022598. 21. Shastri A, Wheat J, Agrawal S, et al. Delayed clearance of SARS-CoV2 in male compared to female patients: high ACE2 expression in testes suggests possible existence of gender-specific viral reservoirs. medRxiv 2020. https://doi.org/1 0.1101/2020.04.16.20060566. 22. Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005;436:112– 6. https://doi.org/10.1038/nature03712; PMID: 16001071. 23. Cheng Z, Zhou J, To KK, et al. Identification of TMPRSS2 as a susceptibility gene for severe 2009 pandemic A(H1N1) influenza and A(H7N9) influenza. J Infect Dis 2015;212:1214–21. https://doi.org/10.1093/infdis/jiv246; PMID: 25904605. 24. Hatesuer B, Bertram S, Mehnert N, et al. Tmprss2 is essential for influenza H1N1 virus pathogenesis in mice. PLoS Pathog 2013;9:e1003774. https://doi.org/10.1371/journal. ppat.1003774; PMID: 24348248. 25. Mikkonen L, Pihlajamaa P, Sahu B, et al. Androgen receptor and androgen-dependent gene expression in lung. Mol Cell Endocrinol 2010;317:14–24. https://doi.org/10.1016/j. mce.2009.12.022; PMID: 20035825. 26. Setlur SR, Mertz KD, Hoshida Y, et al. Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer. J Natl Cancer Inst 2008;100:815–25. https://doi. org/10.1093/jnci/djn150; PMID: 18505969. 27. Guzik TJ, Mohiddin SA, Dimarco A, et al. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res 2020;116:1666–87; PMID: 32352535. 28. Jin JM, Bai P, He W, et al. Gender differences in patients with COVID-19: focus on severity and mortality. Front Public Health

2020;8:152. https://doi.org/10.3389/fpubh.2020.00152; PMID: 32411652. 29. Stefanini GG, Montorfano M, Trabattoni D, et al. ST-elevation myocardial infarction in patients with COVID-19: clinical and angiographic outcomes. Circulation 2020;141:2113–6. https://doi.org/10.1161/CIRCULATIONAHA.120.047525; PMID: 32352306. 30. Chieffo A, Stefanini GG, Price S, et al. EAPCI position statement on invasive management of acute coronary syndromes during the COVID-19 pandemic. Eur Heart J 2020;41:1839–51. https:// doi.org/10.1093/eurheartj/ehaa381; PMID: 32405641. 31. Bangalore S, Sharma A, Slotwiner A, et al. ST-segment elevation in patients with Covid-19 – a case series. N Engl J Med 2020;382:2478–80. https://doi.org/10.1056/ NEJMc2009020; PMID: 32302081. 32. Baldi E, Sechi GM, Mare C, et al. Out-of-hospital cardiac arrest during the Covid-19 outbreak in Italy. N Engl J Med 2020;383:496–8. https://doi.org/10.1056/NEJMc2010418; PMID: 3234864. 33. Van Koeverden ID, de Bakker M, Haitjema S, et al. Testosterone to oestradiol ratio reflects systemic and plaque inflammation and predicts future cardiovascular events in men with severe atherosclerosis. Cardiovasc Res 2019;115:453–62. https://doi. org/10.1093/cvr/cvy188; PMID: 30052805. 34. Ter Horst R, van den Munckhof ICL, Schraa K, et al. Sexspecific regulation of inflammation and metabolic syndrome in obesity. Arterioscler Thromb Vasc Biol 2020;40:1787–800. https:// doi.org/10.1161/ATVBAHA.120.314508; PMID: 32460579. 35. Mancia G, Rea F, Ludergnani M, et al. Renin–angiotensin– aldosterone system blockers and the risk of Covid-19. N Engl J Med 2020;382:2431–40. https://doi.org/10.1056/ NEJMoa2006923; PMID: 32356627. 36. Reynolds HR, Adhikari S, Pulgarin C, et al. Renin–angiotensin– aldosterone system inhibitors and risk of Covid-19. N Engl J Med 2020;382:2441–8. https://doi.org/10.1056/ NEJMoa2008975; PMID: 32356628. 37. Sama IE, Ravera A, Santema BT, et al. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors. Eur Heart J 2020;41:1810–7. https://doi.org/10.1093/eurheartj/ehaa373; PMID: 32388565. 38. Wadman M, Couzin-Frankel J, Kaiser J, et al. A rampage through the body. Science 2020;368:356–60. https://doi. org/10.1126/science.368.6489.356. PMID: 32273451. 39. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 2020;369:m1985. https://doi.org/10.1136/ bmj.m1985; PMID: 32444460. 40. Garner P. For 7 weeks I have been through a roller coaster of ill health, extreme emotions, and utter exhaustion. BMJ Opinion. 5 May 2020. https://blogs.bmj.com/bmj/2020/05/05/ paul-garner-people-who-have-a-more-protracted-illness-needhelp-to-understand-and-cope-with-the-constantly-shifting-

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Sex in COVID-19 bizarre-symptoms (accessed 8 July 2020). 41. Colella TJ, Gravely S, Marzolini S, et al. Sex bias in referral of women to outpatient cardiac rehabilitation? A meta-analysis. Eur J Prev Cardiol 2015;22:423–41. https://doi.org/10.1177/ 2047487314520783; PMID: 24474091. 42. Stamm-Balderjahn S, Brünger M, Michel A, et al. The efficacy

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of goal setting in cardiac rehabilitation – a gender-specific randomized controlled trial. Dtsch Arztebl Int 2016;113:525–31. https://doi.org/10.3238/arztebl.2016.0525; PMID: 27581505. 43. Hyde JS, Mezulis AH. Gender differences in depression: biological, affective, cognitive, and

sociocultural factors. Harv Rev Psychiatry 2020;28:4–13. https://doi.org/10.1097/HRP.0000000000000230; PMID: 31913978. 44. European Institute for Gender Equality. Coronavirus puts women in the frontline. 25 March 2020. https://eige.europa.eu/ news/coronavirus-puts-women-frontline (accessed 8 July 2020).

Special Focus on the ISCHEMIA Trial

What is the Real Message of the ISCHEMIA Trial from a Clinician’s Perspective? Islam Y Elgendy1 and Carl J Pepine2 1. Division of Cardiology, Weill Cornell Medicine-Qatar, Doha, Qatar; 2. Division of Cardiovascular Medicine, University of Florida, Gainesville, FL, US

Disclosure: The authors have no conflicts of interest to declare. Received: 28 May 2020 Accepted: 30 June 2020 Citation: European Cardiology Review 2020;15:e63. DOI: https://doi.org/10.15420/ecr.2020.27 Correspondence: Carl J Pepine, Division of Cardiovascular Medicine, University of Florida, 1329 SW 16th St, PO Box 100288, Gainesville, FL 32610-0288, US. E: carl.pepine@medicine.ufl.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Management goals in patients with stable coronary disease or chronic coronary syndrome include controlling symptoms and reducing the risk of future cardiovascular events.1,2 Randomised trials conducted in the bare metal stents era have indicated that an invasive management strategy, which includes coronary angiography, followed by percutaneous or surgical revascularisation, if indicated, was not superior to optimal medical therapy (OMT) alone in reducing the risk of cardiovascular death or MI.3 However, there have been many advances in revascularisation therapies, as well as medical management, in the past decade. In addition, patients with any degree of ischaemia on functional assessment were eligible for enrolment, which might have led to underenrolment of patients with moderateto-severe ischaemia who might derive the most benefit from revascularisation.4 Moreover, as coronary angiography was performed prior to randomisation, patients with coronary anatomy that might be associated with high risk for adverse outcomes were likely not randomised, but sent directly to revascularisation. These concerns led to continuing controversy regarding the optimal management strategy for patients with stable coronary disease. In this context, the International Study of Comparative Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial sought to determine whether an invasive strategy with coronary angiography and contemporary coronary revascularisation, if indicated, would be superior to OMT alone in patients with moderate-to-severe ischaemia on stress imaging, including echocardiogram, nuclear scan, cardiac magnetic resonance or exercise testing (an option added late in the trial to improve recruitment).5 Most patients (73%) underwent CT coronary angiography (CTCA) analysed by the core lab to exclude those with left main obstruction or non-obstructive coronary disease. Key exclusions included unprotected left main obstruction >50%, advanced kidney disease (estimated glomerular filtration rate <30 ml/min/1.73m2), New York Heart Association class III or IV heart failure, left ventricular dysfunction, angina refractory to medical therapy, acute coronary syndrome within 2 months and percutaneous coronary intervention or coronary artery bypass grafting within the past year.5 The primary outcome was the first occurrence of cardiovascular death or resuscitated cardiac arrest, non-fatal MI or hospitalisation for either unstable angina or heart failure.5 Secondary outcomes included cardiovascular death or MI and quality of life (QOL).5,6 A parallel trial

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compared both strategies in patients with advanced kidney disease or those receiving dialysis.7,8 Between 2012 and 2018, 8,518 patients were screened; 3,339 of these were excluded. The main reasons for exclusion (and their frequencies) were mild ischaemia, non-obstructive coronary disease (~14%) on CTCA and unprotected left main disease (5.1%). Finally, 5,179 patients were randomised from 320 centres in 37 countries. Their median age was 64 years, 77% were men and 35% did not have any angina symptoms at baseline. In the invasive group, 96% of the patients underwent coronary angiography, whereas 26% of patients randomised to the conservative group crossed over to coronary angiography because of inadequate angina control or an ischaemic event. Loss of follow-up was remarkably low (~1%). During a median follow-up of 3.2 years, the rates of the primary outcome (12.3% versus 13.6%) and of cardiovascular death or MI (10.7% versus 12.1%) did not differ significantly between the randomised groups. All-cause mortality was low in both groups (5.6%).5 The invasive group had greater improvement of QOL, but this benefit was observed mainly in those with angina at baseline.6 In the parallel trial for patients with advanced kidney disease, an invasive strategy neither reduced cardiovascular mortality or MI, nor improved the QOL.7,8 The ISCHEMIA trial is the largest trial to date comparing an invasive strategy versus OMT in patients with stable coronary artery disease and moderate-to-severe ischaemia on functional testing. Key strengths included the following: • A rigorous design requiring the presence of obstructive epicardial coronary arteries on CTCA, without left main obstruction, prior to enrolment, reviewed by an independent core lab. This is important, as prior trials randomised patients after the coronary anatomy was identified, so many patients believed to have a high-risk anatomy were likely not randomised.3 • The trial was not industry funded. • Very few patients were lost to follow-up. • A rigorous assessment of outcomes, including QOL measures. • Control of cardiovascular risk factors, including systolic blood pressure and low-density lipoprotein levels, and adherence to medical therapy was high in both groups (~80% at the end of follow-up).

A Clinician’s Perspective Despite these notable strengths, some areas warrant further mention. First, the trial was an ‘open design’. Although outcomes were assessed by an independent committee masked to randomised group assignment, the lack of a sham control for the OMT strategy remains a limitation. Given the results of the Objective Randomised Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina (ORBITA) trial, which found that revascularisation did not increase exercise time compared with the sham-controlled OMT, the absence of a sham-controlled OMT arm in the ISCHEMIA trial might have diminished any gradient between the OMT and revascularisation arms for angina.9 Second, slow recruitment may have reflected the practice pattern of some sites to limit enrolment of the more symptomatic patients, thus contributing to the low event rates observed and reducing the power of the study. Third, the prevalence of significant left main stenosis was 5.1%, which is higher than ‘all-comer’ studies with chest pain (~1%), and could reflect selection bias towards the inclusion of only patients with moderate-to-severe ischaemia on non-invasive stress testing.10 Fourth, although CTCA was performed prior to randomisation to ensure that patients who only had obstructive epicardial coronary artery disease that did not involve the left main artery were enrolled, approximately 16% of patients in the invasive arm did not undergo revascularisation because they had only non-obstructive disease on invasive angiography. Fifth, a considerable proportion of enrolled patients (35%) did not have any angina at baseline, thus they were unlikely to derive any symptom benefit from either revascularisation or OMT. However, angina relief was not a component of the primary end-point but rather a prespecified secondary endpoint of the study. Finally, women represented only 23% of enrollees. While this could be a result of excluding patients with non-obstructive coronary disease, it also suggests considerable bias against recruiting women in landmark trials. This is important because the US population is predominantly women >64 years, and that was the median age for the ISCHEMIA trial. That is, a large group of older women with coronary artery disease were not included. In an exploratory analysis of the ISCHEMIA trial, women were more likely to have more frequent angina independent of the extent of disease on CCTA or ischaemia.11 It is unclear if this underenrolment of women was recognised and/or if attempts were made to better recruit women during the trial. Importantly, the interaction of sex on the outcomes has not been addressed. By inadequately enrolling women, an opportunity to better understand the sex differences in the efficacy of interventions was missed.12

What is the Real Message from the ISCHEMIA Trial? The ISCHEMIA trial confirmed that younger patients (mostly men) with stable symptoms, normal ejection fraction, normal or slightly impaired

Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. https://doi.org/10.1093/eurheartj/ ehz425; PMID: 31504439. Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/AHA/ AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic

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renal function and evidence of moderate-to-severe ischaemia on stress testing could be risk stratified with CTCA to exclude significant unprotected left main disease, and then managed with OMT alone. Invasive coronary angiography could be reserved for those who have refractory angina despite medical therapy. The ISCHEMIA trial also suggested that, in this patient population, an upfront invasive strategy reduces angina frequency and improves QOL, especially in highly symptomatic patients. Interestingly, the Kaplan–Meier curves for cardiovascular mortality or MI were initially in favour of the OMT strategy because of higher rates of peri-procedural MI, but later the curves trended in favour of an invasive strategy driven by lower spontaneous MI. Shared decision-making between treating physicians and patients in light of these findings could help to better provide more personalised care to our patients. However, patients with advanced kidney disease or those receiving dialysis who have stable coronary disease could be best managed with a strategy of OMT alone. The ISCHEMIA trial findings stress the importance of adherence to medical therapy and risk factor control, irrespective of the management strategy. Some frequently encountered groups of patients in clinical practice were excluded from the ISCHEMIA trial, thus the findings should not be extrapolated to them. These include patients with recent acute coronary syndrome, for whom randomised trials have shown benefits of a routine invasive strategy, as well as patients with reduced ejection fraction; although contemporary randomised data are scarce for such patients, observational data suggest revascularisation benefits.13–15 In the ISCHEMIA trial, there was no evidence of interaction of the degree of ischaemia on the outcomes.5 This challenges the routine use of functional testing for assessing stable coronary disease patients, and suggests that an anatomical test, such as CTCA, could be performed to exclude obstructive epicardial coronary artery disease. However, this approach will result in missing the opportunity to evaluate for microvascular and vasospastic angina, which could be diagnosed with functional invasive testing.16 These syndromes are prevalent (~40–50% of patients undergoing invasive angiography for angina), especially in women, and they result in poor QOL.17,18 Importantly, evidence-based management approaches for these syndromes exist. The CORonary MICrovascular Angina (CorMicA) trial showed that a stratified medical therapy approach based on the findings of invasive coronary functional assessment reduced angina and improved QOL in these patients.16 Therefore, adopting a ‘single-test’ strategy to assess patients with stable coronary disease is premature. The ongoing Coronary Microvascular Function and CT Coronary Angiogram (CorCTCA) trial is investigating the merits of an initial CTCA approach, followed by invasive angiography, to guide therapies for patients with microvascular and vasospastic angina.19 Overall, the ISCHEMIA trial has clearly advanced our understanding of contemporary management options for patients with obstructive coronary artery disease, and should foster efforts to include the patient in management decisions.

heart disease. J Am Coll Cardiol 2014;64:1929–49. https://doi. org/10.1016/j.jacc.2014.07.017; PMID: 25077860. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–16. https://doi.org/10.1056/ NEJMoa070829; PMID: 17387127. Hachamovitch R, Hayes SW, Friedman JD, et al. Comparison

of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 2003;107:2900–7. https://doi.org/10.1161/01.CIR.0000072790.23090.41; PMID: 12771008.

Special Focus on the ISCHEMIA Trial 5.

Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med 2020;382:1395–1407. https://doi.org/10.1056/NEJMoa1915922; PMID: 32227755. 6. Spertus JA, Jones PG, Maron DJ, et al. Health-status outcomes with invasive or conservative care in coronary disease. N Engl J Med 2020;382:1408–19. https://doi.org/10.1056/ NEJMoa1916370; PMID: 32227753. 7. Bangalore S, Maron DJ, O’Brien SM, et al. Management of coronary disease in patients with advanced kidney disease. N Engl J Med 2020;382:1608–18. https://doi.org/10.1056/ NEJMoa1915925; PMID: 32227756. 8. Spertus JA, Jones PG, Maron DJ, et al. Health status after invasive or conservative care in coronary and advanced kidney disease. N Engl J Med 2020;382:1619–28. https://doi. org/10.1056/NEJMoa1916374; PMID: 32227754. 9. Al-Lamee R, Thompson D, Dehbi HM, et al. Percutaneous coronary intervention in stable angina (ORBITA): a doubleblind, randomised controlled trial. Lancet 2018;391:31–40. https://doi.org/10.1016/S0140-6736(17)32714-9; PMID: 29103656. 10. Jang JJ, Bhapkar M, Coles A, et al. Predictive model for highrisk coronary artery disease. Circ Cardiovasc Imaging

11.

12.

13.

14.

15.

2019;12:e007940. https://doi.org/10.1161/ CIRCIMAGING.118.007940; PMID: 30712364. Reynolds HR, Shaw LJ, Min JK, et al. Association of sex with severity of coronary artery disease, ischemia, and symptom burden in patients with moderate or severe ischemia: secondary analysis of the ISCHEMIA randomized clinical trial. JAMA Cardiol 2020;5:773–86. https://doi.org/10.1001/ jamacardio.2020.0822; PMID: 32227128. Elgendy IY, Van Spall HGC, Mamas MA. Cardiogenic shock in the setting of acute myocardial infarction: history repeating itself? Circ Cardiovasc Interv 2020;13:e009034. https://doi. org/10.1161/CIRCINTERVENTIONS.120.009034; PMID: 32151160. Elgendy IY, Kumbhani DJ, Mahmoud AN, et al. Routine invasive versus selective invasive strategies for non-ST-elevation acute coronary syndromes: an updated meta-analysis of randomized trials. Catheter Cardiovasc Interv 2016;88:765–74. https://doi. org/10.1002/ccd.26679; PMID: 27515910. Velazquez EJ, Lee KL, Deja MA, et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011;364:1607–16. https://doi.org/10.1056/ NEJMoa1100356; PMID: 21463150. Wolff G, Dimitroulis D, Andreotti F, et al. Survival benefits of invasive versus conservative strategies in heart failure in

16.

17.

18.

19.

patients with reduced ejection fraction and coronary artery disease: a meta-analysis. Circ Heart Fail 2017;10:e003255. https://doi.org/10.1161/CIRCHEARTFAILURE.116.003255; PMID: 28087687. Beltrame JF, Crea F, Kaski JC, et al. International standardization of diagnostic criteria for vasospastic angina. Eur Heart J 2017;38:2565–8. https://doi.org/10.1093/eurheartj/ ehv351; PMID: 26245334. Ford TJ, Stanley B, Good R, et al. Stratified medical therapy using invasive coronary function testing in angina: the CorMicA trial. J Am Coll Cardiol 2018;72:2841–55. https://doi. org/10.1016/j.jacc.2018.09.006; PMID: 30266608. Shaw LJ, Merz CN, Pepine CJ, et al. The economic burden of angina in women with suspected ischemic heart disease: results from the National Institutes of Health–National Heart, Lung, and Blood Institute-sponsored women’s ischemia syndrome evaluation. Circulation 2006;114:894–904. https://doi. org/10.1161/CIRCULATIONAHA.105.609990; PMID: 16923752. Sidik NP, McEntegart M, Roditi G, et al. Rationale and design of the British Heart Foundation (BHF) Coronary Microvascular Function and CT Coronary Angiogram (CorCTCA) study. Am Heart J 2020;221:48–59. https://doi.org/10.1016/j. ahj.2019.11.015; PMID: 31911341.

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Lifelong Learning for Cardiovascular Professionals

European Cardiology Review is part of the Radcliffe Cardiology family. For further information, including access to thousands of educational reviews, visit: www.radcliffecardiology.com

Contents

DOI: https://doi.org/10.15420/ecr.2020.26

Obstructive Sleep Apnoea Syndrome: Continuous Positive Airway Pressure Therapy for Prevention of Cardiovascular Risk María Pilar Resano-Barrio, Ramón Arroyo-Espliguero, María Carmen Viana-Llamas and Olga Mediano DOI: https://doi.org/10.15420/ecr.2020.10

Coronavirus Disease 2019 and Cardiac Arrhythmias

Antoni Martínez-Rubio, Soledad Ascoeta, Fadwa Taibi and Josep Guindo Soldevila DOI: https://doi.org/10.15420/ecr.2020.23

The EXCEL Trial: The Surgeons’ Perspective

Marjan Jahangiri, Krishna Mani, Martin T Yates and Justin Nowell DOI: https://doi.org/10.15420/ecr.2020.34

Factors Related to Maternal Adverse Outcomes in Pregnant Women with Cardiac Disease in Low-resource Settings Philippe Amubuomombe Poli , Elkanah Omenge Orang’o, Ann Mwangi and Felix Ayub Barasa DOI: https://doi.org/10.15420/ecr.2020.04

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ISCHEMIA

What is the Real Message of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) Trial for Academic and Practising Cardiologists? Kreton Mavromatis1 and William E Boden2 1. Atlanta Veteran Affairs Healthcare System, Emory University School of Medicine, Atlanta, GA, US; 2. VA New England Healthcare System, Boston University School of Medicine, Boston, MA, US

Disclosure: Both authors are ISCHEMIA investigators. Received: 26 May 2020 Accepted: 13 July 2020 Citation: European Cardiology Review 2020;15:e64. DOI: https://doi.org/10.15420/ecr.2020.26 Correspondence: Kreton Mavromatis, Atlanta VA Healthcare System, 1670 Clairmont Rd, Mailstop 111B, Decatur, GA 300030, US. E: kmavro@emory.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Defining the best management strategies for patients with stable ischaemic heart disease (SIHD) has been the subject of scientific study for nearly 50 years since the advent of coronary artery bypass grafting (CABG) surgery by Favaloro in 1967 and, a decade later, the development of percutaneous coronary intervention (PCI) by Gruentzig in 1977.1,2 Randomised controlled trials of CABG surgery versus medical therapy were initiated in the late 1970s and 1980s in patients with SIHD and showed that revascularisation reduced MI and mortality in subsets of patients with three-vessel and left main coronary artery disease (CAD).3–5 In the 1990s, randomised controlled trials of PCI versus medical therapy, initially with balloon angioplasty (Angioplasty Compared to Medicine [ACME] and Second Randomised Intervention Treatment of Angina [RITA-2]), were similarly undertaken in SIHD patients and showed significantly better angina relief and treadmill exercise performance with PCI, although no reduction in death or MI.6,7 Nevertheless, the widespread availability of PCI greatly expanded the number of patients who could be revascularised safely and pushed revascularisation therapy to become routine for SIHD patients in many locales.

