ECR 14.3 by Radcliffe Cardiology

European Cardiology Review Volume 14 • Issue 3 • Winter 2019

Volume 14 • Issue 3 • Winter 2019

www.ECRjournal.com

Behavioural Interventions to Reduce Cardiovascular Risk: Where Do We Stand? Gianluigi Savarese

Increasing and Evolving Role of Smart Devices in Modern Medicine Michael R Massoomi and Eileen M Handberg

Novel Aspects of Classification, Prognosis and Therapy in Takotsubo Syndrome Chiara Di Filippo, Beatrice Bacchi and Carlo Di Mario

Cardiology Masters Featuring: Josep Brugada Josep Brugada

ISSN: 1758-3756

E-cigarettes and cardiovascular disease

Platelet Function Guided Strategy with Clopidogrel or Ticagrelor

Role of Smart Devices in Modern Medicine

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

For the ﬁrst time, the ANNUAL SCIENTIFIC MEETING OF THE INTERNATIONAL SOCIETY OF CARDIOVASCULAR PHARMACOTHERAPY (ISCP) will come to the US for its 25TH congress! ISCP 2020 CALL FOR ABSTRACTS Submit your abstract today; selected abstracts will be considered for oral or poster presentations

ABSTRACT THEMES • Acute coronary syndromes • Biomarkers • Cardio-renal syndrome • Clinical trials • Diabetes, NASH, Obesity & related metabolic disorders • Heart Failure and Cardiomyopathies • Hypertension • Lipid therapy, anti-inﬂammatory therapy • Management of Arrhythmias • Peripheral arterial and venous disease • Prevention of cardiovascular disease • Pulmonary hypertension ©overcome

ABSTRACT SUBMISSION DEADLINE

February 8, 2020

Early Bird Registration Deadline: March 21, 2020 For further information, please contact: The ISCP 2020 team: iscp@overcome.eu Tel: +33 (0)1 40 88 97 97 Overcome: Ofﬁcial PCO for ISCP 2020 13-15 rue des Sablons, 75116 PARIS - France

w w w. i s c p 2 0 2 0 . c o m

MAY 7-9

2020

Volume 14 • Issue 3 • Winter 2019

www.ECRjournal.com Official journal of

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

Associate Editor Pablo Avanzas

University Hospital of Oviedo, Oviedo

International Advisers Richard Conti

University of Florida, Gainesville

Wolfgang Koenig

Giuseppe Mancia

Mario Marzilli

Hiroaki Shimokawa

Genetics and Cardiovascular Disease Eliecer Coto

Cardiovascular Disease in Women Angela Maas

Hypertension Maria Lorenza Muiesan

Epidemiology: Meta-analyses Gianluigi Savarese

Technical University of Munich, Munich

University of Milano-Bicocca, Milan

University of Pisa, Pisa

Tohoku University, Sendai

Section Editors Cardiac Imaging John Baksi Royal Brompton Hospital, London

Arrhythmias David Calvo

Hospital Universitario Central de Asturias

Genética Molecular-Laboratorio Medicina, HUCA, Oviedo

Structural Heart Disease: Cardiac Intervention Giuseppe Ferrante

Humanitas Research Hospital, Humanitas University, Milan

Radboud University, Nijmegen

Cardiomyopathies and Athletes Heart Disease Aneil Malhotra St George’s University of London, London

University of Brescia, Brescia

Ischaemic Heart Disease Giampaolo Niccoli

Catholic University of the Sacred Heart, Rome

Karolinska Institutet, Karolinska University Hospital, Stockholm

Pharmacotherapy Juan Tamargo

Universidad Complutense, CIBERCV, Madrid

Editorial Board Ramón Arroyo-Espliguero Head of Service, Hospital General Universitario, Guadalajara

Debasish Banerjee St George’s University of London, London

Vinayak Bapat

Columbia University Medical Centre, New York

Velislav Batchvarov

Thomas Kahan

Felipe Martinez

Alejandro Recio

Careggi University Hospital, Florence

Danderyd University Hospital, Danderyd

National University of Cordoba, Cordoba

Dirk Duncker

Koichi Kaikita

Antoni Martínez-Rubio

UICE-HP Cardiología, HU Virgen Macarena, Seville

Thoraxcentre, Cardiovascular Research School COEUR, University Medical Centre Rotterdam, Rotterdam, NL

Perry Elliott

University College, London

Albert Ferro

St George’s University of London, London

King’s College London, London

Antoni Bayés-Genís

Royal Liverpool University Hospital, Liverpool

Hospital Germans Trias i Pujol, Barcelona

John Beltrame University of Adelaide, Adelaide

Christopher Cannon Harvard Medical School, Boston

Peter Collins Imperial College, London

Derek Connolly

Sandwell & West Birmingham Hospitals NHS Trust, Birmingham

Alberto Cuocolo University of Naples Federico II, Naples

Gheorghe Andrei Dan Colentina University Hospital, Bucharest

Ranil de Silva

Michael Fisher

Augusto Gallino Ente Ospedaliero Cantonale, Bellinzona

Robert Gerber

Conquest Hospital, Hastings

Kumamoto University, Kumamoto

University Hospital of Sabadell, Sabadell

Magdi Saba

Mike G Kirby

John McNeill

St George’s University of London, London

University of Hertfordshire, Hatfield

Keld Per Kjeldsen Copenhagen University Hospital

Monash University, Melbourne

Noel Bairey Merz Cedars-Sinai Heart Institute, Los Angeles

(Holbaek Hospital), Holbæk

Argyrios Ntalias

Sreenivasa Rao Kondapally Seshasai

University of Athens, Athens

Peter Ong

Royal Bournemouth Hospital, Bournemouth, UK

Robert-Bosch-Krankenhaus, Stuttgart

Patrizio Lancellotti

St Bartholomew’s Hospital, London

Denis Pellerin

University of Liège, Liège

Carl Pepine

Mayo Clinic, Minnesota

Gaetano Lanza

University of Florida, Florida

David Goldsmith

Università Cattolica del Sacro Cuore, Rome

Piotr Ponikowski

Amir Lerman

Wroclaw Medical University, Wroclaw

Bernard Gersh St George’s University of London, London

Tommaso Gori Johannes Gutenberg University Mainz, Mainz

Diana Gorog University of Hertfordshire, Hatfield, Hertfordshire

Kim Greaves

Imperial College, London

Sunshine Coast University Hospital, Queensland

Marcelo Di Carli

Eileen Handberg

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

University of Florida, Florida

Polychronis Dilaveris

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

Hippokration General Hospital, Athens

Cover image © AdobeStock

Carlo Di Mario

Koji Hasegawa

Roxy Senior Imperial College, London

Nesan Shanmugam St George’s University of London, London

Sanjay Sharma St George’s University of London, London

Rosa Sicari Italian National Research Council, Rome

Iana Simova National Cardiology Hospital, Sofia

Konstantinos Toutouzas University of Athens, Athens

Isabella Tritto

Mayo Clinic, Minnesota

Eva Prescott

Basil S Lewis

Bispebjerg Hospital, Copenhagen

Dimitrios Tziakas

Axel Pries

Democritus University of Thrace, Xanthi

Charité Universitätsmedizin, Berlin

Mauricio Wajngarten

Valentina Puntmann

University of São Paulo, São Paulo

Lady Davis Carmel Medical Center, Haifa

José Luis López-Sendón La Paz Hospital, Madrid

Alberto Lorenzatti Hospital Córdoba, Cordoba

Silvia Maffei National Research Council, Pisa

Olivia Manfrini University of Bologna, Bologna

Goethe University Hospital Frankfurt, Frankfurt

Hari Raju

University of Perugia, Perugia

Hiroshi Watanabe Hamamatsu University School of Medicine, Hamamatsu

Macquarie University, Sydney

Matthew Wright

Robin Ray

St Thomas’ Hospital, London

St George’s University of London, London

José Luis Zamorano Hospital Ramón y Cajal, Madrid

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use thereof. Published content is for information purposes only and is not a substitute for professional medical advice. Where views and opinions are expressed, they are those of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Cardiology. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS, UK © 2019 All rights reserved ISSN: 1758–3756 • eISSN: 1758–3764 © RADCLIFFE CARDIOLOGY 2019

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Established: April 2005 | Frequency: Tri-annual | Current issue: Winter 2019

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Submissions and Instructions to Authors

• European Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in cardiology medicine and practice. • European Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • European Cardiology Review provides comprehensive update on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

• Contributors are identified by the Editor-in-Chief with the support of the Section Editors and Managing Editor, and guidance from the Editorial Board. • Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief and Section Editors, formalise the working title and scope of the article. • The ‘Instructions to Authors’ document and additional submission details are available at www.ECRjournal.com • Leading authorities wishing to discuss potential submissions should contact the Managing Editor, Ashlynne Merrifield ashlynne.merrifield@radcliffe-group.com

Structure and Format • European Cardiology Review is a tri-annual journal comprising review articles, expert opinion articles and guest editorials. • The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Section Editors and Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of European Cardiology Review is available in full online at www.ECRjournal.com

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European Cardiology Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by Section Editors and an Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors who are recognised authorities in their respective fields. • Peer review – conducted by experts appointed for their experience and knowledge of a specific topic. • An experienced team of Editors and Technical Editors.

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Online All manuscripts published in European Cardiology Review are available free-to-view at www.ECRjournal.com. Also available at www.radcliffecardiology.com are manuscripts from other journals within Radcliffe Cardiology’s cardiovascular portfolio – including Arrhythmia & Electrophysiology Review, Cardiac Failure Review, Interventional Cardiology Review and US Cardiology Review. n

Cardiology

Lifelong Learning for Cardiovascular Professionals

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Contents

Foreword Juan Carlos Kaski

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DOI: DOI: https://doi.org/10.15420/ecr.2019.14.3.FO1

Cardiovascular Epidemiology Behavioural Interventions to Reduce Cardiovascular Risk: Where Do We Stand?

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Gianluigi Savarese DOI: https://doi.org/10.15420/ecr.2019.14.3.GE3

Deciphering the Riddles in Nutrition and Cardiovascular Disease

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Amelia Carro and Josefa María Panisello DOI: https://doi.org/10.15420/ecr.2019.07

Electronic Cigarettes and Cardiovascular Risk: Caution Waiting for Evidence

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Domenico D’Amario, Stefano Migliaro, Josip Andjelo Borovac, Rocco Vergallo, Mattia Galli, Attilio Restivo, Matteo Bonini, Enrico Romagnoli, Antonio Maria Leone and Filippo Crea DOI: https://doi.org/10.15420/ecr.2019.16.2

Electronic Cigarettes and Cardiovascular Risk: Science, Policy and the Cost of Certainty

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Olusola A Orimoloye, Albert D Osei, SM Iftekhar Uddin, Mohammadhassan Mirbolouk and Michael J Blaha DOI: https://doi.org/10.15420/ecr.2019.14.3.GE2

Meditation and Cardiovascular Health: What is the Link?

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Sebastian Schnaubelt, Andreas Hammer, Lorenz Koller, Jan Niederdoeckl, Niema Kazem, Alexander Spiel, Alexander Niessner and Patrick Sulzgruber DOI: https://doi.org/10.15420/ecr.2019.21.2

Electrophysiology and Arrhythmia Predictors of Recurrence of AF in Patients After Radiofrequency Ablation

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Iskren Garvanski, Iana Simova, Lazar Angelkov and Mikhail Matveev DOI: https://doi.org/10.15420/ecr.2019.30.2

Current Controversies and Challenges in Brugada Syndrome

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Afik D Snir and Hariharan Raju DOI: https://doi.org/10.15420/ecr.2019.12.2

Cardiovascular Pharmacotherapy Cost-effectiveness of Platelet Function-Guided Strategy with Clopidogrel or Ticagrelor

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Nikita Lomakin, Anna Rudakova, Liudmila Buryachkovskaya and Victor Serebruany DOI: https://doi.org/10.15420/ecr.2018.29.2

Personalised Approaches to Improving the Effect of Anti-platelet Agents: Where Do We Stand?

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Lucas C Godoy and Michael E Farkouh DOI: https//doi.org/10.154210/ecr.2019.14.3.GE1

Diagnosis and Risk Increasing and Evolving Role of Smart Devices in Modern Medicine

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Michael R Massoomi and Eileen M Handberg DOI: https://doi.org/10.15420/ecr.2019.02

Acute Coronary Syndrome Troponins, Acute Coronary Syndrome and Renal Disease: From Acute Kidney Injury Through End-stage Kidney Disease

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Debasish Banerjee, Charlotte Perrett and Anita Banerjee DOI: https://doi.org/10.15420/ecr.2019.28.2

Novel Aspects of Classification, Prognosis and Therapy in Takotsubo Syndrome

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Chiara Di Filippo, Beatrice Bacchi and Carlo Di Mario DOI: https://doi.org/10.15420/ecr.2019.27.3

Cardiology Masters Featuring: Josep Brugada

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Josep Brugada DOI: https://doi.org/10.15420/ecr.2019.14.2.CM1

Corrigendum Corrigendum to: Sodium–glucose Cotransporter 2 Inhibitors in Heart Failure: Potential Mechanisms of Action, Adverse Effects and Future Developments

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Juan Tamargo DOI: https://doi.org/10.15420/ecr.2019.14.3.CG1

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Foreword

Juan Carlos Kaski is Professor of Cardiovascular Science at St George’s, University of London (SGUL), UK, Honorary Consultant Cardiologist at St George’s Hospital NHS Trust, London, and immediate past director of the Cardiovascular and Cell Sciences Research Institute at SGUL. Professor Kaski is a Doctor of Science, University of London, an immediate past president of the International Society of Cardiovascular Pharmacotherapy (ISCP), and an editorial board member and associate editor of numerous peer-review journals. He is also fellow of the European Society of Cardiology (ESC), American College of Cardiology (ACC), American Heart Association (AHA), Royal College of Physicians (RCP) and more than 30 other scientific societies worldwide. Prof Kaski’s research areas include mechanisms of rapid coronary artery disease progression, inflammatory and immunological mechanisms of atherosclerosis, microvascular angina and biomarkers of cardiovascular risk. Prof Kaski has published more than 450 papers in peer-reviewed journals, more than 200 invited papers in cardiology journals and more than 130 book chapters. He has also edited six books on cardiovascular topics.

uropean Cardiology Review has gone from strength to strength in the past few years, with more than 35,000 readers and 552,297 articles downloaded in 2018–2019. This achievement has been the result of the large number of high-quality manuscripts we receive for assessment for publication and the hard work of our section editors, steering committee members, associate editors and members of the editorial board. I am extremely grateful to everyone for their efforts and generous offers of their time to help build an impressive scientific publication. Radcliffe Cardiology has also played a major role in the development of the journal and the high standard of images both in print and online. Following on this path, the content of the current issue is second to none, with a cardiovascular epidemiology section, edited by Savarese, dealing with cardiovascular risk and disease prevention, that includes scholarly articles on nutritional aspects of cardiovascular risk reduction by Carro and Panisello, the relationship between e-cigarettes and cardiovascular risk by D’Amario et al. and Orimoloye et al. and an intriguing article by Schnaubelt et al. exploring possible links between meditation and cardiovascular health. In the field of electrophysiology and arrhythmias, Garvanski et al. present interesting clinical data regarding factors associated with AF recurrence after radiofrequency ablation. In the same section, Snir and Raju discuss current controversial issues in the diagnosis and management of Brugada syndrome. Incidentally, the fascinating medical career, spanning several decades of hard clinical and research work, of one of the key discoverers of the Brugada syndrome, Josep Brugada, is featured in our Cardiology Masters section. The ISCP cardiovascular pharmacotherapy section features two articles on antiplatelet treatment, one by Lomakin et al., on the costeffectiveness of platelet function guided therapy and another by Godoy and Farkouh on personalised approaches to antiplatelet treatment. Highlighting the rapid technological advances in the age of big data that are having a major impact on the diagnosis and management of cardiovascular conditions, Massoomi and Handberg review the role of smart devices in modern medicine. Acute coronary syndromes continue to attract the attention of cardiologists worldwide and this issue proudly offers a couple of scholarly manuscripts regarding this important topic. One of these is by Banerjee et al., who debate the role of cardiac troponin in the assessment of patients with acute coronary syndrome and renal disease; in the other, Di Filippo et al. critically review the classification, diagnosis and management of takotsubo syndrome. It has been a great pleasure editing this issue and I hope that our readers will find its content both enjoyable and practical.

DOI: https://doi.org/10.15420/ecr.2019.14.3.FO1

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Access at: www.ECRjournal.com

Cardiovascular Epidemiology

Behavioural Interventions to Reduce Cardiovascular Risk: Where Do We Stand? Gianluigi Savarese Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

Disclosure: The author has no conflicts of interest to declare. Citation: European Cardiology Review 2019;14(3):139–40. DOI: https://doi.org/10.15420/ecr.2019.14.3.GE3 Correspondence: Gianluigi Savarese, Division of Cardiology, Department of Medicine, Karolinska Institutet, Norrbacka S1:02, SE 17176 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.

ardiovascular (CV) disease is the leading cause of death worldwide.1 Age, sex and genetic factors have a major impact on CV risk. The importance of behavioural factors, such as tobacco and alcohol use, physical inactivity, unhealthy diet and obesity, is often neglected, although the implementation of lifestyle changes may be a cost-effective strategy for the prevention of CV diseases, also from a population-wide perspective.2

In this special issue of European Cardiology Review, we focus on epidemiology. D’Amario et al. discuss the current evidence on the use of e-cigarettes for smoking cessation.3 Smoking accounts for 11.5% of global deaths. The use of e-cigarettes has significantly contributed to a decline in classic cigarette smoking over the past decade and a recent randomised trial has shown that it is more effective for smoking cessation than nicotine-replacement therapy.4 E-cigarette use results in a significantly lower exposure to toxins and carcinogens than smoking traditional cigarettes. However, whether e-cigarette vapour, containing several substances which may be linked with CV toxicity, may increase CV risk is still under investigation. This is a particularly relevant issue, considering that the use of e-cigarettes is growing in young people and adolescents, where e-cigarettes may represent a path to start smoking rather than to quit.5 As D’Amario et al. state, more studies on the effects of e-cigarettes on CV but also general health are needed, but in the meantime, it is important to remember that ‘no smoke’ is better than ‘electronic smoke’.3 Carro et al. address a different, yet similarly important, lifestyle issue that has a strong effect on CV health: nutrition.6 The authors explore the different dietary patterns recommended by worldwide scientific organisations, with particular focus on the Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH). There is strong evidence supporting the CV benefits linked with the Mediterranean diet. The beneficial effects can be attributed to anti-inflammatory mechanisms and improved control of blood pressure, lipid profile and glucose metabolism, but also arrhythmic risk and gut microbiome. Consequently,

risk of coronary heart disease, ischaemic stroke and other CV diseases has been shown to be reduced in people who adopt a Mediterranean diet. Studies suggest that the DASH diet, which emphasises the importance of low sodium and reduced intake of refined grains, may be beneficial in terms of CV risk reduction by anti-inflammatory and antioxidant mechanisms, and an improvement in glucose metabolism and lipid profile. The cardiovascular effects of alcohol and coffee consumption are often debated. Fermented alcoholic drinks, such as wine, beer and cider, and particularly red wine, may have cardioprotective effects, mainly by improving endothelial function. However, the relationship between alcohol intake and CV risk is U-shaped, with heavy drinkers at higher risk of AF, non-ischaemic dilated cardiomyopathy and obesity. Antioxidant and anti-inflammatory mechanisms may explain the beneficial CV effects of regular coffee consumption (3–5 cups perday). Meat consumption is also frequently a matter of debate. Carro et al. explain that the association between red meat consumption and risk of all-cause and CV mortality may be explained by the high levels of saturated fat, cholesterol and haem iron, which are involved in the atherosclerotic processes. Evidence on white meat is more limited. Finally, Schnaubelt et al. present a systematic review that explores the association between meditation and the risk of CV disease.7 The authors provide evidence, although limited, that supports a role for meditation as a smoking cessation strategy. Data on the antihypertensive effects of meditation are heterogeneous and may reflect the different definition or style of meditation used, with it potentially reducing blood pressure by mechanisms mediated by the autonomic nervous system. A few studies may suggest a link between meditation, improved insulin resistance, atherosclerosis and endothelial function. As the authors state, data suggest a potential role for meditation on CV risk, but the current evidence is limited and mainly derived from observational studies where the risk of residual confounding is high. However, meditation may indirectly improve CV health, by facilitating behaviour changes, such as improved diet and smoking cessation, which may have a direct effect on CV risk.

Access at: www.ECRjournal.com

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Cardiovascular Epidemiology 1.

Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2095–128. https://doi.org/10.1016/S0140-6736(12)61728-0; PMID: 23245604. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by

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representatives of 10 societies and by invited experts). Eur Heart J 2016;37:2315–81. https://doi.org/10.1093/eurheartj/ ehw106; PMID: 27222591. D’Amario D, Migliaro S, Borovac JA, et al. Electronic cigarettes and cardiovascular risk: caution waiting for evidence. Eur Cardiol 2019;14(3):151–8. https://doi.org/10.15420/ ecr.2019.16.2. Hajek P, Phillips-Waller A, Przulj D, et al. A randomized trial of e-cigarettes versus nicotine-replacement therapy. N Engl J Med 2019;380:629–37. https://doi.org/10.1056/NEJMoa1808779; PMID: 30699054.

Orimoloye OA, Osei AD, Uddin SMI, et al. Electronic cigarettes and cardiovascular risk: science, policy and the cost of certainty. Eur Cardiol 2019;14(3):159–60. https://doi.org/10.15420/ecr.2019.14.3.GE2. Carro A, Panisello JM. Deciphering the riddles in nutrition and cardiovascular disease. Eur Cardiol 2019;14(3):141–50. https://doi.org/10.15420/ecr.2019.07.R1. Schnaubelt S, Hammer A, Koller L, et al. Mediation and cardiovascular health: what is the link? Eur Cardiol 2019;14(3):161–4. https://doi.org/10.15420/ ecr.2019.21.2.

EUROPEAN CARDIOLOGY REVIEW

Cardiovascular Epidemiology

Deciphering the Riddles in Nutrition and Cardiovascular Disease Amelia Carro 1 and Josefa María Panisello 2 1. Instituto Corvilud, Asturias, Spain; 2. Fundación para el Fomento de la Salud (FUFOSA), Health Foundation, Madrid, Spain

Abstract Cardiovascular disease is the leading global cause of death in Western countries, and its development is largely associated with unhealthy dietary patterns. A large body of scientific evidence has reported that nutrition might be the most preventive factor of cardiovascular disease death and could even reverse heart disease. Processes of chronic inflammation and oxidative distress share triggers that are modifiable by nutrition. This review aimed to identify potential targets (food patterns, single foods or individual nutrients) for cardiovascular disease prevention, and analyse the mechanisms implicated in their cardioprotective effects.

Keywords Nutrition, cardiovascular disease, prevention, inflammation, diet, lifestyle Disclosure: The authors have no conflicts of interest to declare. Received: 22 June 2019 Accepted: 23 October 2019 Citation: European Cardiology Review 2019;14(3):141–50. DOI: https://doi.org/10.15420/ecr.2019.07 Correspondence: Amelia Carro, Instituto Corvilud, Travesía El Calvario N1, Bajo, 33430 Candás (Asturias), Spain. E: corvilud@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Dietary Patterns Several studies correlate healthy dietary patterns with lower plasma concentrations of pro-inflammatory markers.1 These healthy dietary patterns support greater benefits than the potential effects of a single nutrient supplementation. The current body of evidence shows that healthy dietary patterns share similarities, shown in Figure 1.2 These features fit with the report of the most recent workshop convened by the World Heart Federation, and three models are recommended by the Unites States Dietary Guidelines Advisory Committee: Mediterranean diet (MD), American healthy diet and vegetarian diet (VD).3,4 The latter is a type of plant‐based diet that restricts different types of animal foods (meat, poultry or fish), and has been associated with a lower risk of cardiovascular (CV) risk factors (obesity, hypertension, type 2 diabetes) and coronary heart disease (CHD).5,6 However, VD, as a concept, focuses more on the exclusion of animal sources of food than the quality of plant foods; this raises some heterogeneity and deserves further research to assure the features of a heart healthy diet.7 Thus, recent studies tried to cluster different subtypes of VD according to the frequency of intake of three food groups: healthy plant foods (whole grains, fruits, vegetables, nuts, legumes, coffee, tea), less healthy plant foods (fruit juices, refined grain, potatoes, sugar sweetened and artificially sweetened beverages, sweets and desserts) and animal foods (animal fat, dairy, eggs, fish or seafood, meat and miscellaneous animal foods) given their associations with chronic conditions.8 Diets with higher intake of healthy plant foods and lower in animal foods were associated with a lower risk of incident CV disease (CVD), CVD mortality and all‐cause mortality.5–7 No true association was found with less healthy plant‐based diets and CVD or all‐cause mortality.7 Therefore, health implications of diets high in refined carbohydrates and sugar, and low in fruits, vegetables and animal foods must be acknowledged when assessing individuals with a VD.

Other therapeutic diets, such as the Dietary Approaches to Stop Hypertension (DASH) and the Portfolio diets recommended in the Canadian Cardiovascular Society guidelines, also emphasise the principles of a healthy diet.9,10 The MD and the DASH diet are probably the best-studied dietary patterns in relation to CVD prevention. Both may improve downregulation of low-grade inflammation and better control of bodyweight, further controlling other risk factors, and ultimately are correlated with lower numbers of clinical events.5,11

Mediterranean Diet The MD is defined as the traditional dietary pattern found in the early 1960s in Greece, Southern Italy, Spain and other olive-growing countries of the Mediterranean basin.12 It is a frugal diet that fulfils the definition of “healthy diet” (Table 1), with some distinctive attributes (Figure 1): olive oil the principal source of fat, moderate intake of wine (mainly wine during meals), fish, seafood, poultry, eggs and dairy products (cheese and yoghurt, preferred in the form of low fat), and low consumption of red meat. All kinds of olive oil (virgin, extra virgin olive oil and refined olive oil) contain oleic acid as the main fat, but only unrefined olive oil (virgin and extra virgin olive oil) contain tocopherols, phytosterols, monounsaturated fatty acids (MUFA) and several bioactive polyphenols (hydroxytyrosol, tyrosol, oleocanthal, resveratrol), with postulated antiatherogenic and anti-inflammatory properties.13–15 The evidence supporting CVD benefits is large, strong and consistent, in terms of clinically meaningful rate reductions of CHD, ischaemic stroke and total CVD. Until now, these benefits had been attributed to improvements in blood pressure, lipid profile, glucose metabolism,

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Cardiovascular Epidemiology Figure 1: Healthy Dietary Pattern

Olive oil Fruits

Alcohol (wine/beer)

Vegetables

Butter/fat

Legumes

Processed meats Refined grains

Fish, white meat, eggs

Nuts

Added sugar/SSBs

Whole grains Fibre

Energy drinks

Dairy products

Water Mediterranean diet

Thrombosis

Fasting Glc

BMI

SCFA

LDL-c

TMAO

MEDICATION

LIFESTYLE

Inflammation

Oxidation

CVD risk reduction The Mediterranean diet (MD) fulfils basic principles of a “Healthy Dietary Pattern”, with some distinctive features related to the nutrients included (i.e. olive oil, wine), but also extended to other lifestyle choices that are broadly referred as “Mediterranean Lifestyle Pattern”. The graphic represents the MD with food items grouped according to recommended frequency intake. The green boxes show food items that should sustain the diet and provide the highest energy intake (every main meal). Water is included in this section, with a daily recommended intake of 1.5–2.0 l. As well as water, non-sugar-rich herbal infusions and broths (with lowfat and -salt content) may complete the requirements. Orange boxes include foods to be eaten in moderate amounts, such as: protein animal sources: fish (two or more weekly servings), white meat (two weekly servings) and eggs (two to four weekly servings); dairy products: cheese and yoghurt, preferred in the form of low-fat; and alcohol: moderate consumption of wine and other fermented beverages during meals (one glass per day for women and two glasses per day for men, as a generic reference). The red box represents unhealthy fat-rich foods (butter/fat, processed meat) and the sugary (added sugar, refined grains, candies, pastries and sugar-sweetened beverages; SSBs, such as sweetened fruit juices and soft drinks). These should be consumed in small amounts and left for special occasions. Medication is only considered if required for primary or secondary prevention purposes. Lifestyle: along with recommendations regarding the proportion and frequency of food consumption, the MD incorporates lifestyle and cultural elements aimed to acquire all the benefits from the MD, and to preserve the cultural heritage. Blue boxes exemplify mechanisms that confer the MD its ability to reduce cardiovascular risk. These elements embrace moderation, socialisation, culinary activities, physical activity, adequate rest, seasonality, and traditional, local, eco-friendly and biodiverse products. BMI = body mass index; BP = blood pressure; CVD = cardiovascular disease; Glc = glucose; LDL-c = low-density lipoprotein cholesterol; SCFA = short-chain fatty acids; TMAO = trimethylamine N-oxide.

arrhythmic risk or gut microbiome.5 However, vascular anti-inflammatory effects have recently been hypothesised as a possible mechanism that links MD and low CVD prevalence (Table 2).16–19 This hypothesis was confirmed by the Prevención con Dieta Mediterránea (PREDIMED) findings on MD mechanisms: modulation of the expression of adhesion molecules in leukocytes; improvements in the circulating levels of soluble adhesion molecules, cytokines, chemokines and macrophage inflammatory proteins; and plaque stabilisation after 3 months, and 1, 3 and 5 years of intervention.20 Epigenetic studies of the MD reinforce these results, with proven influence on the methylation status of peripheral white blood cell genes, interactions among MD and the expression of other molecules (cyclooxygenase-2, interleukin-6, apolipoprotein, cholesteryl ester transfer protein plasma), transcription factors and gene polymorphisms (Table 2).21–23 The authors of the PREDIMED study in 2013 recently retracted the original publication as a result of an error in the randomisation procedures

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affecting a portion of participants included.24 The authors re-ran the analyses omitting 1,588 participants from 7,447, and published a corrected version that showed no significant changes in the results of the trial.24,25 In both the original and republished study, the incidence of CVD in the MD groups was lowered by approximately 30% when compared with the control diet.20,24,25 Therefore, the overall conclusion remains unchanged, and PREDIMED remains the largest dietary intervention trial to assess the effects of the MD on CVD prevention.

Dietary Approaches to Stop Hypertension Diet The DASH model follows the “healthy diet” pattern (Figure 1), with critical emphasis on a low intake of sodium and refined grains.26,27 Focusing on inflammatory markers and oxidative stress, several studies have shown the protective effect of the DASH diet on CVD (Table 1) mediated by significant reductions of high-sensitivity C-reactive protein concentrations. Cross-sectional analysis evaluating potential associations between dietary quality (DASH dietary quality score), adiposity, and biomarkers of glucose metabolism, lipid profile and inflammation reveal that a higher adherence to the DASH dietary pattern significantly improves adiposity measures, and lowers concentrations of pro-inflammatory, pro-thrombotic and proatherogenic markers.28 Improvements in lipoprotein profile and glucose homeostasis are also achieved. It has also been shown that a DASH diet increases plasma renin activity and serum aldosterone levels in response to blood pressure reductions.29 The effect of sodium intake on blood pressure differs by genotype at the angiotensinogen, beta2-adrenergic receptor and kallikrein loci.29,30 These findings have implications for understanding the mechanisms through which diet affects blood pressure, the heterogeneity of these effects, and the extent to which dietary and pharmacological interventions can modulate genetic predisposition.29,30

Individual Food Items There are some specific dietary guidelines that are exclusively food based.31–33 Comprehensive dietary modelling is undertaken to ensure nutrient reference values, including targets for sodium, and saturated and trans fat. This section develops some of the features of each of the individual food items and its possible relationship to CVD risk reduction.

Fruits and Vegetables Daily consumption of multiple servings of both fruits and vegetables is strongly and widely recommended, since its total intake has been inversely associated with CVD risk, and seems to be the healthiest and most beneficial source of anti-oxidants for CVD risk reduction.34 The benefits for subgroups have been less studied, and may vary considerably according to their phytochemical and micronutrient composition (Table 3).35–37 Some of the anti-inflammatory mechanisms proposed for fruits and vegetables are summarised in Table 2. Anthocyanins (a subclass of flavonoids) found in blueberries, strawberries, raspberries, red cabbage, red radishes and eggplant have potent anti-inflammatory properties: free radical scavenging, endothelial nitric oxide (NO) regulation, endothelial function modulation and influence on glucose metabolism.35–39 Cruciferous vegetables have been associated with vascular benefits due to their potential to release nitrite via the enterosalivary nitrate–nitrite–NO pathway. Dietary nitrates are secreted by the salivary glands and reduced to nitrite via the action of commensal oral bacteria. Salivary nitrite levels can increase >1,000‐fold greater

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Nutrition and Cardiovascular Disease Table 1: “Healthy Dietary Pattern” Principles

Main features

Plant-based and high consumption of vegetables, fruits, legumes, nuts, whole grain cereals and fish

Warrant high intake of fibre, anti-oxidants, vitamins, minerals, polyphenols, monounsaturated and polyunsaturated fatty acids

Carbohydrates of low glycaemic load

Keep blood sugar levels consistent, avoiding oscillations in glycaemic levels (and subsequent insulin releases)

Reduced consumption of salt, refined sugar, and saturated and trans fats

Mainly in the form of processed foods, red meats, refined cereals, starches, and sugar-added drinks and foods

Examples of “Healthy Dietary Patterns” Vegetarian diet* American healthy diet Mediterranean diet Dietary Approaches to Stop Hypertension (DASH) Portfolio Diet A healthy dietary pattern fulfils basic principles as detailed. Examples of a “Healthy Dietary Pattern” are given. *Vegetarian Diet focuses on restriction of different types of animal foods and is mainly plant-based; it is important to emphasise, however, that some plant-based food items might include carbohydrates of high glycaemic load (fruit juices, refined grain, potatoes, sugar sweetened and artificially sweetened beverages, sweets and desserts) or even saturated fat. Therefore, it is advisable that plant-based food items of a Vegetarian Diet include a higher proportion of whole grains, fruits, vegetables, nuts, legumes, coffee and tea instead.

