ECR 2022 - Volume 17

Volume 17 • 2022

Official journal of

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Volume Volume 17 17 •• 2022 2022

Editor-in-Chief Juan Carlos Kaski

St George’s University of London, London, UK

Deputy Editor Pablo Avanzas

University Hospital of Oviedo, Oviedo, Spain

Section Editors Cardiac Imaging

Biomarkers of CV Risk

Environmental Issues for CV Health

Royal Brompton Hospital, London, UK

Karolinska Institute, Solna, Sweden

Center for Cardiology, University Medical Center Mainz, Mainz, Germany

Pharmacogenomics

Ischaemic Heart Disease

Hospital Universitario Central de Asturias, Oviedo, Spain

St George’s University of London, London, UK

Catholic University of the Sacred Heart, Rome, Italy

Genetics and Cardiovascular Disease

Cardiovascular Disease in Women

Genética Molecular-Laboratorio Medicina, HUCA, Oviedo, Spain

Radboud University Medical Center, Nijmegen, Netherlands

Cardio-oncology

Cardiomyopathies and Athlete’s Heart Disease

John Baksi

Thomas Münzel

Bruna Gigante

Arrhythmias

David Calvo

Eliecer Coto

Azara Janmohamed

Giampaolo Niccoli Telemedicine

Angela HEM Maas

Rebecca Dobson

Fausto J Pinto

Santa Maria University Hospital (CHULN), CCUL, Lisbon School of Medicine, University of Lisbon, Lisbon, Portugal

Heart Failure

Gianluigi Savarese

University of Liverpool Heart & Chest Hospital, Liverpool, UK

St George’s University of London, London, UK

Aneil Malhotra

Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

Structural Heart Disease: Cardiac Intervention

Maria Lorenza Muiesan

Hypertension

Pharmacotherapy

University of Brescia, Brescia, Italy

Universidad Complutense, CIBERCV, Madrid, Spain

Giuseppe Ferrante

Humanitas Research Hospital, Humanitas University, Milan, Italy

Juan Tamargo

Regional Editors

Asia

North America

Shao-Liang Chen

Australasia

Carlos Morillo

Nanjing First Hospital, Nanjing Medical University, Nanjing, China

Christopher Zeitz

Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada

South America

University of Adelaide, Adelaide Medical School; Central Adelaide Local Health Network, Adelaide, Australia

Europe

Alberto Lorenzatti

Peter Ong

Hospital Córdoba, Cordoba, Argentina

Robert-Bosch-Krankenhaus, Stuttgart, Germany

International Advisers Wolfgang Koenig

Technical University of Munich, Munich, Germany

Basil Lewis

Lady Davis Carmel Medical Center and Technion-IIT, Haifa, Israel

Giuseppe Mancia

Mario Marzilli

University of Milano-Bicocca, Milan, Italy

University of Pisa, Pisa, Italy

Hiroaki Shimokawa

Tohoku University, Sendai, Japan

Editorial Board Ignacio J Amat-Santos

Hospital Clínico Universitario de Valladolid, Valladolid, Spain

Dominick Angiolillo

University of Florida College of Medicine, Jacksonville, FL, US

Ramón Arroyo-Espliguero

Hospital General Universitario, Guadalajara, Spain

Lina Badimon

Research Institute-Hospital de la Santa Creu i Sant Pau, IIBSant Pau, CiberCV, Barcelona, Spain

Debasish Banerjee

St George’s University of London, London, UK

Vinayak Bapat

Columbia University Medical Centre, New York, NY, US

Antoni Bayés-Genís

Natalia Berry

Mid Atlantic Permanente Medical Group, Washington DC, US

William E Boden

State University of New York at Buffalo and Buffalo General Hospital, Buffalo, NY, US

Clea Colombo

São Leopoldo Mandic Medical School, São Paulo, Brazil

Derek Connolly

Sandwell & West Birmingham Hospitals NHS Trust, Birmingham, UK

Dana Cramariuc

Hospital Germans Trias i Pujol, Barcelona, Christopher P Cannon Haukeland University Hospital and Spain Harvard Medical School, Boston, MA, US Department of Clinical Science, University of Bergen, Bergen, Norway John F Beltrame Edina Cenko University of Adelaide, University of Bologna, Bologna, Italy Alberto Cuocolo Adelaide, Australia University of Naples Federico II, Naples, Peter Collins Imperial College, London, UK

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Italy

Volume 17 • 2022

Gheorghe Andrei Dan

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Editorial Board (cont.)

Kim Greaves

C Noel Bairey Merz

Colentina University Hospital, Bucharest, Romania

Sunshine Coast University Hospital, Queensland, Australia

Cedars-Sinai Heart Institute, Los Angeles, CA, US

Ranil de Silva

Brian Halliday

Helga Midtbø

Imperial College, London, UK

Imperial College London, UK

Marcelo Di Carli

Eileen M Handberg

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

University of Florida, FL, US

Carlo Di Mario

National Hospital Organization Kyoto Medical Center, Kyoto, Japan

Polychronis Dilaveris

Lezica Cardiovascular Institute, Buenos Aires, Argentina

Careggi University Hospital, Florence, Italy Hippokration General Hospital, Athens, Greece

Natalia Docheva

Heart and Brain Center of Excellence University Hospital, Pleven, Bulgaria

Ingrid Dumitriu

Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

Dirk Duncker

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

Perry Elliott

University College, London, UK

Koji Hasegawa Melina Huerin

Marjan Jahangiri

St George’s University Hospitals NHS Foundation Trust, London, UK

Victoria Jowett

Great Ormond Street Hospital, London, UK

Thomas Kahan

Danderyd University Hospital, Danderyd, Sweden

Koichi Kaikita

Kumamoto University, Kumamoto, Japan

Juan-Pablo Kaski

Christine Espinola-Klein

Centre for Inherited Cardiovascular Diseases, UCL, London, UK

Giulia Ferrannini

University of Hertfordshire, Hatfield, Hertfordshire, UK

Johannes Gutenberg University Mainz, Mainz, Germany Karolinska Institutet, Stockholm, Sweden

Albert Ferro

King’s College London, London, UK

Michael Fisher

Royal Liverpool University Hospital, Liverpool, UK

Ben Freedman

Heart Research Institute, Charles Perkins Centre, University of Sydney, Sydney, and Concord Hospital, Concord, NSW, Australia

Mark M Gallagher

Michael G Kirby

Sreenivasa Rao Kondapally Seshasai

Royal Bournemouth Hospital, Bournemouth, UK

Patrizio Lancellotti

University of Liège, Liège, Belgium

Gaetano Antonio Lanza

Università Cattolica del Sacro Cuore, Rome, Italy

Amir Lerman

Mayo Clinic, Rochester, MN, US

Conquest Hospital, Hastings, UK

Eva Gerdts

Haukeland University Hospital, Bergen, Norway

Dagva Mungunchimeg

National Cardiovascular Center, Shastin Central Hospital, Ulaanbaatar, Mongolia

Kavitha Muthiah

University of New South Wales, Sydney, Australia

Carmela Nappi

University Federico II, Naples, Italy

Amalia Peix

Institute of Cardiology and Cardiovascular Surgery, Havana, Cuba

Denis Pellerin

St Bartholomew’s Hospital, London, UK

Carl Pepine

University of Florida, FL, US

Esther Pérez-David

Hospital Universitario La Paz, Madrid, Spain

Piotr Ponikowski

Wroclaw Medical University, Wroclaw, Poland

Eva Prescott

Bispebjerg Hospital, Copenhagen, Denmark

Axel Pries

Charité Universitätsmedizin, Berlin, Germany

Valentina O Puntmann

Silvia Maffei

National Research Council, Pisa, Italy

Robert Gerber

Ilais Moreno Velasquez

Max Delbrück Centre for Molecular Medicine in the Helmholtz Association, Berlin, Germany

Macquarie University, Sydney, Australia

Augusto Gallino

Valeria Gaudieri

Kolling Institute, Royal North Shore Hospital and Macquarie University, Sydney, Australia

Jiunn-Lee Lin

Taipei Medical University Shuang-Ho Hospital, Taipei, Taiwan

University Federico II, Naples, Italy

Anastasia S Mihailidou

Goethe University Hospital Frankfurt, Frankfurt, Germany

St George’s University Hospitals NHS Foundation Trust, St George’s University of London, London, UK Ente Ospedaliero Cantonale, Bellinzona, Switzerland

Haukeland University Hospital, Bergen, Norway

Olivia Manfrini

University of Bologna, Bologna, Italy

María Martin

Central University Hospital of Asturias, Oviedo, Asturias, Spain

Felipe Martinez

Hariharan Raju Robin Ray

St George’s University of London, London, UK

Alejandro Recio-Mayoral

Hospital Universitario Virgen Macarena, Seville, Spain

Ornella Rimoldi

National University of Cordoba, Cordoba, Argentina

IBFM CNR, Segrate, Italy

Silvia Rollefstad

Bernard J Gersh

Antoni Martínez-Rubio

Mayo Clinic, Rochester, MN, US

University Hospital of Sabadell, Barcelona, Spain

David Goldsmith

Preventive Cardio-Rheuma Clinic, Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway

John McNeill

Helen Routledge

St George’s University of London, London, UK

Monash University, Melbourne, Australia

Tommaso Gori

Barbra Streisand Women’s Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA, US

Johannes Gutenberg University Mainz, Mainz, Germany

Diana A Gorog

University of Hertfordshire, Hatfield, Hertfordshire, UK

Puja Mehta

Guiomar Mendieta

Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain

Worcestershire Royal Hospital, Worcester, UK

Magdi Saba

St George’s University of London, London, UK

Antonia Sambola

Hospital Vall d’Hebron, Barcelona, Spain

© RADCLIFFE CARDIOLOGY 2022 www.ECRjournal.com

Anne Grete Semb

Diakonhjemme Hospital, Oslo, Norway

Roxy Senior

Imperial College, London, UK

Nesan Shanmugam

St George’s University of London, London, UK

Sanjay Sharma

St George’s University of London, London, UK

Vinoda Sharma

Sandwell and West Birmingham Hospitals NHS Trust Birmingham, UK

Rosa Sicari

Italian National Research Council, Rome, Italy

Lilia Sierra-Galan

American British Cowdray Medical Center, Mexico City, Mexico

Iana Simova

National Cardiology Hospital, Sofia, Bulgaria

Isabella Sudano

University Hospital and University of Zurich, Zurich, Switzerland

Doreen Su-Yin Tan

National University of Singapore, Singapore

Jack Wei Chieh Tan

National Heart Centre Singapore, Singapore

Konstantinos Toutouzas

University of Athens, Athens, Greece

Isabella Tritto

University of Perugia, Perugia, Italy

Dimitrios Tziakas

Democritus University of Thrace, Xanthi, Greece

Moisés Vásquez

Hospital Rafael Angel Calderon Guardia, CCSS, San José, Costa Rica

Inga Voges

University Medical Center of SchleswigHolstein, Kiel, Germany

Mauricio Wajngarten University of São Paulo, São Paulo, Brazil

Hiroshi Watanabe

Hamamatsu University School of Medicine, Hamamatsu, Japan

Carolyn M Webb

National Heart and Lung Institute, Imperial College London; Department of Cardiology, Royal Brompton Hospital, London, UK

Matthew Wright

St Thomas’ Hospital, London, UK

José Luis Zamorano

Hospital Ramón y Cajal, Madrid, Spain

Volume 17 • 2022

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Volume 17 • 2022

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Contents The 2021 European Heart Failure Guidelines: The Case for Personalised Therapeutics Nesan Shanmugam https://doi.org/10.15420/ecr.2021.57

Valvular Heart Disease in Patients with Chronic Kidney Disease Konstantina Kipourou, Jamie M O’Driscoll and Rajan Sharma https://doi.org/10.15420/ecr.2021.25

Type 2 MI and Myocardial Injury in the Era of High-sensitivity Troponin Rifly Rafiudeen, Peter Barlis, Harvey D White and William van Gaal https://doi.org/10.15420/ecr.2021.42

European Society of Cardiology Highlights: Late-breaking Trials – COVID-19 Maki Komiyama and Koji Hasegawa https://doi.org/10.15420/ecr.2022.03

Arrhythmias in Chronic Kidney Disease

Zaki Akhtar, Lisa WM Leung, Christos Kontogiannis, Isaac Chung, Khalid Bin Waleed and Mark M Gallagher https://doi.org/10.15420/ecr.2021.52

Circulating MicroRNAs as Novel Biomarkers in Risk Assessment and Prognosis of Coronary Artery Disease Chiara Vavassori, Eleonora Cipriani and Gualtiero Ivanoe Colombo https://doi.org/10.15420/ecr.2021.47

Ethnic and Regional Differences in the Management of Angina: The Way Forward Jack C Barton and Juan Carlos Kaski https://doi.org/10.15420/ecr.2021.60

Slow Coronary Blood Flow: Pathogenesis and Clinical Implications Andrea Aparicio, Javier Cuevas, César Morís and María Martin https://doi.org/10.15420/ecr.2021.46

Circulating Biomarkers in Lower Extremity Artery Disease Louise Ziegler, Ulf Hedin and Anders Gottsäter https://doi.org/10.15420/ecr.2021.58

Cryoablation or Drug Therapy for Initial Treatment of Atrial Fibrillation Jason G Andrade, Ricky D Turgeon, Laurent Macle and Marc W Deyell https://doi.org/10.15420/ecr.2021.38

Role of Direct Oral Anticoagulants for Post-operative Venous Thromboembolism Prophylaxis Han Naung Tun, May Thu Kyaw, Erik Rafflenbeul and Xiuhtlaulli López Suástegui https://doi.org/10.15420/ecr.2021.55

New Trial Evidence on Heart Failure: Highlights from the European Society of Cardiology Congress 2021 Giulia Ferrannini and Gianluigi Savarese https://doi.org/10.15420/ecr.2022.06

Cardiovascular Complications of Chronic Kidney Disease: An Introduction Hilary Warrens, Debasish Banerjee and Charles A Herzog https://doi.org/10.15420/ecr.2021.54

Obituary: C Richard Conti, MD Carl J Pepine https://doi.org/10.15420/ecr.2022.21

Chest Pain in the Cancer Patient

Sara Tyebally, Aruni Ghose, Daniel H Chen, Aderonke T Abiodun and Arjun K Ghosh https://doi.org/10.15420/ecr.2021.45

Asian Pacific Society of Cardiology Consensus Statements on the Diagnosis and Management of Obstructive Sleep Apnoea in Patients with Cardiovascular Disease

Jack Wei Chieh Tan, Leong Chai Leow, Serene Wong, See Meng Khoo, Takatoshi Kasai, Pipin Kojodjojo, Duong-Quy Sy, Chuen Peng Lee, Naricha Chirakalwasan, Hsueh-Yu Li, Natalie Koh, Adeline Tan, Thun How Ong, Aye Thandar Aung, Song Tar Toh and Chi-Hang Lee https://doi.org/10.15420/ecr.2021.59

© RADCLIFFE CARDIOLOGY 2022 www.ECRjournal.com

EDITORIAL

ESC Highlights

The 2021 European Heart Failure Guidelines: The Case for Personalised Therapeutics Nesan Shanmugam St George’s University Hospitals NHS Foundation Trust, St George’s University of London Cardiology Clinical Academic Group, London, UK

Keywords

Heart failure, guidelines, prevention, patient-centred care Disclosure: NS is on the European Cardiology Review editorial board.

Received: 22 November 2021 Accepted: 23 November 2021 Citation: European Cardiology Review 2022;17:e01. DOI: https://doi.org/10.15420/ecr.2021.57 Correspondence: Nesan Shanmugam, St George’s University Hospitals NHS Foundation Trust, Blackshaw Rd, Tooting, London SW17 0QT, UK. E: Nesan.shanmugam@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 non-commercial purposes, provided the original work is cited correctly.

The field of heart failure (HF) has seen the development of unparalleled evidence-based therapies over the last 30 years, with continuous improvement in survival and quality of life for our patients. It is unquestionably an exciting time to be considering or pursuing HF as a subspecialty. Pivotal to and underpinning these advances is the guidance provided by international HF guidelines, particularly from the European Society of Cardiology (ESC). The new 2021 ESC HF guidelines have a total of 41 new and 15 modified recommendations from the 2016 document.1 A significant feature of the new guidelines is the focus on patient-centred care. Notably, this is the first ESC guideline to include patients as full members of the task force, with patients at the centre of the management algorithm in partnership with the multidisciplinary team.

There has been an innovative expansion in the therapeutic tool kit available for physicians managing patients with HF with reduced ejection fraction (HFrEF), with the focus now moving from three to four foundational classes of drugs: angiotensin-converting enzyme inhibitors (ACEI)/ angiotensin receptor-neprilysin inhibitors (ARNI), β-blockers, mineralocorticoid receptor antagonists and the new sodium–glucose cotransporter 2 (SGLT2) inhibitors. All have additive and independent treatment benefits.

It has been fascinating to see the transition of SGLT2 inhibitors from the diabetes arena to the HF world. Dapagliflozin and empagliflozin have both shown clinically significant reductions in mortality and HF hospitalisations and – importantly – improvement in quality of life when combined with gold standard triple neurohormonal modulation/blockade therapies for patients with HFrEF with or without diabetes.2,3 Known as the ‘fantastic four’, there is a real focus on the accelerated initiation of these powerful therapies at lower doses over a 2-week to 4-week window, rather than the traditional sequential sequencing and uptitration of the individual drug classes to target doses.4 Recent trials have clearly demonstrated the rapid positive additive treatment effects of SGLT2 inhibitors, with outcome curves diverging within the first month.

A further new recommendation is the consideration of initiation of sacubitril/valsartan in ACEI-naïve patients hospitalised with HFrEF (class IIb, level B). Initiation in this setting appears to be safe and dramatically reduces subsequent cardiovascular death or HF hospitalisations by 42% compared with enalapril.5 The syndrome of HF is a consequence of complex pathophysiological interactions and multiple comorbidities, and although a generic ‘all sizes fits all’ approach is often recommended in therapeutic guidelines; the ESC HF Task Force must be commended on their efforts to simplify and provide a phenotypic breakdown of various HF conditions. An array of nuanced therapeutic options are recommended depending on the specific patient phenotype (e.g. left bundle branch block and CRT, aortic stenosis and transcatheter aortic valve implantation). This strategic personalised approach will invariably have a positive impact on the overall prognosis of our patients.

In addition, there is a real paradigm shift to provide a more tailored, patientspecific approach using patient profiles, such as heart rate, the presence of AF, symptomatic low blood pressure, kidney function or hyperkalaemia, as guides to initiating and adjusting guideline-directed medical therapy.6 Appropriate sequencing may also enhance the tolerability of medications started later in the sequence, moving away from the previous model of rigid titration of each drug class before commencing the next treatment.

Despite these innovative evidenced-based therapies, it is also clear that delivery of guidelines varies between settings, contributing to disparities in care and worse outcomes for our patients. For example, observed use of ARNI in the UK is almost 50% below expected in primary and secondary care settings.7 This problem has been further compounded by the COVID-19 pandemic, which has led to an unprecedented restructuring of HF service provision with significant disruption to standard pathways for medication delivery. Thirty-seven per cent of patients reported disruption to medication prescription services in the UK during the pandemic.8 Therefore, there is an urgent need to redress this situation and shift back to a patient-centred approach – a central tenet of the updated 2021 ESC HF Guidelines.

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2021 European Heart Failure Guidelines 1.

McDonagh TA, Metra M, Adamo M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599–726. https:// doi.org/10.1093/eurheartj/ehab368; PMID: 34447992.

2. 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.

3. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–24. https://doi.org/10.1056/NEJMoa2022190; PMID: 32865377.

4. Straw S, McGinlay M, Witte KK. Four pillars of heart failure:

contemporary pharmacological therapy for heart failure with reduced ejection fraction. Open Heart 2021;8:e001585. https://doi.org/10.1136/openhrt-2021-001585; PMID: 33653703.

5. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensinneprilysin inhibition in acute decompensated heart failure.

N Engl J Med 2019;380:539–48. https://doi.org/10.1056/ NEJMoa1812851; PMID: 30415601.

6. Rosano GMC, Moura B, Metra M, et al. Patient profiling in heart failure for tailoring medical therapy. A consensus document of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2021;23:872–81. https://doi.org/10.1002/ejhf.2206; PMID: 33932268.

EUROPEAN CARDIOLOGY REVIEW www.ECRjournal.com

7.

NHS Digital. NICE Technology Appraisals in the NHS in England (Innovation Scorecard) to March 2020. Leeds: NHS Digital, 2020. https://digital.nhs.uk/data-and-information/ publications/statistical/nice-technology-appraisals-in-thenhs-in-england-innovation-scorecard/to-march-2020/2.estimates-report#chronic-heart-failure (accessed 10 December 2021).

8. Sankaranarayanan R, Hartshorne-Evans N, Redmond-Lyon S, et al. The impact of COVID-19 on the management of heart failure: a United Kingdom patient questionnaire study. ESC Heart Fail 2021;8:1324–32. https://doi.org/10.1002/ ehf2.13209; PMID: 33463044.

REVIEW

CVD in CKD Patients

Valvular Heart Disease in Patients with Chronic Kidney Disease Konstantina Kipourou ,1 Jamie M O’Driscoll

1,2

and Rajan Sharma1,2

1. Department of Cardiology, St George’s University Hospitals NHS Foundation Trust, London, UK; 2. School of Psychology and Life Sciences, Canterbury Christ Church University, Canterbury, UK

Abstract

Valvular heart disease (VHD) is highly prevalent in patients with chronic kidney disease (CKD) from the early stages to end-stage renal disease (ESRD). Aortic and mitral valves are the most frequently affected, leading to aortic valve and/or mitral annular calcification, which, in turn, causes either valve stenosis or regurgitation at an accelerated rate compared with the general population. Tricuspid regurgitation is also prevalent in CKD and ESRD, and haemodialysis patients are at an increasingly high risk of infective endocarditis. As for pathophysiology, several mechanisms causing VHD in CKD have been proposed, highlighting the complexity of the process. Echocardiography constitutes the gold standard for the assessment of VHD in CKD/ESRD patients, despite the progress of other imaging modalities. With regard to treatment, the existing 2017 European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines on the management of VHD addressing patients with normal kidney function are also applied to patients with CKD/ESRD.

Keywords

Cardiorenal syndrome, chronic kidney disease, end-stage renal disease, valvular heart disease Disclosure: The authors have no conflicts of interest to declare.

Received: 28 May 2021 Accepted: 19 October 2021 Citation: European Cardiology Review 2022;17:e02. DOI: https://doi.org/10.15420/ecr.2021.25 Correspondence: Rajan Sharma, Department of Cardiology, St George’s University Hospitals NHS Foundation Trust, Blackshaw Rd, Tooting, London SW17 0QT, UK. E: rajan.sharma@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 non-commercial purposes, provided the original work is cited correctly.

Chronic kidney disease (CKD) is a major global public health problem, and is defined as a decrease in estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m2 for >3 months or pathological abnormalities of kidney structure or function with preserved GFR.1–3 It is estimated that 9.1% of the global population has CKD, with this percentage almost quadrupling in patients >70 years of age.1,4,5

variants of MAC that occur particularly in patients with ESRD (Figure 1).16 Moreover, it is observed that the greater the impairment in renal function, and therefore the lower GFR, the greater the prevalence of VHD, with most affected patients being at a later stage of CKD (Stage 5 or GFR <15 ml/min/1.73 m2) rather than in an earlier stage (Stage 1 and 2, or GFR >60 ml/min/1.73 m2).8,13,17–19

Patients with CKD, those with end-stage renal disease (ESRD) on haemodialysis and kidney transplant recipients have an increased risk of developing cardiovascular disease (CVD), which includes cardiomyopathy, coronary disease, arrhythmia and valvular heart disease (VHD).5–7 More than half of the ESRD patients on dialysis have concomitant CVD.8 This coexistent disease is termed cardiorenal syndrome.6,9 Due to the complexity of simultaneous cardiac and renal disease, it is difficult to determine which is primary and secondary; however, the mixed disease significantly increases morbidity, mortality and healthcare costs.10

It has been established that the rate of valve calcification is accelerated in ESRD patients compared with the general population, and it can be up to 10-fold quicker in ESRD patients compared with patients with milder stages of CKD and not undergoing haemodialysis.8,16,20–23 More specifically, it has been reported that AV calcification progresses to severe aortic stenosis (AS) one to two decades earlier in CKD/ESRD patients than in the general population (Figure 2).8,11,18,24 Published data on this issue has demonstrated that the change in AV area is more than double (-0.19 cm2/ year) compared with patients without CKD (-0.7 cm2/year).13 A similar pattern to native valves is observed in bioprosthetic valves, where the structural deterioration occurs more quickly in CKD patients than in the general population.11

Mitral and Aortic Valve Disease

VHD is prevalent in patients with CKD (early stages of the disease) and ESRD.8 Aortic and mitral valves are the most frequently affected, leading to aortic valve (AV) calcification or mitral annular calcification (MAC), which, in turn, causes either valve stenosis or regurgitation.6,11 AV disease constitutes the most common VHD in CKD patients and in ESRD patients on haemodialysis.12–14 Mitral valve (MV) disease comes second, with the exception of a few regional variations in which MV disease is the leading VHD in patients with renal insufficiency.6,12–15 Caseous calcification of the mitral annulus and MAC-related calcified amorphous tumour are two

Valve Regurgitation

According to most published work, the structures of left-sided valves that are commonly affected by calcification and thickening are the mitral annulus and the aortic cusps, causing valve regurgitation, valve stenosis or both.25 Aortic regurgitation is usually organic and is caused by calcification of the aortic cusps. Mitral regurgitation (MR) may be either organic, due to MAC, or functional, due to the intravascular volume

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Valvular Heart Disease in Chronic Kidney Disease Figure 1: Transthoracic Echocardiogram Illustrating Caseous Calcification of the Mitral Annulus in a Dialysis Patient A

B

C

A: 2D echocardiogram showing caseous calcification of the mitral annulus in the apical four-chamber view in a dialysis patient. B: 2D echocardiogram showing mitral annular calcification in the apical three-chamber view. C: Apical four-chamber view transthoracic echocardiogram zoomed in on the calcification of the mitral annulus.

overload that is found in this population (e.g. hypertension, anaemia).13 The latter is also responsible for tricuspid regurgitation (TR), which, in most cases, is functional.13

Valve Stenosis

Calcific AS is the most prevalent VHD among patients with ESRD.8,13,26 Mitral stenosis in this population typically includes severe MAC (mostly of the posterior mitral annulus) and thickening of the base of the mitral leaflets, whereas the leaflet tips and commissures are usually less affected.27 For this reason, the incidental finding of MAC in the echocardiogram of a younger adult should arouse suspicion and should be investigated further.28 In contrast to CKD mitral stenosis, it is worth mentioning that in the case of radiation-induced mitral stenosis there is also severe MAC, but mostly in the anterior annulus, as well as calcification of the aortomitral curtain.28 In addition, thickening can be observed at the base or the mid-body of the anterior mitral leaflet.28 Finally, in the case of rheumatic mitral stenosis, calcification and thickening of the subvalvular apparatus, commissural fusion and thickening of the tips of the leaflets are observed.28 However, diagnosis of the aetiology of mitral stenosis is not predominantly based on the above imaging characteristics, but rather on the clinical history. In some cases, mitral stenosis can be also mixed.

Epidemiology

Recent published results show that the prevalence of MAC ranges from 5% to 60% in patients with CKD.8,11,18 In dialysis patients, the reported prevalence ranges from 25% to 59%, especially in those undergoing haemodialysis for >3 years.8,11,12,16,28 MAC occurs approximately four times more often in patients with renal insufficiency compared to the general population, in which prevalence ranges from 8% to 15% depending on

age, with the greatest prevalence seen at an advanced age.29 MAC is more commonly seen in ESRD than CKD.8,11,12,16,18 Conversely, the prevalence of AV calcification ranges from 23% to 85% in CKD patients, and from 28% to 76.5% in dialysis patients.8,11,12,13,16,18 Consequently, we can infer that AV calcification is also markedly prevalent in these patient populations, occurring approximately three times more often than in the general population, in which the prevalence of calcific aortic sclerosis increases with age and occurs in approximately 25% of individuals aged >65 years.13 The prevalence of AV calcification is higher in ESRD than CKD patients.8,11,12,16 In dialysis patients, the prevalence of severe AS ranges from 4% to 13%, with more than half of these patients having low-flow, low-gradient severe AS.11–13 Severe AS is also highly prevalent in ESRD patients compared with the general population, in which the prevalence of severe AS is approximately 3% in individuals aged >75 years, with prevalence increasing with age.13,23,24,26 The prevalence of CKD in patients with severe AS undergoing AV replacement (AVR), either transcatheter (TAVR) or surgical (SAVR), is approximately 50–75%.30–32 Most of these patients have moderate to severe CKD rather than mild to moderate CKD.30–32 Thus, impaired renal function constitutes a common characteristic in patients undergoing AVR. One possible explanation is that longstanding AS impairs forward blood flow from the heart, which, in turn, causes hypoperfusion of the kidneys, leading to CKD.26,33 For this reason, renal dysfunction may be the ‘first symptom’ observed in patients with severe AS.34,35 The prevalence of preoperative advanced CKD, namely GFR <30 ml/min/1.73 m2, is 11.5% in patients with severe MR receiving a MitraClip.36 In addition, CKD is as prevalent in VHD patients as VHD is in CKD patients, with the prevalence of CKD ranging between 25% and 75% in patients with significant VHD.20,23,37–39

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Valvular Heart Disease in Chronic Kidney Disease Figure 2: Transthoracic Echocardiogram Illustrating a Heavily Calcified and Stenotic Tricuspid Aortic Valve A

B

C

A: 2D echocardiogram showing a parasternal short-axis view of a heavily calcified and stenotic tricuspid aortic valve in a patient with chronic kidney disease. B: Parasternal long-axis view of calcified aortic and mitral valves. C: Parasternal short-axis view of a stenotic and calcified aortic valve in a patient with end-stage renal failure.

Pathophysiology

Several theories have been proposed attempting to explain the mechanisms of VHD in CKD patients. These mechanisms are divided into three main categories, namely traditional and non-traditional risk factors for CVD and CKD-related risk factors. Traditional CVD risk factors include advanced age, diabetes, smoking history, hypertension, lipid and lipoprotein metabolism disorders (oxidised LDL, lipoprotein(a)) and obesity.5,6,11,16,18 As such, it is clear that valve and vascular calcification share the same risk factors. Non-traditional risk factors include increases in serum parathyroid hormone concentrations, hyperphosphataemia, hypocalcaemia and vitamin D deficiency.11,18 For this reason, the use of either vitamin K antagonists for non-valvular AF in ESRD patients or excessive vitamin D supplementation in CKD patients raises concerns.11,18 CKD-related risk factors include shear stress-related valvular endothelial damage, anaemia, uraemic toxins and mineral bone disorders (osteoprotegerin, the RANK/receptor activator of nuclear factor-κB ligand [RANKL] axis, fibroblast growth factor 23/klotho), which constitute one of the most important mechanisms causing valve calcification in the early stages of CKD.11,13,16,18,40 The mechanism accelerating VHD in CKD patients appears to be a combination of traditional and non-traditional CVD risk factors and CKD-related risk factors.

Chronic systemic and local inflammation (T lymphocytes, mast cells, macrophages, cytokines) with increased oxidative stress in the calcified and pericalcific regions of the valves constitute additional mechanistic pathways.5,6,11,16 Other possible pathological mechanisms that have been proposed include malnutrition, cachexia, hyperuricaemia and increased sclerostin concentrations.15,18,41,42 The presence of systemic shunting due to dialysis arteriovenous fistulas, which create a volume overload state on the right heart chambers, in turn causing right ventricular dilatation and dysfunction, may also contribute to VHD.13 This leads first to worsening of

TR, followed by exacerbation of MR.13 The fact that different pathophysiological mechanisms causing VHD in CKD patients have been put forward highlights the complexity of the calcification process and may suggest that different mediators may be required at different stages of the process (Figure 3).43

Clinical Presentation

Prior to the typical manifestation of symptomatic VHD, CKD patients commonly have a long asymptomatic period, which may be preceded by trivial symptoms, which are not always obvious due to the inactivity of CKD patients.13 During the symptomatic phase, patients may manifest typical symptoms such as dyspnoea, but also atypical symptoms such as fatigue and muscle weakness, which may be mistakenly attributed to other coexisting conditions such as anaemia and frailty.13 More specifically, CKD patients with AS may manifest one of the three standard symptoms, namely angina, heart failure (e.g. pulmonary oedema) and syncope/ sudden cardiac death.44 CKD patients with AR may develop dyspnoea, palpitations due to frequent and premature left ventricular (LV) beats and peripheral oedema.44 When CKD patients experience MR, they may develop dyspnoea, fatigue, AF and pulmonary oedema.44 Finally, those with MV stenosis may develop AF, thromboembolic stroke and symptoms and signs due to right ventricular failure, such as fatigue and peripheral oedemahepatosplenomegaly.44 Auscultation will reveal the respective standard murmurs in each of these four categories of VHD patients.13,44 Due to the long asymptomatic period, echocardiography plays a major role in the diagnosis of VHD and should always be readily available so that VHD can be promptly diagnosed.13

Diagnosis

Echocardiography plays a leading role in the diagnosis of VHD in CKD/ ESRD patients and constitutes the gold standard for the assessment of

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Valvular Heart Disease in Chronic Kidney Disease Figure 3: Pathophysiological Pathway Leading to the Development of Valve Calcification in Chronic Kidney Disease

Lp(a) Cytokines

PCSK9 inhibitors RAAS inhibitors

Calcified aortic valve OxLDL FGF23 RANKL inhibitors Vitamin K Bisphosphonates

Endothelial dysfunction

Ca

PTH

Mast cell Macrophage T lymphocyte

Mechanistic illustration of the combined pathophysiological pathways leading to the development of valve calcification in patients with chronic kidney disease (CKD). In the early stages of CKD, there is endothelial dysfunction. Because of this, inflammatory cells (T lymphocytes, mast cells, macrophages and cytokines) and molecules that are highly concentrated in the plasma enter the aortic valve, causing thickening. These molecules include harmful types of cholesterol, such as oxidised LDL (OxLDL) and lipoprotein (a) (Lp(a)), minerals (calcium, phosphorus) and those related to bone metabolism dysregulation, such as receptor activator of nuclear factor-kB ligand (RANKL) and fibroblast growth factor (FGF) 23. To prevent some of this happening, we have at our disposal medications such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which act against lipid infiltration, and bisphosphonates, RANKL inhibitors and vitamin K, which act against bone metabolism dysregulation. FGF = fibroblast growth factor; Lp(a) = lipoprotein (a); OxLDL = oxidised LDL; PCSK9 = proprotein convertase subtilisin/kexin type 9; PTH = parathyroid hormone; RAAS = renin– angiotensin–aldosterone system; RANKL = receptor activator of nuclear factor-kB ligand; RAAS = renin–angiotensin–aldosterone system.

valve morphology and the quantification of valve stenosis and/or regurgitation.8,13 The updated 2017 Kidney Disease: Improving Global Outcomes (KDIGO) CKD–mineral bone disorder recommendations suggest that a transthoracic echocardiogram is within the framework of the screening process to detect the presence or absence of VHD in patients with CKD Stage 3a to 5 (GFR <59 ml/min/1.73 m2).13 In the case of valve regurgitation, it is recommended that the echocardiogram is performed on a post-dialysis day, when the patient has their ‘dry weight’, and with blood pressure under control.3 During a routine echocardiogram, apart from assessing the heart valves, it is also important to assess the LV geometric pattern, given that more than half of all ESRD patients have hypertrophy, with concentric hypertrophy the predominant pattern.12,45 In addition, measurement of the LV ejection fraction (LVEF), assessment of LV diastolic function, given that most patients have an impaired relaxation pattern, and measurement of LV global longitudinal strain may help risk stratify patients with renal insufficiency.12,16 Echocardiography plays a central role in the decision-making process for patients with severe AS and CKD who may benefit from valve replacement.

More specifically, prognosis and post-surgical outcome can be predicted using simple and reproducible echocardiographic markers, including relative wall thickness, LV mass index, LVEF, estimated LV filling pressure (E/e¢ ratio), left atrial volume index, pulmonary artery systolic pressure (PASP) and mean transaortic pressure gradient.40,46 In addition,

echocardiography is important for the follow-up and surveillance of patients with VHD. As per the VHD management guidelines, patients must have a follow-up within 3–6 months in the case of severe VHD, within 6–12 months in the case of moderate VHD and within 12 months in the case of mild VHD.11,13 A yearly follow-up of the prosthesis using echocardiography is indicated in patients who have undergone bioprosthetic valve replacement.11 Despite progress in techniques such as cardiac CT and MRI in recent years, these technologies do not have a major role in the diagnosis of VHD in patients with impaired renal function compared with echocardiography, which, importantly, may be due to the risk of developing contrast-induced nephropathy.16 More specifically, cardiac CT is supplementary to echocardiography for the quantification of valve calcification, measuring the calcium of the AV and the mitral annulus (Figure 4).13,47,48 Cardiac CT provides additional information about the exact degree of AS in the case of both low-flow, low-gradient severe AS with reduced ejection fraction and low-flow, low-gradient AS with preserved ejection fraction.13,47,48 In addition, cardiac CT is performed in CKD patients prior to transcatheter valve replacement in order to assess the morphology and size of the aorta and aortic annulus.13,48 Before valve replacement, it is recommended that coronary angiography is performed to assess coronary artery disease.8 In case of low-flow, low-gradient severe AS with reduced ejection fraction, a

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Valvular Heart Disease in Chronic Kidney Disease Figure 4: Cardiac Imaging Demonstrating Valve Calcification A

B

C

D

A–C: CT angiography with contrast images from the same patient who is undergoing dialysis 5 days/week. A: The three cusps of the aortic valve are visualised, and two of the three are severely calcified. B: Severely calcified mitral annulus. C: Caseous calcification of the mitral annulus. D: Periprocedural transoesophageal echocardiography demonstrating severe mitral annular calcification (continuous from the anterolateral commissure, through the entire posterior annulus, through to the posteromedial commissure). There is also mitral annular calcification anteriorly at the aortomitral continuity. There is severe calcification in the body of both the anterior and posterior mitral valve leaflets, extending down into the tips off both leaflets, and subvalve apparatus (at the chordal attachment to the papillary muscles bilaterally), creating a very small orifice.

low-dose dobutamine stress echocardiogram may also be performed for differential diagnosis between truly severe and pseudo-severe AS and in order to determine whether there is contractile reserve.13,47 Dialysis patients have an increased risk of developing infective endocarditis and, if suspected, a transoesophageal echocardiogram should be performed (Figure 5).8 A chest X-ray has a low sensitivity to diagnose VHD in ESRD patients.48

Prognosis

CKD constitutes one of the leading causes of global mortality, and is ranked 12th among the global list of deaths in 2017.1 It is also known that CKD patients have significantly greater all-cause and cardiovascular morbidity and mortality than those with normal renal function, with CVD usually the cause of death, as opposed to renal impairment.11,16,22,49 In addition, the greater the attenuation in GFR, the higher the mortality rate, with ERSD patients on haemodialysis having a ninefold higher mortality rate than the general population.11,16,41 It is evident that CKD patients with concomitant severe AS who are treated conservatively have a poor prognosis, with significantly higher mortality rates than those treated with valve replacement.22,30,38 Both SAVR and TAVR have been recognised as superior to medical treatment in terms of mortality in patients with impaired renal function.22 This is the case even in dialysis and advanced CKD patients (GFR <30 ml/ min/1.73 m2), who have high mortality rates after any kind of cardiac intervention.39,50–54 More specifically, dialysis patients have a 30-day mortality rate of up to 21% following SAVR and a 1-year mortality rate of between 34% and 53% following SAVR.23,32,52,55 These high mortality outcomes have led to the use of TAVR. In ESRD patients undergoing haemodialysis, TAVR is associated with a 30-day mortality rate of up to

8.3%, a 1-year mortality rate of up to 36.8% and a 2-year mortality rate of up to 50%, with sepsis being the most common cause of death.52,55–57 There are conflicting views regarding improvements in renal function following valve replacement in the literature, with some authors reporting an improvement33,34,58 and others reporting a decline.59 Undoubtedly, those who manifest postoperative acute kidney injury (AKI) have significantly elevated mortality risks.13,22,52,56,60–62 Regarding mortality rates of other cardiac interventions, the 30-day mortality rate of CKD patients undergoing balloon aortic valvotomy is up to 10.2%.63 Similar to AVR, the mortality rates after MitraClip implantation increase significantly, up to 53%, when GFR is <30 ml/min/1.73 m2.36,64,65 The effect of postoperative AKI on mortality risk after MV replacement is similar to that after AV replacement.65 Importantly, as many as 30% of CKD patients with severe VHD on the waiting list for surgery will die before receiving treatment, which shows how cardiologically unstable they are.38

Treatment

There are currently no specific guidelines for the management of VHD in non-severe CKD patients (GFR ≥30 ml/min/1.73 m2). Consequently, the existing 2017 European Society of Cardiology (ECS)/European Association for Cardio-Thoracic Surgery guidelines addressing patients with normal kidney function are used.8 As such, for the AV, SAVR is recommended in severe AS patients with low perioperative risk (AV area ≤1 cm2 or ≤0.65 cm2/m2, mean gradient ≥40 mmHg or peak velocity ≥4 m/s) when they manifest symptoms (indication class 1, level b) or when they present with hypotension during exercise testing (class 1, level c), or when LVEF is <50% (class 1, level c) or when one of the following is present: peak velocity across the AV >5.5 m/s, severe valve calcification with a peak velocity progression of ≥0.3m/s per year, markedly elevated neurohormone

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Valvular Heart Disease in Chronic Kidney Disease Figure 5: Vegetation Attached to the Mitral Valve of a Patient With Chronic Kidney Disease A

B

C

A: Mid-oesophageal five-chamber view showing a vegetation attached to the mitral valve of a patient with chronic kidney disease. B: 2D echocardiogram, parasternal long-axis view, showing vegetation on the mitral valve. C: Mid-oesophageal two-chamber view showing a vegetation attached to the mitral valve.

concentrations and PASP >60 mmHg (class 2a, level c). 8,37,47,54 Transcatheter AV implantation is recommended in elderly patients (age >75 years) with severe symptomatic AS when they are not suitable for SAVR due to prohibitive, high or intermediate surgical risk (Society of Thoracic Surgeons/EuroSCORE II ≥4%, logistic EuroSCORE I ≥10%; class 1, level b).47,49,50,56,66 Balloon aortic valvotomy may be considered as a link to either SAVR or TAVR in unstable patients or in patients with symptomatic severe AS who must immediately undergo major non-cardiac surgery (class 2b, level c).47,63 As for the MV, surgery or repair whenever possible is recommended in symptomatic patients with severe primary MR who have an LVEF >30% (class 1, level b).47 Surgery is also indicated in asymptomatic patients with severe primary MR when there is concomitant LV dysfunction, defined as LVEF ≤60% or LV end systolic diameter ≥45 mm (class 1, level b).47 MV surgery should also be considered in asymptomatic patients with preserved LV function when there is newly diagnosed AF secondary to MR, or there is pulmonary hypertension defined as PASP >50 mmHg (class 2a, level b).47 MV repair is preferred over MV replacement whenever possible.47 Finally, percutaneous MV repair (transcatheter MV repair) with the MitraClip device may be considered in patients who are characterised as inoperable or who have high surgical risk, because they meet all the required echocardiographic criteria (class 2b, level c).47 Either percutaneous mitral commissurotomy or MV surgery is indicated in symptomatic patients with clinically significant mitral stenosis, which is defined as a valve area <1.5 cm2 (class 1, level b or c).47 The final therapeutic option is based on the clinical and anatomical characteristics of these patients.47 Surgical or percutaneous treatments are not recommended in patients with significant mitral stenosis and who are asymptomatic, as confirmed by stress testing, unless there is an increased risk of systemic

embolism or haemodynamic decompensation (class 2a, level c).47 For CKD patients, commissurotomy is often not feasible due to extensive valve and subvalve calcification. Medication is not effective in the management of VHD because it does not stop or slow down the progression of calcification in patients with and without CKD.11,48,49 Studies have also shown the beneficial effect of the administration of levosimendan on the incidence of AKI in patients who have preoperative CKD and who are haemodynamically unstable postoperatively.61 In circumstances where the recommendation is valve replacement, there are two prosthetic options: bioprosthesis and mechanical valves.47 In patients with renal impairment, the selection of valve type is determined by the patient’s age, comorbidities, life expectancy, surgical risk, a patient’s personal preference and the probability of accelerating structural valve deterioration due to their main disease, which is the same as for patients without renal impairment.11,47 Generally speaking, bioprosthetic valves are preferred for older patients (>60 years old) as well as for people who do not desire to use anticoagulation in the long term or who are at a high surgical risk.11,47 Conversely, bioprosthetic valves are more prone to rapid structural deterioration in dialysis-dependent patients.47 Therefore, bioprosthetic valves are usually offered to advanced CKD patients because they have a short life expectancy, a low probability of reoperation and a problematic use of vitamin K antagonists.11

Tricuspid Regurgitation

Compared with the bibliography focusing on left-sided valves and CKD, the bibliography focusing on TR is much less. TR is prevalent in CKD and ESRD and due to pulmonary hypertension, which, in turn, is due to high LV filling pressures.67 In most cases TR is functional and thus potentially reversible.13 Treatment involves strict fluid balance and diuretics. Prognosis is poor, especially with the onset of heart failure.68 According to the

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Valvular Heart Disease in Chronic Kidney Disease current European guidelines, TV surgery is indicated in patients suffering from severe primary or secondary TR and who are also undergoing leftsided valve surgery (class 1, level c).47 TV surgery is also recommended in patients with symptomatic, isolated, severe primary TR, as well as in patients with severe, secondary TR with no signs of relevant right ventricular dysfunction.47 Furthermore, TV repair, whenever feasible is more preferable to TV replacement.47 In the case of patients with prohibitive surgical risk, there are other transcatheter options, such as percutaneous annuloplasty and edge-to-edge valve repair.47

Pulmonary Valve Involvement in Chronic Kidney Disease

Research evidence regarding pulmonary valve involvement in CKD is scarce. Therefore it can be characterised as a neglected area of research that should be further investigated in the future. Pulmonary hypertension (PH) is prevalent in CKD and ESRD patients, and its presence is associated with poor prognosis.69 According to 2015 ESC/European Respiratory Society guidelines for the diagnosis and treatment of PH, PH in chronic kidney failure is attributed to unclear and multifactorial mechanisms (Group 5.4 based on clinical classification).70 More specifically, it may be attributed to fluid overload, high cardiac output due to arteriovenous fistula, lung disease (chronic obstructive pulmonary disease, sleep-disordered breathing), left heart disease and other causes.69

Endocarditis

The risk of endocarditis increases with each advanced stage of CKD and is significantly increased in haemodialysis patients with an annual risk of 1%.71 Endocarditis involving a prosthetic AV is especially high risk, with a mortality of 36%.72 There is a preponderance of staphylococcal infections 1.

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Beck H, Titze SI, Hübner S, et al. Heart failure in a cohort of patients with chronic kidney disease: the GCKD study. PLoS One 2015;10:e0122552. https://doi.org/10.1371/journal. pone.0122552; PMID: 25874373.

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Glaser N, Jackson V, Holzmann MJ, et al. Late survival after aortic valve replacement in patients with moderately reduced kidney function. J Am Heart Assoc 2016;5:e004287. https://doi.org/10.1161/JAHA.116.004287; PMID: 27988497.

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Hryniewiecka E, Hryniewiecki T, Różański J, et al. Reversal of Stage 5 chronic kidney disease by aortic valve replacement in kidney transplant recipient: a case report.

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Ronco C, McCullough P, Anker SD, et al. Cardio-renal

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in ESRD. This is due, in part, to the need for constant intravenous access of these patients. Patients requiring valve replacement surgery have a 1-year mortality of 50%.73

Conclusion

VHD is highly prevalent in patients with renal insufficiency, and its progression specifically accelerates in patients with ESRD, exacerbating the already elevated CVD mortality and morbidity risk. Degenerative AV and MV disease are the most prevalent. Echocardiography is the cornerstone of management for the assessment of severity and haemodynamic consequences, as well as for planning interventions. At present, guidelines for heart valve disease management are based on studies that do not include CKD patients, so patients should be managed with a multidisciplinary team of cardiologists and nephrologists.

Endocarditis is more prevalent among CKD patients, with higher mortality than in non-CKD patients, even when valve surgery is performed.

Clinical Perspective

• Although specific guidelines regarding the treatment of patients with valvular heart disease (VHD) and concomitant end-stage renal disease (ESRD) have not been published, valve disease should be assessed more frequently than recommended for the general population with VHD. The rationale for this recommendation is because VHD progresses rapidly in this population and is associated with poor prognosis.

• Given the complexity and the fragility of patients with ESRD and concomitant significant VHD, we should not hesitate to refer patients to more specialised healthcare centres for further investigation due to a potential need for early intervention.

syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J 2010;31:703–11. https://doi.org/10.1093/eurheartj/ehp507; PMID: 20037146.

Ternacle J, Côté N, Krapf L, et al. Chronic kidney disease and the pathophysiology of valvular heart disease. Can J Cardiol 2019;35:1195–207. https://doi.org/10.1016/j. cjca.2019.05.028; PMID: 31472817.

Matsuo H, Dohi K, Machida H, et al. Echocardiographic assessment of cardiac structural and functional abnormalities in patients with end-stage renal disease receiving chronic hemodialysis. Circ J 2018;82:586–95. https://doi.org/10.1253/circj.CJ-17-0393; PMID: 29093429.

Marwick TH, Amann K, Bangalore S, et al. Chronic kidney disease and valvular heart disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference. Kidney Int 2019;96:836–49. https://doi.org/10.1016/j.kint.2019.06.025; PMID: 31543156.

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Prevalence and prognostic implications of mitral and aortic valve calcium in patients with chronic kidney disease. Am J Cardiol 2018;122:1732–7. https://doi.org/10.1016/j. amjcard.2018.08.009; PMID: 30270179.

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Impact of chronic kidney disease on long-term outcome of patients with valvular heart defects. Int Urol Nephrol 2020;52:2161–70. https://doi.org/10.1007/s11255-020-025614; PMID: 32661631.

Dohi K. Echocardiographic assessment of cardiac structure and function in chronic renal disease. J Echocardiogr 2019;17:115–22. https://doi.org/10.1007/s12574-019-00436-x; PMID: 31286437.

Untersteller K, Seiler-Mußler S, Mallamaci F, et al. Validation of echocardiographic criteria for the clinical diagnosis of heart failure in chronic kidney disease. Nephrol Dial Transplant 2018;33:653–60. https://doi.org/10.1093/ndt/ gfx197; PMID: 29106648.

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19. Vavilis G, Bäck M, Occhino G, et al. Kidney dysfunction and the risk of developing aortic stenosis. J Am Coll Cardiol 2019;73:305–14. https://doi.org/10.1016/j.jacc.2018.10.068; PMID: 30678761.

20. Patel KK, Shah SY, Arrigain S, et al. Characteristics and outcomes of patients with aortic stenosis and chronic kidney disease. J Am Heart Assoc 2019;8:e009980. https:// doi.org/10.1161/JAHA.118.009980; PMID: 30686093.

21. Bayliss G. TAVR in patients with end-stage renal disease and critical aortic stenosis: hard choices. J Am Coll Cardiol 2019;73:2816–8. https://doi.org/10.1016/j.jacc.2019.04.007; PMID: 31171087.

22. Witberg G, Shamekhi J, Van Mieghem NM, et al.

Transcatheter aortic valve replacement outcomes in patients with native vs transplanted kidneys: data from an international multicenter registry. Can J Cardiol 2019;35:1114– 23. https://doi.org/10.1016/j.cjca.2019.01.003; PMID: 31202537.

23. Bandyopadhyay D, Sartori S, Baber U, et al. The impact of chronic kidney disease in women undergoing transcatheter aortic valve replacement: analysis from the Women’s INternational Transcatheter Aortic Valve Implantation (WINTAVI) registry. Catheter Cardiovasc Interv 2020;96:198–207. https://doi.org/10.1002/ccd.28752; PMID: 31977142.

24. Cheungpasitporn W, Thongprayoon C, Kashani K. Transcatheter aortic valve replacement: a kidney’s perspective. J Renal Inj Prev 2016;5:1–7. https://doi. org/10.15171/jrip.2016.01; PMID: 27069960.

25. Straumann E, Meyer B, Misteli M, et al. Aortic and mitral valve disease in patients with end stage renal failure on long-term haemodialysis. Br Heart J 1992;67:236–9. https:// doi.org/10.1136/hrt.67.3.236; PMID: 1554541 26. Platania I, Terranova V, Tomasello SD, et al. Mean transaortic gradient is an emerging predictor of chronic kidney disease in elderly patients. Angiology 2017;68:528–34. https://doi. org/10.1177/0003319716672527; PMID: 27814268.

27. Oktay AA, Gilliland YE, Lavie CJ, et al. Echocardiographic assessment of degenerative mitral stenosis: a diagnostic challenge of an emerging cardiac disease. Curr Probl Cardiol 2017;42:71–100. https://doi.org/10.1016/j.

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28. Mansur A, Saleem S, Naveed H, et al. Mitral annular calcification in Stage 5 chronic kidney disease on dialysis therapy. J Ayub Med Coll Abbottabad 2020;32:179–83.

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29. Eberhard M, Schönenberger ALN, Hinzpeter R, et al. Mitral annular calcification in the elderly – quantitative assessment. J Cardiovasc Comput Tomogr 2021;15:161–6. https://doi.org/10.1016/j.jcct.2020.06.001; PMID: 32798185.

30. Parikh PB, Reilly JP. Women with chronic kidney disease undergoing transcatheter aortic valve replacement: caveat emptor. Catheter Cardiovasc Interv 2020;96:208–9. https:// doi.org/10.1002/ccd.29080; PMID: 32652842.

31. Catalano M, Lin D, Cassiere H, et al. Incidence of acute kidney injury in patients with chronic renal insufficiency: transcatheter versus surgical aortic valve replacement. J Interv Cardiol 2019;2019:9780415. https://doi. org/10.1155/2019/9780415; PMID: 31772554.

32. Pineda AM, Harrison JK, Kleiman NS, et al. Clinical impact of baseline chronic kidney disease in patients undergoing transcatheter or surgical aortic valve replacement. Catheter Cardiovasc Interv 2019;93:740–8. https://doi.org/10.1002/ ccd.27928; PMID: 30341970.

33. Calça R, Teles RC, Branco P, et al. Impact of transcatheter aortic valve implantation on kidney function. Arq Bras Cardiol 2019;113:1104–11.

34. Cubeddu RJ, Asher CR, Lowry AM, et al. Impact of transcatheter aortic valve replacement on severity of chronic kidney disease. J Am Coll Cardiol 2020;76:1410–21. https://doi.org/10.1016/j.jacc.2020.07.048; PMID: 32943158.

35. Galper BZ, Goldsweig AM, Bhatt DL. TAVR and the kidney: is this the beginning of a beautiful friendship? J Am Coll Cardiol 2020;76:1422–4. https://doi.org/10.1016/j.jacc.2020.08.015; PMID: 32943159.

36. Estévez-Loureiro R, Settergren M, Pighi M, et al. Effect of advanced chronic kidney disease in clinical and echocardiographic outcomes of patients treated with MitraClip system. Int J Cardiol 2015;198:75–80. https://doi. org/10.1016/j.ijcard.2015.06.137; PMID: 26156318.

37. Rudolph TK, Messika-Zeitoun D, Frey N, et al. Impact of selected comorbidities on the presentation and management of aortic stenosis. Open Heart 2020;7:e001271. https://doi.org/10.1136/openhrt-2020-001271; PMID: 32709699.