Contemporary Studies of Revascularisation During the ‘Optimal Medical Therapy’ Era The medical therapy used in the CABG and early PCI trials consisted primarily of antianginal agents and aspirin, the latter only used in 20% of patients, because statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and thienopyridines had not yet been developed.5 By 2000, as these newer so-called ‘disease-modifying therapies’ came into more widespread clinical use and were combined with strategies of aggressive risk factor intervention and control, the contemporary era of ‘optimal medical therapy’ (OMT) came into existence and formulated a more relevant comparator to revascularisation than antianginal therapies alone. Beginning with the Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation (COURAGE) trial in SIHD patients and, shortly thereafter, the 2nd Bypass Angioplasty Revascularization Investigation in Diabetes (BARI 2D) trial, comparative effectiveness trials of OMT with or without revascularisation were undertaken to address whether prognostically important endpoints such as death or

MI could be favourably affected when either PCI or CABG was added to OMT versus OMT alone.8,9 These trials, which now also include the Fractional Flow Reserve and Angiography for Multivessel Evaluation 2 (FAME 2) trial and, most recently, the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA), have set a new standard for defining whether incremental cardiac event reduction could be achieved by combining both revascularisation with OMT (Table 1).10–14

COURAGE and BARI 2D The COURAGE trial randomised 2,287 SIHD patients to PCI plus OMT or OMT alone.8 The BARI 2D trial randomised 2,368 patients with type 2 diabetes to revascularisation (two strata each randomising patients to OMT with PCI or CABG versus OMT alone as clinically determined by site investigators).9 In the COURAGE trial, PCI plus OMT did not reduce the primary endpoint of death or MI compared with OMT alone over a median 4.6 year follow-up period. Although revascularisation did improve quality of life (QoL) in the COURAGE trial, the QoL improvement was limited to 2 years.15 In BARI 2D, revascularisation with either PCI or CABG surgery did not reduce the primary endpoint of all-cause mortality over a 5-year follow-up, although CABG plus OMT was found to be superior to OMT alone for the secondary endpoint of death, MI or stroke (p=0.01), which was driven solely by a decrease in non-fatal MI. This benefit was not observed for PCI.9

FAME 2 The FAME 2 trial, performed in the early 2010s, was a relatively small trial of 888 SIHD patients who were randomised to fractional flow reserve (FFR)-guided PCI plus medical therapy versus medical therapy alone using more contemporary second-generation drug-eluting stents. The study was stopped early at a median follow-up of only 7 months after an interim analysis revealed the primary endpoint (a composite of death, MI or urgent revascularisation) was substantially reduced in PCItreated patients, driven solely by a reduction in urgent revascularisation.10 Although there was no difference in mortality at both 2 and 5 years of follow-up, there was a statistically marginal reduction in MI in the PCItreated patients.11,12

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ISCHEMIA Table 1: Contemporary Randomised Controlled Trials of Medical Therapy with Revascularisation Versus without Revascularisation in Patients with Stable Ischaemic Heart Disease COURAGE8

BARI 2D9

FAME 210

ISCHEMIA19

Enrolment period

1999–2004

2001–2005

2010–2012

2012–2018

Patients (n)

2,287

2,368

888

5,179

Clinical characteristics

SIHD

Diabetes and SIHD or UIHD

SIHD

Ischaemia evidence

Non-invasive ischaemia evidence or >80% stenosis + classic angina

Non-invasive ischaemia evidence or ≥70% stenosis + classic angina

FFR ≤0.80

Moderate or severe non-invasive ischaemia evidence

Coronary anatomy

Stenosis >70% by ICA (left main >50% excluded)

Stenosis >50% by ICA (left main >50% excluded)

ICA not required (blinded CCTA to exclude non-obstructive CAD and left main >50%)

Revascularisation

PCI (BMS)

PCI (BMS or first-generation DES) or CABG

PCI (second-generation DES)

PCI (second-generation DES) or CABG

Follow-up period (years) Median 4.6 (IQR 3.3–5.7)

Mean 5.3 (range 3.4–7.8)

Median 3.2 (IQR 2.1–4.3)

Primary endpoint outcome

No difference in all-cause death and MI

No difference in all-cause death PCI reduced all-cause death, MI and No difference in CV death, MI, urgent revascularisation (no unstable angina, CHF and difference in death or MI) resuscitated CV death

Quality of life

Improved by PCI out to 2 years

Improved by revascularisation

No difference (PCI reduced angina)

Improved by revascularisation

BMS = bare metal stent; CABG = coronary artery bypass grafting; CCTA = coronary CT angiography; CHF = congestive heart failure; CV = cardiovascular; DES = drug-eluting stent; FFR = fractional flow reserve; ICA = invasive coronary angiography; IQR = interquartile range; PCI = percutaneous coronary intervention; SIHD = stable ischaemic heart disease; UIHD = unstable ischaemic heart disease.

Limitations of COURAGE, BARI 2D and FAME 2 The COURAGE, BARI 2D and FAME 2 trials had limitations. None of these trials was blinded. They all included the enrolment of patients with only mild amounts of inducible ischaemia. In addition, patients were enrolled only after the results of coronary angiography were known, which raised the possibility that SIHD patients with more extensive or severe coronary disease may have been excluded from trial participation due to selection bias. These limitations resulted in incomplete acceptance of the results, with continuing routine revascularisation for mortality and MI reduction in SIHD patients who demonstrated a higher ischaemic burden. In fact, the basis for an interventional approach to SIHD patients with moderate to severe ischaemia was fuelled by observational data from the Cedars-Sinai group in more than 10,000 patients from the 1990s, in whom it was observed that, at levels of baseline ischaemia >10% of the left ventricular myocardium, there was a significant reduction in cardiac events during long-term follow-up, although these findings were not randomised and the medical therapies used antedated the current use of statins, ACE inhibitors, ARBs and thienopyridines.16,17 With nearly 500,000 PCIs and 400,000 CABGs performed in the US in 2014, the public health implications of understanding the effects of revascularisation continued to be enormous.18

ISCHEMIA: Trial Design, Conduct and Results These prior studies and their limitations set the stage for conducting ISCHEMIA, the largest randomised controlled study of revascularisation in patients with SIHD ever conducted and designed to prospectively test the ‘ischaemia hypothesis’ by more thoroughly evaluating the potential risks and benefits of revascularisation by addressing the aforementioned limitations of the prior SIHD strategy trials.19 By design, ISCHEMIA required that all patients have at least a moderate burden of inducible ischaemia at baseline, as demonstrated non-invasively, as a prerequisite for randomisation. Patients were enrolled prior to coronary angiography to eliminate anatomical selection bias, although blinded coronary CT angiography (CCTA) was performed to selectively exclude

patients with left main and non-obstructive disease. After randomisation to an invasive strategy (invasive coronary angiography followed by revascularisation plus OMT) or a conservative strategy (OMT only, with invasive coronary angiography and revascularisation reserved for patients with persistent angina symptoms who failed medical therapy or who were suspected of reaching a study endpoint), revascularisation was performed, either by CABG or PCI, as clinically determined. Specific coronary artery revascularisation was encouraged to be physiologically directed using FFR-guided PCI using second-generation drug-eluting stents. The primary endpoint was a composite of cardiovascular death, MI, hospitalisation for unstable angina, hospitalisation for congestive heart failure and resuscitated cardiac arrest. The major secondary endpoints were cardiovascular death or MI, as well as angina control and QoL. The mean follow-up period was 3.2 years.13 Ultimately, 5,179 patients were randomised from among 8,518 subjects screened for moderate to severe ischaemia at baseline.13 The patients were predominantly men (77%), with 41% having diabetes, 20% having prior MI and the mean LVEF being 60%. Patients had relatively low burdens of angina (95% Canadian Cardiovascular Society 0–2), but more than 50% had severe ischaemia and 45% had three-vessel disease as determined by CCTA. Medical therapy was excellent, with 96% of patients receiving aspirin and 95% of patients receiving statin therapy (66% high-intensity statin, 24% ezetimibe). By the end of the study, the median LDL achieved was 1.66 mmol/l, the median blood pressure achieved was 129/74 mmHg and the median HbA1c was 6.3%.13 More than 95% of patients randomised to the invasive strategy underwent invasive coronary angiography, with 80% of all patients undergoing revascularisation (54% by stenting, 20% by CABG). Those not undergoing revascularisation had disease deemed unsuitable for either CABG or PCI, and, of these, nearly 60% had non-obstructive disease. Of note, 21% of patients assigned to the conservative strategy also underwent revascularisation by the end of the study, mostly due to suspected endpoints or unacceptable angina (a rate of ‘cross-over’ of approximately 6.5% per year).

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The Core Message of ISCHEMIA The five-component primary endpoint did not differ between the invasive and conservatively treated SIHD patients (16.4% and 18.2%, respectively; 95% CI [−4.7, 1.0]). For the secondary endpoint of cardiovascular mortality or MI, the HR for the invasive versus conservative strategies was 0.90 (95% CI [0.77–1.06]; p=0.21. Although the overall rate of MI between the invasive and conservative strategies was not significantly different during follow-up (HR 0.93; 95% CI [0.79– 1.15]; p=0.31), there were more periprocedural MIs early in the invasively treated patients that were counterbalanced by more spontaneous MIs occurring later in the conservatively treated patients. There were no between-group differences in either all-cause mortality (5.6% in each arm; HR 1.05; 95% CI [0.83–1.32]; p=0.67) or cardiovascular mortality (HR 0.87; 95% CI [0.66–1.15]; p=0.33) during follow-up. In addition, there were no differences between the invasive and conservative treatment strategies even in the highest-risk subgroups (e.g. patients with severe ischaemia at baseline, those with three-vessel disease or those with diabetes). The invasively treated patients had better angina control and QoL out to the end of the study than the conservatively treated patients. However, this finding was limited to those patients with angina at baseline and was most demonstrable in those with daily or weekly angina at baseline, although this accounted for only 21% of ISCHEMIA trial patients.9

ISCHEMIA Message Thus, what is the real message of ISCHEMIA to both academic and practising cardiologists alike? Conservative management of SIHD is safe. Even patients with a high ischaemia burden should not be rushed into invasive therapy under the implied guise of reduced MI or mortality. All patients with newly diagnosed SIHD should be initiated on guidelinedirected medical therapy, given information about the risks and benefits of additional invasive therapy and allowed a reasonable period of time to deliberate the decision as to whether to proceed to the catheterisation laboratory. Healthcare providers should make a conscious effort to counteract the impression that immediate invasive therapy reduces the overall risk of MI or death. This is essential if we are to meet our goal of achieving truly meaningful shared clinical decision-making for our patients, with individualised treatment decisions, but only after there has been a transparent and full disclosure of all the benefits and risks of all treatment choices. The invasive approach clearly has benefits. Invasive therapy reduces angina, with greater benefit in more symptomatic patients. It also reduces late spontaneous MIs and hospitalisations for unstable angina, although the rate in ISCHEMIA was very low overall. These benefits

Favaloro RG. Saphenous vein autograft replacement of severe segmental coronary artery occlusion: operative technique. Ann Thorac Surg 1968;5:334–9. https://doi.org/10.1016/S00034975(10)66351-5; PMID: 5647919. Gruentzig AR. Percutaneous transluminal coronary angioplasty. Semin Roentgenol 1981;16:152–3. https://doi.org/10.1016/0037198X(81)90049-3; PMID: 7233248. Coronary artery surgery study (CASS): a randomized trial of coronary artery bypass surgery. Survival data. Circulation 1983;68:939–50. https://doi.org/10.1161/01.CIR.68.5.939; PMID: 6137292. Takaro T, Hultgren HN, Lipton MJ, Detre KM. The VA cooperative randomized study of surgery for coronary arterial occlusive disease II. Subgroup with significant left main lesions. Circulation 1976;54(6 Suppl):III107–17. PMID: 791537. Yusuf S, Zucker D, Chalmers TC. Ten-year results of the randomized control trials of coronary artery bypass graft surgery: tabular data compiled by the collaborative effort of the original trial investigators. Part 1 of 2. Online J Curr Clin Trials 1994;Doc No 145. PMID: 7804524. Parisi AF, Folland ED, Hartigan P. A comparison of angioplasty with medical therapy in the treatment of single-vessel

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need to be considered in the context of the significantly higher rate of early procedural (Type 4A and Type 5) MI, although it remains unclear whether these MI events result in worse clinical outcomes. A detailed MI analysis and longer-term follow-up of ISCHEMIA are important to understand these late benefits and early risks more fully. It is likely that the net benefits will persuade many patients to proceed with the invasive strategy, although, conversely, it is also easy to envision that a conservative strategy may be the preferred approach of patients who are only minimally symptomatic, those who have extensive clinical comorbidities and/or those with limited life expectancies The results of ISCHEMIA would suggest strongly that CCTA is integral to pursuing the conservative strategy, because approximately 15% of ISCHEMIA enrollees were found to have non-obstructive disease on CCTA, despite moderate or severe inducible ischaemia, and were not randomised. For this subgroup, CCTA importantly altered their diagnosis and affected their subsequent therapy, although only a small percentage of patients was followed longitudinally in a registry and thus the prognosis of this subgroup is largely unknown. Another approximately 8% of patients were found to have significant left main disease on CCTA and were not randomised. Historically, patients with left main disease have greater risks of ischaemic events than other coronary disease subgroups and derive greater benefits from revascularisation. Therefore, for these patients, invasive management should generally still be preferred. CCTA may also be helpful in identifying other particularly high-risk subgroups of patients, such as those with diabetes and three-vessel disease. The results of ISCHEMIA to date tell us that clinical outcomes in these subgroups were not favourably altered by revascularisation, but without adequately powered subgroup analyses from ISCHEMIA on such patients, other high-quality contemporary data, such as those derived from the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) and Surgical Treatment for Ischemic Heart Failure (STICH) trials, compels us to still consider revascularisation.20,21

Conclusion As previously noted, ISCHEMIA addressed many of the prior limitations of the COURAGE, BARI 2D and FAME 2 trials and showed consistent results. Based on these collective study findings, we believe it is prudent that SIHD management should move a step further away from routine invasive management and towards a paradigm of greater noninvasive evaluation, aggressive medical therapy and individualised invasive therapy only for subgroups of patients in whom medical therapy fails or where clinical benefit is proven.

coronary artery disease. N Engl J Med 1992;326:10–6. https:// doi.org/10.1056/NEJM199201023260102; PMID: 1345754. Coronary angioplasty versus medical therapy for angina: the Second Randomised Intervention Treatment of Angina (RITA-2) trial. RITA-2 trial participants. Lancet 1997;350:461–8. https:// doi.org/10.1016/S0140-6736(97)07298-X; PMID: 9274581. 8. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–16. https://doi.org/10.1056/ NEJMoa070829; PMID: 17387127. 9. The BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503–15. https://doi.org/10.1056/NEJMoa0805796; PMID: 19502645. 10. De Bruyne B, Pijls NHJ, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367:991–1001. https://doi. org/10.1056/NEJMoa1205361; PMID: 22924638. 11. De Bruyne B, Fearon WF, Pijls NHJ, et al. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med 2014;371:1208–17. https://doi.org/10.1056/ NEJMoa1408758; PMID: 25176289. 7.

12. Xaplanteris P, Fournier S, Pijls NHJ, et al. Five-year outcomes with PCI guided by fractional flow reserve. N Engl J Med 2018;379:250–9. https://doi.org/10.1056/NEJMoa1803538; PMID: 29785878. 13. Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med 2020;382:1395–407. https://doi.org/10.1056/NEJMoa1915922; PMID: 32227755. 14. Spertus JA, Jones PG, Maron DJ, et al. Health-status outcomes with invasive or conservative care in coronary disease. N Engl J Med 2020;382:1408–19. https://doi.org/10.1056/ NEJMoa1916370; PMID: 32227753. 15. Weintraub WS, Spertus JA, Kolm P, et al. Effect of PCI on quality of life in patients with stable coronary disease. N Engl J Med 2008;359:677–87. https://doi.org/10.1056/NEJMoa072771; PMID: 18703470. 16. Hachamovitch R, Hayes SW, Friedman JD, et al. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 2003;107:2900–7.

ISCHEMIA https://doi.org/10.1161/01.CIR.0000072790.23090.41; PMID: 12771008. 17. Hachamovitch R, Rozanski A, Shaw LJ, et al. Impact of ischaemia and scar on the therapeutic benefit derived from myocardial revascularization vs. medical therapy among patients undergoing stress-rest myocardial perfusion scintigraphy. Eur Heart J 2011;32:1012–24. https://doi. org/10.1093/eurheartj/ehq500; PMID: 21258084.

18. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics – 2014 update: a report from the American Heart Association. Circulation 2014;129:e28–292. 19. Maron DJ, Hochman JS, O’Brien SM, et al. International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial: rationale and design. Am Heart J 2018;201:124–35. https://doi.org/10.1016/j.ahj.2018.04.011; PMID: 29778671.

20. Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012;367:2375–84. https://doi.org/10.1056/ NEJMoa1211585; PMID: 23121323. 21. Velazquez EJ, Lee KL, Jones RH, et al. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N Engl J Med 201;374:1511–20. https://doi.org/10.1056/NEJMoa1602001; PMID: 27040723.

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Management and Comorbidities

Obstructive Sleep Apnoea Syndrome: Continuous Positive Airway Pressure Therapy for Prevention of Cardiovascular Risk María Pilar Resano-Barrio,1 Ramón Arroyo-Espliguero,2 María Carmen Viana-Llamas2 and Olga Mediano1,3,4 1. Department of Respiratory Medicine, University Hospital, Guadalajara, Spain; 2. Department of Cardiology, University Hospital, Guadalajara, Spain; 3. Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain; 4. Department of Medicine, University of Alcalá, Alcalá de Henares, Madrid, Spain

Abstract Obstructive sleep apnoea (OSA) syndrome is characterised by the presence of apnoea or obstructive hypopnoea during sleep, accompanied by hypoxia. It is estimated that the syndrome affects approximately 10% of men and 15% of women. Diagnosis and treatment rates have increased in recent years, but the condition remains undiagnosed in a high percentage of patients. Recent evidence suggests that OSA may increase the risk of cardiovascular disease. The relationship between OSA and cardiovascular disease can be explained, at least in part, by the coexistence of cardiovascular risk factors in the two pathologies, such as age, overweight, smoking and sedentary lifestyle. However, OSA has been independently associated with the risk of developing hypertension, cerebrovascular disease, ischaemic heart disease, heart failure and arrhythmias. Clinical trials that have evaluated the efficacy of continuous positive airway pressure (CPAP) treatment in primary and secondary cardiovascular prevention have not demonstrated a significant reduction in the incidence or recurrence of cardiovascular events. This article analyses the relationship between OSA and cardiovascular risk and discusses recent clinical trials on the efficacy of CPAP in primary and secondary cardiovascular prevention.

Keywords Obstructive sleep apnoea syndrome, continuous positive airway pressure, hypertension, cardiovascular disease, cardiovascular risk Disclosure: The authors have no conflicts of interest to declare. Received: 20 March 2020 Accepted: 27 July 2020 Citation: European Cardiology Review 2020;15:e65. DOI: https://doi.org/10.15420/ecr.2020.10 Correspondence: Olga Mediano, Department of Respiratory Medicine, University Hospital, c/Donantes de Sangre s/n, Guadalajara 19002, Spain. E: omediano@sescam.jccm.es Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

The WHO has established that coronary artery and cerebrovascular disease represent the main causes of premature death and disability in developed countries.1 However, the incidence and prevalence of cardiovascular and cerebrovascular disease is also increasing in developing countries as a result of population ageing and changes in lifestyle. For these reasons, the prevention and treatment of cardiovascular disease continues to be one of the key objectives of global health policies. Health initiatives aimed at raising awareness about heart-healthy lifestyle habits and at controlling risk factors such as smoking, dyslipidaemia or arterial hypertension (AHT) are essential strategies in these campaigns. However, a better understanding of the causes of cardiovascular disease, as well as the identification and treatment of new risk factors, is also urgently needed. Recent evidence indicates that obstructive sleep apnoea (OSA) may be a potentially modifiable risk factor for vascular disease.

Sleep Apnoea Syndrome and Cardiovascular Disease Epidemiology, Diagnosis and Treatment OSA is a disorder characterised by snoring and presence of apnoea or obstructive hypopnoea due to the collapse of the upper airway (either partial or complete), accompanied by hypoxia, during sleep. Most of

these respiratory disturbances during sleep cause oxygen desaturations and resaturations and changes in intrathoracic pressure; they end with a micro-awakening, with the resulting fragmentation of sleep and the appearance of excessive daytime sleepiness, which is the most frequent symptom of this disorder. These episodes are assessed by using polysomnography to measure the apnoea–hypopnoea index (AHI), with an AHI ≥5 events/h being considered pathological. The AHI is used to define disease severity: scores of 5–14.9 are considered mild; scores of 15–29.9, moderate; and scores ≥30, severe. The prevalence of OSA has risen over time and varies according to study: depending on the cut-off point of the AHI used, it is currently estimated to affect 10% of men and 15% of women.2 The main risk factors for OSA are obesity, craniofacial or oropharyngeal anatomical abnormalities, male sex and smoking. It is important to stress that in subjects with several cardiovascular risk factors the prevalence of asymptomatic OSA is higher than in healthy adults of the same age and sex, and is unrelated to BMI. Consequently, if we take drowsiness or obesity as defining features of the OSA phenotype, its prevalence in patients with cardiovascular disease may be underestimated.3–5 Given that obesity is an important causative factor, the prevalence of OSA is likely to continue rising in line with the obesity rate. Diagnosis and treatment of OSA have increased in the

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Management and Comorbidities Table 1: Prospective Longitudinal Studies of Incident Hypertension in Patients with Obstructive Sleep Apnoea Authors

Study

Type of Study Patients Follow-up Comparisons (n) (Years)

Associations

Peppard et al. 200015

WSCS

Prospective

709

AHI <5 (versus 0) AHI 5–14.9 AHI ≥15

1.42 [1.13–1.78] 2.03 [1.29–3.17] 2.89 [1.46–5.64]

O’Connor et al. 200916

SHHS

Prospective

2,470

5.2

AHI 15–29.9 (versus 0–4.9) AHI ≥30

1.54 [1.12–2.11]* 2.19 [1.39–3.44]*

1.12 [0.80–1.56]† 1.51 [0.91–2.46]†

Cano-Pumarega et al. 201117

VSC

Prospective

1,180

7.5

RDI 3–6.9 (versus 0–2.9) RDI 7–13.9 RDI ≥14

1.49 [1.09–2.03] 1.84 [1.30–2.61] 2.61 [1.75–3.89]

1.09 [0.78–1.52]‡ 0.94 [0.64–1.39]‡ 1.00 [0.63–1.57]‡

Guillot et al. 201318

SYNAPSE

Prospective

372

AHI ≥30

2.21 [1.43–3.43]

1.77 [1.11–2.80]§

Marín et al. 201219

ZSCS

Prospective

1,889

12.2

Ineligible for CPAP (n=462) Declined CPAP (n=195) Non-adherent to CPAP (n=98) Treated with CPAP (n=824)

1.63 [1.25–2.12]||,¶ 2.89 [2.18–3.84]||,¶ 2.70 [1.90–3.83]||,¶ 1.47 [1.24–1.88]||,¶

1.46 [1.12–1.91]||,** 2.54 [1.90–3.39]||,** 2.20 [1.90–3.39]||,** 1.01 [0.78–1.31]||,**

Appleton et al. 201620

MAILES

Prospective

391

4.6

AHI ≥20 AHI ≥30

– –

1.95 [1.04–3.63]†† 2.24 [1.04–4.81]††

OR [95% CI]

Adjusted OR [95% CI]

*Adjusted for age, sex, race and time since baseline. †Adjusted for age, sex, race, time since baseline and BMI. ‡Adjusted for age, sex and BMI. §Adjusted for sex, obesity, type 2 diabetes and dyslipidaemia. ||HRs for new-onset hypertension (per 100 person-years). ¶Adjusted for AHI, age and sex. **Adjusted for AHI, age, sex, SBP/DBP and BMI. ††Adjusted for age, waist circumference, smoking, alcohol, AHINREM and weight gain over the follow-up period. AHI = apnoea–hypopnoea index; CPAP = continuous positive airway pressure; NREM = non-rapid eye movement; OSA = obstructive sleep apnoea; RDI = respiratory disturbance index; SBP/DBP = systolic/diastolic blood pressure.

last 5–10 years, but current evidence indicates that the disease remains undiagnosed in a high percentage of patients.6,7

than in patients undergoing CPAP or those who do not present severe OSA. 9–12

The first-line treatment for all patients with OSA is continuous positive airway pressure (CPAP). This technique provides pneumatic splinting of the upper airway, thus reducing airflow obstruction and apnoeic events. CPAP improves self-reported sleepiness and quality of life, but patient non-adherence may limit its clinical benefit.8