Table 2: Proposed Mechanisms for the Anti-inflammatory Effects of Dietary Patterns and Individual Food Items Dietary Pattern/Food Item

Pro-inflammatory Markers and Genes

Oxidative Stress Markers

Leukocyte Expression

sVCAM-1, sICAM-1, RANTES, MIP-1beta, TNF-alpha, TNFR-60, IL-1beta, IL-6, IL-7,IL-10, IL-12p70, IL13, IL-18, MMP-9,VEGF, CRP, TCF7L2, ApoA2, CETP, COX-2, MCP-1, LRP1

Lymphocytes: CD11a, CD49d, CD40 Monocytes: CD11a, CD11b, CD49d, CD40

MDA, oxLDL

16–23

sICAM-1, IL-6, CRP, PAI-1

DASH diet28 vegetables, Fruits, legumes48,49 35,38,39

35,38,39

TNF-alpha, TNFR-60, IL-1beta, IL4, IL-6, gamma delta T cell, fibrinogen, sE-selectin

F2-isoprostanes,2,3 dinor-5,6-dihydro15-F2t IsoP

Nuts20,55–57

CRP, IL-6, TNF-alpha, TNF-beta, TNF-R2, sICAM-1, fibrinogen, PF4, resistin

Fermented beverages75–79

IL-1-alpha, IL-5, IL-6, IL-6r, IL-8, IL-10,IL-15, IL-18, CRP, MDC, sVCAM-1, sICAM-1, E selectin, fibrinogen, CD40 ligand, MCP-1, factor VII, PAI1, IFN-gamma, RANTES, TNF-beta

Lymphocytes: LFA-1 monocytes: LFA-1, MAC-1, VLA-4, CCR2, CD36, CD15

SOD, MDA

Coffee92,94 and tea95–98 (polyphenols)

NF-kappa beta, sICAM-1, sE- and sP-selectin, IL-1beta, IL-18, CRP, SAA, CXCL5, CXCL7, CXCL8, CXCL12, CCL2, TNF-alpha, beta-thromboglobulin, RANTES, ApoB

Monocytes: VLA-4, CD40, CD36

oxLDL, 8-iso-prostaglandin F2-alpha, ROS, SOD, Nrf2

Omega-3 PUFA125–127

sVCAM-1, sICAM-1, sP-selectin, TNF-alpha, TNFR, IL-1beta, IL-6, MMP-7, MMP-9, CRP, PAI-1, SAA

Fibre19

sVCAM-1, sICAM-1, TNF-alpha, TNFR2, IL-6, IL-18, CRP, PAI-1

Anti-oxidants/vitamins153,154

IL-6, CRP, TNF-alpha, leptin, tHcy

Polyphenol92,94–98

NF-kappa beta, sICAM-1, sE- and sP-selectin, IL-1beta, IL-18, CRP, SAA, CXCL5, CXCL7, CXCL8, CXCL12, CCL2, TNF-alpha, beta-thromboglobulin, RANTES, ApoB

T-lymphocytes

Monocytes: VLA-4, CD40, CD36

oxLDL, 8-iso-prostaglandin F2alpha, ROS, SOD, Nrf2

ApoA2 = apolipoprotein A2; ApoB = apolipoprotein B; CCL2 = chemokine (C-C motif) ligand 2; CETP = cholesteryl ester transfer protein plasma; COX-2 = cyclooxygenase-2; CRP = C-reactive protein; CXCL = chemokine (C-X-C motif) ligand; DASH = Dietary Approaches to Stop Hypertension; LFA = lymphocyte function-associated antigen 1; IL = Interleukin; LRP1 = low-density lipoprotein receptor-related protein; MDC = macrophage-derived chemokine; MCP-1 = monocyte chemoattractant protein; MD = Mediterranean diet; MDA = malondialdehyde; oxLDL = oxidised LDL; MIP-1beta = macrophage inflammatory protein 1 beta; MMP-9 = metallopeptidase-9; Nrf2 = nuclear factor (erythroid-derived 2)-like 2; omega-3 PUFA = omega-3 polyunsaturated fatty acid; PAI-1 = plasminogen activator inhibitor 1; PF4 = platelet factor 4; RANTES = regulated on activation; SAA = serum amyloid A; sICAM-1 = soluble intercellular adhesion molecule 1; SOD = superoxide dismutase; sVCAM-1 = soluble vascular cell adhesion molecule; TCF7L2 = transcription factor 7-like 2; tHcy = total homocysteine; TNF = tumour necrosis factor; TNFR = tumour necrosis factor receptor; VEGF = vascular endothelial growth factor; VLA-4 = very late antigen-4.

than in the circulation.40 Among leafy green vegetables, nitrate concentrations are most appreciable in spinach, arugula, mesclun, lettuce and Swiss chard.41,42 The European Food Safety Authority has set the Acceptable Daily Intake for nitrate at 3.7 mg/kg (approximately 260 mg for a 70-kg adult).41 A recently published systematic review and meta-analysis reported that intakes of dietary nitrate were significantly associated with a reduction in resting blood pressure,

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improved endothelial function, reduced arterial stiffness and reduced platelet aggregation.43 The amount of vegetable intake recommended in dietary guidelines varies globally, but is usually around five or six servings/day (375–450 g/day). For vegetable types, leafy green vegetables, cruciferous vegetables and tomatoes were inversely associated with CVD risk

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Cardiovascular Epidemiology Table 3: Classification of Vegetable Types with Nutrients and Phytochemicals Associated with Each Vegetable Type 35–37,39 Vegetable classification Cruciferous

Leafy green

Yellow-orange-red

Purple vegetables

Allium

Legumes

• • • • • • • •

• • • • • •

Lettuce Spinach Arugula Mesclun Swiss chard Celery

• • • • • •

• Red cabbage • Red radishes • Eggplant

• Onion • Garlic • Leek

• • • • • •

• • • • •

Nitrate Vitamin K (phylloquinone) Vitamin E (alpha-tocopherol) Vitamin C Carotenoids (lutein, betacarotene) Flavanols (quercetin, isorharmnetin, kaempferol) Folate Iron Zinc Calcium

• Carotenoids (lycopene, • Flavanols (quercetin) alpha-carotene, • Folate (vitamin B9) beta-carotene, beta• Carotenoids cryptoxanthin) (vulgaxanthin) • Manganese • Potassium • Iron • Vitamin C

• Organosulfur compounds (allin, methiin, propiin, isoalliin, allicin) • Flavanols (quercetin, isorharmnetin, kaempferol) • Selenium

• Isoflavones • Saponins • Flavanols (quercetin) • Folate • Iron • Zinc • Calcium • Dietary fibre • Vitamin E • Vitamin B6 • Selenium • Lignans

Cabbage Cauliflower Broccoli Brussels sprouts Red cabbage Red radishes Collard greens Kale

• Organosulfur compounds (isothiocyanates, glucosinolates) • Vitamin E (tocopherols) • Vitamin C • Carotenoids (lutein, zeaxanthin, beta-carotene) • Flavanols (quercetin, isorharmnetin, kaempferol) • Flavanones (naringenin) • Selenium • Calcium

• • • • •

Tomato Carrot Pumpkin Sweet potato Yellow capsicum Red capsicum

Lentils Peas Chickpeas Kidney beans Soybeans Green beans

in non-linear dose–response analyses. The greatest CVD benefits were observed at intakes of ≥200 g/day for cruciferous vegetable, ≥120 g/day for leafy green vegetables and ≥200 g/day for tomatoes.44

Based on these beneficial properties, legumes should be part of any cardiometabolic healthy diet, with a daily intake of around 50–100 g (140–180 kcal/day).50

Daily recommendations on fruit intake range from 100 to 300 g (200 g/day). However, it must be taken in to account that the process of juicing concentrates calories, risking excess energy intake and loss of fibre. There are few studies evaluating the clinical benefits of vegetable juicing versus raw or cooked forms. Until comparative data become available, whole food consumption is preferred, with juicing primarily reserved for situations when daily intake of vegetables and fruits is inadequate. Guidance should be provided to maintain optimal overall caloric intake and to avoid the addition of sugars (e.g. honey) to minimise caloric overconsumption. In addition, there is no evidence of CV benefit with the addition of high-dose antioxidant dietary supplements if these intakes are warranted.

Nuts and Seeds

Legumes Legumes are seeds with complex matrices rich in nutrients and chemicals, carrying a high caloric density that makes them an affordable and sustainable source of protein and fibre. Various effects on CV risk factors provide evidence for CV prevention. These foods have a low glycaemic index, and reduce glycaemia and postprandial insulinaemia, favouring diabetes prevention, especially in the context of a MD.45 Legumes have a hypocholesterolaemic effect (lowering both LDL and triglycerides), but their presumed effect in reducing blood pressure has not been consistently proven.46,47 Legumes are a good source of protein, starch, isoflavones, vitamin B6, folate and iron. The anti-inflammatory effects of this food group are frequently included with vegetables, which makes it difficult to separate its own mechanisms on pro-inflammatory/oxidative stress markers and leukocyte expression (Table 2). However, significant reductions of high-sensitivity C-reactive protein, interleukin-6 and tumour necrosis factor-alpha with a legume-based diet have been demonstrated, independent of caloric intake or weight change.48,49

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Nuts and seeds (almonds, hazelnuts, walnuts, pistachios, cashews, macadamias, pinions, peanuts etc.) are peculiar vegetables with a high fat content (usually exceeding 50% of energy) mainly containing unsaturated fatty acids (UFA), such as oleic MUFA (almonds, hazelnuts) or n-6 polyunsaturated linoleic and n-3 as alpha-linolenic acid (in nuts). Although peanuts are actually vegetables, their composition and UFA content assimilates them to nuts. Nuts and seeds contain other bioactive compounds: L-arginine, soluble fibre, vitamin E, phytosterols, polyphenols, anti-oxidants, potassium, calcium and magnesium. Numerous large prospective cohort studies have demonstrated reductions in CVD morbidity and mortality with the consumption of nuts and seeds.51,52 Mechanisms proposed for favourable CVD outcomes are likely mediated by dose-dependent hypocholesterolaemic effects and improvements of glycaemic profile.53,54 The PREDIMED study provided first-class evidence that regular nut consumption halves the incidence of diabetes, and reduces the incidence of CVD by 30%.20 Additional benefits are derived from the role on oxidative stress, inflammation and vascular reactivity through modulation of inflammatory and oxidants mediators (Table 2).20,55–57 Although the benefits are accepted, there is no standard recommendation for nuts inclusion on dietary patterns. Following a MD, daily supplementation with a serving of mixed nuts (i.e. 15 g walnuts, 7.5 g almonds and 7.5 g hazelnuts) would be enough to get the desired CV effects. Caution must be taken at >75 g, because of the risk of excess caloric intake.

Grains and Tubers Grains are the largest source of energy in almost all diets worldwide. The bran and germ layers present in whole grains are rich in fibre, lignans, micronutrients, fatty acids and other phytonutrients.58

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Nutrition and Cardiovascular Disease Depletion of these nutrients during the milling process partially explains why whole grain consumption is generally related to higher satiety and a lower glycaemic response compared with refined grains.59 High intake of whole grains has been associated with reduced risk of CHD disease, type 2 diabetes and overall mortality.60 Refining grains, in contrast, causes major loss of nutrients and fibre, which has important health implications, including adverse metabolic effects, weight gain, increased risk of CVD and overall mortality.60–62 There are few data linking gluten and CHD. People with coeliac disease or gluten sensitivity might have inflammatory mechanisms more related to zonulin release into the gut than to gliadin, and these altered pathways could predispose to type 2 diabetes and even CHD.63,64 However, there is no current evidence supporting a link between gluten consumption and CHD, and should not be restricted in people without coeliac disease or gluten sensitivity.65 Roots and tubers (the so-called starchy vegetables) are a good source of starch, which may help maintain a healthy gut.66 Gut dysbiosis is associated with intestinal inflammation and has been linked to the development of CVD.67 However, there is no evidence that restoring gut dysbiosis with tubers improves CV outcomes. Intake of potatoes, for instance, provides a large amount of rapidly absorbed carbohydrate (glycaemic load), and its daily consumption has been associated with increased risk of type 2 diabetes, hypertension, weight gain and even CHD (especially consumed in the form of “French fries”).68–71 Evidence does not support strong recommendations on the specific proportion of energy intake from carbohydrates, but keeping this to <60% of energy appears desirable, and consumption of whole grains is emphasised. This would be about 232 g/day of whole grains, and 50 g/day of tubers and starchy vegetables (with a limit of 100 g/day of tubers and starchy vegetables).

Fish and Seafood Fish intake has been associated with reduced risk of CVD, mainly attributed to the particular properties of omega-3 fatty acids (O3FA), which are abundant in fish composition.72,73 O3FA are precursors of eicosanoids, a large component of the central nervous system, a structural element of every cell of the body and a regulator of cardiac rhythm. They are thought to reduce arrhythmias, thrombosis, inflammation and blood pressure, and favourably modify the lipid profile.74 An average weekly intake of 2 g of O3FA in fish might reduce CVD risk by more than one-third.72 Although O3FA from plant sources (specifically alpha-linolenic acid) have been associated with reduced risk of CVD disease and had been proposed as an alternative source to substitute fish, the quantity required is not clear.

Beverages Alcohol Alcoholic beverages contain ethanol (ethyl alcohol) and are classified by the elaboration process as: fermented (by alcohol fermentation; <15% alcohol content): red or white wine, beer or cider; and distillate (by alcohol distillation; 20–60% alcohol content): spirits, such as cognac, whiskey, gin, vodka and rum, and liqueurs flavoured with fruits, herbs or spices. Fermented beverages are believed to provide a greater CV protection than distillate beverages, especially red wine. Its higher polyphenol content favourably modifies oxidation and inflammation parameters

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related to arteriosclerosis by different pathways: higher NO availability (improving endothelial function), increases in HDL cholesterol levels and anti-aggregation/profibrinolytic/anti-inflammation properties (Table 2).75–79 Beer is another type of fermented beverage with moderate polyphenol content that has cardioprotective effects comparable to wine.80,81 Both alcoholic and non-alcoholic beer improve inflammatory biomarkers profile, homocysteine and folic acid levels (Table 2). Alcohol intake and CVD risk show a “U-shaped” relationship, with both abstainers and heavy drinkers carrying a higher risk than moderate drinkers.82,83 Adverse effects of (often heavy) alcohol consumption include a higher risk of atrial fibrillation, non-ischaemic dilated cardiomyopathy and long-term weight gain.84–86 In addition, alcohol is causally linked to upper aerodigestive tract cancers (oral cavity, pharynx, larynx, oesophagus), and those of the colon, liver and female breast. Associations exist for many other types of cancer, but the precise role of alcohol requires further research for it to be fully disentangled from ecological and lifestyle factors.87 By definition, a standard drink contains 14 g of ethanol (17 g of pure alcohol). This equates to 350 ml of beer (5% ethanol), 150 ml of table wine (12% ethanol), or 45 ml of hard liquor or distilled spirits (40% ethanol).88 Although the exact nadir of risk depends on sex, age, ethnicity and baseline disease, it seems that consuming one or two daily drinks derives the lowest risk (2 for men; 1–1.5 for women).89,90 This would be the daily intake recommendation, mainly in the form of fermented beverages.

Coffee Coffee is one of the most widely consumed beverages in the world, representing the liquid extract of coffee beans. It contains many active compounds responsible for its bitter taste, and conferring anti0oxidant and anti-inflammatory actions. Several mechanisms contribute to the sustained CV health effects of coffee. However, the response of each individual component varies, and might interfere with others in a complex relationship. Various genetic polymorphisms affecting caffeine metabolism (i.e. cytochrome P450 1A2 variants), receptor-mediated effects (i.e. adenosine receptors) or non-receptor mediated effects (e.g. low catechol-O-methyltransferase activity) may influence an individual’s response to caffeine. An increased risk of CHD or MI has been reported only among individuals with a genotype associated with slow caffeine metabolism (CYP1A2*1F instead of CYP1A2*1A), or low catechol-O-methyltransferase activity genotype (low catecholamine metabolism).91 The infusion of coffee maintains a high concentration of potassium, magnesium, vitamin E, niacin, polyphenols (mainly chlorogenic acid), micronutrients, lignans and phytochemicals. Chlorogenic and caffeic acids improve the anti-oxidative status of the body by slowing down the process of inflammation, which protects from the hazardous effect of free radicals and against endothelial damage. There is no scientific association with blood pressure elevation and, in turn, it actually lowers diabetes risk in a dose-dependent manner.92 Unlike filtered coffee, some components present in unfiltered coffee (cafestol and kahweol) raise serum lipids.93 Whether these components are involved in the deposition of LDL cholesterol is still debated. Usually, consumption of three or four daily cups of coffee leads to a small increase in HDL cholesterol. The effect on LDL is more complex, since the resistance of LDL to oxidative modification increments significantly after drinking coffee, but the LDL concentration does not (or at least,

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Cardiovascular Epidemiology not significantly).94 Therefore, regular consumption of coffee (3–5 cups/ day, which corresponds to a coffee polyphenol intake of 101–337 mg/ day) can be recommended based on its ability to lower CVD risk.93

Tea Tea contains a significant amount of flavonoids and polyphenols, considered the most abundant dietary anti-oxidants present, and responsible for a wide range of health effects in the prevention of CVD.95 Polyphenols delay progression of atherosclerosis through several mechanisms: regulation of signalling–transcription pathways (including downregulation of pro-inflammatory cytokines) and antioxidant systems (enhanced NO production), prevention of leukocyte migration/plaque infiltration, and reduction of adhesion molecules, among others (Table 2).96 Both short- and long-term tea consumption have shown to improve endothelium-dependent flow-mediated dilation, reverse endothelial vasomotor dysfunction in CHD patients and are associated with favourable changes on lipid profile.97–99 These effects translate into a lower risk of developing CHD and major cardiac events, even all-cause mortality.100,101 The evidence for a favourable CVD profile is based on regular tea consumption (3–5 cups/day) without added sugars, sweeteners or milks and creams (both animal and plant-based), and that should be the proper way to tackle any recommendation on this beverage.

Dairy Products A growing body of nutritional science highlights the complex mechanisms and pleiotropic pathways of cardiometabolic effects of dairy products (i.e. milk, yogurt and cheese) that may be mediated by specific proteins (whey and casein proteins), amino acids (leucine, isoleucine and valine), medium-chain and odd-chain saturated fats, UFA, branched-chain fats, natural trans fats, probiotics, vitamin K1/K2, and calcium, or by processing methods (fermentation/ homogenisation). These intricate processes translate into divergent conclusions regarding CVD: although systematic reviews and metaanalyses show either neutral or a favourable association between dairy intake and CVD-related outcomes, other studies associate dairy fat with a unfavourable risk profile that can be reversed by replacing fat from dairy products with polyunsaturated fatty acid (PUFA) or vegetable fat.102–108 In cohorts utilising objective biomarkers, higher blood levels of dairy fatty acids are consistently associated with a lower incidence of diabetes and neutral/favourable CVD risk profile. Reduced fat dairy products remain a convenient source of some essential vitamins and minerals, and high-quality protein. Obtaining these compounds should not be routinely based on supplements, since fermentation processes and probiotics are a relevant component in the biological pathways and clinical effects of these foods.109 In fact, the VITamin D and OmegA3 TriaL (VITAL) trial has recently shown that diet supplementation with non-dietary vitamin D did not result in a lower incidence of invasive cancer or CV events than a placebo, which highlights the relevance of metabolic pathways in the effects observed with dairy products.110 Although further investigation is required, based on available evidence, the empiric recommendation on reduced-fat in place of regular- and high-fat dairy is adequate, and is included in MD and DASH dietary patterns (average 250 mg/daily, yielding 150 kcal of caloric intake).

Eggs The high cholesterol concentrations found in eggs (200–230 mg/ egg; 350–385 mg/100 g) led to the widespread recommendation of

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limiting egg intake in fear of subsequent increases in total and LDL cholesterol.111 However, eggs are rich in amino acids and several micronutrients that might interplay for the net effect on cholesterol levels and its clinical impact. Clinical studies reveal that cholesterol increases are discrete, with interindividual variability, and are coupled with slight elevations in HDL cholesterol that favour the development of large and low-atherogenic LDL particles.112 In fact, even daily egg consumption is not clearly associated with incident CVD in general populations and might reduce stroke risk.113–115 However, US dietary guidelines raised controversy because of apparently contradictory statements, saying that ‘cholesterol is not a nutrient of concern for overconsumption’, but that ‘individuals should eat as little dietary cholesterol as possible’.7 A recent study involving pooled individual data from six prospective US cohorts found that egg consumption was associated with an increased incidence of CVD and death.116 However, the association was possibly biased and inaccurately proven. A recent meta-analysis and systematic review found no association between egg intake and CHD or total mortality, but, in contrast, lower risk of mortality from stroke.117 Egg consumption has been also associated with hypertension, type 2 diabetes and markers of glucose homeostasis.117,118 The debate on the role of eggs for CVD prevention would remain largely moot until further data (including the genetic basis of cholesterol intake on CVD risk) are clearly defined. In the meantime, the importance of following evidence-based dietary recommendations, such as limiting intake of cholesterol-rich foods, should not be dismissed. Cardiometabolic effects can be derived from the consumption of up to two or three eggs per week, even in people with diabetes.

Oils, Butter and Fats Primary types of dietary fat include saturated fat (SFA), UFA (including MUFA and PUFA) and trans fatty acids. Only dietary trans fatty acids intake demonstrates a consistent and strong association with adverse CVD outcomes. SFA have received widespread controversy, as the increases of total and LDL cholesterol levels undoubtedly translate into either neutral or harmful CVD outcomes in different clinical trials and metanalyses.119–122 It must be acknowledged that SFA are diverse compounds with variable effects on CHD risk depending on many factors apart from the dietary SFA intake, such as the SFA status, biomarkers and the carbon length of the SFA.123 Genetic factors contribute to the risk of CHD related to the dietary intake of C-18 fatty acid. It is advisable to replace long-chain fatty acids (LCFA) with PUFA, MUFA, short-chain fatty acids, whole grains and plant proteins.123,124 Mechanisms for the benefit with long-chain O3FA derived from fish oil might include improvements in the lipid and lipoprotein profile, oxidation, thrombosis, platelet aggregation, endothelial function, blood viscosity, membrane fluidity and plaque stability, modulation of concentration/expression of pro-inflammatory markers (adhesion molecules, cytokines etc.), and immune cells (Table 2).125–127 Noteworthy, benefits of the supplementation with these fatty acids remain to be confirmed.128,129 Although icosapent ethyl administration in patients with elevated triglyceride demonstrated significant reduction in CVD outcomes, the addition of O3FA did not result in a lower incidence of major CV events or cancer than placebo

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Nutrition and Cardiovascular Disease in a primary prevention trial.110,130 In addition, it is not possible to recommend the safest amount of dietary consumption of SFA, especially LCFA, at this time, but studies suggest it should be well below 9% of total caloric intake.123 Coconut oil is 92% SFA, predominantly lauric acid C12:0 and myristic acid (C14:0). Since only 4% of coconut oil has short-chain fatty acids (C-10 or less fatty acids), it acts mostly as a LCFA, with direct portal vein absorption and is highly soluble in water.131 However, there is a lack of prospective studies on CV, and the current literature raises mixed effects on serum lipids and the content of LCFA. In addition, replacement of coconut oil with PUFA and MUFA seems to reduce CHD risk.64 Therefore, this yet scarce evidence does not currently support coconut oil use for the prevention or treatment of CVD, and general recommendations on SFA intake (limited to <9% of total energy intake) should prevail.7,123

Meat The intake of meat has increased in industrialised countries, and actually constitutes the basic component of meals. Although general meat consumption has been reported to be associated with all-cause and specific-cause mortality, the type of meat considered (red, white, processed) might redefine these associations. Red meat and processed meat may increase the risk of all-cause and CV mortality by means of several components that boost CV alterations.132,133 Various red meatassociated agents have been invoked, including SFA, high salt intake, trimethylamine N-oxide generation by microbiota and environmental pollutants contaminating red meat, none of which are specific to red meat. For instance, it has been demonstrated that residues of organochlorine pesticides are present in red meat at concentrations close to the WHO maximum recommendations. Epidemiological evidence and systematic reviews support an association of pesticide exposure with CVD and CV mortality (MI, cerebrovascular disease). These associations might be mediated via oxidative stress and inflammation pathways.134 Other human-specific hypotheses associated with red meat are also plausible, such as infectious agents (viruses) or xenoautoantigens (triggered by metabolic incorporation of a non-human sialic acid N-glycolylneuraminic acid into the tissues of red meat consumers).133 N-glycolylneuraminic acid incorporation from red meat can induce xenosialitis in vascular endothelium, and may contribute to red meat-induced aggravation of atherosclerosis and CVD. Despite all this circumstantial evidence, further research is required to confirm that this process is actually pro-atherogenic in vivo and thus a major causative factor in the development of CVD in humans.134 Very little has been reported about the impact of white meat intake on health; the interpretation of such effects is an arduous task, as individuals consuming more white meat are, at the same time, consuming less red meat. Findings obtained from meta-analyses are weak, and do not report increments on all-cause or CV mortality with 100 g daily consumption.135,136 Therefore, this could be a reasonable recommendation until more studies assessing the effect of white meat consumption on mortality are conducted, and there is no current evidence to support the choice of white over red meat in terms of CV risk reduction.

Added Sugar and Sugar-sweetened Beverages The first associations between excess intake of added sugars,

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metabolic abnormalities and CV risk surfaced in the 1950s, but were eclipsed until recently (2014) by the belief that an excess intake of SFA was the key dietary factor. Sweeteners are mainly being consumed as sugar substitutes that can be classified as nutritive sweeteners (polyols or sugar alcohols) and non-nutritive substitutes. Although almost 75% of packaged foods contain added sugars, sugar-sweetened beverages (SSBs; soda, sweet teas, fruit drinks) account for half of all added sugar intake.137–139 The effects of non-nutritive substitutes, both artificial sweeteners (acesulfame K, aspartame, cyclamate, saccharin, neotame, advantame and sucralose) and natural sweeteners (NSSs; thaumatin, steviol glucosides, monellin, neohesperidin dihydrochalcone and glycyrrhizin) are conflicting.140 NSSs interfere with glucose and energy homeostasis; alter leptin levels; adversely modify lipid profile, inflammatory factors, circulation and composition of gut microbiota; and decrease satiety, consequently increasing the risk of CHD, MI, cerebrovascular accident and vascular death.64,137,140–146 While some studies report an association between NSS use and reduced risk of overweight, obesity and type 2 diabetes, other studies suggest that NSS use could increase all of them, and the risk of metabolic syndrome, CHD and cancer.64 This association might be influenced by gene–SSB interactions.137 In particular, intake of SSBs can exacerbate the effects of chromosome 9p21 variants (i.e. rs4977574), considered the most robust genetic markers on CHD.147 The clinical and epidemiological data available at present are insufficient to make definitive conclusions regarding the benefits of non-nutritive substitutes in displacing caloric sweeteners as related to energy balance, maintenance or decrease in bodyweight and other cardiometabolic risk factors. Based on the previously mentioned evidence, numerous expert bodies have now made recommendations to limit dietary added sugar intake to <10% of calories, and preferably <100 calories daily for women and <150 calories daily for men. Clinicians should recommend careful selection of foods with no or low amounts of added sugars in any form, and elimination of SSB. Patients should also be taught how to read nutrition labelling for added sugars.148,149

Other Nutrients and Bioactive Compounds It is important to focus on the potential benefits of the intake of specific nutrients to avoid possible deficiencies of these nutrients, which can lead to the development of atherosclerotic disease.

Fibre The health benefits of dietary fibre intake are indisputable, while a deficiency of fibre intake is associated with CVD development.150 The implicated mechanisms include decreased glucose/cholesterol absorption, downregulation of expression of oxidative stressrelated cytokines or the inflammatory response mediated by gut microbiota exposed to fibre.19 The influence of long-term fibre intake on gut microbiota responsiveness to specific interventions is now becoming apparent. Increased fibre intake has been shown to improve certain metabolic parameters associated with obesity and its comorbidities (glucose homeostasis, serum cholesterol levels, blood pressure), particularly in conjunction with energy-controlled dietary regimes.151 The association between dietary fibre intake and risk of CHD has been studied through meta-analysis showing a significant dose–response relationship, especially for fibre from cereals and fruits.152

147

Cardiovascular Epidemiology Bioactive Compounds

Polyphenols

Recent research has identified the bioactive compounds that contribute to the beneficial effects of foods rich in anti-oxidants (beta-carotene, vitamin C, vitamin E, selenium) and their potential mechanism: reducing endothelial cells damage, improving the production of NO and inhibiting oxidation of LDL cholesterol (Table 2).153,154

Polyphenols are the most abundant dietary anti-oxidants present in most plant origin foods and beverages, which possess a wide range of health effects in the prevention of CVD.95 The most relevant food sources have been previously described (fruit and vegetables, red wine, black tea, coffee, extra virgin olive oil, nuts), and their potential anti-inflammatory role has been summarised.163

Although the supplement industry began to promote the benefits of anti-oxidant supplements long before scientific evidence was available, recent multiple subsequent trials have reported either neutral or negative results for vitamin E, betacarotene, O3FA, vitamin D or multivitamin supplementation.110,155–160 Thus, although foods rich in anti-oxidants at physiological levels appear to be have health benefits, further investigation will be necessary to better define the role of anti-oxidant supplements in health promotion.161,162

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Conclusion We defined a healthy dietary pattern taking into consideration nutritional adequacy as recommended by most dietary guidelines. A focus exclusively on food groups does not incorporate added fats, sugar and other constituents, and the interplay of intermediate risk factors within inflammation processes. The healthy dietary pattern we proposed allows for flexible, global application of these criteria (Table 1), with foods and amounts tailored to the preferences and cultures of different populations.

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EUROPEAN CARDIOLOGY REVIEW

Cardiovascular Epidemiology

Electronic Cigarettes and Cardiovascular Risk: Caution Waiting for Evidence Domenico D’Amario, 1 Stefano Migliaro, 1 Josip Andjelo Borovac, 2,3 Rocco Vergallo, 1 Mattia Galli, 1 Attilio Restivo, 1 Matteo Bonini, 1 Enrico Romagnoli, 1 Antonio Maria Leone 1 and Filippo Crea 1 1. Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy; 2. Department of Pathophysiology, University Hospital of Split, Split, Croatia; 3. Department of Cardiology, University Hospital of Split, Split, Croatia

Abstract Electronic cigarettes use is a growing trend in contemporary societies, with the propensity to compete with traditional tobacco smoking. Some preclinical studies demonstrated the toxic and detrimental effects of electronic cigarettes liquid components. Its impact on human health remains unknown and insufficiently studied. While some studies suggest that electronic cigarettes use might be associated with endothelial dysfunction, impaired platelet function and increased risk of adverse clinical events, other studies did not confirm these findings and epidemiological data mostly suggest that the use of electronic cigarettes appears to be safer than that of traditional tobacco cigarettes. This article provides an up-to-date overview of the current state of knowledge regarding electronic cigarettes and their impact on human health, with special emphasis on their effect on cardiovascular diseases.

Keywords Electronic cigarettes, cardiovascular system, heart, health, risk, cerebrovascular, tobacco, mortality, smoking Disclosure: The authors have no conflicts of interest to declare. Received: 13 March 2019 Accepted: 29 May 2019 Citation: European Cardiology Review 2019;14(3):151–8. DOI: https://doi.org/10.15420/ecr.2019.16.2 Correspondence: Domenico D’Amario, Department of Cardiovascular and Thoracic Sciences, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy. E: domenico.damario@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The ancient rite of smoking dates back thousands of years, and tobacco smoking has been largely ingrained in our civilization since the arrival of Europeans to the Americas in the 16th century. For a long time, cigarette smoking was perceived as a symbol of wealth, glamour and sophistication, whereas nowadays it is largely recognised as the first preventable or modifiable cause of common diseases in developed societies.1,2 The prevalence of smoking worldwide is substantial and is associated with a high attributable disease burden. In particular, up to 11.5% of global deaths can be linked to smoking.3 Being decisively fought by every medical association and government organisation, smoking addiction has dramatically evolved in recent times, thanks to the widespread distribution of electronic cigarettes. Consequently, classic cigarette smoking among US adults has declined from 20.9% in 2005 to 15.5% in 2016, as shown in the National Health Interview Survey, while the proportion of those who quit smoking increased by almost 10% from 2005 to 2016.4 However, while a significant decline in cigarette smoking has been reported in the majority of developed societies, the upsurge in electronic cigarettes use is a worrying trend, particularly due to the lack of longitudinal data on their safety and health effects.4 Initially seen as a fancy object, electronic cigarettes have rapidly gained attention both as a tool aiding in tobacco smoking cessation and as a substitute for traditional tobacco addiction. Electronic nicotine delivery systems can emulate the gestures, sensations and pharmacological effects of cigarettes without a strictly defined

combustion process. They do so by heating a solution of glycols or glycerol, flavourings and nicotine. The first electronic cigarette device was patented in the 1930s. The first functioning prototypes were created in the 1960s, but their commercialisation failed. In the early 1980s, Phil Ray, a computer pioneer, along with his physician, Norman Jacobson, revisited and designed a more realistic functioning device, but this had a limited commercial impact. These first devices, merely relying on nicotine evaporation, were perceived as ineffective by conventional tobacco users. After a series of other, mostly unsuccessful, attempts at the dawn of the new millennium, the current version of the electronic cigarette was created in Beijing, China, in the early 2000s, by a smoker pharmacist who rediscovered the device after his father died of smoke-related lung cancer. After being patented in 2004, electronic cigarettes had a strong and steady increase in popularity worldwide.5 They launched in Europe in 2006, and then in the US.5,6 Subsequently, intense and controversial intellectual and legal battles began among supporters and opponents of this emerging smoking lifestyle. Currently, there is no clear and unequivocal consensus about the health effects of ‘vaping’, as the act of smoking an electronic cigarette is commonly called. Is this a benign trend without detrimental health risks and consequences or is it a wolf in sheep’s clothing?6 The principal goals of this article are to shed some light on the current state of medical and epidemiological knowledge on electronic cigarettes, and to provide succinct and up-to-date information regarding their potential association with cardiovascular risks.

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Cardiovascular Epidemiology Epidemiology of Electronic Cigarette Usage

How do Electronic Cigarettes Work?

In the US, there has been a constant rise in the number of electronic cigarette smokers. The latest data obtained from the National Health Interview Survey showed that 15.3% of adults had repeatedly used an electronic cigarette, while the incidence of active users (defined as at least one electronic cigarette smoked in the past 30 days) was 3.2%. Interestingly, the population that had the highest propensity for the new trend were current tobacco smokers, while former smokers constituted only a small fraction of new vapers; of note, the proportion of non-smokers who started using electronic smoking devices was rather low.7

These devices try to mimic the experience of smoking by resembling the shape of a conventional cigarette. The most common type of electronic cigarette cartridge contains a propylene glycol or glycerol solution, with or without added nicotine, and generally with a flavour. Heating the compound creates a resistance within the cartridge, generating a vapour that is inhaled by the user. The basic functioning unit of electronic cigarettes is shown in Figure 1. Thousands of flavours are available, and health concerns exist about the potential role and effects of these chemicals. Almost more than 8,000 unique flavours and more than 450 brands of electronic cigarettes have been reported, with limited data suggesting that these substances are potentially detrimental to human health; many of these substances are known irritants or can increase susceptibility to viral infections.22–24 As a consequence of the structure of the device itself, many different heavy metals, such as chromium, manganese and even arsenic, have been reported to be detected in electronic cigarette liquids and aerosols. Moreover, combustion is not part of the process, combustionrelated compounds have been detected in electronic cigarette smoke, including nitrosamines, organic acids and phenolic compounds.25,26

Recent data from the Behavioural Risk Factor Surveillance System (BRFSS) suggest that the use of electronic cigarettes is increasing among never-smokers, to nearly 2 million US adults in 2016.8 The mean prevalence of never-smokers who smoked electronic cigarettes at least once ranges from 0.1 to 3.8%.7,9,10 Those electronic cigarette users who have never smoked conventional cigarettes are defined as ‘sole electronic cigarettearette’ users in the literature. Of note, electronic cigarettes are unlikely to be a trigger for smoking initiation or relapse among adults in the US.11 A low prevalence of cessation among infrequent electronic cigarette users has been well-documented in a study of recent smokers in the US.12 Similarly, individuals with a positive history of cardiovascular disease who recently quit smoking or reported a recent quit attempt were more likely to use electronic cigarettes compared with current smokers and those who did not report a quit attempt.13 In the EU, 20% of current smokers, 4.7% of former smokers and only 1.2% of never-smokers reported having used an electronic cigarette. Epidemiological data also suggest that electronic cigarette users appear to be younger, more educated, with higher income, and a slight and variable prevalence of men and white people.14 Data from the BRFSS also showed that electronic cigarette use is a common habit, especially among younger adults, current cigarette smokers and people with comorbid conditions.9,10 There is an alarming uptrend in the use of electronic cigarettes among US high school students, with a prevalence ranging from 10 to 13% in 2016.15 In the most recent annual National Youth Tobacco Survey, the Centers for Disease Control and Prevention found that the number of high school students using tobacco, including electronic cigarettes, increased by 38%, with most of the new smokers using electronic cigarettes. In this population, electronic cigarette use increased by almost 78%, with the total prevalence of active vapers reaching 21%, up from 12% in 2017. Importantly, 15% of this population combined vaping and smoking of traditional tobacco cigarettes. According to this report, the use of standard cigarettes and cigars did not increase during the observed period.16 Furthermore, the introduction of JUUL, an innovative electronic cigarette that looks like a USB drive, has seen a rapid uptake among youth and young adults.17 This design provides delivery of high nicotine concentrations, while the potential health hazards associated with this product are unknown.18 The most recent report by Bold et al. revealed that electronic cigarette use among young people in public schools was associated with future cigarette use during the threewave period (2013, 2014 and 2015), whereas cigarette use was not associated with future electronic cigarette use.19 In contrast, according to large-scale surveys and cross-sectional analyses of randomised controlled trials, the majority of electronic cigarette users perceive these devices as a tool to quit regular tobacco smoking.20,21

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The average nicotine concentration per cartridge is usually <36 mg/ml, with the most common variants ranging from 6 to 18 mg/ml. Importantly, some biochemical analyses have shown that most of the devices actually provide an effective dose of nicotine that is higher than the concentration declared on the label, while some nicotine-free cartridges were found to deliver nicotine.27,28 Furthermore, it has been documented that more experienced users, who exhibit longer and more frequent aspirations, have higher blood nicotine levels compared to classic tobacco smokers, whereas less experienced users have consistently lower levels of nicotine in their circulation.29–31 Therefore it can be seen that these novel electronic cigarette systems allow users to regulate the amount of nicotine they inhale, thereby raising a valid concern regarding nicotine abuse and its addiction potential.32 Furthermore, vaping low-nicotine versus high-nicotine e-liquid in electronic cigarettes is accompanied by an increase in wattage and larger quantities of potentially harmful e-liquid consumption.33 As the use of alternative nicotine delivery products is increasing worldwide and may surpass the use of conventional cigarettes in some parts of the world, it is a pertinent research question to elucidate the explicit role of nicotine in the development of cardiovascular and other systemic diseases. Recently, nicotine has been implicated in the impairment of vascular function, endothelial dysfunction and increased vascular calcification and stiffness.34

Potential Health Harms of Electronic Cigarettes Unrelated to Cardiovascular Risk No long-term observational data exist about the health effects of these technologies on human health. However, it is an intuitive concept that electronic cigarettes should present fewer health risks than traditional cigarettes.35 In support of this notion, a recent study by Goniewicz et al. demonstrated that substituting tobacco cigarettes with electronic cigarettes may result in significantly lower exposure to the wide array of toxins and carcinogens that are present in tobacco, thus suggesting a role of electronic cigarettes as a potential harm reduction device.36 One study has shown that electronic cigarette smokers have fewer toxins and carcinogens in their urine compared with conventional cigarette smokers.37,38 Nonetheless, the healthrelated effects of the vapour fumes are unknown, and the levels

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Electonic Cigarettes and Cardiovascular Risk of carcinogenic compounds found may vary, largely due to the heterogeneity of the available commercial products. It is known that at high temperatures, propylene glycol may form propylene oxide, a probable human carcinogen, while glycerol produces acrolein, which is a known human toxin.39 Importantly, both of these substances constitute the major ingredients of most refill solutions, and can form formaldehyde and acetaldehyde, which are both established human carcinogens.40–43 Electronic cigarettes also produce aerosols that include polycyclic aromatic hydrocarbons, nitrosamines and silicate particles, which are well-documented carcinogens.44–47 Detrimental carbonyl content was significantly increased in exhaled breath during electronic cigarette use compared with non-vaping users.46 The effects of artificial flavours are similarly uncertain. Some studies suggest a link between some chemical compounds used to emulate specific sweet tastes and respiratory irritation and cytotoxicity.23,48 Current data generally suggest a varying detrimental effect of electronic cigarettes on the inner mucosa of the craniofacial region and respiratory function when compared with standard tobacco, with an especially strong association with asthma.49–51 This association was documented in two independent surveys carried out among teenage electronic cigarette users with a risk of bronchitis symptoms directly related to the frequency of electronic cigarette usage.46,52,53 Detrimental acute effects of electronic cigarettes inhalation were demonstrated in a study conducted by Antoniewicz et al. among 17 healthy individuals, which showed that inhaled electronic cigarette aerosol with nicotine caused a significant increase in heart rate and arterial stiffness, and a sharp increase in flow resistance in the conducting airways.54 Similarly, acute vaping of propylene glycol/ glycerol aerosol at high wattage with or without nicotine induced significant injury to airway epithelium and impaired pulmonary gas exchange.55 Electronic cigarettes also induce an ion channel dysfunction in airway epithelial cells, and this was partially explained by the increased acrolein production, thus associating electronic cigarette use with chronic bronchitis onset and progression, as well as chronic obstructive pulmonary disease severity.56 Additionally, electronic cigarettes induced a greater efflux of inflammatory mediators from chronic obstructive pulmonary disease lung cells, implicating that the use of electronic cigarettes in chronic obstructive pulmonary disease might be associated with a worse clinical picture and exacerbations.57 Oral gum disease has also been associated with electronic nicotine products, with electronic cigarette users having an increased odds of being diagnosed with gum disease and bone loss around teeth (OR 1.76, 95% CI [1.12–2.76] and OR 1.67, 95% CI [1.06–2.63], respectively), compared with nonsmokers.58 Among university students, vaping was associated with illicit drug use, mental health problems and impulsivity.59 Finally, a preclinical study showed that electronic cigarette vapours impaired gonadal function in male rats, although this early finding is yet to be confirmed in human studies.60

Electronic Cigarettes as a Road to Quit Cigarette Addiction The role of this technology in the difficult path to quitting smoking addiction has been postulated and investigated in small-sized studies. By looking and tasting like traditional tobacco and, moreover, by allowing the social rite of smoking as well as the physical hand-to-

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Figure 1: Schematic Diagram of Electronic Cigarette System LED INDICATOR Activates and illuminates when electronic cigarette is used

RECHARGEABLE BATTERY

MICROPROCESSOR Controls device SENSOR atomiser and LED Detects electronic cigarette use and activates microprocessor

ATOMISER Heats liquid contained within the cartridge

MOUTHPIECE Collects and CARTRIDGE delivers “vape” Contains nicotine liquid or liquid without nicotine

mouth gesture, electronic cigarettes could indeed be more effective than other smoking cessation strategies. Preliminary evidence suggests that electronic cigarettes can reduce tobacco cravings and nicotine abstinence symptoms.30,61 A survey study conducted in the US found that electronic cigarette smokers had a higher probability of succeeding in quitting (8.2% versus 4.8%), compared with smokers who did not use electronic cigarettes.62 A small study conducted in Italy demonstrated a cessation rate of 12.5% among electronic cigarette smokers after 24 months.63 This favourable trend is still debated, because other studies have failed to prove a higher rate of quitting. Recently a large meta-analysis found 28% (OR 0.72, 95% CI [0.57–0.91]) lower odds of quitting smoking in patients who used electronic cigarettes compared with those who did not use electronic cigarettes.64–66 In a very recent article by Hajek et al., a pragmatic randomised controlled trial with nearly 1,000 smokers motivated to quit smoking was reported. 67 Participants were randomised to either electronic cigarettes containing nicotine at 18 mg/ml or to a nicotine-replacement product, both accompanied with behavioural support. The results indicated that electronic cigarettes were more effective than standard replacement therapies considering the rate of abstinence at 1 year, although the overall success rate was poor in both examined groups (<1 in 5 for electronic cigarettes and <1 in 10 for nicotine replacement).67 An interesting observation from this trial was that, among participants with sustained abstinence at one year, the cumulative incidence of continued electronic cigarette use was much higher among those that were randomised to electronic cigarettes compared with those that continued to use nicotine replacement in the nicotine-replacement group (80% versus 9%, respectively).68 This important finding further reinforces the need to ascertain potential health consequences of long-term electronic cigarette use. Furthermore, there is also a tangible concern about the role of electronic cigarettes as a bridge towards a classical tobacco addition. A systematic review and meta-analysis of epidemiological studies comprising thousands of US young adults, and a subsequent prospective study, showed that initiation of cigarette smoking is more common among previously electronic cigarette users compared with previous cigarette non-users.69,70 A huge variety of available refill flavours certainly impose a potential to enhance the appeal to novice users, making the initial exposure more pleasurable and perhaps more likely to occur.