38. Chen Y, Au WK, Chan D, et al. Clinical benefit of valvular surgery in patients with chronic kidney disease. Int Heart J 2018;59:759–65. https://doi.org/10.1536/ihj.17-460; PMID: 29925718.

39. Rattanawong P, Kanitsoraphan C, Kewcharoen J, et al.

Chronic kidney disease is associated with increased mortality and procedural complications in transcatheter aortic valve replacement: a systematic review and metaanalysis. Catheter Cardiovasc Interv 2019;94:E116–27. https:// doi.org/10.1002/ccd.28102; PMID: 30681261.

40. Samad Z, Sivak JA, Phelan M, et al. Prevalence and outcomes of left-sided valvular heart disease associated with chronic kidney disease. J Am Heart Assoc 2017;6:e006044. https://doi.org/10.1161/JAHA.117.006044; PMID: 29021274.

41. Ozelsancak R, Tekkarismaz N, Torun D, Micozkadioglu H. Heart valve disease predict mortality in hemodialysis patients: a single center experience. Ther Apher Dial 2019;23:347–52. https://doi.org/10.1111/1744-9987.12774; PMID: 30421548.

42. Ji YQ, Guan LN, Yu SX, et al. Serum sclerostin as a potential novel biomarker for heart valve calcification in patients with chronic kidney disease. Eur Rev Med Pharmacol Sci 2018;22:8822–9. https://doi.org/10.26355/ eurrev_201812_16650; PMID: 30575924.

43. Shuvy M, Abedat S, Eliaz R, et al. Hyperphosphatemia is required for initiation but not propagation of kidney failureinduced calcific aortic valve disease. Am J Physiol Heart Circ Physiol 2019;317:H695–704. https://doi.org/10.1152/

ajpheart.00765.2018; PMID: 31398059.

44. Ureña-Torres P, D’Marco L, Raggi P, et al. Valvular heart disease and calcification in CKD: more common than appreciated. Nephrol Dial Transplant 2020;35:2046–53. https://doi.org/10.1093/ndt/gfz133; PMID: 31326992.

45. Wang H, Liu J, Yao XD, et al. Multidirectional myocardial systolic function in hemodialysis patients with preserved left ventricular ejection fraction and different left ventricular geometry. Nephrol Dial Transplant 2012;27:4422–9. https:// doi.org/10.1093/ndt/gfs090; PMID: 22561582.

46. Takada T, Jujo K, Konami Y, et al. Effect of transcatheter aortic valve implantation on renal function in patients with chronic kidney disease. Am J Cardiol 2020;126:82–8. https:// doi.org/10.1016/j.amjcard.2020.04.001; PMID: 32327190.

47. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS guidelines for the management of valvular heart disease.

Rev Esp Cardiol (Engl Ed) 2018;71:110. https://doi.org/10.1016/j. rec.2017.12.013; PMID: 29425605.

48. Brandenburg VM, Schuh A, Kramann R. Valvular calcification in chronic kidney disease. Adv Chronic Kidney Dis 2019;26:464–71. https://doi.org/10.1053/j.ackd.2019.10.004; PMID: 31831124.

49. Ifedili IA, Bolorunduro O, Bob-Manuel T, et al. Impact of preexisting kidney dysfunction on outcomes following transcatheter aortic valve replacement. Curr Cardiol Rev 2017;13:283–92. https://doi.org/10.2174/157340 3X13666170804151608; PMID: 28782492.

50. Levi A, Codner P, Masalha A, et al. Predictors of 1-year mortality after transcatheter aortic valve implantation in patients with and without advanced chronic kidney disease.

Am J Cardiol 2017;120:2025–30. https://doi.org/10.1016/j. amjcard.2017.08.020; PMID: 28965713.

51. Makki N, Lilly SM. Advanced chronic kidney disease: relationship to outcomes post-TAVR, a meta-analysis. Clin Cardiol 2018;41:1091–6. https://doi.org/10.1002/clc.22993; PMID: 29896847.

52. Al-Rashid F, Bienholz A, Hildebrandt HA, et al. Transfemoral transcatheter aortic valve implantation in patients with endstage renal disease and kidney transplant recipients. Sci Rep 2017;7:14397. https://doi.org/10.1038/s41598-017-14486-7; PMID: 29089579.

53. Hansen JW, Foy A, Yadav P, et al. Death and dialysis after transcatheter aortic valve replacement: an analysis of the STS/ACC TVT registry. JACC Cardiovasc Interv 2017;10:2064– 75. https://doi.org/10.1016/j.jcin.2017.09.001; PMID: 29050623.

54. Sanaiha Y, Mantha A, Ziaeian B, et al. Trends in readmission and costs after transcatheter implantation versus surgical aortic valve replacement in patients with renal dysfunction.

Am J Cardiol 2019;123:1481–8. https://doi.org/10.1016/j. amjcard.2019.01.047; PMID: 30826049.

55. Szerlip M, Zajarias A, Vemalapalli S, et al. Transcatheter aortic valve replacement in patients with end-stage renal disease. J Am Coll Cardiol 2019;73:2806–15. https://doi. org/10.1016/j.jacc.2019.03.496; PMID: 31171086.

56. Gupta T, Goel K, Kolte D, et al. Association of chronic kidney disease with in-hospital outcomes of transcatheter aortic valve replacement. JACC Cardiovasc Interv 2017;10:2050–60. https://doi.org/10.1016/j.jcin.2017.07.044; PMID: 29050621.

57. Conrotto F, Salizzoni S, Andreis A, et al. Transcatheter aortic valve implantation in patients with advanced chronic kidney disease. Am J Cardiol 2017;119:1438–42. https://doi. org/10.1016/j.amjcard.2017.01.042; PMID: 28325569.

58. Lahoud R, Butzel DW, Parsee A, et al. Acute kidney recovery in patients who underwent transcatheter versus surgical aortic valve replacement (from the Northern New England Cardiovascular Disease Study Group). Am J Cardiol 2020;125:788–94. https://doi.org/10.1016/j. amjcard.2019.11.024; PMID: 31924319.

59. Nijenhuis VJ, Peper J, Vorselaars VMM, et al. Prognostic value of improved kidney function after transcatheter aortic valve implantation for aortic stenosis. Am J Cardiol 2018;121:1239–45. https://doi.org/10.1016/j.

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60. Kumar N, Khera R, Fonarow GC, Bhatt DL. Comparison of outcomes of transfemoral versus transapical approach for transcatheter aortic valve implantation. Am J Cardiol 2018;122:1520–6. https://doi.org/10.1016/j. amjcard.2018.07.025; PMID: 30190074.

61. Zangrillo A, Alvaro G, Belletti A, et al. Effect of levosimendan on renal outcome in cardiac surgery patients with chronic kidney disease and perioperative cardiovascular dysfunction: a substudy of a multicenter randomized trial. J Cardiothorac Vasc Anesth 2018;32:2152–9. https://doi. org/10.1053/j.jvca.2018.02.039; PMID: 29580796.

62. Thongprayoon C, Cheungpasitporn W, Srivali N, et al. AKI after transcatheter or surgical aortic valve replacement. J Am Soc Nephrol 2016;27:1854–60. https://doi.org/10.1681/ ASN.2015050577; PMID: 26487562.

63. Parikh PB, Novotny S, Jeremias A, et al. Impact of chronic kidney disease on mortality in adults undergoing balloon aortic valvuloplasty. Cardiovasc Revasc Med 2018;19:448–51. https://doi.org/10.1016/j.carrev.2017.10.012; PMID: 29223500.

64. Doshi R, Patel K, Meraj PM. Association of chronic kidney disease with in-hospital outcomes of transcatheter mitral valve repair. Indian Heart J 2018;70:939–40. https://doi. org/10.1016/j.ihj.2018.06.023; PMID: 30580870.

65. Kalbacher D, Daubmann A, Tigges E, et al. Impact of preand post-procedural renal dysfunction on long-term outcomes in patients undergoing MitraClip implantation: a retrospective analysis from two German high-volume centres. Int J Cardiol 2020;300:87–92. https://doi. org/10.1016/j.ijcard.2019.09.027; PMID: 31748183.

66. Kumar V, Seth A. Transcatheter aortic valve replacement: protect the kidneys to protect the patient. Catheter Cardiovasc Interv 2019;93:749–50. https://doi.org/10.1002/ ccd.28182; PMID: 30859729.

67. Zhang Y, Ding XH, Pang F, et al. The prevalence and independent risk factors of significant tricuspid regurgitation jets in maintenance hemodialysis patients with ESRD. Front Physiol 2020;11:568812. https://doi.org/10.3389/ fphys.2020.568812; PMID: 33391009.

68. Agricola E, Marini C, Stella S, et al. Effects of functional tricuspid regurgitation on renal function and long-term prognosis in patients with heart failure. J Cardiovasc Med (Hagerstown) 2017;18:60–8. https://doi.org/10.2459/ JCM.0000000000000312; PMID: 26258726.

69. Alhamad EH, Al-Ghonaim M, Alfaleh HF, et al. Pulmonary hypertension in end-stage renal disease and post renal transplantation patients. J Thorac Dis 2014;6:606–16.

70. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67–119. https://doi.org/10.1093/eurheartj/ehv317; PMID: 26320113.

71. Ludvigsen LUP, Dalgaard LS, Wiggers H, et al. Infective endocarditis in patients receiving chronic hemodialysis: a 21-year observational cohort study in Denmark. Am Heart J 2016;182:36–43. https://doi.org/10.1016/j.ahj.2016.08.012; PMID: 27914498.

72. Regueiro A, Linke A, Latib A, et al. Association between transcatheter aortic valve replacement and subsequent infective endocarditis and in-hospital death. JAMA 2016;316:1083–92. https://doi.org/10.1001/jama.2016.12347; PMID: 27623462.

73. Leither MD, Shroff GR, Ding S, et al. Long-term survival of dialysis patients with bacterial endocarditis undergoing valvular replacement surgery in the United States. Circulation 2013;128:344–51. https://doi.org/10.1161/ CIRCULATIONAHA.113.002365; PMID: 23785002.

REVIEW

Intervention

Type 2 MI and Myocardial Injury in the Era of High-sensitivity Troponin Rifly Rafiudeen ,1,2 Peter Barlis ,1,2 Harvey D White

3

and William van Gaal

1,2

1. Department of Cardiology, The Northern Hospital, Melbourne, Australia; 2. Department of Medicine, The University of Melbourne, Melbourne, Australia; 3. Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand

Abstract

Troponin has been the cornerstone of the definition of MI since its introduction to clinical practice. High-sensitivity troponin has allowed clinicians to detect degrees of myocardial damage at orders of magnitude smaller than previously and is challenging the definitions of MI, with implications for patient management and prognosis. Detection and diagnosis are no doubt enhanced by the greater sensitivity afforded by these markers, but perhaps at the expense of specificity and clarity. This review focuses on the definitions, pathophysiology, prognosis, prevention and management of type 2 MI and myocardial injury. The five types of MI were first defined in 2007 and were recently updated in 2018 in the fourth universal definition of MI. The authors explore how this pathophysiological classification is used in clinical practice, and discuss some of the unanswered questions in this era of availability of high-sensitivity troponin.

Keywords

Type 2 MI, myocardial injury, high-sensitivity troponin Disclosure: HDW has received grants and personal fees from Eli Lilly, Omthera Pharmaceuticals, Eisai, DalCor Pharma UK, CSL Behring, American Regent, Aanofi-Aventis Australia and Esperion Therapeutics; personal fees from Genentech and AstraZeneca; and grants, personal fees and non-financial support from Sanofi-Aventis, outside of the submitted work. All other authors have no conflicts of interest to declare.

Received: 18 August 2021 Accepted: 21 October 2021 Citation: European Cardiology Review 2022;17:e03. DOI: https://doi.org/10.15420/ecr.2021.42 Correspondence: Rifly Rafiudeen, Northern Hospital Epping, 185 Cooper St, Epping, VIC 3076, Australia. E: rifly.rafiudeen2@nh.org.au 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.

In 1812, John Warren published a description of chest symptoms that he called angina pectoris, without knowledge of the underlying pathogenesis, although, at the time, coronary ‘ossifications’ were being noted during anatomical dissections.1 In the late 19th century, physiologists noticed that occlusion of the coronary artery of a dog resulted in ‘quivering’ of the ventricles and was rapidly fatal.2,3 Around this time it was suggested that coronary thrombosis was the cause of MI.4 In the early 20th century, ECGs showing ST segment change were being used to help diagnose MI.1 By the mid-20th century, the introduction of coronary angiography allowed the natural history of coronary artery disease (CAD) and acute coronary occlusions to be observed.

Aspartate transaminase was the first cardiac biomarker to be used in clinical practice in the 1950s, and was one of three criteria, along with ECG changes and symptoms, in the 1959 WHO definition of MI.5 In the late 1970s, the wave front phenomenon of myocardial necrosis over several hours after coronary artery occlusion was observed in dogs, and around the same time the pathophysiologic mechanism of plaque rupture/erosion triggering thrombotic occlusion was being developed. Since the recognition of the pathophysiological mechanism and the development of targeted reperfusion therapies, mortality in acute ST-elevation MI (STEMI) has reduced from 18% (control group of the GISSI-1 trial in 1986) to 4% in 2006.6,7 In 1979 the WHO added creatinine kinase (CK) as a recommended biomarker for diagnosing MI, followed by the specific CK myocardial band (CK-MB) isoenzyme, which is much more prevalent in cardiac than

in skeletal muscle. The development of immunoassays in the 1980s enabled measurement of CK-MB mass, which allowed earlier detection of myocardial damage, although specificity remained an issue. Attention turned to the contractile apparatus of cardiomyocytes, and after disappointing results with myosin light chains, cardiac troponin (cTn) was first discovered in 1965 by Ebashi and Kodama.8 Katus et al. demonstrated its specificity for myocardial cell damage in comparison with CK-MB in 1991.9 In a similar pattern to the current situation with high-sensitivity troponin (hsTn) assays, large numbers of studies in the 1990s showed that significant numbers of patients classified as having ‘unstable angina’ by WHO criteria actually had elevated cTn.5 The changed definition of MI to include cTn as the preferred biomarker in 2000 was met with concern initially regarding the increase in the positive rate. However, this was replaced with widespread acceptance as biochemical parameters to reduce assay variability were introduced, leading to endorsement of cTn as the biomarker of choice in the first universal definition of MI (UDMI) in 2007.10 The UDMI also introduced the concept of type 2 MI, and the fourth UDMI in 2018 further developed the concept of myocardial injury, with the recognition that myocardial damage as indicated by the new hsTn assays could frequently occur without ischaemia.

Type 2 MI

MI by definition refers to necrosis of cardiomyocytes due to ischaemia.4 Type 2 MI refers to those cases in which this is due to an imbalance

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Type 2 MI in the Era of High-sensitivity Troponin Figure 1: Classification of MI and Myocardial Injury as per the Fourth Universal Definition of MI Troponin elevation WITH ischaemia (i.e. symptoms/ ECG/imaging)

Troponin elevation WITHOUT ischaemia

MI

Myocardial injury

Type 1 (acute plaque rupture/erosion) Type 2 (supply–demand mismatch without acute plaque event) Types 3–5 (death before troponin measurement, associated with PCI or CABG)

One of the most common differences in the literature with regards to the definition of type 2 MI is clinical evidence of ischaemia and whether sepsis is present (sepsis is excluded in the UDMI as a cause of type 2 MI).

Due to heterogeneity, it is difficult to quantify the incidence of type 2 MI as a proportion of all MIs.26,28,32–36 For example, one study using the UDMI and focusing on only coronary care unit/intensive care unit patients reported a 7% incidence, while another study in emergency department patients presenting with elevated troponin reported a 35% incidence.4,28,37 A large study involving almost 5,700 hospitalised patients showed that 62% had an abnormal hsTn, and there was dynamic change in 24%.

However, only 6.1% had a final diagnosis of type 1 MI, suggesting that up to 17.9% may have had a type 2 MI or acute myocardial injury.38

Rise and fall pattern in troponin levels

Yes

Acute myocardial injury

additionally be evidence of clinical ischaemia. Troponin elevations alone, regardless of other clinical features, are prognostic of both cardiac and non-cardiac outcomes.30,31 The presence and magnitude of clinical ischaemia is affected by many factors such as the severity and nature of the concurrent illness, comorbidities, and the degree of underlying CAD.

No

Chronic myocardial injury

Ischaemia refers to clinical evidence of underlying myocardial ischaemia, specifically symptoms, such as chest pain, ECG changes, such as ST segment deviation, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention.

between supply and demand, in contrast to that due to an acute atherothrombotic event.11 Being ultimately a pathophysiological distinction, this continues to create difficulty in the definition of different types of MI in clinical practice, given the resulting heterogeneity in the literature.

Systemic conditions such as sepsis can also be associated with more type 1 MIs (acute plaque events) than type 2 MIs, and this has important prognostic and treatment implications.12–24 Type 2 MI occurs more frequently than type 1 MI.25 Type 2 MI is common in hospitalised patients, on average accounting for 10–20% of MIs.26 Its causes are myriad and range from acute cardiac conditions such as a tachyarrhythmia to non-cardiac conditions, such as anaemia. Complex molecular and cellular signalling pathways are triggered once the cardiomyocyte is exposed to ischaemia, and results in cell death mainly via apoptosis and necrosis. These processes ultimately result in the presence of troponin in plasma, the cornerstone of the UDMI.

Current Definitions

Troponin was incorporated into the first definition of MI by the European Society of Cardiology (ESC) and American College of Cardiology (ACC) in 2000. A rise and/or fall in troponin is required for the clinical diagnosis of all types of MI, along with any one of the following features of clinical ischaemia: symptoms (no duration defined in fourth UDMI), ECG changes, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.27 For the first time in 2007 subtypes were introduced, including type 2 MI. In the most recent fourth UDMI, the concept of ‘myocardial injury’ is further developed as separate from type 2 MI in that there is an absence of evidence of clinical myocardial ischaemia despite an elevation of troponin.11,28,29 If there is an appropriate rise and/or fall in troponin, the myocardial injury is considered acute (Figure 1); and chronic if the levels are stable (<20% change). In type 2 MI, as in all types of MI, there must

More recently, the term MI with non-obstructive coronary arteries (MINOCA) has been used in the literature, including in an ESC position paper, referring to lesions with <50% stenosis.30,39–42 A US consensus statement has considered having an additional functional assessment that is, fractional flow reserve (FFR) >0.80 as a criterion. Crucially, this diagnosis can only be made after confirmation of the diagnosis of MI and the performance of coronary angiography. It is an exclusion diagnosis, encompassing many conditions and including both type 1 and 2 MI. Myocardial injury, myocarditis and takotsubo syndrome do not come under the terminology because they are not MI. Large MI registries show an incidence of MINOCA of 6–13%.41 Type 1 and type 2 MIs are separate but overlap with MINOCA, in that both can occur within and outside the MINOCA definition. In a recent review, type 2 MI comprised 10.5% of MINOCA.43 The unique feature of this term is that knowledge of the coronary anatomy is required, and therefore it usually captures a cohort that has been referred for invasive coronary angiography and who are generally healthier than those not referred for angiography.

The COVID-19 pandemic has seen an increase in the number of MI presentations, including STEMI, with up to 40% with normal coronary arteries.44 Further intravascular ultrasound (IVUS) and optical coherence tomography (OCT) imaging studies are required to define the pathophysiology.

Aetiology of Type 2 MI and Myocardial Injury

There are a myriad of cardiac and non-cardiac conditions that can upset the balance between oxygen supply and demand in the myocardium and cause a type 2 MI.45 Table 1 lists these, along with the causes of myocardial injury, which by definition are non-ischaemic. There are a few common denominators of type 2 MI that can be a result of many of the listed clinical conditions: tachycardia, hypotension, and hypoxia. We postulate that these may be part of the final molecular mechanism by which type 2 MIs occur.

MI after non-cardiac surgery is a unique clinical scenario in which many potential mechanisms may contribute to both type 1 and type 2 MIs. Bleeding, hypotension, hypoxia, hypothermia, tachycardia, microembolism in the coronary circulation, catecholamine surges, and diastolic dysfunction due to preload alterations causing subendocardial ischaemia, may all contribute to the occurrence of type 2 MI perioperatively.32,34,46 These may or may not occur in the setting of pre-existing CAD of varying

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Type 2 MI in the Era of High-sensitivity Troponin Table 1: Cardiac and Non-cardiac Causes of Type 2 MI and Myocardial Injury Type 2 MI (with Clinical Ischaemia) Cardiac

• • • • • •

Arrhythmia Acute heart failure Coronary spasm Endothelial dysfunction Coronary thromboembolism Coronary dissection

Myocardial injury (without Clinical Ischaemia) Non-cardiac

• • • • • • • •

Cardiac

• • • • • •

Hypotension Tachycardia Hypoxia Anaemia Hypertension Pulmonary embolism Non-cardiac surgery Hypovolaemia

Non-cardiac

Chronic heart failure Severe valvular disease Myocarditis Takotsubo syndrome Cardiac contusion Cardiac infiltration

• • • •

Renal impairment Exercise Acute neurological disease Critical illness

This represents the most common way the conditions may present; however, this is not exclusive. Both cardiac and non-cardiac causes of type 2 MI can potentially present without clinical ischaemia, and thus as myocardial injury.

severity, the presence of which usually portends a worse outcome.47 Although both type 1 and type 2 MI are possible on a pathophysiological level, it is thought that the majority are type 2.

Heart failure is another interesting entity that may be associated with different mechanisms of troponin release.48 A non-dynamic pattern in a stable patient may be related to chronic myocardial injury that is nonischaemic, whereas an acute rise may be due to type 1 or type 2 MI. Type 2 MI in heart failure may be mediated by small vessel CAD, increased transmural pressure with increase in left ventricular end-diastolic pressure, endothelial dysfunction, or subendocardial ischaemia.34

Pathological Mechanisms

Myocardial necrosis in type 2 MI occurs from either increased myocardial oxygen demand or decreased supply, or both. Supply is determined by the oxygen-carrying capacity of blood and coronary blood flow, while demand is largely determined by systolic wall tension, contractility, and heart rate (Figure 2). The presence of CAD may play a role, altering the threshold for myocardial ischaemia in any given patient. It has become clear in recent times that plaque growth to the moderate–severe range is the result of one or more subclinical rupture events with efficient lysis and healing, such that patients with type 2 MI and significant stable CAD may actually have had silent plaque rupture events in the past.49 Individual differences in the ability to maintain coronary perfusion under stressful conditions such as critical illness also plays a role.

At the cellular level, it is probable that cardiomyocytes respond similarly to supply–demand ischaemia (i.e. type 2 MI) as in acute coronary thrombosis (i.e. type 1 MI), with membrane permeability changes, release of cytosolic vacuoles, and release of proteolytic degradation products contributing to cell death. The volume of involved cardiomyocytes is localised in type 1 MI to the territory supplied distal to the plaque event, whereas in type 2 MI we hypothesise that it may be a more global ischaemic phenomenon, with some regional myocardial dysfunction depending, among other things, on the severity and distribution of coexistent CAD. This has important implications for treatment strategies.

Appropriately, in type 1 MI the focus has been on the acute plaque event in the epicardial vessel, with successful therapies now in use such as percutaneous coronary intervention (PCI), thrombolysis and anticoagulation. Therapeutic interventions for type 2 MI need to focus on the underlying aetiology, for example anaemia, hypoxaemia and arrhythmia. In type 2 MI, absolute biomarker peaks are usually lower than in type 1 MI.33,50 There are probably several variables at play, but the degree of ischaemia is likely to be lower when compared with the

Figure 2: Determinants of Oxygen Supply– Demand Mismatch Leading to Type 2 MI Increased oxygen demand

Decreased oxygen supply

Increased systolic wall tension

Reduced coronary blood flow

Increased heart rate

Reduced oxygen-carrying capacity of blood

Increased contractility

absolute ischaemia that occurs with complete thrombotic occlusion of an epicardial coronary artery. Relief of a total coronary artery occlusion either spontaneously or following PCI or thrombolytic therapy with troponin washout may result in higher peak troponin levels than in patients with type 2 MI. In myocardial injury that is by definition non-ischaemic, troponin elevation may be mediated by direct toxicity from circulating cytokines, catecholamines, or vasopressors. These factors may also play a part in the aetiology of type 2 MI.33 Tachycardia is one of the ‘final common mechanisms’, and it has been hypothesised that increased heart rate may cause troponin release due to increased wall tension and stretch, from a direct mechanical stimulation of stretch-responsive integrins.9,51 This mechanism probably also plays a role in the troponin elevations seen in patients with severe hypertension and valvular disease. Direct involvement of the inflammatory process in the myocardium, such as in myocarditis, is another mechanism separate from ischaemia that leads to myocardial injury.

Takotsubo syndrome is interesting to consider in relation to type 2 MI: patients can present with all features of an MI, with ischaemic symptoms, ECG changes, rise and/or fall in troponin, and regional wall motion abnormalities on imaging (importantly not isolated to a single vascular territory). There is no acute coronary or plaque event, hence these are not classified as type 1 MIs. The full pathophysiological mechanism is yet to be understood; however, there is an abundance of evidence that sympathetic stimulation is key, and that acute microvascular dysfunction as a result plays a central role.52 Given a distinct pathophysiological mechanism

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Type 2 MI in the Era of High-sensitivity Troponin related to catecholamine excess and the lack of need for a triggering medical illness, such as in type 2 MI (e.g. anaemia, tachyarrhythmia), we consider takotsubo syndrome to be a separate entity to type 2 MI. The left ventricular dysfunction can persist for months; however, it usually resolves due to activation of myocardial cellular survival pathways in the face of the catecholamine surge.

Cardiomyocyte death occurs via two major processes, apoptosis and necrosis (Figure 3).53 Traditionally, apoptosis was thought to be controlled and regulated, whereas necrosis was almost accidental due to physical or chemical stimuli.54,55 However, the discovery of molecules that inhibit receptor-interacting protein kinases (RIP1, RIP3) demonstrated that necrosis, particularly in response to ischaemia, was signal regulated (termed ‘necroptosis’). In myocardial ischaemia, although apoptosis plays a role very early, necrosis is the dominant influence, and the release of cellular contents promotes inflammation and further cell death.54 The complex molecular signalling that occurs following an ischaemic insult provides a rich source of potential therapeutic targets that may be applicable to all types of MI and myocardial injury. A few small molecules have been developed that have shown inhibition of necrosis in nonhuman controlled environments. Nec-1 molecules inhibit RIP1 and markedly reduce infarct size.54,56–58 Necrosulfonamide inhibits mixedlineage kinase domain-like protein (MLKL), thus preventing the deleterious membrane effects leading to cell death.54,58 Following MI, there is a massive accumulation of neutrophils and monocytes (enhanced by extravasation of platelets and endothelial cell leakage), and a subsequent increase in fibroblasts.53,59 The extracellular matrix (ECM) of the myocardium plays an important role in the response to ischaemia. Local fibroblasts can induce further inflammation through interleukin-1, and matrikines released from the ECM initiate proinflammatory actions.53,59,60 The intense inflammatory response in the first few days is followed by fibrotic healing that is largely completed by 7–14 days.59 It may be that the role and type of inflammation in type 2 MI differs from type 1 MI, with higher cytokine, leukocyte and C-reactive protein levels being reported.32 Whether this represents any fundamental difference in molecular pathophysiologic pathways between type 1 and type 2 MI, or simply reflects the systemic illness setting in which type 2 MI often occurs, is not known.

Troponin and Myocardial Damage

Troponin is found in all forms of striated muscle, and cTn has unique regions of amino acid sequences. This means that antibodies can be made against specific epitopes, and ultimately assays for myocardial specific troponins can be made. The cTn complex consists of three highmolecular-weight protein subunits (cTnI, cTnT and cTnC), with cTnI and cTnT the most commonly used in assays.8 Most cTn assays are non-competitive enzyme-linked immunosorbent assays (ELISAs), using the high specificity and affinity of antibodies. After the onset of ischaemia, cardiomyocyte death can occur within 15 minutes, while histological evidence appears at 4–6 hours.54 The cTn is released from myocardium as early as 30 minutes following ischaemia. In MI, cTn peaks at the 24-hour mark, then reduces over the next 5–10 days. cTnT appears primarily as a mixture of free forms and a T:I:C complex, and cTnI appears primarily as the binary I:C complex. The first troponin assays were introduced to clinical practice in 1995, but they took 10–12 hours to become positive after an event due to the relatively high absolute minimum concentration of troponin that was able to be detected (i.e. they

lacked sensitivity).38,61 Standard troponin assays have improved with time but the new high-sensitivity assays are able to detect troponin at a 10-fold lower concentration, allowing for earlier results. Some assays are able to detect troponin within 90 minutes of an index cardiac event (Figure 4).62 cTnT has a biphasic release profile. Release is initially from the cytosolic pool (approx. 10%) and is usually free-form, whereas the subsequent peak and sustained elevation is from the structural pool via degradation (by calpain 1, caspase or matrix metalloproteinase-2) of the contractile apparatus, and is mostly the complexed forms of troponin (Figure 5).8 Apart from apoptosis and necrosis, some other mechanisms by which troponin can be released from cardiomyocytes include normal cell turnover, release of protein degradation products, increased cell membrane permeability and membranous ‘blebs’.60 It is controversial whether troponin may be released without irreversible cell death, however, these mechanisms provide potential avenues for this.8,63 The idea of cytosolic versus structural troponin has been used to distinguish between reversible and irreversible forms of myocardial damage.

Normalisation of troponin within 24 hours suggests a lack of ongoing cardiomyocyte structural degradation given that the half-life of troponin is 2–4 hours, with perhaps only cytosolic troponin having been released, and thus may represent a more reversible type of myocardial damage.51 However, some studies showing that the structural troponin pool is not as resistant to degradation and release as previously thought, and may be released early, have challenged this view.51,64 It is likely that the pool (cytosolic or structural) of troponin released, whether cell death has occurred or not, and whether the injury is reversible or irreversible, all vary depending on the particular circumstance. Acute hypertension resulting in a mild troponin rise that resolves within 24 hours may not represent cell death, and may be reversible, whereas persistent troponin elevation beyond 24 hours in an anaemic, hypotensive patient (i.e. a potential type 2 MI) probably represents cell death, albeit perhaps in a magnitude too small to be detected by imaging or other techniques (which require 1 g of confluent necrotic myocardium).65

Clinical Presentation and Diagnosis

Type 2 MI is generally straightforward to diagnose when there is evidence of clinical ischaemia and a clear triggering factor. Type 2 MI patients may be asymptomatic, might have minimal, if any, ECG changes, and will have troponin levels that are not as high as in type 1 MI.32,33,46,66–69 ST elevation is more common in type 1 MI but can occur in type 2 MI in 5% of patients.70–72 One of the main questions at the bedside is whether it could be a type 1 MI. A small proportion of patients thought to have type 2 MI turn out to have type 1 MI detected by the presence of plaque rupture and thrombus on angiography.25,73–76 However, the sensitivity of detection of thrombus is low.77,78 The treatment implications are significant, given that there are wellestablished therapeutic pathways for type 1 MI that have been shown to improve outcomes, including mortality. Importantly, type 2 MI carries with it a worse prognosis than type 1 MI, with a greater proportion of non-cardiac causes contributing to longer term morbidity and mortality.28,30,37,39,71,79–83 It is likely that the literature investigating type 2 MI has involved a significant proportion of patients who do not meet strict UDMI criteria, given that patients often do not have typically ischaemic symptoms, ECG changes or new imaging evidence. The most important differentiator is the presence/absence of factors that may disturb the oxygen supply– demand balance. In the absence of any of these factors, type 2 MI cannot

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Type 2 MI in the Era of High-sensitivity Troponin Figure 3: Cardiomyocyte Molecular Signalling Pathways Triggered by Ischaemia A

B

Molecular mechanisms Myocardial ischaemia

Autophagy

Apoptosis (dominant in the first 20 min)

Mitochondria mediated

Necrosis/necroptosis (dominant after the first 20 min)

Death receptor mediated

Mitochondria mediated

Death receptor mediated Necrosis pathways

Apoptosis pathways

IFNs

TNF

Effect via surface receptors

MLKL

Cell membrane

Micro-RNAs

Micro-RNAs TNF-R

FADD

DR 3/4/5

Caspase 8

Caspases 3,6,7

Caspase 9

Caspase 8

P1

Endoplasmic reticulum

RI

RI

P3

Activation

FADD

P1

Apof1

PARP

P3

RI

TRADD

RI

FADD

RIP1

Increased permeability

CAD MLKL RI

P1

Cytochrome C

RI

Ca2+ BCL-2 BAX

P3

Damage prevents repair

AIF

Mitochondria

Ca2+ DNA

P

Fragmentation

ROS

PT

P

Mitochondria

M

MPT

Increased permeability depletes ATP

MLKL PGAMS

DRP1 PYGL GLUL GLUD1 ROS Cleaves mitochondria

DRP1

Nucleus

A: Cardiomyocyte apoptosis. Cellular apoptosis, like necrosis, occurs predominantly via the mitochondrial pathway mediated by ROS and internal organelle-associated calcium, and, to a lesser extent, via the death receptor pathway. In the mitochondrial apoptotic pathway, ROS and intracellular calcium trigger MPTP opening, allowing increased mitochondrial permeability. Through mediators, this activates mitochondrial membrane proteins Bax and Bcl-2, which then initiate an efflux of the two primary instigators of cell damage in apoptosis: cytochrome C and AIF.105 AIF causes fragmentation of DNA, while cytochrome C activates Apaf-1 and forms the apoptosome, which then activates multiple caspases downstream. Proteolytic caspases degrade kinases, cytoskeletal proteins, and transcriptional regulators resulting in cell destruction. Degradation activates CAD and PARP, which both feed back to further degrade DNA along with AIF. In death-receptor-mediated apoptosis, locally secreted external proteins bind with death receptors, such as TNF-R, which leads to interactions with the proteins FADD and TRADD. This triggers a cascade involving procaspases 3, 7, and 8, ultimately converging on protein degradation with the mitochondrial pathway. Compared with necrosis, apoptosis is much more tightly regulated and involves more DNA fragmentation and cell shrinkage without significant surface cell membrane leakiness.105 B: Cardiomyocyte necrosis. Necrosis also occurs via death receptor- and mitochondria-mediated pathways. In death receptor-mediated necrosis, TNF-α and local IFNs act at surface receptors (e.g. TNF-R) to initiate necrosome regulatory machine formation, made up of receptor-interacting protein kinases RIP1 and RIP3.54 The necrosome complex activates RIP3 itself, leading to downstream effectors of cell death. These effectors include MLKL phosphorylation, which disturbs membrane permeability; toxic ROS production by PYGL, GLUL, and GLUD1; DRP1, which cleaves mitochondria; and opening of MPTP, which leads to mitochondria-mediated necrosis via ionic disturbances and depleted ATP.54 MPTP can be induced by ionised calcium released through MLKL disruption above, or by ROS produced by the necrosome complex or through apoptotic pathways. During ischaemia, MPTP opening is the major cause of cell death in the first few minutes, and contributes up to 50% of infarct size.54 There is considerable communication between the death receptor and mitochondrial necrotic pathways, and indeed between necrotic and apoptotic pathways. Common mediators are often part of positive feedback mechanisms that can quickly result in large-scale cellular death. AIF = apoptosis-inducing factor; CAD = caspase activated deoxyribonuclease; DR 3/4/5 = death receptor 3/4/5; DRP1 = dynaminrelated protein 1; FADD = Fas-associated protein with death domain; GLUD1 = glutamate dehydrogenase 1; GLUL = glutamate-ammonia ligase; IFN = interferon; MLKL = mixed-lineage kinase domain-like protein; MPTP = mitochondrial permeability transition pore; PARP = poly adenosine diphosphate-ribose polymerase; PGAMS = mitochondrial protein phosphatase; ROS = reactive oxygen species; TNF = tumour necrosis factor; TNF-R = tumour necrosis factor receptor; TRADD = tumour necrosis factor receptor type 1 associated death domain protein.

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Type 2 MI in the Era of High-sensitivity Troponin Figure 4: Limits of Detection of Past and Current Troponin I Assays Assay generations Year implemented

TnI

1.5

1995

cTnI

0.10

2003

TnI – ‘ULTRA’

0.04

2007

[Abbott] hsTnI

0.026 men 0.016 women

Approx. 2010

To peak

First-generation standard troponin assays

Second-generation standard troponin assays

Onset of myocardial ischaemia

Third-generation standard troponin assays

Reducing limit of detection

ULN cut-off (ng/ml)

Cardiac troponin level

cTn assay

High-sensitivity troponin assays

Normal levels

Ischaemia/Micronecrosis

Necrosis

Time

As assays become more sensitive, the initial rise of troponin in MI is detected at earlier time points. Current high-sensitivity troponin I (hsTnI) assays can detect very early rises of troponin after an ischaemic insult, as well as the normal variation in healthy individuals. cTnI = cardiac troponin I; TnI = troponin I; ULN = upper limit of normal. Adapted from: Park et al. 2017.8 Used from Oxford University Press under a Creative Commons (CC BY 4.0) licence.

Figure 5: Molecular Composition of Troponin Complexes, and Mechanisms of Release into the Bloodstream Troponin release Cell membrane

Extracellular matrix

Cytoplasm

Lymphatic system Thin filament

Bound cTn complex

cTnT cTnI cTnC

Free cTnI (2–4% baseline)

Degradation by calpain 1, caspase, MMP-2

Venous system 1. Blebs

Plasma

2. Increased cell membrane permeability • Apoptosis • Necrosis

Free cTnT (6–8% baseline) I:C complex

T:I:C complex

3. Release of degradation products

cTn = cardiac troponin; cTnI = cardiac troponin I; cTnT = cardiac troponin T; MMP-2 = matrix metalloproteinase-2.

be diagnosed. The incidence of coexistent CAD is variable, depending on the population studied.29,37,84–87 The incidence of significant obstructive CAD in type 2 MI ranges from 40% to 78%.25,73,85,88 Older populations with greater cardiovascular risk factors tend to have a higher prevalence of CAD, as well as of type 2 MI.66

Some other clinical associations of type 2 MI are female sex, multiple comorbidities, and lower peak hsTn level than in type 1 MI.26,28,33,37,66,71 One study using hsTnT reported an average level of 618 ng/l in type 1 MI patients compared with 180 ng/l in type 2 MI patients.30 A binary score that is able to be used in the emergency department to differentiate type 1 from type 2 MI, has an area under the receiver operating characteristic curve of 0.71.37 This score assigns a single point each to female sex, absence of radiating chest pain, and a baseline hsTnI <40.8 ng/l; a score of 3 resulted in a 72% probability of type 2 MI, compared with 5% for a score of 0. This differentiation based on criteria that are not essential for the diagnosis of type 2 MI is unlikely to be helpful.

The majority of patients with a clinical diagnosis of type 2 MI do not undergo invasive coronary angiography, with rates of 20–30%.25,73,85 In some selected series of type 2 MI patients who underwent coronary angiography, acute plaque/coronary features have been described in up to 60%.25,73–76 PCI rates in this population range from 25% to 80%, perhaps suggesting that most clinicians favour intervening if a significantly obstructive plaque is seen or if FFR is decreased.73,89,90 There have been no published series using intracoronary imaging, such as OCT or IVUS, specifically in the type 2 MI population to define whether plaque rupture and thrombus are present.

Prognosis

Generally, prognosis after type 2 MI is worse than after type 1 MI, probably reflecting a more comorbid population overall with current critical illness.26,28,33,34,39,41,79–81,91,92 Retrospective studies demonstrate 1-year mortality rates of approximately 25% for patients with type 2 MI, compared with 8–12% for those with type 1 MI.28,37,72,85,93 In one study with a 5-year follow up, type 2 MI mortality (62.5%) was twice as likely to be due to noncardiovascular causes than to cardiovascular causes.4 Although the

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Type 2 MI in the Era of High-sensitivity Troponin excess mortality may be due to non-cardiovascular causes, type 2 MI may predict subsequent cardiovascular outcomes including death to the same degree that type 1 MI predicts outcomes.32,37,91 A recent large study by Raphael et al. further suggests that arrhythmia and post-surgical status as triggering factors for type 2 MI carry a more favourable long-term prognosis than hypoxia, hypotension or anaemia.91 Troponin levels, including hsTn, have been shown to correlate with poor outcomes in patients with type 2 MI.30,31 Higher troponin elevations tend to correlate with vascular death, while lower elevations correlate with nonvascular death.68 In a recent retrospective review of a total of 475 patients who had an MI/ myocardial injury during admission to a tertiary centre, those not meeting the UDMI of type 2 MI, but who met the myocardial injury definition, comprised 46% of the cohort and had similar in-hospital morbidity and mortality to those with type 2 MI.32 There was no difference in the types of provoking conditions that caused myocardial injury compared with type 2 MI, while those patients who met UDMI criteria tended to have more cardiovascular risk factors or known CAD.32 This highlights that the UDMI is a pathophysiological categorisation and therefore, in the clinical context, those patients with myocardial injury and without clinical ischaemia may have an equally serious condition with equally poor prognosis.

Treatment

Despite its prevalence and poor prognosis there have been no randomised trials of treatment for type 2 MI, in contrast to type 1 MI, for which improved management, particularly in shortening the door-to-therapy time and in the development of anti-thrombotic therapy, has resulted in better outcomes.28,94–96 Randomised trials are ongoing, testing β-blockers and angiotensin-converting enzyme inhibitors (ACEIs; MINOCA-BAT; NCT03686696). Patients with type 2 MI have high cardiovascular risk, and in one study were found to be twice as likely to be readmitted at 1 year with type 1 MI than those with myocardial injury.28,37,79,97 The initial management should be to reverse the triggering factors, such as arrhythmia or anaemia. The well-established evidence base for antiplatelets and anticoagulants in type 1 MI has not been shown to be of benefit in type 2 MI, and may cause harm, particularly bleeding, in an elderly cohort. Many patients having a type 2 MI may be on cardiovascular medications, such as β-blockers, anti-hypertensives and statins. Not surprisingly, given the lack of evidence for the type 1 MI treatments in type 2 MI, studies demonstrate at most a 50% prescription rate for antiplatelet therapy, statins, β-blockers and ACEIs or angiotensin II receptor blockers on discharge for type 2 MI patients.32,33,41 Given that by definition a clinical diagnosis of type 2 MI means that the clinician believes there has not been an acute atherothrombotic event, we hypothesise that dual antiplatelets and anticoagulants are not likely to be beneficial. If there is evidence of coexistent CAD, these patients would be categorised in the recent ESC lipid guidelines as being at very high risk, and as requiring statins to reduce LDL cholesterol to <1.4 mmol/l.98 The proprotein convertase subtilisin/kexin type 9 inhibitor has been shown to reduce type 2 MI after acute coronary syndrome.99 Specific therapies targeting the cardiomyocyte signalling mechanisms following ischaemia have thus far proved elusive in humans. Nonetheless, conceptually it is likely that any specific treatments for type 2 MI will come from the cellular response to ischaemia, given that it is the final common

pathway that leads to injury, whatever the initial trigger may be.

One factor that is common to the many triggers for type 2 MI is tachycardia, which, as well as potentially triggering myocardial stretch mechanisms, creates an oxygen supply–demand mismatch by increasing myocardial work (demand) and reducing diastolic time and thus coronary perfusion (supply). In the POISE trial, which used metoprolol as a preventative therapy for perioperative MI in non-cardiac surgery, there was a benefit to β-blockade in preventing MI (HR 0.73; 95% CI [0.60–0.89]; p=0.0017), as defined by the universal definition at the time, which preceded hsTn and the introduction of myocardial injury.100 Unfortunately, this was offset by hypotension and ischaemic strokes (which was thought at least in part to be related to hypotension predisposing to cerebral hypoperfusion). It may also be the case that given that most morbidity and mortality following type 2 MI is from non-cardiovascular causes, prevention of a troponin rise, and thus myocardial damage, might not greatly alter overall prognosis.

The role of invasive coronary angiography with or without PCI, as well as CT coronary angiography, is not well-defined in the type 2 MI population.101 Furthermore, IVUS and OCT have been little used. Referral for angiography is low in this cohort, which often consists of elderly patients who might have renal dysfunction, cognitive impairment, bleeding and/or anaemia.

Delayed functional testing is often used, although there are no long-term outcome studies to help guide selection of the optimal strategy. Trials are currently ongoing to investigate whether routine invasive coronary angiography in type 2 MI and myocardial injury improves prognosis (ANZCTR; ACTRN12618000378224). Ultimately, in any individual case, the clinician must draw on all the information at hand to decide whether the finding of CAD would change management.

Impact of High-sensitivity Troponin

Given that hsTn is approximately 10-fold more sensitive than previous standard assays, minute release of troponin will be detected more frequently. Use of hsTn is expected to result in an increase in the diagnosis of type 2 MI, with even small elevations being recognised.28,34,79 Although a ‘rise and/or fall’ is required in the UDMI, no specific numbers are currently incorporated (the generally accepted delta is in the 20–50% range or an absolute change of 5 mmol/l). Thus it is likely that in clinical practice, type 2 MI will be diagnosed with greater frequency and unstable angina will be less frequent.102 Myocardial injury is also likely to be diagnosed more frequently, with detection of more instances of non-ischaemic myocardial damage. In our opinion, it is foreseeable that myocardial injury may become a more common diagnosis than type 2 or type 1 MI in hospitalised patients.103 Patients with a non-coronary but otherwise cardiac cause of presentation to the emergency department (e.g. arrhythmia or myocarditis) may have higher hsTn levels than those with non-cardiac aetiologies, such as anaemia or hypoxia.104 HsTn might allow greater precision with risk stratification in certain clinical settings of type 2 MI, such as tachyarrhythmia. One study found that patients with tachyarrhythmia who had a positive hsTn (accounting for 47% of all tachyarrhythmia patients) had a significantly higher mortality than those with a negative hsTn, with rates similar to that of non-STelevation MI patients.80

Conclusion

Type 2 MI is common in hospital populations and accounts for at least 25% of all MI. Increased detection of both type 2 MI and myocardial injury

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Type 2 MI in the Era of High-sensitivity Troponin with hsTn means that these entities will be frequently encountered by all clinicians. This is not surprising given the many clinical conditions that can disturb the supply–demand balance of oxygen to the myocardium and the many causes of myocardial injury. Patients with type 2 MI may be asymptomatic. This, combined with a lack of specific treatments for type 2 MI, can create some uncertainty for clinicians at the bedside. Most importantly, type 2 MI patients have a worse prognosis than type 1 MI patients.

hypoxemia, hypertension, hypotension, tachypnoea, bradycardia etc.).32,33 Clearly this will be very challenging in the individual patient and confounded by multiple comorbidities. When there is a grey area, strategies to exclude plaque disruption and acute coronary thrombosis clinically with a certain degree of confidence would be very helpful. It must be remembered that all MIs involve thrombus in the coronary arteries post-mortem (Viramani, personal communication, 2021), and detection of plaque rupture is the critical feature.

Perhaps the most needed next step in the diagnosis of type 2 MI is a more specific clinical definition to streamline future investigation.25,27,33 In current clinical practice there are four main scenarios that are separated partly by their pathophysiology, but mainly by their investigative and management strategies: first, type 1 MI with an acute atherothrombotic event with plaque rupture and thrombus formation, for which PCI or thrombolytic therapy, dual antiplatelets, and anticoagulants are appropriate; second, type 2 MI with some degree of underlying CAD for which statin with or without aspirin may be appropriate, as well as β-blockers and ACEIs if the left ventricular ejection fraction is decreased, along with risk factor modification; third, type 2 MI due to supply–demand mismatch with minor coronary artery stenosis (i.e. MINOCA); and fourth, troponin elevation due to non-ischaemic mechanisms (e.g. myocardial injury).

Given the poor prognosis with type 2 MI, another main area of future investigation should be treatment and prevention. Tachycardia is a common final trigger in type 2 MI, and targeted heart rate reductions need to be evaluated, perhaps alongside such things as oxygen therapy and blood transfusions. The role of angiography and PCI needs to be further defined, and randomised trials are underway.101 The research effort afforded to type 1 MI over the last decade should be afforded to type 2 MI, with emphasis on medical therapies (such as those acting on ischaemic cellular signalling that have shown promise in non-human models) to achieve a reduction in morbidity and mortality. Long-term outcome reports of type 2 MI patients stratified by specific treatment strategy are needed. As well as treatment, the aim is to be able to identify patients at risk of type 2 MI and institute preventative strategies early.

Areas that need ongoing research so that they may be incorporated into a clinical universal definition are impact of hsTn assays; quantification of troponin levels and patterns; and specification of triggering factors for type 2 MI without being too exclusive (for example, the degree of anaemia, 1.

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EDITORIAL

COVID-19

European Society of Cardiology Highlights: Late-breaking Trials – COVID-19 Maki Komiyama

and Koji Hasegawa

Division of Translational Research, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

Keywords

Antiviral treatment, clinical trials, COVID-19, severe acute respiratory syndrome coronavirus 2 Disclosure: KH is on the European Cardiology Review editorial board. MK has no conflicts of interest to declare.

Received: 10 January 2022 Accepted: 10 January 2022 Citation: European Cardiology Review 2022;17:e04. DOI: https://doi.org/10.15420/ecr.2022.03 Correspondence: Koji Hasegawa, Director, 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 non-commercial purposes, provided the original work is cited correctly.

Nearly 2 years after the global outbreak of COVID-19, knowledge about drug treatment for the disease continues to accumulate. Pharmacological treatment for COVID-19 can be broadly divided into antivirals, immunosuppressants and anticoagulants, each with a different mechanism of action and effective timing of medication, depending on the severity of the disease.

The main pathogenesis of COVID-19 is thought to be viral replication in the first few days after onset, and an inflammatory response by host immunity after about 7 days.1 Therefore, it is important to administer antivirals early in the course of the disease and anti-inflammatory drugs in moderate and severe disease after about 7 days of onset.2 Several clinical trials by the WHO are underway around the world to evaluate COVID-19 antiviral treatment. This editorial describes a trial of a new drug therapy for COVID-19, which was presented as late-breaking science at the European Society of Cardiology Congress 2021 (ESC 2021), held on 29 August 2021.

(20.1%) compared with 24.9% in the control group (p<0.05), suggesting colchicine had a beneficial effect in hospitalised patients. On the other hand, the co-primary outcome of death or ventilator use was not significantly different (25.0% in the colchicine group compared with 28.8% in the control group; p=0.08). In addition, death (the co-primary outcome) was also not significantly different at 20.5% in the colchicine group compared with 22.2% in the control group (p>0.05). The use of colchicine was associated with a significant increase in severe diarrhoea (control group: 4.5%, colchicine group: 11.3%; p<0.05).

After the presentation of the trial at ESC 2021, a systematic review and meta-analysis published at the end of November 2021 showed that colchicine did not improve outcomes for all the established endpoints (mortality, ventilator support, intensive care unit admission and length of stay) and that adverse events were significantly increased.5 In conclusion, the efficacy of colchicine in the treatment of COVID-19 is limited and its administration is not recommended.

Colchicine: ECLA PHRI COLCOVID Trial

Icosapent Ethyl: PREPARE-IT-1 and PREPARE-IT-2

The ECLA PHRI COLCOVID trial (NCT04328480) was an RCT to evaluate the effect of colchicine in patients hospitalised with severe COVID-19 disease, with the aim of reducing mortality; its findings were presented by Dr Rafael Diaz at ESC 2021. In this trial, 1,279 patients aged 18 years and older admitted with COVID-19 were randomly assigned to the control (n=639) or colchicine (n=640) treatment group.

In an RCT reported from Canada in August 2021, 100 symptomatic COVID-19 positive outpatients were enrolled and assigned to the EPA group (8 g EPA/ day for 3 days, followed by 4 g EPA/day for 11 days) or to treatment as usual.6 The results showed that the main biomarker endpoint – high-sensitivity C-reactive protein (hs-CRP) – was significantly reduced by 25% in the EPA group (−0.5 mg/l; interquartile range [IQR] −6.9, 0.4; within-group p=0.011), but not in the usual care group, which saw a decrease of 5.6% (−0.1 mg/l; IQR −3.2, 1.7; within-group p=0.51). Furthermore, there was a significant improvement in symptoms as measured by the patient-reported FLU-PRO score. This trial suggests that EPA may ameliorate early inflammation and symptoms in symptomatic outpatients with COVID-19.

Among the secondary outcomes, there was a significant reduction in deaths due to new intubation or respiratory failure in the colchicine group

PREPARE-IT 1 (NCT04460651) is a trial that tested whether EPA use reduces the rate of coronavirus infection in unvaccinated, COVID-19-uninfected

The anti-inflammatory effect of colchicine on the cytokine storm made it a promising candidate for the treatment of COVID-19, and the drug is known to be safe and well tolerated. Randomised controlled trials (RCTs) in hospitalised patients have reported limited clinical benefits of colchicine, such as increased time to clinical deterioration (mean [SD] event-free survival time was 18.6 [0.83] days in the control group versus 20.7 [0.31] in the colchicine group; log-rank p=0.03) and reduced duration of oxygen supplementation therapy and hospitalisation.3,4

The anti-inflammatory effect of icosapent ethyl (EPA), a highly purified omega-3 fatty acid that is a safe and well-tolerated oral therapy, makes it a promising therapy for COVID-19.

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ESC Highlights: Late-Breaking COVID-19 Trials healthy participants. It was presented by Diaz at ESC 2021. A total of 4,244 people were screened in the trial, with a total enrolment of 1,712; the mean age was 40.5 years, and 55% were women. Participants were randomised at a ratio of 1:1 to receive either: EPA (4 g orally twice a day for 3 days, then 2 g twice a day for days 4–60; n=850); or a matching placebo (n=862).

Results showed that EPA treatment did not reduce infection rates, and there were no significant differences between EPA and placebo in adverse events, such as AF or bleeding. The trial is significant in that it demonstrated the excellent safety and tolerability of high doses of EPA (8 g/day).

After the PREPARE-IT 1 trial was presented at ESC 2021, the results of the PREPARE-IT 2 trial (NCT04460651), an RCT examining the efficacy of EPA in reducing the severity of disease, was presented by Diaz at the American Heart Association Annual Scientific Sessions on 15 November. Patients in the PREPARE-IT 2 trial were COVID-19-positive patients aged ≥40 years, and had had symptoms of infection (e.g. fever, cough, sore throat, shortness of breath or myalgia) within the previous 7 days, but without an obvious indication for hospitalisation. These participants were randomised at a ratio of 1:1 to receive either EPA (4 g orally twice a day for 3 days, then 2 g twice a day for 4–28 days; n=1,010) or the corresponding placebo (n=1,042).

Results showed that the primary endpoint of COVID-19-related hospitalisations was not significantly different between EPA and placebo groups at 11.2% versus 13.7% (HR 0.84; 95% CI [0.65–1.08]; p=0.17). In the secondary analyses, there were no significant differences in new ventilator inductions (p=0.65) or total events (non-fatal MI or stroke, and death; p=0.12). The trial did not show efficacy. Further investigation regarding EPA is awaiting.

Rivaroxaban: The MICHELLE Trial

COVID-19 has a higher tendency to lead to thrombosis than other infections, and thrombotic complications (arterial and venous) are independent predictors of poor outcome.7,8 For patients hospitalised with non-severe COVID-19, therapeutic doses of heparin appear to be beneficial, reducing the need for organ support and intubation at high rate, and increasing survival rates, regardless of D-dimer results.9 However, for critically ill patients, therapeutic doses of heparin do not improve outcomes, and it has been suggested that they may be harmful.10,11 The results of the MICHELLE trial, which examined the role of rivaroxaban in extending the duration of post-discharge care, were presented at ESC 2021 and reported in The Lancet.12 In the MICHELLE trial, the mean age 1.