Hypertension and Cerebrovascular Disease

OSA and Cardiovascular Risk Studies in recent years have shown that OSA is an independent risk factor for hypertension and increases the risk of cardiovascular disease. The relationship between OSA and cardiovascular disease can be attributed, at least in part, to the coexistence of cardiovascular risk factors in the two pathologies such as sex, age, overweight, alcohol consumption, tobacco and sedentary lifestyle. The current evidence linking OSA with increased cardiovascular risk is strong. In this study, a search was performed to identify papers on the association between OSA and new-onset hypertension and cardiovascular adverse events in the PubMed database (MeSH: medical subject headings) using the following search strategy: ‘sleep apnoea, obstructive’ [MeSH] and ‘cardiovascular diseases’ [MeSH], with ‘hypertension’, ‘cardiovascular adverse events’, ‘atrial fibrillation’, ‘ischemic heart disease’, and ‘cardiovascular mortality’ as key words. The search was limited to prospective studies and recent metaanalyses. To assess the efficacy of CPAP for the primary and secondary prevention of cardiovascular adverse events, the following search strategy was applied: ‘sleep apnoea, obstructive’ [MeSH] and ‘continuous positive airway pressure’ [MeSH] and ‘cardiovascular diseases’ [MeSH] only in randomised controlled trials. After the electronic search the references cited were also reviewed. Observational (cross-sectional and longitudinal) epidemiological studies have consistently reported higher cardiovascular-related morbidity and mortality rates in patients with severe untreated OSA

AHT is the cardiovascular disease most clearly linked to OSA. Crosssectional population-based studies have consistently found higher rates of hypertension in patients with OSA than in controls, independent of potential confounders such as obesity and age.13 The Sleep Heart Health Study (SHHS) was designed to investigate the relationship between OSA and cardiovascular disease in 6,424 individuals (mean age 65 years) obtained from several cohorts of epidemiological studies of cardiovascular disease in the US.13 All subjects had cardiovascular risk factors and a complete sleep study at baseline. A linear relationship was observed between the severity of OSA, measured on AHI, and the prevalence of AHT, regardless of other factors.13 Approximately 50% of patients with OSA have high blood pressure, and up to 71% of patients with resistant hypertension have a diagnosis of OSA.14 Prospective clinical studies also demonstrate a high incidence of hypertension in patients with OSA and normal blood pressure at baseline, especially in those with severe OSA (Table 1).15–20 Recent meta-analyses suggest a dose–response relationship between OSA severity and the risk of essential hypertension, especially in male Caucasian patients.21,22 Other controlled studies have evaluated the effect of CPAP on blood pressure in patients with OSA and have demonstrated a significant reduction, suggesting a better response in subjects with severe OSA and excessive daytime sleepiness, resistant AHT, and greater adherence. Effective treatment of OSA, especially with CPAP, reduces blood pressure regardless of the baseline figures.23–25 The reduction in blood pressure with CPAP treatment is slight, but significant. In a meta-analysis of 1,820 OSA patients, CPAP treatment was associated with a significant reductions of 2.6 ± 0.6 mmHg in systolic blood pressure and 2.0 ± 0.4 mmHg in diastolic blood pressure.26 The reduction in blood pressure with CPAP is lower than with antihypertensive drugs, but their combined use in patients with resistant AHT can help to reduce it at a later stage.27 The

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Obstructive Sleep Apnoea Syndrome and Cardiovascular Risk antihypertensive effect of CPAP is greater in patients with more severe OSA and in patients with excessive daytime sleepiness.28,29

Cardiovascular Disease There is also evidence of a relationship between OSA and the development and progression of ischaemic heart disease (IHD), heart failure and arrhythmias. The prevalence of OSA in patients with IHD is higher than in the general population, and up to 70% of patients with acute coronary syndrome (ACS) have undiagnosed OSA. The presence of calcifications in the coronary arteries, a subclinical marker of atherosclerosis, was recorded in 67% of patients with OSA versus in 31% of patients without OSA.30 In addition, the SHHS demonstrated that the presence of obstructive apnoea increases the risk of CHD by 30%.13 OSA can induce IHD by various mechanisms: among others, by favouring coronary atherosclerosis through oxidative stress, systemic inflammation and endothelial dysfunction due to intermittent hypoxia. In addition, the increase in platelet activity and aggregation, as well as the reduction in fibrinolytic activity, together with the increase in fibrinogen in patients with OSA may favour coronary artery thrombosis, a pathogenic mechanism of ACS. The presence of OSA may worsen the prognosis of existing IHD. Several prospective observational studies conducted in patients with known IHD have observed an increased risk of cardiovascular events, including recurrent events, in patients with OSA versus subjects without OSA. In a multicentre study that included 1,311 patients undergoing percutaneous revascularisation with a follow-up of 1.9 years, patients with moderate or severe OSA (AHI ≥15) had (regardless of other confounding factors) a 1.5-fold higher risk (adjusted HR 1.57; 95% CI [1.10–2.24]; p=0.013) of an adverse cardiovascular or cerebrovascular event than revascularised patients without OSA.31 OSA has been identified as a possible risk factor for nocturnal cardiac ischaemic events. One study of patients with OSA and ACS reported the occurrence of ACS between 12 am and 6 am in 32% of cases, compared with only 7% in patients without OSA.32 The possible effects of OSA on the recovery of left ventricular systolic function after MI are controversial. It has been reported that, after acute MI, the presence of OSA compromises the recovery of left ventricular function by increasing and remodelling the area of extension of myocardial necrosis.33,34 The risk of recurrence of cardiovascular events after a heart attack is higher in patients with excessive daytime sleepiness, regardless of AHI and oxygen desaturation.35

Heart rhythm disorders have been described in patients with OSA, the most frequent arrhythmias being atrial and ventricular extrasystoles, sinus arrest and atrioventricular conduction block.42 Bradyarrhythmias are usually due to vagal activation that occurs at the end of the apnoeas mediated by hypoxic stimulation on the carotid body, and so the degree of bradycardia is linked to the severity of OSA and especially to the degree of hypoxaemia. Other types of arrhythmia such as AF or ventricular tachycardia usually occur in the context of an associated structural cardiac injury. However, the prevalence of cardiac arrhythmias in patients with OSA is not well known. In the SHHS, the presence of severe OSA (AHI ≥30) was associated with a fourfold increase in the risk of AF, a threefold increase in non-sustained ventricular tachycardia and a twofold increase in complex ventricular extrasystoles compared with subjects without OSA (AHI ≤5).43 In that study the risk of an arrhythmic episode was found to be 18-fold higher during a respiratory event than during normal breathing. A decrease in nocturnal oxygen saturation has been identified as a predictor of AF, independent of obesity.44 Patients with untreated OSA have a higher risk of recurrence of AF after cardioversion than treated patients, and an increased risk of pulmonary vein ablation failure.45 However, several studies demonstrate a higher prevalence of AF in patients with central and non-obstructive apnoeas, suggesting that it is heart failure, rather than OSA, that plays the leading role in this association.46

Cardiovascular Mortality Given the relationship between OSA and its possible clinical consequences, an association between OSA and mortality might be expected. There is sufficient evidence to state that severe OSA (AHI ≥30) is an independent risk factor for mortality. Cross-sectional and prospective population-based studies have also found an increase in cardiovascular mortality in patients with severe untreated OSA or with insufficient use of CPAP. A meta-analysis of cohort studies involving 24,308 participants found that the risk of cardiovascular mortality was threefold higher in patients with severe OSA (AHI ≥30) than in the control group without OSA (HR 2.96; 95% CI [1.45–6.01]; Table 2).47

Clinical Trials in Primary and Secondary Cardiovascular Prevention Clinical trials aiming primarily to assess the effect of CPAP treatment on the development of serious cardiovascular events associated with OSA are relatively recent, such that until now almost all the evidence came from observational studies. Several of these studies have found that treatment with CPAP reduces cardiovascular morbidity and mortality (defined as a set of different cardiovascular events including death due to cardiovascular causes, stroke, or acute MI).

Primary Cardiovascular Prevention OSA may induce or worsen an existing heart failure via various mechanisms regardless of the presence or absence of hypertension. The prevalence of OSA in patients with heart failure and reduced or preserved ejection fraction ranges from 11% to 55%, and the degree of dysfunction seems to be associated with the severity of OSA.36 Conversely, the prevalence of heart failure in patients with OSA may be more than twice that in patients without OSA.37 The SHHS noted an independent association between OSA and the risk of developing heart failure.13,38 A controversial issue is whether OSA increases mortality in patients with heart failure: some studies have found that OSA is an independent risk factor for mortality in patients with heart failure, whether ischaemic or not, while other studies have not demonstrated this association.39–41

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The study by Barbé et al. (the Spanish Sleep and Breathing Network; CERCAS) analysed 725 patients with moderate or severe OSA (AHI ≥20 on polysomnography or cardiorespiratory polygraphy) without daytime sleepiness (Epworth score ≤10) and without previous cardiovascular events.48 The authors studied the effect of CPAP on primary cardiovascular prevention by analysing the incidence of AHT (need for antihypertensive drugs or blood pressure >140/90 mmHg) or the development of non-fatal MI, non-fatal stroke, transient ischaemic attack (TIA), hospitalisation for unstable angina or arrhythmia, heart failure or cardiovascular death with a mean follow-up of 4 years (IQR 2.7–4.4 years). No differences were observed between patients randomised to CPAP and those to conservative treatment in terms of the incidence of AHT or cardiovascular events. However, a post-hoc

Management and Comorbidities Table 2: Meta-analyses of Incident Hypertension and Cardiovascular Events in Patients with Obstructive Sleep Apnoea Authors

Type of Study No. Studies

Patients Groups

Endpoint

Association Pooled RR [95% CI]

Hou et al. 201821

Meta-analysis

26 studies

51,623

Mild OSA (AHI ≥5) Moderate OSA (AHI ≥15) Severe OSA (AHI ≥30) OSA (AHI ≥5)

New-onset hypertension

Resistant hypertension

1.18 [1.09–1.27] 1.32 [1.20–1.43] 2.84 [1.70–3.98] 2.84 [1.70–3.98]

Xia et al. 201822

Meta-analysis

6 prospective and 6,098 1 case–control studies

AHI ≥5 versus AHI ≥30

New-onset hypertension

1.77 [1.30–2.41]

16 cohort studies (11 studies in primary prevention)

24,308

Severe OSA (AHI ≥30)

CHD Stroke Heart failure CV mortality All-cause mortality

1.63 [1.18–2.26] 2.15 [1.42–3.24] 1.44 [0.94–2.21] 2.96 [1.45–6.01] 1.54 [1.21–1.97]

Hypertension

Cardiovascular Disease Xie et al. 201747

Meta-analysis

Prevention Studies (CPAP) da Silva and Zhang 201955

Meta-analysis

9 RCTs

3,314

CPAP versus control

MI Stroke CV mortality All-cause mortality

1.11 [0.76–1.62] 0.77 [0.46–1.28] 0.58 [0.19–1.74] 0.86 [0.60–1.23]

Khan et al. 201856

Meta-analysis

7 RCTs

4,268

CPAP versus control

MACE* MACE* (≥4 h/night of CPAP use) AF/AFl MI Stroke CV mortality All-cause mortality

0.74 [0.47–1.17] 0.43 [0.23–0.80] 0.87 [0.38–1.97] 0.99 [0.57–1.72] 0.95 [0.72–1.24] 0.70 [0.27–1.80] 0.95 [0.67–1.34]

Deng et al. 201845

Meta-analysis

10 studies (3 RCTs)

1,217

CPAP versus control

Recurrent AF (after catheter ablation)

0.60 [0.51–0.70]

Non-fatal MI, stroke and cardiovascular mortality. AFl = atrial flutter; AHI = apnoea–hypopnoea index; CPAP = continuous positive airway pressure; CV = cardiovascular; MACE = major adverse cardiovascular events; OSA = obstructive sleep apnoea; RCT = randomised controlled trial; TIA = transient ischaemic attack. *

sub-analysis suggested that CPAP reduces the incidence of AHT and cardiac events in patients with adherence to treatment ≥4 h/night (incidence density ratio 0.75; 95% CI [0.52–0.98]).

Secondary Cardiovascular Prevention The effect of CPAP treatment on cardiovascular secondary prevention in patients with OSA has been analysed in other randomised clinical trials (Table 3).24,49–54 In the Randomized Intervention with Continuous Positive Airway Pressure in Coronary Artery Disease and Obstructive Sleep Apnea (RICCADSA) study, 244 patients with moderate or severe OSA (AHI ≥15) without daytime sleepiness (Epworth score <10) underwent coronary revascularisation and were randomised to CPAP or conservative treatment for 57 months.52 On intention-to-treat analysis, there were no differences between the two groups in the combined primary cardiovascular endpoint of repeat revascularisation, MI, stroke and cardiovascular mortality. However, patients with adherence ≥4 h/day had a lower cardiovascular risk than untreated patients or those receiving CPAP <4 h/day (HR 0.29; 95% CI [0.10–0.86]). As with the results on the efficacy of CPAP in primary cardiovascular prevention, poor adherence to CPAP treatment affects therapeutic response in patients with OSA. The Sleep Apnea Cardiovascular Endpoints (SAVE) study randomised 2,717 patients aged between 45 and 75 with established cardiovascular or cerebrovascular disease and moderate or severe OSA to usual care or usual care plus CPAP.53 Moderate or severe OSA was defined as an oxygen desaturation index (number of times per hour that the oximetry recording detects a decrease in arterial oxygen saturation ≥4

percentage points from baseline) of at least 12, determined using a home sleep study device (ApneaLink, ResMed). The primary composite endpoint included death from cardiovascular cause, MI (including silent MI), stroke, hospitalisation for heart failure, acute coronary symptoms (including unstable angina) or TIA. The use of CPAP did not significantly reduce recurrent serious cardiovascular events in the intention-to-treat analysis, despite the significant reduction in daytime sleepiness and improved quality of life. However, propensity score-matched analyses showed that patients with good adherence to CPAP treatment (≥4 h/ day) had a lower risk of stroke compared with patients with conventional treatment (HR 0.56; 95% CI [0.32–1.00]), as well as a lower risk of the non-pre-specified composite endpoint of cerebrovascular events (HR 0.52; 95% CI [0.30–0.90]). The recently published Continuous Positive Airway Pressure in Patients with Acute Coronary Syndrome and Obstructive Sleep Apnea (ISAACC) study included 2,834 patients with ACS who underwent respiratory polygraphy.54 Of these, 1,264 had moderate or severe OSA (AHI ≥15/h as measured on cardiorespiratory polygraphy) and were randomly assigned to receive CPAP or usual care. The 1,287 patients with ACS, but without OSA (AHI <15/h) were included as a reference group. The primary endpoint of the study was the development of a composite of cardiovascular events (cardiovascular death or acute MI, stroke, hospital admission due to heart failure, unstable angina or TIA). After a follow-up of 3.35 years, the incidence of cardiovascular events was similar in the two groups (CPAP: 16%; usual care: 17%; HR 0.89; 95% CI [0.68–1.17]). The median adherence to CPAP treatment was 2.78 h/ night. No differences were found in the incidence of cardiovascular

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Obstructive Sleep Apnoea Syndrome and Cardiovascular Risk Table 3: Trials of Obstructive Sleep Apnoea Patients with CPAP in Primary and Secondary Prevention of Cardiovascular Adverse Events Authors

Study

Patients (n, Eligible CPAP versus Patients Controls)

Follow-up Diagnosis (months) of OSA

Groups

Primary Outcome

Results

Secondary Analysis

Primary Prevention Barbé et al. 201248

CERCAS

357/366

Apparently 48 healthy patients

AHI ≥20 + ESS ≤10

CPAP versus control

Incident hypertension or MACE

0.83 (0.63–1.1)

≥4 h/night: OR 0.75 (95% CI [0.52–0.98])

Secondary Prevention Gottlieb et al. 201424

HeartBEAT

97/94

CVD or multiple 3 CV risk factors

AHI 15–50

CPAP versus NSO

24-h mean arterial pressure at 12 weeks

−2.8 mmHg; p=0.02

−0.93 mmHg/h of CPAP use (p=0.03)

McMillan et al. 201449

PREDICT

140/138

Age ≥65 years (CV comorbidity*)

ODI ≥7.5/h (≥4%) + ESS ≥9

CPAP versus control

ESS at 3 months

ESS decreased 2.1 points (p<0.0001)

QALYs (p=0.787)

Huang et al. 201550

–

36/37

Uncontrolled hypertension and CAD.

AHI ≥15

CPAP versus control

Controlled hypertension

69.4% versus 43.2% (p=0.02)

Reduced ESS in CPAP group (p<0.001)

Parra et al. 201551

–

71/69

Acute ischaemic 60 stroke

AHI ≥20

nCPAP versus control

MACE†

CV survival: 100% CV event-free versus 89.9% survival: 89.5% (p=0.015) versus 75.4% (p=0.059)

Peker et al. 201652

RICCADSA

122/122

Revascularised CAD

AHI ≥15 + ESS <10

CPAP versus control

MACE‡

HR 0.80 (95% CI [0.46–1.41])

≥4 h/night: HR 0.29 (95% CI [0.10–0.86])

McEvoy et al. 201653

SAVE

1,346/1,341

CVD

ODI ≥12 CPAP versus (≥4%) + ESS ≤15 control

MACE§

HR 1.10 (95% CI [0.91–1.32])

≥4 h/night: HR 0.52 (95% CI [0.30–0.90]) for cerebral events

633/631

ACS

40.2

AHI ≥15 + ESS ≤10

MACE||

HR 0.89 (95% CI [0.68–1.17])

≥4 h/night: 0.80 (95% CI [0.52–1.23])

Sánchez-de- ISAACC la-Torre et al. 202054

CPAP versus control

* Comorbidity in 8–75% of patients (i.e. ischaemic heart disease 36%, hypertension 75% and AF 30%). †Ischaemic events, stroke recurrence and CV mortality. ‡First event of repeat revascularisation, MI, stroke or CV mortality. §CV mortality, MI, stroke or hospitalisation for unstable angina, heart failure or TIA.||Cardiovascular death or non-fatal events (acute MI, stroke, hospital admission for heart failure, and new hospitalizations for unstable angina or transient ischaemic attack). ACS = acute coronary syndrome; AHI = apnoea–hypopnoea index; CAD = coronary artery disease; CPAP = continuous positive airway pressure; CV = cardiovascular; CVD = cardiovascular disease; ESS = Epworth sleepiness score; MACE = major adverse cardiovascular events; nCPAP = nasal CPAP; NSO = nocturnal supplement oxygen; ODI = oxygen desaturation index; OSA = obstructive sleep apnoea; QALY = quality-adjusted life years; RCT = randomised controlled trial; TIA = transient ischaemic attack.

events in the usual care group versus the reference group without OSA (17% and 15%, respectively). Nor was there an association between the number of cardiovascular events and the hours of CPAP adherence or the severity of OSA. CPAP treatment was associated with a modest improvement in daytime sleepiness and blood pressure, but not with any improvement in quality of life. The fundamental difference between the SAVE and the ISAACC studies concerns the samples used. While the SAVE study included patients with chronic coronary or cerebrovascular disease, the patients in the ISAACC study were in the acute phase of CHD.53,54 Both studies found that treatment with CPAP did not reduce cardiovascular risk in patients with asymptomatic OSA, and highlight the lack of any significant effect of CPAP in secondary cardiovascular prevention.53,54 Two recent metaanalyses also confirm that CPAP does not improve survival or prevent the development of major cardiovascular events in patients with OSA.55,56 There may be several explanations for this. First, poor adherence to CPAP treatment is an important limitation in all studies. The average use is less than 4 h/night, due at least in part to the patients’ low level of symptoms (patients with a high level of

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symptoms were not included for ethical reasons). Perhaps better results would have been recorded if patients with more symptoms had been included, given that excessive daytime sleepiness is a sign of disease severity. For example, the effect of CPAP on blood pressure is greater in patients with more symptoms. However, at present, we cannot claim that better adherence would have produced different results. Factors influencing adherence to CPAP therapy need to be identified, and the issue of whether better adherence improves cardiovascular endpoints needs to be investigated in greater depth.57 Second, the reference procedure for the diagnosis of OSA is polysomnography. AHI is the score used to determine severity, but it may not fully reflect the complexity of the disease. It is common to see patients with low AHI with AHT and high levels of symptoms, and it is also quite common to see patients with AHI >30/h and very low levels of symptoms. AHI does not take into account important aspects of respiratory events such as the magnitude of the associated desaturation or the presence of awakenings. This means that it is likely to include very heterogeneous patients with different disease phenotypes, a circumstance that may explain the negative results. The use of new diagnostic and/or prognostic criteria in patients with OSA that allow

Management and Comorbidities better risk stratification, as well as the use of biomarkers able to identify subgroups of patients with OSA with a high risk of cardiovascular or metabolic events, might facilitate reassessment of the role and efficacy of OSA treatment in both primary and secondary prevention.58 Third, the treatment of OSA with CPAP may not be effective in reducing recurrent cardiovascular events in patients with advanced or symptomatic atherosclerotic vascular disease, such as the patients included in the SAVE and ISAACC studies. Reversing or stabilising an altered vascular structure is more difficult than preventing its initial alteration, therefore the results of these studies do not rule out the possible effect of OSA treatment on primary prevention.57 Moreover, the ischaemic preconditioning generated by the nocturnal cycles of hypoxia–reoxygenation has been considered as one of the causes of the decrease in cardiovascular and cerebrovascular mortality in elderly patients with OSA and may be involved in some way in this apparent lack of efficacy of CPAP in secondary prevention.59 Fourth, it has recently been suggested that the design and development of clinical trials that analyse the hypothetical efficacy of OSA treatment in cardiovascular prevention need to be modified.60 The changes proposed include the modification of the inclusion criteria for patients with OSA to recruit patients with greater severity of disease; the improvement of the diagnostic criteria for asymptomatic OSA; and the inclusion of criteria for arterial oxygen desaturation, bearing in mind that the hypoxaemic burden is considered the main mediator in the increased risk of morbidity and mortality in patients with OSA. The identification and exclusion of patients with OSA with low adherence to CPAP treatment has also been suggested, as has the use of alternative (or complementary) statistical techniques to the intention-to-treat analysis, although this might underestimate the hypothetical efficacy of CPAP by including patients with low adherence. CPAP can reduce various inflammatory biomarkers involved in the onset, progression and instability of atherosclerotic cardiovascular disease and which are elevated in patients with OSA, such as C-reactive protein, tumour necrosis factor alpha, interleukin (IL) 6, IL-8, intercellular adhesion molecule, vascular cell adhesion molecule and selectins.61 In spite of this,

Murray CJL, Lopez AD, eds. The Global Burden of Disease: A comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. Cambridge, MA: Harvard School of Public Health on behalf of the WHO and World Bank, 1996. Heinzer R, Vat S, Marques-Vidal P, et al. Prevalence of sleepdisordered breathing in the general population: the HypnoLaus study. Lancet Respir Med 2015,3:310–8. https://doi.org/10.1016/ S2213-2600(15)00043-0; PMID: 25682233. Kasai T, Floras JS, Bradley TD. Sleep apnea and cardiovascular disease: a bidirectional relationship. Circulation 2012;126:1495– 510. https://doi.org/10.1161/CIRCULATIONAHA.111.070813; PMID: 22988046. Taylor KS, Murai H, Millar PJ, et al. Arousal from sleep and sympathetic excitation during wakefulness. Hypertension 2016;68:1467–747. https://doi.org/10.1161/ HYPERTENSIONAHA.116.08212; PMID: 27698070. Flemons WW, Douglas NJ, Kuna ST, et al. Access to diagnosis and treatment of patients with suspected sleep apnea. Am J Respir Crit Care Med 2004;169:668–72. https://doi.org/10.1164/ rccm.200308-1124PP; PMID: 15003950. Hiestand DM, Britz P, Goldman M, et al. Prevalence of symptoms and risk of sleep apnea in the US population: results from the National Sleep Foundation in America 2005 poll. Chest 2006;130:780–6. https://doi.org/10.1378/ chest.130.3.780; PMID: 16963675. Reuveni H, Tarasiuk A, Wainstock T, et al. Awareness level of obstructive sleep apnea syndrome during routine unstructured interviews of a standardized patient by primary care physicians. Sleep 2004;27:1518–25. https://doi. org/10.1093/sleep/27.8.1518; PMID: 15683143. Tietjens JR, Claman D, Kezirian EJ, et al. Obstructive sleep

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and although it may cause some degree of haemodynamic improvement (by increasing left ventricular ejection fraction) and may even prevent arrhythmias, in clinical studies these potential effects have not been converted into a significant reduction in recurrent cardiovascular events in patients with established cardiovascular disease. More studies are needed to establish the true role of CPAP treatment in patients with OSA in both primary and secondary prevention.