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Cardiovascular Epidemiology Table 1: Clinical and Preclinical Studies that Examined the Effects of Electronic Cigarettes on Cardiovascular Health Study

Type of Study

Observed Effect

Acute inhalation of electronic cigarette aerosols with nicotine among healthy volunteers caused: ↑ heart rate, ↑ arterial stiffness, ↑ flow resistance in conducting airways

Chatterjee et al. 201979

Acute electronic cigarette aerosol inhalation, without nicotine, led to the transient increase of circulating ↑ ICAM-1 and reactive oxygen species ↑

Alzahrani et al. 201973

Daily electronic cigarette use ↑ odds of having a myocardial infarction (OR 1.79, 95% CI 1.20–2.66, p=0.004)

Nocella et al. 2018

↑ Soluble CD-40 ligand, ↑ soluble P-selectin, ↑ platelet aggregation

Electronic cigarette-only use, compared with no product use, was associated with ↑ general health scores, ↑ breathing difficulty scores, ↑ higher proportion of self-reported chest pain, palpitations, CAD, arrhythmia, COPD and asthma

In mice, short-term electronic cigarette exposure ↑ risk of thrombogenesis and ↑ platelet function

Nicotine, but not electronic cigarette vehicles (propylene glycol and glycerol), ↑ acetylcholine-mediated vasodilation, ↑ indices of arterial stiffness, ↑ systolic and diastolic blood pressures and heart rate, ↑ plasma myeloperoxidase

↑ DNA damage, ↑ repair activity in mouse lung, heart and bladder

Antoniewicz et al. 2019

Wang et al. 2018

104

105

Quasim et al. 2018106 Chaumont et al. 2018

107

Lee et al. 2018108 Franzen et al. 2018

Electronic cigarette vaping led to ↑ peripheral and central arterial blood pressure, and ↑ pulse wave velocity

Moheimani et al. 2017109

Electronic cigarettes with nicotine caused ↑ sympathetic tone; ←→ no effect on oxidative stress (plasma paraoxonase)

Boas et al. 201796

↑ Activation of splenocardiac axis

Taylor et al. 2017

No change ←→ in endothelial cell migration in vitro compared with scientific reference cigarette

Moheimani et al. 201780

↑ Cardiac sympathetic activity (habitual use), ↑ oxidative stress (habitual use)

Hom et al. 201676

Platelets from healthy volunteers showed ↑ activation, ↑ adhesion, ↑ inflammation and ↑ aggregation potential upon exposure to electronic cigarette extracts of variable nicotine concentrations

Antoniewicz et al. 2016111

Ten puffs of electronic cigarette vapour ↑ endothelial progenitor cells in the blood of healthy volunteers

Anderson et al. 2016

110

Electronic cigarette aerosol ↑ reactive oxygen species, induced DNA damage and cell death in EC

Vlachopoulos et al. 201678

↑ Aortic stiffness, ↑ blood pressure

Teasdale et al. 201686

No change in ←→ stress response in human coronary artery endothelial cells in culture

Soluble components of electronic cigarettes, including nicotine, caused dose-dependent ↓ lung endothelial barrier function, ↑ oxidative stress, ↑ brisk inflammation

↓ Decreased cardiac development in zebrafish and human embryonic stem cells

Schweitzer et al. 2015

Palpant et al. 2015112

No immediate effects on myocardial relaxation

Szoltysek-Boldys et al. 2014113

No change ←→ in arterial stiffness

Farsalinos et al. 2013

Some electronic cigarette samples had cytotoxic effect on cultured cardiomyoblasts

Farsalinos et al. 2014

C = clinical; CAD = coronary artery disease; COPD = chronic obstructive pulmonary disease; EC = endothelial cell; OR = odds ratio; P = preclinical.

Electronic Cigarettes and Cardiovascular Risks There is no consensus about the effects of electronic cigarettes on the cardiovascular system, with most of the available data coming from preclinical studies. The effects of electronic cigarettes on cardiovascular health are summarised in Table 1, while postulated effects on the heart and vasculature, mainly derived from preclinical studies, are shown in Figure 2. In a large cross-sectional analysis conducted among a US population, electronic cigarette use was associated with lower general health status, higher breathing difficulty scores and greater incidence of cardiac symptoms, such as chest pain, palpitations, arrhythmias or coronary artery disease.71 Very recently, in a cross-sectional analysis of 400,000 adult respondents from the 2016 BRFSS survey, almost 70,000 people reported electronic cigarette use, and this was associated with a 71% increased risk of stroke, 59% higher risk of acute MI and a 40% higher risk of angina and coronary artery disease; moreover, they had twice the risk of switching to regular cigarettes.72 Similarly, in a recent logistic regression analysis performed among the National Health Interview Surveys 2014–2016 population, daily electronic cigarette use, after adjusting for conventional tobacco exposure and other risk factors, was

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significantly associated with a 79% increase in the odds of suffering an acute MI.73 In contrast, pooled data from the BRFSS 2016–2017 sample that included almost 450,000 participants failed to find a significant association between sole electronic cigarette use in never-smokers and cardiovascular disease, whereas dual use of electronic cigarettes and combustible cigarettes was associated with a 36% higher odds of cardiovascular disease compared with tobacco smoking alone.74 Limited data currently exist regarding the general cardiac effects of electronic cigarette smoking. After vaping one electronic cigarette, an acute and significant rise in peripheral arterial pressure was observed together with a steep increment in heart rate, and both changes lasted up to 45 minutes.75 It has also been demonstrated that, among healthy electronic cigarette users, heart rate variability shifted towards a sympathetic predominance with the decreased vagal tone, which are both risk factors of cardiovascular mortality. Interestingly, these effects were unrelated to nicotine, as its plasma levels were virtually undetectable.76 A study used transthoracic echocardiography to evaluate LVF before and after smoking one tobacco cigarette or vaping an electronic

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Electonic Cigarettes and Cardiovascular Risk Figure 2: The Physiological Effects of Electronic Cigarette Inhalation on the Heart and Vasculature

Postulated electronic cigarette effects on

HEART

Heart rate Central arterial pressure Peripheral arterial pressure Odds of having a MI (OR 1.71, 95% CI [120â&#x20AC;&#x201C;2.66]) Sympathetic activity Activation of splenocardiac axis Repair activity of the heart Cardiac development in zebrafish and human embryonic stem cells

VASCULATURE

Arterial stiffness Aortic stiffness Platelet activation and adhesion Thrombogenesis Platelet function Endothelial progenitor cells in peripheral blood Pulse wave velocity

OR = odds ratio; Source: Central images kindly provided by Servier. Servier Medical Art is licensed under a Creative Commons Attribution 3.0 Unported License.

cigarette for 7 minutes with a refill that had a medium-strength nicotine concentration. It was found that while baseline parameters were comparable in both groups, after regular tobacco cigarette use, participants had higher Myocardial Performance Index, prolonged isovolumic relaxation time, and decreased diastolic strain rate and mitral annular early diastolic velocity, thus indicating a relevant diastolic impairment. In contrast, electronic cigarette users had no significant changes in immediate haemodynamic parameters of both systolic and diastolic function.77 In a small prospective study, electronic cigarette smoking for >30Â minutes (which is considered comparable to classic cigarette smoking for >5 minutes) induced an unfavourable acute effect on aortic stiffness and blood pressure, which are known predictors of cardiovascular risk and all-cause mortality.78 In terms of acute effects of electronic cigarette aerosol inhalation in healthy subjects, one study revealed a transient increase in oxidative stress and inflammation parameters, thus suggesting that electronic cigarette exposure without nicotine might drive the onset of vascular pathologies through reactive oxygen species and immune cell adhesion pathways.79 Similarly, a small clinical study by Antoniewicz et al. demonstrated that inhaled electronic cigarette aerosols with nicotine had an acute negative impact on vascular and pulmonary function.54 An in vitro study by Farsalinos et al. showed that the extract from electronic cigarettes (containing different flavours and nicotine quantity) applied to cultured myocardial cells at different dilution, both with or without nicotine, was cytotoxic at different concentrations irrespective of nicotine presence. The base solution consisting of glycerol and propylene glycol was not found to be cytotoxic at any concentration.48 These results seem to suggest that the toxic effects of electronic cigarettes could be elicited by the added flavours. In a similar experimental study, the application of aerosol extracts from electronic cigarettes on vascular endothelial cells for at least

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4 hours induced a significant escalation in reactive oxygen species generation, causing DNA damage and reducing cell viability in a dose-dependent manner. Both apoptosis and programmed necrosis pathways were upregulated; moreover, treatment with alphatocopherol and n-acetylcysteine, which have recognised anti-oxidant properties, provided a partial rescue of these cells, thus suggesting the involvement of reactive oxygen species in this pathological cascade.80 The potential interference with thrombosis and inflammation mechanisms was suggested by another study showing that exposing platelets to electronic cigarette vapour extracts induced a significant upregulation of the pro-inflammatory complementary elements C1 and C3b, even higher than traditional tobacco smoke extracts, and was accompanied with a concomitant boost in platelet activation, aggregation and adhesion capacity. These effects were independent of nicotine concentration, as the presence of pure nicotine extract resulted in the inhibition of platelet functions, suggesting that maybe other constituents of electronic cigarettes can antagonise normal platelet function; nonetheless, the presence of nicotine could somehow perpetuate platelet functional changes in a dose-dependent manner, making its role in electronic cigarette-induced damage even more inconclusive.81 Another link to cellular dysfunction induced by vaping was provided by a study analysing the response of liver Kupffer cells both to classic and electronic cigarette extracts exposure. In both cases, a strong inflammatory response was elicited, paired with increased oxidative stress and systemic cytokine release, which likely affected platelet function and general circulatory homeostasis.82 Platelet function seems to be modified by electronic cigarette vapours. In a mouse model of electronic cigarette exposure, platelets that were exposed to electronic cigarettes were more hyperactive, with a greater propensity towards aggregation induced by dense alpha granules secretion, and activation of alphaIIb-beta3 receptors and protein kinase B-extracellular signal-regulated kinase pathways.83 Moreover,

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Cardiovascular Epidemiology these cells were also less sensitive to prostacyclin-induced inhibition when compared with clean air-exposed cells. These changes could theoretically increase the overall risk of thromboembolic events. Other evidence of the possible irritant and inflammatory effect on cells comes from an in vitro study in which the exposure of tracheobronchial cells to electronic cigarette nicotine-free vapours was related to a concomitant increase in interleukin-6 and interleukin-8 cytokine production with a dose-dependent response and direct evidence of endothelial dysfunction.84 The association with inflammation and endothelial dysfunction is most likely mediated via nitric oxide pathways; although to a lesser degree than standard cigarettes, electronic cigarettes lead to an important increase in soluble nicotinamide adenine dinucleotide phosphate oxidase 2-derived peptides and a concomitant decrease in nitric oxide bioavailability.85 Nonetheless, in human coronary endothelial cells, tobacco smoke, but not electronic cigarette aerosols, was shown to induce nuclear factor erythroid 2-related factor 2 oxidative stress sensing factor transcription.86 In another study, exposure of umbilical endothelial vein cells to electronic cigarette compounds induced cytotoxic pathways, inhibited cell proliferation and altered cellular morphology when compared with regular tobacco.87 An animal study suggested that electronic cigarettes could also hamper metabolic homeostasis. Experiments on 14-day-old mice showed that those exposed to electronic cigarettes had lower bodyweight compared with non-exposed mice, irrespective of nicotine concentration. Furthermore, these vapours could elicit persistent behavioural changes later in adulthood.88 A recent study focused on the new device subtype of the heat-notburn tobacco cigarettes (IQOS in particular), also casting shadows on the potential toxic effect of these products. After 72 hours of exposure to the aerosols generated by heat-not-burn devices, both bronchial epithelial cells and smooth muscle cells suffered a loss of viability, and an increase in lactate dehydrogenase release, collagen I and fibronectin, with a detrimental effect on the mitochondrial respiration chain. Notably, many of these effects were achieved with lower concentrated aerosols than the aerosols produced by standard electronic cigarettes.89 Concerns about cardiac adverse events also directly involve nicotine, which is found at the same concentration in the blood of experienced electronic cigarette users as classic smokers. Nicotine has known pathological effects, mainly related to the excessive release of catecholamines, endothelial dysregulation and increased insulin resistance.90 Nicotine in electronic cigarettes has been shown to increase heart rate after overnight abstinence.91 Regarding lipid metabolism, nicotine in electronic cigarettes has been shown to increase the amount of circulating saturated fatty acids, decreasing the content of unsaturated fatty acids and inducing insulin resistance. Nicotine can also promote endothelial dysfunction, inhibit cellular apoptosis and enhance angiogenesis, thereby raising concerns about its possible role in the pathophysiology of atherosclerosis and even cancer development.92,93 Interestingly, in another experiment, rats exposed to electronic cigarette refill liquid had better metabolic profiles, with decreased total cholesterol, low-density lipoprotein cholesterol and low-density lipoprotein:high-density lipoprotein ratio. However, caution is required in interpreting these results, as this perceivable benefit was accompanied with a significant elevation in liver enzymes, thus

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establishing these apparently beneficial changes as a mere reflection of the toxic damage of electronic cigarette liquid on the liver.94 Recently, electronic cigarettes have been proposed as a possible interfering factor in the splenocardiac axis, a signalling network involving the brain, autonomic nervous system and hematopoietic tissues. Of note, after suffering acute stress, a sympathetic activity can cause efflux of leukocytes and progenitor cells from the bone marrow and spleen; these cells subsequently enter the arterial wall and promote atherosclerosis.95 In young adults who chronically used electronic cigarettes, FDG-PET CT showed increased uptake in the spleen and aortic wall compared with non-users, which is consistent with the engagement of the splenocardiac axis by the substances released by these devices.96 The effect on physical properties of the cardiovascular system come from a study of mice exposed to electronic cigarette vapours for 8 months (4 hours a day for 5 days a week, emulating an equivalent of 20 years of exposure in humans). This resulted in a 2.5-fold increase in aortic stiffness, a 24% lower maximal aortic relaxation in response to methacholine and a trend towards a reduction in left ventricular ejection fraction.97 Nonetheless, in humans, it seems that electronic cigarettes could be less harmful than standard cigarettes, as hypertensive patients who switched to electronic cigarettes benefited from a reduction in mean arterial blood pressure and improved pressure control.98 It should be emphasised that most of the data on the cardiovascular effects of electronic cigarettes are derived from preclinical, crosssectional or small-sized clinical studies in which standard cigarettes were used as a comparison arm, thus providing limiting and conflicting results. A large majority of such studies were also not designed to infer causality. Furthermore, most of these studies focused on the acute effects of electronic cigarette exposure, whereas it is unknown how and if these effects would translate to chronic and longitudinal electronic cigarette use. Likewise, population-wide studies have been confounded by combustible cigarette use, thus making the effect of electronic cigarettes alone challenging for interpretation. Another important issue is the varying pattern of electronic cigarette use among different groups; for example, dual users of electronic cigarettes and combustible cigarettes, former smokers, and never-smokers that use electronic cigarettes. Even within the electronic cigarette smoking population, the large heterogeneity of available electronic cigarette products, different nicotine concentrations and varying levels of daily exposure pose a real difficulty in ascertaining the true effect of electronic cigarettes on general and cardiovascular health. It should also be noted that the National Academies of Sciences, Engineering, and Medicine in 2018 released a report summarising available evidence regarding the public health consequences of electronic cigarette use.99 That report concluded that there is no available evidence as to whether or not electronic cigarette use is associated with clinical cardiovascular disease outcomes and subclinical atherosclerosis. Due to this, further investigation is warranted, as the long-term and longitudinal impacts of electronic cigarettes on cardiovascular health at the present moment remain unclear.

Regulatory Approval of Electronic Cigarettes Regulatory approval of electronic cigarettes varies by country and is constantly evolving to preserve public health interests, as data build

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Electonic Cigarettes and Cardiovascular Risk up. On a global scale, the WHO suggested stopping the promotion of electronic cigarettes to non-smokers and young people, and restricting the possibilities of advertising and indoor use.100 Likewise, the American College of Preventive Medicine’s Prevention Practice Committee recently issued a consensus-based statement recommending that electronic nicotine delivery systems should be screened in the general population, with special emphasis on electronic nicotine delivery systems initiation prevention among youth, but also in smokers intending to quit.101 In 2016, the US Food and Drug Administration (FDA) firmly regulated cigarettes and smokeless tobacco, including electronic cigarettes, prohibiting their sale to teens and even distribution of free samples. However, it allowed commercialisation of flavours and did not impose restrictions on electronic cigarette advertisements. The current FDA regulations also bind manufacturers to submit an application to list the chemicals inside the devices and to prove that their products respect relevant safety standards. Besides FDA indications, many US states have banned the use of electronic cigarettes in areas where traditional smoking is already forbidden. It is an interesting fact that in the largest coordinated enforcement effort in the FDA’s history, the agency issued more than 1,300 warning

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EUROPEAN CARDIOLOGY REVIEW

letters and fines to retailers that illegally sold JUUL and other electronic cigarettes brands to minors.102 This phenomenon shows that there are substantial challenges involving the legal regulation and on-market monitoring of these products. The European Parliament approved a directive that limits the maximum amount of nicotine in electronic cigarettes; products containing >20 mg/ml of nicotine are regulated as medical devices. Finally, as traditional smoking is forbidden in public places in most developed societies, resulting in a tangible reduction in smoking prevalence in the US, it has been postulated that electronic cigarettes could ‘renormalise’ the smoking habit, thus jeopardising the social perception of health risks imposed by tobacco products.103

Conclusion To date, there is no conclusive and clear data on the effects of electronic cigarettes on cardiovascular and general health, especially from a longitudinal perspective. While waiting for more evidence, it seems reasonable to consider electronic cigarettes as a better option when compared with conventional tobacco products, but at the same time it should be fairly obvious that no smoke is better than electronic smoke.

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Available at: https://www.fda.gov/tobacco-products/ctp-newsroom/ warning-letters-and-civil-money-penalties-issued-retailersselling-juul-and-other-e-cigarettes (accessed 7 June 2019). 103. Fairchild AL, Bayer R, Colgrove J. The renormalization of smoking? E-cigarettes and the tobacco “endgame”. N Engl J Med 2014;370:293–5. https://doi.org/10.1056/NEJMp1313940; PMID: 24350902. 104. Nocella C, Biondi-Zoccai G, Sciarretta S, et al. Impact of tobacco versus electronic cigarette smoking on platelet function. Am J Cardiol 2018;122:1477–81. https://doi. org/10.1016/j.amjcard.2018.07.029; PMID: 30170691. 105. Wang JB, Olgin JE, Nah G, et al. Cigarette and e-cigarette dual use and risk of cardiopulmonary symptoms in the Health eHeart Study. PLoS One 2018;13:e0198681. https://doi. org/10.1371/journal.pone.0198681; PMID: 30044773. 106. Qasim H, Karim ZA, Silva-Espinoza JC, et al. Short-term e-cigarette exposure increases the risk of thrombogenesis and enhances platelet function in mice. J Am Heart Assoc 2018;7:e009264. https://doi.org/10.1161/JAHA.118.009264; PMID: 30021806. 107. Chaumont M, de Becker B, Zaher W, et al. differential effects of e-cigarette on microvascular endothelial function, arterial stiffness and oxidative stress: a randomized crossover trial. Sci Rep 2018;8:10378. https://doi.org/10.1038/s41598-01828723-0; PMID: 29991814. 108. Lee HW, Park SH, Weng MW. et al. E-cigarette smoke damages DNA and reduces repair activity in mouse lung, heart, and bladder as well as in human lung and bladder cells. Proc Natl Acad Sci U S A 2018;115:E1560–9. https://doi.org/10.1073/ pnas.1718185115; PMID: 29378943. 109. Moheimani RS, Bhetraratana M, Peters KM, et al. Sympathomimetic effects of acute e-cigarette use: role of nicotine and non-nicotine constituents. J Am Heart Assoc 2017;6: e006579. https://doi.org/10.1161/JAHA.117.006579; PMID: 28931527. 110. Taylor M, Jaunky T, Hewitt K, et al. A comparative assessment of e-cigarette aerosols and cigarette smoke on in vitro endothelial cell migration. Toxicol Lett 2017;277:123–8. https:// doi.org/10.1016/j.toxlet.2017.06.001; PMID: 28658606. 111. Antoniewicz L, Bosson JA, Kuhl J, et al. Electronic cigarettes increase endothelial progenitor cells in the blood of healthy volunteers. Atherosclerosis 2016;255:179–85. https://doi. org/10.1016/j.atherosclerosis.2016.09.064; PMID: 27693003. 112. Palpant NJ, Hofsteen P, Pabon Let al. Cardiac development in zebrafish and human embryonic stem cells is inhibited by exposure to tobacco cigarettes and e-cigarettes. PLoS One 2015;10:e0126259. https://doi.org/10.1371/journal. pone.0126259; PMID: 25978043. 113. Szoltysek-Boldys I, Sobczak A, Zielinska-Danch W, et al. Influence of inhaled nicotine source on arterial stiffness. Przegl Lek 2014;71:572–5. PMID: 25799846.

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Cardiovascular Epidemiology

Electronic Cigarettes and Cardiovascular Risk: Science, Policy and the Cost of Certainty Olusola A Orimoloye, 1,2 Albert D Osei, 1,2 SM Iftekhar Uddin, 1,2 Mohammadhassan Mirbolouk 1,2 and Michael J Blaha 1,2 1. Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, US; 2. American Heart Association Tobacco Regulation and Addiction Center (ATRAC), US

Disclosure: The authors receive research funding from the US Food and Drug Administration. Citation: European Cardiology Review 2019;14(3):159–60. DOI: https://doi.org/10.15420/ecr.2019.14.3.GE2 Correspondence: Michael J Blaha, Johns Hopkins Ciccarone Center, Blalock 524D1, 600 N Wolfe St, Baltimore, MD 21287, US. E: mblaha1@jhmi.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

t often takes time to accumulate enough evidence to deem causal hypotheses plausible truths. Since the introduction of e-cigarettes about a decade ago, studies assessing their potential health effects have resulted in a weak evidence base for causal links to several important clinical outcomes.1 Specifically, according to the National Academies of Science, Engineering, and Medicine’s summary of available evidence on e-cigarettes and their health consequences, there is insufficient evidence to conclude whether e-cigarette use is associated with increased risk of clinical cardiovascular disease (CVD).1 This lack of evidence, unfortunately, may easily be misconstrued by consumers as an absence of harm. As a result, the direction of e-cigarette regulatory policy and healthcare recommendations remains subject to seemingly endless controversy and debate. There is one view that e-cigarettes may be less harmful nicotine delivery vehicles than traditional cigarettes, with potential utility for smoking cessation. Their possible use as quit devices is supported by the results of a recent randomised trial that showed e-cigarettes to be more effective for smoking cessation than nicotine-replacement therapy, when both were accompanied by behavioural support.2 However, in addition to the need for more trials to ascertain reproducibility of these findings, concerns remain about the safety of e-cigarettes. Because ‘safer than cigarettes’ does not necessarily mean safe, there are those who hold the opposing precautionary viewpoint that these products should be tightly regulated in view of lingering concerns about their long-term health effects.3

The rise in e-cigarette use among people who have never smoked and young people introduces another important piece to the e-cigarette and public health puzzle, extending the conversation from a debate on their utility for smoking cessation to questions about the public health implications of e-cigarette use by an ever-growing population of tobacco-naïve youth and adolescents.4,5 In the US, for example, a recent study reported there were an estimated 2 million never-smoking e-cigarette users in 2016.6 With the introduction of JUUL (a sleek, discreet, USB-shaped e-cigarette, especially popular among young people), these estimates are likely to be trending upwards.

In this issue, D’Amario et al. provide a balanced non-systematic narrative review of the e-cigarette evidence base.6 The authors particularly emphasise the mechanistic, epidemiologic and policy aspects, as well as several important studies that have implications for furthering our understanding of potential relationships between e-cigarette use and CVD. In examining the relationship between e-cigarette use and CVD risk, the first question that comes to mind is whether a possible relationship between e-cigarette exposure and CVD risk is plausible from a toxicological standpoint. As discussed by D’Amario et al., there is general agreement that e-cigarette vapour contains a range of substances that may be candidates for cardiovascular toxicity, including volatile organic compounds such as acrolein, flavouring derivatives, higher concentrations of nicotine and toxic metals such as lead, nickel and chromium.6 However, whether these substances increase the risk of CVD at the dose of exposure afforded by e-cigarettes remains the subject of several ongoing studies. Given the cardiovascular health concerns that exposure to these substances raise, a critical public health question arises over the level of evidence that scientists, clinicians and policymakers should consider sufficient to inform healthcare decisions and regulatory policy. 7 Should e-cigarettes be classified as safe because they contain fewer cardiotoxic compounds than traditional cigarettes?8,9 Should toxicity findings from in vitro and animal studies be directly extrapolated to humans? Are transient changes in haemodynamic parameters, which have been demonstrated in acute exposure studies, sufficient to classify these products as harmful?10 Should ‘evidence’ of harm from cross-sectional studies be deemed adequate, despite the possibility of significant confounding?11 Is it ethical to wait for decades for results of longitudinal studies and an aggregation of evidence akin to that which informed the 1964 US surgeon general’s report on smoking and health, while the use of these products by people who have never smoked continues to become more prevalent? For now, the bulk of evidence is derived – as D’Amario et al. correctly noted – from animal studies, acute exposure human studies and cross-sectional epidemiologic studies.6 While these studies hint at potential cardiovascular toxicity, they are by no means definitive.

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Cardiovascular Epidemiology Transient effects on heart rate variability and blood pressure, increased oxidative stress and endothelial dysfunction, toxic effects of flavouring additives on in vitro endothelial cells and cross-sectional associations between e-cigarette use and prevalent CVD have all been reported.10–13 Nevertheless, to be certain of the relationship between e-cigarette use and CVD, more time and large, prospective, epidemiological studies are needed. Initial steps for longitudinal investigation could involve including e-cigarette use assessment in established cardiovascular cohorts. Another strategy may be to establish dedicated cohorts for studying the cardiovascular effects of e-cigarettes and other novel tobacco products. However, given the rapid evolution of the e-cigarette market, their increasing acceptability and widespread concerns that these products

National Academies of Sciences, Engineering, and Medicine. Public Health Consequences of E-Cigarettes. Washington, DC: National Academies Press, 2018. https://doi.org/10.17226/24952. Hajek P, Phillips-Waller A, Przulj D, et al. A randomized trial of e-cigarettes versus nicotine-replacement therapy. N Engl J Med 2019;380:629–7. https://doi.org/10.1056/NEJMoa1808779; PMID: 30699054. Bhatnagar A, Whitsel LP, Blaha MJ, et al. New and emerging tobacco products and the nicotine endgame: the role of robust regulation and comprehensive tobacco control and prevention: a presidential advisory from the American Heart Association. Circulation 2019;139:e937–58. https://doi.org/10.1161/CIR.0000000000000669; PMID: 30862181. Mirbolouk M, Charkhchi P, Kianoush S, al et. Prevalence and distribution of e-cigarette use among US adults: behavioral risk factor surveillance system, 2016. Ann Intern Med 2018;169:429–38. https://doi.org/10.7326/M17-3440; PMID: 30167658.

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may reverse the gains from many decades of smoking cessation efforts, the stakes are high, and time to strengthen the evidence base may be a luxury. The potential public health cost of certainty must therefore be duly considered in reaching decisions on policy and healthcare recommendations. Consequently, in line with the position of the American Heart Association,3 we recommend that, while the health consequences of e-cigarettes continue to be investigated, regulatory bodies must work assiduously to prevent the uptake of e-cigarettes in tobacco-naïve youth and adolescents through flavouring prohibitions, advertising and marketing restrictions, warning labels and robust public health education.

Mirbolouk M, Charkhchi P, Orimoloye OA, et al. E-cigarette use without a history of combustible cigarette smoking among US adults: behavioral risk factor surveillance system, 2016. Ann Intern Med 2019;170:76–9. https://doi.org/10.7326/ M18-1826; PMID: 30304466. D’Amario D, Migliaro S, Borovac JA, et al. E-cigarettes and cardiovascular risk: caution waiting for evidence. Eur Cardiol 2019;14:151–8. https://doi.org/10.15420/ecr.2019.16.2. Qasim H, Karim ZA, Rivera JO, et al. Impact of electronic cigarettes on the cardiovascular system. J Am Heart Assoc 2017;6:e006353. https://doi.org/10.1161/JAHA.117.006353; PMID: 28855171. Keith RJ, Fetterman JL, Orimoloye OA, et al. Characterization of volatile organic compound (VOC) metabolites in cigarette smokers, electronic nicotine device users, dual users and nonusers of tobacco. Nicotine Tob Res 2019. https://doi.org/10.1093/ ntr/ntz021; PMID: 30759242; epub ahead of press. Goniewicz ML, Smith DM, Edwards KC, et al. Comparison of nicotine and toxicant exposure in users of electronic cigarettes and combustible cigarettes. JAMA

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Netw Open 2018;1:e185937. https://doi.org/10.1001/ jamanetworkopen.2018.5937; PMID: 30646298. Moheimani RS, Bhetraratana M, Yin F, et al. Increased cardiac sympathetic activity and oxidative stress in habitual electronic cigarette users: implications for cardiovascular risk. JAMA Cardiol 2017;90025:1–8. https://doi.org/10.1001/ jamacardio.2016.5303; PMID: 28146259. Osei AD, Mirbolouk M, Orimoloye OA, et al. The association between e-cigarette use and cardiovascular disease among never and current combustible cigarette smokers: BRFSS 2016 & 2017. Am J Med 2019;132:949–54. https://doi. org/10.1016/j.amjmed.2019.02.016; PMID: 30853474. Schweitzer KS, Chen SX, Law S, et al. Endothelial disruptive proinflammatory effects of nicotine and e-cigarette vapor exposures. Am J Physiol Lung Cell Mol Physiol 2015;309:L175–87. https://doi.org/10.1152/ajplung.00411.2014; PMID: 25979079. Fetterman JL, Weisbrod RM, Feng B, et al. Flavorings in tobacco products induce endothelial cell dysfunction. Arterioscler Thromb Vasc Biol 2018;38:1607–15. https://doi. org/10.1161/ATVBAHA.118.311156; PMID: 29903732.

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Cardiovascular Epidemiology

Expert Opinion Meditation and Cardiovascular Health: What is the Link? Sebastian Schnaubelt, 1 Andreas Hammer, 2 Lorenz Koller, 2 Jan Niederdoeckl, 1 Niema Kazem, 2 Alexander Spiel, 1 Alexander Niessner 2 and Patrick Sulzgruber 2 1. Department of Emergency Medicine, Medical University of Vienna, Austria; 2. Department of Medicine II, Division of Cardiology, Medical University of Vienna, Austria

Abstract Meditation as a form of body–mind interaction for primary and secondary prevention in cardiovascular disease has been discussed critically in the past. However, data that aimed to link this intervention to a reduction of various aspects of cardiovascular disease, rendering it a potential part of a cost-effective treatment approach in patients at risk, remain scarce and inconclusive. This article aims to provide an overview of currently available evidence in the literature and the potential impact of meditation on cardiovascular health. However, the data highlighted in this article cannot render with certainty directly reproducible effects of meditation on patients’ cardiovascular disease profiles. Meditation may be suggested only as an additional link in the chain of primary and secondary prevention until future research provides sufficient data on this topic.

Keywords Meditation, cardiovascular, health, tobacco, blood pressure, atherosclerosis Disclosure: The authors have no conflicts of interest to declare. Received: 3 March 2019 Accepted: 2 October 2019 Citation: European Cardiology Review 2019;14(3):161–4. DOI: https://doi.org/10.15420/ecr.2019.21.2 Correspondence: Alexander Niessner, Department of Medicine II, Division of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. E: alexander.niessner@muv.ac.at 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 is a major cause of morbidity and mortality worldwide. While traditional treatment protocols follow physical or pharmaceutical interventions, the mental approach of meditation has been used for centuries to induce beneficial changes to the patients’ cardiovascular risk profile. However, scientific refurbishment of this technique has in the past raised questions of legitimation. Therefore, we aimed at providing an overview of currently available evidence in the literature, and subsequently conclude on the potential impact of meditation on cardiovascular health.

Meditation: A Multifaceted Practice Meditation practice is an active mental process involving the pursuit of awareness, attention, concentration and general focus of the practitioner’s mind.1 It can be described as a form of mental training with the aim of regulating cognition and emotion; a specific directing of attention and awareness is meant to influence mental and somatic events.2 Meditation dates back several thousand years, and has a religious (Buddhist and Hindu) connotation and background. It has been used to improve stress management, therefore rendering it feasible to use in a strict therapeutic approach.3–6 A broad variety of meditation practices have been described; however, “focused attention meditation”, “open monitoring meditation”, “compassion meditation” and “loving kindness meditation” roughly

form the main styles. Most forms are intended to be practised once or twice daily.2,7 A short description of the different core meditation strategies is given in Table 1.