2.

3.

4.

5.

Siddiqi HK, Mehra MR. CID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. J Heart Lung Transplant 2020;39:405–7. https://doi. org/10.1016/j.healun.2020.03.012; PMID: 32362390.

Gandhi RT, Lynch JB, Del Rio C. Mild or moderate Covid-19.

N Engl J Med 2020; 383:1757–66. https://doi.org/10.1056/ NEJMcp2009249; PMID: 32329974.

Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial. JAMA Netw Open 2020;3:e2013136. https://doi. org/10.1001/jamanetworkopen.2020.13136; PMID: 32579195.

Lopes MI, Bonjorno LP, Giannini MC, et al. Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD Open 2021;7:e001455. https://doi.org/10.1136/ rmdopen-2020-001455; PMID: 33542047.

Mehta KG, Patel T, Chavda PD, et al. Efficacy and safety of

was 57.1 years, 127 (40%) were women and 191 (60%) were men, and the mean BMI was 29.7 kg/m2. Patients received standard heparin thromboprophylaxis during hospitalisation and were randomly assigned at a ratio of 1:1 to receive low-dose rivaroxaban (10 mg once daily for 35 days) or no anticoagulation after discharge. Eligibility criteria included only patients at high risk of venous thromboembolism (VTE), with a total modified IMPROVE VTE risk score ≥4; or total modified IMPROVE VTE risk score 2 or 3 and D-dimer >500 ng/ml.

The primary efficacy outcome was a composite of symptomatic or fatal VTE, asymptomatic VTE (assessed by screening bilateral lower extremity venous ultrasound and CT pulmonary angiography), symptomatic arterial thromboembolism and cardiovascular death at day 35. In the results, the primary endpoint occurred in five out of 159 (3.14%) patients in the rivaroxaban group and in 15 out of 159 (9.43%) patients in the noanticoagulation group (RR 0.33; 95% CI [0.12–0.90]; p=0.0293). There were no major bleeding events in either group, and the same was true for the incidence of clinically relevant non-major bleeding. This therefore suggests that thromboprophylaxis with rivaroxaban for 35 days improves clinical outcomes without increasing bleeding compared with no anticoagulation after hospital discharge.

These results are promising and results are awaited of trials evaluating post-discharge thromboprophylaxis including HEAL-COVID (NCT04801940), ACTIV-4c (NCT04650087), XACT (NCT04640181) and Effect of the Use of Anticoagulant Therapy During Hospitalization and Discharge in Patients with COVID-19 Infection (NCT04508439).

Conclusion

In general, viruses mutate gradually through repeated replication and epidemics, and it is thought that severe acute respiratory syndrome coronavirus 2 mutates at a rate of about once a fortnight. At present, mutant strains of B.1.1.529 (omicron strains) are rampant in many parts of the world. The omicron strain has about 30 mutations in the projections on the surface of the virus and is attracting attention because of its high infectivity.

Specific antibody drugs against COVID-19 have been reported to be less effective against omicron strains and, given the possibility of further viral mutations, it would be useful to consider the pathogenesis of the infection.

Close attention must be paid to assessing whether candidate drugs against COVID-19 and drugs under development are effective against new mutant strains.

colchicine in COVID-19: a meta-analysis of randomised controlled trials. RMD Open 2021;7:e001746. https://doi. org/10.1136/rmdopen-2021-001746; PMID: 34810227.

6. Kosmopoulos A, Bhatt DL, Meglis G, et al. A randomized trial of icosapent ethyl in ambulatory patients with COVID-19. iScience. 2021;24:103040. https://doi.org/10.1016/j. isci.2021.103040; PMID: 34462732.

7. Komiyama M, Hasegawa K. Anticoagulant therapy for patients with coronavirus disease 2019: urgent need for enhanced awareness. Eur Cardiol 2020;15:e58. https://doi. org/10.15420/ecr.2020.24; PMID: 32944087.

8. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol 2020;75:2950–73. https://doi.org/10.1016/j.jacc.2020.04.031; PMID: 32311448.

9. Lawler PR, Goligher EC, Berger JS, et al. Therapeutic anticoagulation with heparin in noncritically ill patients with

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Covid-19. N Engl J Med 2021;385:790–802. https://doi. org/10.1056/NEJMoa2105911; PMID: 34351721.

10. Goligher EC, Bradbury CA, McVerry BJ, et al. Therapeutic anticoagulation with heparin in critically ill patients with Covid-19. N Engl J Med 2021;385:777–89. https://doi. org/10.1056/NEJMoa2103417; PMID: 34351722.

11. Sadeghipour P, Talasaz AH, Rashidi F. Effect of intermediatedose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized clinical trial. JAMA 2021;325:1620–30. https:// doi.org/10.1001/jama.2021.4152; PMID:33734299.

12. Ramacciotti E, Agati LB, Calderaro D, et al. Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial. Lancet 2021;399:50–9. https://doi. org/10.1016/S0140-6736(21)02392-8; PMID: 34921756.

REVIEW

Cardiovascular Disease in Chronic Kidney Disease

Arrhythmias in Chronic Kidney Disease Zaki Akhtar, Lisa WM Leung , Christos Kontogiannis, Isaac Chung, Khalid Bin Waleed and Mark M Gallagher Department of Cardiology, St George’s University Hospitals NHS Foundation Trust, London, UK

Abstract

Arrhythmias cause disability and an increased risk of premature death in the general population but far more so in patients with renal failure. The association between the cardiac and renal systems is complex and derives in part from common causality of renal and myocardial injury from conditions including hypertension and diabetes. In many cases, there is a causal relationship, with renal dysfunction promoting arrhythmias and arrhythmias exacerbating renal dysfunction. In this review, the authors expand on the challenges faced by cardiologists in treating common and uncommon arrhythmias in patients with renal failure using pharmacological interventions, ablation and cardiac implantable device therapies.

They explore the most important interactions between heart rhythm disorders and renal dysfunction while evaluating the ways in which the coexistence of renal dysfunction and cardiac arrhythmia influences the management of both.

Keywords

Arrhythmia, chronic kidney disease, sudden cardiac death, dialysis, atrial fibrillation Disclosure: ZA has received a grant for a research fellowship from Abbott Medical. MMG has received research funding from Attune Medical and Biotronik, and has acted as a consultant and a paid speaker for Boston Scientific and Cook Medical. All other authors have no conflicts of interest to declare.

Received: 7 November 2021 Accepted: 6 December 2021 Citation: European Cardiology Review 2022;17:e05. DOI: https://doi.org/10.15420/ecr.2021.52 Correspondence: Zaki Akhtar, St George’s Hospital, Blackshaw Rd, London SW17 0QT, UK. E: zakiakhtar@nhs.net 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.

Arrhythmias are common in all age groups, and becoming more prevalent with increasing age.

In young people, most cases reflect the presence of congenital anomalies of the structure or function of the conduction system of the heart. These affect approximately 1% of the general population and, although seen in patients with renal conditions, they have no important association with chronic kidney disease (CKD).

Acquired conditions of the atrial and ventricular myocardium accumulate with age and cause atrial and ventricular tachyarrhythmias and bradyarrhythmias. AF is the most common sustained arrhythmia by far; it increases sharply with age and affects 1.5% of the general population at age 55–59 years and 27% at age >85 years.1 Sustained and recurrent ventricular arrhythmias are less common, but are important as sudden death is often due to ventricular tachyarrhythmia. Complete atrioventricular block and other forms of bradyarrhythmia are common and increase sharply with age.

CKD is even more prevalent than sustained arrhythmia and is associated with an excess of acquired arrhythmia of multiple types, and AF in particular.2 Sudden death is also more common in CKD and accounts for around one-quarter of deaths in dialysis patients.3 Rigorous monitoring can detect a higher incidence of arrhythmia than is evident clinically. Physical or electrocardiographic examination performed in response to symptoms catches a minority of events. In the ARIC study, a 2-week cardiac monitor recorded a high prevalence of non-sustained ventricular tachycardia (30.2%) and AF (7.4%) in patients with CKD, while ectopy was present in >90% of patients.4

The most intensive monitoring is that provided by an implanted device.

Rautavaara et al. studied 71 dialysis patients who were asymptomatic for arrhythmia; in a follow-up of 34 months, they detected AF in 51% of patients, significant bradycardia in 24% and ventricular tachycardia in 23%.5

Mechanisms of Arrhythmia in Renal Failure Common Causes

Renal and cardiac tissue share a vulnerability to damage from conditions that are common throughout the world (Figure 1).

Diabetes and hypertension each account for a large proportion of arrhythmias in the general population, particularly AF. Both conditions are also responsible for a large proportion of cases of end-stage renal failure.

In both cases, CKD and AF are usually late effects of the underlying condition, but that underlying condition commonly goes undiagnosed until the consequences bring it to light.

Uncommon Causes

A number of uncommon and rare syndromes are associated with both arrhythmia and CKD. Despite this rarity, they are important because prompt recognition may permit life-extending specific treatment.

Fabry’s disease is an X-linked lysosomal storage disorder characterised by an accumulation of glycosphingolipids resulting from a deficiency in the enzyme α-galactosidase A.6 There is systemic deposition of glycosphingolipids (particularly globotriaosylceramide) including in the cells of the blood vessels, kidneys and heart.7 Cardiac infiltration

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Arrhythmias in Chronic Kidney Disease Figure 1: Chronic Kidney Disease with Arrhythmia • Klotho deficiency • (+) Fibroblast growth factor-23 • Calcium phosphate accumulation

Increased sympathetic tone/ autonomic imbalance • Renin–angiotensin–aldosterone system activation • α-adrenergic stimulation • Systemic inflammation • (+) Norepinephrine release

Peripheral vascular disease • Endothelial dysfunction • Vascular calcification/ arteriosclerosis • Reduced nitric oxide availability • (+) Stiffness/(−) elasticity

Chronic kidney disease • (+) Action potent duration • (+) Ventricular contraction • (+) Triggered activity • (+) Re-entry and automaticity

Uncommon comorbidities • Amyloidosis • Fabry’s disease

Left ventricular remodelling • Left ventricular hypertrophy • Fibrosis • Apoptosis

Electrolyte disturbances (potassium, magnesium) Uraemia Haemodialysis-induced haemodynamic stress

Cardiac arrhythmias

Heart failure

• Coronary calcification • Ischaemic cardiomyopathy

Common comorbidities • Hypertension • Diabetes

This shows the interactions between chronic kidney disease and arrhythmia and the causes and effects of each.

subsequently results in left ventricular hypertrophy (LVH) secondary to myocardial fibrosis, while renal involvement leads to CKD. Unsurprisingly, cardiac and renal involvement is common in Fabry’s disease; a small study of patients (average age 25 years) with Fabry’s disease found that 42% of patients already had CKD at the point of diagnosis and 33.3% had LVH, suggesting early simultaneous organ involvement.8 Arrhythmias in this population are not rare. An observational study has reported a prevalence of 13.3% in a cohort with Fabry’s disease, although it could be higher as the risk worsens with age.8,9 Atrial, ventricular and bradyarrhythmias have been confirmed.9,10 Myocardial fibrosis is an important substrate for arrhythmias; it is associated with a significantly higher risk of arrhythmias comparatively to patients without fibrosis.11 The risk of arrhythmias may also be compounded by CKD, which is a pro-arrhythmic clinical state in its own right.12 It is therefore unsurprising that the cause of mortality in this group of patients is sudden cardiac death (SCD).13 This may be by ventricular tachyarrhythmias or by bradyarrhythmias.10,13 Amyloidosis, like Fabry’s disease, involves infiltration of both the myocardium and kidneys. There is aggregation and deposition of abnormal protein – amyloid – in the healthy extracellular tissues resulting in organ damage.14 Although there are numerous types, the most common in the western world is primary amyloidosis; here, immunoglobulin lightchain proteins are deposited in the affected organs.14,15 Renal impairment is a feature of this illness, with associated poor outcomes, even when compared to patients with CKD from other aetiologies.14 Nephrotic syndrome ensues progression to end-stage renal failure requiring renal replacement therapy and/or renal transplant.

Despite these interventions, outcomes are unfavourable compared to the general renal failure population.14 There is cardiac involvement not only directly through the disease itself but also from renal replacement therapy; progressive haemodialysis can become inefficient at filtration, resulting in β2-microglobulin deposition from the uraemia.15 Cardiac involvement in amyloidosis results in a restrictive cardiomyopathy leading to diastolic left ventricular (LV) dysfunction. Arrhythmias are common in this subgroup of patients, including AF, ventricular tachyarrhythmias and conduction abnormalities.16 Evidence suggests these patients do not tolerate arrhythmias well due to the poor compliance of the cardiac muscle, which compounds the abnormal filling and ejection of blood.16 Arrhythmia management is also difficult because the tissue has abnormal properties following amyloid infiltration. Traditional pharmacological therapy, including β-blockers, calcium channel blockers and digoxin are poorly tolerated because of the altered haemodynamics, while amiodarone, although it maintains sinus rhythm, is associated with significant side effects.16 Catheter ablation, the treatment of choice in many arrhythmias, also is associated with variable outcomes; a small study found a high 1-year arrhythmia recurrence rate following catheter ablation in patients with amyloidosis compared to a similar set of patients without the condition.17 Although cardiac failure is the most common cause of mortality in patients with amyloidosis, SCD remains a concern.18 SCD can include ventricular arrhythmias but also pulseless electrical activity with electromechanical asynchrony.

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Arrhythmias in Chronic Kidney Disease Chronic Kidney Disease, Mineral Bone Disorders and Anaemia

Electrolytes

A key feature of CKD is the development of CKD mineral bone disorders.

This syndrome is characterised by altered calcium, phosphate, parathyroid hormone, vitamin D and fibroblast growth factor-23 (FGF-23) homeostasis; vascular or soft tissue calcification; and an abnormal bone structure and/ or turnover.19 This has a number of effects on the cardiovascular system.

Calcium is a crucial component of myocyte depolarisation and cardiac contractility, while phosphate is central to adenosine triphosphate, the energy-carrying molecule that cells rely upon.

FGF-23 regulates circulating phosphate and vitamin D levels and is associated with poor outcomes. In a study of 795 patients, FGF-23 was strongly associated with LV hypertrophy and increased LV mass index; higher LV mass index is associated with SCD.20,21 It also may play a role in the calcification of coronary and peripheral arterial vessels which, in turn, lead to cardiovascular events, thereby exacerbating the risk of SCD.22,23 Vitamin D deficiency in CKD has also been found to be associated with cardiac dysfunction. A small prospective control study of 25 patients found that treatment with calcitriol, the active form of vitamin D, markedly reduced LV hypertrophy, resulting in an improvement in LV function.24 This indicates that vitamin D plays a significant role in maintaining cardiovascular health in CKD. The authors discovered an association between calcitriol and lower levels of circulating parathyroid hormone and angiotensin II; they proposed that vitamin D may have lowered the level of these neurohormones, which affect LV mass through direct or indirect mechanisms.

Anaemia is common in people with CKD owing to erythropoeitin deficiency and is associated with excess mortality. A large retrospective study suggested that haemoglobin <6.52 mmol/l was associated with a mortality risk (HR 5.27) and anaemia was independently associated with mortality and cardiovascular events.25 Anaemia in CKD has been associated with LVH, which is an established variable for poor cardiovascular outcomes, and there is evidence suggesting that correction of anaemia results in LVH regression.26 However, randomised controlled trials have demonstrated no cardiovascular benefit and, in some cases, worse outcome from correction of anaemia with erythropoeitin.27,28 This is probably because the benefits from erythropoeitin were negated by the adverse effects from this hormone; promoting red cell production can increase blood viscosity (therefore increase the risk of thrombosis) while attenuating hypertension.

Ischaemia

Patients with CKD develop ischaemic heart disease at a greater rate than the general population.

Although effective lipid-lowering therapy has been available for decades, re-entry around scarring from previous MI is the leading cause of sustained ventricular tachycardia, while ventricular dysfunction from chronic ischaemia is a major cause of heart failure. Between them, these account for a large proportion of SCD. Atrial arrhythmia is not so strongly linked to ischaemia. Typically, atrial flutter is more common in those with ischaemic heart disease than in agematched controls, while AF occurs at similar rates in both groups.

The kidney regulates the excretion or retention of electrolytes and products of metabolism in a continuous manner; dialysis is intermittent, often occurring at intervals of several days. The discontinuous nature of the dialysis process inevitably leads to fluctuations in the levels of any variable that would normally be kept constant by the kidney.

The extent of fluctuation is not itself constant: potassium can accumulate unexpectedly due to changes in diet and variation in the severity of renal dysfunction. During haemodialysis, changes in serum potassium concentration exceeding 1 mmol/l commonly occur in a period of a few hours.29 Trans-membrane ionic gradients drive the electrophysiology of excitable tissues, including the myocardium. Potassium and sodium are involved, but the process is particularly vulnerable to abnormalities in potassium concentration because the resting membrane potential of excitable cells is identical to that of the equilibrium potential of potassium.30 Hyperkalaemia is a common feature of renal failure. It produces characteristic abnormalities of the ECG, including peaked T-waves, P-wave flattening and broadening of the QRS duration.

At higher levels of hyperkalaemia, conduction block, bradyarrhythmias, asystole and ventricular arrhythmias can occur. Physiologically, these are related to the raised extracellular potassium concentration; this shortens the myocyte action potential duration (APD) and slows conduction velocity which, in turn, affects myocardial refractoriness.30 At high extracellular potassium levels, there is risk of heart block and asystole as the conduction velocity slows, with the shortened APD causing widespread myocardial refractoriness. Ventricular arrhythmias in hyperkalaemia are thought to be re-entrant circuits. It is hypothesised that there is APD discordance in localised regions of the heart with progressive hyperkalaemia.

This generates areas of localised block and potentially re-entry.30 Hyperkalaemia in CKD can occur catastrophically as part of a constellation of mutually reinforcing processes featuring bradycardia, renal failure, atrioventricular block, shock and hyperkalaemia (BRASH) itself. This cycle can be triggered by the synergy between bradycardia and hyperkalaemia, each of them easily provoked pharmaceutically.31 For example, β-blockers and calcium channel blockers commonly used for controlling arrhythmias can cause bradycardia, which in patients with renal impairment can trigger BRASH syndrome; the risk is believed to be greatest in elderly patients being treated for AF.31 Once established, this reinforcing sequence can progress to death unless interrupted by supportive care to correct the bradycardia and the hyperkalaemia; temporary pacing may be required as part of this basic support.

Neuropathy

The autonomic nervous system regulates the heart rate in sinus rhythm and in a less precise manner in AF. Feedback mechanisms mediated by this system appear to have a role in stabilising the electrophysiology of the myocardium, or at least the capacity to destabilise it when the system malfunctions.

A role for autonomic dysfunction in the genesis of AF has been hypothesised, and partial cardiac denervation has been proposed as part of the reason for rhythm stabilisation after AF ablation.

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Arrhythmias in Chronic Kidney Disease Autonomic neuropathy is a common consequence of CKD and of the diabetes that often underlies it.32 It is reasonable to hypothesise that this neuropathy might contribute to the arrhythmias seen in patients with CKD.

Of clinical significance, ACE-inhibitor treatment has been found to reduce atrial remodelling in AF and has been applied therapeutically to reduce AF in hypertensive and heart failure patients.49–52

There is evidence suggestive of sympathetic overactivity in CKD. This has numerous adverse effects on the renal-cardiovascular systems.

Sympathetic overactivity can exacerbate hypertension, which can sequentially worsen the renal impairment; hypertension contributes to interstitial fibrosis and glomerulosclerosis.33 Simultaneously, sympathetic overactivity can cause LVH, directly or indirectly, and it has a known association with cardiac arrhythmias.34

Medical Attention

There is strong evidence to suggest patients with CKD are more likely to develop AF.35 This association was suggested to be causal in a canine model via an autonomic cross link. In this study of 28 dogs, renal sympathetic nerve (RSN) activation mediated pro-fibrillatory effects in the pulmonary veins and atria; RSN activation increased AF inducibility.36 Although this is yet to be proven in human studies, it has a theoretical application. Patients with CKD have documented increased RSN activation and RSN denervation has been shown to be an effective therapy for treating AF.37 A better understanding of the mechanism of RSN hyperactivity may present significant therapeutic strategies for arrhythmias.

Inflammation

The pathogenesis of AF in CKD could be linked on a molecular level. A recent study has suggested a role for the NLRP-3 inflammasome in the pathophysiology of AF.38 The NLRP-3 inflammasome is a component of the innate immune system and has been shown to act on cardiomyocytes and atrial fibroblasts.39 Activated cardiomyocytes and fibroblasts can secrete inflammatory cytokines, recruit macrophages and other inflammatory cells, and induce atrial fibrosis.38 Atrial fibrosis is an arrhythmogenic substrate as it disrupts the normal cellular architecture and therefore impairs normal conduction. This increases conduction heterogeneity, producing re-entrant mechanisms to sustain AF.38,39 The significant role of NLRP3 inflammasome in renal injury is recognised and a recent mouse model study (sham-operated versus CKD mice) demonstrated a significantly elevated level of NLRP3 in the cardiac tissue of the CKD mice.40,41 Therefore, it is suggested that CKD upregulates NLRP3 in cardiomyocytes and promotes arrhythmias.

Renin–Aldosterone–Angiotensin System

Patients with CKD have been shown to have inappropriately high reninangiotensin-aldosterone system (RAAS) activity.42 Molecules within the RAAS system have been implicated in inflammation, atrial enlargement and atrial fibrosis.43–45 First, RAAS has been shown to upregulate inflammatory cytokines such as IL-6 and increase cell adhesion.46,47 Second, in an animal study, increased angiotensin-converting enzyme (ACE) expression has been shown to increase atrial size, leading to increased atrial arrhythmias, and angiotensin II, the main active molecule of RAAS, has been implicated in atrial fibrosis and remodelling.39,44,48 Finally, atrial tissue from AF patients has been found to have increased ACE signalling, further implicating the RAAS in the development of atrial fibrosis.

Patients with CKD spend more time in direct contact with healthcare professionals than healthy people of a similar age. This is particularly marked for those receiving haemodialysis or awaiting renal transplantation.

Arrhythmias in this group should be diagnosed promptly and referred appropriately. Dialysis gives an exceptional opportunity to observe the heart rhythm under conditions of haemodynamic stress; effectively, it is a twice-weekly provocation test for a large cohort of vulnerable patients.

Cardiac arrest during haemodialysis occurs at a rate of 1–7.5 per 100,000 haemodialysis sessions, so there is an opportunity to intervene and save lives.53–55 Dialysis services are therefore obliged to maintain vigilance and preparedness.

Causality

With so many mechanisms to choose from, the difficulty lies not in determining whether an association exists between CKD and arrhythmias but in determining the most important mechanisms of connection.

A recent bidirectional Mendelian randomisation study attempted to determine the causality involved in the relationship between CKD and AF. The analysis by Park et al. suggested that genetically predicted AF was significantly associated with CKD and a lower estimated glomerular filtration rate (eGFR) with statistically significant causal estimates. They did not detect an effect of genetically determined eGFR on the incidence of AF. This indicated that AF was possibly a causal risk factor for CKD, but not vice versa.56 It is unlikely that AF is a direct cause of CKD; the relationship is likely to be more complex and involve a multitude of mechanisms. However, this study does suggest that there is a link between arrhythmias and CKD.

Managing Arrhythmia in Renal Disease

Management of arrhythmia begins with the accumulation of diagnostic information. The critical step is to collect electrocardiographic documentation at the right moment.

The symptoms of arrhythmia are protean: palpitations, syncope, presyncope and chest discomfort may occur in any form of tachyarrhythmia and in any bradyarrhythmia.57 More often, arrhythmias produce just a decline in exercise tolerance, dyspnoea on exertion and general malaise.

Because most arrhythmias are intermittent at their onset, documentation and therefore diagnosis are a challenge. Provided the physician is alert to the possibility of an arrhythmia, electronic devices are available to suit the clinical situation.

The choice of device depends on the frequency and duration of the symptomatic events. Frequent but brief symptoms can be assessed on a 24-hour recording; infrequent events of long duration can be documented by performing a standard ECG when the symptoms are present. Symptoms that are both brief and infrequent may require the implantation of a loop recorder.57 Therapy for a patient with arrhythmia should initially address any modifiable underlying condition and should mitigate the risks associated

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Arrhythmias in Chronic Kidney Disease Figure 2: Complexity of Device Implantation A

Figure 3: ICD Extraction after Infection in Patient with Renal Failure

B

C

D

E

F

A

B

C

D

These images show the extraction of an ICD in a patient with renal failure who developed lead-related infection 18 years after implantation of a single-chamber device. The lead was removed using a rotational sheath (A and B). After the patient completed a course of antibiotics, an entirely subcutaneous device was implanted (C), with a chest X-ray confirming the position (D).

Chronically indwelling catheters commonly cause venous stenosis or occlusion, making those veins difficult or impossible for subsequent lead implantation.

An example of complex device implantation in a patient with chronic kidney disease that illustrates the difficulties involved. There is venous stenosis occlusion at the brachiocephalic vein (A) requiring transvenous lead extraction (B) followed by venous angioplasty (C and D) to create space for the cardiac resynchronisation therapy (E and F).

with the arrhythmia. In all cases, valve disease and myocardial ischaemia should be evaluated and, in general, corrected. Heart failure, if present, should be managed optimally. For the renal patient, correction of underlying causes should include optimisation of the control of renal indices. Mitigation of risks includes rate-limiting therapy for any atrial arrhythmia that of >100 BPM and long-term anticoagulation for many patients with persistent atrial tachyarrhythmias.

With underlying conditions corrected, management of renal problems optimised and the risks of thromboembolic complications mitigated, many patients will experience a resolution of arrhythmia episodes or a resolution of arrhythmia-related symptoms and will not require additional therapy.

For those who experience recurrent or continuing symptomatic episodes, specific therapy is indicated to restore and maintain sinus rhythm. This may involve catheter-based procedures, implanted devices, arrhythmia surgery or specific antiarrhythmic drugs alone or in combination.

Exceptions in Renal Failure

Patients with renal impairment are vulnerable to complications that make their management diverge in important ways from the general population.

Device Therapy in Chronic Kidney Disease

Patients with CKD are difficult subjects for device therapy because of the effects of renal replacement therapy on the venous system (Figure 2).

There are important differences between the general population and the CKD population in the risk associated with device therapy, predominantly due to the risk of device infection.

Infection by bacteria introduced during the implantation procedure can manifest as pocket swelling or erosion of the device through the skin at months or years after implantation. More seriously, endovascular infection can result from bacteria introduced at the time of implantation or from bacteria that colonise the leads, often following introduction during dialysis. Once established, either form of infection is near impossible to control without extraction of the device, a substantial undertaking associated with a mortality risk above 0.2% even in the most experienced centres (Figure 3).

The risk of infective complication is significantly higher in patients with renal impairment than in the general population; infection is the second leading cause of death in this cohort.58 A large observational study of 25,675 pre-dialysis patients found that this risk was inversely related to eGFR; the highest risk is associated with the lowest eGFR, with a 3.5-fold higher risk in patients with an eGFR of 30 ml/min/1.73 m2.59 The picture is bleaker for patients on dialysis. The HEMO study, a randomised controlled trial involving 1,846 patients, examined the effects of dialysis dose and flux on patient outcomes found that the there was a 35% annual hospitalisation rate for infection in this group. The risk of infection-related mortality was also found to be high in this subgroup; 23.1% of all deaths in this study were infection related whilst 58% of patients with infection-related first hospitalisation were associated with a severe outcome (death, intensive care stay or prolonged hospital admission).60

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Arrhythmias in Chronic Kidney Disease Figure 4: Extraction of a Pacemaker in a Patient with Dialysis-dependent Chronic Kidney Disease A

B

C

D

have CKD in comparison to those ICD patients who did not have CKD. Conversely, CKD patients have a lower risk of mortality (from SCD) with an ICD, comparatively to those CKD patients who did not have an ICD fitted.69 A subsequent randomised controlled trial of 188 patients on dialysis with a left ventricular ejection fraction of >35% found that prophylactic ICD therapy did not reduce mortality from sudden cardiac death compared to not receiving this therapy.70 Despite this, 13.8% of the ICD group received appropriate ICD therapy for ventricular arrhythmias and there was an overall lower incidence of SCD (10.1%) than in previous reports (22–26%).70 There are notable limitations to this trial: the ICD was implanted in patients with no class I indication so the risk of SCD was lower. The population was also well optimised before enrolment, which may have protected against SCD. The classification of SCD is difficult, especially in the absence of any cardiac monitoring during the terminal event. It is assumed arrhythmic if the patient’s death was sudden, unwitnessed and the patient was well when last observed. Therefore, it is difficult to accurately assess endpoint in the two subgroups.70

A: A rotational dissecting sheath was used to dissect the pacing lead. B and C: A leadless pacemaker is implanted via the right femoral vein at the right ventricle septum. D: A postprocedure chest radiograph shows a leadless pacemaker in the right ventricle.

ICD therapy is, therefore, reserved for those at highest risk of arrhythmiarelated death, including survivors of a cardiac arrest due to ventricular tachycardia or ventricular fibrillation.

Renal impairment has been identified as a potent risk factor for infection in patients with cardiac implantable electronic devices.61 For a patient with CKD, the risk of death from device infection is approximately three times higher, enough to influence the risk-benefit calculation that drives decision-making in device therapy.62 Many rules of thumb used in the general population are therefore not valid in CKD.

When an implanted device is required, the presence of CKD has an important influence on the choice of methodology and equipment.

Mitigation of the risk of infection is the key objective; because the greatest modifiable risk is the seeding of bacteria to device surfaces exposed to the vascular space, measures are taken to minimise the exposed surface area.

ICD therapy is widely used in patients assessed to have a risk of sudden death of >1% per year. Patients with severe impairment of LV systolic function without a reversible cause generally fit this criterion and receive ICD therapy. This is based on the findings of major clinical trials that have demonstrated clear benefit in this cohort of patients.63–65

In the case of ICD therapy, intravascular components can be eliminated completely, using solely components that lie in the subcutaneous space.

These devices lack the capability to treat bradycardia that is universal in transvenous devices but, in many cases, the risk of fatal bradyarrhythmia is less than the risk of fatal infection.

In CKD, the evidence is much less clear; the major ICD trials routinely excluded patients with CKD and the conclusions may therefore not apply to this subgroup. Early evidence suggests that ICD therapy does not benefit patients with loss of kidney function. A retrospective analysis of 61 patients with CKD recruited in MADIT-II did suggest a survival benefit with ICD therapy in patients with an eGFR of >35 ml/min/m2; however, there was no benefit in patients with an eGFR of <35 ml/min/m2 .

Pacing therapy can be delivered through a leadless system (Figure 4); although this lies in the vascular space, it benefits from having a surface area far less than that of a pacing lead.

There is evidence that CKD increases the risk of death in patients receiving an ICD. An observational study of 507 consecutive patients with varying stages of CKD receiving a novel ICD implant found a risk of mortality with renal impairment that increased stepwise by eGFR stage; renal dysfunction was independently associated with mortality in patients receiving an ICD.66

Procedural Risks and Benefits of Ablation

Arrhythmias are very managed definitively by catheter-based procedures.

Circuits are destroyed by radiofrequency (RF) energy, pulsed field energy, laser or cryotherapy delivered by catheters placed via the femoral vessels or, less often, epicardially.

For most symptomatic and recurrent arrhythmias, catheter ablation is the accepted firstline therapy. Catheter ablation has become one of the most common medical procedures, with most of these performed for AF.

This was validated by subsequent meta-analyses, which concluded that CKD in patients with an ICD significantly increased the risk of mortality and suggested that this risk is comparable between earlier stages of renal insufficiency to end-stage renal disease.67,68

Ablation for AF in patients with CKD carries a greater risk than for other patients, including a risk of acute exacerbation of renal dysfunction, but there is evidence that the procedure can result in improved renal function over the long term.71

A study involving two separate meta-analyses performed by Makki et al. evaluated the effect of CKD on ICD and ICD on CKD patient outcomes. The authors concluded that ICD patients have a higher risk of dying if they

A prospective study of 386 patients who underwent AF ablation revealed that eGFR improved with restoration of sinus rhythm within 3 months of the procedure and was maintained up to 1 year after the ablation. Patients

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Arrhythmias in Chronic Kidney Disease Figure 5: Deterioration in Renal Function Seen After AF Ablation A

B

C

D

E

F

100

0

P1 70/36 (49) Examples of ablation for AF illustrating the mechanisms for the post-procedure deterioration in renal function seen in some cases. A and B: Ablation in the manner originally involved X-ray based catheter manipulation and therefore required imaging of the veins by injection of contrast agents. C and D: a more recent innovation, the cryoballoon, is also guided radiologically and contrast agents are generally used. E: most radiofrequency ablation now involves the use of a 3D mapping system, which eliminates the need for contrast. F: because the mapping system is vulnerable to disruption by patient movement, these procedures are usually performed under general anaesthesia or deep sedation, which makes the patient vulnerable to periods of hypotension during the procedure.

with arrhythmia recurrence demonstrated a reduction in the renal function.72 Recurrence following AF ablation is not uncommon in patients with CKD. In a study of 221 patients with a mean follow-up of 32 months following AF ablation therapy, CKD patients had a significantly higher incidence of AF recurrence than non-CKD participants; CKD was identified as independent associated variate with AF recurrence.73 This is consistent with a recent meta-analysis of seven observational studies, which concluded that CKD was significantly associated with higher AF recurrence than in to non-CKD patients (OR 3.71).74 The kidneys are vulnerable to injury from use of radiological contrast media. Early methods of RF ablation for AF necessitated the use of contrast.75 Current RF methods rely on 3D mapping systems, which obviate the need for this medium (Figure 5) but create a need for general anaesthesia or deep sedation combined with analgesia, which can create hypotension severe enough to injure the kidneys.

Cryotherapy is comparable in efficacy to RF methods, but usually involves the use of contrast agents.76 RF ablation without contrast and with meticulous control of arterial pressure is the preferred method.

Pharmacokinetics

Antiarrhythmic drug therapy with agents that modify the function of ion channels can be used selectively in the management of certain

arrhythmias, usually as a bridging measure until an underlying condition is corrected or definitive therapy can be offered. This group of drugs has been shown to increase all-cause mortality in a number of studies in different patient populations, so their long-term use as the sole management strategy has diminished.77–79 There are insufficient data to determine specifically the risks of antiarrhythmic drugs in patients with CKD, but the altered and unpredictable pharmacokinetics of the renal failure state would be expected to augment the risk.

Because these medications act on sodium and potassium channels, the exaggerated fluctuations in ion concentration associated with CKD and dialysis could also pose a risk.

Even β-blocking drugs – a group associated with few dangerous adverse effects in the general population – can cause serious adverse effects in the context of CKD, where altered kinetics combined with electrolyte disturbance can trigger BRASH syndrome.

Bleeding

Bleeding complications are much more common in CKD, and are probably an effect of platelet dysfunction combined with the consequences of hypertension and direct vascular effects.

Bleeding complications occurring at the time of device implantation or ablation account for some of the excess risks of these therapies in CKD

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Arrhythmias in Chronic Kidney Disease Figure 6: Cardiac Problems and Treatments in Chronic Kidney Disease Device infection

Supraventricular arrhythmias S-ICD

Device therapy BRASH

Anticoagulation Antiarrhythmic agents Chronic kidney disease

Ablation Bleeding

Ventricular arrhythmias

Extraction

Bradyarrhymias

This flow diagram depicts the arrhythmias, treatment and potential complications associated with chronic kidney disease. BRASH = bradycardia, renal failure, atrioventricular block, shock and hyperkalaemia; S-ICD = subcutaneous ICD.

patients.80 The risk of spontaneous bleeding, most importantly intracranial bleeding, is high enough to move the balance of risk associated with the use of long-term anticoagulants.

In the general population, AF combined with one other risk for thromboembolism creates a risk that is great enough to justify the haemorrhagic risk of long-term anticoagulation for most patients. In patients with CKD, the increased risk of bleeding is sufficient to outweigh the risk of thromboembolism such that anticoagulation is reserved for those at highest risk of thromboembolism.

When anticoagulants are required, choice is restricted in the CKD population. Warfarin and other vitamin-K antagonists have been almost entirely displaced by direct oral anticoagulant (DOAC) drugs in the general population,based partly on evidence of a safety benefit but mostly due to the inconvenience of the blood testing required to make vitamin-K antagonists safe.81–84 These agents rely on renal clearance and so their application in patients with CKD has limitations. In general, patients with a creatinine clearance (CrCl) of <50 ml/min have been recommended to lower the dose of their DOAC, while those with a CrCl clearance of <15 ml/min are advised against their use.85 Despite this dose reduction in moderate renal impairment (CrCl 30–50 ml/min), DOAC agents have been shown to be safe and efficacious with a comparable bleeding risk and stroke prevention to warfarin.86 There is evidence suggesting that they may be safe in severe renal impairment also, with some reassuring experience in patients receiving renal dialysis.87–88 A Cochrane review of 12,545 patients assessed the efficacy and safety of DOACs versus warfarin in patients with AF and CKD. Of these, 390 had severe renal impairment (CrCl 15–30 ml/min).89 In

keeping with previous evidence, the study concluded that DOACs were as safe and efficacious as warfarin.

Although the study applies mostly to patients with moderate renal failure, it also indicated DOAC use in the severe category was plausible and possibly safe; further work is required. On the basis of current evidence, DOAC therapy is not available to most patients with CKD so the inconvenience of warfarin and similar agents is an added reason to avoid anticoagulation.

Left atrial appendage occlusion, by a catheter-based procedure or removal or occlusion of the appendage by minimally invasive surgery, has the potential to resolve the dilemma of stroke risk and bleeding risk in CKD patients. These interventions have been shown to have a similar efficacy to anticoagulation in preventing stroke in the general AF population, and the catheter-based approach compares favourably to either anticoagulation or no therapy in dialysis patients.90

Economic Impact of Arrhythmias in CKD

The economic impact of AF in CKD is difficult to quantify as it is a cumulative effect. Catheter ablation is expensive, although the costs are improving.

A study based on a registry of 12,027 patients found that catheter ablation was relatively expensive, with first procedure success associated with a significantly lower cost than repeat ablations.91 As the likelihood of arrhythmia recurrence is higher in CKD patients, this is significant.

In comparison to pharmacotherapy, however, catheter ablation is an economically viable option. A cost-effectiveness systematic analysis comparing catheter ablation with pharmacotherapy for AF revealed that ablation therapy in the medium-to-long term was more cost-effective than

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Arrhythmias in Chronic Kidney Disease medical therapy.92 This is probably influenced by the number of repeated hospital admissions associated with arrhythmias managed with pharmacological agents as well as the overall cost of these agents over the lifetime of a patient.

In patients with CKD, medical therapy with anti-arrhythmic agents is also difficult because of the side effects associated with them; the majority have proarrhythmic effects and the metabolic imbalances in CKD are likely to compound this further.

Cardiac rhythm management with device therapy also has upfront costs.

In the heart failure patient, device therapy requires careful consideration of benefit and cost. In the CKD population, this is amplified as this cohort has an overall lower life expectancy than the general population.93 1.

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The evidence of benefit is also not as clear. There are additional risks to consider, including device infection and consequent treatments including transvenous lead extractions (Figure 6), which are costly. Leadless systems are increasingly prevalent and, although they carry a smaller risk of transvenous infections, they are far more expensive.94

Conclusion

Patients with CKD are vulnerable to arrhythmia for many reasons that are well understood and probably through other less familiar mechanisms.

Management of arrhythmia is made more difficult by the presence of severe renal dysfunction, but therapeutic options are available and continue to evolve. Optimal management of arrhythmia not only improves the quality of life of many patients but can, in some cases, extend life and slow the progression of CKD.

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59. James MT. Risk of bloodstream infection in patients with chronic kidney disease not treated with dialysis. Arch Intern Med 2008;168:2333. https://doi.org/10.1001/ archinte.168.21.2333; PMID: 19029498.

60. Allon M, Depner TA, Radeva M, et al. Impact of dialysis dose and membrane on infection-related hospitalization and death: results of the HEMO study. J Am Soc Nephrol 2003;14:1863–70. https://doi.org/10.1097/01.

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61. Bloom H, Heeke B, Leon A, et al. Renal insufficiency and the risk of infection from pacemaker or defibrillator surgery.

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62. Baman TS, Gupta SK, Valle JA, Yamada E. Risk factors for mortality in patients with cardiac device-related infection.

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63. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 1996;335:1933–40. https://doi.org/10.1056/ NEJM199612263352601; PMID: 8960472.

64. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877–83. https://doi.org/10.1056/Nejmoa013474; PMID: 11907286.

65. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37. https://doi. org/10.1056/NEJMoa043399; PMID: 15659722.

66. Turakhia MP, Varosy PD, Lee K, et al. Impact of renal function on survival in patients with implantable cardioverter-defibrillators. Pacing Clin Electrophysiol 200;30:377–84. https://doi. org/10.1111/j.1540-8159.2007.00678.x; PMID: 17367357.

67. Sakhuja R, Keebler M, Lai T-S, et al. Meta-analysis of mortality in dialysis patients with an implantable cardioverter defibrillator. Am J Cardiol 2009;103:735–41. https://doi.org/10.1016/j.amjcard.2008.11.014; PMID: 19231344.

68. Korantzopoulos P, Liu T, Li L, et al. Implantable cardioverter defibrillator therapy in chronic kidney disease: a metaanalysis. Europace 2009;11:1469–75. https://doi.org/10.1093/ europace/eup282; PMID: 19812050.

69. Makki N, Swaminathan PD, Hanmer J, Olshansky B. Do implantable cardioverter defibrillators improve survival in patients with chronic kidney disease at high risk of sudden cardiac death? A meta-analysis of observational studies.

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70. Jukema JW, Timal RJ, Rotmans JI, et al. Prophylactic use of implantable cardioverter-defibrillators in the prevention of sudden cardiac death in dialysis patients. Circulation 2019;139:2628–38. https://doi.org/10.1161/ CIRCULATIONAHA.119.039818; PMID: 30882234.

71. Okawa K, Miyoshi T, Sogo M, et al. Improvement in renal and endothelial function after catheter ablation in patients with persistent atrial fibrillation. J Cardiol 2020;76:610–7. https://doi.org/10.1016/j.jjcc.2020.07.002; PMID: 32682629.

72. Takahashi Y, Takahashi A, Kuwahara T, et al. Renal function after catheter ablation of atrial fibrillation. Circulation 2011;124:2380–7. https://doi.org/10.1161/ CIRCULATIONAHA.111.047266; PMID: 22042886.

73. Naruse Y, Tada H, Sekiguchi Y, et al. Concomitant chronic kidney disease increases the recurrence of atrial fibrillation after catheter ablation of atrial fibrillation: a mid-term followup. Heart Rhythm 2011;8:335–41. https://doi.org/10.1016/j. hrthm.2010.10.047; PMID: 21056121.

74. Lee W, Wu P, Fang C, et al. Impact of chronic kidney disease on atrial fibrillation recurrence following radiofrequency and cryoballoon ablation: a meta-analysis. Int J Clin Pract.

2021;75:e14173. https://doi.org/10.1111/ijcp.14173; PMID: 33756030.

75. Haïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659–66. https:// doi.org/10.1056/NEJM199809033391003; PMID: 9725923.

76. Gallagher MM, Yi G, Gonna H, et al. Multi-catheter cryotherapy compared with radiofrequency ablation in longstanding persistent atrial fibrillation: a randomized clinical trial. Europace 2021;23:370–9. https://doi.org/10.1093/ europace/euaa289; PMID: 33188692.

77. Cardiac Arrhythmia Suppression Trial (CAST) Investigators.

Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321:406–12. https://doi.org/10.1056/NEJM198908103210629; PMID: 2473403.

78. Valembois L, Audureau E, Takeda A, et al. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2019;9:CD005049. https://doi.org/10.1002/14651858.CD005049.pub5; PMID: 31483500.

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79. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 1996;348:7–12. https://doi.org/10.1016/S0140-6736(96)021496; PMID: 8691967.

80. Tompkins C, Mclean R, Cheng A, et al. End-stage renal disease predicts complications in pacemaker and ICD implants. J Cardiovasc Electrophysiol 2011;22:1099–104. https://doi.org/10.1111/j.1540-8167.2011.02066.x; PMID: 21489029 81. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. https://doi.org/10.1056/ NEJMoa0905561; PMID: 19717844.

82. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. https://doi.org.uk/10.1056/ NEJMoa1107039; PMID: 21870978.

83. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104. https://doi.org/10.1056/ NEJMoa1310907; PMID: 24251359.

84. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. https://doi.org/10.1056/NEJMoa1009638; PMID: 21830957.

85. Medicines and Healthcare products Regulatory Agency.

Direct-acting oral anticoagulants (DOACs): reminder of bleeding risk, including availability of reversal agents. Drug Safety Update 2020;13:5–7. https://assets.publishing.service. gov.uk/government/uploads/system/uploads/attachment_ data/file/896274/June-2020-DSU-PDF.pdf (accessed 20 January 2022) 86. Parker K, Thachil J. The use of direct oral anticoagulants in chronic kidney disease. Br J Haematol 2018;183:170–84. https://doi.org/10.1111/bjh.15564; PMID: 30183070.

87. Elis A, Klempfner R, Gurevitz C, et al. Apixaban in patients with atrial fibrillation and severe renal dysfunction: findings from a national registry. Isr Med Assoc J 2021;23:353–8.

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88. De Vriese AS, Caluwé R, Van Der Meersch H, et al. Safety and efficacy of vitamin K antagonists versus rivaroxaban in hemodialysis patients with atrial fibrillation: a multicenter randomized controlled trial. J Am Soc Nephrol 2021;32:1474– 83. https://doi.org/10.1681/ASN.2020111566; PMID: 33753537.

89. Kimachi M, Furukawa TA, Kimachi K, et al. Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease. Cochrane Database Syst Rev 2017;11:CD011373. https://doi.org/10.1002/14651858.

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91. Mansour M, Karst E, Heist EK, et al. The impact of first procedure success rate on the economics of atrial fibrillation ablation. JACC Clin Electrophysiol 2017;3:129–38. https://doi.org/10.1016/j.jacep.2016.06.002; PMID: 29759385.

92. Brüggenjürgen B, Kohler S, Ezzat N, et al. Cost effectiveness of antiarrhythmic medications in patients suffering from atrial fibrillation. Pharmacoeconomics 2013;31:195–213. https://doi.org/10.1007/s40273-013-0028-7; PMID: 23444271.

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94. Akhtar Z, Leung LWM, Sohal M, Gallagher MM. Leadless cardiac resynchronization therapy: a distant Utopia.

Europace 2021;23:81. https://doi.org/10.1093/europace/ euab057; PMID: 33693629.

REVIEW

Risk Stratification and Biomarkers

Circulating MicroRNAs as Novel Biomarkers in Risk Assessment and Prognosis of Coronary Artery Disease Chiara Vavassori ,1,2 Eleonora Cipriani

1

and Gualtiero Ivanoe Colombo

1

1. Unit of Immunology and Functional Genomics, Centro Cardiologico Monzino, IRCCS, Milan, Italy; 2. Cardiovascular Section, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

Abstract

Coronary artery disease is among the leading causes of death worldwide. Nevertheless, available cardiovascular risk prediction algorithms still miss a significant portion of individuals at-risk. Thus, the search for novel non-invasive biomarkers to refine cardiovascular risk assessment is both an urgent need and an attractive topic, which may lead to a more accurate risk stratification and/or prognostic score definition for coronary artery disease. A new class of such non-invasive biomarkers is represented by extracellular microRNAs (miRNAs) circulating in the blood. MiRNAs are non-coding RNA of 22–25 nucleotides in length that play a significant role in both cardiovascular physiology and pathophysiology. Given their high stability and conservation, resistance to degradative enzymes, and detectability in body fluids, circulating miRNAs are promising emerging biomarkers, and specific expression patterns have already been associated with a wide range of cardiovascular conditions. In this review, an overview of the role of blood miRNAs in risk assessment and prognosis of coronary artery disease is given.

Keywords

MicroRNA, biomarkers, prognosis, prevention, cardiovascular risk, coronary artery disease Disclosure: GIC is supported by Fondazione Regionale per la Ricerca Biomedica (FRRB), Research Grant no. CP2_14/2018 ‘INTESTRAT-CAD’ and Italian Ministry of Health, Project ID RCR-2019 –23669118_001. All other authors have no conflicts of interest to declare.

Received: 30 August 2021 Accepted: 5 January 2022 Citation: European Cardiology Review 2022;17:e06. DOI: https;//doi.org/10.15420/ecr.2021.47 Correspondence: Gualtiero I Colombo, Unit of Immunology and Functional Genomics, Centro Cardiologico Monzino IRCCS, Via Carlo Parea, 4 – 20138 Milan, Italy.

E: gualtiero.colombo@cardiologicomonzino.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 non-commercial purposes, provided the original work is cited correctly.

Cardiovascular diseases (CVDs) are the leading cause of death globally, representing a significant concern for public health. Coronary artery disease (CAD) accounts for nearly half of all CVD deaths worldwide.1,2 Despite improvements in primary prevention and treatment, and the development of several risk stratification algorithms to predict 10-year cardiovascular mortality or lifetime risk in different populations, the prevalence of CAD continues to rise.1,3,4 Thus, the identification of novel biomarkers for early and accurate recognition of at-risk individuals is of paramount importance.

Circulating microRNAs (miRNAs) represent optimal non-invasive potential candidates for both diagnostic and prognostic purposes.5 Due to their high stability, phylogenetic conservation and resistance to degradative enzymes, and due to their easy detectability in body fluids thanks to advances in molecular detection techniques, miRNAs may serve as stable and reliable reporters of disease onset and progression. MiRNAs are noncoding RNAs that play a role as ‘fine-tuners’ of gene expression.6 They are key regulators of the cardiovascular system, including heart muscle contraction and growth, conductance of electrical signals, vessel wall homeostasis, response to vascular injury and tissue repair.7 Dysregulation of their expression is involved in cardiovascular pathophysiology, and circulating miRNAs may contribute to the interaction between inflammatory and vascular cells, systemic inflammation, and oxidative stress, and thus to CAD pathogenesis (Figure 1).8–10

In the past two decades, great attention has been paid to the role of miRNAs as diagnostic and prognostic biomarkers, as well as therapeutic targets in heart disease. In the present review, we summarise existing knowledge on miRNAs as biomarkers for risk stratification and prognosis in CAD.

MicroRNA Function and Biogenesis

MiRNAs are short (22–25 nucleotides), non-coding, single-stranded RNA molecules that regulate the expression of 60% of protein-coding genes at the post-transcriptional level by complementary binding to the 3´ untranslated region of the target mRNA, leading to inhibition of translation or mRNA degradation.11,12 They could also interact with the 5´ untranslated region, causing gene expression silencing (Figure 2).13 MiRNA canonical biogenesis consists of several steps: transcription, processing, splicing, export to the cytoplasm, maturation and target binding.14 Briefly, a pri-miRNA (a large structure composed of sequences for several miRNAs) is synthesised by the RNA polymerase II enzyme in the nucleus. Pri-miRNAs are cleaved by the RNA-specific RNase-III-type endonuclease, Drosha, with its cofactor DGCR8, to produce pre-miRNAs (70 nucleotides), which are exported in the cytoplasm via exportin-5 and RanGTP-binding protein. Pre-miRNAs are further processed by Dicer (the cytoplasmic RNase-III endonuclease) into a double-stranded miRNA duplex and loaded on the RNA-induced silencing complex, where the

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MicroRNAs as Novel Risk Biomarkers for CAD Figure 1: Schematic Illustration of MicroRNA Involvement in Coronary Artery Disease Pathogenesis

CAD and miRNA LUMEN Erythrocyte

Atherosclerotic plaque

Monocytes

EC apoptosis miR-21; miR-155; miR-181a, miR-351

EC activation and inflammation

Angiogenesis

miR-10a; miR-30-5p; miR-143/145; miR-146a; miR-181b; miR-100; Let-7a; Let-7b; Let-7g; miR-34a; miR-92a; miR-712/205; miR-103; miR-155; miR-21

miR-126-5p; miR-92a; miR-200; miR-210; miR-221/222

ENDOTHELIUM Cholesterol efflux and reverse transport

LDL

HDL

miR-223; miR-9-5p; miR-27a/b; miR-33; miR-96; miR-144; miR-148; miR-185; miR-758

Cholesterol accumulation and foam cell formation miR-10a; miR-223; miR-30c; miR-125-5p; miR-122; miR-146a

INTIMA

Macrophage activation miR-93; miR-124; miR-223; miR-125a; miR-46; miR-10a; miR-147; miR-124a; miR-150; let-7c; miR-33; miR-142-5p

Ox-LDL

VSMC proliferation and migration

Foam cell Fibrosis miR-21; miR-29; miR-30

miR-22-3p; miR-125b; miR-24; miR-29a; miR-663; miR-638; miR-133; miR-424; miR-195; let-7b; miR-146a

VSMC survival in fibrous cap miR-181b; miR-210; miR-21

BASAL LAMINA

MEDIA MicroRNAs known to be involved in atherosclerotic plaque formation are listed at the site of their action and/or along with the process they influence: endothelial cell apoptosis, activation and inflammation; neo-angiogenesis; cholesterol efflux, reverse transport and accumulation; vascular smooth muscle cell proliferation, migration and survival in fibrous cap; fibrosis; macrophage activation; and foam cell formation. MicroRNAs highlighted in bold blue have been also reported as potential circulating biomarkers for coronary artery disease. CAD = coronary artery disease; EC = endothelial cell; miRNA = microRNA; Ox-LDL = oxidised LDL; VSMC = vascular smooth muscle cell.

guide and passenger strands are selected by Argonaute protein.15 The RNA-induced silencing complex leads the guide strand to bind to its target mRNA through a complementary interaction between the miRNA and target mRNA seeding sequences.14 Extracellular miRNAs are secreted into the blood circulation through several carriers to protect them from digestion: packed in exosomes, microparticles or lipid vesicles; bound to Argonaute-2 or nucleophosmin-1 proteins; or linked with high- or low-density lipoproteins.16–18

MicroRNAs as Circulating Biomarkers

Extracellular miRNAs have been detected in different body fluids, such as pleural, peritoneal, cerebrospinal, seminal and amniotic fluids, urine, breast milk, colostrum, saliva, tears and blood.19 Differently from intracellular mRNAs, extracellular miRNAs circulating in the blood show great stability under harsh conditions (such as extreme environmental basic pH, high temperature, multiple repeated freeze–thaw cycles or prolonged storage) and resistance to endogenous RNase activity.20 Moreover, miRNAs are evolutionarily conserved among species, allowing translation from preclinical models to clinical practice.21 Finally, they are easily detectable by sensitive techniques, such as reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR).

These properties raised enormous interest in their use as biomarkers for various diseases. Indeed, since 2008, when Lawrie et al. first demonstrated the potential of serum miRNAs as biomarkers for diffuse large B-cell lymphoma, several studies have identified specific miRNA expression

signatures in cells, tissues or biological fluids, demonstrating their association with human diseases and/or their prognosis.22 Although the vast majority did not prove to be clinically relevant, specific miRNA expression signatures, especially in serum or plasma, have shown promise as minimally invasive tools for diagnostic/prognostic purposes.

The potential use of circulating miRNAs for diagnostic purposes has been extensively explored in CAD.23,24

Circulating MicroRNAs in Coronary Artery Disease Risk Assessment

Several risk algorithms have been developed for CVD primary prevention, mostly based on traditional cardiovascular risk factors (TRFs; e.g. sex, age, smoking habit, total and HDL cholesterol, systolic blood pressure, treatment, diabetes).3 However, although they represent very useful tools to help clinicians stratify patients based on risk and guide treatment options, the performance of these models is suboptimal, showing the need for new refined and accurate risk stratification models, including novel biomarkers.25 Yet, studies on the role of circulating miRNAs in cardiovascular risk stratification are rather sparse.