Clinical Recommendations Patients who present two of the three cardinal criteria of OSA (snoring, apnoea and/or daytime sleepiness or tiredness) should be referred to the sleep disorders unit and OSA should also be considered in the differential diagnosis of bradyarrhythmia.62 Although the clinical utility of CPAP in secondary cardiovascular prevention has not been demonstrated, the SAVE study recorded an improvement in daytime sleepiness and a reduction in days off work, even in patients initially considered asymptomatic.52 For this reason, physicians should ask specifically about the presence of symptoms suggestive of OSA as part of the routine clinical assessment of patients with cardiovascular pathology.

Conclusion Epidemiological and clinical evidence indicates that OSA may be a potentially modifiable risk factor for arterial vascular disease. OSA has been associated with a higher incidence of hypertension and cardiovascular disease. However, clinical trials on the efficacy of CPAP in primary and secondary cardiovascular prevention have not demonstrated a significant reduction in the incidence and/or recurrence of cardiovascular events. A number of measures are now needed to shed more light on the relationship between OSA, treatment with CPAP and vascular risk: the use of new diagnostic and/or prognostic criteria to improve the clinical stratification of patients with OSA; the identification of variables associated with better adherence to CPAP treatment; the development of new therapeutic techniques for patients with OSA; the use of biomarkers that identify subgroups of patients with OSA with greater vascular or metabolic risk and make it possible to intervene in subclinical phases of atherosclerotic disease; and the modification of the design and development of clinical trials that analyse cardiovascular risk in patients with OSA treated with CPAP.

apnea in cardiovascular disease: a review of the literature and proposed multidisciplinary clinical management strategy. J Am Heart Assoc 2019;8:e010440. https://doi.org/10.1161/ JAHA.118.010440; PMID: 30590966. Wolk R, Kara T, Somers VK. Sleep-disordered breathing and cardiovascular disease. Circulation 2003;108:9–12. https://doi. org/10.1161/01.CIR.0000072346.56728.E4; PMID: 12847053. Quan SF, Gersh BJ. Cardiovascular consequences of sleepdisordered breathing: past, present and future. Report of a workshop from the National Center on Sleep Disorders Research and the National Heart, Lung, and Blood Institute. Circulation 2014;109:951–7. https://doi.org/10.1161/01. CIR.0000118216.84358.22; PMID: 14993147. Marin JM, Carrizo SJ, Vicente E, et al. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046–53. https://doi.org/10.1016/S0140-6736(05)71141-7; PMID: 15781100. Sánchez-de-la-Torre M, Campos-Rodriguez F, Barbe R. Obstructive sleep apnoea and cardiovascular disease. Lancet Respir Med 2013;1:61–72. https://doi.org/10.1016/S22132600(12)70051-6; PMID: 24321805. Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163:19–25. https://doi.org/10.1164/ajrccm.163.1.2001008; PMID: 11208620. Gonçalves SC, Martinez D, Gus M, et al. Obstructive sleep apnea and resistant hypertension: a case-control study. Chest 2007;132:1858–62. https://doi.org/10.1378/chest.07-1170; PMID: 18079220.

15. Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–84. https://doi. org/10.1056/NEJM200005113421901; PMID: 10805822. 16. O’Connor GT, Caffo B, Newman AB, et al. Prospective study of sleep-disordered breathing and hypertension: the Sleep Heart Health Study. Am J Respir Crit Care Med 2009;179:1159–64. https://doi.org/10.1164/rccm.200712-1809OC; PMID: 19264976. 17. Cano-Pumarega I, Durán-Cantolla J, Aizpuru F, et al. Obstructive sleep apnea and systemic hypertension: longitudinal study in the general population: the Vitoria Sleep Cohort. Am J Respir Crit Care Med 2011;184:1299–304. https:// doi.org/10.1164/rccm.201101-0130OC; PMID: 21868499. 18. Guillot M, Sforza E, Achour-Crawford E, et al. Association between severe obstructive sleep apnea and incident arterial hypertension in the older people population. Sleep Med 2013;14:838–42. https://doi.org/10.1016/j.sleep.2013.05.002; PMID: 23831239. 19. Marin JM, Agusti A, Villar I, et al. Association between treated and untreated obstructive sleep apnea and risk of hypertension. JAMA 2012;307:2169–76. https://doi.org/ 10.1001/jama.2012.3418; PMID: 22618924. 20. Appleton SL, Vakulin A, Martin SA, et al. Hypertension is associated with undiagnosed OSA during rapid eye movement sleep. Chest 2016;150:495–505. https://doi.org/10.1016/j. chest.2016.03.010; PMID: 27001264. 21. Hou H, Zhao Y, Yu W, et al. Association of obstructive sleep apnea with hypertension: a systematic review and metaanalysis. J Glob Health 2018;8:010405. https://doi.org/10.7189/ jogh.08.010405; PMID: 29497502. 22. Xia W, Huang Y, Peng B, et al. Relationship between obstructive sleep apnoea syndrome and essential hypertension: a dose-

EUROPEAN CARDIOLOGY REVIEW

Obstructive Sleep Apnoea Syndrome and Cardiovascular Risk

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

response meta-analysis. Sleep Med 2018;47:11–8. https://doi. org/10.1016/j.sleep.2018.03.016; PMID: 29880142. Martínez-García MA, Capote F, Campos-Rodríguez F, et al. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial. JAMA 2013;310:2407–15. https://doi. org/10.1001/jama.2013.281250; PMID: 24327037. Gottlieb DJ, Punjabi NM, Mehra R, et al. CPAP versus oxygen in obstructive sleep apnea. N Engl J Med 2014;370:2276–85. https://doi.org/10.1056/NEJMoa1306766; PMID: 24918372. Montesi SB, Edwards BA, Malhotra A, Bakker JP. The effect of continuous positive airway pressure treatment on blood pressure: a systematic review and meta-analysis of randomized controlled trials. J Clin Sleep Med 2012;8:587–96. https://doi.org/10.5664/jcsm.2170; PMID: 23066375. Fava C, Dorigoni S, Dalle Vedove F, et al. Effect of CPAP on blood pressure in patients with OSA/hypopnea: a systematic review and meta-analysis. Chest 2014;145:762–71. https://doi. org/10.1378/chest.13-1115; PMID: 24077181. Pépin JL, Tamisier R, Barone-Rochette G, et al. Comparison of continuous positive airway pressure and valsartan in hypertensive patients with sleep apnea. Am J Respir Crit Care Med 2010;182:954–60. https://doi.org/10.1164/rccm.2009121803OC; PMID: 20522795. Barbé F, Durán-Cantolla J, Capote F, et al. Long-term effect of continuous positive airway pressure in hypertensive patients with sleep apnea. Am J Respir Crit Care Med 2010;181:718–26. https://doi.org/10.1164/rccm.200901-0050OC; PMID: 20007932. Barbé F, Mayoralas LR, Duran J, et al. Treatment with continuous positive airway pressure is not effective in patients with sleep apnea but no daytime sleepiness. a randomized, controlled trial. Ann Intern Med 2001;134:1015–23. https://doi. org/10.7326/0003-4819-134-11-200106050-00007; PMID: 11388814. Sorajja D, Gami AS, Somers VK, et al. Independent association between obstructive sleep apnea and subclinical coronary artery disease. Chest 2008;133:927–33. https://doi.org/10.1378/ chest.07-2544; PMID: 18263678. Lee CH, Sethi R, Li R, et al. Obstructive sleep apnea and cardiovascular events after percutaneous coronary intervention. Circulation 2016;133:2008–17. https://doi. org/10.1161/CIRCULATIONAHA.115.019392; PMID: 27178625. Kuniyoshi FHS, Garcia-Touchard A, Gami AS, et al. Day-night variation of acute myocardial infarction in obstructive sleep apnea. J Am Coll Cardiol 2008;52:343–46. https://doi. org/10.1016/j.jacc.2008.04.027; PMID: 18652941. Buchner S, Eglseer M, Debl K, et al. Sleep disordered breathing and enlargement of the right heart after myocardial infarction. Eur Respir J 2015;45:680–90. https://doi.org/10.1183/ 09031936.00057014; PMID: 25359347. Buchner S, Satzl A, Debl K, et al. Impact of sleepdisordered breathing on myocardial salvage and infarct size in patients with acute myocardial infarction. Eur Heart J 2014;35:192–9. https://doi.org/10.1093/eurheartj/eht450; PMID: 24164862. Xie J, Sert Kuniyoshi FH, Covassin N, et al. Excessive daytime sleepiness independently predicts increased cardiovascular risk after myocardial infarction. J Am Heart Assoc 2018;7:e007221. https://doi.org/10.1161/JAHA.117.007221; PMID: 29352093. Arias MA, García-Río F, Alonso-Fernández A, et al. Obstructive sleep apnea syndrome affects left ventricular diastolic function: effects of nasal continuous positive airway pressure

EUROPEAN CARDIOLOGY REVIEW

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

in men. Circulation 2005;112:375–83. https://doi.org/10.1161/ CIRCULATIONAHA.104.501841; PMID: 16009798. Lyons OD, Bradley TD. Heart failure and sleep apnea. Can J Cardiol 2015;31:898–908. https://doi.org/10.1016/j. cjca.2015.04.017; PMID: 26112300. Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the Sleep Heart Health Study. Circulation 2010;122:352–60. https://doi.org/10.1161/ CIRCULATIONAHA.109.901801; PMID: 20625114. Yumino D, Wang H, Floras JS, et al. Relationship between sleep apnoea and mortality in patients with ischaemic heart failure. Heart 2009;95:819–24. https://doi.org/10.1136/hrt.2008.160952; PMID: 19131443. Wang H, Parker JD, Newton GE, et al. Influence of obstructive sleep apnea on mortality in patients with heart failure. J Am Coll Cardiol 2007;49:1625–31. https://doi.org/10.1016/j. jacc.2006.12.046; PMID: 17433953. Roebuck T, Solin P, Kaye DM, et al. Increased long-term mortality in heart failure due to sleep apnoea is not yet proven. Eur Respir J 2004;23:735–40. https://doi.org/10.1183/09 031936.04.00060404; PMID: 15176689. Hersi AS. Obstructive sleep apnea and cardiac arrhythmias. Ann Thorac Med 2010;5:10–7. https://doi.org/10.4103/18171737.58954; PMID: 20351955. Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing: the Sleep Heart Health Study. Am J Respir Crit Care Med 2006;173:910–16. https://doi.org/10.1164/rccm.200509-1442OC; PMID: 16424443. Gami AS, Hodge DO, Herges RM, et al. Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol 2007;49:565–71. https://doi.org/10.1016/j. jacc.2006.08.060; PMID: 17276180. Deng F, Raza A, Guo J. Treating obstructive sleep apnea with continuous positive airway pressure reduces risk of recurrent atrial fibrillation after catheter ablation: a meta-analysis. Sleep Med 2018;46:5–11. https://doi.org/10.1016/j.sleep.2018.02.013; PMID: 29773211. Mehra R, Stone KL, Varosy PD, et al. Nocturnal arrhythmias across a spectrum of obstructive and central sleep-disordered breathing in older men: outcomes of sleep disorders in older men (MrOS sleep) study. Arch Intern Med 2009;169:1147–55. https://doi.org/10.1001/archinternmed.2009.138; PMID: 19546416. Xie C, Zhu R, Tian Y, Wang K. Association of obstructive sleep apnoea with the risk of vascular outcomes and all-cause mortality: a meta-analysis. BMJ Open 2017;7:e013983. https:// doi.org/10.1136/bmjopen-2016-013983; PMID: 29275335. Barbé F, Durán-Cantolla J, Sánchez-de-la-Torre M, et al; Spanish Sleep And Breathing Network. Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial. JAMA 2012;307:2161– 8. https://doi.org/10.1001/jama.2012.4366; PMID: 22618923. McMillan A, Bratton DJ, Faria R, et al. Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicentre, randomised trial. Lancet Respir Med 2014;2:804–12. https://doi.org/10.1016/ S2213-2600(14)70172-9; PMID: 25172769. Huang Z, Liu Z, Luo Q, et al. Long-term effects of continuous positive airway pressure on blood pressure and prognosis in hypertensive patients with coronary heart disease and obstructive sleep apnea: a randomized controlled trial. Am J

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

Hypertens 2015;28:300–6. https://doi.org/10.1093/ajh/hpu147; PMID: 25125635. Parra O, Sánchez-Armengol Á, Capote F, et al. Efficacy of continuous positive airway pressure treatment on 5-year survival in patients with ischaemic stroke and obstructive sleep apnea: a randomized controlled trial. J Sleep Res 2015;24:47–53. https://doi.org/10.1111/jsr.12181; PMID: 25040553. Peker Y, Glantz H, Eulenburg C, et al. Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with nonsleepy obstructive sleep apnea. The RICCADSA randomized controlled trial. Am J Respir Crit Care Med 2016;194:613–20. https://doi.org/10.1164/rccm.2016010088OC; PMID: 26914592. McEvoy RD, Antic NA, Heeley E, et al. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med 2016;375:919–31. https://doi.org/10.1056/NEJMoa1606599; PMID: 27571048. Sánchez-de-la-Torre M, Sánchez-de-la-Torre A, Bertran S, et al. Effect of obstructive sleep apnoea and its treatment with continuous positive airway pressure on the prevalence of cardiovascular events in patients with acute coronary syndrome (ISAACC study): a randomised controlled trial. Lancet Respir Med 2020;8:359–67. https://doi.org/10.1016/ S2213-2600(19)30271-1; PMID: 31839558. da Silva Paulitsch F, Zhang L. Continuous positive airway pressure for adults with obstructive sleep apnea and cardiovascular disease: a meta-analysis of randomized trials. Sleep Med 2019;54:28–34. https://doi.org/10.1016/j. sleep.2018.09.030; PMID: 30529774. Khan SU, Duran CA, Rahman H, et al. A meta-analysis of continuous positive airway pressure therapy in prevention of cardiovascular events in patients with obstructive sleep apnoea. Eur Heart J 2018;39:2291–7. https://doi.org/10.1093/ eurheartj/ehx597; PMID: 29069399. Van Ryswyk E, Anderson CS, Antic NA, et al. Predictors of long-term adherence to continuous positive airway pressure in patients with obstructive sleep apnea and cardiovascular disease. Sleep 2019;42:zsz152. https://doi.org/10.1093/sleep/ zsz152; PMID: 31587046. Heinzer R, Eckert D. Treatment for obstructive sleep apnoea and cardiovascular diseases: are we aiming at the wrong target? Lancet Respir Med 2020;8:323–5. https://doi.org/10.1016/S2213-2600(19)30351-0; PMID: 31839559. Lavie L, Lavie P. Ischemic preconditioning as a possible explanation for the age decline relative mortality in sleep apnea. Med Hypotheses 2006;66:1069–73. https://doi. org/10.1016/j.mehy.2005.10.033; PMID: 16513285. Javaheri S, Martinez-Garcia MA, Campos-Rodriguez F. CPAP treatment and cardiovascular prevention. We need to change the design and implementation of our trials. Chest 2019;156:431–7. https://doi.org/10.1016/j.chest.2019.04.092; PMID: 31075218. Nadeem R, Molnar J, Madbouly EM, et al. Serum inflammatory markers in obstructive sleep apnea: a meta-analysis. J Clin Sleep Med 2013;9:1003–12. https://doi.org/10.5664/jcsm.3070; PMID: 24127144. Priori SG, Blomström-Lundqvist C, Mazzani A, et al. 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J 2015;36:2793–867. https://doi.org/10.1714/2174.23496; PMID: 27029760.

COVID-19

Coronavirus Disease 2019 and Cardiac Arrhythmias Antoni Martínez-Rubio, Soledad Ascoeta, Fadwa Taibi and Josep Guindo Soldevila Department of Cardiology, Parc Taulí University Hospital and Institut d’Investigació i Innovació I3PT, Universitat Autònoma de Barcelona, Sabadell, Barcelona, Spain

Abstract The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a very contagious virus, has led to the coronavirus disease 2019 (COVID-19) pandemic. The clinical manifestations of this virus in humans vary widely, from asymptomatic to severe, with diverse symptomatology and even death. The substantial transmission from asymptomatic people has facilitated the widespread transmission of SARS-CoV-2, hampering public health initiatives to identify and isolate infected people during the pre-symptomatic contagious period. COVID-19 is associated with cardiac complications that can progress from mild to life-threatening. The aim of this article is to analyse the present knowledge of COVID-19 and cardiac involvement, the development of arrhythmia risk and its treatment.

Keywords Anti-arrhythmic drug, arrhythmia, coronavirus, COVID-19, infection, SARS-CoV-2, sudden death Disclosure: The authors have no conflicts of interest to declare. Received: 24 May 2020 Accepted: 4 August 2020 Citation: European Cardiology Review 2020;15:e66. DOI: https://doi.org/10.15420/ecr.2020.23 Correspondence: Antoni Martínez-Rubio, Parc Taulí University Hospital (Autonomous University of Barcelona), Department of Cardiology, Parc Taulí 1, E-08208 Sabadell, Barcelona, Spain. E: amartinezrubio@icloud.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

In the last months of 2019 and the beginning of 2020, a novel disease appeared, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a very contagious virus, which causes coronavirus disease 2019 (COVID-19). The clinical manifestations of this virus in humans vary widely from asymptomatic to severe, with diverse symptomatology and even death. The substantial transmission from asymptomatic people has facilitated the widespread transmission of SARS-CoV-2 and contributed to its pandemic potential, thereby hampering public health initiatives to identify and isolate infected people and the estimation of overall infectivity in the general population. Thus, containment measures aimed solely at isolating symptomatic individuals are inadequate. Specifically, potentially exposed people during the pre-symptomatic contagious period need to be identified and isolated for fast interruption of the transmission process. COVID-19 is associated with cardiac complications that can progress from mild to life-threatening. The aim of this review is to analyse the present knowledge of COVID-19 regarding arrhythmia risk and its treatment.

Basic Virology Data The Coronaviridae constitute a family of enveloped, single-stranded, positive-sense, RNA viruses with a characteristic crown, or corona, of electron density seen on transmission electron microscopy. The lifecycle of SARS-CoV-2 is presumed to be similar to SARS-CoV-1 and other coronaviruses.1 SARS-CoV-2 spreads primarily through small respiratory droplets from infected individuals that can travel approximately 1–2 m. Live virus has also been isolated and cultured from faecal specimens, raising the possibility of orofaecal transmission, although clinical evidence for this mode of transmission is lacking.2 The virus can exist in nature on surfaces from hours to several days.3 Several aspects of SARSCoV-2 remain unknown and are under intensive investigation globally.

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SARS-CoV-2 is known to bind to cells via the membrane-bound glycoprotein angiotensin-converting enzyme 2 (ACE2).1 Thus, the role of the ACE2 molecule has been the subject of attention, given that it has a very broad expression in humans (e.g. type II pneumocytes, myocardium and endothelium). At this time, it is unclear if the use of ACE inhibitors or angiotensin receptor blockers (ARB) influences receptor expression, thereby affecting the propensity or severity of SARS-CoV-2 infection. However, in a case-population study from seven Spanish hospitals, analysing data from 1,139 cases (aged 18 years or older with a PCRconfirmed diagnosis of COVID-19 requiring admission) and 11,390 population controls, renin–angiotensin–aldosterone system inhibitors did not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, suggesting that they and should not be discontinued to prevent a severe case of COVID-19.4 Major societies have recommended continuation of ACE inhibitor or ARB therapy in patients with a previous indication for these drugs.5,6

Symptomatology The largest (n=72,314) published registry of COVID-19 patients reported high-level details for putative (47%) and confirmed (63%) COVID-19 cases.7 In this population, predominantly identified by the presence of symptoms (approximately 99%), age plays a major role in the infection rate and also in the prognosis and <2% of cases occurred in individuals <19 years of age. Of confirmed cases, most (81%) were mild, 14% were severe with significant pulmonary infiltrates or signs of respiratory compromise, and 5% were critical with respiratory failure (e.g. mechanical ventilation), shock or multiorgan system failure. The estimated case fatality rate was <1% in patients <50 years; 1.3% in those aged 50–59 years; 3.6% for 60–69 years, 8% for 70–79 years, and 14.8% in those aged ≥80 years.7

COVID-19 and Cardiac Arrhythmias Figure 1: Pathophysiological Mechanisms of Cardiovascular Effects in Coronavirus Disease 2019 Infection COVID-19 infection

Heart (myocytes)

Cell damage

Respiratory system (type II pneumocytes)

Electrical conduction abnormalities

Fulminant myocarditis

Respiratory failure

Systemic inflammation Cytokine release (IL6, IL7, CXCL10)

Hypoxaemia

Plaque rupture

Vascular system (pericytes and endothelial cells)

Micro and macrovascular dysfunction

Hypercoagulability

Sympathetic surge

Arrhythmia

Acute coronary syndrome

Drug COVID-19 = coronavirus disease 2019; IL = interleukin.