Methods Following a predefined search protocol (input combinations of the term “meditation” and the following: “hypertension”, “blood pressure”, “atherosclerosis”, “endothelial”, “metabolic”, “insulin”, “myocardial”, “ischaemia”, “smoking”, “tobacco”, “stress”, “lifestyle” and “prevention”), the databases PubMed/MEDLINE, EMBASE, CENTRAL and Google Scholar were searched for eligible articles (Figure 1). The search was conducted at the end of February 2019. In addition, articles from the reference list of retrieved articles or reviews were screened to detect further sources. Duplicates and papers found to be non-relevant were removed. All selected publications were read in detail as a full text or abstract. All research reporting on the influence of meditation on cardiovascular risk reduction was included. Two independent authors screened and reviewed the included information. Data on practices similar to meditation, such as yoga or various forms of martial arts, were excluded due to their dominant physical character. Eligible original research and reviews were included within the consensus of this manuscript. Based on little evidence in this field, a pooled analysis of different kinds of meditation was performed.

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Cardiovascular Epidemiology Table 1: Meditation Style Examples

benefit of meditation in improving the compliance and adherence of smoking cessation can be assumed based on the current evidence.

Focused attention meditation

Attention is focused on a given object

Open monitoring meditation

The ongoing experience (e.g. feelings and thoughts) is monitored with a background of awareness

Compassion meditation

Awareness upon the thoughts of alleviating suffering from living beings

Loving kindness meditation

Awareness upon kind wishes for happiness and wellbeing

Data from: Raffone et al. 20192 and Levine et al. 2017.7

Figure 1: Flowchart of the Search Protocol Used and Included Studies

3,616 identified through database searching

24 records identified through other sources (previous papers)

Blood Pressure Several randomised trials have evaluated the effect of meditation on arterial hypertension, with varying effects from a reduction of a mean of 21.9 (±8.3)/16.7 (±4.6) mmHg after 8 weeks of meditation treatment to no significant benefit, as shown by Blom et al. in the Hypertension Analysis of stress Reduction using Mindfulness meditatiON and Yoga (HARMONY) trial.18,31–39 Of note, it needs to be highlighted that styles of meditation, which additionally cover physical activity, appear to be even more effective in this regard.7 Whereas the American Heart Association recommends meditation to be considered as an alternative approach to lower patients’ blood pressure, the high variation of study results suggests meditation to be considered as a mere supplement to pharmacotherapeutic hypertension management, physical lifestyle changes and dietary interventions at this juncture.7,40

Myocardial Ischaemia 3,540 records screened

1,562 records removed due to duplication 1881 records removed due to non-eligibility

197 full-text articles screened

152 records removed due to further non-eligibility

45 studies included in analysis

Meditation and its Impact on (Patho-)physiology

In patients presenting with stabile angina, research suggests a reproducible benefit of meditation on exercise duration and total possible workload.41–43 However, as those findings rely on a purely subjective perception of participants, literature lacks a more objectifiable study design including evaluation of myocardial ischaemia by cardiac imaging or cardiac biomarkers. Considering such study designs, Dal Lin et al. investigated the impact of meditation on markers of inflammation and echocardiographic findings in patients after myocardial infarction. As the first investigation on this specific topic using objectifiable endpoints, they observed a decrease in the inflammatory burden and improvements in various echocardiographic measures, such as stroke volume, in the meditation intervention group.44

Neurology and Psychology A broad variety of hypothetical and potential effects of meditation on neurophysiology and neuroanatomy have been published so far.7,8 Anatomical and structural changes, such as tissue augmentation of the cerebral cortex, subcortical grey and white matter, as well as the cerebellum and brain stem, were discussed, and an increasing number of studies suggest that different meditation practices show distinct patterns of brain activity.1,7,9,10 Moreover, improvement in the subjectively experienced levels of general stress, depression and quality of sleep have been reported.8,11–22 Additionally, alterations on a neurophysiological level have been suggested. However, due to a lack of sufficient sample size and randomisation, suchlike series must be assessed carefully and interpreted with caution.7,10,20,23,24 Complex data derived from neuroimaging, such as PET or functional MRI, are promising to produce deeper insight, but are yet to be fully understood.10

Tobacco Use While smoking poses one of the major causes of both the development and progression of cardiovascular disease, its cessation has proved to be a highly effective primary and secondary approach for improved cardiovascular health.25 Meditation as a technique for smoking cessation and/or prevention might be more successful than traditional interventions in this regard.7,26–29 Tang et al. suggested that these results might originate from increased activity in the anterior cingulate and prefrontal cortex.30 Classic study limitations, such as small sample sizes (between 200 and 300 participants) and lack of follow-up, render this topic a subject of future additional research. However, a potential

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Metabolic Syndrome Evidence of the effects of meditation on factors of the metabolic syndrome is scarce.45 There are reports of an intervention of meditation leading to improved insulin resistance and possible links to reduced expression of genes linked to general inflammatory response.46 Similar reports cover an enhanced expression of genes associated with mitochondrial function and insulin secretion after a meditation intervention.47 However, based on limited data and diverging results on this issue, no clear conclusions can be drawn.

Atherosclerosis and Endothelial Function In an investigation by Castillo-Richmond et al., atherosclerosis progression – measured by carotid intima thickness via ultrasound – was reported to possibly be reduced by a meditation programme.7,48 Endothelial function itself – measured by evaluating brachial artery endothelial vasomotor response – has not yet been shown to be effectively influenced my meditation.46,49

Prevention of Cardiovascular Disease In terms of the effect of meditation on the primary prevention of cardiovascular risk, considerable heterogeneity between investigations and overall small sample sizes of various available data prevent profound conclusions on this topic.7,50 Moreover, the overall quality and power of studies investigating the relationship of meditation and secondary prevention of cardiovascular disease remain considerably low. The potential benefits of an intervention such as a meditation programme on quality of life or blood pressure as endpoints,

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Meditation and Cardiovascular Health suggesting a reduction of general cardiovascular risk, must be further researched.7,49,51

Conclusion Available data suggest a potential influence of meditation interventions on various factors of cardiovascular disease. However, many methodological issues have been raised in the past, and future research on this topic must strive for large, randomised trials with sufficient follow-up periods. The investigators’ bias of enthusiasm or even a positive predisposition towards meditation or alternative medical methods in general must be eliminated from further studies.7,52 The heterogenous data may be explained by the different impact of the variously described meditation techniques, which additionally poses a field of interest for future research.53 In clinical practice, meditation as an intervention may be suggested to patients at cardiovascular risk in addition to conservative treatment protocols

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Luders E, Kurth F. The neuroanatomy of long-term meditators. Curr Opin Psychol 2018;28:172–8. https://doi.org/10.1016/j. copsyc.2018.12.013; PMID: 30739005. Raffone A, Marzetti L, Del Gratta C, et al. Toward a brain theory of meditation. Prog Brain Res 2019;244:207–32. https:// doi.org/10.1016/bs.pbr.2018.10.028; PMID: 30732838. Kaliman P, Alvarez-López MJ, Cosín-Tomás M, et al. Rapid changes in histone deacetylases and inflammatory gene expression in expert meditators. Psychoneuroendocrinology 2014;40:96–107. https://doi.org/10.1016/j. psyneuen.2013.11.004; PMID: 24485481. Kalra S, Priya G, Grewal E, et al. Lessons for the healthcare practitioner from Buddhism. Indian J Endocrinol Metab 2018;22:812–7. https://doi.org/10.4103/ijem.IJEM_286_17; PMID: 30766824. Zieff G. Ancient roots – modern applications: mindfulness as a novel intervention for cardiovascular disease. Med Hypotheses 2017;108:57–62. https://doi.org/10.1016/j.mehy.2017.08.001; PMID: 29055403. Sieverdes JC, Adams ZW, Nemeth L, et al. Formative evaluation on cultural tailoring breathing awareness meditation smartphone apps to reduce stress and blood pressure. Mhealth 2017;3:44. https://doi.org/10.21037/ mhealth.2017.09.04; PMID: 29184896. Levine GN, Lange RA, Bairey-Merz CN, et al. Meditation and cardiovascular risk reduction: a scientific statement from the American Heart Association. J Am Heart Assoc 2017;6:pii:e002218. https://doi.org/10.1161/JAHA.117.002218; PMID: 28963100. Lipschitz DL, Kuhn R, Kinney AY, et al. Reduction in salivary α-amylase levels following a mind-body intervention in cancer survivors-an exploratory study. Psychoneuroendocrinology 2013;38:1521–31. https://doi.org/10.1016/j. psyneuen.2012.12.021; PMID: 23375640. Kurth F, Cherbuin N, Luders E. Promising links between meditation and reduced (brain) aging: an attempt to bridge some gaps between the alleged fountain of youth and the youth of the field. Front Psychol 2017;8:860. https://doi. org/10.3389/fpsyg.2017.00860; PMID: 28611710. Fox K, Dixon M, Nijeboer S, Girn M, et al. Functional neuroanatomy of meditation: A review and meta-analysis of 78 functional neuroimaging investigations. Neurosci Behav Rev 2016;65:208–28. https://doi.org/10.1016/j. neubiorev.2016.03.021; PMID: 27032724. Tang Y-Y, Ma Y, Wang J, et al. Short-term meditation training improves attention and self-regulation. Proc Natl Acad Sci U S A 2007;104:17152–6. https://doi.org/10.1073/pnas.0707678104; PMID: 17940025. Black DS, O’Reilly GA, Olmstead R, et al. Mindfulness meditation and improvement in sleep quality and daytime impairment among older adults with sleep disturbances: a randomized clinical trial. JAMA Intern Med 2015;175:494–501. https://doi.org/10.1001/jamainternmed.2014.8081; PMID: 25686304. Klatt MD, Buckworth J, Malarkey WB. Effects of low-dose mindfulness-based stress reduction (MBSR-ld) on working adults. Health Educ Behav 2009;36:601–14. https://doi. org/10.1177/1090198108317627; PMID: 18469160. Pace TWW, Negi LT, Adame DD, et al. Effect of compassion meditation on neuroendocrine, innate immune and behavioral responses to psychosocial stress. Psychoneuroendocrinology 2009;34:87–98. https://doi.org/10.1016/j. psyneuen.2008.08.011; PMID: 18835662. Speca M, Carlson LE, Goodey E, Angen M. A randomized, wait-list controlled clinical trial: the effect of a mindfulness meditation-based stress reduction program on mood and symptoms of stress in cancer outpatients. Psychosom Med 2000;62:613–22. https://doi.org/10.1097/00006842200009000-00004; PMID: 11020090. Goyal M, Singh S, Sibinga EM, et al. Meditation programs for

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because of its non-invasive and cost-effective nature. In particular, as recommended by the European Society of Cardiology, treating psychosocial factors can counteract stress, depression and anxiety, and therefore facilitate behaviour change and improve general quality of life.54,55 The link between meditation and cardiovascular health may yet have to be scientifically confirmed, but to mentally engage with the body might be a first step towards a more individualised way of modern medicine.

Quintessence of this Expert Opinion • Heterogenous data suggest a link between meditation interventions and cardiovascular disease. • Meditation can be suggested to patients in addition to conservative treatment or prophylactic protocols. • In particular, meditation can help to reduce stress, depression and anxiety.

psychological stress and well-being: A systematic review and meta-analysis. JAMA Intern Med 2014;174(3):357–68. https://doi. org/10.1001/jamainternmed.2013.13018. Momeni J, Omidi A, Raygan F, Akbari H. The effects of mindfulness-based stress reduction on cardiac patients’ blood pressure, perceived stress, and anger: a singleblind randomized controlled trial. J Am Soc Hypertens 2016;10:763–71. https://doi.org/10.1016/j.jash.2016.07.007; PMID: 27632925. Fátima Rosas Marchiori M de, Kozasa EH, Miranda RD, et al. Decrease in blood pressure and improved psychological aspects through meditation training in hypertensive older adults: A randomized control study. Geriatr Gerontol Int 2015;15:1158–64. https://doi.org/10.1111/ggi.12414; PMID: 25407688. Rosenkranz MA, Davidson RJ, Maccoon DG, et al. A comparison of mindfulness-based stress reduction and an active control in modulation of neurogenic inflammation. Brain Behav Immun 2013;27:174–84. https://doi.org/10.1016/j. bbi.2012.10.013; PMID: 23092711. Epel ES, Puterman E, Lin J, et al. Meditation and vacation effects have an impact on disease-associated molecular phenotypes. Transl Psychiatry 2016;6:e880. https://doi. org/10.1038/tp.2016.164; PMID: 27576169. Ionson E, Limbachia J, Rej S, et al. Effects of Sahaj Samadhi meditation on heart rate variability and depressive symptoms in patients with late-life depression. Br J Psychiatry 2018:1–7. https://doi.org/10.1192/bjp.2018.265; PMID: 30482255. Gotink RA, Vernooij MW, Ikram MA, et al. Meditation and yoga practice are associated with smaller right amygdala volume: the Rotterdam study. Brain Imaging Behav 2018;12:1631–9. https://doi.org/10.1007/s11682-018-9826-z; PMID: 29417491. Jacobs TL, Epel ES, Lin J, et al. Intensive meditation training, immune cell telomerase activity, and psychological mediators. Psychoneuroendocrinology 2011;36:664–81. https://doi. org/10.1016/j.psyneuen.2010.09.010; PMID: 21035949. Creswell JD, Irwin MR, Burklund LJ, et al. Mindfulnessbased stress reduction training reduces loneliness and pro-inflammatory gene expression in older adults: a small randomized controlled trial. Brain Behav Immun 2012;26:1095–101. https://doi.org/10.1016/j.bbi.2012.07.006; PMID: 22820409. Jha P, Ramasundarahettige C, Landsman V, et al. 21st-century hazards of smoking and benefits of cessation in the United States. N Engl J Med 2013;368:341–50. https://doi.org/10.1056/ NEJMsa1211128; PMID: 23343063. Davis JM, Fleming MF, Bonus KA, Baker TB. A pilot study on mindfulness based stress reduction for smokers. BMC Complement Altern Med 2007;7:2. https://doi.org/10.1186/14726882-7-2; PMID: 17254362. Davis JM, Goldberg SB, Anderson MC, et al. Randomized trial on mindfulness training for smokers targeted to a disadvantaged population. Subst Use Misuse 2014;49:571– 85. https://doi.org/10.3109/10826084.2013.770025; PMID: 24611852. Davis JM, Manley AR, Goldberg SB, et al. Randomized trial comparing mindfulness training for smokers to a matched control. J Subst Abuse Treat 2014;47:213–21. https://doi. org/10.1016/j.jsat.2014.04.005; PMID: 24957302. Brewer JA, Mallik S, Babuscio TA, et al. Mindfulness training for smoking cessation: results from a randomized controlled trial. Drug Alcohol Depend 2011;119:72–80. https://doi. org/10.1016/j.drugalcdep.2011.05.027; PMID: 21723049. Tang Y-Y, Tang R, Posner MI. Brief meditation training induces smoking reduction. Proc Natl Acad Sci U S A 2013;110:13971–5. https://doi.org/10.1073/pnas.1311887110; PMID: 23918376. Manikonda JP, Störk S, Tögel S, et al. Contemplative meditation reduces ambulatory blood pressure and stress-induced hypertension: a randomized pilot trial. J Hum Hypertens 2008;22:138–40. https://doi.org/10.1038/sj.jhh.1002275;

PMID: 17823597. 32. H ughes JW, Fresco DM, Myerscough R, et al. Randomized controlled trial of mindfulness-based stress reduction for prehypertension. Psychosom Med 2013;75:721–8. https://doi. org/10.1097/PSY.0b013e3182a3e4e5; PMID: 24127622. 33. Gregoski MJ, Barnes VA, Tingen MS, et al. Breathing awareness meditation and LifeSkills Training programs influence upon ambulatory blood pressure and sodium excretion among African American adolescents. J Adolesc Health 2011;48:59–64. https://doi.org/10.1016/j. jadohealth.2010.05.019; PMID: 21185525. 34. Schneider RH, Grim CE, Rainforth MV, et al. Stress reduction in the secondary prevention of cardiovascular disease: randomized, controlled trial of transcendental meditation and health education in blacks. Circ Cardiovasc Qual Outcomes 2012;5:750–8. https://doi.org/10.1161/ CIRCOUTCOMES.112.967406; PMID: 23149426. 35. Nidich SI, Rainforth MV, Haaga DAF, et al. A randomized controlled trial on effects of the Transcendental Meditation program on blood pressure, psychological distress, and coping in young adults. Am J Hypertens 2009;22:1326–31. https://doi.org/10.1038/ajh.2009.184; PMID: 19798037. 36. Bai Z, Chang J, Chen C, Li P, et al. Investigating the effect of transcendental meditation on blood pressure: a systematic review and meta-analysis. J Hum Hypertens 2015;29:653–62. https://doi.org/10.1038/jhh.2015.6; PMID: 25673114. 37. Ponte Márquez PH, Feliu-Soler A, Solé-Villa MJ, et al. Benefits of mindfulness meditation in reducing blood pressure and stress in patients with arterial hypertension. J Hum Hypertens 2019;33:237–47. https://doi.org/10.1097/01. hjh.0000539863.81866.ac; PMID: 30425326. 38. Palta P, Page G, Piferi RL, et al. Evaluation of a mindfulnessbased intervention program to decrease blood pressure in low-income African-American older adults. J Urban Health 2012;8:308–16. https://doi.org/10.1007/s11524-011-9654-6; PMID: 22302233. 39. Blom K, Baker B, How M, et al. Hypertension Analysis of Stress Reduction Using Mindfulness Meditation and Yoga: Results From the Harmony Randomized Controlled Trial. Am J Hypertens 2014;27:122–9. https://doi.org/10.1093/ajh/hpt134; PMID: 24038797. 40. Ospina MB, Bond K, Karkhaneh M, et al. Meditation practices for health: state of the research. Evid Rep Technol Assess (Full Rep) 2007:1–263. PMID: 17764203. 41. Zamarra JW, Schneider RH, Besseghini I, et al. Usefulness of the transcendental meditation program in the treatment of patients with coronary artery disease. Am J Cardiol 1996;77:867–70. https://doi.org/10.1016/S00029149(97)89184-9; PMID: 8623742. 42. Ornish D, Brown SE, Scherwitz LW, et al. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. Lancet 1990;336:129–33. https://doi.org/10.1016/01406736(90)91656-U; PMID: 1973470. 43. Cunningham C, Brown S, Kaski JC. Effects of transcendental meditation on symptoms and electrocardiographic changes in patients with cardiac syndrome X. Am J Cardiol 2000;85:653–5. https://doi.org/10.1016/S0002-9149(99)00828-0; PMID: 11078284. 44. Dal Lin C, Marinova M, Rubino G, et al. Thoughts modulate the expression of inflammatory genes and may improve the coronary blood flow in patients after a myocardial infarction. J Tradit Complement Med 2018;8:150–63. https://doi.org/10.1016/j. jtcme.2017.04.011; PMID: 29322004. 45. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683–9. https://doi.org/10.2337/ diacare.24.4.683; PMID: 11315831. 46. Paul-Labrador M, Polk D, Dwyer JH, et al. Effects of a randomized controlled trial of transcendental

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Cardiovascular Epidemiology meditation on components of the metabolic syndrome in subjects with coronary heart disease. Arch Intern Med 2006;166:1218–24. https://doi.org/10.1001/ archinte.166.11.1218; PMID: 16772250. 47. Bhasin MK, Dusek JA, Chang B-H, et al. Relaxation response induces temporal transcriptome changes in energy metabolism, insulin secretion and inflammatory pathways. PLoS ONE 2013;8:e62817. https://doi.org/10.1371/journal. pone.0062817; PMID: 23650531. 48. Castillo-Richmond A, Schneider RH, Alexander CN, et al. Effects of stress reduction on carotid atherosclerosis in hypertensive African Americans. Stroke 2000;31:568–73. https://doi.org/10.1161/01.STR.31.3.568; PMID: 10700487. 49. Younge JO, Gotink RA, Baena CP, et al. Mind-body practices for patients with cardiac disease: a systematic review and

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meta-analysis. Eur J Prev Cardiol 2015;22:1385–98. https://doi. org/10.1177/2047487314549927; PMID: 25227551. Hartley L, Mavrodaris A, Flowers N, et al. Transcendental meditation for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2014:CD010359. https://doi.org/10.1002/14651858.CD010359.pub2; PMID: 25436436. Olex S, Newberg A, Figueredo VM. Meditation: should a cardiologist care? Int J Cardiol 2013;168:1805–10. https://doi. org/10.1016/j.ijcard.2013.06.086; PMID: 23890919. Ospina MB, Bond K, Karkhaneh M, et al. Clinical trials of meditation practices in health care: characteristics and quality. J Altern Complement Med 2008;14:1199–213. https://doi. org/10.1089/acm.2008.0307; PMID: 19123875. Schneider RH, Fields JZ, Salerno JW. Editorial

commentary on AHA scientific statement on meditation and cardiovascular risk reduction. J Am Soc Hypertens 2018;12:e57–e58. https://doi.org/10.1016/j.jash.2018.11.005; PMID: 30503717. 54. Richards SH, Anderson L, Jenkinson CE, et al. Psychological interventions for coronary heart disease: Cochrane systematic review and meta-analysis. Eur J Prev Cardiol 2018;25:247–59. https://doi.org/10.1177/2047487317739978; PMID: 29212370. 55. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 2016;37:2315–81. https://doi.org/10.1093/eurheartj/ehw106; PMID: 27222591.

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Electrophysiology and Arrhythmia

Predictors of Recurrence of AF in Patients After Radiofrequency Ablation Iskren Garvanski, 1,2 Iana Simova, 1 Lazar Angelkov 1 and Mikhail Matveev 2 1. Acibadem City Clinic Cardiology Department, Sofia, Bulgaria; 2. Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Sofia, Bulgaria

Abstract Catheter ablation is a well-known treatment for patients with AF. Despite the growing knowledge in the field, the identification of predictors of recurrence of AF after catheter ablation is one of the primary goals and is of major importance to improve long-term results of the procedure. The aim of this article is to provide an overview of what has been published in recent years and to summarise the major predictors, helping cardiac electrophysiologists in the selection of the right candidates for catheter ablation.

Keywords AF, catheter ablation, recurrence of arrhythmia, pulmonary vein isolation Disclosure: The authors have no conflicts of interest to declare. Received: 17 April 2019 Accepted: 7 August 2019 Citation: European Cardiology Review 2019;14(3):165–8. DOI: https://doi.org/10.15420/ecr.2019.30.2 Correspondence: Iskren Garvanski, Acibadem City Clinic, Okolovrasten pat 127, Sofia, Bulgaria. E: i.garvanski@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

AF is the most common sustained arrhythmia in clinical routine, and is associated with cardiovascular and cerebrovascular complications, dementia and mortality.1 Pulmonary vein isolation (PVI) in patients with symptomatic AF has become a well-established treatment option.2,3 High acute success rates are achievable, but durable efficacy of previously successful PVIs for AF still remains a challenge, and finding the predictors of AF recurrence is of major importance. Success rates vary between 60% and 80%, for paroxysmal AF (PAF), depending on ablation strategies, and between 50% and 60% for persistent AF.4,5 In a consensus document published by the Heart Rhythm Society, an ablation’s success is defined as freedom from symptomatic or asymptomatic AF, atrial tachycardia, or atrial flutter lasting ≥30 seconds after AF ablation.6 1-year success is defined as freedom from arrhythmic events without antiarrhythmic drugs documented from the end of the blanking period (usually 3 months after ablation) to 12 months of followup. Long-term success is considered as freedom from arrhythmic events from the end of the blanking period to at least 36 months of follow-up after the ablation procedure in the absence of antiarrhythmic drugs. AF as a condition includes different clinical subtypes, and the success rate of catheter ablation (CA) of AF is hugely affected by patient characteristics. The identification of the predictors of maintenance of sinus rhythm after CA is of major importance, as it would help in patient selection. In our article, we examine the published data regarding the possible predictors of recurrence after radiofrequency PVI.

Definition of Recurrence Early recurrence (ER) is defined as a recurrence of AF within 3 months of ablation, and ER after CA of AF is fairly common; a study conducted by Joshi et al. showed that the incidence of ER is most frequent soon after the procedure, while it decreases in the following days.7 The

patients were monitored with a loop recorder for the first 3 months after the procedure. Although the prevalence of ER was significant, with almost two-thirds of the patients having ER, it has been widely recognised that a good proportion of patients experiencing ER are free of significant atrial arrhythmias at prolonged observation. In contrast, the occurrence of late recurrence is more frequent in patients with ER.8 Moreover, another study by Bertaglia et al. found 46% of atrial tachyarrhythmias relapse during the first 3 months of follow-up.9 These data suggest that ER is probably linked to the ablation procedure itself. The thermal energy delivery, the local inflammation, and a transient imbalance between sympathetic and parasympathetic tone has been reported after ablation, and may potentially contribute to arrhythmic recurrences in this phase.10–12 A possible incomplete lesion in the atrium in the first days after the procedure and the lack of a complete scar across the wall are another possible cause for early recurrence.13,14 Another possible explanation for the uncertain clinical impact of ER is the occurrence of atrial reverse structural and electrical remodelling after ablation; indeed, maintenance of sinus rhythm positively affects conduction velocities and effective refractory periods of the atria, which renders the atria less susceptible to initiation and perpetuation of arrhythmias.14 Late recurrence is defined as an AF relapse more than 3 months following the intervention (after the blanking period). The main mechanism of that type of recurrence is pulmonary vein “reconnection”, as shown in several studies. Reconnection is the recovery of the electrical conduction between pulmonary veins and the left atrium (LA), and it favours an AF or atrial tachycardia relapse.15 A study conducted by Navinder et al. showed that in patients with structurally normal hearts and symptomatic PAF, the addition of linear lesions to the standard PVI procedure is associated with a greater incidence of left atrial flutter, as compared with segmental PVI alone. The recurrence represented by atrial flutter was due to an

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Electrophysiology and Arrhythmia Figure 1: Predictors of Recurrence of AF after Radiofrequency Ablation Predictors of recurrence of AF after RF ablation

Early recurrence • Structural heart disease • LA diameter • Incomplete PV isolation • Low LA voltage • C-reactive protein

Late recurrence • PV reconnection • Early recurrence • Metabolic syndrome • Low-amplitude F waves • AF duration • LA diameter

Very late recurrence • MB-LATER score • APPLE score • Obesity • Non-PV triggers • Structural heart disease The APPLE score is one point for Age >65 years, Persistent AF, imPaired glomerular filtration rate (<60 ml/min/1.73 m2), Left atrium diameter ≥43 mm, Ejection fraction <50%; MB-LATER score is male, bundle brunch block, left atrium, type of AF (paroxysmal, persistent or long-standing persistent) and early recurrent AF. LA = left atrium; PV = pulmonary vein; RF = radiofrequency.

incomplete linear lesion drawn during the ablation procedure.16 The authors suggested that linear ablation should be avoided as an initial approach to ablation in this population of patients. Moreover, nonpulmonary veins foci, which are localised outside from the circumferential ablation lines, could also contribute to the initiation of AF.17 A few studies with prolonged follow-up periods (>5 years) suggested and introduced a new subtype of AF recurrence called very late recurrences. Relapses of AF long after the ablation are the result of the deterioration of the atrial tissue; progression of atrial fibrosis, enlargement of the LA, and the adverse electrical and molecular remodelling of myocardial tissue are involved in these types of recurrences.18 Thus, very late recurrence accounts for the final stage of the atrial electrical disease, even though further investigation on the topic is warranted (Figures 1 and 2).

Predictors of Recurrence To date, several predictors of recurrence have been identified in various studies. A publication summarising the data from the German Ablation Registry published by Sultan et al. described a few statistically significant predictors of AF recurrence after the ablation procedure. The registry data included a total of 3,703 patients undergoing CA for AF in 40 German centres, and the mean follow-up period was 463 days. The data showed that AF type, female sex and in-hospital AF relapse are strong predictors for AF recurrence, as well as comorbidities, such as impaired renal and cardiac function.19 A few echocardiographic parameters have been evaluated as predictors of AF recurrence. In a literature review by Lizewska-Springer et al., 21 full-text articles were analysed and a few features were outlined.20 Left atrial diameter, right atrial size, right atrial volume index, left ventricle ejection fraction, and diastolic dysfunction carried significant preprocedural prognostic value and outlined the following cut-off

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values as predictors of AF recurrence after CA:LA diameter >50–55 mm or left atrial volume indexed to body surface area >34 ml/m2, E/é >13–15, LA strain assessed by speckle-tracking electrocardiography <20–25% and total atrial conduction time measured by tissue Doppler imaging >150 ms. The presence of LV systolic dysfunction also lowered the CA success rate with a lower LVEF cut-off value of <25%. A systematic review by Balk et al. on the predictors of AF recurrence after radiofrequency CA synthesises the data reported in 2,169 different citations, focusing their attention on the significant preprocedural patient characteristics, such as AF type, AF duration, left atrial diameter, left ventricular ejection fraction, sex, age, the presence of structural heart disease and the presence of hypertension.21 Their meta-analysis showed that not one of these clinical parameters is able to predict arrhythmia recurrences at a high level of evidence. The only clinical parameter that demonstrated a potential link to AF recurrence was AF type. A possible explanation of these results is that the studies on AF ablation are extremely heterogeneous regarding patient selection, patient characteristics, follow-up, variation in most of the clinical variables and procedural features. Hof et al. reported LA volume as an independent predictor of AF recurrence.22 A notable limitation of evaluating LA size in these previous meta-analyses is the fact that dilated LA induced by AF may modify the ellipsoidal shape into a more trapezoidal shape because of atrialisation of pulmonary veins (PVs). Thus, a simple linear dimension may not be representative of LA size, such as anteroposterior diameter measured by the end-systolic LA in the echocardiographic parasternal long axis view. With LA geometry and changes in shape, MRI and CT could be more appropriate methods for evaluation of LA size.23–25 One report revealed that LA volume using magnetic resonance angiographic imaging was not related to the recurrence of AF after ablation.26 The concept of PV volume, measured with CT, as a predictor for AF recurrence was examined by Shimamoto et. al. Their study demonstrated that greater total PV volume and PV ostial area in PAF patients were related to AF recurrence after radiofrequency CA. They suggested a cut-off value of 12.0 cm3/BSA (m2) for the total PV volume, below which there was a good predictive value for sinus rhythm maintenance after CA in their PAF group.27 Regarding early recurrence, Bertaglia et al. observed that the presence of structural heart disease and the lack of successful isolation of all targeted PVs are predictors of early atrial tachyarrhythmia recurrence. A recent study by Mujovic et al. outlines that in patients with early recurrence of AF, the most common finding on repeated electrophysiology study is PV reconnection and the presence of roof line gaps.28 Other studies have indicated hypertension, left atrial enlargement, permanent AF and lack of superior vena cava isolation as predictors of early relapse of AF after ablation.7,29 Otherwise, the termination of AF during the ablation procedure, when compared with failure to terminate the arrhythmia with the necessity of an electrical cardioversion, predicts early and late success.30 A longer cycle length of AF in patients with persistent AF is also associated with termination of the arrhythmia and with overall success of the procedure.31 These data suggest that early recurrence might be associated to the presence of structural heart disease or of significant risks factors for heart disease, which lead to a higher degree of adverse left atrial remodelling and enlargement. A different meaning should be assigned to very early recurrence, which occurs within 48 hours from the ablation procedure.

EUROPEAN CARDIOLOGY REVIEW

AF After Radiofrequency Ablation Chang et al. suggested that longer procedural time and lower LA voltage were independent predictors of very early AF recurrences.32,33 Koyama et al. also reported that an increase in body temperature and C-reactive protein were associated with signs of pericarditis in patients with very early recurrence, hypothesising an inflammatory mechanism as a potential causative factor. In addition to that hypothesis, two recent studies showed that an increased preprocedural N-terminal prohormone of brain natriuretic peptide and an increase in postprocedural C-reactive protein and N-terminal prohormone of brain natriuretic peptide is associated with a higher AF recurrence rate.34,35 Recurrence of AF after the blanking period of 3 months after the ablation is the expression of PVs reconnection or incomplete transmural injury of the radiofrequency energy.36 One study underlined that obesity, metabolic syndrome and early recurrence are independent predictors of AF relapse. Interestingly, the relationship between early and late recurrence has been investigated in several studies.37 A prolonged procedure time and inducibility of AF or AT immediately after ablation have been found to predict independently late recurrence in patients with early recurrences of atrial tachycardia.38 However, some studies failed to find a predictive value of AF/atrial tachycardia inducibility at the end of the RF procedure.39 Koyama found a lower rate of late recurrence among patients that experienced a very early recurrence after ablation, whereas patients that had a relapse after the first 48 hours had a higher rate of recurrence after 6 months.33 Similar results were obtained by Themistoclakis et al.; very early relapse was associated to a better final outcome when compared with recurrence within 1 month.29 These data have been confirmed by a meta-analysis that demonstrated recurrence within the first 30 days as the strongest predictor of future relapse.40 ECG features have also been analysed and related with AF recurrences. Low-amplitude F waves in lead aVF and V1, for example, have been demonstrated to be associated with late AF recurrence after ablation. On surface ECG, the amplitude of the F waves is dependent on the magnitude of the underlying voltage, which related to the magnitude of the remaining viable atrial muscle, therefore the arrhythmia substrate.41 Right atrium enlargement, more than two procedural attempts, AF duration and left atrial enlargement (>43 mm) have also been included in the heterogeneous list of atrial arrhythmia recurrence after ablation.42,43 As already stated above, AF type may predict the outcome of the ablation, as non-PAF is associated with a 60% higher risk to relapse when compared with PAF. These data suggest that the failure to maintain sinus rhythm after >6 months from the procedure is strongly associated with an ineffective ablation procedure, as in the majority of cases it is possible to demonstrate PV reconnection or development of atrial tachycardia around incomplete ablation lines. Furthermore, when PV reconnection is not present, the relapse is the consequence of the adverse electrical and anatomical remodelling associated with AF; repeated ablation attempts, low amplitude ECG waves, and atrial enlargement are strictly linked to myocardial fibrosis and lack of viable myocardial tissue. Therefore, as AF type is a hallmark of the underlying substrate, indication to catheter ablation in patients with non-PAF should be well balanced by cardiac electrophysiologists, as these patients have undoubtedly a worse outcome.

EUROPEAN CARDIOLOGY REVIEW

Figure 2: Predictors of Recurrence of AF After Radiofrequency Ablation Divided Depending on the Underling Substrate

Structural substrate • Structural heart disease • LA diameter • AF duration

Electrical substrate • Low-amplitude F waves • Non-PV triggers • Incomplete PV isolation

Autonomic substrate • Obesity • Metabolic syndrome

LA = left atrium; PV = pulmonary vein.

Very late recurrence has not been deeply evaluated in scientific studies. Recently, the MB-LATER (Male, Bundle brunch block, Left Atrium ≥47 mm, type of AF [paroxysmal, persistent or long-standing persistent] and ER-AF = early recurrent AF) score was developed as a predictive score for very late recurrence.44 The authors found that the MB-LATER score had better predictive ability for very late recurrence than the other widely used scoring systems, such as the APPLE, ALARMc, BASEAF2, CHADS2, CHA2DS2VASc or HATCH score. Validation of the score has been reported in other large long-term follow-up studies.45,46 The APPLE score has been shown to predict low-voltage areas in the atria, which represent advanced remodelling processes, associated with higher rates of arrhythmia recurrences.47 Recurrence occurring >12 months from the procedure is not excessively frequent, and has been related to hypertension and left atrial enlargement.48 Mainigi found that the only predictors of very late recurrence were weight >90 kg and the presence of non-PV triggers in the case of a repeated ablation, whereas other studies underlined the role of right atrial foci.49 In one of the studies with the longest follow-up period, Weerasooriya et al. found that valvular heart disease and nonischaemic cardiomyopathy were predictors of very late recurrence. On the basis of these data, very late recurrence can be considered a new type of AF, not depending on earlier triggers (e.g. PV foci), but originating from other areas of the atrium with a more advanced degree of adverse remodelling.50

Conclusion Radiofrequency ablation of AF is associated with a wide variety of recurrence rates, mostly due to patient-specific preprocedural factors and specific procedural factors. The identification of specific preprocedural markers for higher recurrence rates after ablation procedures in patients with AF would be most helpful to identify good candidates for CA.