Primary Prevention Settings

The main results of studies assessing circulating miRNAs potential as predictors of future cardiovascular events in the general population (i.e. in primary prevention) are shown in Table 1, along with sample type, detection and normalisation methods, miRNA regulation, primary outcome, and factors and covariates for adjustment in multivariable analyses.

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MicroRNAs as Novel Risk Biomarkers for CAD Figure 2: Schematic Illustration of MicroRNA Biogenesis, Mechanisms of Action and Extracellular Release LDL

Lipid vesicle

EXTRACELLULAR SPACE

Lipoproteins HDL

NPM1

Nucleophosmin

Exosomes Argonaute-2

RISC

NUCLEUS Pol-II

Translational repression or deadenylation

Mature miRNA

miRNA gene

Dicer

Pri-miRNA Exportin 5

CYTOPLASM

RISC

5´ Cap

mRNA target

5´ Cap

Pre-miRNA

AAAAAAA

Partial complementarity

Passenger miRNA duplex strand degradation

Drosha, Dgcr8

Pre-miRNA

Ago2

RISC

AAAAAAA

mRNA degradation

Perfect complementarity

MiRNA genes are transcribed by RNA polymerase II in primary miRNA transcripts. These hairpin loop structures are recognised by the DiGeorge Syndrome Critical Region 8 protein, which associates with the Drosha enzyme, a double-stranded RNA-specific ribonuclease III. The cleavage product, the precursor miRNA, is exported by Exportin-5 to the cytoplasm, where it is processed by the Dicer enzyme, first in a duplex conformation and then in a mature miRNA. This could be incorporated into the RNA-induced silencing complex through which, depending on the total or partial complementarity with the target, it leads to mRNA degradation or mRNA translational repression, respectively. Both pre-miRNAs and mature miRNAs can be secreted into the extracellular space through several carriers, such as lipid vesicles, exosomes, LDLs and HDLs, or bind to RNA-binding proteins nucleophosmin 1 and Ago2. Ago2 = Argonaute 2; Dgcr8 = DiGeorge syndrome critical region 8; mRNA = messenger RNA; miRNA = microRNA; NPM1 = nucleophosmin 1; Pol II = polymerase II; pre-miRNA = precursor microRNA; pri-miRNA = primary microRNA transcript; RISC = RNA-induced silencing complex.

An early study that prospectively sought an association between basal miRNA levels and incident MI was that of Zampetaki et al., reporting in 2012 a significant relationship between plasma levels of three miRNAs and MI (miR-126-3p positively associated, while miR-197 and miR-223 inversely associated).26 Using RT-qPCR, they evaluated the baseline plasma expression of seven miRNA candidates (miR-24, miR-126, miR-140, miR-150, miR-197, miR-223 and miR-486) in a population-based cohort of 820 participants (aged 40–79 years) in the Bruneck Study.27 A total of 47 participants experienced fatal or non-fatal MI within the 10-year follow-up period. Seven miRNAs emerged as promising from an initial screening using Taqman miRNA arrays, covering 754 small non-coding RNA, on eight pooled samples of participants with or without atherosclerotic vascular disease matched for various TRFs. They used two distinct approaches to select the subset of miRNAs with the highest predictive ability for future MI (i.e. stepwise Cox regression analyses followed by comparison of the emerging models’ Akaike information criterion; L1 penalisation, based on least absolute shrinkage and selection operator algorithm), which identify the same miRNA signature.

Then, risk estimates for the three miRNAs selected were computed by standard Cox regression analysis adjusting for a set of TRFs. They showed that adding the three miRNAs to a Framingham Risk Score (FRS) model for hard endpoints of coronary heart disease slightly increased both the C-index, the net reclassification index, and the integrated discrimination improvement.28 Finally, to determine the cellular origin of these three miRNAs, they performed a miRNA screening in preparations of thrombin-activated

platelets, and an interventional study by subjecting 11 healthy volunteers to limb ischaemia-reperfusion (which induces platelet activation), assessing plasma levels of 30 candidate miRNAs at various time-points. Through computational analysis, they identified a temporal cluster containing all three MI-predictive miRNAs, characterised by early and sustained elevation, and consisting of miRNAs predominantly expressed in platelets.

In 2016, Bye et al. described a signature of five miRNAs (miR-106a-5p, miR-424-5p, let-7g-5p, miR-144-3p and miR-660-5p) that could predict future fatal acute MI (AMI) in healthy individuals.29 They assessed by RTqPCR the baseline serum levels of a panel of 179 miRNAs in a prospective nested case–control study cohort of 112 healthy individuals (aged 40–70 years) participating in the HUNT study with a 10-year observation period.30 This derivation cohort consisted of 56 cases suffering from fatal AMI within 10 years and 56 controls remaining healthy matched for risk factors.

MiRNAs found to be differentially expressed in the screening were then analysed in an independent validation cohort of 100 healthy participants from the same study, with 50 suffering from fatal AMI and 50 risk factormatched controls reporting no cardiovascular events: 10 miRNAs were confirmed to be differentially expressed in cases versus controls.

The exclusion criteria for both cohorts included previous cardiovascular events and several comorbidities. Interestingly, a sex-specific association was observed, as miR-424-5p and miR-26a-5p were exclusively related to risk in men and women, respectively.

Finally, a model consisting of the five miRNAs with the highest predictive ability for future AMI in both sexes was identified by conditional logistic

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MicroRNAs as Novel Risk Biomarkers for CAD regression followed by a comparison of the Akaike information criterion of the models, providing 77.6% overall correct classification. Adding the five miRNAs to the FRS significantly increased the receiver operating characteristic area under the curve (AUC).

The addition of the 5-miRNA panel significantly improved risk stratification models based on the FRS or the SCORE in predicting mortality, increasing both net reclassification index and integrated discrimination improvement.

Three years later (Velle-Forbord et al.), leveraging the population-based HUNT cohort, the same group showed that a combination of another five miRNAs (miR-21-5p, miR-26a-5p, mir-29c-3p, miR-144-3p and miR-151a5p) added to the FRS was the best predictive risk model for both fatal and non-fatal MI.31 They performed a case–control study, testing by RT-qPCR in baseline serum samples of 195 participants (aged 60–79 years) the 10 candidate miRNAs (let-7g-5p, miR-21-5p, miR-26a-5p, miR-29c-3p, miR106a-5p, miR-144-3p, miR-151a-5p, miR-191-5p, miR-424-5p and miR-451a) previously explored for their potential to predict future fatal MI.29

Using a different approach, in 2020, Gigante et al. tried to identify circulating miRNA signatures that predict major adverse cardiovascular events (MACE; defined as sudden cardiac death, first-time MI or angina requiring hospitalisation) in middle-aged men and women.41 To this end, they took advantage of a prospective Swedish cohort of 60-year-old men and women from the Stockholm Study, selecting the first 100 MACEpresenting individuals and 100 MACE-free individuals in an 11-year followup (matched for sex and time of inclusion in the cohort).42

Specifically, during the 10-year follow-up, 36 and 60 participants experienced either a fatal or a non-fatal MI, respectively, whereas 99 ageand sex-matched controls remained healthy. They used the same logistic regression approach for the best subset to identify the miRNA signature that, along with the FRS for hard CAD, most effectively predicted future MI. The model was evaluated by 10-fold cross-validation for the AUC, and the miRNA panel was shown to add predictive value to the FRS, leading to a significant increase in the AUC. Of note, the addition of other important CAD risk factors (waist:hip ratio, triglycerides, glucose, creatinine) to the FRS did not significantly improve risk prediction.

In 2017, Keller et al. tested the ability of another panel of five candidate miRNAs in predicting cardiovascular outcome.32 Selected miRNAs included miR-34a for its role in cardiac ageing, miR-223 as a regulator of inflammation, and the cardiac-enriched miR-378, miR-133 and miR-499 associated with either cardiac hypertrophy or myocardial damage.33–37 They used as the derivation cohort a sample of low-to-intermediate-risk primary care patients (178 German healthy individuals, median age 55.5 years, interquartile range: 46–69 years) randomly chosen from the prospective longitudinal DETECT study, and as the independent validation cohort, a general population sample (129 healthy participants, mean age 74.7 ± 8.2 years) from the SHIP.38,39 Endpoints were overall mortality and/or cardiovascular events (cardiovascular death, non-fatal MI or need for coronary revascularisation).

Twenty-one participants from the DETECT study reached the combined endpoint within a 5-year follow-up period, 12 of whom died. Baseline plasma levels of the five selected miRNAs were assessed by RT-qPCR. Cox proportional hazards models, adjusted for age, sex and FRS, showed that 5-year all-cause mortality was associated with reduced miR-133 levels and that there was a trend for the association with lower miR-223 levels. Importantly, a score from the multivariate miRNA panel, calculated by a logistic regression model, showed a robust association with overall mortality, withstanding adjustment for the same covariates. No significant association with the combined outcome was observed for either individual miRNAs or the entire panel. However, the 5-miRNA panel improved the ability of the FRS to identify patients at risk to die within 5 years, as indexed by a significant increase in AUC. Then, the authors explored the use of the miRNA panel in primary prevention: 64 individuals without a CVD history, who died within a 12year follow-up, were randomly chosen from the SHIP study, and ageand sex-matched 1:1 with 65 controls. The 5-miRNA panel confirmed in this validation cohort its ability to predict all-cause mortality, independently of established risk scores, such as the FRS or SCORE.28,40

They initially screened a panel of 754 miRNAs, using TaqMan OpenArrays, in baseline plasma samples. Using a random effects logistic regression, adjusted for common TRFs, they identified nine miRNAs potentially associated with an increased rate of future MACEs, being miR-145-3p associated with the largest estimated risk increase, and miR-720 associated with reduced MACE risk.

Then, they identified 16 interacting miRNA pairs associated with an increased probability of an event, by random effects logistic regression models that included only two miRNAs and their interaction (without covariates). Notably, miR-320b was present in all interacting miRNA pairs associated with the risk of MACE, and the expression level of miR-320b influenced the strength of the association of the paired miRNA (the higher miR-320b expression level, the greater the risk associated with each miRNA).

Finally, they performed target prediction of miR-320b and the 16 identified interacting miRNAs, and grouped miRNAs in four clusters: three of these clusters (cluster 1: miR-320b plus miR-145-3p, miR-128a, miR-548d-3p; cluster 2: miR-320b plus let-7g-5p, let-7d-5p, let-7e-5p, miR-196b-5p, miR-191-5p, miR-324-3p; and cluster 4: miR-320b plus miR-301b,miR-3403p, miR-376a) were linked with cardiovascular development and function, and CVDs, as documented by enrichment pathway analysis of the targets.

They then sought validation using an external prospective cohort (58 patients with incident MI and 60 sex-matched controls within 1 year from initial serum sampling, mean age 60 ± 5 years) from the HUNT study.30 Although not significant, they observed a similar pattern of association with the risk of MI, and a trend in a progressive increase in MI risk estimates for miRNAs from clusters 2 and 4.

The same year, Wang et al. reported a negative correlation of miR-423-3p with the risk of CAD events, showing added predictive ability to TRFs.43 To identify the most specific miRNAs associated with CAD, they implemented a multistep design. They initially performed a screening by miRNA sequencing on pooled samples of serum or peripheral blood monocytes from 10 CAD patients and 10 healthy controls, as well as hypoxia-treated vascular endothelial cells (ECs). Out of the 1,022 miRNAs detected in patient serum and 976 in controls, they selected 48 candidates for detection in serum, which were also dysregulated in CAD monocytes and hypoxic ECs. By PCR product sequencing, the authors found that five miRNAs (miR-10a-5p, miR-126-3p, miR-210-3p, miR-423-3p and miR-92a3p) were specifically detectable in serum.

Finally, the serum levels of these five miRNAs were measured by RT-qPCR in two cohorts of sex-matched CAD patients and controls (n=39 versus n=39 and n=30 versus n=21, respectively): miR-10a-5p and miR-423-3p

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MicroRNAs as Novel Risk Biomarkers for CAD emerged as the best-associated candidates, consistently showing a significantly lower expression in CAD patients than in controls. Therefore, the authors used Cox regression analysis to assess the ability of these two miRNAs to predict CAD events in a large-scale general population of 2,812 individuals (China-CVD cohort, mean age 51.2 ± 7.9 years), with a median follow-up of 6 years. CAD events (n=64) were non-fatal, and included AMI and subsequent MI. After adjustment for age, sex and TRFs, they found that only miR-423-3p was associated with CAD event risk. The addition of miR-423-3p to TRF-based models improved prediction performance, including AUC and net reclassification index.

Challenges of MicroRNAs as Predictive Biomarkers

The potential of circulating miRNAs as non-invasive biomarkers for risk stratification is an attractive field. However, miRNAs detected so far have shown poor reproducibility between studies (Table 1). Specifically, miR233 was shown to be predictive of MI or all-cause mortality in two different studies.26,32 Surprisingly, miR-144-3p was part of two different panels reported as predictive of MI by the same group in two subsequent studies of samples from the HUNT cohort, but in the first its levels were increased in cases, in the second its levels were decreased.29,31 Similarly, let-7g-5p had decreased levels in cases with future fatal MI in the study by Bye et al., and instead increased in patients who developed MACE in the study

by Gigante et al.29,41 The conflicting results reported above could be due to several factors.

Sampling is a critical issue; specifically, the choice of anticoagulant and blood fraction could affect the quality of results. Indeed, variability in miRNA detection levels has been observed between serum and plasma.44 An utmost critical step affecting result reproducibility is the normalisation method used. Normalisation strategies include the use of endogenous reference miRNAs, spiking-in of exogenous miRNAs or global mean normalisation to account for technical variability.

Although miR-16-5p and small nucleolar RNA U6 have commonly been used in several studies, there is a substantial lack of consensus on endogenous miRNAs.45 Their amount in plasma or serum samples may be affected by several factors, including haemolysis, physical activity and fasting, and these miRNAs have been shown to be invariant only in specific situations.46 Conversely, a major drawback of the spike-in method is that it is unreliable when quantification of the extracted RNA is not possible, which is often the case for circulating miRNAs. In fact, equal volumes of serum/plasma may contain variable amounts of miRNAs.46 Finally, mean/median normalisation methods are another possibility for quantifying miRNA expression, but produce data that are difficult to compare with other normalisation methods. It is clear that different normalisation methods, as those used in the above-mentioned studies, profoundly affect the final results.

Another issue of fundamental importance is that the clinical outcome was often different among primary prevention studies, ranging from MACE to fatal or non-fatal MI to death from all causes. Clearly, different miRNAs can be expected to predict different events. Furthermore, these studies were conducted on populations of diverse ethnicity, had varying approaches in study design and detection methods, and adopted different statistical models. In addition, there are strong correlations between circulating miRNA levels; thus, different studies may report different, but highly correlated, miRNAs with approximately the same chance of being included in prediction models. Finally, physiological or normal miRNA concentration ranges in blood have yet to be established.

Circulating MicroRNAs and Coronary Artery Disease Prognosis

Risk stratification for future events among patients with CAD is critically important for prognostication. Risk assessment for recurrent cardiovascular events currently relies on myocardial injury markers, such as troponins or N-terminal prohormone of brain natriuretic peptide, but none of them are specific for any particular outcome. This has prompted the search for new reliable biomarkers.

Secondary Prevention Settings

The main findings and characteristics of studies assessing the potential of circulating miRNAs in this context are shown in Table 2, presenting data on acute coronary syndromes (ACS) first and then on chronic coronary syndromes (stable CAD).

In an early study (2011), Widera et al. reported an association of miR-133a and miR-208b levels with the risk of all-cause death in an ACS cohort from Hannover.47 They focused on cardiomyocyte-enriched miRNAs (miR-1, miR-133a, miR-133b, miR208a, miR-208b and miR-499), known to be cardiac selective and rapidly released after AMI.37,48,49 To assess their prognostic value, the authors determined plasma concentrations of the six miRNAs on admission by RT-qPCR in a cohort of 444 consecutive patients (aged 55–73 years) with a final diagnosis of ACS (n=117 unstable angina, n=131 non-ST-segment elevation MI [NSTEMI] and n=196 STsegment elevation MI [STEMI]). All-cause mortality at 6 months (n=34 patients) was the primary endpoint. They found that miR-133a and miR208b baseline levels were significantly related to the outcome at the logrank test, but stepwise Cox regression analyses indicated that they withstood adjustment for age and sex, but not for high-sensitivity troponin T (hsTnT). Moreover, they did not increase the ability of hsTnT in discriminating survivors from non-survivors.

Gidlof et al. used a similar approach to assess the prognostic potential of three cardio-enriched miRNAs (miR-1, miR-208b and miR-499-5p) in patients with suspected ACS, and found that increased baseline plasma levels of miR-208b and miR-499-5p were associated with the risk of death or heart failure (HF) and reduction in systolic function after MI.50 They analysed by RT-qPCR 407 Swedish patients presenting with chest pain suspicious for ACS (n=88 non-MI, n=146 NSTEMI, n=173 STEMI; median age 65 years), after interventional therapies and within 24-72 hours from presentation. A total of 74 patients experienced the combined primary endpoint (death within 30 days of hospitalisation, heart failure, ejection fraction <40%, or cardiogenic shock). Plasma levels of miR-208b and miR499-5p were associated with the outcome, with significant odds ratios adjusted for age, sex and time from admission to sampling. However, again, they did not withstand adjustment for TnT, and their prognostic accuracy was similar to TnT. In keeping with this line of research, Olivieri et al. described an association between admission circulating levels of the cardio-miRNA miR-499-5p and 12-month cardiovascular mortality in elderly NSTEMI patients.51 They elected to test the prognostic potential of two miRNAs (miR-499-5p and miR-21) based on previous observations about their diagnostic performance in the same setting.52 They analysed the baseline expression of these miRNAs by RT-qPCR in plasma samples of 142 Italian NSTEMI patients admitted to the coronary care unit with an interval of 4–9 hours from symptoms onset to admission. Cardiovascular mortality at 12 and 24 months was prospectively defined as the primary endpoint. A total of 54 patients (mean age 85.9 ± 5.4 years) died within 12 months, and 88 survived (mean age 81.7 ± 6.0 years). By multivariate analysis using Cox

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MicroRNAs as Novel Risk Biomarkers for CAD Table 1: MicroRNAs as Potential Biomarkers in Coronary Artery Disease Primary Prevention miRNA ID

Sample

Detection

Normalisation

miR-126-3p miR-197

Plasma

Specific TaqMan probes

U6 or average Ct

miR-34a Plasma

miR-378

↓

Adjustment/ matching

Reference

Age, sex, smoking, SBP, LDL-C, diabetes, history of CVD, other miRNAs, BMI, WHR, HDL-C, CRP, fibrinogen

Zampetaki et al.10

Primary care and ↑ All-cause general mortality

Age, sex, FRS or SCORE

Keller et al.32

General

↑ Fatal MI

Cases and controls were matched for age, sex, smoking, BMI, TG, total cholesterol, HDL-C, glucose, creatinine, SBP

Bye et al.29

General

↑ Fatal and non-fatal MI

Cases and controls were matched for age and sex

Velle-Forbord et al.31

General

↑ MACE

Matched for age; adjusted for sex, diabetes, hypertension, hyperlipidaemia, smoking and obesity

Gigante et al.41

General

↑ Non-fatal MI

Age, sex, CV risk factors

Wang et al.43

General

↓

Specific TaqMan probes

↓ None

↓ ↓

miR-499

↑

miR-106a-5p

↓

miR-424-5p Serum

miR-144-3p

LNA primers, SYBR Green

Global mean or miR-425-5p

↑ Fatal and non-fatal MI

↑ ↓ ↑

miR-660-5p

↑

miR-21-5p

↑

miR-26a-5p miR-29c-3p

Risk

↑

miR-133

let-7g-5p

Population

↑

miR-223

miR-223

Regulation

Serum

miR-144-3p

LNA primers, SYBR Green

↑ miR-425-5p

↓ ↓

miR-151a-5p

↑

miR-320b plus miR-145-3p miR-128a

↑

miR-548d-3p let-7g-5p let-7d-5p let-7e-5p

Serum

miR-196b-5p

LNA primers, SYBR Green

miR-16-5p

↑

miR-191-5p miR-324-3p miR-301b ↑

miR-340-3p miR-376a miR-423-3p

Serum

Specific primers, SYBR green

Global mean

↓

CAD = coronary artery disease; CRP = C-reactive protein; Ct = cycle threshold; CV = cardiovascular; HDL-C = HLD cholesterol; LDL-C = LDL cholesterol; LNA = locked nucleic acids; MACE = major adverse cardiovascular events; miRNA = microRNA; SBP = systolic blood pressure; TG = triglycerides; WHR = waist:hip ratio.

proportional hazards model adjusting for all significantly different variables at admission, they reported a significant increase in the 12-month risk of death among NSTEMI patients whose miR-499-5p admission level was higher than the median. In particular, patients presenting with congestive heart failure had a twofold greater risk of dying within the first 12 months when baseline miR-499-5p exceeded the median. However, the performance of this model was far from optimal, and miR-499-5p was not associated with cardiovascular mortality at 24 months.

Starting with a different hypothesis, Schulte et al. investigated the ability of the three miRNAs described by Zampetaki et al. in a primary prevention

setting, to stratify the risk of future cardiovascular events in patients with documented CAD.26,53 Indeed, miR-126, miR-197 and miR-223 were known to be involved in endovascular inflammation and platelet activation, and as biomarkers in the diagnosis of CAD-related conditions.5,23,24 They measured the serum levels of these miRNAs by RT-qPCR in a cohort of 873 German patients with manifest CAD (median age 64 years [interquartile range 57–69 years], selected from the AtheroGene study), of whom 340 had ACS and 533 had stable angina (SA).54 After a median follow-up of 4 years, 18 cardiovascular deaths were recorded, eight among ACS and 10 among SA patients. The authors used ACS-SA stratified Cox regression models, adjusted for age, sex and further TRFs, followed by 10-fold cross-

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MicroRNAs as Novel Risk Biomarkers for CAD Table 2: MicroRNAs as Potential Biomarkers in Coronary Artery Disease Secondary Prevention miRNA ID miR-133a miR-208b miR-208b miR-499-5p miR-499-5p

Sample

Detection

Normalisation

Plasma

Specific TaqMan probe sets

Spike-in cel-miR-54

Plasma

LNA primers, SYBR Green

miR-17

Plasma

Specific TaqMan probes

miR-17

Serum

Specific TaqMan probes

Spike-in cel-miR-39

miR-197 miR-223

Regulation ↑ ↑ ↑ ↑ ↑ ↑ ↑

miR-19b

↑

miR-132

↑

miR-140-3p miR-150

Serum

miR-186

Specific TaqMan probes

Spike-in cel-miR-39

↑ ↑ ↑

miR-210

↑

miR-199a

miR-142

MVs

Spike-in cel-miR-39

Plasma

Bulge-loop primers, SYBR Green

Spike-in cel-miR-39

miR-223

Reference

ACS

↑ All-cause mortality

Age, sex, (hsTnT)

Widera et al.47

Suspected ACS

↑ Mortality and HF, ↓ LVEF

Age, sex, time from admission to sampling

Gidlof et al.50

NSTEMI

↑ CV mortality

Age, hsCRP, WBC, homocysteine, BMI

Olivieri et al.51

CAD (ACS + SA) or ACS

↑ CV Mortality

Age, sex, BMI, diabetes, hypertension, history of MI, hyperlipidaemia, ever smoker

Shulte et al.53

↑ CV mortality

Age and sex and hypertension, smoking status, hyperlipidaemia, diabetes, history of MI, or cTnI, or NT-proBNP, or LVEF and number of diseased vessels, or type of ACS

Karakas et al.55

Stable CAD

↓ MACE

Age, sex, BMI, diabetes, hypertension, hyperlipoproteinaemia, CKD, use of ACEinhibitors and statins

Jansen et al.57

CAD undergoing PCI

↑ MACE

Age, sex, diabetes, hypertension, HF, medications

Tang et al.59

↑ All-cause and CV mortality

Age, sex, primary diagnosis, history of coronary revascularisation, time to interview, current smoking, BMI, SBP, DBP, LDL-C, glucose, HbA1c, cTnI, BNP, medications

Mayer et al.60

CAD (ACS + SA) or ACS

ACS

↑

↑ ↓

miR-19a miR-133a

Adjustment/ matching

↑

Specific TaqMan probes

miR-1 miR-126

Risk

↑

miR-19a miR-126-3p

Population

Plasma

Specific TaqMan probes

↓ Spike-in cel-miR-39

↓ ↓

Stable chronic CVD (post-ACS, CABG, PCI or stroke)

↓

ACE = angiotensin-converting enzyme; ACS = acute coronary syndrome; BNP = brain natriuretic peptide; CABG = coronary artery bypass graft; CAD = coronary artery disease; cTnI = cardiac troponin I; CKD = chronic kidney disease; CV = cardiovascular; CVD = cardiovascular diseases; DBP = diastolic blood pressure; hsCRP = high-sensitivity C-reactive protein; hsTnT = high-sensitivity troponin T; HF = heart failure; LDL-C = LDL cholesterol; LNA = locked nucleic acids; LVEF = left ventricular ejection fraction; MACE = major adverse cardiovascular events; NSTEMI = non-ST-elevation MI; NT-proBNP = N-terminal prohormone of brain natriuretic peptide; PCI = percutaneous coronary intervention; SA = stable angina; SBP = systolic blood pressure; WBC = white blood cells.

validation of the C-indices, to explore the association with each miRNA, and found that elevated levels of miR-197 and miR-223 were able to predict future cardiovascular death in the overall group. Considering only the ACS subgroup, the prognostic ability of the two miRNAs was even higher, but in SA patients it was not significant. Of note, there was no incremental benefit in prognostic power using any combination of the three miRNAs compared with single miR-197 or miR-223.

The same group (Karakas et al.), followed up on a similar working hypothesis and evaluated the prognostic potential of eight miRNAs they had previously identified as diagnostic of unstable angina.55,56 Using RTqPCR, they assessed baseline serum concentrations of miR-19a, miR-19b, miR-132, miR-140-3p, miR-142-5p, miR-150, miR-186 and miR-210 in a cohort of 1,112 patients with an angiographically documented CAD (430 with ACS, mean age 63 years, and 682 with SA, mean age 64 years)

derived from the above-mentioned study. After a median 4-year followup, 78 cardiovascular deaths or non-fatal MI were recorded (43 among ACS and 35 among SA patients).

Specifically, the authors assessed the association of circulating miRNAs with cardiovascular mortality both in the ACS and the overall cohort by Cox regression correcting for multiple testing (controlling the false discovery rate). All measured miRNAs, except miR-142-5p, were likely to predict cardiovascular death in the ACS group, even after adjustment for age, sex plus TRFs, other emerging risk factors or ACS diagnosis (unstable angina, STEMI, NSTEMI). The best predictors were miR-132, miR-140-3p and miR-210, which were able to markedly increase the c-statistics in the ACS cohort. In the overall CAD cohort, five miRNAs (miR-19b, miR-132, miR140-3p, miR-150 and miR-186) were associated with an increased risk of cardiovascular mortality, again, independent of risk factors and covariates.

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MicroRNAs as Novel Risk Biomarkers for CAD Table 3: MicroRNAs as Potential Predictors of Postoperative AF miRNA ID

Sample

Detection

Normalisation

Regulation

Population

Risk

Adjustment/matching

Reference

Harling et al.64

miR-483-5p

Plasma

miRNA-specific TaqMan primer sets

miR-186

↑

CABG

↑POAF

Matched for age, sex, family history, BMI, previous CV events, hypertension, hypercholesterolaemia, diabetes, smoking, alcohol consumption

miR-23a miR-26a

Serum

Specific primers, SYBR green

Median of miR-423, miR-16, cel-miR-39

↓

CABG

↑POAF

Matched for sex, hypertension, hyperlipaemia, diabetes, smoking

Feldman et al.65

miR-29a

Serum

Specific primers, SYBR green

Spike-in cel-miR-39

↓

CABG

↑POAF

Age, BMI, COPD, hypertension, sleep apnoea

Rizvi et al.67

CABG = coronary artery bypass graft; CV = cardiovascular; COPD = chronic obstructive pulmonary disease; POAF = postoperative AF.

In 2014, Jansen et al. used a different approach, and observed that high levels of miR-126 and miR-199a contained in circulating microvesicles (MVs) were associated with a lower rate of MACE in patients with stable CAD.57 In two German cohorts with a total of 181 patients (mean age 66.7 ± 10.2 years) affected by angiographically documented stable CAD, they quantified by RT-qPCR the baseline arterial blood plasma and MV levels of 10 miRNAs involved in the regulation of vascular function and/or expressed by vascular smooth muscle cells or ECs (miR-126, miR-222, miR-let7d, miR-21, miR-20a, miR-27a, miR-92a, miR-17, miR-130 and miR-199a).58 Occurrence of a first MACE, including non-fatal MI, need for revascularisation and death from cardiac causes, was evaluated within a median follow-up period of 6 years, and 55 events were recorded. No association between miRNA plasma levels and MACE was observed. On the contrary, above-median expression of miR-126 and miR-199a in circulating MVs was associated with a reduced risk of MACE, at univariate analysis. Binary logistic regression, adjusting models for TRFs and medication used, showed that the two miRNAs were not associated with baseline characteristics. Importantly, fluorescence-activated cell sorting analysis revealed that ECs and platelets were the main sources of MVs containing miR-126 and miR-199a, respectively.

At variance with the study by Karakas et al., in 2019, Tang et al. reported that plasma miR-142 was a potential marker for MACE prediction in CAD patients undergoing percutaneous coronary intervention on dual antiplatelet therapy with clopidogrel and aspirin.55,59 To select miRNA candidates, the authors first performed a screening by miRNA sequencing of four pooled plasma samples from 115 Chinese CAD patients stratified according to their sensitivity or resistance to aspirin and/or clopidogrel treatment, as documented by platelet aggregation tests. Differential expression analysis between the four subgroups, followed by RT-qPCR validation in plasma pools and 115 individual samples, revealed that six miRNAs (miR-126, miR-130a, miR-142, miR-27a, miR-21 and miR-106a) were positively associated with clopidogrel antiplatelet efficacy. Based on these results, the six miRNAs were tested by RT-qPCR after percutaneous coronary intervention in a prospective cohort of 1,199 Chinese CAD patients (aged 40–80 years). The primary outcome was MACE, including cardiovascular death, MI or stent thrombosis, within a 3-year follow-up period. Multivariable Cox regression analysis, after correction for multiple comparisons by false discovery rate, revealed that a high plasma level of miR-142 was an independent risk factor for MACE, irrespective of age, sex, comorbidities and medications.

Also, quite at odds with several of the abovementioned studies, Mayer et al. reported that low plasma levels of miR-1, miR-19a, miR-126, miR-133a and miR-223 were associated with a significant increase in 5-year all-

cause and cardiovascular death in stable chronic cardiovascular patients.

47,50,53,55,60 This study originated as a secondary analysis from the Czech EUROASPIRE Survey data.61 A prospective cohort of 826 patients with chronic vascular disease (mean age 65.2 ± 9.3 years) was enrolled 6–36 months after a vascular event (ACS and/or coronary revascularisation for 487 CAD patients, first-ever ischaemic stroke for the other 339 patients). During a median follow-up of 5.6 years, 167 patients died, including 126 from events considered to be of cardiovascular origin.

Based on previous literature, the authors initially quantified by RT-qPCR the plasmatic levels of 10 miRNA (miR-1, miR-19a, miR-21, miR-34a, miR126, miR-133a, miR-197, miR-214, miR-223 and miR-499) in a pilot cohort of 100 patients, 50 dead and 50 age- and sex-matched survivors. Baseline levels of the five miRNAs showing statistical differences between the two groups (see above) were then assessed in the full cohort. Using Cox proportional hazards regression, they found an inverse association between each of the five miRNAs, and a significant increase in both allcause and cardiovascular mortality, despite adjustment for TRFs, primary diagnosis, treatments, increased cardiac troponin I and BNP. Noteworthy, if all five miRNAs were included in a single regression model, only low miR-19a was a significant predictor of both all-cause and cardiovascular mortality, independently of all the other risk factors and covariates. A subgroup analysis showed that low miR-19a predicted all-cause mortality risk only in chronic CAD, but not in post-stroke, patients.

Circulating MicroRNAs and Postoperative AF

Postoperative AF (POAF) is a common complication in CAD patients undergoing coronary artery bypass grafting (CABG) surgery, and is associated with increased 10-year mortality risk.62 Preoperative estimation of the risk for POAF remains a great challenge.63 Circulating miRNAs have been proposed as potential biomarkers to predict the risk of POAF after CABG surgery (Table 3).

In 2017, Harling et al. found that increased preoperative serum levels of miR-483-5p could help to predict the risk of developing POAF in patients undergoing CABG revascularisation.64 They enrolled a prospective cohort of 34 UK patients undergoing non-emergent, on-pump CABG, including 13 who subsequently developed POAF (mean age 64.6 ± 11.3 years) and 21 without POAF (mean age 59.6 ± 12.1 years), matched for age, sex and TRFs, and without previous history of AF. Using a microarray approach, they first investigated the entire miRNAome in the atrial tissue, taken intraoperatively before bypass instigation, of a subgroup of 11 patients with POAF and 11 matched patients without POAF. Then, they quantified by RT-qPCR in the whole cohort the preoperative serum levels of the most upregulated and the most downregulated of the 16 differentially

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MicroRNAs as Novel Risk Biomarkers for CAD expressed miRNAs; that is, miR-483-5p and miR-208a, respectively.

Interestingly, they observed significantly higher levels of miR-483-5p in preoperative serum of POAF patients. The authors reported a predictive ability of this miRNA, as indicated by a significant AUC.

populations examined, different methodological approaches and analytical strategies.

Feldman et al. in 2017 investigated the potential of serum miR-1, miR-23a and miR-26a in identifying patients who develop PAOF after CABG.65 These miRNAs were selected based on previously reported associations with AF.66 Using RT-qPCR, they measured preoperative and postoperative (48 h) serum levels of the three miRNA in a cohort of 48 Brazilian patients undergoing CABG surgery, including 24 POAF (mean age 64.7 ± 7.5 years) and 24 non-POAF (mean age 56.3 ± 9.2 years) matched for sex and TRFs. They found no difference in preoperative circulating miRNA levels between the two groups. Conversely, they observed that miR-23a and miR-26a were significantly reduced in POAF patients after surgery, and showed a moderate predictive ability.

Despite their potential, several problems need to be overcome before circulating miRNAs can be used in clinical practice. An important issue to be addressed is the implementation of standard operating procedures for sample preparation, miRNA isolation, quantification and normalisation across multiple samples, as the sensitivity of diverse methodologies could be substantially different and could lead to inconsistent results.46,69 Measuring circulating miRNAs is still challenging due to their low concentration, and a univocal consensus on miRNA quantification methods is still lacking. The main detection methods available are RTqPCR, next-generation sequencing and microarrays. RT-qPCR is the most widely used method, but the various approaches can yield significantly different results: universal RT or RT with specific primers; preamplification; specific amplification primers with a DNA-binding dye (SYBR Green), or target-specific primers combined with dual-labelled probes that hybridise to complementary target sequences (TaqMan). Next-generation sequencing is highly processive, has no probe-related bias, and enables the discovery of novel miRNAs, but protocols are still cumbersome compared with the other two techniques. Finally, microarrays are relatively inexpensive probe-based assays that require a preamplification step and are less sensitive than the other two techniques.70

In 2020, Rizvi et al. proposed a preoperative multiparameter biomarker to identify the risk of new-onset POAF, which included serum levels of miR29a.67 They hypothesised that combining clinical risk factors for AF with markers of the atrial pathophysiological substrate (fibrosis) and its regulatory miRNAs might have incremental value in identifying patients at risk of POAF. They measured preoperative serum concentrations of peptides reflecting collagen synthesis and degradation, extracellular matrix protein synthesis and deposition, and of miR-29s (miR-29a, miR29b and miR-29c) known to modulate fibrosis, in a US cohort of 90 patients scheduled for an elective CABG procedure with no prior AF (34 with POAF, mean age 72.4 ± 10.8 years, and 56 without POAF, mean age 67.3 ± 10.7 years).68 They observed that procollagen III N-terminal and procollagen I C-terminal peptides were elevated in POAF compared with non-POAF patients, while miR-29 levels were reduced. These markers showed a correlation with atrial fibrosis extent. The model with the highest accuracy in identifying POAF patients was obtained by combining age with procollagen III N-terminal peptide and miR-29a, as assessed using the receiver operating characteristic curve by fitting logistic regression with POAF as the outcome.

Challenges of MicroRNAs as Prognostic Biomarkers

These studies highlighted the potential of circulating miRNAs as promising biomarkers with prognostic value for MACE, mortality or POAF in patients with CAD. Specifically, higher plasmatic levels of miR-208b and miR-4995p were found to be associated with an increased risk of mortality in different studies on ACS cohorts (Table 2).47,50,51 However, there is little overlap in many experimental findings and there is no agreement in the studies on POAF. Surprisingly, in different studies, miR-19a, miR-133a and miR-223 showed opposite regulation in baseline samples of future cases in patients with ACS compared with those with chronic coronary syndrome.47,53,55,60 Intriguingly, miR-126-3p, miR-197 and miR-223 were identified as predictors of all-cause or cardiovascular death in both general population cohorts and cohorts of documented CAD patients, thus extending the applicability of these circulating miRNAs to primary and secondary prevention.26,32,53,57,60 The inconsistent results mentioned above are due to several factors. As with studies on the predictive role of miRNAs, the most critical issues are sampling, normalisation method and clinical endpoint. The clinical outcomes considered were diverse, including either all-cause or cardiovascular death, or a composite endpoint, such as MACE. Other factors influencing reproducibility could be the limited number of cases in many of these studies, the different composition and/or ethnicity of the

Limitations of MicroRNAs in Modern Cardiology Practice

In addition to poorly defined laboratory standards, another crucial issue is the lack of sufficient evidence.

The data presented here underline the need for well-designed clinical studies in larger prospective cohorts of patients, using standardised protocols. Larger sample sizes are crucial to distinguish between healthy or diseased status, and dissect the contribution of confounders, such as age, sex, ethnicity, lifestyle, pre-treatment and disease history. Despite encouraging results, miRNAs are not currently used for the risk stratification or prognosis of CAD. Indeed, although circulating miRNAs have been shown to add predictive capacity to TRFs-based risk scores in several primary prevention studies, the poor reproducibility of the results and the different clinical endpoints considered limit their prospective use in clinical practice.26,29,31,32,43 Furthermore, single miRNAs are rarely disease-specific, whereas combining miRNAs in panels increases specificity and slightly/moderately increases the predictive power of conventional scores. In contrast, secondary prevention studies have also provided conflicting results. In two of them, the miRNAs identified in ACS patients did not add prognostic power to hsTnT.47,50 In other studies, single miRNAs or miRNA panels have shown prognostic ability independent of various TRFs and established biomarkers, but once again there was little consistency and different associations with mortality, positive in ACS patients and negative in patients with chronic CAD.53,55,60 In general, there is a lack of evidence that circulating miRNAs can increase the prognostic power of established biomarkers, such as LDL cholesterol, high sensitivity troponins and N-terminal prohormone of brain natriuretic peptide.

Conclusion

MiRNAs are highly investigated for their role in the pathogenesis of CAD. Nevertheless, evidence for clinical implementation is still lacking. The results of our review show that there is currently insufficient support for the use of any of the presented miRNAs as predictive or prognostic

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MicroRNAs as Novel Risk Biomarkers for CAD biomarkers in clinical settings. However, evidence highlights the potential of circulating miRNAs as novel biomarkers for both primary and secondary CAD prevention. Only a few miRNAs showed risk-predicting ability in more than one study, underscoring the need for further investigation in larger cohorts with standardised methodologies. In particular, standardising 1.

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EXPERT OPINION

Ethnicity

Ethnic and Regional Differences in the Management of Angina: The Way Forward Jack C Barton

1

and Juan Carlos Kaski

2

1. Critical Care and Perioperative Medicine Research Group, Royal London Hospital, London, UK; 2. Molecular and Clinical Sciences Research Institute, St George’s University of London, London, UK

Abstract

For decades, there has been great interest in ethnic differences in the management of angina and stable cardiovascular disease. Clinical decisionmaking is known to be both consciously and unconsciously influenced by a patient’s demographics, and this is due to in part to differences in clinical guidance and opinion. However, the evidence supporting such decision-making is sparse. Nonetheless, there is overwhelming evidence that international, national, regional, institutional, departmental and individual bias disproportionately affect subgroups of the population, resulting in adverse patient outcomes. While without doubt there will be rapid advancements in individualised therapies over the coming years and decades, the most beneficial immediate action clinicians can take is to reduce disparities in both the evidence base and care provision.

Doing so will require great collaborative effort.

Keywords

Angina, coronary artery disease, microvascular angina, ethnicity Disclosure: JCK is Editor-in-Chief of European Cardiology Review. JCB has no conflicts of interest to declare.

Received: 20 December 2021 Accepted: 21 December 2021 Citation: European Cardiology Review 2022;17:e07. DOI: https;//doi.org/10.15420/ecr.2021.60 Correspondence: Jack Barton, Critical Care and Perioperative Medicine Research Group, Royal London Hospital, Whitechapel Rd, London E1 1FR, UK. E: jack.barton@nhs.net 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.

The last 2 years have forced repetitive and uncomfortable processes of introspection as we are faced with undeniable evidence of health inequalities worldwide. The stark reality that the colour of your skin, the neighbourhood in which you were raised and the money in your pocket would determine your risk of mortality during the most dangerous period of our generation is impossible to ignore or act upon.1 In doing so, we are forced to consider not only the academic and policy implications of these factors on communicable diseases but also the impact they have on daily clinical practice when managing patients with non-communicable diseases.

become more readily available, it is highly likely that while some of our existing assumptions may well gain credence, a large proportion will instead be attributed to suboptimal study design and socioeconomic or cultural factors.6

Clinical guidance accounts for ethnic difference in both prevalence of disease and trial data supporting variance in treatment efficacy, perhaps most recognisably in terms of guidance surrounding the management of primary hypertension.2 Supporting data for said guidance has been derived primarily from large observational trials originating from the US in the late 20th and early 21st centuries.3,4

Moreover, in consciously considering variables that disproportionately affect subgroups of our patient population, we may be able to identify system-wide bias or even our own biases that may be contributing to suboptimal outcomes.7

However, these trials should be recognised for what they are – broad brushstrokes susceptible to known and unknown confounders. They are more likely to reflect social and cultural variables than the genetic mechanisms that are commonly used to justify observed differences in outcomes.5 This is ironic, considering that the true meaning of ethnicity reflects a complex, multidimensional social construct rather than a proxy for physical and geographical characteristics.

As the use of polygenic risk scores, genome-wide association studies and other more advanced methods of subcategorising study participants

This, of course, provides little in the way of reassurance for clinicians making daily management decisions for their patients. However, it should, at a minimum, encourage us to be wary of allocating our patients to clearly defined but largely arbitrary groups based upon their age and ethnicity.

What for our cardiovascular pharmacological strategies? While individualising treatment and pharmacotherapy may be an interesting academic exercise and may yield recognisable benefits for our patients, it is important to acknowledge the relatively small impact that many of our most strongly evidenced therapies have.8 In doing so, we must recognise our own susceptibility to unconscious bias in the allocation of even wellvalidated interventions.9 Such is the strength of system-wide, institutional and physician bias or barriers to access of medical services among certain ethnic groups that some studies suggest that appropriate adjustment for said factors all but removes the difference between patient outcomes observed.10 Hence,

© RADCLIFFE CARDIOLOGY 2022 www.ECRjournal.com

Ethnic Differences in the Management of Angina the hesitancy within this article to suggest that any strong data to support adapting treatment based upon ethnicity exist at all.

multicentre international collaborative work to overcome such difficulties are ongoing.18

Additionally, one may argue that cultural factors that influence adherence to and availability of prescribed medications may have a greater influence on the efficacy of treatments than the subtle differences between pharmacodynamics in similar drug classes.

The same bears true for coronary spasm, whereby ethnic difference is likely to have an even greater influence on pharmacological research and clinical decision-making.19 Recent cohort studies in this area suggest that there are differences between the clinical profiles of patients from different ethnic backgrounds. However, much like within microvascular angina, evidence to justify variation in prescribing between patient groups is sparse.

For example, adherence with aspirin therapy in those with and without stable coronary artery disease varies dramatically between ethnic groups.11 It is likely that any interventions targeting problems such as this will have a far greater clinical impact than further investigation into potential genetic differences between ethnic subgroups.12 Of course, this is not to dissuade those looking to expand a body of literature that has guided current best practice, but largely ignored swathes of the population. This is particularly so given that the future of cardiovascular prescribing may well lie in gene-guided therapy, the investigation of which may itself be guided by identification of differences between phenotypical groups.13,14 We are sure even the most disinterested reader would agree that justifying high-risk prescribing decisions based upon CYP2C19 presence would at least go some way to reducing our own anxieties, if not reducing risk to our patients.

Unfortunately, to the authors’ knowledge, scientific progress in the management of stable coronary artery disease and angina has been poor and has lagged over the past decade regarding ethnic differences observed in response to both rate-controlling drugs and more novel therapies. As researchers, we shoulder a large proportion of the blame for this, as reporting of ethnicity within recent literature remains pitiful and, in studies that do report ethnicity, the majority still recruit participants from a majority white cohort of patients.15 Research into less prevalent, diagnosable and treatable conditions such as microvascular angina may approach these challenges from a different and more bountiful vantage point. Primary studies into such conditions may draw from the lessons of large early trials into their occlusive, highly prevalent counterparts, and actively recruit subgroups of the population who were disproportionately represented in the 20th century.

Additionally, one may argue that research into ethnic and thus potential genetic differences in the pathophysiology and thus the amenability to pharmacotherapy of microvascular angina may yield more significant results than those observed in stable coronary artery disease. We arrive at this rather more positive conclusion from considering that the underlying pathophysiology of the condition includes a range of heterogenous and, to some extent, distinct mechanisms observed disproportionately in certain subsets of the population.16 However, the difficulties in diagnosis and a lack of international consensus on the management of microvascular angina means that understanding of the implications of variables such as ethnicity is limited. The relatively low prevalence (or at least recorded prevalence) of such conditions means that recruiting trial participants from black and ethnic minority groups is likely to remain difficult.17 However, active efforts in the form of large,

That is not to say that there is not a clear disparity in the rates of prescription of certain therapies between ethnic groups, which may itself contribute to the observed difference in mortality.19 Again, we appear biased not only as researchers, but also as clinicians.

The key academic issue, as with microvascular angina, is primarily related to a lack of multicentre, large-scale trials investigating different phenotypes.18 This is unsurprising given the great difficulty in diagnosing and managing these conditions, and thus the even greater difficulty in organising and recruiting to large-scale trials.

Ultimately, there is clear evidence that organising efforts into reducing disparity in recognition, diagnosis, management decisions and adherence with pharmacotherapies between ethnic groups is likely to yield the most significant short- to medium-term benefits. Yet the observed differences in outcomes between ethnic groups is likely to at least in part result from a true and meaningful difference in genetic phenotypes that will in the long term be used to guide our pharmacotherapies.

For now and in the the foreseeable future, it remains certain that most of this difference is due to cultural and social factors, as well as our individual and systemic biases. To overcome both the procedural and academic barriers to optimal anginal care in the future, large-scale, cohesive, collaborative effort is necessary.

We are now in a better position than ever to facilitate this. We have both the technology and the will to rapidly amass huge amounts of data to guide our efforts.20 Nonetheless, we must ensure that we do not perpetuate the same errors in research as occurred throughout the late 1900s and, unfortunately, to present day. We must be wary of drawing conclusions based on observational data that is exposed to known and unknown confounders, particularly when drawing arbitrary lines in patient populations based upon ethnicity. We must also ensure we actively recruit patients of black and ethnic minority backgrounds, publishing data on them while recognising the limitations of drawing conclusions based upon these data.

Over the coming decades, there will be great advances in clinicians’ ability to guide cardiovascular pharmacotherapy based upon genotyping, which may or may not go some way to reducing the differences in outcomes observed between ethnic groups. However, such advancements will be nothing more than a drop in the ocean in comparison to what could be achieved by reducing inequality between said groups and targeting public health interventions towards those who need it most.

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cardiovascular disease: a meta-analysis of randomized trials. Am Heart J 2011;162:115–24.e2. https://doi.org/10.1016/j. ahj.2011.04.006; PMID: 21742097.

Shaw LJ, Shaw RE, Merz CNB, et al. Impact of ethnicity and gender differences on angiographic coronary artery disease prevalence and in-hospital mortality in the American College of Cardiology – National Cardiovascular Data Registry.

Circulation 2008;117:1787–801. https://doi.org/10.1161/ CIRCULATIONAHA.107.726562; PMID: 18378615.

Iribarren C, Tolstykh I, Somkin CP, et al. Sex and racial/ethnic disparities in outcomes after acute myocardial infarction: a cohort study among members of a large integrated health care delivery system in northern California. Arch Intern Med 2005;165:2105–13. https://doi.org/10.1001/ archinte.165.18.2105; PMID: 16217000.

Brown DW, Shepard D, Giles WH, et al. Racial differences in the use of aspirin: an important tool for preventing heart disease and stroke. Ethn Dis 2005;15:620–6; PMID: 16259485.

Lev EI, Bliden KP, Jeong YH, et al. Influence of race and sex on thrombogenicity in a large cohort of coronary artery disease patients. J Am Heart Assoc 2014;3:e001167. https:// doi.org/10.1161/JAHA.114.001167; PMID: 25332180.

Zhang H, Xiang Q, Liu Z, et al. Genotype-guided antiplatelet treatment versus conventional therapy: a systematic review and meta-analysis. Br J Clin Pharmacol 2021;87:2199–215. https://doi.org/10.1111/bcp.14637; PMID: 33140858.

Jafrin S, Naznin NE, Reza MS, et al. Risk of stroke in CYP2C19 LoF polymorphism carrier coronary artery disease patients undergoing clopidogrel therapy: an ethnicitybased updated meta-analysis. Eur J Intern Med 2021;90:49– 65. https://doi.org/10.1016/j.ejim.2021.05.022;

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PMID: 34092486.

15. Tahhan AS, Vaduganathan M, Greene SJ, et al. Enrollment of older patients, women, and racial and ethnic minorities in contemporary heart failure clinical trials: a systematic review. JAMA Cardiol 2018;3:1011–9. https://doi.org/10.1001/ jamacardio.2018.2559; PMID: 30140928.

16. Kaski JC, Crea F, Gersh BJ, Camici PG. Reappraisal of ischemic heart disease. Circulation 2018;138:1463–80. https://doi.org/10.1161/CIRCULATIONAHA.118.031373; PMID: 30354347.

17. Suda A, Takahashi J, Beltrame JF, et al. International prospective cohort study of microvascular angina – rationale and design. Int J Cardiol Heart Vasc 2020;31:100630. https://doi.org/10.1016/j.ijcha.2020.100630; PMID: 32984497.

18. Shimokawa H, Suda A, Takahashi J, et al. Clinical characteristics and prognosis of patients with microvascular angina: an international and prospective cohort study by the Coronary Vasomotor Disorders International Study (COVADIS) Group. Eur Heart J 2021;42:4592–600. https://doi. org/10.1093/eurheartj/ehab282; PMID: 34038937.

19. Sato K, Takahashi J, Odaka Y, et al. Clinical characteristics and long-term prognosis of contemporary patients with vasospastic angina: ethnic differences detected in an international comparative study. Int J Cardiol 2019;291:13–8. https://doi.org/10.1016/j.ijcard.2019.02.038; PMID: 30819587.

20. George J, Mathur R, Shah AD, et al. Ethnicity and the first diagnosis of a wide range of cardiovascular diseases: associations in a linked electronic health record cohort of 1 million patients. PLoS One 2017;12:e0178945. https://doi. org/10.1371/journal.pone.0178945; PMID: 28598987.

REVIEW

Ischaemic Heart Disease

Slow Coronary Blood Flow: Pathogenesis and Clinical Implications Andrea Aparicio , Javier Cuevas , César Morís

and María Martín

Area de Gestión Clínica del Corazón, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain

Abstract

Coronary slow flow (CSF) phenomenon, also known as cardiac syndrome Y, is defined as the delayed opacification of the coronary vasculature at the distal level. Different hypotheses and theories have been postulated about its substrate and mechanism, such as microvascular and endothelial dysfunction. Several studies have confirmed that CSF is a cause of ischaemia detected by non-invasive testing. Clinically, it can present as angina pectoris, acute coronary syndrome and sudden cardiac death. It has an incidence of 1–5% in patients undergoing coronary angiography and has been most frequently found in young men who are smokers with metabolic syndrome. There are no established treatments for CSF and further studies are still necessary.

Keywords

Coronary slow flow, angina, angiography, acute coronary syndrome Disclosure: MM is on the European Cardiology Review editorial board; this did not influence peer review. All other authors have no conflicts of interest to declare.

Acknowledgements: AA and JC contributed equally.

Received: 31 August 2021 Accepted: 5 December 2021 Citation: European Cardiology Review 2022;17:e08. DOI: https;//doi.org/10.15420/ecr.2021.46 Correspondence: María Martín, Area de Gestión Clínica del Corazón, Hospital Universitario Central de Asturias, Avda de Roma s/n 33001, Oviedo, Asturias, Spain.

E: mmartinf7@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 non-commercial purposes, provided the original work is cited correctly.

Coronary slow flow (CSF) phenomenon, also known as cardiac syndrome Y, is characterised by angiographically normal or near-normal coronary arteries with delayed opacification of the distal vasculature.1 Far from being a simply angiographic finding, it has clinical implications, such as angina, acute coronary syndrome and sudden death. The prevalence ranges from 1–5% of coronary angiograms and it is more frequent in young male smokers.2 Researchers have been trying to characterise this phenomenon and understand its pathophysiological mechanisms. Myocardial biopsy studies have demonstrated the presence of microvascular disease and an increased resting coronary vasomotor tone.3,4 Different therapeutic options have been used and oral calcium channel blockers (CCBs) have proven to be the most effective as they attenuate the associated microvascular dysfunction.2 There is still a great deal that is unknown about its nature and prognosis, which we cover in this review.

How is Coronary Slow Flow Defined?

CSF was first described in 1972 by Tambe et al. after they identified it in six patients.5 It is defined as the delayed opacification of the coronary vasculature at the distal level in the absence of significant obstructive artery disease as a consequence of a primary coronary microvascular disorder.6 It has been considered to be an early stage of atherosclerotic disease according to some studies.7 An increased resting coronary vasomotor tone in coronary resistance vessels has been reported and Sezgin et al. revealed that endothelium-dependent flow-mediated dilatation is impaired in these patients secondary to elevated homocysteine levels.8 Lower nitric oxide (NO) and elevated NO synthase levels with impaired endothelial function

have also been demonstrated in several studies.8–11 The three coronary vessels can be involved. Multivessel involvement with CSF represents a more severe and diffuse condition with a worse prognosis.12 In the absence of coronary obstructive lesions, delayed contrast opacification is considered a marker of increased microvascular resistance and characteristically unequivocal of the phenomenon of CSF, which may cause angina secondary to myocardial ischaemia and lead to acute coronary syndrome.1 Beltrame proposed a definition of CSF based on the following angiographic criteria:13

• No evidence of obstructive epicardial coronary artery disease.

• Delayed distal vessel contrast opacification, as evidenced by either: thrombolysis in MI-2 (TIMI-2) flow (requiring ≥3 beats to opacify the vessel) or corrected TIMI frame count >27 frames.