The most common symptoms are fever in up to 90%, followed by cough, fatigue, sputum production and shortness of breath.8 Less common symptoms include headache, myalgia, sore throat, nausea, vomiting, and diarrhoea, but anosmia and dysgeusia have also been described. Blood abnormalities include lymphopenia, elevations in D-dimer, lactate dehydrogenase, transaminases and C-reactive protein (CRP), and interleukin (IL)-6, ferritin and others.8–12 Development of acute respiratory disease syndrome (ARDS), along with acute cardiac injury, have been described as independent predictors of death.13 Importantly, hypoxaemic respiratory failure is the leading cause of death in COVID-19, contributing to 60% of deaths.14

Cardiac Involvement The reported rate of cardiac injury varies between studies, from 7% to 28% of hospitalised patients, and is related to worse outcomes, including intensive care unit (ICU) admission and death.9,10,12–15 Importantly, early cardiac injury has been reported, even in the absence of respiratory symptoms and signs of interstitial pneumonia.16 The mortality rate for those hospitalised with subsequent evidence of cardiac injury was significantly higher than for those without cardiac injury (51.2% versus 4.5%, respectively, p<0.001) and hence, along with ARDS, it is an independent predictor of death.13 The presence of previous cardiovascular risk factors (such as diabetes or arterial hypertension) or cardiac disease (previous MI or heart failure), as well as the presence of other clinically relevant comorbidities (e.g. older age, renal failure or prior lung disease), seems to worsen the prognosis of infected people.10–12,15 Furthermore, the infection is also associated with de novo cardiac complications (approximately 8–12% of myocardial lesions and 7–16% of myocarditis and arrhythmias).17

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SARS-CoV-2 infection can affect the cardiac structures via various mechanisms of injury (Figure 1), such as by direct damage to the myocytes and the vascular cells, and also indirectly by cytokine expression after systemic inflammation. The infection provokes a disarray of the coagulation and fibrinolytic system, with a clinical picture consistent with disseminated intravascular thrombosis. Therefore, empiric anticoagulation is being used in some centres. In addition, an oxygen supply/demand mismatch or severe hypoxia caused by respiratory failure may modulate the cardiac affects, which may include myocarditis, acute coronary syndrome (ACS; type 2 MI) and arrhythmia, which might lead to acute or chronic heart failure.12–19 Furthermore, the arrhythmia occurrence (e.g. AF with fast ventricular response) may facilitate ischaemia, which can also cause arrhythmias (e.g. VF). In addition, some cardiotoxic drugs or drugs affecting the electrical properties of the heart may facilitate proarrhythmia (e.g. drugs prolonging the QT interval may facilitate torsades de pointes tachycardia). Thus, patients with SARS-CoV-2 infection may have heart rhythm disturbances due to a variety of mechanisms, which are interrelated and inter-facilitated. The role of stress (takotsubo) cardiomyopathy in COVID-19 patients is not known. However, several of the proposed mechanisms of COVID-19-related cardiac injury are also thought to be implicated in the pathophysiology of stress cardiomyopathy (particularly microvascular dysfunction, cytokine storm and sympathetic surge), and one typical takotsubo syndrome triggered by SARS-CoV-2 infection has already been reported.20

Arrhythmia The clinical manifestations (i.e. palpitations, syncope etc.) of bradyarrhythmias or tachyarrhythmias in COVID-19 do not differ from the usual presentation. No specific ECG patterns have been described

COVID-19 Figure 2: Acute Treatment Recommendations for Patients with Ventricular Tachycardia and VF New episode of VT/VF in COVID-19

Urgent cardioversion/ defibrillation

Haemodynamic stability YES

Monomorphic VT

Polymorphic VT/VF

QTc-prolonging antiviral therapy

QTc prolonged or TdP VT

IV amiodarone

Yes

Cardioversion if ventilated

Recurrence or continuing VT

IV lidocaine IV beta-blocker (esmolol) Recurrent VT or VF

IV beta-blocker (esmolol) IV lidocaine or procaininamide Recurrence or continuing VT Cardioversion

Recurrence or continuing VT

IV amiodarone

Yes

IV magnesium Isoprenaline Stop QT-prolonging antiviral drugs Recurrent TdP or bradycardia Temporary pacing

IV amiodarone

COVID-19 = coronavirus disease 2019; IV = intravenous; QTc = corrected QT interval; TdP = torsades de pointes; VT = ventricular tachycardia. Sources: European Society of Cardiology 202018 and Giudicessi et al. 2020.21

in SARS-CoV-2-infected people. Thus, ECG diagnostic criteria are the same for infected and for the general population. Surprisingly, there is limited literature regarding arrhythmias in COVID-19. The true incidence and type of arrhythmia is unknown. A large observational multicentre study from China of data on 1,099 patients did not report any arrhythmia.8 In a case series of 138 hospitalised patients with COVID-19, 16.7% (n=23) developed nonspecified arrhythmias during their hospitalisation; higher rates were noted in patients admitted to the ICU (44.4%, n=16).10 A case series of 187 hospitalised patients provided insight into specific arrhythmias, reporting sustained ventricular tachycardia (VT) or VF in 5.9% (n=11) of the patients.9 Interestingly, the incidence of these arrhythmias was 1.5% and 17.3% in those patients without and with troponin elevation (p<0.001),9 suggesting that new-onset malignant ventricular arrhythmias could be a marker of acute myocardial injury, and therefore a more aggressive immunosuppressive and antiviral treatment is needed. Figure 2 shows recommendations for acute therapy for patients with VT/VF.18,21 After recovery from COVID-19, the need for secondary prophylactic ICD, catheter ablation, or wearable defibrillator (in the case of suspected transient cardiomyopathy due to myocarditis) needs to be evaluated. There is currently no specific recommendation for acute myocarditis treatment. Furthermore, there are no specific reports on COVID-19 in patients with channelopathies. There are, however, some special considerations. In patients with congenital long QT syndrome with SARS-CoV-2 infection, QT-prolonging antiviral drugs must be closely monitored and reconsidered if the corrected QT interval (QTc) is prolonged >500 ms or

if it increases >60 ms from baseline.21 Electrolyte disturbances must be avoided and kalaemia should be kept at >4.5 mEq/l. To avoid fevertriggered ventricular tachyarrhythmias in patients with Brugada syndrome, fever must be intensively treated (mainly with paracetamol) and continuous ECG monitoring is recommended. Drug interactions with antivirals should also be strictly monitored in patients with catecholaminergic polymorphic VT taking beta-blockers and flecainide. Catecholamines should be avoided if possible in these patients.18,22 Also, as part of the anti-arrhythmia treatment, all possible underlying reversible triggers (e.g. hypoxia, acidosis, electrolyte abnormalities and ischaemia) for arrhythmias should be eliminated. The true incidence of new-onset AF in SARS-CoV-2 infection is unknown. Half of severely ill patients with cardiac involvement present with AF, given that it may be triggered by the infection alterations (e.g. fever, hypoxia and adrenergic tone).23 In a report from Italy, a retrospective chart review identified a history of AF in 24.5% of 355 COVID-19 patients who died (mean age 79.5 years).24 If inpatients present with AF or flutter with haemodynamic stability, a rate control strategy is reasonable, whereas cardioversion should be considered if haemodynamic instability occurs. Discontinuation of antiarrhythmic drugs should be considered in patients with new-onset AF/ flutter with haemodynamic stability under antiviral treatment, using rate control therapy with beta-blockers with/without digoxin. Anticoagulation should be guided by CHA2DS2-VASC score. Direct oral anticoagulants (DOACs) are preferred over vitamin K antagonists in eligible patients (i.e. those without mechanical prosthetic heart valves,

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COVID-19 and Cardiac Arrhythmias moderate to severe mitral stenosis or antiphospholipid syndrome) in order to avoid the need for regular determination of international normalised ratio but, considering possible drug–drug interactions, appropriate doses should be ensured.25,26 There is no specific information regarding the use of DOACs in COVID-19 patients. If necessary, apixaban, edoxaban and rivaroxaban (but not dabigatran) can be given in a crushed form. This is because dabigatran should always be given in capsule form in clinical use to avoid unintentionally increased bioavailability of dabigatran etexilate. However, if antiretroviral drugs are used, apixaban and rivaroxaban should be avoided because of potential interactions.18 Severely ill patients may be switched to parenteral anticoagulation, given that heparin does not present significant drug–drug interactions with COVID-19 treatment (except azithromycin, which should not be coadministered with unfractionated heparin). After recovery from COVID-19, the therapeutic choices of rate or rhythm control of AF/flutter should be re-evaluated, but long-term anticoagulation should be continued based on CHA2DS2-VASC score.18,22,25,26 Transient atrioventricular block has been rarely reported in COVID-19.27 A lower heart rate than expected in patients with fever has been observed in COVID-19 patients. In addition, some drugs used for COVID-19. (e.g. chloroquine and, less frequently, hydroxychloroquine) might increase the likelihood for AV block (sometimes after many weeks of treatment). Thus, patients must be informed about possible corresponding symptoms (i.e. dizziness or syncope). If persistent bradycardia occurs, all drugs that might aggravate this clinical problem should be stopped and heart rate-increasing drugs (e.g. isoprenaline or atropine), or temporary pacing must be considered. Implantation in patients with an indication for a permanent device should be delayed if possible to diminish the risk of nosocomial infection. Although amiodarone has experimental antiviral properties that should be further analysed, anti-arrhythmic drugs should be used with caution to avoid proarrhythmia.28 However, in critically ill patients with haemodynamic instability caused by recurrent VT/VF, IV amiodarone is the anti-arrhythmic drug of choice, but its combination with other QTprolonging drugs (e.g. hydroxychloroquine and/or azithromycin) should be avoided.18,22 Ventricular function and myocardial involvement should be assessed on echocardiography in patients with new severe ventricular arrhythmias. However, all diagnostic and therapeutic procedures should be restricted to those mandatory for immediate therapeutic management of critically ill patients, in order to preserve healthcare resources and minimise the risk of nosocomial infection.

benefits.31 Thus, the precise role of this drug (and several others) deserves further investigation.15 The antiviral properties (inhibition of membrane fusion) of chloroquine were previously observed in HIV and other viruses.32,33 Similarly, hydroxychloroquine is being widely used with an emergency authorisation.18,19,34–36 However, data are needed to prove efficacy against SARS-CoV-2 in humans. In an observational study, among patients hospitalised in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality.35 However, in a US multi-centre retrospective observational study analysing data from 2,541 patients, treatment with hydroxychloroquine alone and in combination with azithromycin was associated with reduction in COVID-19-associated mortality when controlling for COVID-19 risk factors.36 It should be noted that chloroquine and hydroxychloroquine prolong the QT interval and may induce life-threatening arrhythmias.37,38 Thus, caution should be used in starting these agents in patients with QTc >450 ms. Concomitant use of other QT-prolonging agents is not recommended, and abnormal electrolyte levels must be avoided.37,38 Importantly, kalaemia must be maintained in a high to normal range. Other antiviral strategies (e.g. specific neutralising antibodies) are under investigation. Detailed lists of interactions of antiviral and commonly used drugs are available at https://www.covid19-druginteractions.org from the University of Liverpool; at https://www.crediblemeds.org; and also in Driggin et al.16 Importantly, single-lead ECG with handheld devices will underestimate the QTc interval. Thus, for QT measurement, it is recommended to record 12-lead ECG, multi-lead handheld ECG, or single-lead handheld ECG in at least three lead positions.39 Both the absolute and delta QTc (incremental QTc) is required to establish the baseline risk and proarrhythmia.39 It is important to balance the risk of QTc measurement inaccuracy versus the risk of 12-lead ECG measurements in the pandemic situation. Maybe only high-risk patients should undergo systematic 12-lead ECG. Previous authors have been developing scores to predict the risk of QT prolongation with drugs. Although they are not validated for COVID-19, they are a clinical option.40

Monitoring and follow-up of patients with implanted devices (e.g. pacemakers and ICDs) should be done remotely as much as possible. In this context, elective procedures should be postponed and urgent ones undertaken only after consideration of pharmacological alternatives and in designated catheterisation laboratory areas with appropriate personal protection equipment.

Advanced stages of COVID-19 are related to cytokine storm syndromes with elevated levels of inflammatory biomarkers (e.g. IL-6 and highsensitivity CRP), identifying patients at high risk of progressing to severe disease and even death.12,41 Therefore, corticosteroids and IL-6 inhibitors have been used for patients with refractory shock or advanced ARDS in small cohorts.42 Very limited data suggesting that adjunctive azithromycin to hydroxychloroquine might be useful has been published.18 However, this drug might prolong the QT interval and special caution should be paid if combined with hydroxychloroquine. Several other anti-inflammatory therapies are being investigated and might change the scenario in the future. Vaccines against SARS-CoV-2 are obviously meaningful but unavailable yet, although promising results begin to be published.43,44

Other Treatments

Conclusion

Presently, there are no coronavirus-specific drugs available, and different approaches based on previous antiviral experience are used.29 The most widely applied inhibitor of viral genome replication agent against SARS-CoV-2 is remdesivir, which has in vitro activity against the virus.18,29,30 In addition, remdesivir has been reported to reduce the time to clinical improvement, but without statistically significant clinical

Because of limited testing and a large asymptomatic population, the true burden of SARS-CoV-2-infected people is still unknown and underestimated. Differing prevalences and clinical results might be (at least partially) explained by major differences in testing capacities between countries and regions, and by differences in test quality (sensitivity and specificity) but also by differences between populations.

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COVID-19 Diverse (direct and indirect) mechanisms may facilitate cardiac involvement resulting in myocarditis, ACS and diverse cardiac arrhythmias. Several antiviral strategies are under investigation. It can be hypothesised that (as for HIV treatment) a combination of drugs will probably achieve the best clinical results. Vaccines against SARS-CoV-2 are urgently needed. Anti-arrhythmic treatments for COVID-19 are

10.

11.

12.

13.

14.

15.

Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270–3. https://doi.org/10.1038/s41586-0202012-7; PMID: 32015507. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 2020;323:1843–4. https://doi.org/10.1001/jama.2020.3786; PMID: 32159775. van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med 2020;382:1564–7. https://doi.org/10.1056/ NEJMc2004973; PMID: 32182409. De Abajo F, Rodriguez Martín S, Lerma V, et al. Use of renin– angiotensin–aldosterone system inhibitors and risk of COVID19 requiring admission to hospital: a case-population study. Lancet 2020; 395:1705-1714. https://doi.org/10.1016/S01406736(20)31030-8; PMID: 32416785. American College of Cardiology. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. 17 March 2020. https://www.acc.org/latest-in-cardiology/ articles/2020/03/17/08/59/hfsa-acc-aha-statement-addressesconcerns-re-using-raas-antagonists-in-covid-19 (accessed 3 September 2020). European Society of Cardiology. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers. 13 March 2020. https://www.escardio.org/ Councils/Council-on-Hypertension-(CHT)/News/positionstatement-of-the-esc-council-on-hypertension-on-aceinhibitors-and-ang (accessed 3 September 2020).). Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020;323:1239–42. https://doi.org/10.1001/jama.2020.2648; PMID: 32091533. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708–20. https://doi.org/10.1056/NEJMoa2002032; PMID: 32109013. Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID19). JAMA Cardiol 2020;5:811–8. https://doi.org/10.1001/ jamacardio.2020.1017; PMID: 32219356. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061–9. https:// doi.org/10.1001/jama.2020.1585; PMID: 32031570. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020;180:934–43. https://doi.org/10.1001/ jamainternmed.2020.0994; PMID: 32167524. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054–62. https:// doi.org/10.1016/S0140-6736(20)30566-3; PMID: 32171076. Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol 2020;5:802–10. https://doi.org/10.1001/ jamacardio.2020.0950; PMID: 32211816. Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020;46:846–8. https:// doi.org/10.1007/s00134-020-05991-x; PMID: 32125452. Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. J Am Coll Cardiol 2020;75:2352–71. https://doi.org/10.1016/j.jacc.2020.03.031; PMID: 32201335.

similar or identical to that for non-infected individuals. However, the avoidance of QT prolongation is essential, and possible drug–drug interactions must be considered. Elective procedures should be delayed, whereas urgent situations might require immediate treatment by trained and sufficiently equipped teams to ensure that healthcare workers do not become hosts or vectors of virus transmission.

16. Inciardi RM, Lupi L, Zaccone G, et al. Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020; 5:819–24. https://doi.org/10.1001/jamacardio.2020.1096; PMID: 32219357. 17. Siripanthong B, Nazarian S, Muser D, et al. Recognizing COVID19-related myocarditis: the possible pathophysiology and proposed guideline for diagnosis and management. Heart Rhythm 2020;17:1463–71. https://doi.org/10.1016/j. hrthm.2020.05.001; PMID: 32387246. 18. European Society of Cardiology. ESC guidance for diagnosis and management of CVD during the COVID-19 pandemic. https://www.escardio.org/Education/COVID-19-and-Cardiology (accessed 10 May 2020). 19. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. JAMA 2020;323:2052–9. https://doi.org/10.1001/jama. 2020.6775; PMID: 32320003. 20. Meyer P, Degrauwe S, Van Delden C, et al. Typical takotsubo syndrome triggered by SARS-CoV-2 infection. Eur Heart J 2020;41:1860. https://doi.org/10.1093/eurheartj/ehaa306; PMID: 32285915. 21. Giudicessi JR, Noseworthy PA, Friedman PA, et al. Urgent guidance for navigating and circumventing the QTc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 29 (COVID-19). Mayo Clin Proc 2020;95:1213–21. https://doi.org/10.1016/j.mayocp.2020. 03.024; PMID: 32359771. 22. Dan GA, Martinez-Rubio A, Agewall S, et al. Antiarrhythmic drugs – clinical use and clinical decision making: a consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group on Cardiovascular Pharmacology, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and International Society of Cardiovascular Pharmacotherapy (ISCP). Europace 2018;20:731–2. https://doi. org/10.1093/europace/eux373; PMID: 29438514. 23. Liu PP, Blet A, Smyth D, Li H. The science underlying COVID-19: implications for the cardiovascular system. Circulation 2020;142:68–78. https://doi.org/10.1161/CIRCULATIONAHA. 120.047549; PMID: 32293910. 24. Onder G, Rezza G, Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA 2020;323:1775–6. https://doi.org/10.1001/ jama.2020.4683; PMID: 32203977. 25. Martínez-Rubio A, Dan GA. Cardiovascular pharmacotherapies focus: are low doses of direct-acting oral anticoagulants justified and appropriate in patients with nonvalvular atrial fibrillation? Eur Cardiol 2016;11:115–7. https://doi.org/10.15420/ ecr.2016.11.2.ED2; PMID: 30310458. 26. Martínez-Rubio A, DiazNuila Alcazar M, Soria Cadena A, Martinez-Torrecilla R. Using direct oral anticoagulants in patients with atrial fibrillation: assessment, monitoring and treatment reversal. Eur Cardiol 2016;11:118–22. https://doi. org/10.15420/ecr.2016:30:1; PMID: 30310459. 27. Azarkish M, Laleh Far V, Eslami M, Mollazadeh R. Transient complete heart block in a patient with critical COVID-19. Eur Heart J 2020;41:2131. https://doi.org/10.1093/eurheartj/ ehaa307; PMID: 32285920. 28. Aimo A, Baritussio A, Emdin M, Tascini C. Amiodarone as a possible therapy for coronavirus infection. Eur J Prev Cardiol 2020. https://doi.org/10.1177/2047487320919233; PMID: 32295404; epub ahead of press. 29. Kalil AC. Treating COVID-19: off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA 2020;323:1897–8. https://doi.org/10.1001/jama.2020.4742; PMID: 32208486. 30. Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019

novel coronavirus in the United States. N Engl J Med 2020;382:929–36. https://doi.org/10.1056/NEJMoa2001191; PMID: 32004427. 31. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebocontrolled, multicenter trial. Lancet 2020;395:1569–78. https://doi.org/10.1016/S0140-6736(20)31022-9; PMID: 32423584. 32. Savarino A, Gennero L, Chen HC, et al. Anti-HIV effects of chloroquine: mechanisms of inhibition and spectrum of activity. AIDS 2001;15:2221–9. https://doi.org/10.1097/ 00002030-200111230-00002; PMID: 11698694. 33. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J 2005;2:69. https://doi.org/10.1186/1743-422X-2-69; PMID: 16115318. 34. Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov 2020;6:16. https://doi.org/10.1038/ s41421-020-0156-0; PMID: 32194981. Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA 2020;323:2493–502. https://doi.org/10.1001/ jama.2020.8630; PMID: 32392282. Arshad S, Kilgore P, Chaudhry Z, et al. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. Int J Infect Dis 2020;97:396403. https://doi.org/10.1016/j.ijid.2020.06.099; PMID: 32623082. 35. Bessière F, Roccia H, Delinière A, et al. Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit. JAMA Cardiol 2020;5:1067–9. https:// doi.org/10.1001/jamacardio.2020.1787; PMID: 32936266. 36. Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020;5:1036–41. https:// doi.org/10.1001/jamacardio.2020.1834; PMID: 32936252. 37. Cheung CC, Davies B, Gibbs K, et al. Multi-lead QT screening is necessary for QT measurement: implications for management of patients in the COVID-19 era. JACC Clin Electrophysiol 2020;6:878–80. https://doi.org/10.1016/j.jacep.2020.04.001; PMID: 32703574. 38. Tisdale JE, Jaynes HA, Kingery JR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes 2013;6:479–87. https://doi.org/10.1161/CIRCOUTCOMES. 113.000152; PMID: 23716032. 39. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033–4. https://doi.org/10.1016/S01406736(20)30628-0; PMID: 32192578. 40. Alhazzani W, Moller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med 2020;48:e440–69. https://doi.org/10.1097/ CCM.0000000000004363; PMID: 32224769. 41. Yu J, Tostanoski LH, Peter L, et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science 2020;369:806–11. https://doi.org/10.1126/science.abc6284; PMID: 32434945. 42. Chandrashekar A, Liu J, Martinot AJ, et al. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science 2020;369:812–7. https://doi.org/10.1126/science.abc4776; PMID: 32434946.

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Special Focus on the EXCEL Trial

The EXCEL Trial: The Surgeons’ Perspective Marjan Jahangiri, Krishna Mani, Martin T Yates and Justin Nowell Department of Cardiac Surgery, St. George’s Hospital, London, UK

Abstract There have been several investigations comparing the efficacy of percutaneous coronary intervention and coronary artery bypass grafting surgery for treatment of left main stem disease. This includes the Evaluation of XIENCE versus Coronary Artery Bypass Graft Surgery for Effectiveness of Left Main Revascularizaton (EXCEL) trial, which has garnered significant controversy surrounding its experimental design and reporting of its results. The authors review the methodology, results, caveats and statements on the EXCEL trial. They also review the other trials in the management of left main stem disease comparing percutaneous coronary intervention with coronary artery bypass grafting, as well as the SYNTAX score and its role in future guidelines for revascularisation. These findings have significant implications for current practice, influencing the growing role for multidisciplinary team meeting and allowing clinicians and patients to make the right choice.

Keywords Coronary artery disease, left main stem, percutaneous coronary intervention, coronary artery bypass graft surgery, clinical trials Disclosure: The authors have no conflicts of interest to declare. Received: 20 August 2020 Accepted: 5 October 2020 Citation: European Cardiology Review 2020;15:e67. DOI: https://doi.org/10.15420/ecr.2020.34 Correspondence: Marjan Jahangiri, Department of Cardiac Surgery, St George’s Hospital, London SW17 0QT, UK. E: marjan.jahangiri@stgeorges.nhs.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

With evolving stent technology, improvements in percutaneous coronary intervention (PCI) techniques and the use of antithrombotic medications, the role of PCI in the treatment of left main stem (LMS) disease has expanded from being confined to salvage scenarios to intermediate- and lower-risk patients. However, the role and benefits of coronary artery bypass grafting (CABG) surgery in the treatment of multivessel disease and LMS disease have been well established with long-term follow-up. In order to assess the role and efficacy of PCI in LMS disease compared with CABG, several randomised clinical trials have been performed. In this review, some of the earlier and later trials will be compared. In recent months, one of them – the Evaluation of XIENCE Versus Coronary Artery Bypass Graft Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial – has attracted a significant amount of scientific and media attention.1 This review will outline the methodology of EXCEL, as well as other trials on the management of LMS disease and summarise the debates around EXCEL including statements from professional societies as well as the impact of these trials on real-world practice.

PCI Versus CABG for the Treatment of Left Main Stem Disease Earlier trials demonstrated the efficacy and safety of first-generation drug-eluting stents (DES) and later trials compared the secondgeneration DES with CABG. The outcome measures used in these trials include the occurrence of major adverse cardiac and cerebrovascular events (MACCE) at short and medium term, early and late mortality of cardiac and all-cause reasons, complete revascularisation at the time of primary procedure and rate of repeat revascularisation during follow-up. The trials include Synergy Between PCI with Taxus and Cardiac Surgery (SYNTAX), Premier of Randomized Comparison of

Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease (PRECOMBAT), Left Main Coronary Artery Stenting (LEMANS), Nordic Baltic British Left Main Revascularisation (NOBLE) and EXCEL.2–6 Evidence from the SYNTAX trial showed the benefits of CABG in LMS with a SYNTAX score of >32.2,3 However, in patients with a SYNTAX score of <32, PCI and CABG showed similar results. The SYNTAX trial was not powered to address the efficacy of PCI versus CABG and therefore further studies like NOBLE and EXCEL were needed. EXCEL and NOBLE are non-inferiority randomised trials designed to compare and evaluate the efficacy of PCI and CABG in patients with LMS disease.