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irchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines K for the management of atrial fibrillation developed in collaboration with EACTS. Eur J Cardiothorac Surg 2016;50:e1–88. https://doi.org/10.1093/ejcts/ezw313; PMID: 27663299. Haissaguerre M, Jais 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. Di Biase L, Elayi CS, Fahmy TS, et al. Atrial fibrillation ablation strategies for paroxysmal patients: randomized comparison between different techniques. Circ Arrhythm Electrophysiol 2009;2:113–9. https://doi.org/10.1161/CIRCEP.108.798447; PMID: 19808455. Ganesan AN, Shipp NJ, Brooks AG, et al. Long-term outcomes of catheter ablation of atrial fibrillation: a systematic review and meta-analysis. J Am Heart Assoc 2013;2:e004549. https:// doi.org/10.1161/JAHA.112.004549; PMID: 23537812. Steven D, Sultan A, Reddy V, et al. Benefit of pulmonary vein isolation guided by loss of pace capture on the ablation line: results from a prospective 2-center randomized trial. J Am Coll Cardiol 2013;62:44–50. https://doi.org/10.1016/j. jacc.2013.03.059; PMID: 23644091. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Heart Rhythm 2012;9:632–96.e21. https://doi.org/10.1016/j. hrthm.2011.12.016; PMID: 22386883. Joshi S, Choi AD, Kamath GS, et al. Prevalence, predictors, and prognosis of atrial fibrillation early after pulmonary vein isolation: findings from 3 months of continuous automatic ECG loop recordings. J Cardiovasc. Electrophysiol 2009;20:1089– 94. https://doi.org/10.1111/j.1540-8167.2009.01506.x; PMID: 19549038. Andrade JG, Khairy P, Verma A, et al. Early recurrence of atrial tachyarrhythmias following radiofrequency catheter ablation of atrial fibrillation. Pacing Clin Electrophysiol 2012;35:106–16. https://doi.org/10.1111/j.1540-8159.2011.03256.x; PMID: 22054110. Bertaglia E, Stabile G, Senatore G, et al Predictive value of early atrial tachyarrhythmias recurrence after circumferential anatomical pulmonary vein ablation. Pacing Clin Electrophysiol 2005; 28:366–71. https://doi.org/10.1111/j.15408159.2005.09516.x; PMID: 15869666. Grubman E, Pavri BB, Lyle S, et al. Histopathologic effects of radiofrequency catheter ablation in previously infarcted human myocardium. J Cardiovasc Electrophysiol 1999;10:336–42. https://doi.org/10.1111/j.1540-8167.1999.tb00680.x; PMID: 10210495. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation 2004;109:327–34. https://doi.org/10.1161/01. CIR.0000112641.16340.C7; PMID: 14707026. Hsieh MH, Chiou CW, Wen ZC, et al. Alterations of heart rate variability after radiofrequency catheter ablation of focal atrial fibrillation originating from pulmonary veins. Circulation 1999;100:2237–43. https://doi.org/10.1161/01. CIR.100.22.2237; PMID: 10577997. Fenelon G, Brugada P. Delayed effects of radiofrequency energy: mechanisms and clinical implications. Pacing Clin Electrophysiol 1996;19:484–9. https://doi. org/10.1111/j.1540-8159.1996.tb06520.x; PMID: 8848397. Li XP, Dong JZ, Liu XP, et al. Predictive value of early recurrence and delayed cure after catheter ablation for patients with chronic atrial fibrillation. Circ J 2008;72:1125–9. https://doi.org/10.1253/circj.72.1125; PMID: 18577822. Verma A, Kilicaslan F, Pisano E, et al. Response of atrial fibrillation to pulmonary vein antrum isolation is directly related to resumption and delay of pulmonary vein conduction. Circulation 2005;112:627–35. https://doi. org/10.1161/CIRCULATIONAHA.104.533190; PMID: 16061753. Sawhney N, Anousheh R, Chen W, et al. Circumferential pulmonary vein ablation with additional linear ablation results in an increased incidence of left atrial flutter compared with segmental pulmonary vein isolation as an initial approach to ablation of paroxysmal atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:243–8. https://doi.org/10.1161/ CIRCEP.109.924878; PMID: 20339034. Hsieh MH, Tai C, Lee S, et al. The different mechanisms

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between late and very late recurrences of atrial fibrillation in patients undergoing a repeated catheter ablation. J Cardiovasc Electrophysiol 2006;17:231–5. https://doi.org/10.1111/j.15408167.2005.00323.x; PMID: 16643390. Ausma J, Wijffels M, Thoné F, et al. Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat. Circulation 1997;96:3157–63. https://doi.org/10.1161/01. CIR.96.9.3157; PMID: 9386188. Sultan A, Lüker J, Andresen D, et al. Predictors of atrial fibrillation recurrence after catheter ablation: data from the German Ablation Registry. Sci Rep 2017;7:16678. https://doi. org/10.1038/s41598-017-16938-6; PMID: 29192223. Liżewska-Springer A, Da˛browska-Kugacka A, Lewicka E, et al. Echocardiographic predictors of atrial fibrillation recurrence after catheter ablation: a literature review. Cardiol J 2018. https://doi.org/10.5603/CJ.a2018.0067; PMID: 29924375; epub ahead of press. Balk EM, Garlitski AC, Alsheikh-Ali Alawi A, et al. Predictors of atrial fibrillation recurrence after radiofrequency catheter ablation: a systematic review. J Cardiovasc Electrophysiol 2010;21:1208–16. https://doi.org/10.1111/j.15408167.2010.01798.x; PMID: 20487117. Hof I, Chilukuri K, Arbab-Zadeh A, et al. Does left atrial volume and pulmonary venous anatomy predict the outcome of catheter ablation of atrial fibrillation? J Cardiovasc Electrophysiol 2009;20:1005–10. https://doi.org/10.1111/j.15408167.2009.01504.x; PMID: 19493152. Cozma D, Popescu BA, Lighezan D, et al. Left atrial remodeling: assessment of size and shape to detect vulnerability to atrial fibrillation. Pacing Clin Electrophysiol 2007;30:S147–50. https://doi.org/10.1111/j.15408159.2007.00626.x; PMID: 17302693. Tsao HM, Yu WC, Chen HC, et al. Pulmonary vein dilation in patients with atrial fibrillation: detection by magnetic resonance imaging. J Cardiovasc Electrophysiol 2001;12:809–13. https://doi.org/10.1046/j.1540-8167.2001.00809.x; PMID: 11469433. Pritchett AM, Jacobsen SJ, Mahoney DW, et al. Left atrial volume as an index of left atrial size: a populationbased study. J Am Coll Cardiol 2003;41:1036–43. https://doi. org/10.1016/S0735-1097(02)02981-9; PMID: 12651054. Tsao HM, Wu MH, Huang BH, et al. Morphologic remodeling of pulmonary veins and left atrium after catheter ablation of atrial fibrillation: insight from long-term follow-up of three-dimensional magnetic resonance imaging. J Cardiovasc Electrophysiol 2005;16:7–12. https://doi.org/10.1046/j.15408167.2005.04407.x; PMID: 15673379. Shimamoto K, Miura F, Shimatani Y, et al. Pulmonary vein volume predicts the outcome of radiofrequency catheter ablation of paroxysmal atrial fibrillation. PLoS ONE 2018;13:13:e0201199. https://doi.org/10.1371/journal. pone.0201199; PMID: 30044877. Mujovic N, Milan Marinković M, Marković N, et al. The relationship of early recurrence of atrial fibrillation and the 3-month integrity of the ablation lesion set. Sci Rep 2018;8:9875. https://doi.org/10.1038/s41598-018-28072-y; PMID: 29959347. Themistoclakis S, Schweikert RA, Saliba Walid I, et al. Clinical predictors and relationship between early and late atrial tachyarrhythmias after pulmonary vein antrum isolation. Heart Rhythm 2008;5:679–85. https://doi.org/10.1016/j. hrthm.2008.01.031; PMID: 18325850. Heist K, Chalhoub F, Barrett C, et al. Predictors of atrial fibrillation termination and clinical success of catheter ablation of persistent atrial fibrillation. Am J Cardiol 2012;110:545–51. https://doi.org/10.1016/j. amjcard.2012.04.028; PMID: 22591670. Drewitz I, Willems S, Salukhe TV, et al. Atrial fibrillation cycle length is a sole independent predictor of a substrate for consecutive arrhythmias in patients with persistent atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:351–60. https://doi. org/10.1161/CIRCEP.110.945279; PMID: 20511536. Chang SL, Tsao HM, Lin YJ, et al. Characteristics and significance of very early recurrence of atrial fibrillation after catheter ablation. J Cardiovasc Electrophysiol 2011;22:1193–8. https://doi.org/10.1111/j.1540-8167.2011.02095.x; PMID: 21615812. Koyama T, Sekiguchi Y, Tada H, et al. Comparison of characteristics and significance of immediate versus early versus no recurrence of atrial fibrillation after catheter ablation. Am J Cardiol 2009;103:1249–54. https://doi.

org/10.1016/j.amjcard.2009.01.010; PMID: 19406267. 34. C arballo D, Noble S, Carballo S, et al. Biomarkers and arrhythmia recurrence following radiofrequency ablation of atrial fibrillation. Int J Med Res 2018;46:5183–94. https://doi. org/10.1177/0300060518793807; PMID: 30178684. 35. Miake J, Kato M, Ogura K, et al. Pre-ablation levels of brain natriuretic peptide are independently associated with the recurrence of atrial fibrillation after radiofrequency catheter ablation in patients with nonvalvular atrial fibrillation. Heart Vessels 2019;34:517. https://doi.org/10.1007/s00380-018-12675; PMID: 30238353. 36. Deisenhofer I, Estner H, Zrenner B, et al. Left atrial tachycardia after circumferential pulmonary vein ablation for atrial fibrillation: incidence, electrophysiological characteristics, and results of radiofrequency ablation. Europace 2006;8:573–82. https://doi.org/10.1093/europace/eul077; PMID: 16864612. 37. Cai L, Yin Y, Ling Z, et al. Predictors of late recurrence of atrial fibrillation after catheter ablation. Int J Cardiol 2013;164:82–7. https://doi.org/10.1016/j.ijcard.2011.06.094; PMID: 21737164. 38. Choi JI, Pak HN, Park JS, et al. Clinical significance of early recurrences of atrial tachycardia after atrial fibrillation ablation. J Cardiovasc Electrophysiol 2010;21:1331–7. https://doi. org/10.1111/j.1540-8167.2010.01831.x; PMID: 20586828. 39. Kawai S, Mukai Y, Inoue S, et al. Predictive value of the induction test with atrial burst pacing with regard to long‐ term recurrence after ablation in persistent atrial fibrillation. J Arrhythmia 2019;35:223–9. https://doi.org/10.1002/joa3.12150; PMID: 31007786. 40. D’Ascenzo F, Corleto A, Biondi-Zoccai G, et al. Which are the most reliable predictors of recurrence of atrial fibrillation after transcatheter ablation?: a meta-analysis. Int J Cardiol 2013;167:1984–9. https://doi.org/10.1016/j.ijcard.2012.05.008; PMID: 22626840. 41. Cheng Z, Deng H, Cheng K, et al. The amplitude of fibrillatory waves on leads aVF and V1 predicting the recurrence of persistent atrial fibrillation patients who underwent catheter ablation. Ann Noninvasive Electrocardiol 2013;18:352–8. https://doi.org/10.1111/anec.12041; PMID: 23879275. 42. Zhao L, Jiang W, Zhou L, et al. Why atrial fibrillation recurs in patients who obtained current ablation endpoints with longstanding persistent atrial fibrillation. J Interv Card Electrophysiol 2013;37:283–90. https://doi.org/10.1007/s10840013-9808-4; PMID: 23832381. 43. McCready JW, Smedley T, Lambiase PD, et al. Predictors of recurrence following radiofrequency ablation for persistent atrial fibrillation. Europace 2011;13:355–61. https://doi. org/10.1093/europace/euq434; PMID: 21148171. 44. Mujovic N, Marinkovic M, Markovic N, et al. Prediction of very late arrhythmia recurrence after radiofrequency catheter ablation of atrial fibrillation: The MB-LATER clinical score. Sci Rep 2017;7:40828. https://doi.org/10.1038/srep40828; PMID: 28106147. 45. Deng H, Shantsila A, Xue Y, et al. Using the MB‐LATER score for predicting arrhythmia outcome after catheter ablation for atrial fibrillation: The Guangzhou atrial fibrillation project. Int J Clin Pract 2018;72:e13247. https://doi.org/10.1111/ijcp.13247; PMID: 30144238. 46. Schumacher K, Kornej J, Bollmann A, et al. Prediction of very late arrhythmia recurrence after catheter ablation in patients with atrial fibrillation using APPLE and MB-LATER scores: the Leipzig AF ablation registry, Eur Heart J 2018;39(Suppl_1):ehy564.367. https://doi.org/10.1093/ eurheartj/ehy564.367. 47. Kornej J, Büttner P, Sommer P, et al. Prediction of electroanatomical substrate using APPLE score and biomarkers. EP Europace 2019;21:54–9. https://doi.org/10.1093/europace/ euy120; PMID: 29893827. 48. Hsieh MH, Tai CT, Tsai CF, et al. Clinical outcome of very late recurrence of atrial fibrillation after catheter ablation of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2003;14:598–601. https://doi.org/10.1046/j.15408167.2003.03047.x; PMID: 12875420. 49. Mainigi SK, Sauer WH, Cooper JM, et al. Incidence and predictors of very late recurrence of atrial fibrillation after ablation. J Cardiovasc Electrophysiol 2007;18:69–74. https://doi.org/10.1111/j.1540-8167.2006.00646.x; PMID: 17081214. 50. Weerasooriya R, Khairy P, Litalien J, et al. Catheter ablation for atrial fibrillation: are results maintained at 5 years of followup? J Am Coll Cardiol 2011;57:160–6. https://doi.org/10.1016/j. jacc.2010.05.061; PMID: 21211687.

EUROPEAN CARDIOLOGY REVIEW

Electrophysiology and Arrhythmia

Current Controversies and Challenges in Brugada Syndrome Afik D Snir 1 and Hariharan Raju 2 1. Royal Prince Alfred Hospital, Sydney, Australia; 2. Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia

Abstract More than three decades since its initial description in 1993, Brugada syndrome remains engulfed in controversy. This review aims to shed light on the main challenges surrounding the diagnostic pathway and criteria, risk stratification of asymptomatic patients, pharmacological and interventional risk modification strategies as well as our current pathophysiological understanding of the disease.

Keywords Brugada syndrome, ICD, quinidine, radiofrequency ablation Disclosure: The authors have no conflicts of interest to declare. Received: 10 February 2019 Accepted: 6 June 2019 Citation: European Cardiology Review 2019;14(3):169–74. DOI: https://doi.org/10.15420/ecr.2019.12.2 Correspondence: Hariharan Raju, Suite 203, 2 Technology Place, Macquarie University, Sydney, NSW 2109, Australia. E: hari.raju@mqhealth.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.

Brugada syndrome was first described in 1993 in a case series of eight patients with recurrent polymorphic ventricular tachycardia (VT) and stereotypical electrographic characteristics in the context of a structurally normal heart.1 Since then, the syndrome has been extensively studied and recognised worldwide as a major cause of sudden cardiac death (SCD) in otherwise healthy patients.2 Recent data support the premise that Brugada syndrome is the most common single underlying aetiology for sudden unexplained death with negative autopsy, representing 28% of cases in the UK.3 Yet more than 30 years since its recognition, there are many questions and uncertainties surrounding the pathophysiology, diagnosis, risk assessment and management of Brugada syndrome. This article aims to examine some of these issues with consideration of recently published data.

Diagnostic Process Three distinct ECG patterns have been associated with Brugada syndrome (Figure 1); however, the type 2 and type 3 ECG patterns are less specific for the condition. 2,4 The diagnosis of Brugada syndrome requires documentation of the type 1 ECG pattern (consisting of coved-type ST-segment elevation of ≥2mm followed by a negative T wave in the right precordial leads V1 and/or V2) either on a spontaneous ECG or following IV administration of a class I antiarrhythmic agent such as flecainide or ajmaline.2,5 The 2013 diagnostic criteria excluded the requirement for associated clinical features, with diagnosis based purely on the ECG phenotype.5 However, to avoid overdiagnosis of low-risk patients, a further consensus statement on J wave syndrome has proposed the reintroduction of additional clinical evidence to support the diagnosis in patients having type 1 ECG only in the context of sodium channel blockade.4 These clinical criteria include documented VF or polymorphic VT; syncope of probable arrhythmic cause; family history

of SCD in a relative younger than 45 years; type 1 ECG in family members; nocturnal agonal respiration; and inducibility of VT/VF at programmed stimulation with one or two premature beats. The J wave syndrome consensus group also proposed the novel Shanghai scoring system that takes into account various ECG, clinical history and family history, similar to the Schwartz score used for diagnosis of long QT syndrome (Table 1).5 However, this scoring system is controversial because it was based on expert opinion, rather than appropriate experimental data, and it has not yet been validated. Past observations have shown that men more commonly present with spontaneous type 1 ECG pattern.1 Cranial displacement of the right precordial ECG leads from the fourth to the second or third intercoastal space – the high right precordial leads – has been shown to increase the sensitivity of the detection of the type 1 ECG pattern, possibly due to better anatomical correlation with the right ventricular outflow tract (RVOT), with no apparent change in prognostic value.2,6,7 In addition, a normal ECG does not rule out Brugada syndrome, as many patients with confirmed diagnosis only have intermittent Brugada ECG patterns.8,9 It has been suggested that prolonged 24-hour ambulatory monitoring using 12-lead ECG with high right precordial lead placement should be used for patients with a normal initial ECG with suspected Brugada syndrome. This may improve diagnostic yield without the risk associated with drug provocation.10,11 Other ECG findings that are non-diagnostic but are often associated with Brugada syndrome are shown in Table 2. In addition, Brugada syndrome remains a diagnosis of exclusion after considering other differential diagnoses that may chronically or acutely mimic the Brugada ECG pattern (Table 2).12 Normal cardiac structure and function on cardiac imaging is necessary to diagnose Brugada syndrome, since cardiomyopathies are recognised mimics. A reproducible type 1 ECG

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Electrophysiology and Arrhythmia Figure 1: Brugada Syndrome ECG Patterns A

On the other hand, previous studies have reported worrying falsenegative rates on pharmacological challenge testing of symptomatic and asymptomatic patients, with ajmaline being acknowledged as having greatest sensitivity.14,15 It has therefore been suggested that it is worthwhile to repeat a negative pharmacological test using a different agent in cases of high clinical suspicion.12 As with the case of non-pharmacological ECG recording, use of high right precordial lead position during ajmaline challenge testing has been shown to significantly increase the sensitivity of the test.16

Risk Stratification

A: Type 1 Brugada pattern; B: Type 2 Brugada pattern; C: Type 3 Brugada pattern (on high right precordial lead placement).

Table 1: The Proposed Shanghai Score System for Diagnosis of Brugada Syndrome ECG (12-lead/ambulatory)

Points*

One item from this category must apply Spontaneous type 1 Brugada ECG pattern at nominal or high leads

3.5

Fever-induced type 1 Brugada ECG pattern at nominal or high leads

Type 2 or type 3 Brugada ECG pattern that converts with provocative drug challenge

Clinical History Unexplained cardiac arrest or documented VF/polymorphic VT

Nocturnal agonal respirations

Suspected arrhythmic syncope

Syncope of unclear mechanism/aetiology

AF in patient <30 years without alternative aetiology

0.5

Family History First- or second-degree relative with confirmed Brugada syndrome

Suspicious SCD (fever, nocturnal, aggravating drugs) in first- or second-degree relative

Unexplained SCD <40 years in first- or second-degree relative and negative autopsy

0.5

Genetic Test Results Probable pathogenic mutation in Brugada syndrome susceptibility gene 0.5 Score â&#x2030;Ľ3.5 points: probable/definite Brugada syndrome 2â&#x20AC;&#x201C;3 points: possible Brugada syndrome <2 points: non-diagnostic *

Points only awarded for highest score in each category

SCD = sudden cardiac death; VT = ventricular tachycardia. Adapted from: Antzelevitch et al. 2017.4 Used with permission from Oxford University Press.

with sodium channel blockade is helpful to differentiate Brugada syndrome from phenocopies where there is uncertainty over diagnosis after an acute event. The benefit of using confirmatory diagnostic testing in all patients with non-diagnostic type 2 or 3 Brugada ECG pattern is questionable. Considering the low risk of asymptomatic patients without a spontaneous type 1 ECG, current consensus recommends testing with a class I antiarrhythmic agent to support the diagnosis only if the patient has at least one associated clinical feature.4,13

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Symptomatic presentation with previous aborted cardiac arrest or sustained ventricular arrhythmia carries the highest risk of recurrent arrhythmic event in the form of VT/VF, with a previously reported annual rate of about 8%, and secondary prevention with ICD implantation is recommended.5,17 Syncope is a common presentation, occurring in about 30% of patients, and arrhythmia-related syncope is also a well-established risk factor, with an annual event rate of about 2%.11,17 Therefore, it is recommended that a vasovagal cause of syncope is ruled out as these do not seem to carry any additional risk.12,18 Nevertheless, most patients diagnosed with Brugada syndrome are asymptomatic and present a greater challenge for risk stratification and management decisions.12,19 While the established risk of arrhythmic events is much lower for asymptomatic patients at about 1% annually overall, many cases of SCD still occur in this population.12,17,20 Yet despite multiple investigations into predictors of arrhythmic events in asymptomatic patients, no consensus is available for a risk stratification strategy in this population.12 A spontaneous type 1 Brugada ECG pattern is an important established risk factor for cardiac events, which has been reported to confer a three- to fourfold higher risk in asymptomatic patients.21,22 Despite this, only conservative surveillance and risk modification of lifestyle is universally recommended in asymptomatic patients.13 In contrast, a family history of SCD at any age is not an independent prognostic indicator for cardiac events in either symptomatic or asymptomatic patients.19,23 While a multitude of ECG parameters have been associated with increased risk of cardiac arrhythmias, two that have been consistently reported as independent risk factors are abnormal QRS fragmentation (defined as four spikes in one, or eight spikes in all of the leads V1, V2 and V3) and early repolarisation pattern in inferior and/or lateral leads.17,26â&#x20AC;&#x201C;29 In addition, AF is more commonly seen in Brugada syndrome than in the general population and has been reported as a risk factor for ventricular arrhythmias in several studies.25,26,30,31

Electrophysiological Study for Risk Stratification There is ongoing debate regarding the prognostic value of conducting electrophysiological study (EPS) with programmed electrical stimulation for risk stratification in patients without a history of cardiac arrest. Several investigations have demonstrated a positive association between the induction of VT/VF during EPS and the risk of future ventricular arrhythmias, while others have failed to do so.19,21,24,32,33 One important limitation (and potential source of bias) of studies in this area is that patients with a positive EPS are more likely to receive ICD implantation. Therefore, this population may have a higher frequency of recorded ventricular arrhythmias that may not result in cardiac arrest

EUROPEAN CARDIOLOGY REVIEW

Current Controversies and Challenges in Brugada Syndrome than in patients with negative EPS and no ICD.17,19 Another limitation is the lack of homogeneity between different EPS protocols in the literature.34 While aggressive stimulation protocols with ≥3 extrastimuli are more sensitive, they were found to be less specific than moderate protocols (≤2 extrastimuli).18,35

Table 2: Commonly Associated ECG Findings and Differential Diagnoses of Brugada-like ECG Pattern

Despite previous reports describing a strong negative predictive value of EPS in patients without cardiac arrest, a recent systematic review concluded that a negative EPS does not reliably indicate low risk in asymptomatic patients in the presence of other high-risk features (such as spontaneous type 1 ECG, for example).18,34,36 Moreover, the negative predictive value is a function of the low event rate in this low risk population, further limiting the clinical value of EPS.

First degree AV block and left-axis deviation of the QRS

ECG Findings Commonly Associated with Brugada Syndrome Decrease in ST-segment elevation during tachycardia at maximal stress–exercise test and reappearance in the recovery phase

Right bundle branch block Minor QT prolongation Late potentials in the signal-averaged ECG Fragmented QRS in leads V1–V3 VPBs with left bundle branch block morphology originating from the RVOT AF

Gender-specific Risk Brugada syndrome is about 7–10 times more prevalent in men, and male gender is associated with a higher incidence of ventricular arrhythmias and SCD at diagnosis and follow-up.17,37,38 However, despite the less favourable prognosis generally observed in men, gender alone may not be an independent prognostic indicator and the majority of men remain asymptomatic.17,19 Risk stratification in women with Brugada syndrome has been more challenging as most studies have mainly consisted of male participants. Available data suggest some classical risk factors, such as spontaneous type 1 ECG pattern, are not prognostic in women.38,39 A recent study including 494 women (31% of the total study population) has confirmed the prognostic value of symptomatic presentation with cardiac arrest or syncope in women.40 The only independent risk factors found in asymptomatic women – the majority of patients – were QRS fragmentation and duration >120 ms on ECG. Notably, asymptomatic women without QRS fragmentation had a very low event rate of only 0.1% per year. Previous smaller studies have described the presence of sinus node dysfunction and increased PR interval duration as the best independent markers of cardiac events in asymptomatic women.16,38 Of note is that these gender-specific observations are only relevant for adults (≥18 years), with no significant difference in phenotypic presentation in children.41,42

Early repolarisation in the inferior or infero-lateral leads

Deferential Diagnoses of Conditions that can Mimic the Brugada ECG Pattern Acute conditions

Chronic conditions

Acute ischemia/infarction (particularly of the RVOT region)

Atypical right bundle branch block

Prinzmetal angina

Left ventricular hypertrophy

Myocarditis/pericarditis

Pulmonary arterial hypertension

Pulmonary embolism

Mechanical compression of the RVOT (e.g. pectus excavatum)

Dissecting aortic aneurysm

Duchenne muscular dystrophy

Electrolyte abnormalities (hyper/ hypokalemia, hypercalcaemia)

Fridreich’s ataxia

Hyperthermia/hypothermia

Athlete’s heart

Post-defibrillation/ post-electrocution

Chagas disease Arrhythmogenic cardiomyopathy

AV = atrioventricular; RVOT = right ventricular outflow tract; VPB = ventricular premature beats. Adapted from: Polovina et al. 2017.11 Reproduced with permission from Elsevier.

Results from several large registry studies have failed to establish an independent association between genotype status and prognosis in Brugada syndrome.12,13 However, recent data suggest that mutations specifically involving the pore region of the SCN5A gene carry a more severe phonotype and were found to be independently associated with the risk of adverse cardiac events in both symptomatic and asymptomatic patients.45

Genotype and Prognosis The genetic characterisation of Brugada syndrome has proven to be challenging. The most common and well established Brugada syndrome genotype involve loss of function mutations in the SCN5A gene, representing between 15–30% of diagnosed patients.43 The SCN5A gene encodes for the cardiac voltage-gated sodium channel (Nav1.5) that is activated during the initial rapid depolarisation (phase 0) of the cardiac action potential cycle. About 300 mutations in the SCN5A gene have already been described, yet the role for genetic testing in the diagnosis of Brugada syndrome is limited due to the presence of ‘benign’ SCN5A variants in the general population.4,43 It is clear that the genetic basis for Brugada syndrome is heterogenous and no pathogenic genotype can be currently identified in the majority of patients.12 Moreover, while numerous mutations in several other myocardial genes have also been suggested there is insufficient evidence to establish their unequivocal causality in the pathogenesis of Brugada syndrome.44

EUROPEAN CARDIOLOGY REVIEW

Risk Modification Treatments The mainstay of treatment in high-risk patients remains ICD implantation.12 Important risk-reducing strategies for all patients include avoiding excessive alcohol intake, immediate treatment of fever with antipyretics as well as avoidance of potentially aggravating medications (Table 3).5

Quinidine Therapy Treatment with quinidine can be considered as an adjunct to ICD in patients experiencing electrical storms or frequent appropriate shocks, or as an alternative to ICD in patients with contraindications to implantation. Quinidine reduces the Ito current during epicardial repolarisation and normalises the action potential and prevent re-entry and polymorphic VT formation in experimental models.47 The efficacy of quinidine monotherapy in long-term prevention of malignant ventricular arrhythmias after ICD implantation has been

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Electrophysiology and Arrhythmia Table 3: List of Potential Aggravating Drugs for People with Brugada Syndrome 2,46 Antiarrhythmic Drugs Sodium channel blocker (e.g. flecainide)* Calcium channel blockers (e.g. verapamil, diltiazem, nifedipine) Beta-blockers (e.g. propranolol) Amiodarone Psychotropic Drugs Tricyclic antidepressants (amitriptyline, nortriptyline, clomipramine)* Phenothiazines (cyamemazine, trifluoperazine,* perphenazine)

One substantial problem with quinidine therapy used as an alternative to ICD implantation is the issue of poor adherence and treatment discontinuation or interruption due to associated adverse effects, most commonly gastrointestinal.48 While treatment with low-dose quinidine (<600 mg daily) is associated with greater tolerability, it has only been investigated in a small number of patients.54,55 Another important, but less common, adverse effect of quinidine is QT interval prolongation that can result in the paradoxical initiation of ventricular arrhythmias.56 These concerns have limited the use of quinidine as a risk modification agent in low-risk asymptomatic people with Brugada syndrome, although an ongoing international registry study hopes to provide evidence to support this (NCT00789165).

Selective serotonin reuptake inhibitors (e.g. fluoxetine, paroxetine) Antipsychotics (loxapine,* thioridazine)

Role of Radiofrequency Ablation in Brugada Syndrome

Anti-epileptics (oxcarbazepine,* carbamazepine, phenytoin, lamotrigine)

Radiofrequency ablation (RFA) of arrhythmogenic zones in the right ventricular epicardium has emerged over the past decade as a possible future curative treatment option for Brugada syndrome. However, only a small number of studies with limited follow-up periods have reported successful results with RFA in symptomatic Brugada patients.

Lithium

Anaesthetics/Analgesics Propofol* Bupivacaine/procaine* Tramadol Ketamine Antianginal Drugs Nitrate (e.g. isosorbide dinitrate) Nicorandil Other Drugs Histamine H1 antagonist (dimenhydrinate, diphenhydramine) Indapamide Metoclopramide Cocaine intoxication* Alcohol intoxication* Cannabis* Drugs that people with Brugada syndrome are strongly advised to avoid. Adapted from: Antzelevitch et al. 2005.2 Used with permission from Wolters Kluwer Health.

demonstrated in multiple studies.48 A retrospective study showed total elimination of appropriate ICD shocks in 66% (19 of 29) of patients with previous arrhythmic storm or frequent shocks over a mean period of 60 ± 41 months.49 The authors observed a significant and clinically relevant reduction in number of shocks experienced in the remaining patients. Two main approaches have been previously reported for quinidine monotherapy as an alternative to ICD implantation. The first is guided by the effect of quinidine therapy on inducible VF during EPS. Three long-term prospective studies have reported high rates (76–90%) of prevention of inducible VT during programmed ventricular stimulation while on regular quinidine (600–900 mg daily) for both symptomatic and asymptomatic patients.50–52 No cardiac deaths or definite ventricular arrhythmias were reported while on appropriate quinidine therapy in all patient groups. The second approach is the empirical use of quinidine for prevention of arrhythmic events without electrophysiological verification. This has so far been mainly evaluated by a randomised trial of quinidine versus placebo of 50 patients with previously implanted ICD.53 While treatment appeared to be effective with no associated arrhythmic events observed, no significant result could be obtained due to low event rate in the placebo group as well as high rates of treatment discontinuation.

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The first to describe a successful RFA procedure in Brugada were Nademanee et al. using a selected cohort of nine high-risk patients with frequent ICD shocks for ventricular arrhythmias.57 All patients were found to have a unique arrhythmogenic focus at the anterior RVOT on epicardial mapping as well as typical type 1 ECG and inducible VT/VF at baseline. Following ablation, the ECG had normalised in 89% and VT/VF was no longer inducible in 78% of the cohort. Only one of the nine patients had a single subsequent arrhythmic event during the follow-up period (20 ± 6 months). More recently, Brugada et al. and Pappone et al. described an improved technique for successful elimination of the Brugada syndrome phenotype with epicardial RFA.58,59 The mapping was performed before and after administration of flecainide/ajmaline which resulted in identification of more extensive arrhythmogenic segments in the RV epicardium beyond the RVOT. In the larger and more recent study, the described RFA procedure showed normalisation of ECG and nondeducibility of VT/VF in all of the 135 patients with symptomatic Brugada syndrome and previous ICD.59 Additionally, a type 1 ECG could not be provoked with ajmaline following RFA in the vast majority. During a median follow-up period of 10 months only two patients required a repeat procedure due to recurrent VF. The only adverse effect reported for all the above studies was mild uncomplicated pericarditis after ablation.58,59 RFA treatment is therefore recommended for symptomatic patients with recurrent ICD shocks or as an alternative to ICD implantation when contraindicated.13,60 Whether this is a suitable alternative to ICD for people with high risk, or even an option for low risk people as a potential ‘cure’ remains to be determined.

Is Brugada Syndrome a Channelopathy or Cardiomyopathy? Two main pathophysiogical mechanisms have been described for the formation of ventricular tachyarrhythmias leading to SCD in Brugada syndrome. Historically, Brugada syndrome was perceived as a repolarisation disorder, caused by the unequal expression of transient outward potassium current (mediated by a reduction in early sodium inflow) between the epicardium and inner myocardial

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Current Controversies and Challenges in Brugada Syndrome layers. This results in abbreviation of the epicardial action potential and susceptibility to the formation of re-entry polymorphic ventricular tachycardia triggered by a premature ventricular complex (PVC), due to the epicardial-to-endocardial transmembrane ionic imbalance.61 The evidence for this theory is mainly derived from transmembrane action potential recording in canine right ventricular wedge preparations and is consistent with the clinical effects seen with quinidine, which reduces outward potassium current.62,63 The depolarisation theory is modelled around action potential conduction delay in the RVOT relative to the surrounding myocardium. Under such circumstances, ventricular tachyarrhythmias can be triggered by the resulting unequal membrane potential around the RVOT border, similar to the formation of ventricular tachyarrhythmia seen in circumstances of regional myocardial ischaemia.64 This theory is supported by several clinical studies demonstrating relative conduction delay in the RVOT.65–67 Brugada syndrome was originally described as a disease of cardiac ion channel dysfunction leading to sudden death in otherwise healthy people without the presence of associated structural heart disease.2 However, evidence demonstrating normalisation of the pathognomonic ECG pattern and elimination of the arrhythmic disposition in most patients following radiofrequency ablation of the RVOT epicardium supports the theory that structural abnormalities play an important role in the pathophysiology of Brugada syndrome.68 Indeed, recent results suggest that microanatomical changes such as increased collagen, fibrosis and reduced gap junction expression, which may be mediated by underlying pan-myocardial inflammation, are responsible for the characteristic electrographic pattern and arrhythmic susceptibility.68,69

rugada P, Brugada J. Right bundle branch block, persistent B ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome: a multicenter report. J Am Coll Cardiol 1992;20:1391–6. https://doi. org/10.1016/0735-1097(92)90253-J; PMID: 1309182. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference. Circulation 2005;111:659–70. https://doi.org/10.1161/01. CIR.0000152479.54298.51; PMID: 15655131. Papadakis M, Papatheodorou E, Mellor G, et al. The diagnostic yield of Brugada syndrome after sudden death with normal autopsy. J Am Coll Cardiol 2018;71:1204–14. https://doi. org/10.1016/j.jacc.2018.01.031; PMID: 29544603. Antzelevitch C, Yan G-X, Ackerman MJ, et al. J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge. Europace.2017;19:665–94. https://doi.org/10.1093/europace/euw235; PMID: 28431071. Priori SG, Wilde AA, Horie M, et al. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Europace. 2013;15:1389–406. https:// doi.org/10.1093/europace/eut272; PMID: 23994779. Nagase S, Hiramatsu S, Morita H, et al. Electroanatomical correlation of repolarization abnormalities in Brugada syndrome: detection of type 1 electrocardiogram in the right ventricular outflow tract. J Am Coll Cardiol. 2010;56:2143–5. https://doi.org/10.1016/j.jacc.2010.06.050; PMID: 21144977. Miyamoto K, Yokokawa M, Tanaka K, et al. Diagnostic and prognostic value of a type 1 Brugada electrocardiogram at higher (third or second) V1 to V2 recording in men with Brugada syndrome. Am J Cardiol 2007;99:53–7. https://doi. org/10.1016/j.amjcard.2006.07.062; PMID: 17196462. Veltmann C, Schimpf R, Echternach C, et al. A prospective study on spontaneous fluctuations between diagnostic and non-diagnostic ECGs in Brugada syndrome: implications for correct phenotyping and risk stratification. Eur Heart J 2006;27:2544–52. https://doi.org/10.1093/eurheartj/ehl205; PMID: 16952922. Richter S, Sarkozy A, Veltmann C, et al. Variability of the diagnostic ECG pattern in an ICD patient population with Brugada syndrome. J Cardiovasc Electrophysiol 2009;20:69–75. https://doi.org/10.1111/j.1540-8167.2008.01282.x; PMID: 18775043.

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As a result of these findings, Brugada syndrome and arrhythmogenic cardiomyopathy have been proposed to be part of the same disease spectrum.70 Although these two conditions have distinct macropathological appearance, known genetic predisposition and clinical features, several overlapping manifestations can be seen.2 The Brugada ECG pattern is seen in some patients with arrhythmogenic cardiomyopathy and sudden death can occur in the initial phase of the condition in the absence of its characteristic structural changes.71 Experimental data suggest that the arrhythmogenic process in both conditions is mediated by dysfunction of a complex protein network in the myocardial intercalated disc microarchitecture called the connexome.71 Nevertheless, while dysfunction of the connexome process may represent a common aetiology for Brugada syndrome and arrhythmogenic cardiomyopathy, the phenotypic presentation in Brugada syndrome appears to be restricted to microanatomical changes and sodium channel dysfunction in the RVOT region. It therefore appears that the pathophysiology of disease generation and progression is more complex than initially described and greater understanding of these underlying processes is likely to improve the diagnosis and management of Brugada syndrome.

Conclusion Brugada syndrome has been clouded in controversy since its first description more than three decades ago. While expert consensus has been reached on many aspects of the disease, a significant number of core issues such as the underlying pathophysiology of the disease, diagnostic criteria and risk stratification of asymptomatic patients remain unresolved. The unravelling of its underlying pathological mechanisms coupled with improved techniques and protocols for invasive mapping and ablation procedures shine an optimistic light on the possibility of a future cure for the syndrome.