• The delayed distal vessel opacification is in at least one epicardial vessel.

A definitive diagnosis can only be made once secondary causes have been ruled out such as no-reflow phenomenon, coronary embolism, ectatic artery or administration of exogenous vasoconstrictors.13 CSF is a specific pathological entity that should be considered as a clinical syndrome rather than simply an angiographic phenomenon.14,15 Figure 1 shows the diagnostic criteria for CSF.

The Pathophysiology of Coronary Slow Flow

Angina is the term used to define symptoms secondary to myocardial ischaemia. Atherosclerotic coronary disease continues to be the main cause; however, it does not always correlate with angiographic evidence

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Slow Coronary Blood Flow: Pathogenesis and Clinical Implications Figure 1: Diagnostic Criteria for Coronary Slow Flow, as Proposed by Beltrame 201213 Proposed diagnostic criteria for primary coronary slow flow

Absence of obstructive lesions

Delayed opacification of distal vessels

Ectatic artery

Rule out secondary causes

Administration of exogenous vasoconstrictors

of obstructive coronary lesions and coronary arteries can be normal or near normal but with a slow progression of contrast material. There are several hypotheses and theories about the substrate and mechanism for CSF, but microvascular and endothelial dysfunction are highly suspected.

The normal coronary vasculature consists of epicardial vessels with little resistance to blood flow; and the microvasculature is the main source for regulation of myocardial flow. Coronary vascular tone is regulated via the endothelium and reflects the balance of opposite factors such as endothelin, the most potent vasconstrictor agent, and vasodilators agents such as NO, which seems to be the most important contributor to acute regulation of vascular tone.16 Beltrame et al. reported the presence of an increased resting coronary vasomotor tone in coronary resistance vessels in patients with CSF, suggesting the presence of microvascular spasm.9 Otherwise on the molecular level, endothelin-1 and neuropeptide Y (hence ‘syndrome Y’) have been implicated as possible mediators of the microvascular constriction response.17 Sezgin et al. revealed that endotheliumdependent flow-mediated dilatation is impaired in patients with CSF; and Camsari et al. demonstrated a decreased level of NO in these patients supporting the theory of endothelial dysfunction.8,18 Other authors have theorised that high homocysteine levels are responsible for endothelial dysfunction in CSF.19,20 Pekdemir et al. demonstrated that the decreased fractional flow reserve in patients with CSF was attributed to increased resistance in the epicardial coronary arteries due to diffuse atherosclerotic disease.21 This supports the theory that CSF caused by the deterioration of endothelial function could be considered a precursor of atherosclerosis. Similarly, the study by Yilmaz et al. showed that patients with CSF have a high incidence of metabolic syndrome responsible for microvascular dysfunction.7 However, other theories have emerged that challenge the hypothesis of endothelial dysfunction in the pathogenesis of CSF. Kopetz et al. published the first study that assessed endothelial function and biomarkers of endothelial activation in a large group of CSF patients compared to a healthy control cohort.22 They found that endothelial function was not impaired in patients with CSF and concluded that abnormalities in endothelial function and the endothelial NO pathway do not play a major role in the pathogenesis of CSF suggesting that further investigations are needed to elucidate the importance of other biological factors, such as platelet activation or the role of endothelin.

Otherwise, regarding small vessel involvement in CSF, the study by Mangieri et al., which used an endomyocardial biopsy and histopathological

Involvement of at least one epicardial vessel

No-reflow phenomenon

Coronary embolism

investigation, revealed not only the thickening of the vessels with reduction of their lumen, but also mitochondrial abnormalities and reduction in glycogen content; the histopathological abnormalities are suggestive of small vessel disease which could contribute to increased flow resistance.3 In the same way, Beltrame et al. indicated that CSF was associated with a chronically elevated resting coronary microvascular tone characterised by a low oxygen saturation in the coronary sinus.23 Besides endothelial dysfunction, other authors have proposed that inflammatory phenomena and conditions associated with changes in platelet properties and changes in blood rheological properties could also be associated with CSF.24 Li et al. examined inflammatory mechanisms and showed that the plasma concentration of high-sensitivity C-reactive protein and interleukin-6 was increased in CSF patients.25 Additionally, higher levels of plasma soluble adhesion molecules, such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin have been described in these patients, as well as other inflammatory markers such as serum acid uric levels and increased red cell distribution width.26,27 Anatomical factors have also been implicated in the pathogenesis of CSF. Studies with multidetector CT coronary angiography have demonstrated that the angulations of the main coronary arteries from the aorta were smaller in these patients. Wang et al. have also shown a higher tortuosity and more distal branches in coronary arteries in this cohort.6,28 As we have seen and, in conclusion, various and heterogeneous theories have tried to explain the pathogenesis of CSF, with questions still pending that will require longer series and new studies if they are to be resolved.

(Figure 2).

Clinical Aspects of Coronary Slow Flow

CSF is usually associated with recurrent angina at rest or mixed rather than with angina on exertion.13 Other clinical forms of presentation are acute coronary syndrome, ST-segment elevation MI, ventricular arrhythmias and even sudden cardiac death probably due to increased QTc dispersion (QTcd) in these patients.29,30 In most cases it occurs in young men who are smokers and have a predisposition to develop metabolic syndrome, postulating endothelial dysfunction as a common pathophysiological mechanism between both.6,7,13 In the study by Hawkins et al., male sex and obesity predicted the presence of CSF as independent risk factors and patients with a diagnosis of CSF had significantly lower levels of HDL.12 Mosseri et al. studied six patients with CSF and found that the clinical presentation was varied, although the symptoms improved with sublingual nitrates in all of them. In four of them,

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Slow Coronary Blood Flow: Pathogenesis and Clinical Implications the left ventricular (LV) ejection fraction was preserved and end-diastolic pressure was at the high limit of normality, which reflects a reduced compliance in the left ventricle. Supraventricular arrhythmias and conduction disorders were identified in four of the patients, probably in relation to the associated small vessel disease. Only one patient experienced electrical changes during the episode of pain, probably due to the balanced ischaemia that involves the simultaneous microvascular involvement.31–33 A question of special interest is the development of ventricular arrhythmias and sudden death in these patients attributed to increased QTc dispersion.

The study by Atak et al. found that QTc dispersion (defined as the difference between the maximum and minimum QTc interval in a 12-lead ECG) was increased in patients with CSF and it was mainly due to a shortened minimum QTc interval. This increased LV repolarisation heterogeneity can be attributed to myocardial ischaemia caused by microvascular dysfunction or CSF.30 According to the review by Wang et al., metabolic syndrome was more frequent in patients with CSF in the presence of higher levels of total cholesterol, low-density lipoprotein and fasting blood glucose and a higher BMI.6 In addition, a relationship between this phenomenon and increased insulin resistance and glucose intolerance has been described.34,35 Everything points to a common pathophysiology of endothelial dysfunction between metabolic syndrome and CSF. In a more recent study carried out by Sanghvi et al., hypertension, dyslipidaemia and smoking were identified as independent predictors of CSF, with acute coronary syndrome being the most frequent presentation.36 With respect to the detection of ischaemia, Ciavolella et al. reported that 69% of their patients with CSF had functional and perfusion abnormalities that matched the coronary territories that demonstrated the delayed contrast dye run-off.37 In the same way, Alvarez et al. also reported a high percentage of patients with CSF and abnormal ischaemic evaluation.2 These studies confirm that CSF is a cause of ischaemia detected by noninvasive testing.

Whereas all three coronary arteries can be involved, several case series have shown that the left anterior descending artery was most frequently affected.24 Ventricular dysfunction has also been described related to CSF, these patients can present with impaired LV systolic and diastolic function which has an impact on exercise capacity. 38,39 Several studies have correlated these findings. Wang et al. performed a study to evaluate LV and right ventricular (RV) systolic and diastolic function using 2D longitudinal strain and strain rate. They found a deterioration of ventricular function in patients with CSF with similar findings to previous published research, such as Baykan et al. using tissue Doppler imaging.40,41 These findings reveal the need to develop therapeutic interventions in patients with CSF, not only to alleviate symptoms but also to improve LV and RV function.

Prevalence and Predictors of Coronary Slow Flow

Figure 2: Pathogenic Pathways and Clinical Presentation of Coronary Slow Flow Phenomenon Small vessels disease

Endothelial dysfunction

Increased vasomotor tone

Coronary slow flow

Inflammatory phenomena

Platelet function disorder

Ventricular arrythmias

Anatomical factors

Ischaemia Systolic and diastolic ventricular dysfunction

Angina at rest or mixed

Sudden death

Acute coronary syndrome

also observed that this phenomenon probably relates to small vessel dysfunction and is associated with significant morbidity and possibly mortality, finding smoking as the most commonly associated factor.1 In 2016, Sanati et al. carried out a cross-sectional study to investigate the demographic and clinical findings of the CSF phenomenon at a tertiary centre in Iran. They found a prevalence of 2% similar to other previous reports. The most frequently affected coronary artery was the left anterior descending. As a conclusion of their research, hypertension and a low HDL-c level could be independent predictors of CSF.24 In India, Mukhopadhyay et al. conducted the first case-control study to analyse clinical presentation, angiographic profile and risk factors associated with CSF. Eighty patients were analysed with classic cardiovascular risk factors (age, sex, BMI, diabetes, hypertension, dyslipidaemia and smoking) as well as haematological and biochemical parameters (haematocrit, platelet count, uric acid, homocysteine, fibrinogen, high sensitivity C-reactive protein and HbA1c) were assessed.

BMI was the only independent factor associated with CSF.42 Another case-control study carried out in Japan by Li et al. among 124 patients, showed that the adenosine phosphate-induced platelet aggregation rate was an independent predictor of CSF. LV global and regional diastolic function was impaired in CSF patients and the number of coronary arteries involved determined the severity of LV dysfunction, underlining the need for follow-up in CSF patients with three involved coronary arteries.43

The CSF phenomenon is not a very common finding in routine coronary angiography. Since Tambe et al. first reported this condition as a new angiographic finding, its real incidence is not well known. In 1996, Mangieri et al. reported an incidence in their institution of about 7% of patients with chest pain, normal epicardial coronary arteries and abnormal coronary progression of dye.3,5 In other series, an incidence of 1–5% of patients undergoing coronary angiography has been found.

More recently, Rouzbahani et al. performed a cross-sectional study to investigate the prevalence and predictors of CSF, finding a prevalence in their population similar to previous studies (1.43%) with BMI and hypertension being independent predictors of the presence of CSF as reported by other authors.44 The prevalence of CSF according to different studies is summarised in Table 1.

A case-control study conducted by Beltrame et al. obtained a prevalence of 65 of CSF cases among a total of 6,000 coronary angiograms. They

CSF remains under-recognised and the specific standard of care for treatment has not yet been established. It has been suggested that the

Treatment of Coronary Slow Flow

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Slow Coronary Blood Flow: Pathogenesis and Clinical Implications Table 1: Prevalence of Coronary Slow Flow According to Different Studies Author

Study Type

Prevalence

Mangieri et al. 1996

Observational

7%

Beltrame et al. 20021

Case−control

1%

Hawkins et al. 201212

Observational

5.5%

Case−control

2%

Cross-sectional

1.43%

3

Sanati et al. 201624 Rouzbahani et al. 2021

44

Table 2: Treatment Proposed for Coronary Slow Flow Author

Drug Therapy

Administration Mechanism

Li et al. 201245

Diltiazem

Oral

Attenuation of vascular smooth muscle spasm

Alvarez and Siu, 20182

Nifedipine

Intracoronary/oral

Attenuation of vascular smooth muscle spasm

Mehta et al. 201946

Nicardipinio

Intracoronary

Attenuation of vascular smooth muscle spasm

Li et al. 200748 Cakmak et al. 200849

Statins

Oral

Effects on endothelial function, as well as antithrombotic and anti-inflammatory actions

Albayrak et al. 200950

Nebivolol

Oral

Improving endothelial function

possible pathophysiology of this entity underlies the microcirculation.

Taking into account the demonstrated role of calcium antagonists in patients with microvascular angina, vasospastic angina and CSF, which share a common pathophysiology, Li et al. carried out a clinical trial between 2004 and 2009 in which CSF patients were randomly assigned to a treatment group for diltiazem sustained release capsules 90 mg twice daily (n=40) or a placebo control group. This study aimed to observe the chronic effects of oral diltiazem in patients with CSF. They concluded that patients treated with diltiazem showed a significant improvement in relation to coronary flow, exercise test tolerance and angina, possibly through the attenuation of vascular smooth muscle.44 Once it had been demonstrated that oral CCBs could attenuate the microvascular effects associated with CSF, Alvarez et al. conducted a study evaluating the subsequent use of oral CCBs in patients whose angiographic slow flow had been resolved with intracoronary CCBs.2 They analysed 15 patients diagnosed with CSF, none of whom had been previously treated with CCBs or nitrates. They observed an immediate angiographic improvement of the phenomenon after administration of intracoronary nifedipine. Subsequently, they administered CCBs orally with a follow-up of 13.6 months and observed that all subjects improved symptomatically from their chest pain. As previously mentioned, although the specific standard of care for treatment has not yet been established, symptomatic improvement with CCBs has been shown. Similarly, Mehta et al. confirmed in 30 patients that intracoronary nicardipine was highly effective in reversing CSF implicating a microvascular spasm in the pathogenesis of CSF. Previous studies with mibefradil (a calcium T-channel blocker) also reduced angina frequency and improved physical quality of life, supporting the microspastic pathogenesis of CSF.45–47 Li et al. also hypothesised about the possible effect of statins on CSF.

Increasing evidence suggests that the reduction of cardiovascular events conferred by statins is related not only to cholesterol reduction but also to direct effects on endothelial function, as well as antithrombotic and antiinflammatory actions. Therefore, these authors hypothesise that these pleiotropic effects of statins may be beneficial for these patients due to their pharmacological basis.48 In another study with statins, Cakmak et al. also concluded that 40 mg simvastatin improved myocardial perfusion in patients with CSF.49 Nebivolol has also been shown to be useful for the treatment of CSF. Albayrak et al. investigated the efficacy of nebivolol in patients with SCF by monitoring its effects on endothelial function and different markers of inflammation. They confirmed that nebivolol was effective at improving endothelial function in patients with CSF, controlling chest pain, and having a favourable effect on brachial artery dilation in patients with CSF.50 It may also be beneficial to improve oxidative stress parameters and reduces QTc interval in patients with CSF in which, as we have previously mentioned, QT interval dispersion is increased, reducing the risk of ventricular arrhythmias.51,52 The efficacy of nitrates is controversial – in some studies CSF was not reversed with intracoronary nitroglycerin administration while others have shown increase in the coronary flow.3 Several studies have compared its effects with other drugs and Ozdogru et al. compared the effects of intracoronary nitrate and diltiazem in patients with CSF during coronary angiography showing that although both therapies improved the TIMI frame count, diltiazem was superior to nitroglycerine.53 In the same way, Sani et al. compared the efficacy of nicorandil versus nitroglycerin for alleviation of angina symptoms in CSF in a randomised trial.54 Patients reported greater reductions in pain intensity with nicorandil versus nitroglycerin. These results were similar to those previously reported by Sadamatsu et al.55 Otherwise, in the acute setting, different therapies can be used; dyridamole have been shown to have beneficial effects with different routes of administration, such as intracoronary, IV or oral.3 Other intracoronary drugs, such as verapamil, adenosine or nitroprusside, have also been used for the management of acute patients.56 Also in the acute presentation, Chalikias et al. have recently published the use of intracoronary atropine, with an anticholinergic effect, as an appropriate agent to quick reversal of CSF.57 In conclusion, different agents and therapies have been studied for CSF and previous reports have shown the benefit of using dipyridamole by decreasing the microvascular tone, and others have proved the effects of angiotensin-converting enzyme inhibitors by modulating coronary microvascular tone but until now there is no clear treatment for this phenomenon.58,59 Evidence for the management of these patients is weak as there are no large randomised control trials but CCBs are the most promising treatment. Further studies are needed in the acute setting and for outpatients. A summary of treatment for CSF is shown in Table 2.

Prognosis of Coronary Slow Flow

CSF could be considered within the atherosclerosis spectrum caused by microvascular dysfunction or even a systemic phenomenon. Few studies have analysed the prognosis of CSF and some authors considered this entity as a syndrome different to any kind of coronary heart disease. Due to its unknown pathogenesis many questions still remain and prognosis of CSF is not clearly determined. Years ago it was considered a benign entity with ‘normal’ coronary arteries and many patients were discharged.

However, as previously mentioned, these patients can present with various asymptomatic clinical conditions including sudden cardiac death

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Slow Coronary Blood Flow: Pathogenesis and Clinical Implications Table 3: Differential Diagnosis Between Coronary Slow Flow and Syndrome X Differential Diagnosis

Coronary Slow Flow

Syndrome X

Type of patients

Young male smokers

Post-menopausal women

Clinical presentation

Angina, acute coronary syndrome, ventricular arrhythmias

Stress-related angina

Response to vasodilators

Vasodilator response to papaverine, adenosine

Absent response

Coronary resistance at rest

Elevated resting microvascular tone

Normal resting microvascular tone

Prognosis

More severe myocardial ischaemia Risk of ventricular arrhythmias and sudden death

More benign, less ischaemia and lower risk of ventricular arrhythmias

due to ischaemia and ventricular arrhythmias. Otherwise, chronic and recurrent angina pectoris, without a definitive treatment, negatively affects quality of life.14 The recent study published by Candemir et al. showed that ischaemic myocardial scar in MRI may be present in patients with CSF; this finding should be investigated in further and longer studies and could help to clarify not only the pathogenesis but also the prognosis of CSF.60

Final Questions About Coronary Slow Flow

Since its first description, many questions have been raised about CSF. Previous authors considered it to be an angiographic subgroup of syndrome X.61 However, given its peculiarities, some authors have considered this entity to be a syndrome, as proposed by Li et al., differentiating it from syndrome X and even naming it syndrome Y, given the proposed role of neuropeptide Y.4,14,62 The former occurs more frequently in postmenopausal women, while the latter, as previously mentioned, is more frequent in male smokers and characterised by 1.

2.

3.

4.

5.

6.

7.

8.

Beltrame JF, Limaye SB, Horowitz JD. The coronary slow flow phenomenon – a new coronary microvascular disorder.

Cardiology 2002;97:197–202. https://doi. org/10.1159/000063121; PMID: 12145474.

Alvarez C, Siu H. Coronary slow-flow phenomenon as an underrecognized and treatable source of chest pain: case series and literature review. J Investig Med High Impact Case Rep 2018;6:1–5. https://doi.org/10.1177/2324709618789194; PMID: 30038914.

Mangieri E, Macchiarelli G, Ciavolella M, et al. Slow coronary flow: clinical and histopathological features in patients with otherwise normal epicardial coronary arteries. Cathet Cardiovasc Diagn 1996;37:375–81. https://doi.org/10.1002/ (SICI)1097-0304(199604)37:4<375::AID-CCD7>3.0.CO;2-8; PMID: 8721694.

Beltrame J, Limaye SB, Wuttke R, et al. Coronary hemodynamic and metabolic studies of the coronary slow flow phenomenon. Am Heart J 2003;146:84–90. https://doi. org/10.1016/S0002-8703(03)00124-8; PMID: 12851612.

Tambe AA, Demany MA, Zimmerman HA, et al. Angina pectoris and slow flow velocity of dye in coronary arteries – a new angiographic finding. Am Heart J 1972;84:66–71. https://doi.org/10.1016/0002-8703(72)90307-9; PMID: 5080284.

Wang X, Nie Sh. The coronary slow flow phenomenon: characteristics, mechanisms and implications. Cardiovasc Diagn Ther 2011;1:37–43. https://doi.org/10.3978/j.issn.22233652.2011.10.01; PMID: 24282683.

Yilmaz H, Demir I, Uyar Z. Clinical and coronary angiographic characteristics of patients with coronary slow flow. Acta Cardiologica 2008;63:579–84. https://doi. org/10.2143/AC.63.5.2033224; PMID: 19014000.

Sezgin AT, Barutcu I, Sezgin N, et al. Contribution of plasma lipid disturbances to vascular endothelial function in patients with slow coronary flow. Angiology 2006;57:694–

9.

10.

11.

12.

13.

14.

15.

16.

17.

delayed coronary opacification. Otherwise, the CSF prognosis is not as benign as syndrome X. CSF should also be distinguished from the delay of contrast in the context of reperfusion therapy or other secondary causes such as coronary ectasia, coronary spasm or coronary embolisms.4 Differential diagnosis between CSF and syndrome X is reflected in Table 3.

Another questionable aspect is whether we are dealing with a localised coronary condition or a systemic disease. As reflected by Wang et al. reduced endothelial function is implicated in CSF as measured by flowmediated dilatation of the brachial artery, suggesting that endothelial dysfunction appears to be a generalised process affecting both coronary and peripheral vasculature. Previous studies demonstrated an increased carotid intima-media thickness (IMT) in patients with CSF with a significant correlation between coronary IMT and carotid IMT, all these findings support the hypothesis of a systemic vascular involvement in this group of patients.6,63 Anxiety and depression have been associated with CSF. The pathogenesis of CSF involves mechanisms similar to those linked to anxiety/depression (inflammation, microvascular abnormalities, endothelial dysfunction and anatomical factors of epicardial arteries) which could support the hypothesis that it is a systemic disease.64 There are many questions to be resolved about CSF pathogenesis, treatment and prognosis. Further and longer case series will help us to understand this partially unknown phenomenon.

Conclusion

Over the years, there have been many publications about CSF phenomenon or syndrome. Far from being a simple finding in coronary angiography, it is an entity defined with diagnostic criteria, responsible for symptoms ranging from angina to ventricular arrhythmias, with ischaemia demonstrated. Its pathogenesis has not been completely clarified and the creation of national and international registries would help to clarify and spread knowledge about this phenomenon.

701. https://doi.org/10.1177/0003319706295472; PMID: 17235109.

Beltrame JF, Turner SP, Horowitz JD. Persistence of the coronary slow flow phenomenon. Am J Cardiol 2001;88:938. https://doi.org/10.1016/S0002-9149(01)01839-2; PMID: 11676972.

Sezgin N, Barutcu I, Sezgin AT, et al. Plasma nitric oxide level and its role in slow coronary flow phenomenon. Int Heart J 2005;46:373–82. https://doi.org/10.1536/ihj.46.373; PMID: 16043934.

Tanriverdi H, Evrengul H, Enli Y, et al. Effect of homocysteine-induced oxidative stress on endothelial function in coronary slow-flow. Cardiology 2007;107:313–20. https://doi.org/10.1159/000099068; PMID: 17264512.

Hawkins BM, Stavrakis S, Rousan TA, et al. Coronary slow flow: prevalence and clinical correlations. Circ J 2012;76:936–42. https://doi.org/10.1253/circj.CJ-11-0959; PMID: 22293446.

Beltrame JF. Defining the coronary slow flow phenomenon.

Circ J 2012;76:818–20. https://doi.org/10.1253/circj.CJ-120205; PMID: 22374148.

Li JJ, Wu YJ, Xue-Wen XW. Should slow coronary flow be considered as a coronary syndrome? Med Hypotheses 2006;66:953–6. https://doi.org/10.1016/j.mehy.2005.11.025; PMID: 16413138.

Leone MC, Gori T, Fineschi M. The coronary slow flow phenomenon: a new cardiac ‘Y’ syndrome? Clin Hemorheol Microcirc 2008;39:185–90. https://doi.org/10.3233/CH-20081079; PMID: 18503124.

Vane JR, Anggard EE, Botting RM. Regulatory functions of the vascular endothelium. N Engl J Med 1990;323:27–36. https://doi.org/10.1056/NEJM199007053230106; PMID: 2113184.

Finley JJ, Savage MP. Coronary slow flow phenomenon: more than just an angiographic curiosity. Interventional

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REVIEW

Risk Stratification and Biomarkers

Circulating Biomarkers in Lower Extremity Artery Disease Louise Ziegler ,1 Ulf Hedin

2

and Anders Gottsäter

3,4

1. Division of Internal Medicine, Department of Clinical Sciences, Karolinska Institute, Danderyd Hospital, Stockholm, Sweden; 2. Vascular Surgery Division, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; 3. Department of Medicine, Lund University, Malmö, Sweden; 4. Department of Medicine, Skåne University Hospital, Malmö, Sweden

Abstract

Lower extremity artery disease (LEAD), a chronic condition with disturbed lower extremity circulation due to narrowing of the arteries, is predominantly caused by atherosclerosis and is associated with the presence of cardiovascular risk factors and an increased risk of cardiovascular events. LEAD is prevalent among older individuals and predicted to rise with the ageing population. In progressive disease, the patient experiences symptoms of ischaemia when walking and, in advanced critical limb-threatening ischaemia, even at rest. However, LEAD is asymptomatic in most patients, delaying diagnosis and treatment. In this setting, circulating biomarkers may facilitate earlier diagnosis in selected individuals. This review provides a broad overview of the circulating biomarkers investigated to date in relation to LEAD and discusses their usefulness in clinical practice.

Keywords

Peripheral artery disease, lower extremity artery disease, biomarkers Disclosure: The authors have no conflicts of interest to declare.

Received: 20 December 2021 Accepted: 31 January 2022 Citation: European Cardiology Review 2022;17:e09. DOI: https://doi.org/10.15420/ecr.2021.58 Correspondence: Louise Ziegler, Division of Internal Medicine, Department of Clinical Sciences, Karolinska Institute, Danderyd Hospital, Entrévägen 2, 182 57 Stockholm, Sweden. E: louise.dencker-ziegler@regionstockholm.se 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.

Lower Extremity Artery Disease: Definition, Epidemiology and Clinical Presentation

Lower extremity artery disease (LEAD), primarily an atherosclerosis -driven disease, causes varying degrees of disturbances in blood perfusion to the lower limb.1,2 The prevalence of LEAD in the general population has been reported to be 3–10%, although prevalence varies depending on the age of the population, reaching around 18% for those aged ≥65 years.2,3 In early stages, LEAD is usually asymptomatic, and the impaired limb circulation is only evident as an ankle–brachial index (ABI) ≤0.90. With progression of the disease, intermittent claudication (IC) may occur, characterised by muscle fatigue and lower extremity pain triggered by physical activity and directly relieved when resting.4 In the more severe critical limb-threatening ischaemia (CLTI), the patient experiences pain at rest and/or presents with ischaemic ulceration or gangrene of the foot.4 The mere presence of LEAD, either asymptomatic or symptomatic, is a significant predictor of increased risk of cardiovascular events (CVE) and cardiovascular mortality.5–7 Among individuals with IC, there is a low risk of progression to CLTI, with only 2% requiring lower extremity amputation within 10 years from diagnosis.8 Conversely, in the CLTI population, firstyear rates of amputation in most studies are greater than 15–20% and 1-year mortality rates increase markedly from a few per cent in IC to 20– 30% in CLTI.9,10

Compensatory development of new capillary networks (angiogenesis) and expansion of collateral arteries (arteriogenesis) are physiological responses to progressing limb ischaemia also encompassing pathological processes such as inflammation, apoptosis and vascular remodelling.11 In the constantly hypoperfused tissue in CLTI, chronic inflammation induces endothelial dysfunction and oxidative stress, with subsequent mitochondrial damage, generation of free radicals, muscle degeneration, connective tissue damage, fibrosis and eventually risk of gangrene.12–14 These events are possible targets for treatment and potential sources of diagnostic and prognostic biomarkers.

Methods

The aim of this review is to provide a comprehensive overview of the most promising established and emerging circulating biomarkers for LEAD and to discuss the usefulness of these biomarkers in screening, risk stratification and monitoring of therapeutic effect in line with personalised medicine. The biomarkers are grouped according to their mechanism in atherothrombotic disease, as shown in Figure 1. In addition, major biomarkers with data regarding their discriminative performances are summarised in Table 1.

The search terms used in this review were: ‘lower extremity artery disease’ or ‘peripheral artery disease’ or ‘intermittent claudication’ or ‘critical limb-threatening ischemia’ or ‘critical limb ischaemia’ and ‘biomarker’. In additional searches, the term ‘biomarker’ was changed to the names of specific biomarkers.

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Circulating Biomarkers in Lower Extremity PAD Figure 1: Lower Extremity Artery Disease Biomarkers Grouped by Origin or Mechanism

Markers of oxidative stress Markers of endothelial activation and dysfunction

Markers of the thrombosis cascade

resulting ischaemia and subsequent tissue damage. Given the established contribution of low-grade chronic inflammation in all stages of atherosclerosis, it is conceivable that inflammatory processes, such as those reflecting endothelial cell activation, synthesis and secretion of proinflammatory factors, the expression of adhesion molecules for inflammatory cells and prothrombotic activity, have been targeted in the search for disease biomarkers. These early processes, including monocyte recruitment, are driven by the innate immune system, and inflammatory cells or tissue cells activated during inflammation have been associated with a poor prognosis in LEAD.18,19

Interleukin-6 Inflammatory biomarkers

Overarching inflammatory, coagulation and metabolic pathway biomarkers

Lower extremity artery disease

Cardiac biomarkers

Markers of lipid metabolism Tissue remodelling and angiogenesis markers

The biomarkers presented in this review are grouped by their biological origin, pathophysiological mechanism or prior clinical application.

Biomarkers: Introduction and Definitions

The definition of a biomarker used in this review is the one presented by the Food and Drug Administration and the National Institutes of Health, specifically: “A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention.”15 The biomarker concept should be distinguished from clinical outcome assessments (i.e. evaluations of mental or physical status). To be of clinical value, a biomarker must be stable in the pre-analytical context, measurable without too much effort or cost and provide information on diagnosis and/or prognosis specific to the condition in question. In addition, a novel biomarker should add information incremental to the diagnostic tools and markers already used in clinical practice.

In this review, we focus on circulating biomarkers evaluated for diagnosis or assessment of prognosis in LEAD in combination with existing clinical biomarkers.

Circulating Biomarkers

As an adjunct to the clinical assessment tools, circulating biomarkers may contribute to the diagnostics of LEAD, prediction of future deterioration, including cardiovascular disease (CVD) progression in general, and evaluation of treatment effects. Despite demonstrated associations and biological relevance, most biomarkers are insufficient to reclassify individuals correctly above and beyond existing clinical and circulating biomarkers, such as ABI, which carries strong predictive power for CVD mortality.16 Moreover, due to large intraindividual variations in concentration, single-biomarker assessments may be of limited value.17 The biomarkers presented in this review are grouped by pathophysiological origin and mechanism (Figure 1).

Inflammatory Biomarkers

LEAD is primarily a consequence of progressive atherosclerosis, with or without atherothrombosis, in the lower extremity vasculature, with

Interleukin (IL)-6, central in atherosclerosis development and progression, is part of the IL-1β/IL-6/C-reactive protein (CRP) pathway. IL-6 signals through two different pathways, with the classical IL-6 signalling pathway being the main mediator of the acute phase reaction with subsequent expression of adhesion molecules and the proliferation and transformation of vascular smooth muscle cells into foam cells.20 The proinflammatory IL-6 trans-signalling pathway has not been analysed in LEAD. In several case-control studies, IL-6 concentrations were higher in individuals with LEAD.17,21–23 This relationship was true also before and after treadmill exercise.24 In the Edinburgh Artery study of middle-aged men and women, IL-6 was associated with deterioration in ABI after 5 and 12 years follow-up independent of cardiovascular risk factors, baseline CVD and ABI.25 In line with the Edinburgh cohort, later studies have demonstrated that walking endurance in LEAD patients was inversely associated with high IL-6 concentrations.21,26,27 Moreover, persistently elevated IL-6 concentrations were associated with a more rapid functional decline compared with subjects with fluctuating or persistently low IL-6 concentrations.28 In addition, decreased size of the calf muscle as a surrogate marker of impaired leg function was associated with IL-6.29 In CLTI patients with diabetes, IL-6 was correlated with negative vascular outcome after endovascular revascularisation and was an independent predictor of in-stent restenosis 6 months after stenting in the femoropopliteal artery.30,31

C-Reactive Protein

CRP is an acute-phase reactant and product of classical IL-6 signalling.

Several studies have shown that CRP is associated with the risk of CVE, although causality has not been demonstrated. Several case-control studies reported higher CRP concentrations in subjects with LEAD than in healthy controls.17,21,32–34 The Physicians’ Health study and the populationbased prospective ARIC cohort study demonstrated that CRP independently predicted incident LEAD.35,36 In the Rotterdam cohort study, CRP predicted progression of atherosclerosis, including LEAD, independently of traditional cardiovascular risk factors and in the Edinburgh Artery study and a prospective study by Aboyans et al., the same was shown specifically for LEAD.25,37,38 However, not all studies did demonstrate an association between CRP and LEAD.39 In patients with symptomatic LEAD, CRP was associated with an increased risk of future atherothrombotic events both in the lower extremities and in other vascular beds.32,40–42 Combining high-sensitivity C-reactive protein (hsCRP) measurement with the assessment of ABI improved cardiovascular risk stratification in patients with LEAD.32,43 However, hsCRP alone has been shown to be inferior to ABI in the prediction of disease severity.44 These results were confirmed by a systematic meta-analysis of prospective studies investigating CRP as a predictor of CVE in LEAD patients.45 Moreover, several studies have shown an inverse association between

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Circulating Biomarkers in Lower Extremity PAD Table 1: Summary of the Major Circulating Biomarkers in Lower Extremity Artery Disease Presented in This Review Major Circulating Biomarkers Assessed

Pathophysiological Pathway/Mechanism

Type of Biomarker

Discriminative Performance

IL-617,21–31

IL-1/IL-6/CRP pathway

Diagnostic, prognostic

IL-6, CRP, TNF-α and risk factors: AUC 1.00 for MALE and 0.91 for MACE30

CRP17,21,32–48

IL-1/IL-6/CRP pathway

Diagnostic, prognostic

Diagnosing LEAD: AUC 0.81134 Predicting composite of amputation, revascularisation, all-cause death: AUC 0.5740 CRP, IL-6, TNF-α and risk factors: AUC 1.00 for MALE and 0.91 for MACE30

TNF-α21,23,24,27,30,49,50

Adipokine and cytokine

Prognostic

TNF-α, IL-6, CRP and risk factors: AUC 1.00 for MALE and 0.91 for MACE30

GDF-1558–61

Member of the TGF-β superfamily; regulation of inflammatory processes

Prognostic

Predicts all-cause mortality in LEAD with 90.0% sensitivity, 52.6% specificity60 Predicts all-cause mortality together with TRAIL-R2: AUC 0.7461

Inflammation

Endothelial Activation and Dysfunction VCAM-1, ICAM-117,21,23–26,28,53–56

Mediate leucocyte endothelial adhesion Diagnostic, prognostic and transmigration

Diagnosing LEAD (VCAM-1): AUC 0.7653

Inhibitor of NO production

Diagnostic, prognostic

Predict cardiovascular death: AUC 0.64970

IL-1/IL-6/CRP pathway

Diagnostic, prognostic

Diagnosing LEAD: AUC 0.87034

Oxidative Stress ADMA63,67–71

Coagulation Fibrinogen33,35,43,73,77–79,81–84

Cardiac NT-proBNP 43,88–92

Precursor to BNP secreted by Diagnostic, prognostic cardiomyocytes during ventricular stretch

Predicting all-cause mortality in LEAD: AUC 0.7491

Lp(a)95–97

LDL-like particle bound to apoB100

Diagnostic

Risk factors, OxPL/apoB100, Lp(a) diagnosing LEAD: AUC 0.759 in women and 0.736 in men97

Lp-PLA298–102

Modifies oxidised LDL

Diagnostic

Diagnosing LEAD: AUC 0.807100

Non-coding single-stranded RNAs from EVs, regulate gene expression

Diagnostic

Diagnosing LEAD: AUC >0.93 for miR-15b, miR-16 and miR-363123

Lipid Metabolism

Auxiliary Circulating miRNAs123–125

ADMA = asymmetric dimethylarginine; apoB100 = apolipoprotein B100; AUC = area under the curve; BNP = B-type natriuretic peptide; CRP = C-reactive protein; EVs = extracellular vesicles; GDF-15 = growth differentiation factor-15; IL = interleukin; LEAD = lower extremity artery disease; Lp(a) = lipoprotein (a); Lp-PLA2 = lipoprotein-associated phospholipase A2; MACE = major adverse cardiovascular events; MALE = major adverse limb events; miRNA = microRNA; NO = nitric oxide; NT-proBNP = N-terminal pro B-type natriuretic peptide; OxPL = oxidised phospholipids; TGF-β = transforming growth factor-β; TNF-α = tumour necrosis factor-α; TRAIL-R2 = tumour necrosis factor-related apoptosis-inducing ligand receptor 2; VCAM-1 = vascular cell adhesion molecule-1.

CRP and ABI, severe clinical LEAD and functional deterioration.19,25,33,34,46,47 High CRP concentrations also correlated negatively with walking duration.21,48 In addition, high CRP was associated with an enhanced risk of postoperative vascular events and failure of endovascular revascularisation in LEAD patients.30

Tumour Necrosis Factor-α

Tumour necrosis factor (TNF)-α is a central mediator of inflammatory reactions inducing matrix metalloproteinase synthesis and contributing to atherosclerotic plaque instability. In case-control studies, TNF-α and circulating TNF-α receptor levels were higher in patients with LEAD than in healthy subjects.21,23,49 In a pre- and post-exercise analysis, TNF-α concentrations were still higher in subjects with LEAD, regardless of treadmill training.24 Moreover, TNF-α expression and circulating levels of TNF-α were inversely associated with walking duration.21,50 Conversely, in a study of patients with verified LEAD, TNF-α concentrations were significantly correlated with an angiographic score, but an association with treadmill performance could not be demonstrated.27 TNF-α concentrations were associated with increased vascular risk in CLTI patients with diabetes after endovascular intervention.30

Markers of Endothelial Activation and Dysfunction Adhesion Molecules

Cell adhesion molecules (CAMs) are transmembrane glycoproteins that create binding sites for cell–cell and cell–extracellular matrix adhesion.

CAMs, expressed on vascular endothelium and leucocytes subsequent to proinflammatory stimuli, mediate the tethering, rolling, adhesion to the endothelium and transmigration of recruited leucocytes into the subendothelial layer. In atherosclerosis, the three CAM families of importance are selectins, the immunoglobulin superfamily and integrins.

Selectins Selectins are involved in inflammatory responses, such as atherosclerosis, and consist of three different types: E-selectin, expressed on endothelial cells; L-selectin, expressed on leucocytes; and P-selectin, expressed on platelets and endothelial cells.

Significantly higher concentrations of E-, L- and P-selectins have been reported in LEAD patients compared with controls.17,22,23 In addition, higher plasma P-selectin was associated with increased LEAD risk in MESA.51 However, the results regarding selectins in LEAD are not consistent.52

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Circulating Biomarkers in Lower Extremity PAD Intercellular Adhesion Molecule-1 and Vascular Cell Adhesion Molecule-1 Soluble intercellular adhesion molecule (sICAM-1), part of the immunoglobulin superfamily, is mainly expressed on endothelial cells and leucocytes, whereas soluble vascular cell adhesion molecule-1 (sVAM-1) is restricted to vascular endothelial cells, where it mediates leucocyte– endothelium adhesion and promotes signal transduction between adhered cells.

Several studies have demonstrated higher sICAM-1 and/or sVCAM-1 concentrations in LEAD patients compared with healthy controls, and these adhesion molecules have been proposed as suitable for the detection of LEAD.17,21,23,24,53 When investigating biomarker levels in relation to exercise, VCAM-1 and ICAM-1 concentrations were higher in LEAD patients both before and after treadmill exercise.24 ICAM-1, but not VCAM1, was independently associated with an increased risk of progressing to symptomatic LEAD in the prospective Physician’s Health Study that included apparently healthy middle-aged men.54 These results in men were later reproduced in both women and men in the Edinburgh Artery Study and in women exclusively in the Women’s Health Study.25,55 In addition, higher sICAM-1 and sVCAM-1 concentrations were associated with reduced walking ability in some studies, whereas there was no association between sVCAM-1 and walking capacity in another study.21,26,28 However, sVCAM-1 was associated with reduced calf muscle area and strength in LEAD.29 Regarding cardiovascular risk, high sVCAM-1 concentrations predicted increased risk in individuals with LEAD and improved the prognostic value of ABI.56

Other Circulating Inflammatory Biomarkers

Neopterin, synthesised by activated macrophages upon interferon-γ stimulation, possesses pro-oxidant properties and is a marker of macrophage activity and inflammation in atherosclerosis. Neopterin concentrations have been demonstrated to be higher in asymptomatic and symptomatic LEAD patients than in healthy controls and to be negatively correlated with ABI.23,34,57 In addition, neopterin was found to be an effective predictor of LEAD.34 Growth differentiation factor (GDF)-15 is involved in the regulation of cell growth, repair and apoptosis. GDF-15 is constitutively expressed in the reproductive organs, although its expression can be swiftly induced in other cell types by proinflammatory cytokines, such as IL-1β and TNF-α.

Several studies have demonstrated GDF-15 to be a biomarker of acute coronary syndrome and mortality in coronary artery disease (CAD).58 In addition, GDF-15 concentrations are stable over time in CAD patients, suggesting that it is a marker of chronic disease.58 In two cohorts with asymptomatic and symptomatic LEAD, including CLTI patients, strong correlations were demonstrated between circulating GDF-15 and future lower extremity amputation and all-cause mortality.59 Moreover, GDF-15 predicted these outcomes equally efficiently as the combination of nine traditional vascular risk factors.59 Other studies have confirmed that GDF15 may be an effective predictor of all-cause mortality in LEAD patients.60,61 Thus, circulating GDF-15 could be of value in predicting which CLTI patients would benefit from intensified treatment and/or surgical intervention.

Markers of Oxidative Stress

Oxidative stress is one of the pathogenetic mechanisms underpinning atherosclerosis, with the production of reactive oxygen species (ROS) and reduction in nitric oxide (NO) being associated with endothelial dysfunction. In LEAD, dysfunctional mitochondria mediate ROS production

in lower extremity muscles.62 The short ROS half-life prevents direct measurement, thus more stable molecular targets of ROS can function as indirect oxidative stress markers. Markers of oxidative stress, such as asymmetric dimethylarginine (ADMA), and 8-hydroxy-2-deoxyguanosine (8-OHdG), have been seen to be elevated in LEAD.63,64 Moreover, in a case-control study, men and women with LEAD had lower serum concentrations of NO metabolites and higher concentrations of the main producer of ROS, the NADPH oxidase 2-derived peptide (NOX2-dp) compared with controls.65 In fact, NOX2-dp exhibited a negative correlation with ABI.65 Levels of the oxidative stress marker 8-OHdG were also inversely correlated with markers of NO generation, indicating a connection between NO shortage and oxidative stress in LEAD.64 Furthermore, 8-OHdG levels were correlated negatively with walking capacity.64

Asymmetric Dimethylarginine

ADMA is the natural inhibitor of NO synthase, an enzyme catalysing NO production, by affecting the NO precursor arginine. Thus, ADMA is a potential marker of endothelial dysfunction, and several studies have demonstrated associations between elevated circulating ADMA concentrations, traditional cardiovascular risk factors and an increased risk of CVD.66 Accordingly, plasma ADMA concentrations were higher in LEAD patients than in controls in a case-control study.63 In another casecontrol study, ADMA concentrations did not differ between patients with CLTI, IC and healthy controls, whereas the ratio between arginine and ADMA was lower in CLTI patients than in IC patients and healthy controls.67 Consistent data from prospective cohorts of asymptomatic or symptomatic LEAD patients have shown that increased plasma ADMA concentrations predict future CVE and both cardiovascular and all-cause mortality.68–71 Taken together, the available data suggest that ADMA may be a promising biomarker above all for detecting morbidity and mortality in LEAD patients.

Homocysteine

Circulating homocysteine (Hcy) mediates endothelial dysfunction when elevated. Moreover, there is evidence that Hcy potentiates the production of ROS.72 Approximately 30% of individuals with LEAD had increased circulating Hcy concentrations, compared with 1% in the general population.8 In addition, high Hcy concentrations were associated with worse functional outcome in LEAD.26

Markers of the Coagulation Cascade

With endothelial dysfunction and subsequent inflammation and atherosclerosis, the local haemostatic balance is shifted towards a procoagulant state accompanied by resolving fibrinolysis, which is more distinct in LEAD than in CAD.73

Procoagulant Markers

In both the COMPASS and VOYAGER trials, studying prophylactic treatment with the combination of aspirin and a low dose of the oral anticoagulant rivaroxaban in individuals with LEAD, a reduction in adverse lower limb events, cardiovascular death, MI and stroke was seen, corroborating the central role for a prothrombotic state in the pathology and complications of LEAD.74–76 Plasminogen Activator Inhibitor-1 The serine protease inhibitor plasminogen activator inhibitor (PAI)-1 prevents fibrinolysis and heightens the hypercoagulable state by inhibiting tissue plasminogen activator (tPA). In case-control studies, PAI-1 concentrations were higher both at rest and after exercise in LEAD patients compared with healthy controls.17,77–79

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Circulating Biomarkers in Lower Extremity PAD Thrombin Activation Circulating concentrations of thrombin fragment 1+2 (F1+2) and thrombin– antithrombin III complex (TAT) are specific and sensitive markers of thrombin generation and have been seen to be higher in LEAD patients compared with controls.80 In addition, CLTI patients have even higher TAT concentrations than IC patients.79 In a case-control study of CLTI patients scheduled for revascularisation, CLTI patients preoperatively exhibited a prothrombotic condition together with fibrinolysis mirrored by increased TAT and fibrinogen and enhanced tPA and D-dimer compared with controls.73 Immediately after reperfusion, F1+2 and TAT had further increased as a sign of thrombin generation, whereas fibrinogen concentrations were decreased.73 This prothrombotic and fibrinolytic state persisted throughout the first postoperative month. In another study, subjects with LEAD exhibited increases in TAT and thrombin formation after exercise.77

Platelet-Activating Factors

Tissue Factor and von Willebrand Factor Tissue factor (TF) and von Willebrand factor (vWF) are part of the initial steps of the coagulation cascade, with the damaged integrity of the endothelium exposing TF to coagulation factors (F) VII and FVIIa and vWF promoting platelet adhesion.

Concentrations of both TF antigen and vWF were higher in individuals with LEAD compared with non-LEAD controls, and TF antigen concentrations were higher in CLTI than in other stages of LEAD.78,79 Moreover, subjects with LEAD exhibited a general platelet-activating state with elevated concentrations of platelet factor 4, sVCAM-1 and P-selectin.80 Fibrinogen Fibrinogen is an acute-phase reactant regulated by IL-6 and a marker of inflammation. In addition, fibrinogen stimulates platelet aggregation and is converted to fibrin by thrombin. Fibrinogen concentrations have been reported to be higher in individuals with LEAD than in healthy controls.33,77–79 In some studies, circulating fibrinogen predicted LEAD, including IC.35,81–83 Moreover, fibrinogen concentrations increased with the severity of LEAD.79 High fibrinogen concentrations were also associated with the risk of fatal CVE and predicted mortality in LEAD.43,84 Fibrinogen was higher in CLTI patients undergoing infrainguinal bypass compared with controls.73 In the same study, fibrinogen levels decreased immediately after reperfusion, possibly mirroring augmented thrombin-mediated conversion into fibrin.73

Markers of Fibrinolysis

D-Dimer D-dimer, a protein fragment arising from dissolving blood clots, is an indirect marker of fibrinolysis and is thus associated with the presence of venous and arterial thrombosis.

Circulating D-dimer concentrations were higher in subjects with LEAD than in healthy controls before and after treadmill exercise.17,77–79 Moreover, data are available regarding associations between increased D-dimer concentrations and both the presence and severity of LEAD.33,79 High D-dimer concentrations have been shown to be associated with poor calf muscle characteristics and inferior functional capacity.26,29,48 In addition, increased D-dimer concentrations in LEAD predicted CVE risk and mortality.43,85,86 In CLTI patients admitted for revascularisation, active fibrinolysis mirrored by enhanced D-dimer levels was seen before intervention and persisted in the first month after the intervention.73 Despite plentiful research demonstrating the association between D-dimer and LEAD, there are conflicting data. In the prospective Edinburgh

Artery Study, elevated D-dimer was associated with LEAD progression, although the association was not independent of the IL-1/IL-6/CRP pathway, and it was demonstrated that individuals with concomitant increases in D-dimer and IL-6 experienced the largest deterioration.87 Moreover, in a prospective study of individuals with LEAD followed for a median of 3 years, baseline D-dimer concentrations were neither associated with the risk of progression of LEAD nor with incident CVE, except for an increased risk of MI.39 Tissue Plasminogen Activator tPA is a protease present on vascular endothelial cells and is active in the conversion of plasminogen to plasmin, mediating the dissolution of blood clots. Circulating concentrations of tPA antigen were increased in LEAD compared with healthy controls, and higher in patients with more severe disease.77,79 Subjects with LEAD had higher tPA antigen plasma concentrations at rest and after treadmill exercise.77 CLTI patients scheduled for revascularisation exhibited a prothrombotic state with high TAT and active fibrinolysis mirrored by enhanced tPA and D-dimer levels.73

Cardiac Biomarkers

Increased concentrations of N-terminal pro B-type natriuretic peptide (NTproBNP), a marker of cardiac failure and myocardial ischaemia, have been reported in subjects with LEAD and, together with copeptin, were associated with the incidence of LEAD during long-term follow-up. 88,89 In the ARIC prospective cohort study, NT-proBNP and high-sensitivity troponin T (hsTnT), a marker of acute MI, were found to be predictive of incident LEAD.90 Moreover, high NT-proBNP and hsTnT independently predicted increased all-cause mortality in LEAD.43 In addition, hsTnT, but not carotid intima–media thickness or ABI, was predictive of reduced survival rate in a prospective LEAD cohort.91 Conversely, NT-proBNP was found to independently predict all-cause mortality after a 5-year follow-up in symptomatic LEAD patients,92 consistent with what has previously been demonstrated in heart failure.93

Markers of Lipid Metabolism

Oxidised LDL (oxLDL) possesses proatherogenic properties and, compared with healthy controls, levels of total cholesterol, LDL, oxLDL and oxLDL antibodies were higher in subjects with LEAD.94 In addition, oxLDL levels were positively correlated with total cholesterol and LDL.

Lipoprotein(a)

Lipoprotein(a), or Lp(a), is an LDL-like particle bound to an apolipoprotein B100 protein. Epidemiological studies and Mendelian randomisation (MR) analyses have demonstrated the association between Lp(a) and atherosclerotic CVD. Lp(a) concentrations and a single nucleotide polymorphism in its encoding gene LPA were also associated with LEAD, indicating causality between Lp(a) and LEAD.95 Circulating Lp(a) was an independent predictor of LEAD.96,97 In addition, Lp(a) concentrations were positively correlated with disease severity, total cholesterol, LDL and apolipoprotein B.96

Lipoprotein-Associated Phospholipase A2

Lipoprotein-associated phospholipase A2 (Lp-PLA2) contributes to oxLDL modification, one of the earliest steps in the atherosclerosis process. LpPLA2 binds to LDL particles in the circulation and is expressed by macrophages in atherosclerotic lesions. Lp-PLA2 activity and mass were, either alone or together with CRP, predictors of LEAD risk in two population-based cohorts of middle-aged or elderly individuals.98,99 These results were reproduced in a prospective cohort study analysing the risk of future LEAD-related hospitalisation associated with high Lp-PLA2 levels

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Circulating Biomarkers in Lower Extremity PAD in subjects free of LEAD at baseline.100 In a hospital-based Chinese crosssectional study, Lp-PLA2 concentrations were associated with the prevalence of LEAD independent of inflammatory markers such as hsCRP, Hcy and fibrinogen.101 Conversely, in a population-based US multi-ethnic cohort study of 45–84 year olds, Lp-PLA2 activity and mass were not associated with an increased risk of incident LEAD.102 Thus, results are conflicting regarding Lp-PLA2 as a predictor of LEAD.

symptomatic LEAD, VGEF-A increased after home-based or supervised exercise.113,114

Adiponectin

In LEAD patients, circulating angiopoietin-2 and the soluble Tie2 receptor were increased compared with healthy controls.111 Moreover, no difference was seen in plasma angiopoietin-2 concentrations between IC and CLTI patients, whereas concentrations of the soluble Tie2 receptor were higher in CLTI than IC patients.111 In a prospective cohort of symptomatic LEAD, increased angiopoietin-2 was found to be independently associated with an enhanced risk of major adverse CVE and all-cause mortality.115

Adiponectin is an adipokine active in glucose and fatty acid metabolism that enhances insulin sensitivity and has anti-inflammatory and antioxidative properties. Lower adiponectin concentrations have been reported in men than in women, although adiponectin concentrations are lower in women with than without metabolic syndrome.103 These sex differences in anti-inflammatory adiponectin may contribute, in part, to higher CVD risk in men and women with metabolic syndrome. In relation to LEAD, adiponectin concentrations were lower in women who developed LEAD than in those that did not.104 In line with this finding in women, high adiponectin concentrations were associated with a decreased risk of developing symptomatic LEAD in men.105 Moreover, in men with symptomatic LEAD, but not in their female counterparts, low adiponectin concentrations were associated with a higher risk of non-fatal CVE.106

Angiopoietin-2 and the Tie2 Receptor Together with VGEF-A, angiopoietin-2 stimulates neovascularisation. The cognate angiopoietin-2 receptor is the Tie2 receptor expressed mainly on the vascular endothelium.

Overarching Inflammatory, Coagulation and Metabolic Pathway Biomarkers Extracellular Vesicles

Matrix metalloproteinases (MMPs) are proteases with the ability to degrade extracellular matrix. MMPs are secreted by inflammatory cells and are active in vascular remodelling during the development and progression of atherosclerosis, including plaque rupture. MMP2 and MMP9 are also involved in the activation and regulation of platelet aggregation. In LEAD, concentrations of MMP2 and MMP9, and to some extent MMP3, were increased compared with healthy controls, and the progression and severity of LEAD have been associated with high concentrations of MMP2 and MMP9. 17,22,23,107

Circulating extracellular vesicles (EVs), including exosomes, microparticles and apoptotic bodies, are secreted by different types of cells upon stimulation, and carry nucleic acids, proteins, lipids and metabolites from the host cell, thereby mediating vascular homeostasis and intercellular communication. The concentrations and types of circulating EVs in the blood and the effects mediated by EVs differ depending on the stimulus causing their secretion. In LEAD, platelet-derived EVs are by far the most common type, followed by EVs from endothelial cells, erythrocytes and leucocytes.116 Case-control studies have demonstrated higher levels of platelet-derived EVs in individuals with LEAD than in healthy controls, although one study did not show any difference between the groups.116–118 In addition, levels of platelet-derived EVs were correlated with LEAD severity.119 Circulating levels of endothelial cell-derived EVs, especially when containing proinflammatory monomeric CRP, were higher in LEAD.120

Galectin-3: Marker of Fibrosis and Calcification

Circulating MicroRNAs

Tissue Remodelling and Angiogenesis Markers Matrix Metalloproteinases

Galectin-3 is induced by oxidative stress and is involved in inflammation, angiogenesis and fibrosis via mediation of cell–cell and cell–matrix interactions. Galectin-3 is also involved in macrophage maturation and has been associated with atherosclerotic CVD and LEAD.108 Levels of galectin-3 predicted incident LEAD and were higher in subjects with pathological ABI than in individuals without LEAD.36,109 Moreover, in LEAD patients, high galactin-3 concentrations were associated with an increased risk of cardiovascular mortality.108

Markers of Angiogenesis

Because angiogenesis is a physiological response to tissue ischaemia, circulating angiogenic factors may be relevant surrogates for disease severity via the increased production of angiogenic mitogens such as vascular endothelial growth factor (VEGF)-A and angiopoietin-2.