The SYNTAX Trial The SYNTAX trial was a multicentre randomised controlled trial of 1,800 patients with three-vessel or LMS disease comparing CABG with PCI using Taxus Express paclitaxel-eluting stents (Boston Scientific).2 A noninferiority comparison of the primary endpoint of MACCE was undertaken at 1 and 5 years. The 5-year results were published in 2014.7 In the LMS subgroup (n=705) there were no significant differences in mortality at 5 years (12.8% PCI versus 14.6% CABG; p=0.53), the occurrence of MACCE (36.9% PCI versus 31% CABG; p=0.12) and MI (8% PCI versus 5% CABG). However, CABG had a higher stroke rate (1.5% PCI versus 4.3% CABG; p=0.05) and PCI had a significantly higher rate of repeat revascularisation (26.7% PCI versus 15.5% CABG; p<0.001). In patients with high SYNTAX scores, MACCE was significantly increased with PCI (high score, 46.5% PCI versus 29.7% CABG; p=0.003).8 At 10 years, no significant difference existed in all-cause

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Special Focus on the EXCEL Trial death between PCI and CABG. However, CABG provided a significant survival benefit in patients with three-vessel disease, but not in patients with LMS disease.9

The SYNTAX Score and its Role The SYNTAX score is a method of quantifying the angiographic appearance of coronary artery lesions based on their anatomical location and complexity to treat by PCI. It is an additive score of all the lesions and therefore reflects the quantity of myocardium at risk. It has been shown to be predictive of adverse outcomes following PCI but less so after CABG, since the success of CABG does not only depend on the lesions themselves, but also on nature of the coronary lesions among other factors.10

In the EXCEL trial at 5 years, the authors reported that a primary outcome event had occurred in more patients with PCI, but this was not significant (22.0% PCI versus 19.2% CABG; p=0.13).1 However, the incidence of all-cause mortality was significantly higher in the PCI group (13.0% PCI versus 9.9% CABG, OR 1.38, 95% CI [1.03–1.85]). The incidences of cardiovascular death (5.0% PCI versus 4.5% CABG, 0.5 percentage points, OR 1.13) and MI (10.6% PCI versus 9.1% CABG) were not significantly different. All cerebrovascular events were less frequent after PCI than after CABG (3.3% PCI versus 5.2% CABG; −1.9 percentage points; OR 0.61), although the incidence of stroke was not significantly different (2.9% versus 3.7%; −0.8 percentage points; OR 0.78). They report that repeat revascularisation was more frequent after PCI than after CABG (17.2% versus 10.5%). The authors conclude that there was no significant difference between PCI and CABG in respect of the composite outcome of death, stroke or MI at 5 years.

It must be remembered that as a static, non-physiological anatomical score it does not take account of patient factors, such as comorbidities, cardiac function or patient preference. Although current European guidelines recommend the SYNTAX score as an assessment of severity of coronary artery disease, they do not recommend its routine use to determine PCI versus CABG.11 SYNTAX scoring should be interpreted with caution in the context of a balanced multidisciplinary team (MDT).

EXCEL and NOBLE have shown contradictory results both at 3- and 5-year follow-up. This is probably related to their inclusion criteria, possible crossover of patients in EXCEL from PCI group to CABG between 3 and 5 years and several other factors, which are argued comprehensively by Park et al.15 A summary of these trials is shown in Table 1.

PRECOMBAT

Non-inferiority Trials

The PRECOMBAT trial was a randomised controlled trial of 600 patients with unprotected LMS disease to undergo PCI with a sirolimus-eluting stent or CABG. Once again this was a non-inferiority study, with the primary endpoint being MACCE.4,5 In PRECOMBAT, mortality at 5 years was 5.7% for PCI versus 7.9% for CABG (p=0.32) and MACCE was 17.5% for PCI versus 14.3% for CABG (p=0.26). The incidence of MI (2% PCI versus 1.7% CABG; p=0.76) and stroke (0.7% PCI versus 0.7% CABG; p=0.99) were not significantly different. However, as in the SYNTAX trial, the rate of repeat revascularisation was higher in the PCI group (13.0% PCI versus 7.3% CABG; p=0.020).

Randomised controlled trials are thought to be the gold standard in comparing two modalities of treatment compared to registries, which may or may not be propensity matched. The main strength of a randomised controlled trial is avoiding bias. However, there are several weaknesses, including a very small number of potentially eligible patients who can be included resulting in only a small number of patients being studied, atypical patient populations, short duration of follow-up, large number of crossovers and being expensive. In contrast, registries can recruit large number of patients, represent real-world practice and they are relatively cheap. However, they suffer from bias and confounding factors at various levels.

NOBLE NOBLE was a prospective, randomised, open-label, non-inferiority trial carried out at 36 hospitals in nine northern European countries.12,13 A total of 1,201 patients with LMS disease requiring revascularisation were enrolled and randomly assigned (1:1) to receive PCI or CABG. Of note, NOBLE did not use SYNTAX score as a criterion, but instead excluded patients with more than three additional coronary lesions or more complex coronary lesions. A total of 598 patients were allocated to PCI and 603 to CABG. At 5 years, all-cause mortality and cardiac death occurred in 9% and were the same after both procedures with MACCE rates of 28% for PCI versus 19% for CABG (p=0.0002). The latter exceeded the non-inferiority threshold and CABG was significantly better than PCI. Non-procedural MI was higher after PCI (8% PCI versus 3% CABG; p=0.0002). Patients treated with PCI had higher rates of repeat revascularisation (17% PCI versus 10% CABG; p=0.0009).12

EXCEL The EXCEL trial is a prospective, randomised, open-label, non-inferiority trial of 1,905 patients of low or intermediate anatomical complexity. A total of 948 patients received fluoropolymer-based-cobalt-chromium everolimus-eluting stent and 957 underwent CABG. At 3 years, death, stroke, MI or revascularisation occurred in 23.1% of the patients in the PCI group and in 19.1% in the CABG group (p=0.01 for noninferiority; p=0.10 for superiority).14

There has been an explosion of non-inferiority trials in cardiovascular diseases like the trials described in this paper. Bikdeli et al. report that non-inferiority cardiovascular trials are increasingly being published by the highest impact journals, with 79% funded by private industries and 8% funded by non-profit organisations.16 Between 1990 and 2016, 111 cardiovascular non-inferiority trials were published. Eighty-six of these trials, many of which were large multicentre studies, claimed tested new interventions were non-inferior to the compared therapy and only eight demonstrated inferiority.

Adverse Media Attention The publication of the EXCEL trial was followed by serious concerns raised about its methodology and the integrity of its results.17–19 The trial was the subject of a BBC Newsnight programme in December 2019.20 The programme raised concerns about the validity of the conclusions of the trial, whether important data had been withheld, and raised the possibility that the study was inherently flawed from the outset because of conflicts of interest amongst the investigators, given that it had been financed by stent manufacturers. As a result of these very serious allegations, the European Association of Cardiothoracic Surgery (EACTS) and European Society of Cardiology (ESC) guideline group withdrew their support for the joint EACTS/ESC statement on the management of patients with LMS disease, until a full

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EXCEL Trial: The Surgeons’ Perspective Table 1: The 5-year Outcomes of Randomised Trials Comparing PCI with CABG in the Treatment of Left Main Stem SYNTAX2

PRECOMBAT5

NOBLE12

EXCEL1

Publication year

2014

2015

2020

2019

Number of patients

705

600

1,201

1,905

Length of follow-up

5 years

MACCE

Composite death, stroke or MI

17.5 versus 14.3% (p=0.26)

28 versus 19% (p=0.0002)

22 versus 19.2% (p=0.13)

Primary Outcome (PCI versus CABG) 36.9 versus 31% (p=0.12)

Secondary Outcomes (PCI versus CABG) All-cause mortality

12.8 versus 14.6% (p=0.53)

5.7 versus 7.9% (p=0.32)

9 versus 9% (p=0.68)

13 versus 9.9%

8.2 versus 4.8% (p=0.1)

2 versus 1.7% (p=0.76)

8 versus 3% (p=0.0002)

10.6 versus 9.1%

Stroke

1.5 versus 4.3% (p=0.03)

0.7 versus 0.7% (p=0.99)

4 versus 2% (p=0.11)

2.9 versus 3.7%

Repeat revascularisation

26.7 versus 15.5% (p<0.001)

13 versus 7.3% (p=0.020)

17 versus 10% (p=0.0009)

17.2 versus 10.5%

CABG = coronary artery bypass graft; MACCE = major cardiac or cardiovascular events; PCI = percutaneous coronary intervention.

independent analysis of the EXCEL trial data had been carried out.18,19 EACTS summarised its concerns because of the 35% increased risk of death in the PCI group, failure of the authors to publish the data using the Universal Definition of MI, emerging mortality data that was available to the data safety monitoring board not being made available to the guideline task force and alleged conflict of interest. Later, in a letter to EXCEL primary investigators, Domenico Pagano on behalf of EACTS invited the authors to make the raw data available to the Clinical Trials Unit at University College London for re-analysis.19 The British Cardiovascular Intervention Society (BCIS) also released a statement on 11 December 2019 reassuring the patients undergoing stent procedures and that patients with LMS disease will be discussed by a multidisciplinary heart team and the outcome of this discussion will be shared with patients in order to reach a final decision.21

(and indeed all other cardiothoracic surgical societies throughout the world who have expressed an opinion) that on current evidence coronary bypass surgery is superior to stenting in the treatment of the vast majority of patients with LMSS and remains the best treatment that we can offer. Nevertheless when the risks of surgery are significant, stenting for LMSS may be a safer alternative in some circumstances.” Many of our patients understandably find the adverse media attention and various statements confusing and worrying. We discuss this in more detail in the Patient’s Choice section. Unpublished data of a survey of the understanding of patients of the extent and nature of their coronary artery disease shows that almost no patient can tell the difference between LMS disease, triple vessel disease and/or significant coronary artery disease.

Controversies of the EXCEL Trial The president of the Society for Cardiothoracic Surgery (SCTS), Mr Richard Page, wrote on 18 December 2019: “A number of colleagues are understandably concerned that the joint statement [by SCTS, British Cardiovascular Intervention Society and British Cardiovascular Society] did not clarify the current situation/evidence for the treatment of Left Main Stem stenosis, given that doubts have been raised about the integrity of Excel.22,23 There was uncertainty within the cardiac surgical community as to the position taken by the SCTS. Clearly an explanation is required, which is why I am writing to you again. Very soon after the Newsnight programme we were made aware of patients and relatives who were concerned as to whether they were receiving the right treatment, even to the extent that some were questioning if stents were safe in any situation. Therefore there was a real and pressing need to be able to reassure patients and their families that they could trust cardiovascular physicians and surgeons in the UK to give balanced and appropriate advice, and that each and every patient will have access to specific and individualised treatment, notwithstanding the questions raised regarding the validity of the Excel trial. We did not feel that a statement from SCTS alone would be constructive to the situation and it would be more sensible and reassuring to patients, relatives and the NHS to see collaboration and a joint statement from the professional societies that are responsible for all aspects of decision making in this pattern of coronary disease.” A further letter to SCTS members from the President on 17 February 2020 provided an update on the situation: “The SCTS agrees with EACTS

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There are several controversies of the methodology and conduct of the EXCEL trial that have been addressed, including the following:16,24 • The EXCEL investigators use the Society for Cardiovascular Angiography and Interventions (SCAI) definition of peri-procedural MI rather than the Universal Definition of MI.25,26 The use of SCAI caused the reporting of 37% higher occurrence of MI in the CABG group. Furthermore, the use of Universal Definition of MI would have allowed a fairer comparison of EXCEL with other trials. In addition, Ruel et al. showed that the SCAI definition of MI exaggerated procedural MI after CABG.27 • The incidence of all-cause mortality was significantly higher in the PCI group (13.0% PCI versus 9.9% CABG; OR 1.38; 95% CI [1.03– 1.85]). There is an increasing divergence during the follow-up period for death in favour of CABG. At 5 years, the mortality rate was significantly higher in the PCI group compared to CABG. The EXCEL investigators had classified all-cause mortality as a secondary endpoint and reported that its statistical significance was uncertain. The majority of the trials have all-cause mortality as a primary endpoint and therefore hiding of all-cause mortality is disingenuous. • Repeat revascularisation, which has been shown to be an independent predictor of death, MI and stroke, was significantly higher in the PCI group.28 Repeat revascularisation as an outcome measure has significant implications for patient’s quality of life and health service economy and has been used as a primary outcome measure in earlier trials.29,5 We believe that repeat revascularisation should have

Special Focus on the EXCEL Trial been considered as primary endpoint. Furthermore, repeat revascularisation during follow-up was performed less frequently after CABG than PCI and was associated with increased mortality after both procedures.30 • The HR of the composite of death, stroke and MI shifted from being in favour of PCI at 30 days to CABG during the follow-up period. This indicates that CABG is the preferred option in patients with longer life expectancy. • Unlike the PCI group, the CABG group was heterogeneous in both using off-pump technique and arterial grafting. Overall 29.4% of the CABG operations were off-pump. In a subgroup analysis, Benedetto et al. reported a significantly higher all-cause mortality in the offpump compared to on-pump patients at 3 years (8.8% off-pump versus 4.5% on-pump).31 Furthermore, there is strong evidence in patients undergoing CABG for the use of multiple arterial grafting improving survival.32–35 However, only 24% of patients in EXCEL received bilateral mammary arteries and 6% received radial arteries. In such a heterogeneous population, it is difficult to assess the impact of the known benefits of arterial revascularisation.36 These factors should be taken into account when analysing the EXCEL data.

Assessment of Left Main Stem Coronary angiography has traditionally been the gold-standard for diagnosis of coronary artery disease and uses anatomical evaluation of the coronary arteries through multiple angiographic views and thereby identify stenoses that necessitate further intervention.37 Studies have demonstrated a poor correlation between angiographic appearance of a coronary artery to the true degree of stenosis in some cases which can be observer dependent.38 Fractional flow reserve (FFR) has been increasingly used along with angiography in PCI. FFR is measured during coronary catheterisation by passing a pressure-monitoring guide wire distal to the coronary lesion and inducing maximal hyperaemia, usually through intravenous or intracoronary adenosine administration to cause vasodilation.39 It measures the drop in perfusion pressure across a stenosis, therefore representing its physiological effect on myocardial blood flow. Its use is widespread in PCI, though its role in CABG remains uncertain. We carried out a systematic review and meta-analysis to evaluate current evidence on outcomes following FFR-guided CABG compared to angiographyguided CABG.40 We showed that there was no reduction in repeat revascularisation or postoperative MI with FFR. In addition, FFR-guided CABG provided a reduction in mortality, but this was not reported to be due to cardiac causes. There may be a role for FFR in CABG, but largescale randomised trials are required to establish its value.

inform Heart Teams of current best evidence on the topic.41 In 2013, Head et al. reported that the concept of the Heart Team was not widely implemented. Decision-making was shown to remain suboptimal, there was large variability in PCI to CABG ratios, which could have been predominantly the consequence of physician-related factors, raising concerns regarding overuse, underuse and inappropriate selection of revascularisation.42 Our group showed that despite the introduction of joint cardiology and surgical international guidelines, a significant number of patients were receiving inappropriate PCI against those guidelines.43 Subsequent guidelines in 2018 specifically recommend the use of Heart Team for decision making in patients with coronary artery disease.10 They give a Class 1C recommendation (meaning it is recommended or indicated based on expert opinion) for interdisciplinary protocols for common case scenarios to implement the appropriate revascularisation strategy in accordance with current guidelines. Furthermore, they state individual discussion should occur for all complex cases and that the Heart Team should provide a balanced multidisciplinary decision-making process. This decision-making process is guided by the combined personal experience of the Heart Team in conjunction with current best evidence. Evidence obtained from large randomised controlled trials will often be relied upon by the Heart Team. Therefore, it is imperative that such studies have been conducted with integrity and the results reported accurately. Assessing the effectiveness and reproducibility of a coronary Heart Teams decisions is difficult. A study from the UK has previously shown that 93% of decisions on 399 patients are implemented and when rediscussed at a later date 80% of decisions are unchanged.44 This of course does not account for patients who are treated without the benefit of Heart Team discussion. In day-to-day practice, clinicians are unable to discuss the nuanced findings of these trials for each patient. Therefore, the role of Heart Team and MDT have been emphasised.45,42 In the UK, CABG comprises approximately 40% of the adult cardiac surgery operations per annum. A total of 14,527 isolated nonemergency CABG operations were performed between April 2017 and March 2018.46 However, data are not available as to what proportion had LMS disease. Similarly, there is a significant number of PCIs performed for multivessel disease, but it is difficult to extract from the BCIS database what percentage had LMS disease. The question is whether every single patient with LMS can be discussed in an MDT with Heart Team setting.

The Role of the Multidisciplinary Team Meeting “The mind is an attribute of the individual. There is no such thing as a collective brain. The primary act – the process of reason – must be performed by each man alone. We can divide a meal among many men. We cannot digest it in a collective stomach. No man can use his lungs to breathe for another man. No man can use his brain to think for another.” The Fountainhead, Ayn Rand, 1943

The authors of this article suspect that only a small proportion of LMS patients are discussed at MDTs. The treatment decision is cliniciandependent and is often related to the culture of a unit. Unfortunately, the decision around management of LMS patients can often become dominated by a discussion around technical feasibility of PCI. This conflation of two separate issues may not always be in the wider interest for patients with this disease.

The Heart Team is an integral part of the patient care pathway for those with complex coronary artery disease. In 2014, the first joint ESC/EACTS guidelines on myocardial revascularisation were published to help

The Patient’s Choice It is difficult for clinicians – let alone patients – to navigate their way around these complex trials with their inherently nuanced conclusions.

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EXCEL Trial: The Surgeons’ Perspective Patients need accurate information in order to make an informed decision. The quality of any discussion can influence which decision is reached. Many patients exhibit a high degree of suggestibility, meaning that it is possible to influence their decision-making in a particular direction, depending on how or even the order in which information is relayed. An example of this is if a patient is asked if they would like a procedure that will help them. The proposed procedure is not surgery, but similar to an angiogram, and they could go home soon after. This is then contrasted with major cardiac surgery, describing a midline chest incision, deliberately stopping the heart, multiple limb incisions and a 1-week hospital stay plus a total recovery time of 3 months. What may be perceived by cardiologists as a prohibitive risk for surgery, then becomes conflated with patient choice. Four pillars of medical ethics ensure that, when considered together, everyone receives the same standard of healthcare. The same principles also serve to provide guidance to doctors in approaching the care of their patients. These four pillars are autonomy, beneficence, non-maleficence and justice. The founding ethical principle that is mainly undermined in the above scenarios is patient autonomy. That is, the universal right of competent adults to make informed decisions about their own medical care. Thus, by failing to appraise patients properly of the risks and benefits of all treatments, including no treatment, patient choice is suddenly transformed, to something more akin to dealer’s choice. For the uninitiated, the latter phrase also describes a particular style of poker, where each player may deal a different variant.

Informed Decision-making In view of some of the controversies highlighted by the EXCEL trial data and its natural extrapolation to the management of coronary artery disease in general, there is perhaps now an opportunity to improve the role of the MDT/Heart Team. A more systematic approach would be to openly discuss all patients with LMS who require elective coronary intervention, with a structured proforma completed in each case. Essential information should include presence of important risk factors such as diabetes, defining the vessels to be grafted, potential benefits of complete versus incomplete revascularisation, therefore possibility and extent of arterial grafting and consultation by both the cardiologist and the cardiac surgeon. The Heart Team meeting should have an agreed attendance of cardiologists, surgeons and others to achieve quoracy. It would also benefit from a neutral chair. The final decision as to the mode of treatment should be based on real-world evidence and not “let’s wait for the next generation of stents and use of multiple and stronger anti-platelet medications”. Facts emerging

Stone GW, Kappetein AP, Sabik JF, et al. Five-year outcomes after PCI or CABG for left main coronary disease. N Engl J Med 2019;381:1820–30. https://doi.org/10.1056/NEJMoa1909406; PMID: 31562798. Head SJ, Davierwala PM, Serruys PW, et al. Coronary artery bypass grafting vs. percutaneous coronary intervention for patients with three-vessel disease: final five-year follow-up of the SYNTAX trial. Eur Heart J 2014;35:2821–30. https://doi.org/10.1093/eurheartj/ehu213; PMID: 24849105. Holm NR, Mäkikallio T, Lindsay MM, et al. Percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis: updated 5-year outcomes from the randomised, non-inferiority NOBLE trial. Lancet 2020;395:191–9. https://doi.org/10.1016/S01406736(19)32972-1; PMID: 31879028. Park SJ, Kim YH, Park DW, et al. Randomized trial of stents versus bypass surgery for left main coronary artery disease. N Engl J Med 2011;364:1718–27. https://doi.org/10.1056/ NEJMoa1100452; PMID: 21463149. Ahn JM, Roh JH, Kim YH, et al. Randomized trial of stents

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from the most recent trials have not, by and large, been catalysed by newer stent technology.

Conclusion We have attempted to set out the context of the recent events that have led to confusion. The SYNTAX trial was the first randomised trial to compare CABG and PCI in patients with complex coronary disease. The definitive results confirmed that CABG should remain the standard of care for patients with complex coronary lesions. For patients with less complex lesions, or LMS disease, SYNTAX found that PCI is an acceptable alternative, even though it was not designed to assess the overall efficacy of PCI versus CABG. It was against this background, that the EXCEL trial was designed to investigate the newer-generation DES versus CABG in patients with low-risk or intermediate-risk LMS disease. The initial conclusion of the EXCEL authors, that there was no significant difference between PCI and CABG in respect of the composite endpoints of death, stroke or MI at 5 years, has subsequently been called into question. This is related to controversies regarding the trial methodology, disagreements about which definition of peri-procedural MI was used and alleged investigator conflicts of interest. The EXCEL debacle has, to some extent, undermined public confidence in medical research in general and in clinical trials in particular. It is unlikely that there will be a further large randomised trial aimed at addressing the issue of the optimum method of revascularisation for LMS disease but further subgroup analyses from these trials may be hypothesis generating. There are already good quality data that suggest CABG confers a survival advantage for patients with LMS disease. Most authors recommend genuine discussions take place between cardiologists and cardiac surgeons regarding optimal treatment for complex coronary artery disease or LMS disease. This does not always happen in the way that it should. In some cases the invasiveness of CABG is emphasised to engineer patient choice in favour of PCI. We advocate a systematic approach to the Heart Team Meeting, with a structured proforma, agreed quorum and a neutral chair. We must apply judicious management to coronary artery disease. Who should lead this clarion call? We invite key opinion leaders of cardiac surgery and cardiology, namely their respective professional organisations, to rise to the challenge of ensuring the treatment of particularly LMS patients is based on sound ethical and scientific principles. We owe this much to our patients; nothing less will suffice and they are the ultimate beneficiaries.

versus bypass surgery for left main coronary artery disease: 5-year outcomes of the PRECOMBAT Study. J Am Coll Cardiol 2015;65:2198–206. https://doi.org/10.1016/j.jacc.2015.03.033; PMID: 25787197. Buszman PE, Buszman PP, Banasiewicz-Szkróbka I, et al. Left main stenting in comparison with surgical revascularization: 10-year outcomes of the (Left Main Coronary Artery Stenting) LE MANS Trial. JACC Cardiovasc Interv 2016;9:318–27. https:// doi.org/10.1016/j.jcin.2015.10.044; PMID: 26892080. Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013;381:629–38. https://doi. org/10.1016/S0140-6736(13)60141-5; PMID: 23439102. Morice MC, Serruys PW, Kappetein AP, et al. Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the synergy between percutaneous coronary intervention with Taxus and cardiac surgery trial. Circulation 2014;129:2388–94. https://doi.org/10.1161/

CIRCULATIONAHA.113.006689; PMID: 24700706. Thuijs D, Kappetein AP, Serruys PW, et al. Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomized controlled SYNTAX trial. Lancet 2019;394:1325–34. https://doi.org/10.1016/S01406736(19)31997-X; PMID: 31488373. 10. Head SJ, Farooq V, Serruys PW, et al. The SYNTAX score and its clinical implications. Heart 2014;100:169–77. https://doi. org/10.1136/heartjnl-2012-302482; PMID: 23539552. 11. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy394; PMID: 30165437. 12. Holm NR, Mäkikallio T, Lindsay MM, et al. Percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis: updated 5-year outcomes from the randomised, non-inferiority NOBLE trial. Lancet 2020;395:191–9. https://doi.org/10.1016/S01406736(19)32972-1; PMID: 31879028. 9.