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Cardiovascular Pharmacotherapy

Cost-effectiveness of Platelet Function-Guided Strategy with Clopidogrel or Ticagrelor Nikita Lomakin, 1 Anna Rudakova, 2 Liudmila Buryachkovskaya 3 and Victor Serebruany 4 1. Cardiology Division, Central Clinical Hospital, Presidential Affairs Department, Moscow, Russia; 2. Chemical Pharmaceutical Academy, St Petersburg, Russia; 3. National Medical Cardiology Center, Moscow, Russia; 4. Stroke Unit, Johns Hopkins University, Baltimore, MD, US

Abstract Some patients treated with dual antiplatelet therapy (DAPT) following acute coronary syndrome (ACS) can still exhibit heightened residual platelet reactivity (HRPR), which is potentially linked to adverse vascular outcomes. Better tailored DAPT strategies are needed to address this medical need. Aim: To assess the cost-effectiveness of guided DAPT with clopidogrel or ticagrelor in addition to aspirin when using VerifyNow P2Y12 testing in post-ACS patients. Methods: The costs were calculated per 1,000 patients aged >55 years. It was assumed that all patients received either generic clopidogrel or ticagrelor for 1 year, and underwent VerifyNow P2Y12 assay testing before DAPT maintenance. Results: Guided DAPT will prevent five more MIs and six more deaths per 1,000 patients than a standard prescription of generic clopidogrel. The total predictive value of costs per patient is 32% lower if a guided strategy is used than if ticagrelor is given to all patients. Conclusion: Assessment of heightened residual platelet reactivity with P2Y12 assay in triaging DAPT post-ACS patients for 1 year is a cost-effective strategy that would reduce financial burden compared to routine administration of more expensive antiplatelet agents.

Keywords Acute coronary syndrome, antiplatelet therapy, outcomes, clopidogrel, ticagrelor, cost-effectiveness Disclosure: The authors have no conflicts of interest to declare. Received: 6 December 2018 Accepted: 21 March 2019 Citation: European Cardiology Review 2019;14(3):175–8. DOI: https://doi.org/10.15420/ecr.2018.29.2 Correspondence: Nikita Lomakin, Central Clinical Hospital, Presidential Affairs Department of Russian Federation, 15 Marshala Timoshenko St, Moscow, Russia. E: lomakinnikita@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Antiplatelet agents are part of secondary prevention following acute coronary syndrome (ACS). Current European and Russian guidelines recommend dual antiplatelet therapy for 1 year after ACS.1,2 Prasugrel is not marketed in Russia, so high-risk patients have been given ticagrelor. The proportion of generic clopidogrel administered has been steadily rising, with the average cost of treatment decreasing annually by 16–17% (Table 1). However, a considerable number of patients on clopidogrel have high residual platelet reactivity (HRPR), potentially leading to inadequate protection and an excess of thrombotic events.3–6 It seems reasonable to switch those patients exhibiting HRPR to ticagrelor. Since the cost of ticagrelor is significantly higher than that of generic clopidogrel, assessing platelet reactivity with the VerifyNow P2Y12 assay may optimise the care of post-ACS patients by identifying those with HRPR, who may benefit from ticagrelor.7 This study’s objective was to evaluate cost-effectiveness of guided DAPT with clopidogrel or ticagrelor with aspirin in patients after ACS in Russia. To identify which patients would benefit from ticagrelor we used the VerifyNow P2Y12 assay to test platelet reactivity.

healthcare system, based on the results of the PLATelet Inhibition and Patient Outcomes (PLATO) trial. 8 The index modelling was 5 years. The average age of patients starting therapy was 55 years. The model included a decision tree to assess the costs and clinical effectiveness of therapy for 1 year after ACS, after which patients entered the Markov model, whereby the outcomes of therapy were analysed over the next 4 years. It was assumed that patients treated with generic clopidogrel or branded ticagrelor underwent a VerifyNow P2Y12-based assay before the maintenance phase, with a cut-off of >230 platelet reactivity units (PRU) for ticagrelor, while the remaining patients continue with generic clopidogrel. For this modelling, we applied conventional daily doses of clopidogrel (75 mg), or ticagrelor (180 mg), both on top of aspirin (100 mg). The magnitude of platelet inhibition was consistent with clinical trial data.8–10 We deliberately avoided loading antiplatelet strategies, focusing exclusively on maintenance regimen modelling. It was assumed that effectiveness and safety in patients with high reactivity of platelets were comparable to those observed in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial.11

Methods A two-step simulation analysis was carried out by extrapolating the TreeAge ™ Pro software program algorithm into the Russian

ACS may cause a temporary increase in HRPR. Therefore, it was assumed in the simulation that the incidence of HRPR in ACS patients

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Cardiovascular Pharmacotherapy Table 1: Russian Public Procurement of Generic Clopidogrel in 2010–2013 Year

Parameters

2010

2011

2012

2013

Annual courses of treatment with generic clopidogrel (n)

38,695

73,059

118,486

160,777

Increase in the number of courses of treatment with clopidogrel per annum (%)

–

88.9

62.2

35.7

Increase in the average cost of annual course of generic clopidogrel (US$)

354

297

245

206

Decrease in the average cost of annual course of treatment with clopidogrel (%)

–

Source: Based on Pharmexpert Marketing Research Centre data.

Figure 1: Cost-effectiveness of Platelet Function-guided Strategy with Clopidogrel or Ticagrelor: Study Flow Chart PLATO population n=calculated per 1,000 patients

12 months

Verify Now P2Y12

Generic clopidogrel

Ticagrelor

PRU >230

PRU <230

Ticagrelor

Generic clopidogrel

5 years

P2Y12 inhibitor cessation 12 months–5 years MACEs according to Russian Federation epidemiological data Treatment expenses: state insurance price list medication expenses; weighted average price state purchases

MACEs = major adverse cardiovascular events; PRU = platelet reactivity units.

would be 13%.8.9,12 However, since a PRU test is usually performed during admission for ACS, it was estimated that 32% of patients would receive ticagrelor.10 It was expected that, after 1 year, all patients would discontinue DAPT, and be denied the additional therapeutic effect of these drugs thereafter. The incidence of non-fatal MI and non-fatal stroke, starting from the second year, was consistent with published epidemiological data.13,14 Mortality of patients was calculated on the basis of epidemiological data for Russia, with relative risk adjustments made for various cardiovascular events.15 Costs for stroke treatment were calculated on the basis of compulsory medical insurance tariffs in St Petersburg for 2014, with consideration for severity of the disease in the Russian population (minor stroke, modified Rankin scale [mRS] 0–2: 51%; moderate stroke, mRS 3-4: 19%; severe stroke, mRS 5: 1%; fatal stroke: 29%). This totalled US$1,468.16,17 Death in the acute phase of MI was 16%, in line with Russian national statistics, and stroke death was 29%.17–19 Costs for treatment of non-fatal MI, taking into account the early rehabilitation period, were US$2,440, while the average cost for bleeding events amounted to US$245. The cost of generic clopidogrel and ticagrelor conformed with the average-weighted cost of public procurement in 2013, with clopidogrel working out at US$206 a year and ticagrelor at US$1,222. The cost of performing a PRU test in the course of modelling was set at US$33.

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The impact of cardiovascular events on quality of life was set from published reports.20,21 The cost and life expectancy were discounted at 3.5% per year. With regards to cost-effectiveness, WHO recommendations applied. In short, an acceptable level of additional costs per 1 year of life with consideration for quality (quality-adjusted life year [QALY]) should not exceed three times the gross domestic product (GDP) per capita.22,23 When the value of additional costs per 1 QALY does not exceed national GDP per capita, the proposed intervention is considered to be economically highly effective and should be widely used in clinical practice. The study design is shown in Figure 1 and main modelling parameters in Table 2.

Results Providing early, guided DAPT will prevent five MIs and six deaths per 1,000 patients compared to uniform prescription of generic clopidogrel (Table 3). The costs per one additional year of survival with a tailored strategy (US$12,550) was only slightly higher (US$12,440) than when taking the uniform approach. The costs for one additional QALY were US$14,460, and US$16,993 respectively. The total predictive value of costs per patient was 32% lower with guided strategy than with uniformed ticagrelor in all patients. Blindly prescribing ticagrelor without a platelet test increases the affiliated cost more than twice compared to generic clopidogrel. Since the GDP per capita for Russia in 2013 was US$15,500, performing a PRU test in patients post ACS and prescribing DAPT, dependent on the assay results, can be considered as a highly effective economic strategy (Table 4).

Discussion This analysis revealed that assessment of HRPR with P2Y12 assay in triaging DAPT for post-ACS patients for 1 year is a cost-effective strategy, with a lower financial burden than the routine administration of more expensive antiplatelet agents. This is important since inexpensive generic clopidogrel, including local formulations, are consistently growing and dominate Russian pharmaceutical market. In contrast, branded ticagrelor cost about six times more, so would incur an obvious financial burden. There are certain limitations. Firstly, many considerations are based on the results of the PLATO trial. Since low-risk patients and medically managed patients were not included in our model, economic considerations may be attributed to ST-segment elevation ACS only if they were planned to undergo primary percutaneous coronary intervention. Therefore, it is difficult to apply this model to the entire ACS cohort. In addition, in PLATO, 46% of the patients in the ticagrelor group received clopidogrel before randomisation and, within 24 hours before or after randomisation, 34% of the patients in this group received a

EUROPEAN CARDIOLOGY REVIEW

Cost-effectiveness of Guided Antiplatelet Therapy Table 2: Modelling Parameters Used to Assess Cost-effectiveness Parameters

Reference Case

Range of Values, Used Insensitivity Analysis

Quality of life of patients within 1 year after ACS, independent of the development of cardiovascular events Non-fatal Ml

0.77

0.75–0.80

Non-fatal stroke

0.70

0.63–0.76

No cardiovascular events

0.84

0.84–0.85

Haemorrhage

−0.02

−0.04–0

Dyspnoea

−0.01

−0.02–0

Probability of adverse events within 1 year after ACS Non-fatal MI against the background of aspirin therapy

0.1223

0.1191–0.1255

Non-fatal stroke against the background of aspirin therapy

0.013

0.0045–0.0403

Non-fatal stroke against the background of clopidogrel and aspirin therapy

0.0112

0.0039–0.0347

Any haemorrhage against the background of aspirin therapy

0.1745

0.1712–0.1781

Death of any causes against the background of aspirin therapy

0.0619

0.0562–0.0681

Relative risk of complications against the background of clopidogrel plus aspirin therapy compared with aspirin monotherapy Non-fatal Ml

0.77

0.67–0.89

Non-fatal stroke

0.86

0.63–1.18

Haemorrhage

1.69

1.47–1.94

Death

0.91

0.78–1.06

Odds ratio of complications against the background of ticagrelor plus aspirin compared with clopidogrel plus aspirin therapy Non-fatal Ml

0.84

0.75–0.95

Non-fatal stroke

1.17

0.91–1.52

Haemorrhage

1.05

0.96–1.15

Dyspnoea

1.84

1.68–2.02

Death

0.78

0.69–0.89

0.78

0.76–0.80

Quality of life of patients, starting from the second year after ACS Non-fatal Ml Non-fatal stroke

0.7

0.52–0.87

No cardiovascular events

0.84

0.84–0.85

Condition after Ml

0.82

0.80–0.84

Condition after stroke

0.70

0.63–0.78

Probability of cardiovascular events, starting from the second year after ACS Annual incidence of MI

0.0428

Annual incidence of stroke

0.0102

0.0403–0.0454 0.0072–0.0145

Risk of death in the absence of cardiovascular events after ACS compared with 2.21 the general population

0.18–4.24

Risk of death after non-fatal MI compared with the general population

5.84

3.72–7,97

Risk of death after MI compared with the general population

2.21

0.18–4.24

Risk of death after non-fatal stroke compared with the general population

7.43

6,50–8.50

Risk of death after stroke compared with the general population

2.07

1.30–3.32

Main modelling parameters used for cost-effectiveness evaluation of platelet reactivity assay based on VerifyNow P2Y12 ACS = acute coronary syndrome.

Table 3: Cardiovascular Events

Cardiovascular Complication

Clopidogrel

Ticagrelor

PRU test→clopidogrel/ticagrelor

MI (%)

22.0

20.6

21.5

Stroke (%)

4.0

4.2

4.0

Fatality rate (%)

22.2

21.2

21.8

Statistics are for cardiovascular events for the 5 year-period following acute coronary syndrome, according to various approaches to antiplatelet drug selection. PRU = platelet reactivity units.

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Cardiovascular Pharmacotherapy Table 4: Cost-effectiveness

Parameters

Clopidogrel

Ticagrelor

Cost, US$ (000s)

0.86

1.84

PRU-test→Clopidogrel/ ticagrelor 1.25

Median life expectancy(years)

4.1561

4.2345

4.2035

Median life expectancy with allowance for quality (QALY)

3.4525

3.5099

3.4830

Additional costs compared with clopidogrel, $US (000s)

0.97

0.38

Additional life expectancy compared with clopidogrel, years

0.0784

0.031

Additional life expectancy with allowance for quality compared with clopidogrel (QALY)

0.0574

0.0269

Effectiveness of additional costs compared with clopidogrel $US (000s)/year

12.44

12.55

Effectiveness of additional costs compared with clopidogrel $US (000s)/QALY

16.99

14.46

Cost-effectiveness of platelet reactivity assay based on VerifyNow P2Y12 in Patients after ACS. PRU test = P2Y12 reaction test; QALY = quality-adjusted life year.

loading dose of clopidogrel (300–675 mg), which could also affect the effectiveness and safety of the variants of DAPT applied here.8 In addition, some randomised evidence, in particular the negative Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption versus Continuation One Year after Stenting (ARCTIC) trial, did not include the benefits of monitoring HRPR during DAPT and to guide dosing strategy.24

ational guidelines on the diagnosis and treatment of N patients with acute myocardial infarction with ST-segment elevation. Kardiovaskulyarnaya Terapiya i Profilaktika 2007;6(8 suppl 1):1–28 [in Russian]. National guidelines for the treatment of acute coronary syndromes without ST-segment elevation. Kardiovaskulyarnaya Terapiya i Profilaktika 2006;8(5 suppl 1):1–34 [in Russian]. https:// doi.org/10.15829/1728-8800-2006-0. Aradi D, Komócsi A, Vorobcsuk A, et al. Prognostic significance of high on-clopidogrel platelet reactivity after percutaneous coronary intervention: systematic review and meta-analysis. Am Heart J 2010;160:543–51. https://doi. org/10.1016/j.ahj.2010.06.004; PMID: 20826265. Brar S, ten Berg J, Marcucci R, et al. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention: a collaborative meta-analysis of individual participant data. J Am Coll Cardiol 2011;58:1945–54. https://doi. org/10.1016/j.jacc.2011.06.059; PMID: 22032704. Combescure C, Fontana P, Mallouk N, et al. Clinical implications of clopidogrel non-response in cardiovascular patients: a systematic review and meta-analysis. J Thromb Haemost 2010;8:923–33. https://doi.org/10.1111/j.15387836.2010.03809.x; PMID: 20156305. Reny JL, Fontana P, Hochholzer W, et al. Vascular risk levels affect the predictive value of platelet reactivity for the occurrence of MACE in patients on clopidogrel. Systematic review and meta-analysis of individual patient data. Thromb Haemost 2016;115:844–55. https://doi.org/10.1160/TH15-090742; PMID: 26607655. Gurbel P, Bliden K, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND Study. Circulation 2010;121: 1188–99. https://doi.org/10.1161/ CIRCULATIONAHA.109.919456; PMID: 20194878. Wallentin L, Becker R, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57. https://doi.org/10.1056/

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10.

11.

12.

13.

14.

15.

16.

Another shortcoming is that the current analysis covered generic clopidogrel, specifically the Russian pharmaceutical market, while branded clopidogrel was used in PLATO.

Conclusion Within the Russian healthcare system assessment of platelet reactivity with VerifyNow P2Y12 assay in patients with ACS followed by DAPT modification is a more cost-effective approach to reducing treatment costs then the routine use of newer antiplatelet agents.

NEJMoa0904327; PMID:19717846. Storey R, Becker R, Harrington R, et al. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J 2011;32:2945–53. https://doi.org/10.1093/eurheartj/ ehr231; PMID: 21804104. Bonello L, Tantry U, Marcucci R, et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010;56:919–33. https://doi.org/10.1016/j.jacc.2010.04.047; PMID: 20828644. Fileti L, Campo G, Valgimigli M. Latest clinical data on testing for high on-treatment platelet reactivity. Rev Cardiovasc Med 2011;12:S14–S22; PMID:22080983. Campo G, Parrinello G, Ferraresi P, et al. Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome. J Am Coll Cardiol 2011;57:2474–83. https://doi.org/10.1016/j. jacc.2010.12.047; PMID:21679849. Marcucci R, Gori AM, Paniccia R, et al. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet re-activity to ADP detected by a point-ofcare assay: a 12-month follow-up. Circulation 2009;119:237–42. https://doi.org/10.1161/CIRCULATIONAHA.108.812636; PMID:19118249. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494–502. https://doi.org/10.1056/NEJMoa010746; PMID:11519503. Crespin DJ, Federspiel JJ, Biddle AK, et al. Ticagrelor versus genotype-driven antiplatelet therapy for secondary prevention after acute coronary syndrome: a costeffectiveness analysis. Value Health 2011;14:483–91. https://doi. org/10.1016/j.jval.2010.11.012; PMID: 21669373. WHO. Life tables by country. Russian Federation. Geneva:

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WHO; 2018. Available at: http://apps.who.int/gho/ data/?theme=main&vid=61360 (accessed 4 July 2019). Secrieru EM, Moravian SV, Zakharova AB. Some features of formation of statistical data on hospital morbidity using the federal reporting data. Social Aspects of Population Health 2009;3: [in Russian]. Applications to the General Agreement on Tariffs tariff for medical care (medical services) and the terms of payment for medical care provided in the framework of the existing territorial program of compulsory health insurance for citizens of the Russian Federation in St Petersburg in 2014. Available at: http://www.spboms.ru/kiop/main?page_id=338. Tengs TO, Lin TH. A meta-analysis of quality-of-life estimates for stroke. Pharmacoeconomics 2003;21:191–200. https://doi.org/10.2165/00019053-200321030-00004; PMID: 12558469. Rudakova AV, Parfenov VA. Pharmacoeconomic aspects of prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: the use of apixaban compared with warfarin and acetyl-salicylic acid. Rational Pharmacotherapy in Cardiology 2014;10:275–82. https://doi.org/10.20996/18196446-2014-10-3-275-282. Bagust A, Boland A, Blundell M, et al. Ticagrelor for the treatment of acute coronary syndromes: a single technology appraisal. Liverpool: Liverpool Reviews and Implementation Group, University of Liverpool, 2011. Available at: http://tinyurl.com/y4nzruya (accessed 1 May 2019). Coleman C, Limone B. Cost-effectiveness of universal and platelet reactivity assay-driven antiplatelet therapy in acute coronary syndrome. Am J Cardiol 2013;112:355–62. https://doi. org/10.1016/j.amjcard.2013.03.036; PMID: 23631863. WHO. Investing In health for economic development. Report of the Commission on Macroeconomics and Health. Geneva: WHO, 2001. Collet JP, Cayla G, Elhabad S, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012;367:2100–9. https://doi.org/10.1056/NEJMoa1209979; PMID:23121439.

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Cardiovascular Pharmacotherapy

Personalised Approaches to Improving the Effect of Anti-platelet Agents: Where Do We Stand? Lucas C Godoy 1,2 and Michael E Farkouh 1 1. Peter Munk Cardiac Centre and Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto, Ontario, Canada; 2. Instituto do Coracao (InCor), Faculdade de Medicina FMUSP, Universidade de Sao Paulo, São Paulo, Brazil

Citation: European Cardiology Review 2019;14(2):179–80. DOI: https//doi.org/10.154210/ecr.2019.14.3.GE1 Correspondence: Michael Farkouh, Peter Munk Cardiac Centre, 585 University Avenue – 4N474, Toronto, Ontario, M5G 2N2, Canada. E: michael.farkouh@uhn.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.

lopidogrel is the most widely prescribed P2Y12 inhibitor in the world despite the development of newer and more potent agents.1,2 Clopidogrel is administered as a pro-drug and needs to be metabolised by the cytochrome P450 enzymes (particularly by CYP2C19) in order to have biological activity.3 Patients with loss of function (LOF) variants of the CYP2C19 gene have decreased serum levels of clopidogrel after oral administration. Consequently, platelet reactivity in these patients remain higher, when compared to patients with wild-type CYP2C19. With a less-potent platelet inhibition, clot formation would continue to occur and these patients would remain more vulnerable to recurrent ischaemic events.4 Test for both platelet reactivity and the CYP2C19 genetic variant are currently available, and have the theoretical potential to help clinicians to better choose the anti-platelet agent to be used, but the clinical evidence behind their use is still limited, preventing guidelines from routinely recommending these tests.5 The utility of evaluating platelet reactivity to tailor antiplatelet strategies has been widely studied, with disappointing findings. In the Gauging Responsiveness with A VerifyNow assay – Impact on Thrombosis And Safety (GRAVITAS) trial, patients with high platelet reactivity were randomised to receive clopidogrel 150 mg or 75 mg after percutaneous coronary intervention (PCI). Although the higher dose of clopidogrel reduced platelet reactivity significantly (by 22%), no difference in the composite of cardiovascular death, nonfatal MI or stent thrombosis was found.6 Similarly, in the Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption versus Continuation One Year after Stenting (ARTIC) trial, a plateletfunction monitoring strategy, coupled with adequate anti-platelet therapy adjustments, led to lower platelet reactivity, without any significant difference in clinical endpoints.7 In the recently published Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes (TROPICAL-ACS) trial, a guided de-escalation strategy from prasugrel to clopidogrel after an acute coronary syndrome (ACS), monitored by

a platelet reactivity test, was non-inferior to conventional strategy with prasugrel.8 Given the uncertainty of evidence and the high cost of the alternative agents to clopidogrel and the cost of the platelet reactivity tests, local cost–effectiveness analyses are necessary before widely adopting these strategies. In the current edition of European Cardiology Review, a simulated analysis of DAPT postACS driven by testing for platelet reactivity gives some hope that a personalised approach to anti-platelet therapy is still worth exploring.9 We believe that the randomised trial evidence mentioned above is too convincing to resurrect this approach. Pharmacogenomic testing for mutations affecting clopidogrel metabolism has not been widely evaluated to date. A 2010 metaanalysis highlighted that carriers of one or two LOFs for the CYP2C19 allele had higher rates of cardiovascular death, MI and stroke (HR 1.55; 95% CI [1.11–2.17]; p=0.01 for one LOF, and HR 1.76; 95% CI [1.24–2.50]; p=0.002 for the presence of two LOF alleles).10 In the Platelet Inhibition and Patient Outcomes (PLATO) genetic sub-study, which included slightly more than half of the 18,624 patients from the original trial, a trend was observed for reduced cardiovascular outcomes in patients with a CYP2C19 LOF allele treated with ticagrelor compared with clopidogrel, although no formal interaction was observed in this subgroup (p for interaction 0.46).11 In a multicentre non-randomised study published last year, patients with a LOF CYP2C19 allele prescribed clopidogrel had a higher risk of cardiovascular events compared to patients treated with other agents (HR 2.26%; 95% CI [1.18 to 4.32]; p=0.013).12 Additionally, the Pharmacogenetics of Clopidogrel in Patients with Acute Coronary Syndromes (PHARMCLO) trial was stopped recently due to issues concerning the certification of the genotyping test in use. Despite being prone to bias, the partial results for approximately onequarter of the original trial population were promising, with a marked reduction in the composite of cardiovascular death, MI, stroke and major bleeding in patients randomised to the pharmacogenomic arm compared to standard of care arm at 12 months (15.9% versus 25.9%, HR 0.58; 95% CI [0.43 to 0.78]; p<0.001).13

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179

Cardiovascular Pharmacotherapy The results of the Tailored Antiplatelet Therapy Following PCI (TAILORPCI; NCT01742117) are awaited.14 TAILOR-PCI is a multicentre, prospective, randomised clinical trial comparing a prospectively genotyping guided anti-platelet therapy versus conventional treatment with clopidogrel in post-PCI patients. In the pharmacogenomics arm, patients with CYP2C19 LOF will be treated with ticagrelor, while those with wild type alleles will be prescribed clopidogrel. The primary

arve AM, Seth M, Sharma M, et al. Contemporary use K of ticagrelor in interventional practice (from Blue Cross Blue Shield of Michigan Cardiovascular Consortium). Am J Cardiol 2015;115:1502–6. https://doi.org/10.1016/j. amjcard.2015.02.049; PMID: 25846767. Goodman SG, Nicolau JC, Requena G, et al. Longer-term oral antiplatelet use in stable post-myocardial infarction patients: Insights from the long Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease (TIGRIS) observational study. Int J Cardiol 2017;236:54–60. https://doi.org/10.1016/j.ijcard.2017.02.062; PMID:28268087. Yousuf O, Bhatt DL. The evolution of antiplatelet therapy in cardiovascular disease. Nat Rev Cardiol 2011;8:547–59. https:// doi.org/10.1038/nrcardio.2011.96. PMID: 21750497. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213–60. https://doi.org/10.1093/eurheartj/ehx419; PMID: 28886622. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: an update of the

180

outcome is the composite of cardiovascular death, MI, stroke, stent thrombosis and severe recurrent ischaemia, to be assessed at 12 months. Results are expected in 2020. Until then, we are resigned to treating patients with guideline-driven strategies that discourage a personalised approach. The story around pharmacogenomics approaches has not yet been written.

2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/ SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Circulation 2016;134:e123–55. https://doi. org/10.1161/CIR.0000000000000404; PMID: 27026020. Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 2011;305:1097–105. https://doi. org/10.1001/jama.2011.290; PMID: 21406646. Collet JP, Cuisset T, Range G, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012;367:2100–9. https://doi.org/10.1056/NEJMoa1209979; PMID: 23121439. Sibbing D, Aradi D, Jacobshagen C, et al. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet 2017;390:1747–57. https://doi.org/10.1016/S01406736(17)32155-4; PMID: 28855078. Lomakin N, Rudakova A, Buryachkovskay L, Serebruany V.

10.

11.

12.

13.

14.

Cost-effectiveness of platelet function guided strategy with clopidogrel or ticagrelor. Eur Cardiol 2019;14(3):175–8. https//doi.org/10.154210/ecr.2018.29.2. Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA 2010;304:1821–30. https://doi. org/10.1001/jama.2010.1543; PMID: 20978260. Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010;376:1320–8. https://doi.org/10.1016/S01406736(10)61274-3; PMID: 20801498. Cavallari LH, Lee CR, Beitelshees AL, et al. Multisite investigation of outcomes with implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention. JACC Cardiovasc Interv 2018;11:181–91. https://doi.org/10.1016/j.jcin.2017.07.022; PMID: 29102571. Notarangelo FM, Maglietta G, Bevilacqua P, et al. Pharmacogenomic approach to selecting antiplatelet therapy in patients with acute coronary syndromes: the PHARMCLO Trial. J Am Coll Cardiol 2018;71:1869–77. https://doi. org/10.1016/j.jacc.2018.02.029; PMID: 29540324. Pereira NL, Sargent DJ, Farkouh ME, Rihal CS. Genotypebased clinical trials in cardiovascular disease. Nat Rev Cardiol 2015;12:475–87. https://doi.org/10.1038/nrcardio.2015.64; PMID: 25940926.

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Diagnosis and Risk

Increasing and Evolving Role of Smart Devices in Modern Medicine Michael R Massoomi and Eileen M Handberg Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL, US

Abstract Today is an age of rapid digital integration, yet the capabilities of modern-day smartphones and smartwatches are underappreciated in daily clinical practice. Smartphones are ubiquitous, and smartwatches are very common and on the rise. This creates a wealth of information simply waiting to be accessed, studied and applied clinically, ranging from activity level to various heart rate metrics. This review considers commonly used devices, the validity and accuracy of the data they obtain and potential clinical application of the data.

Keywords mHealth, Apple Watch, Fitbit, Garmin, iPhone, smartwatch, iOS, Health App, S Health, Samsung Health, Google Health, Android, Fitness Tracker, single-lead ECG, Kardia, AF Disclosure: The authors have no conflicts of interest to disclose. Received: 14 May 2019 Accepted: 23 July 2019 Citation: European Cardiology Review 2019;14(3):181–6. DOI: https://doi.org/10.15420/ecr.2019.02 Correspondence: Eileen M Handberg, 1600 SW Archer Rd, PO Box 100277, Gainesville, FL 32610-027 7, US. E: eileen.handberg@medicine.ufl.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Today is an age of rapid digital integration. A decade ago, technological advancement was represented by a bulky desktop computer. With the constant evolution of microprocessors and sophistication of programming, the capacity of the mainframe has been surpassed and miniaturised, so that the pinnacle of technology and innovation is quite literally in the palm of our hands. This opens a world of possibilities, because technology is more advanced, affordable and accessible than ever before. Technological advancement has been applied to all categories of applications from games to health and wellness. This development now provides both an opportunity and challenge to healthcare providers to take advantage of this ever-growing volume of personal data collected on our patients. Technology development in the healthcare sector is extensive and expanding rapidly, and a review of emerging technologies would illustrate the amazing future potential to help practitioners manage patients remotely. This article focuses on what could happen during today’s clinic appointments for patients who currently have smartphones and wearable fitness trackers. We consider the prevalence of these devices, capabilities, accuracy and clinical applications so that clinicians can optimise patient management.

Demographics Smartphones are ubiquitous, carried and used by nearly all adolescents and adults today. The two dominant smartphone operating systems are Android and iOS, so dominant, in fact, that collectively they account for approximately 98% market share. In Europe, the market share in 2018 was approximately 70% Android and 28% iOS, whereas in the US and UK the market share in 2018 was approximately 54% iOS and 45% Android. By device, the Apple iPhone has the largest market share in the US and UK (55%), whereas Samsung holds the greatest market share in Europe (33%), with the Apple iPhone close behind (28%).1 These statistics serve to emphasise the importance of becoming

familiar with the two dominant operating systems and the healthrelated features they offer.

Basic Smartphone Capabilities Having established that nearly everyone carrying a phone has a smartphone translates to the fact that nearly every patient has additional untapped data on hand that could be used to assess health parameters, such as activity levels and heart rate (HR) and, if fully utilised by the patient, much more information, such as weight and blood pressure (BP) logs. All Apple iPhones come with a pre-installed app called Health. Simply open the app and enter some basic demographics and it is ready to use. The Health app can also display historical data, including steps, distance and flights of stairs climbed, which are logged when the phone is carried by the user. Android devices have an analogous capability via user-installed apps, such as S Health (Samsung Health) or Google Fit. In the authors’ experience, most iPhone users are not even aware of the Health app. Smartphones are equipped with a multitude of sensors, including accelerometers, barometers and global positioning systems (GPS), allowing for metrics such as distance travelled, elevation gain and estimated calorie expenditure to be assessed. Some apps even use the torch and camera to act as a photoplethysmograph to read HR and the regularity or irregularity of rhythm. However, this is not the intended use of the camera and torch, and the data obtained have been shown to be highly variable.2 The various apps generally have the same user interface on either Android or Apple iOS, and many are free. With a little instruction and a tap of the screen, patients can record a walk and review distance

Access at: www.ECRjournal.com

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Diagnosis and Risk Figure 1: Blood Pressure Log in iOS Health App

home while rushing to make their appointment, because they rarely forget to bring their phone. In addition, such logging allows providers to see BP displayed as a graph over time, including ranges (Figure 1), and allows for better identification of temporal trends in BP for safer and more effective titration of BP medication. It also more actively engages patients in their own healthcare and has the potential to help increase adherence.

Addition of Sensors to Smartphones In addition to smartphones being able to acquire primary data, they serve as a hub allowing for additional sensors to be used. AliveCor offers a small hand-held device (Kardia), which allows for on-demand, single-lead ECG recording. The device is small enough to be attached to a smartphone or can easily be kept in a pocket or purse. Patients can record a 30-second Lead 1 ECG tracing simply by placing their fingers on the contacts. This tracing is then reviewed by an algorithm to distinguish AF or other heart rhythms from sinus rhythm. Combining physician review with the algorithm increases accuracy, especially in the case of AF.4 To date, over 30 million ECGs have been recorded using the AliveCor device. Recently, AliveCor has released the Kardia 6L, which can record 6 leads in a simple-to-use device using just the hands and a thigh.

Views can be customised for different time periods and time scales. List view is also available.

travelled, elevation gain, pace and estimated calorie expenditure. This can be motivating to patients and help them track and make progress.1

These devices could replace traditional ambulatory ECG monitoring in some patients with palpitations. Because the device is owned by the patient, they can keep it with them indefinitely, allowing for longer-term monitoring without using intermittent monitors for a patient trying to capture a rare episode of palpitations. In some instances, this may potentially save patients from having a loop recorder implanted. It can even be used in guest mode on a friend or bystander who may be having symptoms.

Smartwatches An under-appreciated feature with great potential is the electronic medical ID. The iOS Health app has this functionality built in, allowing users to input their key information, including medical conditions, medications, allergies and emergency contacts (Figure 3). US patients can even sign up on the Health app for organ donation with Donate Life America. Android apps have a similar functionality. In case of an emergency presentation, such as a cardiac arrest, physicians can easily access this information on a patient’s phone and directly call a patient’s emergency contact to notify them of the patient’s condition and obtain more history. A medical ID takes only a minute or two to set up, yet this feature is underutilised by both patients and clinicians. How far do we go with information on a smartphone-based medical ID? Is this a legal document? What if a patient’s medical ID states ‘do not resuscitate’? These are questions that need to be addressed today because these scenarios exist. We must not only consider these dilemmas, but also those that have not yet presented themselves. Patients are also able to enter their own biometric information (e.g. weight and BP) for storage and easy review (Figures 1 and 2). Many scales and BP cuffs can automatically upload information to smartphones. Home BP monitoring is recommended for patients with hypertension, including the use of a BP journal to assist with ongoing management.3 We have all had patients come into the clinic carrying a few scraps of paper with their BP readings on them. Now, for most patients, we can instruct them how to log these in their phones, solving the problem of patients who leave their paper-based BP log at

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Currently, smartwatches are perhaps the best additional sensors to be added to a smartphone. Smartwatches have grown immensely in popularity, and Apple quickly dominated the entire watch industry, not just the smartwatch industry. In fact, Apple shipped more watches in the last quarter of 2016 than the entire Swiss watch industry combined, including Rolex and Swatch. Apple Watch quickly became the leading device, with 49% market share in 2016.5 Over 18 million Apple Watches were sold in 2017. Fitbit, Garmin, Xiaomi and Samsung are also popular devices. There is much similarity and overlap in the capabilities of the devices, except for a few leading technologies present in the Apple Watch Series 4 and 5, which are reviewed below. Competition and advancing technology push this market forward with better devices at lower prices, making them increasingly accessible to consumers. In 2016, Men’s Health journal estimated that one in five Americans wears a fitness tracker.6 These data confirm the large size of this sector in technology, and the eagerness to use such devices by the general public. This is where it becomes our responsibility as clinicians to help guide patients in using the devices effectively and to their fullest. The addition of a smartwatch adds significant information without the need to carry a phone. A user with an Apple Watch, for example, will readily have metrics available, including steps, flights of stairs climbed, distance walked, stand hours, estimated energy expenditure (EE) and HR. These metrics are also available via Fitbit, Samsung and Garmin devices (Figure 4).

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Role of Smart Devices in Modern Medicine Figure 2: Weight Log in iOS Health App, Plotted Over a 1-year Period

Figure 3: Medical ID on iOS/iPhone

Each data point represents the average weight for that month, and the time scale can be zoomed to a daily view, allowing for multiple weights to be logged in each day, if desired.

Accuracy and Validity of Smartwatch Data Prior to discussing the use of smartwatch data in daily practice, a review of accuracy is warranted, especially as it pertains to HR and EE. Several studies have shown that in sinus rhythm there was strong agreement between ECG HR and that recorded by the Apple Watch and Fitbit.7,8 The Apple Watch demonstrated the strongest agreement with ECG across a variety of activities, including sitting, walking, running and cycling, within 5â&#x20AC;&#x201C;10% of the ECG. In the setting of faster HRs and atrial arrhythmias, there was some underestimation of HR with smartwatches compared with ECG. Predictors of increased error in HR measurement include darker skin tone, larger wrist circumference and higher BMI. Several other studies have validated the accuracy of wrist-worn devices for HR assessment.9â&#x20AC;&#x201C;11 The data tell a different story regarding EE. Compared against a reference standard of indirect calorimetry by expired gas analysis, all wrist-worn devices tested had a large margin of error of approximately 27%, typically overestimating expenditure.8 Dooley et al. studied HR and EE assessment with Apple Watch, Fitbit and Garmin, and their findings are consistent with other studies showing reliability and accuracy of the devices for HR assessment, but overestimation of EE with wide error margins.12 Attention to this fact is important in counselling patients who may make dietary decisions based on the calorie expenditure reported by their devices. The inaccuracy of EE does not render this information useless. A study with over 2,000 participants using Fitbits over 6 months showed that a higher number of steps per day and highly active minutes per week were predictors of increased weight loss.13 For example, patients walking <5,000 steps a day lost an average of 3.7%

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body weight, whereas those who walked >10,000 steps a day lost an average of 9% body weight. These metrics are easily measured by any modern activity tracker, and it appears that there may be benefit in having patients track this information. Furthermore, we as healthcare providers may review this information quickly and easily, allowing us to help patients play an active role in their health while holding them accountable to reach achievable goals. The study by Painter et al. also demonstrated that a high frequency of weighins (three per week) was associated with increased weight loss at 6 months. 13 Such information is easily obtained by a scale at home and can be entered into health apps for easy tracking of progress, which is shown to correlate with achieving weight loss goals.13 Smartwatches also use gentle cues to nudge the wearer to live a more active life. They provide stand reminders every hour to help reduce sedentary behaviour; they also keep an easily accessible historic log of activity levels, which opens the door to many clinical applications. The use of step count has been studied as a potential marker of clinical improvement in treating patients with angina.14 Another novel

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Diagnosis and Risk Figure 4: Fitbit Display

use of these data may include incorporating step count and activity level obtained by a smartwatch into a frailty model used to risk stratify patients prior to a procedure.