Vascular Endothelial Growth Factor-A Increased circulating VGEF-A concentrations mirror pronounced angiogenesis. VGEF-A concentrations were higher in LEAD patients than in non-LEAD controls, and concentrations increased with the severity of the disease.110–112 Contrary to these findings, VEGF-A concentrations were lower in LEAD cases in a case-control study using controls with other cardiovascular risk factors and comorbidities other than LEAD.49 This finding highlights the difficulties with biomarkers mirroring processes active in systemic diseases. In relation to exercise-dependent changes in

MicroRNAs (miRNAs) are small, non-coding and single-stranded RNAs originating from EVs.121 MiRNAs are able to control gene expression at the post-transcriptional level, thereby inhibiting protein synthesis. MiRNAs are highly stable and expressed in a disease-specific manner, and therefore suitable as diagnostic biomarkers for CVD.122 A small case-control study performing transcriptomics on peripheral blood cells identified a group of miRNAs (miR-16, miR-363 and miR-15b) that had previously been associated with vascular pathophysiology as predictors of LEAD with outstanding diagnostic accuracy.123 In a larger case-control study, circulating (serum) concentrations of miRNAs (miR-130a, miR-27b, miR210) were associated with LEAD.124 Moreover, in an all-male aortic aneurysm case-control study, four circulating miRNAs (let-7e, miR-15a, miR-196b and miR-411) were found to be associated both with aortic aneurysm and LEAD.125

Perspectives

Neither diagnostic nor prognostic circulating biomarkers for LEAD are used clinically today. When suspicion is raised, a diagnosis of LEAD with ABI is cheap and easy with a trained operator. In primary care, where sometimes both equipment and skills to measure ABI are lacking, circulating biomarkers would add value to screening for LEAD. Notwithstanding, disease-specific biomarkers predictive of incident LEAD are challenging to find because the organ-specific features of LEAD, primarily hypoperfusion with subsequent ischaemic tissue damage, are

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Circulating Biomarkers in Lower Extremity PAD not present until later stages of the disease. Conversely, biomarkers indicating general atherosclerosis could function as a first-line screening marker for LEAD accompanied by ABI when appropriate. Later in the course of the disease, and certainly in symptomatic patients, organspecific prognostic biomarkers may be of value together with imaging to stratify risk and evaluate the benefit of preventive medical treatment and/ or interventional procedures. In addition, the association between LEAD and increased cardiovascular risk defines an important role for assessment of LEAD in personalised medicine5. Today, preventive medication for patients with LEAD is limited to drugs targeting traditional cardiovascular risk factors. In the development of novel, specific therapeutic targets for patients with LEAD, biomarkers representing pathways discussed in this review may be used to identify individuals suitable for treatment and to monitor the treatment effects of pharmacotherapies.

The traditional deductive approach in biomarker research has been challenged in recent years by inductive strategies using unbiased, largescale, high-throughput plasma proteomic profiling. Such analyses demand large cohorts with enough statistical power to demonstrate associations and extensive bioinformatics to process large amounts of data. Conversely, new mechanisms and possible molecular targets can be discovered in corners previously not scrutinised.

Recent developments also highlight the future need for LEAD biomarkers.

Using MR analysis and randomised controlled trials, the causal association between procoagulant factors and LEAD has been strengthened, and followed by the introduction of low-dose anticoagulant drugs in addition to antiplatelet therapy.126,75,76,2 However, biomarkers guiding the selection of patients for treatment and monitoring treatment effects are still lacking.

The association between LEAD and inflammatory markers from the IL-1β/ IL-6/CRP pathway displays consistent results in epidemiological studies 1.

2.

3.

4.

5.

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8.

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Frank U, Nikol S, Belch J, et al. ESVM guideline on peripheral arterial disease. Vasa 2019;48(Suppl 102):1–79. https://doi.org/10.1024/0301-1526/a000834; PMID: 31789115.

Fowkes FGR, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013;382:1329–40. https://doi.org/10.1016/ S0140-6736(13)61249-0; PMID: 23915883.

McDermott MM, Greenland P, Liu K, et al. Leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment. JAMA 2001;286:1599–606. https://doi.org/10.1001/ jama.286.13.1599; PMID: 11585483.

Subherwal S, Patel MR, Kober L, et al. Peripheral artery disease is a coronary heart disease risk equivalent among both men and women: results from a nationwide study. Eur J Prev Cardiol 2015;22:317–25. https://doi. org/10.1177/2047487313519344; PMID: 24398369.

Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992;326:381–6. https://doi. org/10.1056/NEJM199202063260605; PMID: 1729621.

Sigvant B, Lundin F, Wahlberg E. The risk of disease progression in peripheral arterial disease is higher than expected: a meta-analysis of mortality and disease progression in peripheral arterial disease. Eur J Vasc Endovasc Surg 2016;51:395–403. https://doi.org/10.1016/j. ejvs.2015.10.022; PMID: 26777541.

Norgren L, Hiatt WR, Dormandy JA, et al. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg 2007;45(Suppl S):S5–67. https://doi.org/10.1016/j.jvs.2006.12.037; PMID: 17223489.

Duff S, Mafilios MS, Bhounsule P, Hasegawa JT. The burden of critical limb ischemia: a review of recent literature. Vasc Health Risk Manag 2019;15:187–208. https://doi.org/10.2147/ VHRM.S209241; PMID: 31308682.

and, in a recent randomised controlled trial, inhibition of the IL-1β/IL-6/ CRP pathway with canakinumab dampened LEAD progression.127 In addition, positive associations between Lp(a) and LEAD in cohort and case-control studies, together with a demonstrated causal association between apolipoprotein B and LEAD in MR analyses, point to lipids as potential causal targets.128 With this is mind, the need for biomarkers in selecting patients for targeted treatment and the identification of individuals at risk of future hospitalisation for LEAD is pivotal. In such a setting, Lp-PLA2 holds great promise.100

Conclusion

The pathophysiology underpinning LEAD is multifactorial and, together with the effective diagnostic and predictive tools already at hand, will likely require a multiple-biomarker approach to provide incremental predictive value. Moreover, the impact of each causal pathway differs in individual patients, demanding biomarkers to evaluate the magnitude of the respective pathway in risk stratification assessments and to guide clinicians in which patients to treat and how to treat them. Many of the biomarkers presented in this review are associated with several inflammatory and/or atherosclerosis-related conditions, complicating interpretation. In this setting, the relatively new field of disease-specific circulating miRNAs as diagnostic and prognostic biomarkers is promising as analyses become cheaper and easier to use.122 Due to the late onset of symptoms and lack of diagnostic circulating biomarkers, LEAD patients are often diagnosed in late stages of the disease and, when diagnosed, biomarkers to guide the selection of patients for treatment and the monitoring of treatment effects are missing.

However, the field is expanding, with many promising biomarkers continuously being investigated, together with potential targets for pharmacological treatment.

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REVIEW

Atrial Fibrillation

Cryoablation or Drug Therapy for Initial Treatment of Atrial Fibrillation Jason G Andrade ,1,2,3 Ricky D Turgeon ,1 Laurent Macle

3

and Marc W Deyell

1,2

1. University of British Columbia, Canada; 2. Center for Cardiovascular Innovation, Vancouver, Canada; 3. Montreal Heart Institute, Université de Montréal, Canada

Abstract

AF is a common chronic and progressive disorder. Without treatment, AF will recur in up to 75% of patients within a year of their index diagnosis.

Antiarrhythmic drugs (AADs) have been proven to be more effective than placebo at maintaining sinus rhythm and remain the recommended initial therapeutic option for AF. However, the emergence of ‘single-shot’ AF ablation toolsets, which have enabled enhanced procedural standardisation and consistent outcomes with low rates of complications, has led to renewed interest in determining whether first-line catheter ablation may improve outcomes. The recently published EARLY-AF trial evaluated the role of initial cryoballoon ablation versus guideline-directed AAD therapy. Compared to AADs, an initial treatment cryoballoon ablation strategy resulted in greater freedom from atrial tachyarrhythmia, superior reduction in AF burden, greater improvement in quality of life and lower healthcare resource utilisation. These findings are relevant to patients, providers and healthcare systems when considering the initial treatment choice for rhythm-control therapy.

Keywords

Guidelines, AF, antiarrhythmic drug therapy, cryoballoon ablation, arrhythmias Disclosure: JGA reports grants and personal fees from Medtronic, grants from Baylis and personal fees from Biosense Webster. MWD reports grants and personal fees from Biosense Webster and personal fees from Medtronic, Abbott and Boston Scientific. LM reports grants and personal fees from Biosense Webster, Abbott, Medtronic, Servier and BMS-Pfizer. RDT has no conflicts of interest to declare.

Funding: This work was not funded. The EARLY-AF trial was funded by a peer-reviewed grant from the Cardiac Arrhythmia Network of Canada (grant number SRG15-P15-001), with additional unrestricted support from Medtronic and Baylis Medical.

Acknowledgments: The authors thank the patients who participated in the trials, as well as the study sites and coordinators.

Received: 26 July 2021 Accepted: 27 October 2021 Citation: European Cardiology Review 2022;17:e10. DOI: https://doi.org/10.15420/ecr.2021.38 Correspondence: Jason Andrade, Gordon and Leslie Diamond Health Care Centre, 9th Floor, 2775 Laurel St, Vancouver, BC, V5Z 1M9, Canada. E: jason.andrade@vch.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 non-commercial purposes, provided the original work is cited correctly.

AF is the most common sustained arrhythmia encountered in clinical practice. It is a chronic and progressive disorder initially characterised by exacerbations and remissions leading to reductions in quality of life (QOL) with AF comparable to that observed in patients with chronic heart failure or receiving chronic haemodialysis. Furthermore, AF is associated with an increased risk of stroke and heart failure, leading to reduced overall survival.1–3 The contemporary goals of AF management are improving arrhythmia-related symptoms and QOL, as well as reducing the morbidity and healthcare utilisation associated with AF.4

shown to be superior to AAD therapy when AADs have been ineffective, or are contraindicated or poorly tolerated.10

Without treatment, AF will recur in up to 75% of patients within a year of their index episode.5–7 Antiarrhythmic drugs (AADs) have been proven to be more effective than placebo for the maintenance of sinus rhythm.

However, they have only modest efficacy at maintaining sinus rhythm and are associated with significant cardiac adverse effects (e.g. bradydysrhythmia, negative inotropy and pro-arrhythmia) and noncardiac adverse effects (e.g. end-organ toxicity), including increased mortality with the long-term use of amiodarone and sotalol (OR 2.73; 95% CI [1.00–7.41]; p=0.049 and OR 4.32; 95% CI [1.59–11.70]; p=0.013, respectively).8,9

AF Ablation as a First-line Therapy

Over the past 20 years, catheter ablation, which is centred on the electrical isolation of triggering foci within the pulmonary veins, has been

While it has been postulated that early intervention may provide significant benefits, i.e. catheter ablation as an initial therapy prior to AADs, we cannot extrapolate the evidence supporting the role of catheter ablation as a second-line therapy as these trials were performed in patients who had already failed pharmacotherapy, thus weighting the benefit towards catheter ablation.

Studies have attempted to answer whether a population may exist whereby the effectiveness of a catheter ablation procedure would be sufficiently high, and the risks sufficiently low, that it would be appropriate to offer ablation as an initial therapy. Prior trials of first-line radiofrequency (RF) catheter ablation have been primarily limited by their relatively small sample size, high rates of cross-over from AADs to ablation and the use of intermittent non-invasive rhythm monitoring, which has limited the ability to detect a difference between treatment groups.11–13 In aggregate, the three randomised studies of first-line RF ablation reported a relatively low absolute success rates (46–53% freedom from atrial tachyarrhythmia in the ablation arm versus 28–44% in the AAD arm), and consequently low relative benefit with first-line RF ablation (RR 0.81 for any arrhythmia; 95%

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Cryoballoon Ablation as the Initial AF Treatment Figure 1: Recurrence of Any Atrial Tachyarrhythmia, Stratified by Ablation Energy Ablation Study or subgroup

Events

AAD

Total

Events

Risk Ratio

Risk Ratio

M-H, Random [95% CI]

M-H, Random [95% CI]

Total

Weight

0.50 [0.29–0.86] 0.63 [0.51–0.78] 0.57 [0.36–0.91] 0.61 [0.51–0.73]

6.1.1 Cryoablation Cryo-FIRST EARLY-AF STOP-AF First Subtotal [95% CI]

16 66

107 154

33 101

111 149

21

104 365

35

99 359

8.3% 29.8% 10.4% 48.5%

148 61

28.5% 23.0%

0.84 [0.67–1.05] 0.76 [0.58–0.99]

209

51.5%

0.81 [0.68–0.96]

568

100.0%

0.69 [0.59–0.82]

103 169 Total events Heterogeneity: τ2=0.00; χ2=0.72; d.f.=2 (p=0.70); I2=0% Test for overall effect: Z=5.38 (p<0.00001) 6.1.2 Radiofrequency ablation MANTRA-PAF RAAFT-2 Subtotal [95% CI]

69 36

146 66

83 44

212

105 127 Total events Heterogeneity: τ2=0.00; χ2=0.37, d.f.=1 (p=0.54); I2=0% Test for overall effect: Z=2.45 (p=0.01) Total [95% CI]

577

208 296 Total events Heterogeneity: τ2=0.01; χ2=6.19; d.f.=4 (p=0.19); I2=35% Test for overall effect: Z=4.31 (p<0.0001) Test for subgroup differences: χ2=4.99; d.f.=1 (p=0.03); I2=80.0%

0.2

0.5 Favours ablation

1

2

5

Favours AAD

AAD = antiarrhythmic drug; M-H = Mantel-Haenszel. Source: Andrade et al. 2021.14 Reproduced with permission from Elsevier.

CI [0.68–0.96]; p=0.01; Figure 1, and RR 0.62 for symptomatic arrhythmia; 95% CI [0.38–1.01]; p=0.06; Figure 2).14

Guideline Recommendations

Given the relatively low success rate, the lack of procedural standardisation, and the inconsistent procedural endpoints, the major North American and European guidelines provide only a conditional recommendation for catheter ablation as first-line therapy.15–17 Specifically, reserving it for rare individual circumstances, or highly-selected patients with symptomatic paroxysmal (Class IIA in European Society of Cardiology [ESC] and American Heart Association [AHA]/American College of Cardiology [ACC]/Heart Rhythm Society [HRS] guidelines) or persistent AF (Class IIB in ESC and AHA/ACC/HRS guidelines, with the ESC suggesting that first-line ablation be restricted to those without major risk factors for AF recurrence).15,16 Likewise, the Canadian Cardiovascular Society (CCS) guidelines provide a weak recommendation for first-line catheter ablation in select patients with symptomatic AF. However, in contrast to the ESC and ACC/AHA/HRS, the CCS makes no distinction between those with paroxysmal or persistent AF.17

The Early Aggressive Invasive Intervention for AF Trial: EARLY-AF Design

The emergence of single-shot AF ablation toolsets has led to renewed interest in determining whether first-line catheter ablation may improve outcomes. In contrast to point-by-point RF ablation, single-shot AF ablation toolsets has enabled enhanced procedural standardisation, ensuring consistent outcomes with low rates of complications.

Despite varying operator skillsets, cryoballoon ablation has been shown to be associated with a high acute procedural success and long-term freedom from recurrent AF, with low rates of serious complications.18,19 This balance of generalisability, safety and efficacy suggests that cryoballoon ablation may be a preferred toolset for initial (e.g. first-line) ablation.

The EARLY-AF trial sought to evaluate the role of initial cryoballoon ablation versus initial AAD therapy as the first treatment of AF in AAD-naïve patients.20 The study was a multicentre parallel-group, single-blinded randomised clinical trial, with blinded end-point ascertainment conducted at 18 clinical centres in Canada. The trial enrolled 303 patients, randomising 154 to undergo initial cryoballoon ablation and 149 to receive initial AAD therapy.9 Patients enrolled in the study were relatively young and free of significant comorbidities. At baseline, the mean age was 58.6 years, 29.4% were female, 37% had hypertension, 9% had heart failure and 3% had previous stroke or transient ischaemic attack. Enrolled patients had been diagnosed with AF a median of 1 year prior to enrolment. Patients were highly symptomatic (mean AF effect on quality of life [AFEQT] score of 59.4) and were experiencing a median of three symptomatic AF episodes per month (interquartile range [IQR] 1–10).

Patients randomised to cryoballoon ablation underwent circumferential pulmonary vein isolation using a second-generation cryoballoon, with the procedure endpoint of bidirectional conduction block. Complete pulmonary vein isolation was confirmed in all patients, with a median left atrial time of 74 minutes (IQR 56–94) and procedure duration of 106 minutes (IQR 89– 131), including a mandatory 20-minute observation period.

Patients randomised to AAD therapy had their AADs aggressively optimised using standardised titration protocols.9,20 Class IC sodium-channel blockers were the most frequently prescribed agents, with the most frequently prescribed AAD being flecainide (used in 83.2% of patients) at a median daily dose of 200 mg (IQR 125–250). Multiple AAD trials were required in 46 patients (30.9%). All patients in the AAD group exited the 90-day treatment optimisation period on a therapeutic dose of AAD.

Primary and Secondary Outcomes

All patients in the EARLY-AF trial received an implantable cardiac monitor for continuous rhythm monitoring, with all arrhythmia events undergoing

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Cryoballoon Ablation as the Initial AF Treatment Figure 2: Recurrence of Symptomatic Atrial Tachyarrhythmia, Stratified by Ablation Energy Study or subgroup

Ablation Events Total

AAD Events Total

Weight

Risk Ratio M-H, Random [95% CI]

Risk Ratio Random [95% CI]

6.2.1 Cryoablation Cryo-FIRST EARLY-AF STOP-AF First Subtotal [95% CI]

0 17

107 154

0 39

111 149

24.4%

0

104 365

0

99 359

24.4%

Not estimable 0.42 [0.25–0.71] Not estimable 0.42 [0.25–0.71]

148 37

31.4% 13.6%

0.76 [0.56–1.04] 0.20 [0.08–0.53]

17

39

Total events Heterogeneity: Not applicable Test for overall effect: Z=3.23 (p=0.001) 6.2.2 Radiofrequency ablation MANTRA-PAF RAAFT

46 4

146 33

61 22

RAAFT-2

31

66

36

61

30.6%

0.80 [0.57–1.11]

Subtotal [95% CI] 245 Total events 81 119 Heterogeneity: τ2=0.13; χ2=7.58; d.f.=2 (p=0.02); I2=74% Test for overall effect: Z=1.91 (p=0.06)

246

75.6%

0.62 [0.38–1.01]

Total [95% CI]

605

100.0%

0.56 [0.36–0.87]

610

98 158 Total events Heterogeneity: τ2=0.14; χ2=11.44; d.f.=3 (p=0.010); I2=74% Test for overall effect: z=2.57 (p=0.01) Test for subgroup differences: χ2=1.08; d.f.=1 (p=0.30); I2=7.1%

0.2

0.5 Favours ablation

1

2

5

Favours AAD

AAD = antiarrhythmic drug; M-H = Mantel-Haenszel. Source: Andrade et al. 2021.14 Reproduced with permission from Elsevier.

independent adjudication by a committee blinded to treatment allocation.

The primary outcome was the first recurrence of any atrial tachyarrhythmia, defined as AF, atrial flutter or atrial tachycardia lasting ≥30 seconds between 91 and 365 days after treatment initiation (i.e. catheter ablation or AAD initiation).

Secondary outcomes including the first recurrence of symptomatic atrial tachyarrhythmia between 91 and 365 days, AF burden, disease-specific and generic QOL, healthcare utilisation (cardioversion, emergency department visit, and hospitalisation, alone and in aggregate) and adverse events. Serious adverse events were defined as those causing death or functional disability, warranting intervention, or resulting in or prolonging hospitalisation for more than 24 hours.

Rhythm Outcomes

Documented recurrence of any atrial tachyarrhythmia occurred in 42.9% of patients randomised to cryoballoon ablation and 67.8% of patients randomised to AADs within 1 year following treatment initiation (HR 0.48; 95% CI [0.35–0.66]; p<0.001; Figure 3A).9 Symptomatic atrial tachyarrhythmias occurred in 11.0% of patients randomised to ablation, and 26.2% of patients randomised to AADs at 1 year (HR 0.39; 95% CI [0.22–0.68]; Figure 3B). These results correspond to a number needed to treat (NNT) of four to prevent one asymptomatic atrial tachyarrhythmia recurrence and an NNT of seven to prevent one symptomatic atrial tachyarrhythmia recurrence.

The absolute difference in mean AF burden between patients randomised to ablation and patients randomised to AADs was 3.3% ± 1.0% (Figure 4).

This difference corresponded to the equivalent of 1 day less of AF per month for patients randomised to ablation.

Quality of Life Outcomes

The change in disease-specific and generic QOL scores at 1 year was significantly improved in both groups. For the disease-specific AFEQT questionnaire, those randomised to ablation attained a 26.9 ± 1.9 points improvement from baseline at 1 year, with those randomised to AADs achieving a 22.9 ± 2.0 points improvement from baseline (Table 1). For the generic European Quality of Life-5 Dimensions (EQ-5D) survey, the improvement in QOL score was 0.12 ± 0.02 and 0.06 ± 0.02 for the ablation and antiarrhythmic groups, respectively. At 1 year the mean treatment effect (the difference between randomised groups) was 8.0 ± 2.2 points in favour of ablation for the AFEQT score and 0.07 ± 0.03 points for the EQ-5D score.

These between-group differences exceeded the minimally clinically relevant difference (e.g. 5 points on AFEQT score and 0.03 points on EQ-5D score).21

Healthcare Utilisation

While the overall outcome of healthcare utilisation was not significantly different between randomised groups, the first-line ablation group had a numerical reduction in the individual healthcare utilisation events (cardioversion, emergency department visits and hospitalisation; Table 1).

Safety Outcomes

Serious adverse events occurred in 3.2% of patients randomised to ablation (three self-limited phrenic nerve palsies and two pacemaker implantations for bradydysrhythmia) and 4.0% of patients randomised to AADs (three wide-complex dysrhythmias, two pacemaker implantations for bradydysrhythmia and one heart failure exacerbation), with no significant difference between groups (Table 1). Any safety endpoint was observed in 9.1% of patients randomised to ablation and 16.1% of patients randomised to AADs, with no significant difference between groups.

Implications

The design of the EARLY-AF trial included several unique features in an effort to address the limitations of the previous first-line ablation studies.

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Cryoballoon Ablation as the Initial AF Treatment Figure 3: Freedom from Atrial Tachyarrhythmia in the EARLY-AF Trial A. Any atrial tachyarrhythmia recurrence on continuous cardiac monitoring + censored

1.0

Ablation

0.8

Ablation

0.6

Antiarrhythmic 0.6 0.4

0.4

0

+ censored

1.0

0.8

0.2

B. Symptomatic atrial tachyarrhythmia recurrence

Antiarrhythmic Absolute reduction 24.9%; NNT 4 HR 0.48; (95% CI [0.35–0.66]); p<0.001 0

2

4

6

8

10

12

0.2 0

Absolute reduction 15.2%; NNT 6–7 HR 0.39; (95% CI [0.22–0.68]); p<0.001 0

2

Follow-up time (months)

4

6

8

10

12

Follow-up time (months)

A: Freedom from any atrial tachyarrhythmia; B: freedom from symptomatic atrial tachyarrhythmia. NNT = number needed to treat.

Table 1. Primary and Secondary Outcomes in the EARLY-AF Study Endpoint

Ablation Group (n=154)

Antiarrhythmic Group (n=149)

Treatment Effect (95% CI)

Recurrence of any atrial tachyarrhythmia

66 (42.9)

101 (67.8)

0.48 (0.35–0.66)*

AF burden Median (IQR) Mean

0 (0–0.08) 0.6 ± 3.3

0.13 (0–1.60) 3.9 ± 12.4

-3.3 ± 1.0†

Symptoms Documented recurrence of symptomatic arrhythmia Asymptomatic at 6 months Asymptomatic at 12 months

17 (11.0) 129 (83.8) 131 (85.1)

39 (26.2) 90 (60.4) 109 (73.2)

0.39 (0.22–0.68)* 1.34 (1.17–1.55) 1.17 (1.05–1.30)

Quality of life Change from baseline EQ-5D score at 6 months Change from baseline EQ-5D score at 12 months Change from baseline AFEQT score at 6 months Change from baseline AFEQT score at 12 months

0.08 ± 0.02 0.12 ± 0.02 24.4 ± 1.6 26.9 ± 1.9

0.07 ± 0.02 0.06 ± 0.02 17.9 ± 1.6 22.9 ± 2.0

0.03 ± 0.03‡ 0.07 ± 0.03‡ 10.5 ± 2.2‡ 8.0 ± 2.2‡

Healthcare utilisation Cardioversion Emergency department visit Hospitalisation >24 hours

30 (19.5) 10 28 5

36 (24.2) 14 30 13

0.81 (0.53–1.24)§ 0.69 (0.32–1.51)§ 0.90 (0.57–1.43)§ 0.37 (0.14–1.02)§

Safety Any serious adverse event related to trial regimen Any safety endpoint

5 (3.2) 14 (9.1)

6 (4.0) 24 (16.1)

0.81 (0.25–2.59)§ 0.59 (0.29–1.21)§

Data with ± values are mean ± SE, except for AF burden, which is mean ± SD. Data in the second and third columns are observed data, and data in column four are model-based effect estimates. *The treatment effect is expressed as the HR and 95% CI, which were calculated using Cox regression. †The between-group absolute difference in AF burden, expressed as the beta coefficient ±SE, was calculated using linear regression analysis. ‡Changes in quality of life scores at 6 months and 12 months from baseline are expressed as least-squares means ± SE and were analysed using a linear mixed-effects model for repeated measures, including group, visit, and interaction between group and visit. §The treatment effect is expressed as the RR and 95% CI. AFEQT = AF effect on quality of life; EQ-5D = European quality of life-5 dimensions; IQR = interquartile range.

Specifically, while intermittent non-invasive rhythm monitoring is the most widely used method of ascertaining arrhythmia recurrence, it lacks sensitivity in detecting sporadic arrhythmias (e.g. paroxysmal AF), which leads to under-detection of recurrences. This under-detection leads to inflated estimates of treatment success and introduces misclassification errors that impact the accuracy and precision of comparative risk estimates. Instead, the EARLY-AF trial relied on implantable loop recorders, which facilitated precise determination of the presence and timing of arrhythmia recurrence, as well as accurately quantified enumerable outcomes such as arrhythmia burden. Second, in an effort to ensure that the treatment comparison was robust, the dose of AADs in the pharmacotherapy group was aggressively up-titrated using standardised protocols over a 3-month treatment optimisation period with a goal of complete suppression of AF on loop recorder monitoring.20 Third, the trial

employed pre-specified protocols, including the establishment of an independent committee, in order to ensure that no patient crossed over between randomised groups prior to the occurrence of a primary endpoint event.

Results in Context

The EAST-AFNET 4 trial recently tested an early rhythm-control strategy in patients with newly-diagnosed AF (enrolled median 36 days after AF diagnosis). This trial predominantly employed pharmacological rhythm control, demonstrating that early rhythm control significantly reduced the composite primary outcome of cardiovascular death, stroke, and hospitalisation for worsening heart failure and acute coronary syndrome by 21% (from 5.0% per year to 3.9% per year) but increased serious adverse events related to AAD therapy (4.9% versus 1.4% in the usual care

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Cryoballoon Ablation as the Initial AF Treatment

Instead, the EARLY-AF trial focuses on the question of ‘how’ rhythm control can be effectively achieved in highly symptomatic patients with treatmentnaïve AF. While the majority of patients enrolled in the EAST-AFNET 4 trial were treated with AAD therapy (only 8.0% and 19.4% undergoing AF ablation at baseline and 2 years of follow-up), the EARLY-AF trial demonstrated that an initial cryoballoon ablation approach was superior to AADs for the outcomes of atrial tachyarrhythmia recurrence, arrhythmia burden and QOL. These findings are relevant to patients, providers, and healthcare systems when considering the initial treatment choice for rhythm-control therapy.

In addition to EARLY-AF, two other multicentre randomised trials have compared initial cryoballoon ablation to AADs in patients with symptomatic, treatment-naïve paroxysmal AF: the Cryo-FIRST trial and the STOP-AF First trial.23,24 In total these three randomised trials included 724 patients in their intention-to-treat or modified intention-to-treat populations.9,23,24 In pooled analysis, initial cryoballoon ablation significantly reduced the recurrence of atrial tachyarrhythmia when compared with first-line AAD therapy (risk ratio 0.61; 95% CI [0.51–0.73]), with a NNT of seven (weighted absolute risk reduction of 19%; Figure 3B).14 In addition, patients treated with initial cryoballoon ablation were significantly more likely to be free of symptoms at 12 months of follow-up (80% versus 68%, risk ratio 1.16; 95% CI [1.05–1.28]). While both treatment groups improved from baseline, initial cryoballoon ablation was associated with a significantly greater improvement in QOL (mean between-group difference of 8.46-point in the disease-specific AFEQT; 95% CI [5.86–11.06]). While no study was individually powered for healthcare utilisation endpoints, pooled analysis demonstrates that significantly fewer patients randomised to first-line cryoballoon ablation experienced the composite healthcare utilisation outcome (risk ratio 0.71; 95% CI [0.56–0.90]), with a NNT of 12 to prevent one healthcare utilisation endpoint (weighted absolute risk reduction of 9%). This was driven by a significant reduction in all-cause hospitalisation (risk ratio 0.38; 95% CI [0.23–0.63]; weighted absolute risk reduction of 12%), with non-significant reductions in emergency department visits (risk ratio 0.78; 95% CI [0.50–1.20]) and cardioversions (risk ratio 0.60; 95% CI [0.31–1.18]). Despite the invasive nature of an AF ablation procedure, the risk of serious treatment-related adverse events was comparable between initial cryoballoon catheter ablation and initial AAD therapy (risk ratio 0.74; 95% CI [0.35–1.56]), with ablation having a lower risk of any adverse event (risk ratio 0.70; 95% CI [0.54–0.89]).

Unanswered Questions and Extrapolation of Results

Despite the wealth of data from these studies, several unanswered questions remain. Specifically, first if these results are generalisable to other ablation energy sources or to patients with more advanced forms of AF, and second if early ablation results in beneficial effects on progression to more persistent forms of AF. Regarding generalisability, recent randomised clinical trials have observed similar outcomes for patients with AAD-refractory AF treated with cryoballoon ablation and contact-force RF ablation.25 However, previous studies of first-line RF ablation failed to demonstrate a clinically meaningful difference in arrhythmia outcomes, QOL improvement, and healthcare utilisation.11–13 It is possible that the difference in results may be related to the greater heterogeneity in outcomes observed after RF ablation, where

Figure 4: AF Burden in Patients Treated with Firstline Ablation Versus First-line AAD Therapy AF burden by treatment group

5

4

AF burden (% time in AF)

group).22 Effectively, the EAST-AFNET 4 trial has provided convincing evidence of the benefits of aggressively pursuing sinus rhythm maintenance, answering the question of ‘why’ we might pursue rhythm control for patients with newly-diagnosed AF.

Ablation group had a 3.3% ± 1.0% lower mean AF burden (p=0.002)

3

2

1

0

First-line antiarrhythmic

First-line ablation

Mean AF burden is depicted as the diamond, with the difference represented by the dotted line.

AAD = antiarrhythmic drug.

annual procedure volume has been significantly associated with efficacy.26 Conversely, cryoballoon ablation outcomes have not been not significantly associated with operator and centre volume, suggesting that the ‘singleshot’ pulmonary vein isolation produced by cryoballoon allows a variety of operators to achieve more consistent and reproducible procedural outcomes. As such, in the absence of comparative trials, it may be reasonable to extrapolate the results of these first-line cryoballoon studies to RF ablation performed in high-volume centres, particularly when guided by standardised workflow (e.g. the CLOSE protocol). However further study is required to determine whether the results of first-line catheter ablation are comparable in lower volume RF ablation centres.

Moreover, the majority of patients enrolled in these studies were young, relatively healthy, and predominantly afflicted with paroxysmal AF. Strictly speaking, it is not known whether the results of these first-line ablation studies can be extrapolated to patients with more advanced (e.g. persistent) forms of AF. However, there is evidence to suggest that these results may be applicable in this population as comparable relative reductions in AF burden observed after ablation of both paroxysmal AF and persistent AF.27 Regarding the second question, it is postulated that intermittent AF episodes result in cumulative electrical and structural atrial remodelling, enabling the progression from paroxysmal to persistent forms of AF. To date, several observational studies have suggested that a shorter time interval between the AF diagnosis and catheter ablation is associated with improved outcomes.28,29 Recently the randomised ATTEST trial observed that ablation performed better than guideline-directed AAD therapy in delaying the progression from paroxysmal to persistent AF.30 Longer-term follow-up of the patients enrolled in the first-line cryoablation studies will provide further insight.

Conclusion

An initial treatment strategy of first-line cryoballoon ablation in patients with treatment-naïve AF was superior to AADs. Compared to AADs, an initial treatment strategy of cryoballoon catheter ablation resulted in greater freedom from atrial tachyarrhythmia recurrence, a superior reduction in AF burden, greater improvement in QOL, and significantly lower subsequent healthcare resource utilisation. These findings are relevant to inform patients, providers and health care systems regarding the choice of initial rhythm-control therapy in patients with treatmentnaïve AF.

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Cryoballoon Ablation as the Initial AF Treatment 1.

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Freemantle N, Lafuente-Lafuente C, Mitchell S, et al. Mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide, and propafenone, for the management of atrial fibrillation. Europace 2011;13:329–45. https://doi.org/10.1093/ europace/euq450; PMID: 21227948.

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Calkins H, Reynolds MR, Spector P, et al. Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: two systematic literature reviews and metaanalyses. Circ Arrhythm Electrophysiol 2009;2:349–61. https:// doi.org/10.1161/CIRCEP.108.824789; PMID: 19808490.

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14. Andrade JG, Wazni OM, Kuniss M, et al. Cryoballoon ablation as initial treatment for atrial fibrillation: JACC Stateof-the-Art Review. J Am Coll Cardiol 2021;78:914–30. https:// doi.org/10.1016/j.jacc.2021.06.038; PMID: 34446164.

15. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC). Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021;42:373–498. https://doi.org/10.1093/eurheartj/ehaa612; PMID: 32860505.

16. 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. J Am Coll Cardiol 2019;74:104–32. https://doi.org/10.1016/j.jacc.2019.01.011; PMID: 30703431.

17. Andrade JG, Aguilar M, Atzema C, et al. The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society comprehensive guidelines for the management of atrial fibrillation. Can J Cardiol 2020;36:1847–948. https://doi. org/10.1016/j.cjca.2020.09.001; PMID: 33191198.

18. Andrade JG, Khairy P, Guerra PG, et al. Efficacy and safety of cryoballoon ablation for atrial fibrillation: a systematic review of published studies. Heart Rhythm 2011;8:1444–51. https://doi.org/10.1016/j.hrthm.2011.03.050; PMID: 21457789.

19. Cardoso R, Mendirichaga R, Fernandes G, et al. Cryoballoon versus radiofrequency catheter ablation in atrial fibrillation: a meta-analysis. J Cardiovasc Electrophysiol 2016;27:1151–9. https://doi.org/10.1111/jce.13047; PMID: 27422848.

20. Andrade JG, Champagne J, Deyell MW, et al. A randomized clinical trial of early invasive intervention for atrial fibrillation (EARLY-AF) – methods and rationale. Am Heart J 2018;206:94–104. https://doi.org/10.1016/j.ahj.2018.05.020; PMID: 30342299.

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21. Holmes DN, Piccini JP, Allen LA, et al. Defining clinically important difference in the atrial fibrillation effect on qualityof-life score. Circ Cardiovasc Qual Outcomes 2019;12:e005358. https://doi.org/10.1161/CIRCOUTCOMES.118.005358; PMID: 31092022.

22. Kirchhof P, Camm AJ, Goette A, et al. Early rhythm-control therapy in patients with atrial fibrillation. N Engl J Med 2020;383:1305–16. https://doi.org/10.1056/NEJMoa2019422; PMID: 32865375.

23. Kuniss M, Pavlovic N, Velagic V, et al. Cryoballoon ablation vs. antiarrhythmic drugs: first-line therapy for patients with paroxysmal atrial fibrillation. Europace 2021;23:1033–41. https://doi.org/10.1093/europace/euab029; PMID: 33728429.

24. Wazni OM, Dandamudi G, Sood N, et al. Cryoballoon ablation as initial therapy for atrial fibrillation. N Engl J Med 2021;384:316–24. https://doi.org/10.1056/NEJMoa2029554; PMID: 33197158.

25. Andrade JG, Champagne J, Dubuc M, et al. Cryoballoon or radiofrequency ablation for atrial fibrillation assessed by continuous monitoring: a randomized clinical trial. Circulation 2019;140:1779–88. https://doi.org/10.1161/ CIRCULATIONAHA.119.042622; PMID: 31630538.

26. Providencia R, Defaye P, Lambiase PD, et al. Results from a multicentre comparison of cryoballoon vs. radiofrequency ablation for paroxysmal atrial fibrillation: is cryoablation more reproducible? Europace 2017;19:48–57. https://doi. org/10.1093/europace/euw080; PMID: 27267554.

27. Poole JE, Bahnson TD, Monahan KH, et al. Recurrence of atrial fibrillation after catheter ablation or antiarrhythmic drug therapy in the CABANA trial. J Am Coll Cardiol 2020;75:3105–18. https://doi.org/10.1016/j.jacc.2020.04.065; PMID: 32586583.

28. Hussein AA, Saliba WI, Barakat A, et al. Radiofrequency ablation of persistent atrial fibrillation: Diagnosis-to-ablation time, markers of pathways of atrial remodeling, and outcomes. Circ Arrhythm Electrophysiol 2016;9:e003669. https://doi.org/10.1161/CIRCEP.115.003669; PMID: 26763227.

29. Bunch TJ, May HT, Bair TL, et al. Increasing time between first diagnosis of atrial fibrillation and catheter ablation adversely affects long-term outcomes. Heart Rhythm 2013;10:1257–62. https://doi.org/10.1016/j.hrthm.2013.05.013; PMID: 23702238.

30. Kuck KH, Lebedev DS, Mikhaylov EN, et al. Catheter ablation or medical therapy to delay progression of atrial fibrillation: the randomized controlled atrial fibrillation progression trial (ATTEST). Europace 2021;23:362–9. https:// doi.org/10.1093/europace/euaa298; PMID: 33330909.

REVIEW

Anticoagulation

Role of Direct Oral Anticoagulants for Post-operative Venous Thromboembolism Prophylaxis Han Naung Tun ,1 May Thu Kyaw,2 Erik Rafflenbeul

3

and Xiuhtlaulli López Suástegui

4

1. Larner College of Medicine, University of Vermont, Burlington, VT, US; 2. Heart and Vascular Centre, Victoria Hospital, Yangon, Myanmar; 3. Department of Cardiology, Schoen Clinic Hamburg Eilbek, Hamburg, Germany; 4. Emergency Department, Intensive Care Unit Hospital Regional de Alta Especialidad de Zumpango, Instituto Mexicano del Seguro Social, Zumpango de Ocampo, Mexico

Abstract

Venous thromboembolism (VTE) is one of the leading causes of post-operative morbidity and mortality. Over previous decades, heparin and warfarin were the predominant therapeutic options for post-operative thromboprophylaxis. However, their use is limited by drawbacks including a narrow therapeutic range, numerous food and drug interactions, and the need for regular monitoring for dose adjustments. Recently, direct oral anticoagulants (DOACs), such as dabigatran etexilate (a direct thrombin inhibitor) and apixaban, rivaroxaban and edoxaban (direct factor Xa inhibitors), have been developed to overcome these issues. DOACs have shown promising results in Phase III clinical trials for post-operative VTE prophylaxis. This review summarises the pharmacological profile of DOACs and highlights the use of DOACs in post-operative VTE prophylaxis based on the available clinical trial data.

Keywords

Direct oral anticoagulants, venous thromboembolism, deep vein thrombosis, post-operative Disclosure: The authors have no conflicts of interest to declare.

Received: 23 November 2021 Accepted: 28 January 2022 Citation: European Cardiology Review 2022;17:e11. DOI: https://doi.org/10.15420/ecr.2021.55 Correspondence: Xiuhtlaulli López Suástegui, Calle Capulines Mz 78 Lt 48, Jardines Ojo de Agua, Tecamac Estado de México, CP 55770, Mexico.

E: xiuhtlaulli@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 non-commercial purposes, provided the original work is cited correctly.

Venous thromboembolism (VTE) encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE). Patients undergoing major surgery (especially major orthopaedic surgery) are prone to VTE, both symptomatic and asymptomatic, by activating all three components of Virchow’s triad (endothelial injury, stasis and hypercoagulability). The position of the limb during surgery, tourniquet use and prolonged post-operative immobilisation lead to venous stasis. Elevated pro-thrombotic factors, such as interleukin-6, C-reactive protein and tumour necrosis factor-α, induced by tissue injury, trigger tissue factor release and thrombin expression, platelet activation and initiate the coagulation cascade.1–3 Haemorrhage during surgery reduces antithrombin III levels and thus an imbalance between coagulation–fibrinolytic systems, exacerbating hypercoagulability.

There are several risk prediction scores for VTE after major surgery.4 The incidence of DVT in clinical medicine and general surgery is 10–40%, compared to 40–60% in major orthopaedic surgery. In 2008, the American College of Chest Physicians (ACCP) classified the risks of VTE in hospitalised patients into three categories: low, moderate and high risk.

Orthopaedic patients who have undergone hip or knee arthroplasty or sustained hip fracture, major trauma or spinal cord injury are included in the high-risk category.5 Table 1 summarises the risks of DVT and PE after different types of surgery.

Early mobilisation, along with mechanical and pharmacological prophylaxis, effectively reduce the risk of post-operative VTE. Traditional

post-operative anticoagulation regimens include two steps: initial treatment with a rapidly acting parenteral anticoagulant, usually lowmolecular-weight heparin (LMWH) 1 mg/kg/day, followed by an oral vitamin K antagonist (VKA), such as warfarin. The duration of warfarin treatment depends on the nature of the operation and the patient’s mobility status and prothrombotic risks. Hypercoagulability and impaired venous function can persist up to 6 weeks after surgery, indicating the necessity for extended post-operative thromboprophylaxis.6,7 However, LMWH and warfarin have some limitations, such as the need for daily injections, the risk of heparin-induced thrombocytopenia, regular dose monitoring, a narrow therapeutic window and various drug and food interactions. These limitations led to the development of direct oral anticoagulants (DOACs). With a rapid onset of action and predictable pharmacokinetic and pharmacodynamic profiles, DOACs can be prescribed in fixed doses without routine therapeutic monitoring, thus replacing parenteral anticoagulants and warfarin for VTE prophylaxis and treatment.8

Direct Oral Anticoagulants

Unlike warfarin, which inhibits various steps in the coagulation cascade (vitamin K-dependent clotting factors II, VII, IX and X), DOACs target specific steps. They can be categorised into two broad groups: direct thrombin inhibitors (dabigatran) and selective factor Xa (FXa) inhibitors (rivaroxaban, apixaban and edoxaban). These commonly used DOACs are approved for post-operative VTE thromboprophylaxis in light of their

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Role of Newer Oral Anticoagulants for Post-operative Prophylaxis Table 1: Risk of Deep Vein Thrombosis; and Pulmonary Embolism After Different Types of Surgery Authors

Surgery

Risk of VTE (DVT/PE)

Kahn and Shivakumar 4

Total hip arthroplasty

DVT in 54%

Total knee arthroplasty

DVT in 64%

Total hip arthroplasty

DVT in 8.0–24.0%

Total knee arthroplasty

DVT in 14.0–49.0%

Alvarado et al. 2020

Spine surgery

VTE in 0.3–31%

Tian et al 2019.69

Thoracic surgery

VTE in 8.4%

Ambrosetti et al. 2004

CABG surgery

DVT in 17.4%

Reis et al. 199171

CABG surgery

DVT in 44.8%

CABG surgery

PE in 3.2%

CABG surgery

PE in 6.2%

Kim et al. 2013

67

68

70

Josa et al 1993.

72

Beck et al 2018.

73

CABG = coronary artery bypass graft; DVT = deep vein thrombosis; PE = pulmonary embolism; VTE = venous thromboembolism.

favourable efficacy and safety profiles compared with LMWH and warfarin.

In 2018, Ingrasciotta et al. studied the pharmacokinetics of DOACs and their clinical use.9 DOACs can be a better option than warfarin because of predictable pharmacokinetic properties, increased tolerability, fewer interactions and ease of use. However, because DOACs undergo hepatic metabolism and renal excretion, careful dose adjustment is required in people with hepatic or renal impairment. FXa inhibitors are contraindicated in those with creatinine clearance (CrCl) <15 ml/min, whereas dabigatran is contraindicated when CrCl is <30 ml/min. Table 2 compares the pharmacological properties of different DOACs.

General Recommendations for Venous Thromboembolism Prophylaxis

In 2015, a systematic review and meta-analysis by Ho et al. showed that VTE prophylaxis was associated with a reduced risk of PE (RR 0.45; 95% CI [0.28–0.72]; p=0.0008) or symptomatic VTE (RR 0.44; 95% CI [0.28– 0.71]; p=0.0006). This review recommended initiating pharmacological VTE prophylaxis as soon as possible after cardiac surgery for patients who have no active bleeding.10 Sarker et al. reported that combined treatment with rivaroxaban and heparin is of great clinical value in post- coronary artery bypass grafting (CABG) deep vein thrombosis (DVT) patients.11 A 2-year (2015–2016) retrospective cohort analysis comparing LWMH and DOACs for thromboprophylaxis in operative spinal trauma patients showed that DOAC thromboprophylaxis was associated with less chance of DVT than LMWH (1.8 versus 7.4%, respectively) and PE (0.3 versus 2.1%, respectively).12 Analysis from the National Joint Registry for England Wales, Northern Ireland and Isle of Man compared DOACs to aspirin in 218,650 total hip arthroplasty (THA) and total knee arthroplasty (TKA) patients, finding that DOACs were associated with a lower risk of VTE.13 In 2011, the American Academy of Orthopaedic Surgeons recommended the use of pharmacological agents and/or mechanical compressive devices for the prevention of VTE in patients undergoing elective hip or knee arthroplasty (grade of recommendation: moderate).14 The ACCP’s 2012 guidelines suggest the use of mechanical devices (intermittent pneumatic compression devices) plus pharmacological prophylaxis during hospitalisation in patients at high risk for VTE after major orthopaedic surgery.15 The guidelines recommend apixaban, dabigatran and rivaroxaban for a minimum of 10–14 days, and up to 35 days for VTE prophylaxis in patients undergoing THA or TKA (grade of recommendation: grade 1B, strong, moderate quality).15 The National Institute for Health and

Care Excellence (NICE) 2019 guideline recommends apixaban, rivaroxaban, dabigatran for VTE prevention after THA or TKA.16 The American Society of Hematology (ASH) 2019 guideline suggests apixaban, rivaroxaban, dabigatran over LMWH for VTE prevention after THA or TKA (conditional recommendation based on moderate certainty in the evidence of effects).17 The Scottish Intercollegiate Guidelines Network (SIGN) 2014 recommends rivaroxaban or dabigatran, combined with mechanical prophylaxis unless contraindicated, in patients undergoing THA or TKA (grade A recommendation).18 Moreover, the 2019 European Society of Cardiology guidelines on PE recommend DOACs (apixaban, dabigatran, edoxaban or rivaroxaban) in preference to VKA (recommendation Class I, level of evidence A) for acute-phase treatment of intermediate or low-risk PE.19

Direct Thrombin Inhibitors Dabigatran

Dabigatran etexilate is the pro-drug of dabigatran. Dabigatran selectively blocks the activity of thrombin and is mainly (90%) eliminated by kidneys, so dose adjustment should be considered those with renal insufficiency.

The usual dosage of dabigatran is 220 mg once daily or 150 mg once daily if CrCl is 30–50 ml/min. It is contraindicated if CrCl <30 ml/min. Four Phase III trials (RE-NOVATE, RE-NOVATE II, RE-MODEL, RE-MOBILIZE) have compared the efficacy and safety of dabigatran with enoxaparin for VTE prophylaxis after THA or TKA.20–23 In all four trials, the primary efficacy outcome was total VTE events (symptomatic or venographic DVT and/or symptomatic pulmonary embolism) and all-cause mortality during treatment. The primary safety outcome was the occurrence of bleeding events (major, clinically relevant non-major bleeding and minor bleeding events).

In the randomised, double-blind, non-inferiority RE-NOVATE trial, a total of 3,494 patients undergoing THA were randomised to 220 or 150 mg dabigatran once daily or enoxaparin 40 mg once daily for 28–35 days. The primary efficacy outcome (reducing the risk of a VTE) occurred in 6.0% of those receiving dabigatran 220 mg, 8.6% of those receiving dabigatran 150 mg and 6.7% of those receiving enoxaparin. Major bleeding events were detected in 2.0%, 1.3% and 1.6%, respectively.20 In RE-NOVATE II (also a randomised, double-blind, non-inferiority trial), comprising 2,055 patients who underwent THA, extended (28–35 days) prophylaxis with dabigatran 220 mg once daily was as effective as enoxaparin 40 mg once daily in reducing risk of total VTE and all-cause mortality (dabigatran 7.7% versus enoxaparin 8.8%; risk difference 1.1; 95% CI [−3.8, 1.6]) with p<0.0001 for non-inferiority, and similar safety profiles.21 The randomised, double-blind, non-inferiority RE-MODEL trial examined dabigatran 150 or 220 mg once daily versus enoxaparin 40 mg once daily for 6–10 days in 2,076 patients who underwent TKA. Dabigatran 220 mg or 150 mg had similar efficacy and safety profiles compared to enoxaparin for VTE prophylaxis after TKA. Total VTE and all-cause mortality occurred in 36.4% of those receiving dabigatran 220 mg, 40.5% of those receiving dabigatran 150 mg, and 37.7% of those receiving enoxaparin. Major bleeding occurred in 1.5%, 1.3% and 1.3%, respectively.22 The fourth Phase III trial, the RE-MOBILIZE trial, compared dabigatran 220 mg or 150 mg once daily versus enoxaparin 30 mg twice daily in 1,896 patients undergoing TKA for 12–15 days. Although dabigatran is effective when compared to once-daily enoxaparin, this trial demonstrated that dabigatran showed inferior efficacy to twice-daily enoxaparin.23 The pooled analysis of three of the trials (RE-NOVATE, RE-MODEL, REMOBILIZE) did not show any difference in efficacy and safety profiles

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Role of Newer Oral Anticoagulants for Post-operative Prophylaxis Table 2: Comparison of the Pharmacological Properties of Direct Oral Anticoagulants Characteristics

Dabigatran

Rivaroxaban

Apixaban

Edoxaban

Molecular weight

628 Da

436 Da

460 Da

536 Da

Target

FIIa

FXa

FXa

FXa

Pro-drug

Dabigatran etexilate

No

No

No

Approximate bioavailability

6%

100%

66%

50%

Metabolism

Hepatic

Hepatic

Hepatic

Hepatic

Approximate plasma protein binding

35%

90%

87%

50%

Approximate plasma half-life

12–17 h

5–13 h

8–15 h

9–11 h

Renal excretion

90%

30%

25%

35%

Approximate time to peak effect

2h

2–4 h

1–3 h

1–2 h

Dosing regime

Twice daily

Once daily

Twice daily

Once daily

Dose monitoring

Not needed

Not needed

Not needed

Not needed

Antidote

Idarucizumab

Andexanet alfa

Andexanet alfa

None

Time to haemostasis after stopping the drug

12 h

5–9 h

8–15 h

4–10 h

Reversal of action

Yes

Yes

Yes

No

VTE prophylaxis dose

150 or 220 mg once daily

10 mg once daily

2.5 mg twice daily

30 mg once daily

Interactions

P-gp inhibitors

CYP3A4/P-gp inhibitors

CYP3A4/P-gp inhibitors

CYP3A4/P-gp inhibitors

CYP = cytochrome P450; P-gp = P-glycoprotein; VTE = venous thromboembolism. Source: Werth et al. 2012,8 Ingrasciotta et al. 2018,9 and Yeh et al. 2015.74

between the dabigatran and enoxaparin groups.24 The BISTRO II trials showed that dabigatran was effective and safe across a range of doses (dabigatran 50 mg twice daily, 150 mg twice daily, 300 mg once daily and 225 mg twice daily) compared to enoxaparin 40 mg once daily.25 In 2016, Rosencher et al. conducted an international, open-label, prospective, observational, single-arm study of dabigatran 220 mg once daily in over 5,000 patients undergoing THA or TKA. The data supported the safety and efficacy findings of previous dabigatran Phase III trials.26 Moreover, in 2015, Wurning et al. proved that switching from LMWH to dabigatran was safe and effective for VTE prophylaxis after THA or TKA.27 Based on these trials, dabigatran is recommended by ACCP, NICE, ASH and SIGN for DVT prevention after THA (28–35 days) and TKA (10 days).15–18 However, dabigatran has not been studied in hip fracture surgery.

Factor Xa Inhibitors Rivaroxaban

Rivaroxaban is a Food and Drug Administration (FDA) approved oral direct factor Xa inhibitor for prevention of thromboembolism after THA and TKA that requires no routine laboratory monitoring. The safety and efficacy of rivaroxaban was studied in the RECORD study program, which is composed of four separate randomised, double-blind, Phase III clinical trials (RECORD 1, 2, 3 and 4).28–31 The primary efficacy endpoint in all RECORD trials was total VTE, symptomatic or asymptomatic DVT, non-fatal PE and all-cause mortality.

In the RECORD 1 and RECORD 2 trials, which included a total of 7,050 patients undergoing THA, rivaroxaban 10 mg once daily was superior to enoxaparin 40 mg once daily for VTE prophylaxis with similar safety profiles.28,29 In the RECORD 3 trial, involving 2,531 patients who underwent TKA, a 10–14 day course of rivaroxaban 10 mg once daily significantly reduced the incidence of VTE compared to enoxaparin 40 mg once daily (rivaroxaban 9.6% versus enoxaparin 18.9%; p<0.001) without increasing bleeding events.30 The fourth RECORD trial, RECORD 4, compared a 10–14 day course of rivaroxaban 10 mg once daily with enoxaparin 30 mg twice daily in 3,148 patients undergoing TKA. Rivaroxaban was significantly

superior to twice-daily enoxaparin (rivaroxaban 6.9% versus enoxaparin 10.1%; p=0.0118) for the prevention of VTE after TKA.31 A pooled analysis of the four RECORD trials proved that, compared with enoxaparin (either enoxaparin 40 mg once daily or enoxaparin 30 mg twice daily), rivaroxaban 10 mg once daily reduces the incidence of VTE and allcause mortality after elective THA or TKA (rivaroxaban 0.5% versus enoxaparin 1.0%; p=0.001), with a small increase in bleeding.32 In 2014, Levitan et al. conducted a post hoc analysis to assess the benefit–risk profile for rivaroxaban versus enoxaparin in the RECORD studies, which showed rivaroxaban resulted in greater benefits than harms compared with enoxaparin.33 The ODIXa-HIP and ODIXa-KNEE studies showed that rivaroxaban 2.5–10 mg twice daily has favourable efficacy and safety profiles compared to enoxaparin for prevention of VTE after THA or TKA.34,35 In 2014, Turpie et al. conducted the XAMOS, Phase IV, non-interventional, open-label cohort study to assess the safety and effectiveness of rivaroxaban compared with other pharmacological VTE prophylaxis (standard of care; SOC). The crude incidence of symptomatic VTE was 0.89% in the rivaroxaban group versus 1.35% in the SOC group (OR 0.65; 95% CI [0.49–0.87]). This study confirmed that rivaroxaban has a favourable benefit–risk profile compared to SOC after major orthopaedic surgery.36 Moreover, the Ortho-TEP registry showed that rivaroxaban was associated with fewer VTE and bleeding events than fondaparinux in patients undergoing major orthopaedic surgery.37 In 2020, Smith et al. evaluated that prolonged (35-day) prophylaxis with rivaroxaban is cost effective for VTE prophylaxis after TKA.38 Again, Sarker et al. reported that combined treatment with rivaroxaban and heparin is of great clinical value in post-CABG DVT patients.11 Based on these trials, rivaroxaban has been recommended by ACCP, NICE, ASH and SIGN for DVT prevention after THA and TKA.15–18 The recommended dosing is rivaroxaban 10 mg once daily with the first dose administered 6–10 hours post-surgery for 28–35 days (after THA) or 10–14 days (after TKA). However, rivaroxaban has not been studied in hip fracture surgery.