Special Focus on the EXCEL Trial 13. Mäkikallio T, Holm NR, Lindsay M, et al. Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial. Lancet 2016;388:2743–52. https://doi.org/10.1016/S01406736(16)32052-9; PMID: 27810312. 14. Stone GW, Sabik JF, Serruys PW, et al. Everolimus-eluting stents or bypass surgery for left main coronary artery disease. N Engl J Med 2016;375:2223–35. https://doi.org/10.1056/ NEJMoa1610227; PMID: 27797291. 15. Park DW, Ahn JM, Park SJ et al. Percutaneous coronary intervention in left main disease: SYNTAX, PRECOMBAT, EXCEL and NOBLE-combined cardiology and cardiac surgery perspective. Ann Cardiothorac Surg 2018;7:521–6. https://doi. org/10.21037/acs.2018.04.04; PMID: 30094217. 16. Bikdeli B, Welsh JW, Akram Y, et al. Noninferiority designed cardiovascular trials in highest-impact journals. Circulation 2019;140:379–89. https://doi.org/10.1161/ CIRCULATIONAHA.119.040214; PMID: 31177811. 17. Gomes WJ, Albuquerque LC, Jatene FB, et al. The transfiguration of the EXCEL trial: exceeding ethical and moral boundaries. Eur J Cardiothorac Surg 2020;58:30–4. https://doi. org/10.1093/ejcts/ezaa121; PMID: 32413905. 18. Pagano D. Changing Evidence, Changing Practice. EACTS. 19 December 2019. https://www.eacts.org/changing-evidencechanging-practice (accessed 12 October 2020). 19. Pagano D. Letter to EXCEL investigators. EACTS. 6 January 2020. https://www.eacts.org/wp-content/uploads/2020/01/ Letter-to-EXCEL-Investigators.pdf (accessed 12 October 2020). 20. Cardiovascular News. BBC Newsnight investigation of EXCEL prompts EACTS to reject 2018 European recommendations on left main disease. 9 December 2019. https:// cardiovascularnews.com/eacts-issues-response-to-bbcnewsnight-investigation-of-excel-trial (accessed 12 October 2020). 21. Banning A. The EXCEL Trial – BBC Newsnight, 9 December 2019. BCIS. 11 December 2019. https://www.bcis.org.uk/news/ the-excel-trial-bbc-newsnight-9-december-2019 (accessed 12 October 2020). 22. Page R. SCTS letter. 18 December 2019. https://scts.org/ wp-content/uploads/2020/01/12-SCTS-statement.pdf (accessed 12 October 2020). 23. Banning A, Page R, Ray S. Joint society statement, SCTS BCS BCIS. 2020. https://scts.org/wp-content/uploads/2020/01/09Joint-Society-Statement-SCTS-BCS-BCIS.pdf (accessed 12 October 2020). 24. Taggart D. Response by David Taggart, MD, PhD to the EXCEL statement. TCTMD. 19 December 2019. https://www.tctmd. com/slide/response-david-taggart-md-phd-excel-statement (accessed 12 October 2020). 25. Moussa ID, Klein LW, Shah B, et al. Consideration of a new definition of clinically relevant myocardial infarction after coronary revascularization: an expert consensus document from the Society for Cardiovascular Angiography and Interventions (SCAI). J Am Coll Cardiol 2013;62:1563–70. https://

doi.org/10.1016/j.jacc.2013.08.720; PMID: 24135581. 26. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction (2018). Glob Heart 2018;13:305–38. https://doi.org/10.1016/j.gheart.2018.08.004; PMID: 30154043. 27. Ruel M, Falk V, Farkouh ME, et al. Myocardial revascularization trials. Circulation 2018;138:2943–51. https://doi.org/10.1161/ CIRCULATIONAHA.118.035970; PMID: 30566019. 28. Parasca CA, Head SJ, Milojevic M, et al. Incidence, characteristics, predictors, and outcomes of repeat revascularization after percutaneous coronary intervention and coronary artery bypass grafting: the SYNTAX Trial at 5 years. JACC Cardiovasc Interv 2016;9:2493–507. https://doi. org/10.1016/j.jcin.2016.09.044; PMID: 28007201. 29. Ong AT, Serruys PW. Complete revascularization: coronary artery bypass graft surgery versus percutaneous coronary intervention. Circulation 2006;114:249–55. https://doi. org/10.1161/CIRCULATIONAHA.106.614420; PMID: 16847164. 30. Giustino G, Serruys PW, Sabik JF 3rd, et al. Mortality after repeat revascularization following PCI or CABG for left main disease: the EXCEL trial. JACC Cardiovasc Interv 2020;13:375–87. https://doi.org/10.1016/j.jcin.2019.09.019; PMID: 31954680. 31. Benedetto U, Puskas J, Kappetein AP, et al. Off-pump versus on-pump bypass surgery for left main coronary artery disease. J Am Coll Cardiol 2019;74:729–40. https://doi.org/10.1016/j. jacc.2019.05.063; PMID: 31395122. 32. Aldea GS, Bakaeen FG, Pal J, et al. The Society of Thoracic Surgeons clinical practice guidelines on arterial conduits for coronary artery bypass grafting. Ann Thorac Surg 2016;101:801– 9. https://doi.org/10.1016/j.athoracsur.2015.09.100; PMID: 26680310. 33. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2011;124:2610–42. https://doi. org/10.1161/CIR.0b013e31823b5fee; PMID: 22064600. 34. Taggart DP, Gaudino MF, Gerry S, et al. Effect of total arterial grafting in the Arterial Revascularization Trial. J Thorac Cardiovasc Surg 2020. https://doi.org/10.1016/j. jtcvs.2020.03.013; PMID: 32305186; epub ahead of press. 35. Puskas JD, Sadiq A, Vassiliades TA, et al. Bilateral internal thoracic artery grafting is associated with significantly improved long-term survival, even among diabetic patients. Ann Thorac Surg 2012;94:710–6. https://doi.org/10.1016/j. athoracsur.2012.03.082; PMID: 22677228. 36. Thuijs DJFM, Head SJ, Stone GW, et al. Outcomes following surgical revascularization with single versus bilateral internal thoracic arterial grafts in patients with left main coronary artery disease undergoing coronary artery bypass grafting: insights from the EXCEL trial. Eur J Cardiothorac Surg 2019;55:501–10. https://doi.org/10.1093/ejcts/ezy291; PMID: 30165487. 37. Scanlon PJ, Faxon DP, Audet AM, et al. ACC/AHA guidelines for coronary angiography. A report of the American College of Cardiology/American Heart Association Task Force on practice

38.

39.

40.

41.

42.

43.

44.

45.

46.

guidelines (Committee on Coronary Angiography). Developed in collaboration with the Society for Cardiac Angiography and Interventions. J Am Coll Cardiol 1999;33:1756–824. https://doi. org/10.1016/s0735-1097(99)00126-6; PMID: 10334456. Beauman GJ, Vogel RA. Accuracy of individual and panel visual interpretations of coronary arteriograms: implications for clinical decisions. J Am Coll Cardiol 1990;16:108–13. https://doi. org/10.1016/0735-1097(90)90465-2; PMID: 2358583. Pijls NH, Van Gelder B, Van der Voort P, et al. Fractional flow reserve. A useful index to evaluate the influence of an epicardial coronary stenosis on myocardial blood flow. Circulation 1995;92:3183–93. https://doi.org/10.1161/01. cir.92.11.3183; PMID: 7586302. Jayakumar S, Bilkhu R, Ayis S, et al. The role of fractional flow reserve in coronary artery bypass graft surgery: a metaanalysis. Interact Cardiovasc Thorac Surg 2020;30: 671–8. https:// doi.org/10.1093/icvts/ivaa006; PMID: 32167555. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541–619. https://doi. org/10.1093/eurheartj/ehu278; PMID: 25173339. Head SJ, Kaul S, Mack MJ, et al. The rationale for Heart Team decision-making for patients with stable, complex coronary artery disease. Eur Heart J 2013;34: 2510–8. https://doi. org/10.1093/eurheartj/eht059; PMID: 23425523. Yates MT, Soppa GK, Valencia O, et al. Impact of European Society of Cardiology and European Association for Cardiothoracic Surgery guidelines on myocardial revascularization on the activity of percutaneous coronary intervention and coronary artery bypass graft surgery for stable coronary artery disease. J Thorac Cardiovasc Surg 2014;147:606– 10. https://doi.org/10.1016/j.jtcvs.2013.01.026; PMID: 23402690. Pavlidis AN, Perera D, Karamasis GV, et al. Implementation and consistency of Heart Team decision-making in complex coronary revascularisation. Int J Cardiol 2016;206: 37–41. https://doi.org/10.1016/j.ijcard.2016.01.041; PMID: 26774827. Patel MR, Calhoon JH, Dehmer GJ, et al. ACC/AATS/AHA/ASE/ ASNC/SCAI/SCCT/STS 2017 appropriate use criteria for coronary revascularization in patients with stable ischemic heart disease: a report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society of Thoracic Surgeons. J Nucl Cardiol 2017;24:1759–92. https://doi. org/10.1007/s12350-017-0917-9; PMID: 28608183. National Adult Cardiac Surgery Audit. NICOR, 2019. https://www. hqip.org.uk/wp-content/uploads/2019/09/national-adultcardiac-surgery-summary-report-2019-final.pdf (accessed 12 October 2020).

EUROPEAN CARDIOLOGY REVIEW

Management and Comorbidities

Factors Related to Maternal Adverse Outcomes in Pregnant Women with Cardiac Disease in Low-resource Settings Philippe Amubuomombe Poli 1, Elkanah Omenge Orang’o1, Ann Mwangi2 and Felix Ayub Barasa3 1. Department of Reproductive Health, Moi University School of Medicine, Eldoret, Kenya; 2. Department of Behavioural Sciences, Moi University School of Medicine, Eldoret, Kenya; 3. Department of Cardiology, Moi Teaching and Referral Hospital, Eldoret, Kenya

Abstract Background: Cardiac disease is an important life-threatening complication during pregnancy. It is frequently seen in pregnant women living in resource-limited areas and often results in premature death. Aim: The aim of this hospital-based longitudinal study was to identify factors related to adverse maternal and neonatal outcomes in pregnant women with cardiac disease in low-resource settings. Methods: The study enrolled 91 pregnant women with congenital or acquired cardiac disease over a period of 2 years in Kenya. Results: Maternal and early neonatal deaths occurred in 12.2% and 12.6% of cases, respectively. The risk of adverse outcomes was significantly increased in those with pulmonary oedema (OR 11, 95% CI [2.3–52]; p=0.002) and arrhythmias (OR 16.9, 95% CI [2.5–113]; p=0.004). Limited access to care was significantly associated with adverse maternal outcomes (p≤0.001). Conclusion: Many factors contribute to adverse maternal and neonatal outcomes in pregnant women with cardiac disease. Access to comprehensive specialised care may help reduce cardiac-related complications during pregnancy.

Keywords Adverse outcomes, cardiac disease and pregnancy, cardiac events, obstetric events, resource-limited settings, therapeutic abortion Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: The authors thank Edwin Were, Paul Nyongesa, Andrew Cheruiyot and Joy Marsha Alera for their valuable support from the conception to the end of this study. Received: 17 February 2020 Accepted: 14 August 2020 Citation: European Cardiology Review 2020;15:e68. DOI: https://doi.org/10.15420/ecr.2020.04 Correspondence: Philippe Amubuomombe Poli, Department of Reproductive Health, Moi University, School of Medicine, PO Box 4606–30100, Eldoret, Kenya. E: philippe_poli@yahoo.fr Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Pregnancy in women with cardiac disease is associated with lifethreatening complications. Although there has been progress in the field, cardiac disease in pregnancy remains among the leading causes of maternal and neonatal mortality and morbidity.1–3 Many studies have shown correlations between pregnancy-related haemodynamic changes and cardiac events.4–7 However, few studies have investigated factors related to adverse outcomes in the context of resource-limited settings. In addition, the condition has been poorly studied in most developing regions, leading to a poor understanding of the effects of cardiac disease on pregnancy outcomes among both clinicians and affected women of reproductive age. The aim of this study was to identify factors related to adverse maternal and neonatal outcomes in pregnant women with cardiac disease in low-resource settings.

Methods This hospital-based longitudinal case series study was conducted between October 2016 and October 2018 in Kenya. The inclusion criteria were abnormal echocardiography and ECG findings in pregnant women and/or women in the postpartum period, as reviewed by an independent cardiologist. The study was approved on 27 September 2016 by the Moi University, Moi Teaching and Referral Hospital Institutional Research and Ethics

Committee (IREC; Approval no. FAN: IREC1756). All women enrolled in the study provided written informed consent.

Definitions of Abnormal Echocardiogram and Electrocardiogram Findings Abnormal echocardiogram findings were defined as follows: • left ventricular (LV) dysfunction with an ejection fraction <55%; • diastolic dysfunction (E/A ratio <1 and a diastolic time [DT] >200 ms, and the presence of LV hypertrophy [LVH] in patients with Grade I diastolic dysfunction); • right ventricular hypertrophy (RVH), with subcostal wall thickness ≥6 mm (classified as mild, moderate or severe); • wall motion abnormalities (hypokinesia, akinesia or dyskinesia); or • valvular abnormalities. Abnormal ECG findings were defined as the presence of arrhythmias and ST and QRS segment abnormalities.

Data Collection Patients with a confirmed diagnosis of cardiac disease were interviewed and the following data were collected: maternal age, education level, marital status, occupation, residence location, health

Access at: www.ECRjournal.com

Management and Comorbidities Figure 1: Maternal Adverse Cardiac Outcomes

and IV). In addition, the mWHO risk tool was used in to divide patients into groups, as follows9:

30%

Frequency

25%

• low risk (mWHO Category I): no detectable increased risk of maternal mortality and no or a mild increased risk for morbidity; • medium risk (mWHO Category II): minor increased of maternal mortality or moderate morbidity; • high risk (mWHO Categories II–III and III): significant increased risk of maternal mortality or severe morbidity; and • extremely high risk (mWHO Category IV): extremely high risk of maternal mortality or severe morbidity.

23.3%

20% 16.7% 15%

15.6%

10% 4.4%

5% 0%

0.0% Left heart failure

Pulmonary oedema

Arrhythmias

Cardiac arrest

Systemic embolism

Cardiac event

insurance coverage, parity, BMI, tobacco and alcohol use, type of cardiac disease, New York Heart Association (NYHA) functional class and modified WHO (mWHO) risk index, comorbidities (diabetes, chronic hypertension, hyperthyroid disease, renal disease, coagulopathy, HIV/AIDS, venous thromboembolism, anaemia, malnutrition and mental illness), preconception care, cardiac disease prior to current pregnancy, treatment prior or during pregnancy, prior surgical cardiac intervention, mode of admission, maternal antenatal care history, level of care facility attended according to the national health system, gestational age at the time of enrolment and number of foetuses. Foetal wellbeing was assessed using obstetric ultrasound and was defined as a normal biophysical profile (foetal heart rate, breathing movements, body movements, muscle tone and amniotic fluid index) or the absence of foetal abnormalities. For pregnancy dating, if the difference between the last menstrual period and the ultrasound findings was >7 days, the ultrasound assessment was used as the reference. In addition, details regarding the mode and place of delivery were recorded. The severity of cardiac disease was lesion specific and included mitral stenosis (MS), mitral regurgitation (MR), aortic stenosis, aortic regurgitation (AR), tricuspid stenosis, tricuspid regurgitation and pulmonary arterial hypertension. These lesions were classified as mild, moderate or severe. The severity of MS was defined as follows:

Details of mWHO risk categories are provided in Supplementary Material Box 1. Adverse maternal outcomes (prespecified adverse outcomes) were defined as the occurrence of cardiac and obstetric events. Cardiac events included heart failure (HF), pulmonary oedema, arrhythmias, cardiac arrest, endocarditis and thromboembolic events. Chest radiography was used to confirm the clinical diagnosis of pulmonary oedema. Obstetric events consisted of preterm labour and preterm delivery, antepartum or postpartum haemorrhage, depression, stillbirth, miscarriage, therapeutic abortion, admission to the intensive care unit (ICU) and maternal death, all of which were recorded according to gestation period. The primary outcome of the study was the occurrence of one or more adverse events, whereas secondary outcomes were successful delivery or recovery or improvement within 6 weeks postpartum.

Statistical Analysis Data were analysed using IBM SPSS version 20.0. (IBM). Categorical data are described as frequencies and percentages, whereas continuous data are described as interquartile range, mean ± SD or median values. The Kolmogorov–Smirnov test was used to verify the normal distribution of quantitative data. Significance was set at twotailed p<0.05. The chi-squared test was used to compare categorical between groups based on outcomes. Fisher’s exact test or Monte Carlo correction was used for chi-squared analysis when more than 20% of the cells had an expected count <5. The ORs and 95% CIs for maternal adverse outcomes were calculated using logistic regression.

Results • mild: mitral valve area (MVA) >1.5 cm2 or a mean gradient <6 mmHg; • moderate: MVA 1.0–1.5 cm2 or a mean gradient 6–12 mmHg; and • severe: MVA <1.0 cm2 or a mean gradient >12 mmHg. Heart valvular diseases were defined according to the European Association of Echocardiography and American Society of Echocardiography recommendations for the echocardiographic assessment of valve lesions.8 Regurgitant valve lesions, including MR, AR, pulmonary hypertension and tricuspid regurgitation , were quantified on the basis of a visual inspection of echocardiographic findings. Congenital heart disease was classified according to the size of the lesion rather than its anatomical position; lesions were classified as small, moderate or large. Cardiomyopathies were classified as hypertrophic or dilated. The type of cardiac disease was defined as rheumatic heart disease (RHD), congenital heart disease or cardiomyopathy. NYHA functional classes were used to define patients as asymptomatic (NYHA Class I) or symptomatic (NYHA Classes II, III

There were 91 pregnant women with cardiac disease recruited to the study. Of those, 98.9% had complete follow-up data, and one was lost to follow-up. The socio-demographic characteristics of the women are summarised in Supplementary Material Table 1. The distribution of cardiac diseases and maternal clinical characteristics are summarised in Supplementary Material Table 2.

Maternal Outcomes Figure 1 shows maternal cardiac adverse outcomes. Maternal cardiac events occurred in 60% of women, with the most common complication being HF, which accounted for 23.3% of all cardiac events, followed by pulmonary oedema (16.7%) and arrhythmias (15.6%). Maternal cardiac arrest was the least common adverse cardiac event, occurring in 4.4% of women. HF and arrhythmias predominantly occurred in the second trimester, between 14 and 28 weeks’ gestation, in 25.9% and 14.8% of women, respectively. Pulmonary oedema was also frequent in the postpartum period (18.5%). Obstetric adverse outcomes (Figure 2) occurred in 75.6% of women, with preterm delivery being the most

EUROPEAN CARDIOLOGY REVIEW

Factors Related to Maternal Adverse Outcomes Table 1: Maternal Clinical Characteristics Associated With Adverse Outcomes Maternal and neonatal outcomes

Chi-squared

p-value

OR [95% CI]

p-value

Good (n=65)

Adverse (n=25)

RHD

59 (90.8)

21 (84.0)

0.838

0.455*

0.5 [0.1–2.1]

0.366

Cardiomyopathies

4 (6.2)

3 (12.0)

0.86

0.392*

[0.4–10.0]

0.362

1.3 [0.1–15.1]

0.828

–

Type of Heart Disease

CHD

2 (3.1)

1 (4.0)

12 (18.5)

1 (4.0)

0.048

1.000

0.071

NYHA Functional Class I†

[0.3–27.1]

0.328

8 [0.9–71.6]

0.063

7 (28.0)

8.4 [0.9–80.3]

0.065

10 (15.4)

1 (4.0)

–

15 (23.1)

4 (16.0)

III

7 (10.8)

3 (12.0)

33 (50.8)

28 (43.1)

7 (28.0)

III

15 (23.1)

10 (40.0)

10 (15.4)

I†

6.922

mWHO Risk Category 2.7 [0.3–27]

0.41

4.3 [0.4–50]

0.246

17 (68.0)

5.2 [0.6–43]

0.133

3.129

0.355**

Intervention Prior to Pregnancy MVR

1 (1.5)

1 (4.0)

2.5 [0.2–41.6]

0.523

BVR

1 (1.5)

0 (0.0)

0 [0]

Balloon valvuloplasty

3 (4.6)

0 (0.0)

0 [0]

0.999

None†

60 (92.3)

24 (96.0)

–

Heart failure

16 (24.6)

5 (20.0)

3.9 [0.8–18]

0.081

Pulmonary oedema

8 (12.3)

7 (28.0)

11.1 [2.3–52]

0.002

1.987

0.569

Cardiac Events

Arrhythmias

6 (9.2)

8 (32.0)

16.9 [2.5–113]

0.004

Cardiac arrest

0 (0.0)

4 (16.0)

2 × 1010 [0]

0.999

No event†

35 (53.8)

1 (4.0)

–

PPH

8 (12.3)

2 (8.0)

2.1 [0.3–13.3]

0.447

Miscarriage

0 (0.0)

3 (12.0)

1 × 1010 (0]

0.999

28.424

<0.001

Obstetric Events

TOP

2 (3.1)

6 (24.0)

20.6 [2.9–143]

0.002

Preterm delivery

18 (27.7)

2 (8.0)

0.9 [0.1–5.5]

0.924

Depression

2 (3.1)

2 (8.0)

8.3 [0.8–75.7]

0.062

ICU admission

2 (3.1)

4 (16.0)

16.5 [2.3–120]

0.006

Pre-eclampsia

9 (13.8)

4 (16.0)

1.2 [0.3–4.3]

0.795

Stillbirth

0 (0.0)

2 (8.0)

1 × 1010 [0]

2 (3.1)

0 (0.0)

1 × 1010 [0]

0.999

22 (33.8)

0 (0.0)

–

Vaginal delivery†

52 (80.0)

10 (40.0)

Caesarean section

12 (18.5)

7 (28.0)

TOP + miscarriage

3 (4.6)

8 (32.0)

APH No event

†

33.449

<0.001

Mode of Delivery 23.233

<0.001**

–

2.2 [0.6–7.5]

0.223

52 [5.9–452]

<0.001

Unless indicated otherwise, data are given as n (%). *Fisher’s exact test. **Monte Carlo method. †No p-value. APH = antepartum haemorrhage; BVR = biological valve replacement; CHD = congenital heart disease; ICU = intensive care unit admission; MVR = mechanical valve replacement; mWHO = modified WHO; NYHA = New York Heart Association; PPH = postpartum haemorrhage; RHD = rheumatic heart disease; TOP = termination of pregnancy.

common (22.2%), followed by pre-eclampsia (14.4%) and postpartum haemorrhage (11.1%), termination of pregnancy (8.9%), postpartum depression (4.4%), miscarriage (3.3%), and stillbirths (2.2%). These events contributed to 16.2% of all maternal deaths; 8.8% of adverse events required admission to the ICU. Maternal cardiac and obstetric events according to gestation period are summarised in Supplementary Material Table 3. Supplementary Material Figure 1 shows maternal

EUROPEAN CARDIOLOGY REVIEW

deaths according to type of cardiac disease: 12.2% of patients died as a result of their cardiac disease. RHD was the leading cause of maternal death, responsible for eight deaths (73% of all deaths, but 10% of all women with RHD).