Heart Rate Monitoring Perhaps the most underutilised information readily available by smartwatches is HR monitoring. Apple Watch, Fitbit, Garmin and many other smartwatches record HR data. Fitbit and Garmin watches monitor HR continuously, whereas the Apple Watch monitors HR continuously during exercise and periodically otherwise, at 3- to 10-minute intervals based on activity level. Smartwatches use photoplethysmography (PPG)-based sensors able to distinguish pulsatile changes in blood volume under the skin, allowing for HR detection. This technology is generally capable of recognising HRs between 30 and 210 BPM. Combining HR with accelerometer data allows discrimination of resting and walking HR (Figure 5). HR data may be used clinically ‘on the fly’ in many ways. Resting HR can be used as a measure of general fitness and to set a clear baseline for people with bradycardia. In patients with baseline sinus bradycardia, these devices can answer the question of chronotropic response, or guide decisions in titration of dose to achieve goal resting HR in patients on rate-lowering therapy. In patients with known AF, HR data can be used to determine adequate rate control. In patients with paroxysmal AF, significant changes in resting HR could be indicative of the onset of AF and help determine the duration of episodes, although this is an extrapolation of data and not necessarily the intended use; however, the beauty of mHealth is integration of such information in novel ways. In patients with palpitations, smartwatches can help determine the presence of tachyarrhythmias or bradyarrhythmias, including frequency and duration. This information can help determine whether a short- or long-term ECG monitor may be appropriate to capture an episode and identify the arrhythmia. The smartwatch data may be

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reviewed at each appointment as an additional tool to determine the recurrence of a supraventricular tachycardia. These uses would be extrapolations based on HR data, which can be obtained from most smartwatch fitness trackers today. However, the Apple Watch has distinguished itself with unmatched capabilities, having important implications for both patients and healthcare providers. The latest models of Apple Watch, the Series 4 and 5, are capable of screening for falls, AF, bradycardia, tachycardia and even single-lead ECG recording. The Apple Watch Series 4 and 5 can detect AF in the background by combining accelerometer and PPG-derived HR and HR variability. PPG-based detection of AF has been validated with high accuracy.15 A user can be notified that they may be in AF, and those with a Series 4 or 5 Apple Watch can immediately obtain a single-lead ECG right on the watch, for more accurate determination of the rhythm. “My Apple Watch says I may have AF,” has become a chief complaint from patients arriving at the emergency department or general practice or cardiology appointments. There are presumed benefits to early detection, such as more effective stroke risk reduction and prevention, given that one in five patients presenting with ischaemic stroke is newly diagnosed with AF.16 The recent Apple Watch Study demonstrated that the technology was rapidly mobilised to enrol over 419,000 participants in 8 months to determine whether the irregular pulse watch notification was able to identify AF on the watch and an ECG patch.17,18 The notification occurred in 0.52% of participants, and AF was identified in 34% of the 450 who used the patch, resulting in a positive predictive value of 71%. Although promising, there is concern about the potential for falsepositive heart rhythms, and increased testing and anxiety for patients, but this was prior to the release of the Series 4 and 5 devices and their built-in ECG confirmation of rhythm, which will improve positive predictive value. This technology is not intended to monitor the burden of AF. Knowing these limitations should not deter use, but rather encourage it in an appropriate manner.

EUROPEAN CARDIOLOGY REVIEW

Role of Smart Devices in Modern Medicine Figure 5: iOS Health App Heart Rate Display

Novel Applications The use of smartwatches is most common in the young to middleaged population, but the advanced features of the Apple Watch Series 4 and 5 make it very appealing for use in the elderly, who are at increased risk for both falls and AF. When a fall is detected, the watch will display an alert that can be used to contact emergency services with a tap or may be dismissed if the fall was detected in error or assistance is not needed. The watch can also contact emergency services automatically if a fall is detected and there is no movement for about a minute. This feature can offer some piece of mind to families caring for members who may be alone and are at risk for falling, but the availability of this feature is probably not known to most family caregivers.

Limitations for Use Limitations do exist, of course. The use of this technology is intimidating to some patients and physicians who may not consider themselves tech savvy and may not be comfortable reviewing these novel data sources. Patients need to be capable of understanding how to use the devices and apps and, unfortunately, the less likely users are often the same patients who may benefit the most from such monitoring, such as those who are less educated or some of the elderly population. As in every area of medicine, patient selection is key, and it comes as no surprise that frequent monitoring and availability of biometric data may be anxiety provoking for some.19 These challenges should not be used as reasons to avoid utilisation. As our population ages, we will continue to see more patients who are more tech savvy, and the proportion of patients uncomfortable with this technology should decline. An additional limitation relates to the amount of data. There is, of course, the potential for artefact and false-positive abnormalities. Furthermore, how do we deal with a potentially overwhelming number of patient requests to review biometric data? Data overload and patient misunderstandings in what this information means are certainly issues

EUROPEAN CARDIOLOGY REVIEW

that will become more common, and as physicians we should be proactive in educating patients and setting achievable expectations. In one study, 58% of smartphone users surveyed had downloaded a health app onto their device, with fitness and nutrition being the most common types of apps.20 Not surprisingly, younger age, higher income and higher education level predicted higher-level use of such apps. Obesity was also a predictor of the use of these apps, suggesting that this subgroup of users is interested in health improvement. Some concerns among users included cost, burden of data entry and security of health information.20

Patient Recommendations Because almost all patients carry a smartphone, as providers we can educate patients and encourage higher-level use of the devices they already have. A simple use may include showing a patient with poorly controlled hypertension how to enter home BP values into the iOS Health app for easy review at follow-up visits. Patients seeking to improve their fitness level may use smart devices to track activity and progress with real-time feedback. A HR monitoring smartwatch may be helpful for patients who have AF, especially with rapid HR or palpitations, because it would allow for simple, continuous HR monitoring. A Fitbit or Garmin account may be accessed from a computer or other smartphone, allowing for remote monitoring of HR and activity data. This may be particularly useful for family and caregivers to keep an eye on elderly loved ones. Smartphones and watches also have shortcuts to allow easy access to emergency services, as noted above. Of course, this is not an exhaustive list of uses, but rather the tip of the iceberg. Although this is not intended to be a product review, it is important for clinicians to be familiar with common devices, their limitations and how to combine the cost and feature set of the watch to help patients select a device that will serve them well. In general, the

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Diagnosis and Risk entry point for a reliable wearable fitness tracker with HR monitoring is US$99–129 (Fitbit Inspire HR, Garmin vivosmart 4), with several additional models increasing in cost, screen size and functionality. This includes popular Fitbit and Garmin models with easy-to-navigate user interfaces via smartphone apps. These devices include long battery life with several days between charging. The Apple Watch Series 5 has recently replaced the Series 4 with the same entry point of US$399–429. The Series 5 adds an ‘always on display’ and a compass, but no new health-related features over the Series 4, which is available used or refurbished. Apple Watch requires daily charging but, in turn, offers a high-quality display and more advanced features, such as single-lead ECG recording and detection of falls and AF (Series 4 and later). Series 3 Apple Watches are still available at a lower price point (US$199), forgoing the advanced features of the later series. The Apple Watch does require an iPhone and cannot be used with Android devices, whereas Fitbit and Garmin smartwatches can be used with essentially all smartphones. On-demand ambulatory ECG monitoring may be added to any smartphone via the Kardia device, which is available for US$99 for single-lead ECG and US$149 for the 6-lead device..

Future Directions mHealth is exciting not only for what it can do today, but for the seemingly endless possibilities of what it will be able to do tomorrow. Having a smartwatch capable of constant HR monitoring is becoming the norm, and the technology continues to evolve. There are prototypes of wrist-worn devices that can sense radial artery pulsation and use the data to estimate central aortic pressure (e.g. BPro Cardio Pulse-Wave Device). Further work is being done to extrapolate BP from PPG-based

ramer JN, Kunzler F, Mishra V, et al. Investigating intervention K components and exploring states of receptivity for a smartphone app to promote physical activity: protocol of a microrandomized trial. JMIR Res Protoc 2019;8:e11540. https:// doi.org/10.2196/11540; PMID: 30702430. Coppetti T, Brauchlin A, Muggler S, et al. Accuracy of smartphone apps for heart rate measurement. Eur J Prev Cardiol 2017;24:1287–93. https://doi.org/10.1177/2047487317702044; PMID: 28464700. American Heart Association. Monitoring your blood pressure at home. 2017. Available at: www.heart.org/en/health-topics/ high-blood-pressure/understanding-blood-pressure-readings/ monitoring-your-blood-pressure-at-home (accessed 6 August 2019). Bumgarner JM, Lambert CT, Hussein AA, et al. Smartwatch algorithm for automated detection of atrial fibrillation. J Am Coll Cardiol 2018;71:2381–8. https://doi.org/10.1016/ j.jacc.2018.03.003; PMID: 29535065. Canalys. Media Alert: Apple Watch has its best quarter and takes nearly 80% of total smartwatch revenue in Q4. 2017. Available at: www.canalys.com/newsroom/media-alertapple-watch-has-its-best-quarter-and-takes-nearly-80-totalsmartwatch-revenue-q (accessed 30 August 2019). Do Fitness Trackers Actually Help You Get Fit? What the Science Says. www.mensjournal.com/health-fitness/ do-fitness-trackers-actually-help-you-get-fit-what-thescience-says-w445205 (accessed 30 August 2019). Koshy AN, Sajeev JK, Nerlekar N, et al. Smart watches for heart rate assessment in atrial arrhythmias. Int J Cardiol

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data and blood glucose via optical sensors of various wavelengths. It is quite plausible that, in the not-too-distant future, a smartwatch will be capable of reading HR, rhythm, BP and blood glucose, all non-invasively and in the background.

Conclusion Only a few years ago it was hard to believe that a smartwatch no larger than a typical watch would be able to make phone calls, send and receive text messages, track sleep and activity, record HR in the background and record a single-lead ECG, but this technology is readily available and becoming increasingly affordable. In addition to their amazing capabilities today, these devices hold great potential for tomorrow as technology advances, allowing for more capabilities while we continue to study and learn how to use these metrics to improve patient care. This is the new era of medicine, and there is a plethora of untapped information waiting to be studied and applied. Limitations do exist, but they are recognisable and not prohibitive to use. Perhaps ‘physical examination’ should now include looking for and asking whether patients are wearing a smartwatch and exploring and recording the data reported on these devices. Device interrogation now has a new meaning and is no longer limited to pacemakers, ICDs and loop recorders. This opportunity to pick such low-hanging fruit should not be missed. The information is there; we simply need to know how to review it. It is our responsibility as clinicians to understand the meaningfulness and limitations of smart devices and to be able to counsel our patients and use this information in daily practice. Not doing so leaves a wealth of unused information and potential on the table.

2018;266:124–7. https://doi.org/10.1016/j.ijcard.2018.02.073; PMID: 29887428. Shcherbina A, Mattsson CM, Waggott D, et al. Accuracy in wrist-worn, sensor-based measurements of heart rate and energy expenditure in a diverse cohort. J Pers Med 2017;7:pii: E3. https://doi.org/10.3390/jpm7020003; PMID: 28538708. Bai Y, Hibbing P, Mantis C, Welk GJ. Comparative evaluation of heart rate-based monitors: Apple Watch vs Fitbit Charge HR. J Sports Sci 2018;36:1734–41. https://doi.org/10.1080/02640414. 2017.1412235; PMID: 29210326. Gillinov S, Etiwy M, Wang R, et al. Variable accuracy of wearable heart rate monitors during aerobic exercise. Med Sci Sports Exerc 2017;49:1697–703. https://doi.org/10.1249/ MSS.0000000000001284; PMID: 28709155. Khushhal A, Nichols S, Evans W, et al. Validity and reliability of the Apple Watch for measuring heart rate during exercise. Sports Med Int Open 2017;1:E206–11. https://doi. org/10.1055/s-0043-120195; PMID: 30539109. Dooley EE, Golaszewski NM, Bartholomew JB. Estimating accuracy at exercise intensities: a comparative study of selfmonitoring heart rate and physical activity wearable devices. JMIR Mhealth Uhealth 2017;5:e34. https://doi.org/10.2196/ mhealth.7043; PMID: 28302596. Painter SL, Ahmed R, Hill JO, et al. What matters in weight loss? An in-depth analysis of self-monitoring. J Med Internet Res 2017;19:e160. https://doi.org/10.2196/jmir.7457; PMID: 28500022. Birkeland K, Khandwalla RM, Kedan I, et al. Daily activity measured with wearable technology as a

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novel measurement of treatment effect in patients with coronary microvascular dysfunction: substudy of a randomized controlled crossover trial. JMIR Res Protoc 2017;6:e255. https://doi.org/10.2196/resprot.8057; PMID: 29263019. Krivoshei L, Weber S, Burkard T, et al. Smart detection of atrial fibrillation. Europace 2017;19:753–7. https://doi.org/10.1093/ europace/euw125; PMID: 27371660. Jaakkola J, Mustonen P, Kiviniemi T, et al. Stroke as the first manifestation of atrial fibrillation. PLoS One 2016;11:e0168010. https://doi.org/10.1371/journal.pone.0168010; PMID: 27936187. Apple Heart Study demonstrates ability of wearable technology to detect atrial fibrillation. http://med.stanford.edu/news/ all-news/2019/03/apple-heart-study-demonstrates-ability-ofwearable-technology.html (accessed 30 August 2019). Apple Heart Study Identifies AFib in Small Group of Apple Watch Wearers. www.acc.org/latest-in-cardiology/ articles/2019/03/08/15/32/sat-9am-apple-heart-studyacc-2019 (accessed 30 August 2019). Morrissey EC, Casey M, Glynn LG, et al. Smartphone apps for improving medication adherence in hypertension: patients’ perspectives. Patient Prefer Adherence 2018;12: 813–22. https://doi.org/10.2147/PPA.S145647; PMID: 29785096. Krebs P, Duncan DT. Health app use among US mobile phone owners: a national survey. JMIR Mhealth Uhealth 2015;3:e101. https://doi.org/10.2196/mhealth.4924; PMID: 26537656.

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Acute Coronary Syndrome

Troponins, Acute Coronary Syndrome and Renal Disease: From Acute Kidney Injury Through End-stage Kidney Disease Debasish Banerjee 1,2, Charlotte Perrett 1 and Anita Banerjee 3 1. Renal and Transplantation Unit, St George’s University Hospital NHS Foundation Trust, London, UK; 2. Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, UK; 3. Women’s Health, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Abstract The diagnosis of acute coronary syndromes (ACS) is heavily dependent on cardiac biomarker assays, particularly cardiac troponins. ACS, particularly non-ST segment elevation MI, are more common in patients with acute kidney injury, chronic kidney disease (CKD) and end-stage kidney disease (ESKD), are associated with worse outcomes than in patients without kidney disease and are often difficult to diagnose and treat. Hence, early accurate diagnosis of ACS in kidney disease patients is important using easily available tools, such as cardiac troponins. However, the diagnostic reliability of cardiac troponins has been suboptimal in patients with kidney disease due to possible decreased clearance of troponin with acute and chronic kidney impairment and low levels of troponin secretion due to concomitant cardiac muscle injury related to left ventricular hypertrophy, inflammation and fibrosis. This article reviews the metabolism and utility of cardiac biomarkers in patients with acute and chronic kidney diseases. Cardiac troponins are small peptides that accumulate in both acute and chronic kidney diseases due to impaired excretion. Hence, troponin concentrations rise and fall with acute kidney injury and its recovery, limiting their use in the diagnosis of ACS. Troponin concentrations are chronically elevated in CKD and ESKD, are associated with poor prognosis and decrease the sensitivity and specificity for diagnosis of ACS. Yet, the evidence indicates that the use of high-sensitivity troponins can confirm or exclude a diagnosis of ACS in the emergency room in a significant proportion of kidney disease patients; those patients in whom the results are equivocal may need longer in-hospital assessment.

Keywords Acute kidney injury, chronic kidney disease, end-stage kidney disease, acute coronary syndrome, cardiac troponin, non-ST segment elevation MI Disclosure: DB has received grants from the British Heart Foundation (PG 10/71/28462) and Wellcome (ISSF 204809/Z/16/Z) and honoraria from Astra Zeneca, Pfizer and Vifor Pharma. All other authors have no conflicts of interest to declare. Received: 12 April 2019 Accepted: 7 August 2019 Citation: European Cardiology Review 2019;14(3):187–90. DOI: https://doi.org/10.15420/ecr.2019.28.2 Correspondence: Debasish Banerjee, Room G2.113, Second Floor, 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.

The development of increasingly sensitive and specific serum cardiac biomarkers has led a revolution in the diagnosis and management of acute coronary syndrome (ACS). However, although the troponins now in use are considered highly sensitive cardiac biomarkers in the general population, the interpretation of troponins in patients with acute kidney injury (AKI), chronic kidney disease (CKD) and end-stage kidney disease (ESKD) has long caused diagnostic uncertainty. The metabolism and excretion of troponins are affected by changes in estimated glomerular filtration (eGFR) rates, making single values often unhelpful.1,2 Diagnosis of an acute coronary episode using the recommended serial measurements of cardiac biomarkers is more important than ever in the renal population due to the higher prevalence of non-ST-segment elevation MI (NSTEMI). However, increasing evidence shows that it is important not to disregard the results even in those patients in whom there is no dynamic change in troponin values. Studies show that the chronically elevated troponin concentrations seen in CKD and ESKD patients are associated with

increased cardiovascular events and mortality.3 This careful and considered approach to looking at troponins means that although they are a useful component of the ACS diagnostic pathway, they can also act as a trigger for addressing cardiac risk factors in this highrisk population. AKI is a common diagnosis among hospitalised patients. A recent meta-analysis, using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI, demonstrated that one in five adults hospitalised worldwide (21.6%) experienced AKI, and that this was associated with high morbidity and mortality.4 The incidence of AKI is increasing, particularly among the elderly, a population that also experiences multiple comorbidities, including a high incidence of ACS.5 The common causes of AKI are sepsis, hypovolaemia, nephrotoxins and urinary obstruction. Kidney function and renal clearance change rapidly during the evolution of AKI to its peak and then during recovery. This means careful consideration is required with regard to the interpretation of serum biomarkers and drugs used to treat ACS that are metabolised and secreted by the kidneys.

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Acute Coronary Syndrome Figure 1: Diagnostic Algorithm for Symptoms of Acute Coronary Syndrome in Patients with an Abnormal Renal Profile Typical or atypical ACS symptoms and abnormal renal profile

ECG ST Consider AKI (cTn may rise and fall)

+ cTn*

Treat as STEMI

Known CKD or ESKD (baseline cTn may be high)

Normal baseline cTn** No significant rise† at 1 or 3, 6 hours

Normal or high baseline cTn* AND significant rise†† at 1, 3 or 6 hours or new ECG or imaging findings

Elevated baseline cTn* No significant rise† at 1,3 or 6 hours

Rule out ACS

Treat as NSTEMI

Consider high-risk, control risk factors

ACS = acute coronary syndrome; AKI = acute kidney injury; CKD = chronic kidney disease; cTn = cardiac troponin; ESKD = end-stage kidney disease; NSTEMI = non-ST-elevation MI. *cTn >99th percentile of upper limit of normal; **cTn <99th percentile of upper limit of normal. †Significant increase in cTn <3 ng/l; ††significant rise of >20% or 99th percentile of upper limit of normal.

Metabolism of Cardiac Biomarkers by the Kidney The kidneys play a major role in the metabolism and clearance of small peptides and proteins.6 For example, insulin concentrations increase with decreasing kidney function due to reduced excretion. Peptides and small proteins are partially filtered through the glomerular filtration barrier and enter the proximal tubule where they are reabsorbed by the megalin–cubilin complex and are metabolised in the lysosome.6,7 Various serum biomarkers, including cardiac biomarkers, are handled by the kidney in a similar manner. Therefore, interpretation of the serum concentrations of these biomarkers presents an additional challenge in the context of AKI, where glomerular filtration changes rapidly during on-going injury and then recovery. Similarly, the concentrations of these peptides are chronically elevated in patients with CKD and ESKD.

Cardiac Biomarkers of Acute Coronary Syndrome In the past 50 years, numerous serum biomarkers have been discovered and are now used in conjunction with ECG changes and clinical presentation in the diagnosis of ACS. Initially, non-specific markers, such as white blood cell count, were used. The first enzyme biomarker to be used was aspartate aminotransferase in the 1960s, followed by the discovery of lactate dehydrogenase and creatinine kinase later that decade, and the muscle/brain fraction of creatinine kinase (CK-MB) in the 1970s.8 However, over the past three decades, cardiac biomarkers, particularly troponins, have become increasingly sensitive and specific, and are now the cornerstone for the diagnosis of ACS. Troponins as cardiac-specific biomarkers were described for the first time in the late 1980s.9 Troponins T, I and C are components of the cardiac troponin complex, which is integral to actin–myosin interaction and cardiac muscle contraction.6 Troponin C exists in the skeletal muscle and hence is not cardiac specific. Non-functional free subfractions of troponin move from the myocardial cell cytoplasm into the circulation promptly after myocardial injury.10 Unbound cytosolic troponin T (cTnT), which is

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released after acute injury, is approximately 6% of all troponin T pool in the cell, and 3% for cardiac troponin I (cTnI) pool. cTnI is a smaller molecule than cTnT (~187 versus 288 amino acids, respectively).10 In one study from the late 1990s, serum cardiac biomarkers were measured in 67 samples from 24 ESKD patients without any history of acute heart disease and no regional wall motion abnormalities on echocardiogram.11 CK-MB was increased in at least one sample in 30% of patients, whereas cTnT was increased in 71%. In the same study, troponin T was demonstrated in skeletal muscle biopsy, suggesting possible expression of troponin T in skeletal muscle with myopathy associated with ESKD.11 However, cross-reaction with the skeletal muscle isoform of troponin T is now considered less significant due to improvements in immunoassays.12 Cardiac biomarkers are integral to current diagnosis of MI. The universal definition of MI states that there must be an increase in cardiac biomarkers (preferably cardiac troponin) with at least one value above the 99th percentile of the upper reference limit and/or a fall in cardiac biomarkers along with a list of other clinical features, such as specific ECG or echocardiographic changes.13

Cardiac Troponins in Chronic Kidney Disease and End-stage Kidney Disease Although there have been advances in the sensitivity and specificity of cardiac biomarkers, the interpretation of troponin in CKD and dialysis patients remains a challenge. Many studies have investigated concentrations of cardiac troponins with decreasing glomerular filtration. One such study explored cardiac troponin concentrations in 489 patients referred for 51Cr EDTA or isohexol eGFR estimation due to any clinical indication.14 Patients were divided by the presence or absence of prior MI, heart failure, chronic angina or atrial fibrillation, and those with recent ACS were excluded. Concentrations of cTnT, cTnI, copeptin, N-terminal pro B-type natriuretic peptide (NT-proBNP), heart-type fatty acid binding protein (H-FABP) and cystatin C were higher in patients with increasing CKD stages, regardless of prior history of cardiac disease.14

EUROPEAN CARDIOLOGY REVIEW

Cardiac Troponins in Kidney Disease Studies looking at the behaviour of cardiac biomarkers in dialysis patients offer different explanations as to how concentrations may be affected by treatment, and suggest some differences in behaviour between the different types of troponins.15 For example, some studies suggest that haemoconcentration may increase troponin levels, whereas others suggest that troponin levels may be lower as a result of dialysis clearance.

p<0.001) compared with patients with normal renal function.20 This also helps highlight the subtle differences between using hs-cTnT and hs-cTnI in the renal population. Subsequent attempts at modifications of the rule-in and rule-out thresholds did not improve the safety or overall efficacy of the algorithm.20

Part of the universal definition of MI states that at least one troponin value must be above the 99th percentile upper reference limit.13 However, chronic, stable, elevated troponin concentrations have been demonstrated in the CKD population in the absence of any clinical evidence of a myocardial ischaemic event.16 Perhaps the most commonly adopted approach to this problem is to look for a change of more than 20% between two values taken several hours apart, although there is no real evidence to support this strategy and there is a potential to underestimate myocardial events.17

AKI is common in patients with ACS. In a large American retrospective study, 26.6% of patients diagnosed with ACS also had AKI (defined in that study as a rise in serum creatinine of 0.3 mg/dl).21 Prompt diagnosis of ACS in patients also diagnosed with AKI is important to ensure appropriate, tailored management for both conditions.

The European Society of Cardiology (ESC) recommends an algorithm to rapidly rule in or rule out NSTEMI using high-sensitivity cardiac troponin concentrations, regardless of renal function.18 In reality, applying this to renal patients presents some issues. A large European prospective multicentre study of 4,726 consecutive patients with suspected ACS examined the use of high-sensitivity (hs-)cTnI in those with and without renal impairment.19 Of the 904 (19%) with renal impairment (eGFR <60 ml/min/1.73 m2), only 17% were identified as low risk based on troponin concentration <5 ng/l at presentation, compared with 56% without renal impairment (p<0.001).19 The positive predictive value and specificity when troponin concentrations were in the 99th percentile were lower in patients with renal impairment, at 50.0%, 95% CI [45.2–54.8%] and 70.9%, 95% CI [67.5–74.2%]), respectively, than in those without any renal impairment (62.4%, 95% CI [58.8–65.9%] and 92.1%, 95% CI [91.2–93.0%], respectively).19 However, the data suggest that these elevated troponin concentrations in the CKD population should not be completely discounted. At 1 year, patients with renal impairment and elevated cardiac troponin concentrations >99th percentile had a twofold greater risk of a major cardiac event than those with normal renal function.19 Elevated cardiac troponin concentrations have been associated with poor outcomes among both CKD and ESKD patients. A 2014 metaanalysis of 11 studies, adjusted for coronary artery disease and age, demonstrated a threefold increase in mortality with chronically elevated cTnT in ESKD patients.3 A further large multicentre cohort study of 3,254 patients using the ESC 0/1-hour algorithm in patients with and without renal dysfunction (defined as eGFR <60 ml/min/1.73 m2) found that the prevalence of NSTEMI was higher in the 487 patients with renal dysfunction than in those with normal function (13% versus 30%).20 That study used both hs-cTnT and hs-cTnI. Compared with patients with normal renal function, hs-cTnT concentrations in patients with renal dysfunction had comparable sensitivity of rule out (100.0% versus 99.2%; p=0.559), lower specificity of rule in (88.7% versus 96.5%; p<0.001) and lower overall efficacy (51% versus 81%; p<0.001).20 The authors concluded that this was likely the result of the lower percentage of patients with renal dysfunction who were eligible for rule out compared with patients with normal renal function (18% versus 68%; p<0.001).20 In patients with eGFR <60 ml/min/1.73 m2, hs-cTnI had comparable sensitivity of rule out (98.6% versus 98.5%; p=1.0), lower specificity of rule in (84.4 versus 91.7%; p<0.001) and lower overall efficacy (54% versus 76%;

EUROPEAN CARDIOLOGY REVIEW

Acute Coronary Syndrome Biomarker and Acute Kidney Injury

Several possible mechanisms play a role in the increase in cardiac biomarkers in AKI. During AKI there may be a degree of non-ischaemic myocardial necrosis or myocardial injury, as seen with heart failure, cardiac arrhythmias and cardiac interventions. Furthermore, conditions that may precipitate AKI, such as sepsis and hypotension, may also cause a comparable myocardial injury, and hence increase cardiac biomarkers (by definition, a type 2 MI).22 Decreased elimination of biomarkers, due to reasons discussed above, may also result in a rise in levels. Deterioration of kidney function with evolving AKI and improvement during recovery phase may result in a rise and fall of biomarker levels – this may mimic the rise and fall of biomarkers seen with MI, leading to a degree of diagnostic uncertainty. Standardising patient selection, blood sampling, assays and definitions between studies examining cardiac biomarker levels in patients with AKI mean data are limited. In an early study, serum cardiac biomarkers were compared between patients with AKI and those with CKD (creatinine 120–200 µmol/l), severe CKD (creatinine 200–400 µmol/l) and on haemodialysis.23 The patients with AKI had severe AKI (creatinine >500 µmol/l), and many had multiorgan dysfunction requiring continuous venovenous haemodiafiltration. Active ischaemic heart disease was ruled out with clinical features, ECG and echocardiogram. Concentrations of cTnT and cTnI were highest in patients with AKI. On serial measurements of three AKI patients, recovery of renal function was associated with a fall in cTnT to undetectable levels.23 In another study of 19 AKI stage 2 and 3 patients, 39 samples were obtained at admission, peak creatinine and discharge.1 Patients with multiorgan failure, ACS, pericarditis, myocarditis, sepsis, heart failure, pulmonary embolism and cardiac arrhythmias were excluded.1 Concentrations of hs-cTnT were elevated in 32% of patients.1 The patients with elevated hs-cTnT were older and had minor ECG abnormalities.1 Concentrations of hs-cTnT, hs-cTnI and CK-MB tended to fall with AKI recovery and hospital discharge.1 That study helpfully demonstrated that, even when removing confounders such as ACS and sepsis, AKI still results in elevated cardiac biomarkers.1 Very interesting observations were made from a large database of 17,113 matched cTnT and creatinine values in 10,418 patients admitted to a single hospital.2 The cardiovascular disease history of the patients was unknown, and 3,108 pairs of results were obtained within a short period of time (median 15 hours; interquartile range 7–25 hours).2 Within that short period, the cTnT values rose and

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Acute Coronary Syndrome fell with increasing and decreasing kidney function, suggesting renal clearance as a cause of the rise and fall rather than cardiac injury.2 Concentrations of cTnT increased and decreased with kidney function >120 and 5 ml/min, respectively.2

Conclusion We have reviewed the interesting and growing literature available on the topic of troponin interpretation in kidney patients from AKI through to ESKD. Although considerable advances have been made in the use of cardiac biomarkers to aid diagnosis, it is clear that a degree of caution is required in their application to renal patients. In terms of practical clinical implications, a few conclusions can be drawn, although these are far from definitive. It is clear that it is important not to completely discount high troponin concentrations in CKD and ESKD patients. Elevated troponins are associated with increased cardiovascular risk, and discounting this means we run the

ong D, de Zoysa JR, Ng A, Chiu W. Troponins in acute kidney S injury. Ren Fail 2012;34:35–9. https://doi.org/10.3109/088602 2X.2011.623440; PMID: 22010639. Chung JZ, Dallas Jones GR. Effect of renal function on serum cardiac troponin T – population and individual effects. Clin Biochem 2015;48:807–10. https://doi.org/10.1016/j. clinbiochem.2015.05.004; PMID: 25977070. Michos ED, Wilson LM, Yeh HC, et al. Prognostic value of cardiac troponin in patients with chronic kidney disease without suspected acute coronary syndrome: a systematic review and meta-analysis. Ann Intern Med 2014;161:491–501. https://doi.org/10.7326/M14-0743; PMID: 25111499. Susantitaphong P, Cruz DN, Cerda J, et al. World incidence of AKI: a meta-analysis. Clin J Am Soc Nephrol 2013;8:1482–93. https://doi.org/10.2215/CJN.00710113; PMID: 23744003. Hsu RK, McCulloch CE, Dudley RA, Lo LJ, Hsu CY. Temporal changes in incidence of dialysis-requiring AKI. J Am Soc Nephrol 2013;24:37–42. https://doi.org/10.1681/ASN.2012080800; PMID: 23222124. Haraldsson B, Nyström J, Deen WM. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev 2008;88:451–87. https://doi.org/10.1152/physrev.00055.2006; PMID: 18391170. Christensen EI, Birn H. Megalin and cubilin: synergistic endocytic receptors in renal proximal tubule. Am J Physiol Renal Physiol 2001;280:F562–73. https://doi.org/10.1152/ ajprenal.2001.280.4.F562; PMID: 11249847. Collinson PO, Garrison L, Christenson RH. Cardiac biomarkers - A short biography. Clin Biochem 2015;48:197–200. https://doi. org/10.1016/j.clinbiochem.2014.11.014; PMID: 25464015. deFilippi C, Seliger S. The cardiac troponin renal disease diagnostic conundrum: past, present, and future. Circulation 2018;137:452–454. https://doi.org/10.1161/

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risk of mismanaging cardiac risk factors, underinvestigating a very high-risk population or, indeed, missing acute events. Drawing upon the full combination of biomarkers, ECG, cardiac imaging, clinical history and physical examination (and, where appropriate, coronary angiography) will be vital in diagnosing and treating patients correctly (Figure 1). To date, adjusted algorithms for the interpretation of troponin in renal patients have been, at best, partially successful. It seems sensible to continue to use serial troponins in kidney disease patients as advised by the Joint Task Force of the ESC, American College of Cardiology Foundation, the American Heart Association and the World Heart Federation for diagnosis in patients without kidney disease.24 More research is needed to discover new biomarkers and to better use the available biomarkers in AKI, CKD and ESKD patients for the early diagnosis of and better outcomes after ACS.

CIRCULATIONAHA.117.031717; PMID: 29378755. 10. B abuin L, Jaffe A. Troponin: the biomarker of choice for the detection of cardiac injury. CMAJ 2005;173:1191–202. https:// doi.org/10.1503/cmaj/051291; PMID: 16275971. 11. McLaurin MD, Apple FS, Voss EM, et al. Cardiac troponin I, cardiac troponin T, and creatine kinase MB in dialysis patients without ischemic heart disease: evidence of cardiac troponin T expression in skeletal muscle. Clin Chem 1997;43:976–82. PMID: 9191549. 12. Apple FS, Ricchiuti C, Voss EM. Expression of cardiac troponin T isoforms in skeletal muscle of renal disease patients will not cause false-positive serum results by the second generation cardiac troponin T assay. Eur Heart J 1998;19(Suppl N):N30–3. PMID: 9857936. 13. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012;60:1581–98. https://doi.org/10.1016/j.jacc.2012.08.001; PMID: 22958960. 14. Bjurman C, Petzold M, Venge P, et al. High-sensitive cardiac troponin, NT-proBNP, hFABP and copeptin levels in relation to glomerular filtration rates and a medical record of cardiovascular disease. Clin Biochem 2015;48:302–7. https://doi. org/10.1016/j.clinbiochem.2015.01.008; PMID: 25637776. 15. Roberts MA, Hedley AJ, Ierino F. Understanding cardiac biomarkers in end-stage kidney disease: frequently asked questions and the promise of clinical application. Nephrology (Carlton) 2011;16:251–60. https://doi.org/10.1111/j.14401797.2010.01413.x; PMID: 21342319. 16. Twerenbold R, Wildi K, Jaeger C, et al. Optimal cutoff levels of more sensitive cardiac troponin assays for the early diagnosis of myocardial infarction in patients with renal dysfunction. Circulation 2015;131:2041–50. https://doi.org/10.1161/ CIRCULATIONAHA.114.014245; PMID: 25948542. 17. Morrow DA, Bonaca MP. Real-world application of ‘delta’

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troponin: diagnostic and prognostic implications. J Am Coll Cardiol 2013;62:1239–41. https://doi.org/10.1016/j. jacc.2013.06.049; PMID: 23933544. Roffi M, Patrono C, Collet JP, et al. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2016;37:267–315. https://doi.org/10.1093/eurheartj/ehv320; PMID: 26320110. Miller-Hodges E, Anand A, Shah ASV, et al. High-sensitivity cardiac troponin and the risk stratification of patients with renal impairment presenting with suspected acute coronary syndrome. Circulation 2018;137:425–35. https://doi. org/10.1161/CIRCULATIONAHA.117.030320; PMID: 28978551. Twerenbold R, Badertscher P, Boeddinghaus J, et al. 0/1-hour triage algorithm for myocardial infarction in patients with renal dysfunction. Circulation 2018;137:436–51. https://doi. org/10.1161/CIRCULATIONAHA.117.028901; PMID: 29101287. Amin AP, Salisbury AC, McCullough PA, et al. Trends in the incidence of acute kidney injury in patients hospitalized with acute myocardial infarction. Arch Intern Med 2012;172:246–53. https://doi.org/10.1001/archinternmed.2011.1202; PMID: 22332157. Chapman AR, Adamson PD, Mills NL. Assessment and classification of patients with myocardial injury and infarction in clinical practice. Heart 2017;103:10–8. https://doi. org/10.1136/heartjnl-2016–309530; PMID: 27806987. Collinson PO, Hadcocks L, Foo Y et al. Cardiac troponins in patients with renal dysfunction. Ann Clin Biochem 1998;35:380–6. https://doi.org/10.1177/000456329803500306; PMID: 9635103. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). Circulation 2018;138:e618–e651. https://doi.org/10.1161/ CIR.0000000000000617; PMID: 30571511.