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Role of Newer Oral Anticoagulants for Post-operative Prophylaxis Apixaban

Apixaban is an oral direct FXa inhibitor, approved by the FDA for thromboembolism prophylaxis after THA and TKA. Apixaban does not require routine laboratory monitoring for its anticoagulant effect, but it is contraindicated in patients with severe renal impairment (CrCl <15 ml/ min). Apixaban was evaluated in the ADVANCE study programs (ADVANCE 1, 2 and 3), which compared apixaban with enoxaparin. All trials were randomised, double-blind, double-dummy, non-inferiority, Phase III trials.

In these trials, enoxaparin was started 12 hours pre-operatively and apixaban was started 12–24 hours after wound closure. The primary efficacy outcome was the incidence of symptomatic or asymptomatic DVT, non-fatal PE, or all-cause mortality during treatment. The primary safety outcome was the incidence of bleeding events (major or clinically relevant non-major bleeding).

In the ADVANCE 1 trial, a 10–14-day course of apixaban 2.5 mg twice daily was compared with enoxaparin 30 mg twice daily for VTE prophylaxis in 3,195 patients undergoing TKA. The primary efficacy endpoint was reached in 9.0% of the apixaban group versus 8.8% of the enoxaparin group (RR 1.02; 95% CI [0.78–1.32]; p=0.06 for non-inferiority). Bleeding risk was significantly lowered in apixaban-treated patients (2.9% versus 4.3% for apixaban versus enoxaparin respectively; p=0.03). Therefore, apixaban did not meet the prespecified statistical criteria for non-inferiority, despite the low bleeding risk.39 The ADVANCE-2 and ADVANCE-3 trials compared apixaban 2.5 mg twice daily with enoxaparin 40 mg once daily in patients undergoing TKA and THA, respectively. The prophylaxis was continued for 10–14 days after TKA and 35 days after THA. The ADVANCE-2 trial showed incidence of VTE was significantly reduced in the apixaban (15%) versus the enoxaparin (24%) group (RR 0.62; 95% CI [0.51–0.74]; p<0.0001). Bleeding events occurred in 4% of the apixaban group and 5% of the enoxaparin group (p=0.09).40 In the ADVANCE-3 trial, the primary efficacy endpoint was reached in 1.4 versus 3.9% of the apixaban- and enoxaparin-treated patients, respectively (RR 0.36; 95% CI [0.22–0.54]; p<0.001 for both noninferiority and superiority). Major and clinically relevant non-major bleeding was not different between the two groups (apixaban 4.8% versus enoxaparin 5%).41 In 2012, Raskob et al. conducted a pooled analysis of the ADVANCE 2 and ADVANCE 3 trials that included 8,464 patients. VTE events were statistically lower in the apixaban (0.7%) group versus the enoxaparin (1.5%) group (risk difference, apixaban minus enoxaparin, −0.8%; 95% CI [−1.2, −0.3]; onesided p<0.0001 for non-inferiority; two-sided p=0.001 for superiority) without increasing bleeding risk (risk difference −0.6; 95% CI [−1.5, 0.3]). It was concluded that apixaban 2.5 mg twice daily is more effective than enoxaparin 40 mg once daily without increasing bleeding events.42 The APROPOS trial was a randomised, eight-arm, parallel group, multi-centre, Phase II trial, that compared different doses of apixaban (5, 10 or 20 mg once daily or 2.5, 5 or 10 mg twice daily) with enoxaparin or warfarin titrated to an international normalized ratio 1.8–3.0 in patients undergoing TKA. Apixaban 2.5 mg twice daily or 5 mg once daily has a favourable benefit– risk profile compared with SOC (enoxaparin or warfarin).43 A meta-analysis and trial-sequential analysis of four trials (APROPOS, ADVANCE 1, 2 and 3) concluded that apixaban 2.5 mg twice daily seems equally effective and safe to LMWH twice daily, and superior to with LMWH once daily.44 In 2019, a study by Torrejon Torres et al. revealed that apixaban or intermittent pneumatic compression, or a combination of the two, is the most costeffective for VTE prophylaxis after lower limb arthroplasty.45 Based on these trials, apixaban is recommended by the ACCP, NICE and ASH for DVT prevention after THA and TKA.15–17 Currently, apixaban is

approved in the EU for the prevention of VTE in patients undergoing major orthopaedic surgery at a dose of 2.5 mg twice daily commencing 12–24 hours after surgery for 10–14 days (knee replacement surgery) and 32–38 days (hip replacement surgery). However, apixaban has not been studied in hip fracture surgery. Therefore, apixaban is not currently recommended for hip fracture surgery.

Edoxaban

Edoxaban is an oral, direct, FXa inhibitor. It does not require routine monitoring of therapeutic effect but it is contraindicated in severe renal impairment (CrCl 15–30 ml/min). Three Phase II dose-ranging studies showed that compared to placebo, enoxaparin or dalteparin, edoxaban has a statistically significant (p<0.001) dose-dependent reduction in VTE events in patients undergoing major orthopaedic surgery with a similar bleeding risk.46–48 The STARS program (STARS-E3, STARS-J4 and STARS-J5) compared the efficacy and safety of edoxaban 30 mg once daily with enoxaparin 20 mg twice daily in patients undergoing major orthopaedic surgery. The prophylaxis was given for 11–14 days following surgery. The primary efficacy endpoint was the incidence of VTE. Safety endpoints were the incidence of bleeding events, major, or clinically relevant non-major bleeding. In the STARS-E3 trial, a randomised, double-blind, noninferiority, Phase III trial, 716 patients undergoing TKA were randomised to either edoxaban or enoxaparin. VTE occurred in 7.4% of those receiving edoxaban versus 13.9% for enoxaparin; relative risk reduction 46.8%; p<0.001 for non-inferiority and p=0.010 for superiority.49 The STARS-J4 trial was a multi-centre, randomised, open-label, active-comparator, Phase III trial that studied 92 patients undergoing hip fracture surgery.

The incidence of thrombotic events was 6.5% in the edoxaban group and 3.7% in the enoxaparin group. Major and clinically non-relevant minor bleeding occurred in 3.4% of the edoxaban group and 6.9% of the enoxaparin group.50 Another randomised, double-blind, non-inferiority, Phase III trial, STARS-J5, studied 610 patients undergoing THA. The efficacy outcome occurred in 2.4% of the edoxaban group versus 6.9% of the enoxaparin group (relative risk reduction 65.7%; p<0.001 for noninferiority). Bleeding occurred in 2.6% of edoxaban-treated patients versus 3.7% of enoxaparin-treated patients; p=0.475.51 In a pooled analysis of the STARS-E3 and STARS-J5 trials, the incidence of VTE was 5.1% and 10.7% for edoxaban and enoxaparin, respectively, p<0.001. There was also no significant difference in bleeding rates (4.6% for edoxaban and 3.7% for enoxaparin, p=0.427).52 Based on these results, edoxaban has recently been approved for VTE prophylaxis after major orthopaedic surgery in Japan at a dose of 30 mg once daily.53

Comparison Between Direct Oral Anticoagulants

Zhang et al. conducted a retrospective study to compare the efficacy and safety of apixaban and rivaroxaban after lumbar spine surgery. A total of 480 patients were randomised to apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily for 14 days. All patients were provided with graduated compression stockings for 6 weeks, and calf-length intermittent pneumatic compression devices while in-hospital with mobilisation encouraged. VTE events, bleeding and D-dimer changes were assessed.

There was no significant intergroup difference in the incidences of thrombotic events between apixaban (5%) and rivaroxaban (3.75%), p>0.05. Total bleeding and minor bleeding were significantly lower in the apixaban group (p<0.05). Moreover, postoperative D-dimer level changes were lower in the apixaban group than in the rivaroxaban group.

Therefore, apixaban and rivaroxaban were equally effective for postoperative VTE prophylaxis.54

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Role of Newer Oral Anticoagulants for Post-operative Prophylaxis Table 3: Current Approved Direct Oral Anticoagulant Regimens for Venous Thromboembolism Prophylaxis after Major Orthopaedic Surgery DOACs

Indications

Recommended Dose

Recommended Duration

Approved by

Dabigatran

VTE prophylaxis after major orthopaedic surgery

150–220 mg once daily

THA 28–35 days TKA (10 days)

ACCP (2012),15 NICE (2019),16 ASH (2019),17 SIGN (2010)18

Rivaroxaban

VTE prophylaxis after major orthopaedic surgery

10 mg once daily

THA 28–35 days TKA (10–14 days)

ACCP (2012),15 NICE (2019),16 ASH (2019),17 SIGN (2010)18

Apixaban

VTE prophylaxis after major orthopaedic surgery

2.5 mg twice daily

THA 32–38 days TKA (10–14 days)

ACCP (2012),15 NICE (2019),16 ASH (2019)17

Edoxaban

VTE prophylaxis after major orthopaedic surgery

30 mg once daily

Japanese guidelines75

ACCP = American College of Chest Physicians; ASH = American Society of Hematology; DOAC = direct oral anticoagulants; NICE = National Institute for Health and Care Excellence; SIGN = Scottish Intercollegiate Guidelines Network; THA = total hip arthroplasty; TKA = total knee arthroplasty; VTE = venous thromboembolism.

A systematic review and meta-analysis has been conducted comparing dabigatran, rivaroxaban and apixaban versus enoxaparin for DVT prophylaxis after THA or TKA. The meta-analysis included 38,747 patients from 16 Phase II and Phase III trials.55 Compared with enoxaparin, VTE risk was lower with rivaroxaban (RR 0.48; 95% CI [0.31–0.75]), and similar with dabigatran (RR 0.71; 95% CI [0.23–2.12]) and apixaban (RR 0.82; 95% CI [0.41–1.64]). However, the risk of bleeding was higher with rivaroxaban (RR 1.25; 95% CI [1.05–1.49]), similar with dabigatran (RR 1.12; 95% CI [0.94–1.35]), and lower with apixaban (RR 0.82; 95% CI [0.69–0.98]).55 In 2017, a network meta-analysis was conducted to compare the efficacy and safety of anticoagulants for VTE prevention after hip and knee arthroplasty. The outcomes revealed that rivaroxaban and apixaban were superior to enoxaparin for reducing VTE. Rivaroxaban was associated with similar bleeding risks compared with enoxaparin 30 mg twice daily and higher bleeding risks compared with enoxaparin 40 mg once daily.

However, apixaban was associated with a decreased major or clinically relevant non-major bleeding compared with either dose of enoxaprin.56 Three meta-analyses have demonstrated that DOACs (dabigatran, apixaban and rivaroxaban) reduce the risk of VTE compared to placebo.

Based on these studies, apixaban may have the most favourable efficacy and safety profiles for post-operative VTE prophylaxis. However, there are no direct comparative trials between different types of DOACs, so a definite opinion on whether apixaban is the best DOAC cannot be made regarding these data.57–59

Bleeding Risks of Direct Oral Anticoagulants

Bleeding (major and minor) is the most common complication of DOACs. A population-based cohort study showed that the risk of gastrointestinal bleeding with DOACs (dabigatran and rivaroxaban) was similar to warfarin.60 Chai-Adisaksopha et al. performed a systematic review and meta-analysis of twelve randomised controlled trials. The bleeding risk of DOACs was assessed in 102,607 patients with VTE or AF. Compared with VKAs, DOACs significantly reduced the risk of overall major bleeding (RR 0.72; p<0.01), fatal bleeding (RR 0.53; p<0.01), intra-cranial bleeding (RR 0.43; p<0.01), clinically relevant non-major bleeding (RR 0.78; p<0.01) and total bleeding (RR 0.76; p<0.01).61

Management of Direct Oral Anticoagulants in Perioperative Settings

The management of patients taking DOACs in the perioperative setting is important. The pharmacokinetic properties of DOACs, renal function, bleeding risks, nature of the surgical procedure and thromboembolic risk of patients should all be considered.62 Although periprocedural bridging

anticoagulation with LMWH or unfractionated heparin has been used in some high-thromboembolic risk-patients, a systematic review and metaanalysis proved that there was no difference in thromboembolic risk between bridged and non-bridged patients (RR 1.26; 95% CI [0.61–2.58]; p=0.53). However, bridging anticoagulation increased risk of overall bleeding (RR 2.83; 95% CI [2.00–4.01]; p<0.0001) and major bleeding (RR 3.00; 95% CI [1.78–5.06], p<0.0001).63 Dabigatran undergoes 90% renal elimination. In high-bleeding-risk procedures, it is recommended to discontinue dabigatran 48–72 hours prior to surgery in patients with normal renal function or mild impairment (CrCl >50 ml/min), 72–96 hours with moderate renal impairment (CrCl 30–49 ml/min) and 96–144 hours with severe renal impairment (CrCl <29 ml/min). In low-bleeding-risk procedures, dabigatran does not need to be interrupted if renal function is normal. Dabigatran should be resumed between 48–72 hours after high-bleeding-risk procedures and 24 hours after low-bleeding-risk procedures. Rivaroxaban should be discontinued 48 hours prior to high-bleeding-risk procedures. In low-bleeding-risk procedures, rivaroxaban should be withheld 24 hours prior to surgery with normal renal function (CrCl >90 ml/min), 48 hours with mild renal impairment (CrCl 60–90 ml/min), 72 hours with moderate renal impairment (CrCl 30–59 ml/min), and 96 hours with severe renal impairment (CrCl 15–29 ml/min). Rivaroxaban can be restarted as soon as after haemostasis is achieved in low-bleeding-risk procedures and after 48–72 hours in high-bleeding-risk procedures. For apixaban, it is recommended that it is withheld for 24–48 hours with mild renal impairment (CrCl <60 ml/min), 72 hours with moderate renal impairment (30–59 ml/min) and 96 hours with severe renal impairment (CrCl <30 ml/min) in high-bleeding-risk procedures. In low-bleeding-risk procedures, apixaban may be continued without interruption. Following surgery, apixaban may be resumed after 24–48 hours depending on bleeding risks. Edoxaban is suggested to be discontinued 24 hours prior to low-bleeding-risk procedures and 72 hours prior to high-bleeding-risk procedures. During prolonged gaps without anticoagulation, bridging anticoagulation with heparin may be considered in high thromboembolic risk patients, although a meta-analysis does not support this regime.62 If emergency surgery cannot be delayed for at least 12 hours from the last DOAC intake, specific reversal agents should be considered. A randomised, double-blind, placebo-controlled study showed prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran.64 Idarucizumab was approved in 2015 as the specific reversal agent for dabigatran and andexanet alfa (a recombinant modified FXa protein) was approved in

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Role of Newer Oral Anticoagulants for Post-operative Prophylaxis 2018 for the reversal of the anticoagulation action of rivaroxaban and apixaban in cases of life-threatening or uncontrolled bleeding, or where rapid reversal of anticoagulation is required.65,66

Conclusion

In summary, based on these above clinical data, DOACs have similar or superior efficacy and safety profiles compared to routine SOC (LMWH and 1.

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warfarin) for VTE prophylaxis after major orthopaedic surgery. Table 3 summarises the current approved DOACs guidelines for VTE prophylaxis after major orthopaedic surgery. However, the data regarding the role of DOACs after non-orthopaedic surgery are limited. Therefore, regarding post-operative VTE prophylaxis, the risks of thromboembolism and bleeding should be assessed and managed on an individual basis to obtain optimal outcomes.

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Sobieraj DM, Coleman CI, Pasupuleti V, et al. Comparative efficacy and safety of anticoagulants and aspirin for extended treatment of venous thromboembolism: a network meta-analysis. Thromb Res 2015;135:888–96. https://doi. org/10.1016/j.thromres.2015.02.032; PMID: 25795564.

Cohen AT, Hamilton M, Bird A, et al. Comparison of the nonVKA oral anticoagulants apixaban, dabigatran, and rivaroxaban in the extended treatment and prevention of venous thromboembolism: systematic review and network meta-analysis. PLoS One 2016;11:e0160064. https://doi. org/10.1371/journal.pone.0160064; PMID: 27487187.

Abraham NS, Singh S, Alexander GC, et al. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. BMJ 2015;350:h1857. https://doi.org/10.1136/bmj.h1857; PMID: 25910928.

Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood 2014;124:2450–8. https://doi. org/10.1182/blood-2014-07-590323; PMID: 25150296.

Sunkara T, Ofori E, Zarubin V, et al. Perioperative management of direct oral anticoagulants (DOACs): a systemic review. Health Serv Insights 2016;9(Suppl 1):25–36. https://doi.org/10.4137/hsi.s40701; PMID: 28008269.

Kuo HC, Liu FL, Chen JT, et al. Thromboembolic and bleeding risk of periprocedural bridging anticoagulation: a systematic review and meta-analysis. Clin Cardiol 2020;43:441–9. https://doi.org/10.1002/clc.23336; 31944351.

Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of Rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover

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Goriacko P, Yaghdjian V, Koleilat I, et al. The use of idarucizumab for dabigatran reversal in clinical practice: a case series. P T 2017;42:699–703; PMID: 29089726.

Heo YA. Andexanet alfa: first global approval. Drugs 2018;78:1049–55. https://doi.org/10.1007/s40265-018-09404; PMID: 29926311.

Kim KI, Kang DG, Khurana SS, et al. Thromboprophylaxis for deep vein thrombosis and pulmonary embolism after total joint arthroplasty in a low incidence population. Knee Surg Relat Res 2013;25:43–53. https://doi.org/10.5792/ ksrr.2013.25.2.43; PMID: 23741698.

Alvarado AM, Porto GBF, Wessell J, et al. Venous thromboprophylaxis in spine surgery. Glob Spine J 2020;10(1 Suppl):65S–7S. https://doi.org/10.1177/2192568219858307; PMID: 31934524.

Tian B, Li H, Cui S, et al. A novel risk assessment model for venous thromboembolism after major thoracic surgery: a Chinese single-center study. J Thorac Dis 2019;11:1903–10. https://doi.org/10.21037/jtd.2019.05.11; PMID: 31285883.

Ambrosetti M, Salerno M, Zambelli M, et al. Deep vein thrombosis among patients entering cardiac rehabilitation after coronary artery bypass surgery. Chest 2004;125:191–6. https://doi.org/10.1378/chest.125.1.191; PMID: 14718440.

Reis SE, Polak JF, Hirsch DR, et al. Frequency of deep venous thrombosis in asymptomatic patients with coronary artery bypass grafts. Am Heart J 1991;122:478–82. https://doi. org/10.1016/0002-8703(91)91004-7; PMID: 1858629.

Josa M, Siouffi SY, Silverman AB, et al. Pulmonary embolism after cardiac surgery. J Am Coll Cardiol 1993;21:990–6. https://doi.org/10.1016/0735-1097(93)90358-8; PMID: 8450170.

Beck KS, Cho EK, Moon MH, et al. Incidental pulmonary embolism after coronary artery bypass surgery: long-term clinical follow-Up. AJR Am J Roentgenol 2018;210:52–7. https://doi.org/10.2214/ajr.17.18186; PMID: 29064757.

Yeh CH, Hogg K, Weitz JI. Overview of the new oral anticoagulants: opportunities and challenges. Arterioscler Thromb Vasc Biol 2015;35:1056–65. https://doi.org/10.1161/ atvbaha.115.303397; PMID: 25792448.

Kobayashi T, Nakamura M, Sakuma M, et al. Japanese guidelines for pulmonary thromboembolism (PTE) prophylaxis is effective for a decrease in the incidence of PTE. Blood 2005;106:4110. https://doi.org/10.1182/blood.

V106.11.4110.4110.

EDITORIAL

ESC Highlights

New Trial Evidence on Heart Failure: Highlights from the European Society of Cardiology Congress 2021 Giulia Ferrannini

1

and Gianluigi Savarese

1,2

1. Division of Cardiology, Department of Medicine, Karolinska Institute, Stockholm, Sweden; 2. Heart, Vascular and Neuro Theme, Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden

Disclosure: GF has received grant support from the Erling-Persson family foundation and from the Swedish Heart and Lung Foundation as well as speaker fees from the European Society of Cardiology, outside the present work. GS has received personal fees from Società Prodotti Antibiotici, Roche, Servier, GENESIS, Cytokinetics and Medtronic; grants and personal fees from Vifor and AstraZeneca; grants from Novartis, Boston Scientific, Bayer, Merck, Pharmacosmos and Boheringer Ingelheim, all outside the present work; and is an editorial board member of European Cardiology Review; this did not influence acceptance.

Received: 24 January 2022 Accepted: 25 January 2022 Citation: European Cardiology Review 2022;17:e12. DOI: https://doi.org/10.15420/ecr.2022.06 Correspondence: Gianluigi Savarese, Division of Cardiology, Department of Medicine, Karolinska Institutet, Eugeniavägen 27, S1:02, 171 76 Stockholm, Sweden.

E: gianluigi.savarese@ki.se 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.

Long-awaited results from several heart failure (HF) trials were presented at the European Society of Cardiology (ESC) Congress 2021.

EMPEROR-Preserved Trial and EMPEROR-Pooled Analysis

This pattern of effects was consistent in both sexes and was also observed for other HF outcomes, including time to first HHF, total (first and recurrent) HHF and change in Kansas City Cardiomyopathy Questionnaire clinical summary score at 52 weeks.3

For the first time, the EMPEROR-Preserved trial proved the efficacy of a pharmacological product in patients with HF with preserved ejection fraction (HFpEF).1 In this study, 5,988 patients with symptomatic HF, ejection fraction (EF) >40% and high levels of natriuretic peptides were randomised to the sodium–glucose cotransporter-2 inhibitor (SGLT2i) empagliflozin (10 mg once daily) or a placebo.

Major renal events, including a sustained decrease in eGFR by ≥40% or to <10–15 ml/min/1.73 m2, dialysis initiation or renal transplantation were investigated in EMPEROR-Pooled.4 Significant heterogeneity was found between the two trials, with a HR for renal events of 0.51 (95% CI [0.33– 0.79]) in EMPEROR-Reduced and 0.95 (95% CI [0.73–1.24]) in EMPERORPreserved (p=0.016).

Compared with placebo, empagliflozin was able to significantly reduce the primary outcome – a composite of hospitalisation for HF (HHF) and cardiovascular death – by 21% over a median follow-up of 26.2 months.1 It was the reduction in HHF that drove this result, with the risk of cardiovascular death alone not significantly lower.

Therefore, the effect of empagliflozin on major renal outcomes might be affected by EF in patients with HF, with virtually no benefit in HFpEF. This finding also challenges whether eGFR slope analysis, used in EMPERORPreserved to show the effect of empagliflozin, is an appropriate surrogate marker for renal outcomes in HF.

The effect of empagliflozin on the primary outcome was consistent across several pre-specified subgroups and regardless of the presence of diabetes. The rate of decline in estimated glomerular filtration rate (eGFR) was slower in patients who received empagliflozin than in those given the placebo.

Effect of Dapagliflozin on Ventricular Arrhythmias, Resuscitated Cardiac Arrest or Sudden Death

Since the benefit of empagliflozin in patients with HF with reduced EF (HFrEF) had previously been showed in the EMPEROR-Reduced trial, a pooled analysis of the two EMPEROR trials was performed to investigate the whole EF spectrum.2 A total of 9,718 patients (of whom 4,860 received empagliflozin and 4,858 received a placebo) were divided into six groups according to EF: <25%, 25–34%, 35–44%, 45–54%, 55–64% and ≥65%.3 The magnitude of the effect of empagliflozin on HHF and cardiovascular death was similar in the groups with EF <25% up to EF <55–64%, with a relative risk reduction in a range of 25–35% compared with placebo; however, it was attenuated in patients with an EF ≥65% (HR 1.05; 95% CI [0.70–1.58]).3

This post-hoc analysis of the DAPA-HF trial investigated the hypothesis that dapagliflozin is able to reduce the risk of ventricular arrhythmias, resuscitated cardiac arrest and sudden death, which are major causes of death in HFrEF.5 In particular, in DAPA-HF, there were 115 ventricular arrhythmias, eight resuscitated cardiac arrests and 206 sudden deaths, the last accounting for 41% of all cardiovascular deaths in DAPA-HF. The risk of the primary outcome was lower in the dapagliflozin group than in the control group (HR 0.79; 95% CI [0.63-0.99]); independent predictors included natriuretic peptides concentration, previous ventricular arrhythmias, EF, previous MI, BMI, systolic blood pressure, male sex and serum sodium levels.

The Kaplan-Meier curves for the primary outcome diverged after approximately 9 months, suggesting a benefit of dapagliflozin through

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Highlights from the ESC Congress 2021 cardiac remodelling. This finding was consistent across the subgroups, except for the subgroup characterised by levels of natriuretic peptides above the median value, who showed no benefit from dapagliflozin.

natriuretic peptides were implanted with a pulmonary artery pressure monitoring system, and randomly assigned to either haemodynamicguided HF management or standard care.6

The results were consistent regardless of the presence of an ICD although, plausibly, dapagliflozin is less likely to reduce the risk of events in patients who already have a device.5

There was no difference between the two groups in the primary outcome, which was a composite of all-cause death, HF hospitalisations and urgent HF hospital visits. However, a prespecified COVID-19 sensitivity analysis suggested the COVID-19 pandemic had a significant impact, warranting a separate analysis of pre-pandemic data only. In this subset, patients who were treated according to haemodynamic data had a significantly lower risk of the primary endpoint than those receiving standard care (HR 0.81; 95% [CI 0.66–1.00]; p=0.0049).

GUIDE-HF Trial

GUIDE-HF tested the hypothesis that haemodynamic-guided treatment in HF could reduce HF hospitalisations.6 One thousand patients with symptomatic HF and either a recent HF hospitalisation or elevated 1.

Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021;385:1451–61. https://doi.org/10.1056/NEJMoa2107038; PMID: 34449189.

2. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–24. https://doi.org/10.1056/NEJMoa2022190; PMID: 32865377.

3. Butler J, Packer M, Filippatos G, et al. Effect of empagliflozin

in patients with heart failure across the spectrum of left ventricular ejection fraction. Eur Heart J 2022;43:416–26. https://doi.org/10.1093/eurheartj/ehab798; PMID: 34878502.

4. Packer M, Butler J, Zannad F, et al. Empagliflozin and major renal outcomes in heart failure. N Engl J Med 2021;385:1531– 3. https://doi.org/10.1056/NEJMc2112411; PMID: 34449179.

5. Curtain JP, Docherty KF, Jhund PS, et al. Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF. Eur Heart J

EUROPEAN CARDIOLOGY REVIEW www.ECRjournal.com

2021;42:3727–38. https://doi.org/10.1093/eurheartj/ehab560; PMID: 34448003.

6. Lindenfeld J, Zile MR, Desai AS, et al. Haemodynamicguided management of heart failure (GUIDE-HF): a randomised controlled trial. Lancet 2021;398:991–1001. https://doi.org/10.1016/S0140-6736(21)01754-2; PMID: 34461042.

EDITORIAL

CVD in CKD Patients

Cardiovascular Complications of Chronic Kidney Disease: An Introduction Hilary Warrens ,1 Debasish Banerjee

1

and Charles A Herzog

2,3

1. St George’s University of London, St George’s NHS Foundation Trust, London, UK; 2. Division of Cardiology, Department of Internal Medicine, Hennepin Healthcare, Minneapolis, MN, US; 3. Department of Medicine, University of Minnesota, Minneapolis, MN, US

Keywords

Cardiovascular disease, chronic kidney disease, prevention, comorbidities Disclosure: DB is on the European Cardiology Review editorial board; this did not influence acceptance.

Received: 13 November 2021 Accepted: 22 November 2021 Citation: European Cardiology Review 2022;17:e13. DOI: https://doi.org/10.15420/ecr.2021.54 Correspondence: Debasish Banerjee, Room 2.113, Grosvenor Wing, St George’s Hospital, Blackshaw Rd, Tooting, London SW17 0QT, UK. E: debasish.banerjee@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 non-commercial purposes, provided the original work is cited correctly.

Cardiovascular disease (CVD) is the primary cause of morbidity and mortality in chronic kidney disease (CKD). CVD mortality risk doubles and triples in CKD stages 3 and 4, respectively.1 This relationship is complex and bidirectional, with each condition increasing the incidence and progression of the other.2,3 Indeed, the heart and kidney are inextricably linked, as exemplified by the cardiorenal syndrome whereby dysfunction of one organ induces and advances dysfunction in the other.4,5 CVD assessment and management are complicated by the presence of CKD and its comorbidities. Additional CKD-related risk factors and alternative pathophysiology also contribute to CKD-CVD.1 CKD patients are largely excluded from clinical studies, resulting in a poor generalisability of assessment tools and a poor evidence base for the safety and efficacy of available treatments. Systematic reviews in 2006 found that CKD patients were excluded from 56–75% of CVD trials. This was even higher for patients with end-stage kidney disease (ESKD).6,7 Updated reviews in 2018 demonstrated continued underrepresentation with 46–57% of CVD studies excluding CKD patients.8,9 Recent recommendations to promote inclusion of CKD patients have considered the role for regulatory and financial incentives, modifications to study design and collaboration between cardiologists and nephrologists. These strategies are needed if we are to obtain the essential data to guide management of this vulnerable population.10 Indeed, current treatment options are associated with a high burden of adverse events, complications and concerns about dose adjustments particularly for renally-excreted medications.1 Clinicians act with caution, resulting in CVD being under-treated in many cases.11 This article aims to address the current understanding of CKD-CVD and the limitations. It will focus on coronary artery disease (CAD), arrhythmias, heart failure (HF) and valvular heart disease (VHD).

Risk Factors and Presentation

Traditional cardiovascular risk factors, such as hypertension and diabetes, are very common in CKD. Further CKD-related CVD risk factors also contribute, such as uraemia, anaemia, inflammation, oxidative stress and factors related to dialysis.1,12 These CKD-related factors contribute more with a decline in estimated glomerular filtration rate (eGFR). This is reflected in the pathophysiology of CVD in CKD patients as non-

atherosclerotic cardiac events becoming increasingly common as CKD progresses (Figure 1).1,13–15 CVD and related events often present atypically in CKD and with fewer symptoms. Only 44% of late-stage CKD patients have classical pain with an acute MI (AMI) compared with preserved renal function.16 These patients more commonly present with AMI than with stable angina.17 They also more commonly present with non-ST segment elevation MI than STelevation MI.18 As such, a high clinical suspicion must be maintained.

Assessment

CKD and related variables such as eGFR and albuminuria are rarely included in CVD risk prediction tools, limiting their use for stratification, investigation and management of these patients. Moreover, these tools are believed to underestimate CVD risk in CKD. Recent data-driven evidence has increased utility in early-stage CKD, but generalisability to ESKD remains poor.1,19 Biochemical and radiological investigations to stratify risk among patients are also challenging; investigations may cause adverse effects which affects the interpretation of results. Cardiac biomarkers such as troponins and N-terminal pro B-type natriuretic peptide are frequently raised in CKD, limiting their specificity for cardiac abnormality.1,20,21 Research is needed to elucidate the significance of CKD-specific troponin thresholds and the value of serial measurements for CAD and AMI diagnosis.22 Gold standard radiological investigations including CT angiography and pharmacological MRI stress test may cause contrast-induced nephropathy and nephrogenic systemic sclerosis, respectively and the risks must be balanced against diagnostic significance.23,24 Pharmacological stress echocardiography and nuclear myocardial perfusion scans are more widely available and are not subject to the same risk profiles, however they provide a lower sensitivity and specificity when compared to the gold standard tools, and when used in non-CKD patients.24–26

Coronary Artery Disease

CAD is common in CKD, with incidence rising linearly as eGFR declines.

Simultaneous management of CAD is challenging and it is associated with

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CVD in CKD: An Introduction

2-year survival probability following CVD event

Figure 1: Changing Cardiovascular Disease Risk in Progressing Chronic Kidney Disease Non-atherosclerotic CVD events e.g. LVH, arrhythmias, SCD, haemorrhagic stroke

0.8

0.5 Atherosclerotic CVD events e.g. AMI, ischaemic stroke, PAD 1

3

5 dialysis

Heart Failure

time

About half of all patients with heart failure (49%) have CKD and the combination is associated with greater mortality and hospitalisation.3,32 HF and mortality risk worsen as renal function declines and this is independent of age, duration of HF or diabetes.32 Diagnosis is challenging as symptoms of fluid overload such as dyspnoea and peripheral oedema are common to HF and CKD.21

KDIGO CKD stages

Traditional risk factors e.g. hypertension, diabetes

Non-traditional risk factors e.g. uraemia, anaemia, inflammation, oxidative stress, arterial/valvular calcification, dialysis-related factors

As CKD progresses, the risk of CVD events rises. Mortality following cardiovascular events also increases. Non-atherosclerotic causes contribute more than atherosclerotic causes as CKD progresses. This is reflected in the respective contribution of traditional and non-traditional risk factors in early and late-stage disease. Time is also an important factor – the longer time spent in each stage of CKD before commencing dialysis will result in longer exposure to the risk factors and greater accumulated damage and risk.1,13–15 AMI = acute MI; CKD = chronic kidney disease; CVD = cardiovascular disease; KDIGO = Kidney Disease: Improving Global Outcomes Group; LVH = left ventricular hypertrophy; PAD = peripheral arterial disease; SCD = sudden cardiac death.

Figure 2: Annual Rates of Sudden Cardiac Death Prevalence 5% Incidence (first year) 7%

Haemodialysis

Heart failure Non-dialysis CKD GP

The ISCHEMIA-CKD trial showed no significant mortality benefit after revascularisation in stable CAD for CKD patients.31 Revascularisation also poses significant risks that must be considered, including contrastinduced acute kidney injury, poor access sites for cardiac catheterisation, post-procedure infection, potential implications for vascular access for dialysis and duration of dual antiplatelet therapy.1 CKD patients are also less likely to receive guideline-recommended treatments for acute coronary syndrome. Risk-benefit analyses are challenging as these patients face a higher risk of ischaemic and haemorrhagic complications, and the mortality benefit of invasive strategies declines with worsening eGFR.20

4%

Pharmacological management for HF with reduced ejection fraction (HFrEF) is efficacious in CKD stages 1–3. However, evidence is sparse for their use in CKD stages 4–5 as these patients are largely excluded from clinical trials. Guidelines support use of renin-angiotensin-aldosterone system inhibiting drugs for CKD-HF, yet they are often underused because of the risk of hyperkalaemia.33 Alternative pharmacological management with diuretics and ß-blockers may cause drug resistance and electrolyte derangement.21 Additionally, optimising CKD-related conditions can alleviate HF. There is a strong evidence base for using IV iron for irondeficiency anaemia in CKD-HF.34 Notably, empagliflozin has demonstrated efficacy in treatment of HFrEF and HF with preserved ejection fraction, for which there were previously no treatments.35,36 Empagliflozin is a sodium-glucose cotransporter 2 inhibitor that was primarily used in the treatment of type 2 diabetes, a common CKD cause and comorbidity. It has also been shown to slow the rate of renal function decline, regardless of CKD severity.35,37

Arrhythmias

Approximately 1.5–2.7%

<0.1%

CKD = chronic kidney disease; GP = general population. Source: Turakhia et al. 2019.41 Reproduced with permission from Oxford University Press.

a poor prognosis in these patients.27 The mainstay of CAD management is lipid-lowering medications. Statins become less beneficial with CKD progression, with no clear benefit in dialysis patients. Newer medications are efficacious and safe in mild/moderate CKD, but effects are unclear in advanced disease. The SHARP trial and subsequent studies have argued that concomitant use of statins and ezetimibe may safely attenuate cardiovascular risk even for ESKD, although further investigation is needed.28,29 The alternative management of CAD is revascularisation. Although revascularisation reduces cardiovascular symptoms, it only appears to confer survival benefit in CKD patients with a high baseline cardiovascular risk, and is associated with a higher rate of renal failure.30 The burden of permanent dialysis treatment must therefore be weighed up against the symptomatic benefits of coronary revascularisation.

CKD predisposes individuals to arrhythmias, most commonly AF with 16– 21% of CKD patients and 15–40% of dialysis patients have AF.38,39 AF also increases risk of CKD and its progression.40 The conditions share many risk factors and unlike numerous CVD risk scores, the AF CHA2DS2-VASc and HAS-BLED scores work similarly in CKD as in the general population.41,42 Managing AF and stroke risk in these patients is challenging due to the safety and efficacy of available treatments. Direct oral anticoagulants (DOAC) are non-inferior to warfarin when creatinine clearance is 30–50 mL/min, and are markedly safer.41,43 However, in later-stage CKD, there is conflicting evidence for using DOACs at adjusted dose and insufficient evidence to support warfarin use.41,44 These patients have a high risk of bleeding and other adverse effects. In these patients, consideration must also be given to the competing risk of death in CKD when assessing risk benefit in AF stroke prevention.45

Sudden Cardiac Death

Sudden cardiac death is very common in CKD, particularly in ESKD (Figure 2). Numerous risk factors have been identified, but further research is essential to elucidate the contribution of these risk factors and to facilitate prevention strategies.41

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CVD in CKD: An Introduction Figure 3: The Delivery and Benefits of the Multidisciplinary Clinic for CKD Patients with HF Multidisciplinary clinic for CKD patients with heart failure

Anaemia nurse

Cardiologist

β-blockers, ACEi, MRA, ivabradine SLT2i, CRT

Cared for by

Treated with

Nephrologist

IV iron

Diuretic

Improved quality of life

Benefits

Fewer deaths

Fewer hospitalisations

ACEi = angiotensin converting enzyme inhibitor; CRT = cardiac resynchronisation therapy; MRA = mineralocorticoid receptor antagonist; SLT2i = sodium–glucose cotransporter 2 inhibitor.

Source: Banerjee and Wang. 2021.52 Reproduced with permission from Oxford University Press.

Valvular Heart Disease

VHD is common in CKD and is associated with significantly reduced survival with 5-year mortality with at least mild aortic stenosis (AS) or mitral regurgitation (MR) being >50% greater than people without CKD.46 The primary pathophysiological mechanism is valvular calcification, which is more prevalent than in the general population, worsens with declining renal function and is independently associated with adverse cardiovascular outcomes.47–49 Clinical presentation of VHD can often be mistaken for CKD as symptoms also include dyspnoea and fatigue.

Calcimimetic drugs have been considered for VHD prevention in CKD, but this requires further study. Valvular regurgitation in these patients is often functional and potentially reversible with adjustment of volume status using dialysis. Strict volume status control may prevent the progression of VHD, but no medical intervention has shown benefit.49 Surgical and transcutaneous atrial valve replacement are commonly performed in these patients. These procedures carry similar risks and benefits compared to the general population in CKD stages 1–3. While this improves symptoms throughout CKD, rates of complications, progression to dialysis and mortality risk increase unacceptably with worsening eGFR.50,51 Percutaneous mitral valve replacement with MitraClip is also commonly performed, improving cardiac function, symptoms and renal function in CKD patients regardless of eGFR at baseline. However, these patients face worse outcomes with higher rates of hospitalisation and mortality.

Careful patient selection for these interventions is therefore essential.

Additionally, consideration of patients’ individual treatment goals, such as symptomatic relief versus life-prolonging treatment, are pivotal to informing risk-benefit analyses and patient-centred shared decisionmaking.49

The Multidisciplinary Approach

The complex bidirectional relationship between CVD and CKD, combined with common multimorbidity and limitations of standardised risk scores, benefit from corroboration between specialists. A multidisciplinary team approach including cardiologist, nephrologists and allied healthcare professionals improves management and patient-centred HF care through joint clinics (Figure 3).52

Conclusion

CVD is very common in CKD and vice versa. The presence of each condition promotes incidence and progression of the other. Despite the high prevalence, morbidity and mortality of these comorbid conditions, there are significant limitations to our current knowledge and management of this vulnerable group. CKD patients are grossly underrepresented in CVD research, limiting generalisability of available data. Standardised risk scores that are often used to guide investigations and management in CVD are likely to underestimate risk in CKD. Moreover, investigations have poorer sensitivity and specificity and may come with unacceptable adverse effects.

Drug management is complex due to limited evidence, dose adjustments due to renal function and adverse effects. As such, these patients are less likely to receive guideline-recommended management. Interventions are

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CVD in CKD: An Introduction largely safe and effective in CKD stages 1–3, but there is insufficient evidence to support their use in later-stage kidney disease. If interventions are used in CKD stages 4–5, they are more strongly associated with adverse effects and complications.

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Wanner C, Amann K, Shoji T. The heart and vascular system in dialysis. Lancet 2016;388:276–84. https://doi.org/10.1016/ S0140-6736(16)30508-6; PMID: 27226133.

United States Renal Data System. Cardiovascular disease in patients with CKD. In: 2020 Annual Data Report. 2020. https:// adr.usrds.org/2020/chronic-kidney-disease/4-cardiovasculardisease-in-patients-with-ckd (accessed 24 August 2021).

Wheeler DC, London GM, Parfrey PS, et al. Effects of cinacalcet on atherosclerotic and nonatherosclerotic cardiovascular events in patients receiving hemodialysis: the EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) trial. J Am Heart Assoc 2014;3:e001363. https://doi.org/10.1161/JAHA.114.001363; PMID: 25404192.

Sosnov J, Lessard D, Goldberg RJ, et al. Differential symptoms of acute myocardial infarction in patients with kidney disease: a community-wide perspective. Am J Kidney Dis 2006;47:378–84. https://doi.org/10.1053/j. ajkd.2005.11.017; PMID: 16490615.

Go AS, Bansal N, Chandra M, et al. Chronic kidney disease and risk for presenting with acute myocardial infarction versus stable exertional angina in adults with coronary heart disease. J Am Coll Cardiol 2011;58:1600–7. https://doi. org/10.1016/j.jacc.2011.07.010; PMID: 21958887.

Shroff GR, Li S, Herzog CA. Trends in discharge claims for acute myocardial infarction among patients on dialysis. J Am Soc Nephrol 2017;28:1379–83. https://doi.org/10.1681/ ASN.2016050560; PMID: 28220031.

As CKD progresses and the incidence of CVD rises, we have less knowledge and fewer management options. The complexity of these comorbid conditions necessitates a multidisciplinary approach to improve patient-centred care.

19. Anker SD, Gillespie IA, Eckardt KU, et al. Development and validation of cardiovascular risk scores for haemodialysis patients. Int J Cardiol 2016;216:68–77. https://doi. org/10.1016/j.ijcard.2016.04.151; PMID: 27140339.

20. Collet JP, Thiele H, Barbato E, et al. 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021;42:1289–367. https://doi.org/10.1093/eurheartj/ ehaa575; PMID: 32860058.

21. House AA, Wanner C, Sarnak MK, et al. Heart failure in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2019;95:1304–17. PMID: 31053389.

22. Banerjee D, Perrett C, Banerjee A. Troponins, acute coronary syndrome and renal disease: from acute kidney injury through end-stage kidney disease. Eur Cardiol 2019;14:187–90. https://doi.org/10.15420/ecr.2019.28.2; PMID: 31933690.

23. Rudnick MR, Leonberg-Yoo AK, Litt HI, et al. The controversy of contrast-induced nephropathy with intravenous contrast: what is the risk? Am J Kidney Dis 2020;75:105–13. https://doi. org/10.1053/j.ajkd.2019.05.022; PMID: 31473019.

24. Dilsizian V, Gewirtz H, Marwick TH, et al. Cardiac imaging for coronary heart disease risk stratification in chronic kidney disease. JACC Cardiovasc Imaging 2021;14:669–82. https://doi.org/10.1016/j.jcmg.2020.05.035; PMID: 32828780.

25. Winther S, Svensson M, Jørgensen HS, et al. Diagnostic performance of coronary CT angiography and myocardial perfusion imaging in kidney transplantation candidates.

JACC Cardiovasc Imaging 2015;8:553–62. https://doi. org/10.1016/j.jcmg.2014.12.028; PMID: 25869350.

26. Wang LW, Fahim MA, Hayen A, et al. Cardiac testing for coronary artery disease in potential kidney transplant recipients. Cochrane Database Syst Rev 2011;12:CD008691. https://doi.org/10.1002/14651858.CD008691.pub2; PMID: 22161434.

27. Sarnak MJ, Amann K, Bangalore S, et al. Chronic kidney disease and coronary artery disease: JACC state-of-the-art review. J Am Coll Cardiol 2019;74:1823–38. PMID: 31582134.

28. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial.

Lancet 2011;377:2181–92. https://doi.org/10.1016/S01406736(11)60739-3; PMID: 21663949.

29. Stanifer JW, Charytan DM, White J, et al. Benefit of ezetimibe added to simvastatin in reduced kidney function.

J Am Soc Nephrol 2017;28:3034–43. https://doi.org/10.1681/ ASN.2016090957; PMID: 28507057.

30. Charytan DM, Natwick T, Solid CA, et al. Comparative effectiveness of medical therapy, percutaneous revascularization, and surgical coronary revascularization in cardiovascular risk subgroups of patients with CKD: a retrospective cohort study of medicare beneficiaries. Am J Kidney Dis 2019;74:463–73. https://doi.org/10.1053/j. ajkd.2019.04.018; PMID: 31255335.

31. 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. PMID: 32227756 32. Löfman I, Szummer K, Dahlström U, et al. Associations with and prognostic impact of chronic kidney disease in heart failure with preserved, mid-range, and reduced ejection fraction. Eur J Heart Fail 2017;19:1606–14. https://doi. org/10.1002/ejhf.821; PMID: 28371075.

33. Murphy D, Ster IC, Kaski JC, et al. The LIFT trial: study protocol for a double-blind, randomised, placebo-controlled trial of K+-binder Lokelma for maximisation of RAAS inhibition in CKD patients with heart failure. BMC Nephrol 2021;22:254. https://doi.org/10.1186/s12882-021-02439-2; PMID: 34229607.

34. Macdougall IC, Bircher AJ, Eckhardt K-U, et al. Iron management in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2016;89:28–39. https://doi.org/10.1016/j.kint.2015.10.002; PMID: 26759045.

35. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure.

2020;383:1413–24. https://doi.org/10.1056/NEJMoa2022190; PMID: 32865377.

36. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med

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Zannad F, Ferreira JP, Pocock SJ, et al. Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: insights from EMPERORReduced. Circulation 2021;143:310–21. https://doi.org/10.1161/ CIRCULATIONAHA.120.051685; PMID: 33095032.

Ananthapanyasut W, Napan S, Rudolph EH, et al. Prevalence of atrial fibrillation and its predictors in nondialysis patients with chronic kidney disease. Clin J Am Soc Nephrol 2010;5:173–81. https://doi.org/10.2215/CJN.03170509; PMID: 20007681.

Königsbrügge O, Posch F, Antlanger M, et al. Prevalence of atrial fibrillation and antithrombotic therapy in hemodialysis patients: cross-sectional results of the Vienna InVestigation of AtriaL Fibrillation and Thromboembolism in Patients on HemoDIalysis (VIVALDI). PLoS One 2017;12:e0169400. https:// doi.org/10.1371/journal.pone.0169400; PMID: 28052124.

Bansal N, Xie D, Kelvin T, et al. Atrial fibrillation and risk of ESRD in adults with CKD. Clin J Am Soc Nephrol 2016;11: 1189– 96. https://doi.org/10.2215/CJN.10921015; PMID: 27073197.

Turakhia MP, Blanksetijn PJ, Carrero JJ, et al. Chronic kidney disease and arrhythmias: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Eur Heart J 2018;39:2314–25. https://doi. org/10.1093/eurheartj/ehy060; PMID: 29522134.

Bonde AN, Lip GYH, Kamper AN, et al. Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study. J Am Coll Cardiol 2014;64;2471–82. https://doi. org/10.1016/j.jacc.2014.09.051; PMID: 25500231.

Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2021;42:373–498. https://doi.org/10.1093/eurheartj/ehaa612; PMID: 32860505.

Hylek EM. Apixaban for end-stage kidney disease: More questions for the randomized trials. Circulation 2018;138: 1534–6. https://doi.org/10.1161/CIRCULATIONAHA.118.036449; PMID: 30354524.

Shih CJ, Ou SM, Chao PW, et al. Risks of death and stroke in patients undergoing hemodialysis with new-onset atrial fibrillation: a competing-risk analysis of a nationwide cohort.

Circulation 2016;133:265–72. https://doi.org/10.1161/ CIRCULATIONAHA.115.018294; PMID: 26680239.

Samad Z, Sivak JA, Phelan M, et al. Prevalence and outcomes of left-sided valvular heart disease associated with chronic kidney disease. J Am Heart Assoc 2017;6:e006044. https://doi.org/10.1161/JAHA.117.006044; PMID: 29021274.

Guerraty MA, Chai B, Hsu JY, et al. Relation of aortic valve calcium to chronic kidney disease (from the Chronic Renal Insufficiency Cohort study). Am J Cardiol 2015;115:1281–6. https://doi.org/10.1016/j.amjcard.2015.02.011; PMID: 25791240.

Raggi P, Bellasi A, Gamboa C, et al. All-cause mortality in hemodialysis patients with heart valve calcification. Clin J Am Soc Nephrol 2011;6:1990–5. https://doi.org/10.2215/ CJN.01140211; PMID: 21700824.

Marwick TH, Amann K, Bangalore S, et al. Chronic kidney disease and valvular heart disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2019;96:836– 49. https://doi.org/10.1016/j.kint.2019.06.025; PMID: 31543156.

Thourani VH, Keeling WB, Sarin EL, et al. Impact of preoperative renal dysfunction on long-term survival for patients undergoing aortic valve replacement. Ann Thorac Surg 2011;91:1798–806. https://doi.org/10.1016/j. athoracsur.2011.02.015; PMID: 21536247.

Hansen JW, Foy A, Yadav P, et al. Death and dialysis after transcatheter aortic valve replacement: an analysis of the STS/ACC TVT Registry. JACC Cardiovasc Interv 2017;10:2064– 75. https://doi.org/10.1016/j.jcin.2017.09.001; PMID: 29050623.

Banerjee D, Wang AYM. Personalizing heart failure management in chronic kidney disease patients. Nephrol Dial Transplant 2021. https://doi.org/10.1093/ndt/gfab026; PMID: 33591313; epub ahead of press.

OBITUARY

Obituary: C Richard Conti, MD

P

rof C Richard (“Dick”) Conti, MD, MACC, EFESC, FCP(SA), FAHA, passed away unexpectedly on 21 February 2022. As his long-time colleague and close friend, I am honoured to have been invited by Editor-in-Chief Prof Juan Carlos Kaski to write this obituary for European Cardiology Review, where Dick served on the Editorial Board as an International Advisor for many years.

Dick was born in Bethlehem, PA, and graduated from Lehigh University in Eastern Pennsylvania.

He received his MD in internal medicine and cardiology training at Johns Hopkins University, Baltimore, PA, and then joined the cardiology faculty in 1968 as an Associate Professor of Medicine, serving as Medical Director of the Cardiovascular Diagnostic Laboratory and the Wellcome Research Laboratory. During the Vietnam era, he served as Captain, Medical Corp, in the US Army.

In early 1974, he recruited several of us to move with him to the University of Florida (UF) College of Medicine in Gainesville, FL, where he served as Professor of Medicine and Chief of the Cardiology Division for a quarter of century until 1998. During this period, he developed a division that achieved national and international recognition and was awarded the newly created American Heart Association Eminent Scholar Chair in Cardiovascular Education in 1988. After he retired, he received the 2015 UF College of Medicine Faculty Council’s Lifetime Achievement Award.

One of his earliest and most important accomplishments was chairing the NHLBI National Cooperative Study comparing intensive medical therapy (IMT) with urgent coronary bypass surgery for acute management of unstable angina (1972–78). This pioneering prospective randomised trial confirmed that such patients could be stabilised with IMT, including propranolol and long-acting nitrates in pharmacological doses, with good control of angina in most and no increase in early mortality or myocardial infarction.

Later, if angina failed to respond to IMT, elective coronary artery bypass grafting could be performed with a lower risk and good clinical results.

Dick was committed to education and excellence. During his career, he held positions on most American College of Cardiology (ACC) Committees and Task Forces, including the Board of Trustees, and was elected President 1989–90. He served on the Editorial Boards of the ACC and European Society of Cardiology (ESC) journals and many other peer-reviewed cardiovascular disease journals. During his long tenure (2000–10) as Editor of the ACC’s audio journal ACCEL Audio, his commitment to education was well documented in the recordings of his probing interviews and commentaries. Dick worked tirelessly to encourage medical students, residents and fellows to become involved in academic pursuits. He was a key part of the Florida ACC Chapter for over three decades and initiated the Chapter’s young investigator activities.

Through his international efforts and love of travel, he was involved in many ACC, ESC and other cardiology educational efforts throughout the world. Notably, he assisted the ESC in its growth and development in the late 1980s–2000s. More recently, he worked to assist the Chinese with their educational programmes via The Great Wall International Conference of Cardiology, which he helped to initiate and co-chaired with Prof Dayi Hu since 1989. He actively participated in the annual meetings in Beijing and their publications until the COVID-19 pandemic.

Dick Conti was incredible in his persistence for excellence in patient care and education, and these traits were also reflected in all other aspects of his work. Simply put, he made us all better cardiologists and better people. European Cardiology Review, and cardiology at large, have lost an important part of their history with Dick’s passing. He is survived by his wife of 64 years, Ruth, daughters Jill, Jamie and Jennifer, son Richard, five grandchildren and two great-grandchildren.

Carl J Pepine Division of Cardiovascular Medicine, University of Florida, Gainesville, FL, US

Citation: European Cardiology Review 2022;17:e14. DOI: https://doi.org/10.15420/ecr.2022.21 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.

© RADCLIFFE CARDIOLOGY 2022 www.ECRjournal.com

REVIEW

Cardio-oncology

Chest Pain in the Cancer Patient Sara Tyebally ,1 Aruni Ghose ,2 Daniel H Chen ,1,3 Aderonke T Abiodun

1

and Arjun K Ghosh

1,3

1. Cardio-Oncology Service, Barts Heart Centre, St Bartholomew’s Hospital, London, UK; 2. Oncology Department, St Bartholomew’s Hospital, London, UK; 3. Hatter Cardiovascular Institute, UCL Institute of Cardiovascular Science, University College London Hospital, London, UK

Abstract

Chest pain is one of the most common presenting symptoms in patients seeking care from a physician. Risk assessment tools and scores have facilitated prompt diagnosis and optimal management in these patients; however, it is unclear as to whether a standardised approach can adequately triage chest pain in cancer patients and survivors. This is of concern because cancer patients are often at an increased risk of cardiovascular mortality and morbidity given the shared risk factors between cancer and cardiovascular disease, compounded by the fact that certain anti-cancer therapies are associated with an increased risk of cardiovascular events that can persist for weeks and even years after treatment. This article describes the underlying mechanisms of the most common causes of chest pain in cancer patients with an emphasis on how their management may differ to that of non-cancer patients with chest pain. It will also highlight the role of the cardio-oncology team, who can aid in identifying cancer therapy-related cardiovascular side-effects and provide optimal multidisciplinary care for these patients.