Trends for Factors Associated With Adverse Outcomes Socio-demographic factors such as maternal age, marital status and

Management and Comorbidities Table 2: Severity of Cardiac Disease According to Type of Lesion Maternal and neonatal outcomes Good (n=65)

Chi-square

p-value*

OR [95% CI]

p-value

4.124

0.248

Adverse (n=25)

Mitral Stenosis None†

22 (33.8)

11 (44.0)

–

Mild

16 (24.6)

2 (8.0)

0.25 [0.05–1.3]

0.097

Moderate

11 (16.9)

3 (12.0)

0.545 [0.13–2.4]

0.418

Severe

16 (24.6)

9 (36.0)

1.125 [0.38–3.4]

0.832

None†

26 (40.0)

15 (60.0)

–

Mild

10 (15.4)

3 (12.0)

0.52 [0.12–2.191]

0.373

Moderate

27 (41.5)

2 (8.0)

0.128 [0.03–0.62]

0.010

Severe

2 (3.1)

5 (20.0)

4.333 [0.75–25.2]

0.102

None†

59 (90.8)

23 (92.0)

–

Moderate

1 (1.5)

1 (4.0)

2.565 [0.15–42.8)]

0.512

Severe

5 (7.7)

1 (4.0)

0.513 [0.06–4.6]

0.552

None†

60 (92.3)

23 (92.0)

–

Moderate

2 (3.1)

1 (4.0)

0 [0]

0.999

Severe

3 (4.6)

1 (4.0)

0.833 [0.08–8.4]

0.877

Mitral Regurgitation 14.860

0.001

Aortic Stenosis 1.121

0.655

Aortic Regurgitation 0.545

Tricuspid Regurgitation None†

35 (53.8)

10 (40.0)

–

Mild

3 (4.6)

0 (0.0)

0 [0]

0.999

Moderate

14 (21.5)

3 (12.0)

2.143 [0.61–7.5]

0.234

Severe

13 (20.0)

12 (48.0)

4.231 [1.35–13.3]

0.013

None†

35 (53.8)

10 (40.0)

–

Mild

3 (4.6)

0 (0.0)

0 [0]

0.999

Moderate

13 (20.0)

3 (12.0)

0.808 [0.19–3.4]

0.771

Severe

14 (21.5)

12 (48.0)

3 [1.06–8.5]

0.039

7.079

0.056

PAH 5.893

0.104

VSD None†

62 (95.4)

24 (96.0)

–

Severe

2 (3.1)

1 (4.0)

1.292 [0.11–14.9]

0.838

Moderate

1 (1.5)

0 (0.0)

0 [0]

0.759

Unless indicated otherwise, data are given as n (%). *Monte Carlo method. †No p-value. PAH = pulmonary arterial hypertension; VSD = ventricular septal defect.

occupation were not significantly associated with adverse outcomes. However, a low education level (primary), which was not significantly associated with adverse outcomes (p=0.126), increased the odds of adverse outcomes 3.3-fold after adjustment for confounders (95% CI [1.0–11]; p=0.049). In addition, residence location was significantly associated with adverse outcomes (p=0.009), with 100% of women from rural areas experiencing some form of adverse outcome. However, adjustment for confounders, residence location was not associated with an increased risk of adverse outcomes (Supplementary Material Table 4). The type of cardiac disease, NYHA functional class, mWHO risk category and prior cardiac surgery intervention were not significantly associated with adverse outcomes (Table 1). However, any cardiac event was significantly associated with adverse maternal outcomes (p≤0.001). After adjustment for confounders, pulmonary oedema and arrhythmias were associated with significant 11- and 17-fold increases, respectively, in the odds of adverse outcomes.

Obstetric adverse events were significantly associated with adverse outcomes (p≤0.001). After adjustment for confounders, therapeutic abortion and late maternal ICU admission were associated with significant 20.6-fold (95% CI [2.9–143]) and 16.5-fold (95% CI [2.3–120]) increases in the risk of adverse outcomes, respectively. Mode of delivery was also significantly associated with adverse outcomes (p≤0.001). After adjustment for confounders, only therapeutic abortion remained significant and was associated with a 52-fold increase in the odds of adverse outcomes (95% CI [5.9–452]; p≤0.001). Limited access to quality antenatal care, parity, place of delivery and the level of the facility that provided care were significantly associated with adverse outcomes (Supplementary Material Table 5). After adjustment for confounders, delivery at home increased the risk of adverse outcomes approximately 23-fold (95% CI [2.3–224]; p=0.007). Mode of delivery and limited access to quality care were significantly associated with maternal adverse outcomes, increasing the risk fourfold and 19-fold, respectively (Supplementary Material Table 5).

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Factors Related to Maternal Adverse Outcomes Figure 2: Maternal Adverse Obstetric Outcomes

25% 22.2%

Frequency

20%

14.4%

15%

12.2%

11.1% 10%

8.9% 6.7% 4.4%

3.3% 2.2%

2.2%

Stillbirths

APH

0% Preterm delivery

Preeclampsia

PPH

TOP

ICU admission

Postpartum depression

Miscarriage

Death

Obstetric event APH = antepartum haemorrhage; ICU = intensive care unit; PPH, postpartum haemorrhage; TOP = termination of pregnancy.

MR (mild, moderate and severe) was significantly associated with adverse outcomes (p=0.001; Table 2). After adjustment for confounders, moderate MR was found to be protective against adverse outcomes (OR 0.128; 95% CI [0.03–062]; p=0.010). MS, aortic stenosis, AR, tricuspid disease and ventricular septal defects were not significantly associated with maternal adverse outcomes. After adjustment for confounders, severe tricuspid disease and severe pulmonary arterial hypertension were associated with 4.2-fold (95% CI [1.3–13.3]) and threefold (95% CI [1.1–8.5]) increased risks of maternal adverse outcomes, respectively.

Discussion The rate of cardiac adverse events was higher in the present study than in previous studies.6,7 This study had similar findings to the Cardiac Disease in Pregnancy (CARPREG) II study, where most cardiac complications occurred during the antepartum period, followed by the postpartum period, and cardiac complications during the intrapartum being the least frequent.7 This is not surprising because more than half the women in the present study who were diagnosed with cardiac disease during pregnancy were not receiving treatment. The delay in the decision to seek care could be the main reason for the higher rate of cardiac events in this study. HF, the leading cardiac complication, occurred most often in the second trimester. This is congruent with findings of previous studies regarding the gradual haemodynamic changes in pregnancy and the occurrence of HF in pregnant women with cardiac disease.10–14 However, the finding of the present study is in contrast with those of the CARPREG II Study, in which HF was predominantly reported during the third trimester and postpartum period.7 However, in contrast with the CARPREG II study, the present study considered HF and pulmonary oedema as two different cardiac complications. Among participants who experienced pulmonary oedema during the antepartum period, one who had severe mitral stenosis and aortic stenosis developed fatal acute pulmonary oedema following administration of 12 mg of dexamethasone for foetal lung maturity. Corticosteroid-induced pulmonary oedema in patients with

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Table 3: Multivariate Logistic Regression Outcomes Variable

p-value

OR (95% CI)

Mode of delivery

0.013

4.6 (1.3–15.1)

Limited access to ANC

0.020

19.3 (1.6–233.3)

ANC = antenatal care.

rheumatic heart disease have not been investigated. However, fluid retention, known as one of the cardiovascular effects of corticosteroids, could explain the occurrence of acute adverse event. Therefore, if the risk of corticosteroid therapy to the mother outweigh the benefit to the foetus, it is wise for the clinician to withhold the treatment. Instead, preterm infant should benefit surfactant administration after delivery. Cardiac arrhythmias frequently occurred during the antepartum period, AF being the predominant arrhythmia. AF frequently occurred in the group of patients who did not have arrhythmias at time of admission but developed complications during termination of pregnancy (TOP). Misoprostol, a synthetic prostaglandin (PG) E1, was the drug used for TOP in all patients who underwent therapeutic abortion. The rate of obstetric adverse events in the present study was sevenfold times higher than that reported in previous studies.6,7 An incidental finding of cardiac arrhythmias was reported among women who underwent therapeutic abortion with PGE1 from mid-pregnancy. The observed adverse outcomes ranged from arrhythmias to death. To date, no data are available regarding the cardiovascular effects of misoprostol, a drug widely used in resource-limited settings for the induction of labour and TOP. However, the European Society of Cardiology (ESC) has reported theoretical risks of coronary vasospasm and arrhythmias as side effects of PGE1.5 We acknowledge the recent recommendation in the ESC guidelines suggesting the use of 100 µg PGE1 for the termination of pregnancy up to 9 weeks or surgical abortion beyond 9 weeks.5

Management and Comorbidities In the present study, most patients who underwent TOP because of their risk index category received two to three doses of ≥200 µg misoprostol at 4-hour intervals, depending on how the individual patient responded to the initial dose. Most women who died after TOP died because of similar complications, including pulmonary oedema (confirmed by autopsy) and AF. They also had similar characteristics, including severe MS, severe pulmonary hypertension and tricuspid disease. This incidental finding needs further investigation in a larger sample size. However, carrying out such study poses ethics dilemma for approval. In addition, the authors critically examined the recommendation to initiate TOP in mid-pregnancy based on the mWHO risk category index and concluded that the recommendation lacked expert consensus. Moreover, previous studies acknowledged the limitations of predictors and risk scores when making decisions and recommended additional alternative management options, including obtaining expert opinion, hospitalisation of extremely high-risk patients up to delivery or exclusive care in a specialist unit.15–17 Furthermore, percutaneous balloon mitral commissurotomy in the second trimester is currently recommended for mothers with severe valvular heart lesions who do not respond to medical treatment.18,19 Therefore, we recommend TOP in only women presenting with refractory HF. At term or nearly at term, mechanical Foley catheter induction of labour is preferred. However, low-dose oxytocin has been safely used in low-risk patients.20 Most ICU admissions in the present study occurred during the postpartum period. However, most of these patients had poor outcomes. A lack of health insurance was a major contributor to poor outcomes due to limited access to ICUs in private hospitals when public hospital ICUs are full. The authors acknowledge the expert consensus regarding timely ICU admission for labour and delivery of high-risk and extremely high-risk patients.5,16,17 However, the cost of ICU care and a lack of adequate infrastructure and trained staff are major obstacles in resource-limited settings.21–23 In this study, most of the high- and extremely high-risk patients were managed and delivered at the cardiac care unit (CCU), and only one mother died out of 22 deliveries at the CCU. Therefore, the CCU is a good alternative to the ICU for monitoring high- and extremely high-risk pregnant women in labour or after delivery. Demographic factors and adverse outcomes in pregnant women with cardiac disease have been investigated across the world. For example, in the CARPREG II study maternal age <18 and >35 years was reported to be associated with adverse outcomes.7 This is in contrast with the findings in the present study because, in the context of developing countries, age alone cannot explain the occurrence of adverse outcomes. Adverse outcomes are the product of an interplay of multiple factors, including poor health literacy, disease severity, poor healthseeking behaviour and poverty. In addition, previous studies have described the association between maternal education level and adverse outcomes.24–26 Similarly, a low maternal education level increased the odds of maternal adverse outcomes, which can clearly be explained by poor health literacy, and a low socioeconomic level translates to poverty, both of which affect the decision to seek care. Residence location was associated with maternal adverse outcomes, especially in rural dwellers, but was not found to increase the risk of adverse outcomes. This can be explained by limited timely access to tertiary hospital care and poverty. The Registry of Pregnancy and Cardiac Disease (ROPAC), recently recognised limited access to specialised care as one of the causes of poor outcomes in developing areas.6 In addition, adverse outcomes likely occur because of the

trifecta of a delay in seeking care, reaching the right facility and receiving appropriate treatment.27 RHD was the predominant cardiac disease in pregnancy, and accounted for most adverse outcomes. This is congruent with previous studies that identified RHD as the leading cause of death in developing countries. Moreover, Diao et al. reported that up to 34% of maternal deaths were attributable to rheumatic disease.³ In the present study, every 10th pregnant woman admitted with RHD died during pregnancy. This is evidence that mortality due to RHD is still far from controlled in most developing areas. Almost all rheumatic disease-related deaths or observed adverse outcomes were reported in women with severe MS and/or complex heart disease, including severe pulmonary hypertension and severe tricuspid disease. Pieper and Hoendermis, along with other investigators, reported similar findings in which valvular disease, especially MS, was the leading cause of secondary pulmonary hypertension, which is associated with high mortality in affected pregnant women.9,28 NYHA functional class was not associated with adverse outcomes. This contrasts with results from previous studies in which advanced cardiac functional class was repeatedly reported to predict poor maternal and foetal outcomes.6,7 These conflicting results are due primarily to differences in the study populations. The mWHO risk category was not associated with adverse outcomes. van Hagen et al., from the ROPAC, reported a similar finding that was particularly evident in data from developing countries where the mWHO risk category tool did not perform well.6 This may be related to the interaction of multiple factors, including socio-demographic and clinical factors, especially the lack of universal access to state-of-the-art care by multidisciplinary expert teams; access to these teams would minimise the effects of practice differences in the management of such high-risk patients. In addition, Balci et al. found another weakness in the mWHO risk classification: expert knowledge is sometimes more important than individual risk assessment.29 Such knowledge or expertise is lacking in resourcelimited settings. Surgical intervention prior to pregnancy was not found to be associated with adverse outcomes. This could be related to the low number of patients who underwent surgical correction before pregnancy. The original CARPREG study risk prediction tool did not include this variable; however, in the CARPREG II study, prior cardiac intervention for placement of a mechanical prosthesis increased the rate of adverse outcomes.7 These adverse outcomes are primarily teratogenic effects and abortion associated with anticoagulation, especially warfarin, or thromboembolic events associated with mechanical valve prosthesis.19 This study recognises that surgical cardiac interventions use new technologies that are out of reach of the majority of patients in developing countries. To date, Kenya is among the few countries in subSaharan Africa with the capability to perform heart surgery, with five facilities across the country. Although surgical treatment is available in locations relatively accessible to patients, the low socioeconomic level of most patients is a major obstacle to obtaining treatment for cardiac diseases. Notably, not all patients are eligible for cardiac intervention. In their study, van Hagen et al. found that percutaneous balloon commissurotomy, which is also performed during the second trimester of pregnancy, significantly improved maternal and perinatal outcomes.18 The place and mode of delivery were associated with adverse outcomes. Infants born at home died within 3 days of birth, and their

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Factors Related to Maternal Adverse Outcomes mothers were likely to be admitted to the ICU. The plausible explanation of complications related to home births is that the delivery can be assisted by an unskilled person or in an unsafe environment with limited access to essential newborn care or management of cardiac events that may occur after delivery. In their retrospective study, Titaley et al. reported both maternal and neonatal complications were associated with home birth, even if the deliveries were conducted by trained nurses.30 Caesarean delivery was significantly associated with the risk of adverse outcomes. This is not surprising because the use of anaesthetic agents (general or regional anaesthesia) is known to be an important factor triggering cardiac events, especially cardiac arrest.9,31,32 To reduce anaesthesia-related mortality and morbidity in women with cardiac disease and based on the cardiovascular effects of each drug, expert application of regional anaesthesia is the preferred method, although it has minimal

10.

11.

Ashrafi R, Curtis SL. Heart disease and pregnancy. Cardiol Ther 2017;6:157–73. https://doi.org/10.1007/s40119-017-0096-4; PMID: 28681178. Ertekin E, Van Hagen IM, Salam AM, et al. Ventricular tachyarrhythmia during pregnancy in women with heart disease: data from the ROPAC, a registry from the European Society of Cardiology. Int J Cardiol 2016;220:131–6. https://doi. org/10.1016/j.ijcard.2016.06.061; PMID: 27376569. Diao M, Kane A, Ndiaye MB, et al. Pregnancy in women with heart disease in sub-Saharan Africa. Arch Cardiovasc Dis 2011;104:370–4. https://doi.org/10.1016/j.acvd.2011.04.001; PMID: 21798468. Soma-Pillay P, Nelson-Piercy C, Tolppanen H, Mebazaa A. Physiological changes in pregnancy. Cardiovasc J Afr 2016;27:89–94. https://doi.org/10.5830/CVJA-2016-021; PMID: 27213856. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al. 2018 ESC guidelines for the management of cardiovascular diseases during pregnancy: the Task Force for the Management of Cardiovascular Diseases During Pregnancy of the European Society of Cardiology (ESC). Eur Heart J 2018;39:3165–241. https://doi.org/10.1093/eurheartj/ehy340; PMID: 30165544. van Hagen IM, Boersma E, Johnson MR, et al. Global cardiac risk assessment in the Registry of Pregnancy and Cardiac Disease: results of a registry from the European Society of Cardiology. Eur J Heart Fail 2016;18:523–33. https://doi. org/10.1002/ejhf.501; PMID: 27006109. Silversides CK, Grewal J, Mason J, et al. Pregnancy outcomes in women with heart disease: the CARPREG II study. J Am Coll Cardiol 2018;71:2419–30. https://doi.org/10.1016/j. jacc.2018.02.076; PMID: 29793631. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015;16:233–71. https://doi. org/10.1093/ehjci/jev014; PMID: 25712077. Elkayam U, Goland S, Pieper PG, Silverside CK. High-risk cardiac disease in pregnancy: part I. J Am Coll Cardiol 2016;68:396–410. https://doi.org/10.1016/j.jacc.2016.05.048; PMID: 27443437. Adam K. Pregnancy in women with cardiovascular diseases. Methodist Debakey Cardiovasc J 2017;13:209–15. https://doi. org/10.14797/mdcj-13-4-209; PMID: 29744013. Meah VL, Cockcroft JR, Backx K, et al. Cardiac output and related haemodynamics during pregnancy: a series of metaanalyses. Heart 2016;102:518–26. https://doi.org/10.1136/

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benefits.9,31 Moreover, women with pulmonary hypertension were found to have an increased risk of developing cardiac events with general anaesthesia, whereas general anaesthesia appeared to be the safest means of successful delivery in women with aortic stenosis.9,31 However, evidence has shown that caesarean delivery confers no advantage for maternal and neonatal outcomes.32–34 Indeed, caesarean delivery should only be performed for obstetric indications, defined as inability for the mother to achieve vaginal delivery at specific-time.

Conclusion Maternal adverse outcomes in women with cardiac disease are multifactorial in origin and include clinical and non-clinical factors. Timely access to comprehensive care and expertise regarding the management of cardiac diseases during pregnancy can contribute significantly to reducing maternal mortality and morbidity due to cardiac diseases.

heartjnl-2015-308476; PMID: 26794234. 12. Sanghavi M, Rutherford JD. Cardiovascular physiology of pregnancy. Circulation 2014;130:1003–8. https://doi. org/10.1161/CIRCULATIONAHA.114.009029; PMID: 25223771. 13. Liu LX, Arany Z. Maternal cardiac metabolism in pregnancy. Cardiovasc Res 2014;101:545–53. https://doi.org/10.1093/cvr/ cvu009; PMID: 24448314. 14. Moussa HN, Rajapreyar I. Comment on ACOG Practice Bulletin No. 212: pregnancy and heart disease. Obstet Gynecol 2019;134:881–2. https://doi.org/10.1097/ AOG.0000000000003497; PMID: 31568352. 15. Pieper PG. Pre-pregnancy risk assessment and counselling of the cardiac patient. Neth Heart J 2011;19:477–81. https://doi. org/10.1007/s12471-011-0188-z; PMID: 21901506. 16. Cardiovascular disorders. In: Cunningham F, Leveno K, Bloom S, et al., eds. Williams Obstetrics. 24th ed. New York: McGrawHill, 2014. 17. Pieper PG. The pregnant woman with heart disease: management of pregnancy and delivery. Neth Heart J 2012;20:33–7. https://doi.org/10.1007/s12471-011-0209-y; PMID: 22068733. 18. van Hagen IM, Thorne SA, Taha N, et al. Pregnancy outcomes in women with rheumatic mitral valve disease: results from the registry of pregnancy and cardiac disease. Circulation 2018;137:806–16.https://doi.org/10.1161/ CIRCULATIONAHA.117.032561; PMID: 29459466. 19. RHD Australia, National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand. Pregnancy in patients with rheumatic heart disease. In: The Australian Guideline for Prevention, Diagnosis and Management of Acute Rheumatic Fever and Rheumatic Heart Disease. 2nd ed. 2012; 98–136. https://ranzcog.edu.au/RANZCOG_SITE/media/ RANZCOG-MEDIA/Women%27s%20Health/RHD-guideline.pdf (accessed 7 September 2020). 20. Dogra Y, Suri V, Aggarwal N, Dogra RK. Induction of labor with oxytocin in pregnancy with low-risk heart disease: a randomized controlled trial. Turk J Obstet Gynecol 2019;16:213– 18. https://doi.org/10.4274/tjod.galenos.2019.59932; PMID: 32231850. 21. Dünser MW, Towey RM, Amito J, Mer M. 2017; Intensive care medicine in rural sub-Saharan Africa. Anaesthesia 2017;72:181– 9. https://doi.org/10.1111/anae.13710; PMID: 27868190. 22. Bajwa SK, Bajwa SJ, Kaur J, et al. Is intensive care the only answer for high risk pregnancies in developing nations? J Emerg Trauma Shock 2010;3:331–6. https://doi. org/10.4103/0974-2700.70752; PMID: 21063554. 23. Lalani HS, Waweru-Siika W, Kussin PS. Reply: critical care in sub-Saharan Africa: is it ready for prime time? Ann Am Thorac

Soc 2019;16:157–8. https://doi.org/10.1513/AnnalsATS.201809630LE; PMID: 30321062. 24. Tunçalp Ö, Souza JP, Hindin MJ, et al. Education and severe maternal outcomes in developing countries: a multicountry cross-sectional survey. BJOG 2014;121(Suppl 1):57–65. https:// doi.org/10.1111/1471-0528.12634; PMID: 24641536. 25. Dingemann C, Sonne M, Ure B, et al. Impact of maternal education on the outcome of newborns requiring surgery for congenital malformations. PLoS One 2019;14:e0214967. https:// doi.org/10.1371/journal.pone.0214967; PMID: 30958858. 26. Ugwuja EI, Akubugwo EI, Ibiam UA, Obidoa O. Maternal sociodemographic parameters: impact on trace element status and pregnancy outcomes in Nigerian women. J Health Popul Nutr 2011;29:156. https://doi.org/10.3329/jhpn. v29i2.7858; PMID: 21608425. 27. Calvello EJ, Skog AP, Tenner AG, Wallis LA. Applying the lessons of maternal mortality reduction to global emergency health. Bull World Health Organ 2015;93:417–23. https://doi.org/10.2471/ BLT.14.146571; PMID: 26240463. 28. Pieper PG, Hoendermis ES. Pregnancy in women with pulmonary hypertension. Neth Heart J 2011;19:504–8. https:// doi.org/10.1007/s12471-011-0219-9; PMID: 22068738. 29. Balci A, Sollie-Szarynska KM, van der Bijl AGL, et al. Prospective validation and assessment of cardiovascular and offspring risk models for pregnant women with congenital heart disease. Heart 2014;100:1373–81. https://doi. org/10.1136/heartjnl-2014-305597; PMID: 25034822. 30. Titaley CR, Dibley MJ, Roberts CL. Type of delivery attendant, place of delivery and risk of early neonatal mortality: analyses of the 1994–2007 Indonesia Demographic and Health Surveys. Health Policy Plan 2012;27:405–16. https://doi.org/10.1093/ heapol/czr053; PMID: 21810892. 31. Ruys TP, Roos-Hesselink JW, Pijuan-Domènech A, et al. Is a planned Caesarean section in women with cardiac disease beneficial? Heart 2015;101:530–6. https://doi.org/10.1136/ heartjnl-2014-306497; PMID: 25539946. 32. Dsouza MC, Shivappagoudar VM, Kedlaya A, et al. Anaesthetic management of a patient with severe aortic stenosis for caesarean section: a case report. Int J Res Med Sci 2015;3:2854– 6. https://doi.org/10.18203/2320-6012.ijrms20150840. 33. Easter SR, Rouse CE, Duarte V, et al. Planned vaginal delivery and cardiovascular morbidity in pregnant women with heart disease. Am J Obstet Gynecol 2020;222:77e1–11. https://doi. org/10.1016/j.ajog.2019.07.019; PMID: 31310750. 34. Hrycyk J, Kaemmerer H, Nagdyman N, et al. Mode of delivery and pregnancy outcome in women with congenital heart disease. PLoS One 2016;11:e0167820. https://doi.org/10.1371/ journal.pone.0167820; PMID: 28006009.

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