Keywords

Cardio-oncology, cardiotoxicity, chest pain, acute coronary syndrome.

Disclosure: The authors have no conflicts of interest to declare.

Received: 27 August 2021 Accepted: 10 January 2022 Citation: European Cardiology Review 2022;17:e15. DOI: https://doi.org/10.15420/ecr.2021.45 Correspondence: Sara Tyebally, Cardio-Oncology Service, Barts Heart Centre, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, UK. E: s.tyebally@nhs.net 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.

Chest pain is one of the most frequent symptoms in patients seeking treatment in primary care and the emergency department (ED).1 It accounts for up to 6% of attendances to the ED and 20% of emergency admissions to hospital.2,3 The development and introduction of a standardised approach in the management of these patients through risk assessment scores has improved the time to diagnosis and reduced hospital admissions alongside mortality and morbidity.4 However, it is unclear as to whether a standardised approach can adequately triage chest pain events in cancer patients and survivors.

These specific cohorts of cancer patients are particularly vulnerable, given the link between cancer and excess risk of heart disease. Moreover, cancer treatments, including chemotherapy, immunotherapy and radiation therapy, are associated with an increased risk in cardiovascular events that can persist for weeks or even years after the completion of treatment.5–7 In addition, nearly two-thirds of these patients are aged 65 years or older, with a higher prevalence of comorbidities than younger patients, making their evaluation a distinctive challenge.8 Last, there remains a concern that healthcare providers might falsely attribute symptoms of heart disease, such as fatigue and dyspnoea to cancer, therefore resulting in suboptimal management.9 It is paramount that healthcare providers are aware of the additional risks that cancer patients and survivors face, given that cardiovascular disease is now the leading cause of death in many cancer survivors, ahead of cancer recurrence. Unfortunately, patients with cancer have been excluded from most major cardiology trials and registries, and their

cardiovascular management remains largely empirical and extrapolated from non-cancer cardiac patients.10 A multidisciplinary approach to the management of these complex patients, facilitated by the cardio-oncology team, will produce the best outcomes.11 This review will cover the most common causes of chest pain in patients with cancer, with an emphasis on its underlying mechanisms and how its management may differ to that of non-cancer patients with chest pain. It will also highlight the importance of prompt referral to the cardio-oncology team, who can aid in identifying cancer therapy-related cardiovascular side-effects and provide optimum multidisciplinary care for these patients.

Potential Causes of Chest Pain in Cancer Patients

Cancer patients and survivors can present with chest pain due to multiple causes (Figure 1).

Acute Coronary Syndromes

Coronary artery disease (CAD) and cancer often co-exist.12 A variety of anti-cancer therapies have a significant impact on the cardiovascular system, and can cause endothelial damage, vasospasm, platelet activation and/or aggregation, and attraction of elevated LDL cholesterol particles (Table 1). Cancer disease has been reported to be present in up to 17% of patients with acute coronary syndrome (ACS), and approximately 1 in 10 patients undergoing percutaneous coronary intervention (PCI) have either a current or historical diagnosis of cancer, with prostate, breast, colon and lung cancers being the four most common types of cancer encountered.13,14 Unfortunately, cancer patients requiring PCI are often at

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Chest Pain in the Cancer Patient Figure 1: Potential Causes of Chest Pain in Cancer Patients and Survivors

Valvular heart disease

Acute coronary syndromes

(Radiotherapy, anthracyclines, secondary to infective endocarditis or non-bacterial thrombotic endocarditis)

•

Coronary vasospasm (fluoropyrimidines, taxanes, TKIs, alkylating agents)

•

Coronary artery thrombosis (cisplatin, VEGFi, malignancy)

•

Accelerated atherosclerosis (radiotherapy, TKIs, ICIs, hormone therapy)

•

Tumour compression (primary tumour, metastases)

Arrhythmia •

AF or atrial flutter (TKIs, alkylating agents, taxanes)

•

Bradycardia or conduction abnormalities (ICIs, radiotherapy, VEGFi, TKIs, thalidomide)

•

QT prolongation (arsenic trioxide, anthracyclines, antimetabolite, electrolyte abnormalities)

•

Non-cardiac

Ventricular arrhythmia (secondary to myocarditis, ischaemia or torsades de pointes from QTc prolongation, TKIs)

•

Pulmonary embolism

•

Pneumonitis

•

Malignant pleural effusion

Myocarditis Pericarditis or pericardial effusion

(ICIs, CAR T-cell therapy, radiotherapy, infection due to immunosuppression)

(Radiotherapy, infection due to immunosuppression, antimetabolites, anthracyclines, taxanes, alkylating agents, ICIs)

CAR = chimeric antigen receptor; ICI = immune checkpoint inhibitor; TKI = tyrosine kinase inhibitor; VEGFi = vascular endothelial growth factor inhibitor.

an increased risk of complications, adverse cardiac events and mortality, and the underlying causes are likely to be multifactorial.15 Different cancer subtypes are associated with different adverse outcomes. For example, colon cancer with metastases has the strongest independent association with major bleeding events, with almost a fivefold increase in risk.14 Patients with metastatic cancer, irrespective of cancer type, have a poorer prognosis after PCI and are at an increased risk of in-hospital mortality and PCI complications, including major bleeding events.14 A retrospective study by Borovac et al. showed that a lymphoma diagnosis is independently associated with an increased likelihood of adverse short-term clinical outcomes, higher rates of bleeding, vascular complications, and in-hospital mortality once adjustments for differences in baseline characteristics were applied in those undergoing PCI.15 Cancer patients with ACS tend to present more atypically compared with non-cancer patients. Less than one-third of cancer patients with ACS (30.3%) present with chest pain, 44% experience dyspnoea, and 23% present with hypotension.16 Therefore, it is important to have a higher clinical suspicion when screening cancer patients for ACS.

Initial investigations include a 12-lead ECG and serial serum troponin levels. An echocardiogram is helpful in determining regional wall motion abnormalities and left ventricular ejection fraction. Further investigations may include ischaemia testing or, when appropriate, invasive coronary angiography.

The management of these patients can often be challenging because they are often excluded from prospective studies and trials assessing the efficacy and safety of ACS treatment. As a result, their treatment is often not supported by a strong evidence base, and current guidelines for invasive and conservative treatment of ACS are not easily applied to all cancer patients. Potential concerns that may arise include the presence of anaemia, thrombocytopenia and coagulopathy in cancer patients.

Approximately 10% of cancer patients have platelet counts <100 × 109/l, which increases the risk of bleeding, the propensity for thrombus formation, and other adverse cardiac events.17 A prophylactic platelet transfusion should be considered at a threshold of 20,000/ml in patients with solid tumours, and for those with demonstrated necrotic tumours, due to the increased risk of bleeding at these sites.18 There is no minimum platelet count indicator for a diagnostic coronary angiogram.18 For platelet

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Chest Pain in the Cancer Patient Table 1: Cancer Treatments Frequently Associated with Acute Coronary Syndromes and Their Pathophysiological Mechanisms Anti-cancer Treatment Agent

Proposed Mechanism

Fluoropyrimidines (e.g. 5-fluorouracil, capecitabine, gemcitabine)

Coronary vasospasm, thrombosis, endothelial injury

Vascular endothelial growth factor inhibitors (e.g. bevacizumab)

Endothelial dysfunction, coronary vasospasm, vascular remodelling, inflammation, platelet activation, increased plaque vulnerability

Alkylating agents (e.g. cisplatin)

Pro-coagulant state, coronary thrombosis (endothelial damage, thromboxane production, platelet activation and aggregation)

Immunomodulatory agents (e.g. lenalidomide, pomalidomide)

Arterial thrombosis

Hormone therapy (e.g. abiraterone)

Accelerated atherosclerosis

Anti-microtubule agents (e.g. paclitaxel, docetaxel)

Coronary vasospasm

Vinca alkaloids (e.g. vincristine, vinblastine)

Coronary vasospasm

Tyrosine kinase inhibitors (e.g. niolotinib and ponatinib)

Endothelial dysfunction, prothrombotic state, increased plaque vulnerability

Radiotherapy (e.g. mantle radiotherapy)

Endothelial injury, plaque rupture, thrombosis, fibrosis of the vessel wall, accelerated atherosclerosis

counts <30 × 109/l, revascularisation and dual antiplatelet therapy (DAPT) may be recommended after a preliminary multidisciplinary evaluation (interventional cardiology, cardio-oncology, oncology and haematology) and a risk–benefit analysis.18 For anaemic patients, red blood cell transfusion is generally recommended when haemoglobin is less than 7 g/dl, and consultation with haematology and oncology specialists is recommended for severely anaemic cancer patients undergoing cardiac catheterisation.18 Another important consideration is vascular access in cancer patients. For cancer patients who are suitable candidates for both radial and femoral access, the radial artery is generally preferred. In cancer patients on haemodialysis, those with abnormal Allen’s tests in both arms, multiple radial procedures or a-lines, bilateral mastectomy, or for whom a complex intervention is anticipated, femoral access may be the preferred approach.18 In general, when PCI is indicated, careful patient selection based on performance status, cancer prognosis, type of malignancy and anticipated cancer therapy can often determine the timing of the intervention, the access site, and the revascularisation approach. For example, in cancer patients with an expected survival of less than 1 year, percutaneous revascularisation may be considered for patients with acute ST-elevation MI and high-risk non-ST-elevation MI. In patients with stable angina, it would be reasonable to ensure that every effort made to optimise medical therapy before resorting to an invasive strategy.18 In the event that PCI is required in patients awaiting cancer surgery, balloon angioplasty without stenting or implantation with newer generation drug-eluting stents may be required in order to minimise and reduce the duration of DAPT, given that any interruption in DAPT may lead to in-stent thrombosis, especially in the types of cancer with an increased propensity for thrombosis.

Due to the above considerations necessary in cancer patients presenting with ACS, the need for early referral to the cardio-oncology team to facilitate multidisciplinary decision-making on a case-by-case basis is imperative.

Mechanisms of ACS in Cancer Patients

The mechanisms of CAD and ACS can differ significantly in cancer patients compared with the general population.19

These findings underscore the importance of both primary and secondary prevention in this population. Clinical evaluation and, when necessary, testing for detection of myocardial ischemia is key to identifying patients with latent pre-existing CAD. This may have implications for the selection of cancer treatment.20

Coronary Artery Vasospasm

Fluoropyrimidines, which include 5-fluorouracil (5-FU) and capecitabine, form the cornerstone of several different chemotherapy regimens and are known to cause MI via coronary artery vasospasm in cancer patients, with an incidence of 2–34% for 5-FU and 3–9% for capecitabine.21–24 These agents alter the tone of vascular smooth muscle cells. Pre-existing CAD remains a risk factor for fluoropyrimidine-related vasospastic angina, which most probably reflects the observation that vasospasm tends to occur at sites of thrombus and plaque formation; however, its exact underlying mechanisms have yet to be fully understood.25,26 Patients on 5-FU or capecitabine presenting with chest pain should have their fluoropyrimidine infusion ceased immediately, followed by treatment with medical anti-anginal therapy aimed at symptomatic relief, such as calcium channel blockers and/or nitrates, which have been shown to abolish symptoms in up to 69% of affected patients.23 Once a patient has been diagnosed with fluoropyrimidine-related cardiotoxicity, rechallenge is not advised in most patients, given that rates of recurrence of cardiotoxicity as high as 90% have been reported, along with a mortality rate of up to 13%.23 However, careful consideration of the risks against the potential benefits of re-treatment is advised for each individual.27 Other chemotherapeutic agents that can cause coronary artery vasospasm include vascular endothelial growth factor inhibitors (VEGFi), with an incidence of 1–15%.28 Paclitaxel and docetaxel can induce severe coronary vasospasm, which has also been reported to cause ACS. Hypomagnesaemia, which frequently accompanies cisplatin therapy, may provoke vasospasm of the coronary arteries.29,30 Chemotherapy may be continued when results from all non-invasive and/ or invasive tests are normal.21,22 Any potentially modifiable risk factors and diseases should be optimised prior to rechallenge with vasotoxic therapy.

Coronary Artery Thrombosis

Cancer is recognised as a prothrombotic venous and arterial state and the

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Chest Pain in the Cancer Patient incidence of arterial thrombosis specifically is higher in cancer patients, in whom spontaneous coronary thrombosis without underlying atherosclerosis has been observed.31 This may occur through circulating microparticles, secretion of procoagulant factors, and alterations in platelet activity and endothelial function.32 Patients across all age groups with myeloproliferative neoplasms are at significant risk compared with matched controls, with the highest rates at and shortly after diagnosis.33 Advanced cancer stage is also associated with an increased risk of arterial thromboembolism; in patients who do develop arterial thromboembolism this carries a poor prognosis, with a threefold increased HR for death compared with non-cancer patients.31 Chemotherapeutic agents may also increase the risk of arterial thrombosis.

Cisplatin is associated with a 6–10% risk of venous or arterial thrombosis, while VEGFi are associated with a 3.8% risk of arterial thrombosis.34,35 Treatment options include acute percutaneous recanalisation of the blocked artery when indicated. The optimal anti-thrombotic strategy to treat acute arterial thromboembolism in patients with cancer is, however, unclear. This cohort of patients sometimes receive empirical long-term anticoagulation because of concerns regarding cancer-mediated hypercoagulability, however, this decision is best made via close collaboration with the patient’s oncologist and/or haematologist and cardiologist.

Atherosclerosis/Accelerated Atherosclerosis

CAD is more prevalent in cancer patients due to their shared risk factors (e.g. obesity, smoking, age, sedentary lifestyle).36,37 Cancer therapies may also lead to an increased rate of coronary atherosclerosis and therefore the incidence of cardiovascular events has been increasing in younger patients over the years. Radiation causes vascular endothelial damage, which in turn promotes inflammation and accelerates atherosclerosis.

Coronary ostia and proximal segments are typically involved, and the most exposed coronary arteries are the left anterior descending artery during left breast irradiation and the left main stem, circumflex, and right coronary arteries during treatment for mediastinal Hodgkin’s lymphoma.38 For cancer survivors the incidence of fatal MI in patients treated with mediastinal radiation therapy is 1.5–threefold greater than in those who had not received radiation therapy, with the risk of damage heavily dependent on the dose and radiation field.39,40 In this cohort of patients, the indications for screening with non-invasive cardiac imaging remain unclear. However, aggressive cardiac risk factor modification and followup in late-effects clinics are essential.

Chemotherapeutic agents may also cause accelerated atherosclerosis.

Such agents include VEGFi, tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs) and hormone therapies such as abiraterone.

Common cardiovascular events during treatment with these agents include rapidly progressive peripheral artery occlusive disease and acute myocardial ischaemic events.

Acute Coronary Syndrome via Tumour Compression

Patients with cancer can also develop signs and symptoms of myocardial ischaemia because of coronary artery compression by various primary and secondary cardiac tumours. Primary angiosarcoma of the coronary arteries leading to ACS is extremely rare.41 ACS secondary to tumour compression usually signifies advanced disease and management should be in close consultation with the oncology team.42

Myocarditis

Contemporary anticancer immunotherapy has changed the landscape of treatment for patients with a variety of malignancies who historically had a poor prognosis. However, any therapy that modulates the immune system has the potential to be associated with myocarditis. Most recently, this clinical entity has been most observed in the setting of ICIs and chimeric antigen receptor (CAR) T-cell therapy.43–45 The incidence of ICI-associated myocarditis is unclear given the lack of routine cardiac monitoring in most immunotherapy trials; however, it has been reported to range from 0.06% to 1% of patients prescribed an ICI, with its prevalence reported to be higher with combination immune therapies. Although the risk factors for ICI-associated myocarditis are not well characterised, diabetes and obesity have been independently associated with higher occurrence.46 ICI-associated myocarditis occurs early at a median time of 1–2 months, with most of the cases occurring within 3 months after starting ICI therapy.43,47 Patients typically present with a wide range of symptoms including chest pain, shortness of breath, non-specific symptoms, such as fatigue and myalgia, and in some instances, sudden cardiac death.48,49 Clinicians should be vigilant for immune-mediated myocarditis, particularly due to its early onset, non-specific symptomatology and fulminant progression.

Initial investigations include a 12-lead ECG and serial troponin levels.

Echocardiographic findings may vary from a normal examination to reduced thickening, reduced global longitudinal strain, regional and global wall motion abnormalities and/or diastolic dysfunction.46,50 Cardiac MRI also offers helpful information regarding the presence of prior MI scar, diffuse fibrosis and interstitial oedema.51 With regards to treatment, although data from rigorous studies of treatment for immune-related adverse events are unavailable to date, consensus guidelines recommend high-dose steroids with progressive tapering, dependent on patient symptoms and cardiac troponin levels.52 In cases in which an improvement is not seen, other immunosuppressant agents such as infliximab, rituximab and mycophenolate mofetil can be considered.52 Rechallenge may be considered (often with a single agent) in the context of an individualised approach after a multidisciplinary discussion.

Another possible anti-cancer treatment that may cause myocarditis is CAR T-cell therapy. CAR T-cell immunotherapy is associated with potentially lifethreatening cytokine release syndrome, which in turn may lead to myocardial injury, arrhythmia, cardiomyopathy and circulatory collapse.45,53,54 It usually develops early on after CAR T-cell infusion (median time, 2.2 days) with the highest risk in the first 2 weeks after infusion.55 Fortunately, current data suggest that CAR T-cell-related cardiovascular complications are acute and transient, with the incidence of persistent left ventricular systolic dysfunction at 6 months being very low, and with no late cardiovascular effects observed at 1-year follow up.56,57 Supportive treatment, as well as tocilizumab, an anti-interleukin-6 receptor antibody, is the cornerstone of treatment. Recent findings suggest that pre-existing cardiovascular risk factors and disease may increase the risk of such cardiotoxicity, and prompt recognition, as well as treatment, may favourably alter the outcomes.58 In essence, a multidisciplinary approach is crucial for the management of patients on novel immunotherapies, and cardio-oncologists play a fundamental role in the comprehensive care of these patients.

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Chest Pain in the Cancer Patient Another less common cause of myocarditis in cancer patients is radiation myocarditis secondary to high-dose radiation treatment. This can eventually result in myocardial fibrosis with subsequent restrictive cardiomyopathy. Management of radiation-caused cardiomyopathy is similar to the treatment of other types of cardiomyopathy and is typically symptomatic treatment.59

Pericardial Disease

Malignant involvement of the pericardium is detected in 1–20% of autopsy studies of cancer patients.60 The spectrum of the acute clinical presentation can include acute pericarditis, pericardial effusion with or without cardiac tamponade, or pericardial constriction. Pericardial disease in cancer patients can be as a result of their cancer treatment, such as chemotherapy or radiotherapy. Determining the aetiology and providing effective treatment can often be challenging.

Pericarditis

Pericarditis is the commonest form of pericardial disease and is responsible for around 5% of chest pain presentations to EDs.61,62 Mortality rates can reach 1%.63 In an unselected cohort of pericarditis patients, approximately 5% of cases were attributable to underlying cancer.62 The underlying mechanisms responsible for acute pericarditis in cancer patients include direct metastasis to the heart, pericardial haemorrhage, infections due to immunosuppression, and cancer therapies such as fludarabine, cytarabine, doxorubicin, docetaxel and cyclophosphamide, as well as radiation therapy. Acute pericarditis can occur during radiotherapy itself or within weeks after radiotherapy.64–66 ICIs may also cause acute pericarditis, and it can occur with coexisting myocarditis.67 The treatment of acute pericarditis is usually as per recommended guidelines in the general population. However, it should be noted that many cancer patients may have a predisposition to bleeding due to abnormal blood counts or coagulation abnormalities secondary to their disease or treatment. It can thus be challenging to introduce routine therapy such as non-steroidal anti-inflammatory agents in this context. As a result, there is often a greater and earlier use of other agents, for example colchicine and steroids, although this may not alter outcomes.63 In the case of radiotherapy-induced acute pericarditis, treatment of the primary malignancy should not be withheld because of this.68

Pericardial Effusion and Cardiac Tamponade

Cancer has been noted to be the most common cause of pericardial effusion in the Western world.69,70 In cancer patients, pericardial effusion can be caused by cancer invasion or it can occur secondary to anti-cancer treatment including radiation therapy, or secondary to infection due to underlying immunosuppression. The presence of a pericardial effusion in cancer patients carries significant morbidity and mortality.62,71,72 Patients with pericardial effusions or tamponade can present with symptoms such as syncope, chest pain or palpitations. The symptoms could also be subtle, such as dyspnoea, non-specific chest discomfort and simple fatigue.

The mainstay of treatment is to allow sufficient drainage of the pericardial fluid to relieve the symptoms and prevent recurrence. Pericardiocentesis is an easier and less invasive procedure than pericardial window surgery, enabling prompt treatment at the time of diagnosis. However, pericardiocentesis leads to a recurrence rate of up to 20% at 30 days, which is higher than the rate of recurrence after surgical drainage (1–10%).

Rarely, malignant pericardial effusions are managed with intrapericardial injection of chemotherapeutic agents.73

Pericardial Constriction

In cancer patients, constrictive pericarditis can be caused by radiation exposure or chemotherapy, or it can occur as a sequela of previous episodes of pericarditis in which scarring with loss of pericardial elasticity has occurred over time. Cancer patients may present with non-specific chest pains although more commonly may report fatigue and exertional dyspnoea. The definitive treatment for chronic constrictive pericarditis remains pericardiectomy performed in experienced cardiac centres.

Arrhythmias

Rhythm abnormalities can occur in cancer patients due to anti-cancer treatment, potential drug–drug interactions during the course of treatment and metabolic and electrolyte derangements. The real incidence of cancer therapy-induced arrhythmias is likely to be underestimated because routine cardiac monitoring is often not performed.

AF is the most common sustained arrhythmia and is increasing in both prevalence and incidence.74 Currently, the prevalence of AF in cancer patients ranges between 2% and 15%, with higher rates reported for certain classes of antineoplastic drugs such as TKIs.75 In addition, cancer and AF share common risk factors such as age, smoking, alcohol use and obesity.76 Patients with AF are at an increased risk of cerebrovascular events, and anticoagulation may be necessary to reduce such risks. Recent comparative effectiveness data for patients with AF and cancer consistently have shown that direct oral anticoagulants are associated with lower or similar risks of bleeding and stroke compared with warfarin.77 Ultimately, multidisciplinary care that accounts for individualised risk factors, patient preference and periodic clinical reassessment is warranted to identify the optimal anticoagulation regimen.77 Other arrhythmias include conduction disease, QT prolongation and ventricular tachycardias.

Patients may present with chest pain although more commonly may report palpitations, pre-syncopal symptoms or symptoms related to heart failure. A proportion of patients would be asymptomatic, with the diagnosis being made only on routine monitoring.

The role of the cardio-oncology team in the prevention and management of arrhythmias in cancer patients is multifold, and includes baseline assessment upon cancer diagnosis, monitoring and management during active cancer, and long-term surveillance in cancer survivors.

Valvular Disease Valvular Disease Secondary to Radiation Therapy/Chemotherapy

Radiation exposure is a risk factor in the development of clinically significant valvular heart disease. In a post-mortem series the incidence was high, with 81% of patients who had received radiotherapy in the past showing evidence of mild valvular damage.78 There is a latent interval of 10–20 years between radiation exposure and the development of clinically significant heart valve disease.

Patients may present with chest pain (more commonly seen with aortic stenosis), however, they are more likely to report symptoms of heart

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Chest Pain in the Cancer Patient failure such as worsening shortness of breath on exertion and peripheral oedema.

gastrointestinal cancers. This can be secondary to dyspepsia, obstruction from local tumours or strictures from previous radiotherapy treatment.

Radiation-associated valvular disease is a complex disease that requires an integrated and multidisciplinary approach. With regard to patients suitable for percutaneous or surgical intervention, individualised timing and technique are critical, and therefore these patients should be managed at high-volume centres with experience in managing radiationassociated valvular disease.79

Conclusion

Non-cardiac Chest Pain

It is important to consider other causes of chest pain that may be noncardiac in origin. These include pulmonary embolism given that it is more commonly seen in patients with cancer who have a sevenfold increased risk for venous thromboembolism, with an overall absolute risk of 7% in the first year of a cancer diagnosis and up to 20% depending on the type of cancer and treatments used.80–82 Other respiratory causes include malignant pleural effusions and pneumonitis, which can occur secondary to anti-cancer therapies including radiation therapy. Gastrointestinal pathology is another frequent cause of non-cardiac chest pain in patients with upper 1.

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67. Chahine J, Shekhar S, Mahalwar G, et al. Pericardial involvement in cancer. Am J Cardiol 2021;145:151–9. https:// doi.org/10.1016/j.amjcard.2020.12.092; PMID: 33460602.

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69. Gornik HL, Gerhard-Herman M, Beckman JA. Abnormal cytology predicts poor prognosis in cancer patients with pericardial effusion. J Clin Oncol 2005;23:5211–6, https://doi. org/10.1200/JCO.2005.00.745; PMID: 16051963.

70. Wilkes JD, Fidias P, Vaickus L, Perez RP. Malignancy-related pericardial effusion: 127 cases from the Roswell Park Cancer Institute. Cancer 1995;76:1377–87. https://doi. org/10.1002/1097-0142(19951015)76:8<1377::aidcncr2820760813>3.0.co;2-m; PMID: 8620412.

71. Imazio M, Colopi M, De Ferrari GM. Pericardial diseases in patients with cancer: contemporary prevalence, management and outcomes. Heart 2020;106:569–74, https://doi.org/10.1136/heartjnl-2019-315852; PMID: 31980441.

72. Søgaard KK, Farkas DK, Ehrenstein V, et al. Pericarditis as a marker of occult cancer and a prognostic factor for cancer mortality. Circulation 2017;136:996–1006. https://doi. org/10.1161/CIRCULATIONAHA.116.024041; PMID: 28663234.

73. Jeon HW, Cho DG, Park JK, et al. Prognostic factors affecting survival of patients with cancer-related pericardial effusion managed by surgery. World J Surg Oncol 2014;12:249. https://doi.org/10.1186/1477-7819-12-249; PMID: 25091001.

74. Schnabel RB, Yin X, Gona P, et al. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study. Lancet 2015;386:154–62. https://doi.org/10.1016/S01406736(14)61774-8; PMID: 25960110.

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76. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021;42:373–498. https://doi.org/10.1093/eurheartj/ehaa612; PMID: 32860505.

77. Shah S, Norby FL, Datta YH, et al. Comparative effectiveness of direct oral anticoagulants and warfarin in patients with cancer and atrial fibrillation. Blood Adv 2018;2:200–9. https://doi.org/10.1182/ bloodadvances.2017010694; PMID: 29378726.

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REVIEW

Management and Comorbidities

Asian Pacific Society of Cardiology Consensus Statements on the Diagnosis and Management of Obstructive Sleep Apnoea in Patients with Cardiovascular Disease Jack Wei Chieh Tan ,1,2 Leong Chai Leow,3 Serene Wong,4,5,6 See Meng Khoo,4,5,6 Takatoshi Kasai ,7 Pipin Kojodjojo ,8 Duong-Quy Sy ,9 Chuen Peng Lee ,10 Naricha Chirakalwasan ,11,12 Hsueh-Yu Li,13 Natalie Koh,1 Adeline Tan,14 Thun How Ong,3 Aye Thandar Aung ,15 Song Tar Toh 16,17 and Chi-Hang Lee 5,8 1. Department of Cardiology National Heart Centre Singapore, Singapore; 2. Department of Cardiology, Sengkang General Hospital, Singapore; 3. Department of Respiratory and Critical Care Medicine; Singapore General Hospital, Singapore; 4. Division of Respiratory & Critical Care Medicine, Department of Medicine, National University Hospital, Singapore; 5. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 6. Fast and Chronic Programmes, Alexandra Hospital, Singapore; 7. Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; 8. Department of Cardiology, National University Heart Centre Singapore, Singapore; 9. Clinical Research Center, Lam Dong Medical College, Dalat, Vietnam; Pham Ngoc Thach Medical University, Ho Chi Minh City, Vietnam; 10. Department of Respiratory and Critical Care Medicine, Tan Tock Seng Hospital, Singapore; 11. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 12. Excellence Center for Sleep Disorders, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; 13. Department of Otolaryngology – Head and Neck Surgery, Sleep Center, Chang Gung Memorial Hospital, Taoyuan City, Taiwan; 14. Division of Respiratory Medicine, Department of Medicine, Ng Teng Fong General Hospital, Singapore; 15. Department of Cardiovascular Medicine, Mandalay General Hospital, Mandalay, Myanmar; 16. Department of Otorhinolaryngology – Head and Neck Surgery, Singapore General Hospital, Singapore; 17. Singhealth Duke-NUS Sleep Centre, Singapore

Abstract

Obstructive sleep apnoea (OSA) is strongly associated with cardiovascular disease (CVD). However, evidence supporting this association in the Asian population is scarce. Given the differences in the epidemiology of CVD and cardiovascular risk factors, as well as differences in the availability of healthcare resources between Asian and Western countries, an Asian Pacific Society of Cardiology (APSC) working group developed consensus recommendations on the management of OSA in patients with CVD in the Asia-Pacific region. The APSC expert panel reviewed and appraised the available evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Consensus recommendations were developed and put to an online vote. Consensus was reached when 80% of votes for a given recommendation were in support of ‘agree’ or ‘neutral.’ The resulting statements provide guidance on the assessment and treatment of OSA in patients with CVD in the Asia-Pacific region. The APSC hopes for these recommendations to pave the way for screening, early diagnosis and treatment of OSA in the Asia-Pacific region.

Keywords

Obstructive sleep apnoea, cardiovascular disease, Asia-Pacific, consensus Disclosure: JWCT has received honoraria from AstraZeneca, Bayer, Amgen, Medtronic, Abbott Vascular, Biosensors, Alvimedica, Boehringer Ingelheim and Pfizer; research and educational grants from Medtronic, Biosensors, Biotronik, Philips, Amgen, AstraZeneca, Roche, Ostuka, Terumo and Abbott Vascular; and consulting fees from Elixir and CSL Behring; and is on the European Cardiology Review editorial board; this did not influence peer review. TK is affiliated with an institution receiving endowment from Philips, ResMed and Fukuda Denshi. All other authors have no conflicts of interest to declare.

Funding: This work was funded through Asian Pacific Society of Cardiology by unrestricted educational grants from the Lee Foundation.

Acknowledgements: Medical writing support was provided by Ivan Olegario.

Received: 11 December 2021 Accepted: 7 February 2022 Citation: European Cardiology Review 2022;17:e16. DOI: https://doi.org/10.15420/ecr.2021.59 Correspondence: Jack Wei Chieh Tan, National Heart Centre, 5 Hospital Dr, Singapore 169609. E: jack.tan.w.c@singhealth.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 non-commercial purposes, provided the original work is cited correctly.

Obstructive sleep apnoea (OSA) is strongly associated with cardiovascular disease (CVD).1 A few studies in Asia have reported an OSA prevalence ranging from 4.1% to 7.5% in men and from 2.1% to 4.5% in women, with an overall prevalence of 8.5% in the general adult population aged >18 years.2,3 Furthermore, a multi-ethnic southeast Asian country has shown an increase in prevalence to 30%.4 The influence of ethnicity on prevalence has also been demonstrated.4,5

The reported prevalence rates of OSA in patients with coronary heart disease, stroke, heart failure (HF) and arrhythmia are as high as 65%, 75%, 55% and 50%, respectively.6–10 In studies on Asian patients with coronary artery disease undergoing percutaneous coronary intervention or surgical revascularisation, the prevalence of OSA is around 45–50%.11,12 However, the prevalence of OSA among Asian patients with other forms of CVD is less well established.

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APSC Consensus on OSA in CVD Patients Given the limited published clinical evidence and country-specific guidelines on the management of OSA in patients with CVD in the AsiaPacific region, the Asian Pacific Society of Cardiology (APSC) developed consensus recommendations to guide general cardiologists, internal medicine specialists practicing cardiology and sleep physicians in the Asia-Pacific region on the diagnosis and treatment of OSA in patients with CVD. These recommendations are intended to improve screening, early diagnosis and treatment throughout the Asia-Pacific region.

Methods

The APSC convened an expert consensus panel to review the literature on the screening, assessment and treatment of OSA, discuss gaps in current management, determine areas where further guidance is needed and develop consensus recommendations on the diagnosis and management of OSA in patients with CVD. The 16 panel experts were members of the APSC who were nominated by national societies and endorsed by the APSC’s consensus board or invited international experts. The expert consensus panel comprised cardiologists and sleep specialists from Japan, Myanmar, Singapore, Taiwan, Thailand and Vietnam.

After a comprehensive literature search, applicable articles were reviewed and appraised using the Grading of Recommendations Assessment, Development, and Evaluation system, as follows: 1. High (authors have high confidence that the true effect is similar to the estimated effect.

2. Moderate (authors believe that the true effect is probably close to the estimated effect).

3. Low (true effect might be markedly different from the estimated effect).

4. Very low (true effect is probably markedly different from the estimated effect).13 Using these levels of evidence, the authors adjusted the level of evidence if the estimated effect when applied to the Asia-Pacific region might differ from the published evidence because of various factors such as ethnicity, cultural differences and/or healthcare systems and resources.

The available evidence was then discussed during a consensus meeting held in April 2021. Consensus recommendations were developed during the meeting, which were then put to an online vote. Each recommendation was voted on by each panel member using a three-point scale (agree, neutral, or disagree). Consensus was reached when 80% of votes for a given recommendation were agree or neutral. In the case of nonconsensus, the recommendations were further discussed via email and revised accordingly until the criteria for consensus were fulfilled.

Consensus Recommendations Screening and Diagnosis Recommendation 1. Any one of the following conditions should prompt the clinician to screen patients for OSA: • hypertension; • type 2 diabetes; • obesity; • coronary artery disease; • stroke; • HF; or • arrhythmia.

Level of evidence: Very low.

Level of consensus: 81.25% agree; 12.5% neutral; 6.25% disagree.

Recommendation 2. Symptoms of OSA or screening questionnaires, such as STOP-Bang, may be used to screen for OSA in patients with CVD. Level of evidence: Low. Level of consensus: 87.5% agree; 12.5% neutral; 0% disagree.

Recommendation 3. Patients with the following conditions should be referred to a sleep specialist for sleep testing: • resistant hypertension; • AF requiring cardioversion/ablation; or • unexplained pulmonary hypertension.

Level of evidence: Moderate.

Level of consensus: 100% agree; 0% neutral; 0% disagree.

Recommendation 4. In patients suspected of OSA after screening with significant cardiopulmonary disease (HF, congenital heart disease or complicated valvular disease), polysomnography (Level I) should be used to diagnose OSA. Level III or Level IV sleep studies should not be used to diagnose OSA in these patients because of the complexity of the clinical scenario, which may lead to misdiagnosis.

Level of evidence: Very low.

Level of consensus: 87.5% agree; 12.5% neutral; 0% disagree.

Recommendation 5. In patients with a high pre-test probability of moderate to severe OSA without significant cardiopulmonary disease or stroke, home sleep apnoea testing (Level III or IV) or polysomnography (Level I/II) may be used to diagnose OSA. Level of evidence: Moderate.

Level of consensus: 93.75% agree; 0% neutral; 6.25% disagree.

Recommendation 6. Sleep studies conducted on patients with CVD should be scored and reported by an adequately trained sleep specialist.

Level of evidence: Very low.

Level of consensus: 87.5% agree; 12.5% neutral; 0% disagree.

Because of the association between OSA and CVD, it is not surprising that patients with certain CVDs and/or cardiovascular risk factors have a disproportionately high prevalence of OSA (Figure 1).6–10 Hence, the panel voted to screen patients with these conditions, namely hypertension, type 2 diabetes, obesity, coronary artery disease, stroke, HF and arrhythmia.

This recommendation is in line with the 2009 recommendations from the Adult Obstructive Sleep Apnea Task Force of the American Academy of Sleep Medicine (AASM).14 Certain physical features should also prompt physicians to screen for OSA (Figure 1). It should be noted that the AsiaPacific classification of BMI has a lower cut-off value for the obesity category (25 kg/m2) than the WHO’s classification (30 kg/m2).15 However, some expert panel members noted that screening patients with these fairly prevalent conditions may lead to cardiologists needing to screen a high proportion of patients in daily practice. Others noted that the benefit of screening varies across the conditions, with some conditions, such as hypertension, obesity, coronary artery disease, HF and AF (rather than other arrhythmias), having stronger evidence of benefit.

A number of screening questionnaires are available that can be used to screen patients for OSA. During the expert panel meeting, most of the

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APSC Consensus on OSA in CVD Patients Figure 1: Patient Characteristics That May Suggest Obstructive Sleep Apnoea Modified Mallampati III/IV

PHYSICAL CHARACTERISTICS* • Modified Mallampati III/IV • Adenotonsillar hypertrophy • Tongue ridging • Small, receding chin • Neck circumference >40 cm • Obesity (BMI ≥25 kg/m2)

SYMPTOMS • Snoring • Choking or gasping during sleep • Excessive daytime sleepiness • Unrefreshing sleep, fatigue ortiredness • Repetitive awakenings • Nocturia

Table 1: STOP-Bang Questionnaire Question

Adenotonsillar hypertrophy

Tongue ridging

Hard palate Tongue

Soft palate not visible (obstructed by tongue)

Tonsils extending way beyond tonsillar pillars

Ridging along lateral tongue

COMORBIDITIES (Prevalence of OSA) • Hypertension (30–83%) • Heart failure (12–55%) • Type 2 diabetes (18–86%) • Pulmonary hypertension (16–89%) • Obesity (25%) • Coronary artery disease (38–65%) • Stroke (57–75%) • Arrhythmias (20–50%)

*Not all of these physical characteristics need to be present to suspect OSA. OSA = obstructive sleep apnoea. Level of consensus: 100% agree; 0% neutral; 0% disagree. Sources: Javaheri et al.

2017, Doumit and Prasad 2016, Garvey et al. 2015, Romero-Corral et al. 2010 and Kholdani et al.

2015.6–10

panellists reported that STOP-Bang is one of the most commonly used questionnaires at their respective institutions, largely because of its ease of administration compared with other questionnaires, such as the Berlin questionnaire (Tables 1, 2 and 3).16 STOP-Bang was also shown to have the best diagnostic accuracy for OSA.17 A study conducted on a multi-ethnic Asian population also concluded that the STOP-Bang questionnaire could be used as a screening tool among Asians in view of its moderate sensitivity and high negative predictive value for patients with moderate-to-severe OSA and severe OSA.18 The benefit of interventions in patients without OSA symptoms, such as excessive daytime sleepiness, remains unclear. A rapid and easy-toperform screening test is needed; thus, the panellists also voted that checking for symptoms of OSA is a reasonable screening tool for daily practice (Figure 1).

Patients with resistant hypertension, AF requiring cardioversion/ablation, or unexplained pulmonary hypertension have an exceptionally high risk of severe cardiovascular adverse events. In these patients, treatment for OSA, if present, has been shown to confer benefit.19–23 Hence, the panel voted in favour of early referral to a sleep specialist for prompt evaluation in such patients. Several panellists also noted that after thorough evaluation, sleep specialists may be able to identify underlying causes of these conditions without needing to proceed to sleep testing or to identify patients who would not benefit from further sleep testing.

The 2020 European Society of Cardiology guidelines on the management of AF recommended that OSA treatment should be optimised to reduce AF recurrences and improve AF treatment results, with a Class IIB recommendation (level of evidence C), and stated: “It remains unclear how and when to test for OSA and implement OSA management in the standard work-up of AF patients.”24 In the multidisciplinary clinical management strategy proposed by Tietjens et al., diagnostic sleep testing for all patients with recurrent AF following either cardioversion or ablation, including those without symptoms of sleep-disordered breathing (SDB), as well as AF patients who are persistently symptomatic, challenging to pharmacologically

Response

STOP Snoring? Do you snore loudly (loud enough to be heard through closed doors or your bed-partner elbows you for snoring at night)?

Yes or No

Tired? Do you often feel tired, fatigued, or sleepy during the daytime (such as falling asleep during driving or talking to someone)?

Yes or No

Observed? Has anyone observed you stop breathing or choking/ gasping during your sleep?

Yes or No

Pressure? Do you have or are being treated for high blood pressure?

Yes or No

BANG BMI? BMI more than 35 kg/m2?

Yes or No

Age? Age older than 50 years?

Yes or No

Neck size large? Is your shirt collar 16 inches/40 cm or larger (measured around the Adam’s apple)?

Yes or No

Gender? Are you a man?

Yes or No

Source: Used with permission from http://www.stopbang.ca/osa/screening.php52

Table 2: STOP-Bang Questionnaire Interpretation Interpretation OSA: Low risk

Yes to 0–2 questions

OSA: Intermediate risk:

Yes to 3–4 questions

OSA: High risk:

• • • •

Yes to 5–8 questions; or Yes to 2 or more of 4 STOP questions + male gender; or Yes to 2 or more of 4 STOP questions + BMI >35 kg/m2; or Yes to 2 or more of 4 STOP questions + neck circumference 16 inches/40 cm.

OSA = obstructive sleep apnoea. Source: Used with permission from http://www.stopbang.ca/osa/ screening.php52

Table 3: STOP-Bang Diagnostic Accuracy for Detecting Moderate to Severe Obstructive Sleep Apnoea (Apnoea–Hypopnoea Index >15) and Severe Obstructive Sleep Apnoea (Apnoea–Hypopnoea Index >30) Moderate to Severe OSA (AHI >15)

Severe OSA (AHI >30)

Sensitivity: 92.9% (95% CI [84.1–97.6]) Specificity: 43.0% (95% CI [33.5–52.9]) PPV: 51.6% (95% CI [42.5–60.6]) NPV: 90.2% (95% CI [78.6–96.7])

Sensitivity: 100% (95% CI [91.0–100.0]) Specificity: 37.0% (95% CI [28.90–45.6]) PPV: 31.0% (95% CI [23.0–39.8]) NPV: 100% (95% CI [93.0–100.0])

AHI = apnoea–hypopnoea index; NPV = negative predictive value; OSA = obstructive sleep apnoea; PPV = positive predictive value. Source: Chung et al. 2008.16 Adapted with permission from Wolters-Kluwer.

rate control or managed via rhythm control strategies, when there is a suspicion for sleep apnoea based on comprehensive sleep assessment.19 The APSC consensus agrees with these recommendations and acknowledged the importance of an accurate diagnosis in these patients.

Hence, the panel voted in favour of an early referral to a sleep specialist for all AF patients requiring cardioversion or ablation (e.g. those persistently symptomatic despite initial rate/rhythm control strategies), regardless of the presence of clinically suspected SDB.

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APSC Consensus on OSA in CVD Patients Patients with significant cardiopulmonary disease (HF with reduced ejection fraction, congenital heart disease or complicated valvular disease) are at a high risk of central sleep apnoea (CSA) or mixed sleep apnoea.6,25 Polysomnography (Level I) rather than home sleep apnoea testing (HSAT) should be the diagnostic test of choice if patients have coexisting and significant cardiopulmonary disease, a history of stroke, or suspected non-respiratory sleep disorders (Table 4). This recommendation is in line with AASM and American Heart Association (AHA)/American College of Cardiology (ACC) guidelines.18,26 Other conditions that may affect the accuracy of HSAT include potential respiratory muscle weakness due to neuromuscular conditions, chronic opiate use and environmental or personal factors that may interfere with the conduct and interpretation of HSAT.26 In contrast, among patients with a high pre-test probability of moderate to severe OSA (including those with very severe OSA) after screening but without significant cardiopulmonary disease or stroke, both HSAT (Level III or IV) and polysomnography (Level I) may be used to diagnose OSA.27,28 In this context, clinicians may use the AASM definition of high pre-test probability of moderate to severe OSA, which includes patients with daytime hypersomnolence and at least two of the following: habitual loud snoring, witnessed apnoea or gasping/choking, or diagnosed hypertension.26 Finally, because of the complexity of interpreting sleep studies, such tests conducted on patients with CVD should be scored and reported by a qualified or adequately trained sleep specialist.29 The expert panel also reported that at some centres in the region, sleep tests are scored by a registered sleep technologist and interpreted by a sleep specialist.

Figure 2 summarises the screening and testing pathway for patients with CVD. However, one panellist cautioned that some patients with HF may require further sleep testing, even with a negative OSA screening questionnaire or in the absence of signs and symptoms of OSA.

Treatment and Referral Recommendation 7. All patients undergoing OSA treatment should also undergo lifestyle modification and educational and behavioural interventions for OSA, as well as for weight loss if they are classified as overweight or obese.

Level of evidence: Very low.

Level of consensus: 100% agree; 0% neutral; 0% disagree.

Recommendation 8. OSA treatment improves daytime sleepiness and cognitive function. In observational studies, continuous positive airway pressure (CPAP) therapy for OSA is strongly associated with reduced rates of adverse cardiovascular events, but randomised control trial evidence to support CPAP therapy in non-sleepy OSA patients with CVD is inconclusive.

Level of evidence: Low. Level of consensus: 93.75% agree; 6.25% neutral; 0% disagree.

Recommendation 9. Patients with HF and OSA may undergo CPAP therapy, which has been shown to improve ventricular function, symptoms and quality of life.

Level of evidence: Moderate.

Level of consensus: 93.75% agree; 6.25% neutral; 0% disagree.

Recommendation 10. Patients undergoing rhythm control for AF who have moderate to severe OSA should undergo CPAP therapy to reduce the risk of AF recurrence.

Level of evidence: Low. Level of consensus: 93.75% agree; 6.25% neutral; 0% disagree.

Recommendation 11. Patients with CVD and OSA whose OSA symptoms persist despite treatment or who are non-adherent to OSA therapy should be reviewed by a sleep specialist.

Level of evidence: Very low.

Level of consensus: 100% agree; 0% neutral; 0% disagree.

All patients with CVD and OSA should be educated with regard to their diagnosis, risk factors and the natural history and consequences of OSA.15,30 They should also be educated on the impact of their treatment and encouraged to continue treatment. Furthermore, all patients should be educated on lifestyle modifications, sleep hygiene and behavioural interventions that may help to minimise the impact of OSA. These include interventions to help reduce weight in patients who are classified as overweight or obese; improved sleep positions in cases of positional OSA; and the avoidance of alcohol and medications that may worsen OSA (e.g. benzodiazepines, barbiturates, other anti-epileptic drugs, sedative antidepressants, antihistamines and opiates). When such medications are necessary, their use should be closely monitored and the dose carefully titrated, if possible.

Weight loss and exercise should be recommended to all patients with OSA who are classified as overweight or obese.14,30–35 Weight loss has been shown to improve overall health and metabolic parameters, decrease the apnoea–hypopnoea index (AHI), reduce blood pressure and improve quality of life for patients with OSA, although weight loss alone rarely leads to complete remission of OSA. Given that obesity and inactivity are cardiovascular risk factors, weight loss and exercise are also recommended in patients with CVD and OSA. Exercise may also modestly improve OSA, even in the absence of significant weight loss. A 2014 metaanalysis found that a supervised exercise program significantly improved AHI (mean change, −6 events/hour), sleep efficiency, subjective sleepiness and cardiorespiratory fitness, even without substantial weight loss.36 In a randomised clinical trial (RCT), 2,717 adults aged between 45 and 75 years with moderate to severe OSA and coronary or cerebrovascular disease were randomised to undergo CPAP plus usual care or usual care alone. The study found that the primary composite endpoint of death from cardiovascular causes, MI, stroke, hospitalisation for unstable angina, HF, or transient ischemic attack was not significantly reduced by CPAP therapy. However, CPAP therapy significantly reduced daytime sleepiness (p<0.001) and significantly improved the physical and mental subscales of the 36-Item Short Form Health Survey of the Medical Outcomes Study.37 It should be noted that this study excluded patients with severe daytime sleepiness (Epworth Sleepiness Scale score of >15), although these patients are most likely to benefit from CPAP therapy.

Some observational studies have suggested that CPAP therapy may be effective in reducing cardiovascular outcomes (e.g. all-cause mortality, cardiovascular mortality, MI, stroke, repeat revascularisation) in patients with coronary artery disease, including after percutaneous coronary intervention.38–41 However, this benefit has not been confirmed in RCTs. A meta-analysis of nine RCTs (n=3,314) on adult patients with

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APSC Consensus on OSA in CVD Patients Table 4: American Academy of Sleep Medicine Classification of Sleep Apnoea Evaluation Level

Level I: Standard Polysomnography

Level II: Comprehensive Portable Polysomnography

Level III: Modified Portable Sleepapnoea Testing

Level IV: Continuous (Single or Dual) Bioparameter Recording

Minimum recording channels

EEG, EOG, chin EMG, ECG, airflow, respiratory effort and oxygen saturation.

Same as for Level I except heart rate instead of ECG is acceptable.

Recording of ventilation (at least two channels of respiratory movement, or respiratory movement and airflow), ECG or heart rate and oxygen saturation.

Only one or two physiological variables need to be recorded.

Personnel are needed for preparation.

Ability to intervene is not required for all studies.

Personnel are needed for preparation.

Ability to intervene is not required for all studies.

Personnel are needed for preparation.

Ability to intervene is not required for all studies.

Other characteristics Body position must be documented or objectively measured.

Leg movement recording (EMG or motion sensor) is desirable but optional.

Personnel and ability Trained personnel must be in constant to intervene attendance and able to intervene.

EOG = electrooculogram; EMG = electromyogram.

polysomnography-diagnosed OSA and any CVD found that the primary outcomes (i.e. all-cause death, cardiovascular death, acute MI, stroke and any major cardiovascular event) were not significantly reduced in patients undergoing CPAP therapy (pooled RR 0.93; 95% CI [0.70–1.24]; I2 49%).42 Possible reasons for this lack of benefit in the primary outcome include the overall low adherence to CPAP therapy, the inclusion of patients with low levels of symptoms or a heterogeneous pool of patients with different disease phenotypes and arterial oxygen desaturation and the potential lack of efficacy of CPAP in reducing recurrent cardiovascular events in patients with advanced or symptomatic atherosclerotic vascular disease.43–45 The 2017 AHA/ACC guidelines on HF identified CPAP therapy as a reasonable treatment strategy (class IIb) to improve sleep quality and daytime sleepiness in patients with CVD and OSA.46 Furthermore, CPAP therapy has beneficial haemodynamic effects, such as diminished systemic venous return, right ventricular preload and left ventricular afterload, as well as improved pulmonary total vascular resistance and ventricular diastolic function.47,48 Patients with paroxysmal AF, including those undergoing rhythm control strategies, such as cardioversion or ablation and moderate to severe OSA should undergo CPAP therapy to reduce the risk of recurrence. Multiple observational studies have assessed the ability of CPAP therapy to reduce the AF burden after ablation or cardioversion. Although limited by methodological issues and small sample sizes, these studies largely support the use of CPAP therapy in reducing the burden of AF.49 Furthermore, data from 1,841 patients with OSA and AF in the ORBIT-AF registry showed that patients who undergo CPAP therapy are less likely to progress to more permanent forms of AF than patients who do not undergo CPAP therapy (p=0.021).50 The proposed management of patients with CVD after HSAT in patients with a high pre-test probability is outlined in Figure 3. Figure 4 shows the proposed management of patients with CVD after polysomnography. In this algorithm, the first-line treatment for mild OSA is conservative management, which includes a combination of weight loss, positional sleep therapy, optimised treatment for nasal obstruction and oromyofunctional therapy. One panellist noted that oromyofunctional therapy requires adequate training of healthcare professionals, which may limit its implementation in some areas of the Asia-Pacific region.

Some expert panel members emphasised that co-management with a

Figure 2: Proposed Algorithm on Screening and Sleep Testing of Obstructive Sleep Apnoea in Cardiovascular Disease Patients Patient with cardiovascular disease

Are any of the following present?

• Resistant hypertension* • Unexplained pulmonary hypertension • AF requiring cardioversion or ablation YES

NO Signs or symptoms of OSA NO No further or positive OSA screening sleep questionnaire? testing YES With significant underlying cardiopulmonary disease or other indications for PSG?† YES

Refer to sleep specialist

PSG (Level I)

NO PSG (Level I) or HSAT (Level III or IV)

*Above-goal blood pressure despite therapy with three or more oral antihypertensive agents (commonly including a long-acting calcium channel blocker, a renin-angiotensin system blocker and a diuretic); or adequate blood pressure control requiring four or more agents.53 †Potential respiratory muscle weakness caused by neuromuscular disorders, documented awake hypoventilation or suspected sleep-related hypoventilation, chronic opioid use, severe insomnia, or suspected sleep-related movement disorder such as restless leg syndrome. HSAT = home sleep apnoea test; OSA = obstructive sleep apnoea; PSG = polysomnography. Level of consensus: 93.75% agree; 6.25% neutral; 0% disagree.

Figure 3: Proposed Management of Cardiovascular Disease Patients after the Home Sleep Apnoea Test in Patients with High Pre-test Probability of Obstructive Sleep Apnoea HSAT (Level Ill or IV)

Mild or no OSA

Moderate to severe OSA

Non-diagnostic or suboptimal test

Consider PSG (Level l)

• First- line: CPAP • Second-line: MAD, weight loss, surgery for those with favourable anatomy

Consider PSG (Level l)

CPAP = continuous positive airway pressure; HSAT = home sleep apnoea test; MAD = mandibular advancement device; OSA = obstructive sleep apnoea; PSG = polysomnography. Level of consensus: 93.75% agree; 0% neutral; 6.25% disagree.

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APSC Consensus on OSA in CVD Patients Figure 4: Proposed Management of Cardiovascular Disease Patients after Polysomnography PSG (Level 1)

Refer to sleep specialist

Other coexistent sleep disorders

Significant SDB

Mild OSA

Moderate to severe OSA

First-line: Conservative management including combination of weight loss, positional sleep therapy, optimise treatment of nasal obstruction, oromyofunctional therapy.

CSA or Mixed SDB

Co-manage with sleep specialist

Co-manage with sleep specialist to consider:

First-line: CPAP.

First-line: Optimise medical management of cardiovascular disease.

Second-line: MAD, weight loss, surgery for those with favourable anatomy.

Second-line: CPAP, MAD or surgery may be considered if significant symptoms persist.

Second-line: Fixed CPAP. Third-line: BPAP with backup rate.

Fourth-line: ASV (EF >45%), O2, drugs.

ASV = adaptive servo ventilation; BPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; CSA = central sleep apnoea; EF = ejection fraction; MAD = mandibular advancement device; OSA = obstructive sleep apnoea; PSG = polysomnography; SDB = sleep-disordered breathing. Level of consensus: 87.5% agree; 6.25% neutral; 6.25% disagree.

sleep specialist is encouraged in patients with moderate to severe OSA, or for patients with mild OSA if the attending cardiologist has inadequate expertise in its treatment. They also noted that a referral to an otorhinolaryngologist or dental sleep specialist for alternative OSA therapies may be needed in some patients with moderate to severe OSA. Finally, they emphasised the complexity of treating patients with CSA or mixed SDB; hence, referral to a sleep specialist is recommended. One panellist dissented, arguing that the treatment of CSA or mixed SDB using oxygen or pharmacotherapy remains controversial. The medical treatment of any associated CVD in patients with CSA or mixed SDB should also be optimised to improve outcomes.

Limitations

As a result of the obesity epidemic, the prevalence of OSA in Asia has increased in recent decades. However, the awareness of OSA in patients in Asia is low.51 These consensus recommendations aim to guide practising cardiologists and internal medicine specialists 1.

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Conclusion

Management of patients with CVD and OSA should be individualised and should consider the patient’s symptoms, clinical characteristics and comorbidities, as well as patients’ and caregivers’ concerns and preferences. Clinicians should also be aware of the challenges that may limit the applicability of these consensus recommendations, such as limited access to specific interventions and technologies, limited availability of resources, accepted local standards of care, cultural factors and individualised expertise in OSA management.

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