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Acute Coronary Syndrome

Novel Aspects of Classification, Prognosis and Therapy in Takotsubo Syndrome Chiara Di Filippo, Beatrice Bacchi and Carlo Di Mario Careggi University Hospital, Florence, Italy

Abstract Takotsubo syndrome (TTS) can be considered a transient form of acute heart failure that mimics an acute coronary syndrome. Although many hypotheses have been formulated, the precise physiopathology of TTS remains unknown. TTS is associated with a heterogeneous clinical course, which ranges from benign to poor outcome, comprising life-threatening phenotypes. In the acute phase, TTS patients may experience complications including left ventricular outflow tract obstruction, cardiogenic shock, arrhythmias and thromboembolic events. Furthermore, after the acute episode, physiological abnormalities can persist and some patients continue to suffer cardiac symptoms. To recognise patients at higher risk earlier, many variables have been proposed and risk stratifications suggested. There is no solid evidence regarding specific therapy and the proper management of TTS patients, either in the acute phase or long term. This review describes the current knowledge regarding diagnostic criteria, prognosis and therapy in TTS.

Keywords Takotsubo syndrome, diagnostic criteria, outcome, treatment Disclosure: The authors have no conflicts of interest to declare. Received: 10 April 2019 Accepted: 5 August 2019 Citation: European Cardiology Review 2019;14(3):191–6. DOI: https://doi.org/10.15420/ecr.2019.27.3 Correspondence: Carlo Di Mario, Structural Interventional Cardiology, University Hospital Careggi, Largo Brambilla, 3, Florence, Italy. E: carlo.dimario@unifi.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.

Takotsubo syndrome (TTS) is a transient form of acute heart failure that mimics an acute coronary syndrome (ACS), with comparable acute adverse outcome.1 Many hypotheses have been formulated, but the pathophysiology of TTS is still not fully understood. Recently, it was demonstrated that specific alterations in neurological response and sympathetic activation after emotional stimuli are present in TTS patients. These findings confirm the importance of brain–heart interaction in the development of this pathological process.2

Establishing Diagnosis The evolution of diagnostic criteria in recent years reflects a renewed interest in TTS (Table 1). Despite these new developments, wellestablished, universally agreed TTS diagnostic criteria are still lacking. The first diagnostic criteria for TTS were published by Japanese scholars of this condition in 2003, when TTS was still considered a relatively rare and somewhat mysterious entity more typical of Asia.3 Soon after, the Mayo Clinic group published their diagnostic criteria, which are still widely used today.4 Before then, TTS had been an obscure paragraph in small print at the bottom of the chapter on acute MI, considered for differential diagnosis and assumed to have excellent prognosis after the acute phase. In 2006, the American College of Cardiology and American Heart Association defined TTS as a primary acquired cardiomyopathy,5 and this definition was rapidly adopted by the European Society of Cardiology (ESC). The initial paradigm that TTS meant a pseudoinfarction with

normal coronary arteries was challenged by a revision of the Mayo Clinic Diagnostic Criteria in 2008.6 The authors of that revision highlighted the fact that obstructive bystander coronary lesions and classical ischaemic wall motion abnormalities in other territories are possible in TTS patients.6 Different criteria for TTS have been proposed by others, including Japanese Guidelines,the Gothenburg criteria, Johns Hopkins criteria, Takotsubo Italian Network proposal and the ESC Heart Failure Association (HFA) TTS Taskforce criteria, all of which have contributed to expanding and better specifying the pathognomonic features of a syndrome that was acknowledged to account for 2.2% of all cases of ACS.7–12 Based on experience obtained during development of the largest international TTS registry, the International Takotsubo (InterTAK) Registry, the following novel diagnostic criteria have recently been introduced:13 • TTS patients are characterised by transient acute left ventricular (LV) dysfunction (hypokinesia, akinesia or dyskinesia) that presents not only as the typical diffuse apical ballooning described in textbooks, but also involving the mid-ventricular and basal walls or causing only focal motion abnormalities. Right ventricular involvement can coexist. Patients with typical localised regional wall motion patterns can also transition to develop involvement of other segments. Regional wall motion abnormalities that extend beyond a single epicardial vascular distribution are considered an important feature

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Acute Coronary Syndrome Table 1: Diagnostic Criteria Mayo Clinic, 20086

Italian Network, 201410

ESC HFA Taskforce, 201611

InterTak Registry, 201813

Transient wall motion abnormalities

√

Stress as trigger

√

Optional

√

Coronary artery

Absence of atherosclerosis

Atherosclerosis can coexist

New ECG abnormalities

√

√*

Cardiac biomarkers

Troponin

√

Neurological trigger

√

Recovery No evidence of myocarditis

√

No evidence of phaeochromocytoma

√

Postmenopausal women

√

Optional

√

*Also includes QTc prolongation. ESC = European Society of Cardiology; HFA = Heart Failure Association; InterTAK = International Takotsubo.

• •

•

• • • •

distinguishing TTS from common ischaemic MI. Review of the large InterTAK Registry database showed that regional wall motion abnormalities in the myocardial territory subtended by a single coronary artery can also be present in TTS patients (focal TTS). An emotional, physical or combined trigger can precede a TTS event, but this is not obligatory. Neurological disorders (e.g. subarachnoid haemorrhage, stroke, transient ischaemic attack or seizures) and phaeochromocytoma may serve as triggers of TTS. New ECG abnormalities are very often present (not always the typical diffuse anterior ST-segment elevation, but also ST-segment elevation in different locations, ST-segment depression, T-wave inversion and prolongation of the QTc interval). Rare cases exist without any ECG changes. Levels of cardiac biomarkers (troponin and creatine kinase) are moderately elevated in most cases, often out of proportion with the severity and diffusion of the regional wall motion abnormalities. Significant elevation of B-type natriuretic peptide is common. Significant coronary artery disease (CAD) is not a contradiction in TTS. Infectious myocarditis must be excluded. Postmenopausal women are predominantly affected.

Of note, the InterTAK, Japanese and ESC HFA TTS Taskforce diagnostic criteria also include phaeochromocytoma as a specific cause of TTS, even if most other criteria mention phaeochromocytoma only with regard to differential diagnosis.7,11,13 Indeed, phaeochromocytoma can lead to a catecholamine storm with LV dysfunction, ECG abnormalities and increased biomarkers, as well as hypercontraction of sarcomeres and contraction band necrosis indistinguishable from TTS. Based on LV functional changes most often observed in the initial echocardiographic or angiographic examination, TTS is classified into four different types: apical ballooning and three atypical types, namely midventricular, basal and focal wall motion patterns. The apical ballooning type is the most common, and occurs in 80% of TTS patients. It is characterised by hypo-, a- or dyskinesia of the midventricular and apical parts of the anterior, septal, inferior and lateral walls of the LV, associated with hyperkinesia of the basal segments. A peculiarity of apical TTS is the nipple type, described as a small to a very small region of preserved contractility in the most

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apical portion of an otherwise globally akinetic apex. When the region of preserved contractility is limited to the most apical portion of a globally a- to dyskinetic ventricular apex, it could be considered as a TTS variant of an extensive type of midventricular involvement or an early stage of mechanical recovery of classical apical ballooning. The midventricular type of TTS has been described in approximately 4–40% of patients with TTS. The basal type is rare, and only evident in 1–3% of all cases of TTS. The presence of CAD should not be considered as an exclusion criterion; indeed, the prevalence of CAD in TTS patients is approximately 10%. In 1.5–7% of cases the wall motion abnormalities are limited to the distribution of a single coronary artery identifying a focal TTS type. In this situation, the differential diagnosis of TTS, ACS or myocarditis will ultimately require cardiac MRI demonstrating myocardial edema rather than late gadolinium enhancement in case of TTS.14

Predicting Outcome Figure 1 shows variables predicting outcome in TTS. The clinical features of TTS can vary widely and include life-threatening phenotypes. A new risk classification based on the trigger type, the InterTAK Classification, defined TTS secondary to neurological disease as the one associated with the worst short-term prognosis.15 TTS secondary to physical stressors has also shown higher long-term mortality compared with ACS, whereas a more favourable outcome was associated with emotional triggers. Hence, based on the triggering factor, TTS can either be a benign or life-threatening condition. Many other variables have been proposed as markers of prognosis in TTS patients. Male sex and old age are associated with higher mortality and complication rates, probably due to the more frequent coexistence of underlying comorbidities.16,17 Among echocardiographic parameters, a low LV ejection fraction (LVEF) on admission has been demonstrated to be an independent predictor of mortality in TTS patients in terms of both in-hospital and long-term outcome.18,19 Patients with LVEF ≤35% were usually older, triggered by physical events and had a higher number of comorbidities. Indeed, it has been suggested that severe systolic dysfunction could identify a more vulnerable phenotype of TTS and that the apparent LVEF normalisation at follow-up still conceals persistent structural and functional abnormalities.19

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Takotsubo Syndrome In the acute phase, TTS patients may experience complications including LV mechanical complications (free wall or septal rupture), LV outflow tract obstruction (LVOTO), cardiogenic shock (CS), arrhythmias and thromboembolic events. The presence of LVOTO, mitral valve regurgitation (MVR) and right ventricular involvement may be linked to higher CS rate, whereas a severely reduced LVEF has been correlated not only with CS, but also with increased risk of developing life-threatening arrhythmias. Regarding CS, Di Vece et al. suggested that parameters easily detectable on admission, such as apical TTS, physical stress, lower LVEF, diabetes and AF, may identify patients at higher risk. AF was identified as a predictor of poor short- and long-term prognosis, probably because of the haemodynamic consequences of the loss of atrial contraction and the increased risk of thromboembolic events.21 20

Conversely, the morphological type of TTS and the coexistence of a CAD were not found to be related to the incidence of in-hospital complications. Considering electrocardiographic signs, QTc interval prolongation seems to be associated with a higher risk of ventricular arrhythmias,22 especially polymorphic tachycardia, whereas the predictive role of ST-segment elevation is controversial.23

Figure 1: Variables Predicting Outcome

TTS related to neurological trigger

TTS related to physical trigger

Age >75 years

QTc prolongation and arrhythmias

Cardiogenic shock

LVEF ≤35%

Unfavourable outcome

MV regurgitation

RV involvement

LVOTO Free wall or septal rupture

LVEF = left ventricular ejection fraction; LVOTO = left ventricular outflow tract obstruction; MV = mitral valve; RV = right ventricle; TTS = takotsubo syndrome.

Delivering Treatment There are no randomised clinical trials on TTS. The lack of solid evidence and the reversible nature of TTS justify a medical approach focused on supportive care and treating complications promptly until the patient has recovered.

effects have been observed for specific triggers,15 we recommend careful investigation for the potential stressor of TTS. Furthermore, if the trigger includes a medical condition causing persistent pain or discomfort and an elevated sympathetic drive, appropriate specific treatment should be rapidly initiated.

Acute Phase Management Once the presence of an ACS is ruled out, the acute management of TTS should be based on risk stratification, with aggressive monitoring for early detection and prompt treatment of complications in high-risk patients, reserving more conservative management for patients at low risk. In-hospital admission to a high-dependency unit or a ward capable of performing 48–72 hours of electrocardiographic monitoring is required for all patients.

Risk Stratification Lyon et al. stratified lower- and higher-risk patients primarily on the basis of LVEF.11 In milder cases with an LVEF >45% and no complications, the patient can be discharged early from hospital.11 If LVEF is 35–45%, heart failure medications, including angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and betablockers (BBs), should be considered.24 Diuretics or nitroglycerine can be used to reduce congestive symptoms. Special attention should be paid to patients at risk of LVOTO, which can be worsened by vasodilators and may respond favourably to BBs. Highrisk patients need intensive care, including invasive pressure lines to monitor arterial and central venous pressure. Serial echocardiographic examinations are mandatory for assessment of cardiac filling and ventricular function, as well as for the early identification of any mechanical complication, such as LVOTO.

Trigger Identification Many emotional or physical triggers of TTS have been described, but in some cases no stressor can be identified. Because different prognostic

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Management of Acute Complications CS represents one of the leading causes of mortality in the acute phase of TTS. Because CS can result from a large adyskinetic area or be a consequence of hypercontractility of the basal segments leading to LVOTO, echocardiography is required to identify the mechanism and adapt treatment. In patients with LVOTO, prevention of hypovolaemia with appropriate crystalloid infusion is indicated. Failure to detect the presence of LVOTO can lead to the use of drugs such as diuretics, vasodilators or inotropic agents to treat hypotension and lung congestion that can aggravate the obstruction and trigger a dangerous vicious circle. Some studies suggest that BBs may reduce LVOTO by decreasing basal hypercontractility, increasing LV filling and reducing heart rate. However, randomised studies to confirm or contest short- and longterm usefulness of BBs in TTS management, and, if useful, which BB to use, are lacking and the evidence available is conflicting. In the Spanish REgistry for TAKOtsubo cardiomyopathy (RETAKO), the use of BB in patients with CS was associated with a lower 1-year all-cause mortality, whereas, Isogai et al. found no benefit in the early use of BB to reduce in-hospital mortality in TTS patients.25,26 Propranolol, esmolol and metoprolol can reduce LVOTO in TTS patients.27–30 Esmolol use may also have an additional advantage represented by its rapid onset and short duration of action. In any case, before starting BB therapy, the presence of phaeochromocytoma must be excluded.

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Acute Coronary Syndrome Figure 2: Management and Long-term Follow-up Strategies for Patients with Takotsubo Syndrome

Risk stratification and trigger identification

Intermediate risk ACEI or BB Diuretics or nitroglycerine (in case of congestive symptoms) Antiplatelet therapy (?)

Low risk Consider early discharge

High risk Intensive care

ECG monitoring Management of acute complications

Cardiogenic shock LVOTO • IV fluids • Short-acting BB • Consider ivabradine • Vasopressors may be useful • Avoid inotropes • Avoid diuretics and nitroglycerine • Cardiac mechanical support (avoid IABP)

Ventricular arrhythmias

Ventricular thrombosis

Pump failure

• Levosimendan • Cardiac mechanical support • VA-ECMO Impella

• Check QTc • Correct electrolyte imbalance • Consider BB • Consider wearable defibrillator

• Anticoagulation (usually 1–3 months)

Long-term follow-up Assess ventricular recovery

Manage long-term symptoms

Detect recurrences

ACEI = angiotensin-converting enzyme inhibitor; BB = beta-blockers; IABP = intra-aortic balloon pump; LVOTO = left ventricular outflow tract obstruction; VA-ECMO = venoarterial extracorporeal membrane oxygenation.

Ivabradine can reduce heart rate without altering myocardial contractility and could be an alternative to BBs, especially when tachycardia is associated with severely depressed myocardial function.31 In case of shock and concomitant LVOTO, peripherally acting vasopressor drugs (phenylephrine or vasopressin) may be useful because they increase blood pressure without worsening LVOTO.32 Inotropic agents, increasing basal segment contraction, may provoke or exacerbate LVOTO, worsening haemodynamic instability. Furthermore, given the presumptive role of catecholamines in the pathophysiology of TTS, the use of inotropic agents may have more deleterious consequences than possible benefit, so that the use of exogenous catecholamines should be discouraged. This recommendation is made stronger by recently published data on the reduced shortand long-term survival of TTS patients treated with catecholamines, although this evidence may be the result of a selection bias, because patients needing inotropic agents may represent a more severe TTS phenotype.33 Levosimendan can play an important role in the management of CS, improving cardiac function and reducing mortality. The potential contraindications to most of the drugs used to support pressure in CS suggests an early consideration of mechanical support devices as a bridge to recovery. Treating TTS patients in CS with cardiac mechanical support, including intra-aortic balloon pumps (IABPs), such as Impella, and/or venoarterial extracorporeal membrane oxygenation (VA-ECMO), may improve their prognosis.20

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Before considering IABPs, LVOTO must be first excluded because the reduction in afterload by IABPs may worsen obstruction and haemodynamic instability. However, based on results of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial, IABPs are not recommended as routine therapy for patients with CS.34 Lyon et al. suggested avoiding the use of IABPs in TTS patients.11 Some case reports indicate that Impella may represent a valid therapeutic option in TTS complicated by CS and LVOTO, potentially leading to more rapid LV function recovery and better clinical outcome.35 VA-ECMO has also been proposed for patients with refractory CS; its early role may be lifesaving in TTS patients who are not responding to conventional treatment, and especially in the presence of LVOTO.36 Continuous ECG monitoring at least for 24 hours is recommended in TTS patients because arrhythmic complications (ventricular arrhythmias, AF or conduction disorders) could occur.24 Polymorphic ventricular tachycardia (torsades de pointes) has been documented in association with QTc prolongation.37 Therefore, drugs acting on the QT interval, as well as catecholamines (because of their potential proarrhythmic effects), should be avoided and electrolyte imbalances should be checked and corrected.24 However, the correlation between a long QTc and ventricular arrhythmias is not universally endorsed, and monomorphic ventricular tachycardia has been described in patients with a normal QT interval, and is probably associated with an increased 1-year mortality rate.38 BBs may be useful in preventing ventricular arrhythmias and in case of a long

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Takotsubo Syndrome QTc. However, BBs should be avoided in patients with bradycardia considering the risk of bradycardia-induced ventricular tachycardia. As in ST-elevation MI patients, the presence of malignant ventricular arrhythmias in the acute phase of TTS does not require an ICD, with the rare exceptions of patients with severe persistent impaired LV function. In this context, a wearable defibrillator (‘left jacket’) could be considered as a bridge or an alternative to an ICD to protect against life-threatening arrhythmias until LV function recovers and the risk of recurrence is assessed. AF is the most frequent arrhythmic complication described in TTS, and it has been associated with worse clinical presentation.21 In case of complete atrioventricular block, the conduction disorder could persist beyond the acute and subacute phase of the disease, thus justifying permanent implantation of a pacemaker in these patients.

Hypercoagulable State Apical ballooning with high troponin levels on admission was described as a marker of high thromboembolic risk.39 Thromboembolic complications may be associated with the catecholamine surge, endothelial dysfunction and blood stasis caused by the regional wall akinesia. Although it has been proposed that prophylactic oral anticoagulation be considered in high-risk patients, its role in the treatment of TTS remains to be determined.39 However, oral anticoagulation is recommended to prevent embolic episodes when a ventricular thrombus is detected, usually for 1–3 months and at least until the thrombus resolves and LV function recovers.11 Development of a thrombus in the right ventricle in patients with TTS has also been described, strengthening the usefulness of right ventricle assessment by transthoracic echocardiography.40 Considering that TTS could be triggered by neurological disease, bleeding risk should be assessed before starting anticoagulation, in addition to the potential risk of LV rupture. The effects of catecholamines on platelet activation and endothelial dysfunction have been described, but there is still no agreement regarding antiplatelet therapy in TTS patients.41,42 Because TTS often mimics an ACS, many patients initially receive antithrombotic treatment, but once MI is excluded, it has been suggested to that P2Y12 receptor antagonists are withdrawn.11 Aspirin was found to be unrelated to any improvement in reducing the recurrence of TTS.43,44 In contrast, in a retrospective study, the use of aspirin, alone or in combination with clopidogrel, was described as an independent predictor of a lower incidence of cardiac events during hospitalisation.45 Because a benefit was found in short-term outcomes,

T emplin C, Ghadri JR, Diekmann J, et al. Clinical features and outcomes of Takotsubo (stress) cardiomyopathy. N Engl J Med 2015;373:929–38. https://doi.org/10.1056/NEJMoa1406761; PMID: 26332547. Templin C, Hanggi J, Klein C, et al. Altered limbic and autonomic processing supports brain-heart axis in Takotsubo syndrome. Eur Heart J 2019;40:1183–7. https://doi.org/10.1093/ eurheartj/ehz068; PMID: 30831580. Abe Y, Kondo M, Matsuoka R, et al. Assessment of clinical features in transient left ventricular apical ballooning. J Am Coll Cardiol 2003;41:737–42. https://doi.org/10.1016/ S0735-1097(02)02925-X.

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TTS patients may be discharged with an indication to continue antiplatelet therapy for at least 2 months, especially if there is evidence of concomitant coronary atherosclerosis.24,46 The addition of BBs and ACEIs can also contribute to reducing mortality.

Long-term Management In TTS patients, it is unclear whether heart failure therapies should be continued once the patient’s LV function has normalised. Although most patients recover rapidly after the acute episode, increasing evidence indicates that physiological abnormalities may persist, and some patients continue to suffer cardiac symptoms after the acute episode. Templin et al. showed that ACEIs or ARBs were associated with improved 1-year survival and a lower prevalence of recurrence.1 Recently, it was suggested that BBs are associated with lower major adverse cardiac events (cardiac death, heart failure, acute MI, TTS recurrence), especially in patients with an ejection fraction ≤35% at discharge.19 In the same study, ACEIs and ARBs were associated with fewer cardiac deaths at long-term follow-up, but had no effect on overall mortality.19 A meta-analysis has reported that BBs, ACEIs, ARBs, statins and aspirin have no benefit on mortality and recurrence in TTS patients.43 All TTS patients should be followed-up to assess complete ventricular recovery, manage long-term symptoms and detect recurrences. In addition, patients’ comorbidities should be carefully monitored because most of the long-term mortality in TTS seems related to coexisting non-cardiac conditions. Indeed, it has been suggested that the eventual neurological or psychiatric stressors are treated, because they are observed more frequently in the case of TTS recurrence.47 Recurrences can occur with different triggering factors and ballooning patterns. Moreover, it has been shown recently that beta1-adrenoceptor-selective antagonists are not useful in preventing recurrences.47 However, because there is no agreement regarding the long-term management of TTS, individualised treatment is often required (Figure 2).

Conclusion TTS is an emerging condition associated with a heterogeneous clinical course, which ranges from a rapid, full recovery to poor early and long-term outcomes. Neither the physiopathological mechanisms underlying this disorder nor the risk for individual patients of developing adverse LV remodelling, heart failure or other complications are fully understood. The lack of rigorously tested treatment strategies for TTS patients represents an important limitation in guiding everyday clinical practice. Risk stratification is the future challenge to enable appropriate decisions to be made regarding the clinical management of TTS patients, in terms of both in-hospital and long-term outcomes, in order to offer better individualised patient care.

ybee KA, Prasad A, Barsness GW, et al. Clinical B characteristics and thrombolysis in myocardial infarction frame counts in women with transient left ventricular apical ballooning syndrome. Am J Cardiol 2004;94:343–6. https://doi. org/10.1016/j.amjcard.2004.04.030; PMID: 15276100. Maron BJ, Towbin JA, Thiene G, et al. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on

Epidemiology and Prevention. Circulation 2006;113:1807–16. https://doi.org/10.1161/CIRCULATIONAHA.106.174287; PMID: 16567565. Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155:408–17. https://doi. org/10.1016/j.ahj.2007.11.008; PMID: 18294473. Kawai S, Kitabatake A, Tomoike H; Takotsubo Cardiomyopathy Group. Guidelines for diagnosis of takotsubo (ampulla) cardiomyopathy. Circ J 2007;71:990–2. https://doi.org/10.1253/ circj.71.990; PMID: 17527002. Schultz T, Shao Y, Redfors B, et al. Stress-induced

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EUROPEAN CARDIOLOGY REVIEW

Cardiology Masters

Featuring: Josep Brugada

In the Cardiology Masters section of European Cardiology Review, we bring you an insight into the career of a key contributor to the field of cardiology. In this edition, we feature Josep Brugada. DOI: https://doi.org/10.15420/ecr.2019.14.3.CM1

Josep Brugada is a Professor of Medicine at the University of Barcelona, director of the Paediatric Arrhythmia Unit at Sant Joan de Déu Hospital and senior consultant at Hospital Clinic. He studied medicine at the University of Barcelona before moving to the University of Montpellier, France, to specialise in cardiology. He continued his training in Maastricht to further specialise in the clinical and basic aspects of cardiac arrhythmias, where he worked simultaneously in the Basic and the Clinical Electrophysiology Laboratory. Prof Brugada has received many awards during his career. These include the Fritz–Acker Prize to Scientific Research of the German Society of Cardiology, the Josep Trueta Award of the Academy for Medical Sciences of the Catalan Society of Medicine, for the discovery and description, along with his brother, Pedro Brugada, of the ‘Brugada syndrome’ and the Rey Jaime I Award in Clinical Medicine in 2015. To date, he has published more than 400 articles on cardiac arrhythmias and presented 300 international lectures. Between 2007 and 2009, Prof Brugada was the President of the European Heart Rhythm Association. He is on the editorial board of many leading cardiology journals and has been invited as a member of several national and international societies and committees. In 2013, he started his humanitarian action and visits Africa four times a year to treat children with arrhythmias.

uring the 1980s and early 1990s, if you wanted to know more about my career – or the careers of my older brother, Pedro, and my younger brother, Ramon – all you had to do was ask our father. In fact, you probably didn’t need to ask. He kept dozens of scrapbooks, each overflowing with every titbit of news published by or about any of the three of us. And he made it a point to regularly regale friends and acquaintances with tales of his three cardiologist sons who – in his estimation – were clearly the most amazing sons any father had ever had.

But both he – and especially my prescient mother – were determined that my brothers, my sister Dolors, and I, would grow to have better lives. It was my mother who insisted that we stay in school and ultimately attend the University of Barcelona, 120 km south of Banyoles, Spain, the small Catalan village where we were raised. It was an expensive proposition, but my parents’ hard work and unyielding determination made it happen (Figure 1). Our mother even insisted that we learn to speak English, because, she said, it was the language of the future.

You could hardly blame him. He was a brilliant man himself, but he never had the opportunities we had – opportunities he and my mother helped create for us. He supported our family by raising and selling rabbits and chickens, keenly aware, as he liked to explain, that the difference between profit and loss could be as narrow as the margin of a penny or two per animal. He worked a back-breaking schedule, rising at 4 or 4.30 am every morning and often working 14 or 15 hours a day before returning home as late as 10.00 pm at night.

Thankfully, both of our parents lived long enough to see their dedication come to fruition and their improbable dreams come true. Three sons, three cardiologists – something no one could have predicted. Until then, there had never been a single physician in our family.

The final triumph for my father came just weeks before he died at the age of 74 years. Pedro, Ramon and I published the first book on

Access at: www.ECRjournal.com

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Cardiology Masters Figure 1: Josep’s Parents Pepi and Ramon

Figure 2: Josep and His Wife Anna

Brugada syndrome. Seeing his name on the cover thrilled him and bolstered his conviction that he had helped raise the most remarkable sons on the planet.

A whirlwind of excitement followed. I took a couple of days off, went with my friends back to Montpellier and stayed with them while I brushed up on my French – I spoke it at the time, but not fluently – and prepared for the entrance exam.

A Role Model How my brothers and I ended up where we did remains a bit of a mystery. We weren’t especially close growing up, largely because we were spaced so far apart. Pedro is 6 years older than I, and Ramon is 8 years younger. I was much closer to Dolors, who was just 2 years older than I.

It was 1983, and when I passed the test, Anna and Helena soon joined me for a 4-year adventure that would change everything. It seems remarkable but true, in retrospect, that if my friends from medical school had decided to visit us in Spain 1 month later, I probably never would have been a cardiologist.

However, Pedro was a role model who, according to our mother, showed an interest in medicine at a very young age – an interest I don’t remember myself having as a child.

One More Obstacle

Still, I was an impressionable 10-year-old when Pedro began studying medicine. It seemed remarkable, and as time went on I too became increasingly interested in the medical world. These days, it’s impossible to start medical careers at such a young age, but Pedro was only 16 years when he began his medical studies, and I followed in his footsteps. As he had before me, I became a physician at the age of 22 years. At the age of 23 years, I married Anna, now my wife of almost 40 years, and at that remarkably young age the roadmap of our future lives seemed to be unfolding before us (Figure 2). By 25 years, I was a husband and a father – our daughter, Helena, was born 2 years after we were married – and the only physician in Riudarenes, a tiny village north of Barcelona where I worked as a general practitioner. But by the time I was 25 years old, I was also becoming restless, thirsting for something that would provide more action than being a general practitioner in a small village. It was then that fate intervened, as it so often does, and a chance event dramatically transformed my life and my future. Two close friends from medical school – a young man and young woman who had since married – came to visit Anna and me one weekend. At the time they were studying cardiology at the University of Montpellier in France, and seemed to be having the time of their lives. Why didn’t we join them there, they urged, but we would need to act fast, because the application deadline for the new year was just a couple of weeks away.

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However, when those 4 years came to an end I wasn’t yet a cardiologist, and there were no guarantees. In fact, I had no idea how many of my classmates would fail to make it over the final hurdle – the national cardiology specialty exam in Paris, an extremely challenging written test. How challenging? Of the 240 who took it that year, only eight of us passed. I knew I was well prepared, and I was confident, but I admit that the low success rate was shocking to me. I had figured maybe 20% or 30% would pass, not 3%. Fortunately, one of the major issues covered in the exam involved physiology research I was doing at the time. I had been working with animal models in Dr Antoine Sassine’s laboratory, studying different cardiac arrhythmias and the effects of different drugs on the electrical properties of the heart. Although my brother Pedro was working with the Dutch cardiologist Hein Wellens and was already well known in the field of cardiac arrhythmia, he was in The Netherlands at the time, and in the preinternet days, it was a lot more difficult – and a lot more expensive – to communicate internationally. As such, the help he could provide, though welcome, was limited. Pedro’s reputation helped me connect with my first important mentor, Professor Paul Puech, the legendary and marvellous French cardiologist who died last year at the age of 92 years old. Professor Puech helped facilitate the work I was doing in clinical cardiology, which also gave me a leg up.

Going Dutch Shortly after the exhilaration I experienced when I was notified that I had passed, Anna and I had another momentous decision to make.

EUROPEAN CARDIOLOGY REVIEW

Cardiology Masters: Dr Josep Brugada Figure 3: Josep Brugada in Clinical Practice

I’d planned to return to clinical practice in Spain, but I’d also received an intriguing offer to combine clinical work and research at the Royal Netherlands Academy of Arts and Sciences in the Netherlands with Maurits Allessie, Hein Wellens and Pedro. The chance to do both, and to reunite with Pedro, was too tempting to refuse. So, in 1987, we set off on our next great adventure and eventually spent the next 4 years immersing ourselves in another new culture. The Netherlands didn’t disappoint. The environment was warm and welcoming, and the entire experience was fantastic. By this time, we also had a son, Pau, and our children learned to speak Dutch and easily adapted to the Dutch lifestyle. They were happy and rewarding years, but the feeling of wanting to return home is stronger than any other feeling. Fate stepped in again during one extraordinary week in 1991. An offer to work at the Montreal Heart Institute was followed days later by an offer from Prof Paco Navarro to return to the University of Barcelona, where I’d initially trained as a student, to initiate an arrhythmia unit.

Figure 4: From Left, Ramon, Pedro, Georgia Sarquella-Brugada (Their Niece, a Cardiology Interventionist) and Josep

But when I arrived back in Barcelona, there was no arrhythmia unit – I had to develop it from scratch. It was only a one-person unit at first, but within a year, our success rate and our patient volume began to soar and we started hiring more physicians to work in my unit. After starting from zero, I became involved with everything in the hospital. Over time, I became a professor of medicine at the university, was named Chief of the Arrhythmia Unit, then Chief of the Cardiology Department, Director of what we call the Thorax Institute, and finally, in 2009, Chief Medical Officer of the hospital. In 2015, I stepped away from my administrative positions, went back to clinical practice, and then came back as a senior consultant in cardiology. I’m still in clinical practice (Figure 3).

Family Tradition When Anna heard of the offer, she reminded me about a conversation we’d had 8 years earlier, before leaving Spain for France. Why, she’d asked at the time, would I consider leaving? Because, I’d said then, someday I wanted to return to Barcelona and work as a cardiologist. The very opportunity of which I’d spoken had arrived, she reminded me. So we agreed: it was time to go home.

Though I’ve led an enviable life, I’ve also experienced great sadness tinged with irony. Our beloved sister, Dolors, was stricken by sudden cardiac death at the age of 50 years old – at a time when her brothers were doing research in the field. It was nearly as unexpected as it was heart-breaking. She was very fit, and we had no family history of sudden death.

Home Again

But the family tradition lives on in Dolors’ talented and extremely bright daughter, Georgia, who works as a cardiology interventionist in our paediatric ward (Figure 4).

To have a successful career at the University Hospital Clínic de Barcelona – probably the most important hospital in Spain in terms of scientific production – you not only have to be a good doctor, you also have to be able to do research. Fortunately, I brought extensive research experience with me from all my years in France and the Netherlands. Having had the chance to work with Paul Puech, Antoine Sassine, Hein Wellens, Maurits Allessie and Pedro, I was at the forefront of the revolution taking place in the field of arrhythmias in cardiology. Until the 1980s and 1990s, we had spent a lot of time studying arrhythmias, but we didn’t have the tools to cure people. That changed with the introduction of catheter ablation. It was exciting. Patients who had suffered many episodes of tachycardia, who had been admitted to emergency rooms in some cases dozens of times, were simply cured, using ablation techniques. That changed not only their lives, but also our clinical practice.

EUROPEAN CARDIOLOGY REVIEW

I am the chief of the paediatric arrhythmia unit in our paediatric hospital, and I believe I was the first person in Spain to do arrhythmia procedures in children. I still work there 2 days per week, with Georgia, and I still do a lot of procedures in children from all over Spain. In fact, our unit is the only recognised reference unit in the country, which is something I’m very proud of. One of my cardiac arrhythmia patients weighed about 1.5 kg, or less than 4 pounds. At the time of the surgery, he was the smallest arrhythmia patient ever. Now that young man is about 15 years old and doing very well. Now, he no longer holds the record. Last January, Georgia and I operated on a premature 30-week newborn with incessant tachycardia. She weighed 1.3 kg at the time and was in very

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Cardiology Masters Figure 5: The Mozambique Team

Figure 6: Brugada Brothers: From Left, Josep, Ramon and Pedro

poor condition. She has recovered completely, her heart is beating very well, and she’s beautiful.

world, was largely created by former fellows of mine. These include Luis Aguinaga, Roberto Keegan, Luis Carlos Saenz, Marcio Figueiredo, Carlos Kalil and Ulises Rojel, to name a few.

Needless to say, procedures like these require very special expertise. They remind you that your career and all the hard work you’ve done is worth it.

I have had much recognition around the world and have been awarded many prizes, but these are minor compared to the joy I get from teaching, researching and doing clinical work.

Giving Back In recent years I’ve also made it a priority to give back what society has given me. For example, I use part of my time off and my holidays to go to Africa three or four times a year, and have been doing so for the last 7 years. There, I work with children, because technology that’s useful and valid in children in Barcelona and New York should also be accessible to children in Mozambique and other extremely poor countries. I try to keep in mind Mother Teresa’s credo that if you cannot feed everyone, just feed one. I cannot cure everybody or solve all the world’s problems, but I can treat patients one by one, and I’ve now done more than 700 interventions in Africa (Figure 5). I’m also doing what I can elsewhere. I’ve trained more than 200 people in electrophysiology from all over the world, and about half are from South America. In fact, I would estimate that about 60% of all the arrhythmia units in South America are directed by people who I have trained. I’m delighted that whenever I travel to South America, it seems as if there’s always an ex fellow of mine who wants to pick me up at the airport. I am also very proud that the Latin American Heart Rhythm Society, which is very well respected throughout the

Of course, from a scientific standpoint, the discovery of a rare cardiac arrhythmia that commonly causes sudden death and that’s brought about by a genetic defect is what I am most proud of. Brugada syndrome has led to respect and recognition all over the world, and the fact that initially Pedro and I discovered it together, then Ramon characterised the genetic aspect of the disease, is a source of great family pride. It will stay in the medical books forever, which means that our name and the name of our father will stay in the books forever (Figure 6).

No Plans to Stop For now, I’ve just turned 61 years old and I have no plans to stop doing what I’m doing. Helping people is just so rewarding. I suppose someday, they may retire me and say: “You’re no longer able to do all these things, so please go home”. Or maybe one day my wife will say it’s time to stop, and go to the beach and just enjoy our granddaughters, Júlia and Erin, and the many other grandchildren I hope will come in the future. For as long as I can, I’ll continue to do all the things I’m doing, because I’m so happy doing them. It’s difficult for me to imagine when or why I’d stop.

DOI: https://doi.org/10.15420/ecr.2019.14.3.CM1

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Corrigendum

Corrigendum to: Sodium–glucose Cotransporter 2 Inhibitors in Heart Failure: Potential Mechanisms of Action, Adverse Effects and Future Developments Juan Tamargo Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense, CIBERCV, Madrid, Spain

Citation: European Cardiology Review 2019;14(3):201. DOI: https://doi.org/10.15420/ecr.2019.14.3.CG1 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 the article by Juan Tamargo entitled Sodium–glucose Cotransporter 2 Inhibitors in Heart Failure: Potential Mechanisms of Action, Adverse Effects and Future Developments (European Cardiology Review 2019;14(1):23–32. https://doi.org/10.15420/ecr.2018.34.2), the following correction should be made: Figure 1 should indicate an increase (↑) in haemoglobin and haematocrit, not a decrease (↓). The corrected figure appears below. The author apologises for this error.

Figure 1: Potential Mechanisms Involved in the Cardioprotective and Renoprotective Effects of Sodium–glucose Cotransporter 2 Inhibitors SGLT2 inhibition

Metabolic responses

Direct cardiac effects

Metabolic shift

Osmotic diuresis and natriuresis

glucagon erythropoietin

Inhibits NHE1 activity FA oxidation glucose oxidation BHOB oxidation P/O ratio cardiac hypertrophy, fibrosis and remodelling

Positive inotropism

Direct renal effects

glucosuria HbA1c glucotoxicity insulin resistance bodyweight and visceral adiposity uricosuria oxidative stress inflammation markers vascular dysfunction

cardiac efficiency

haemoglobin and haematocrit

plasma volume interstitial fluid blood pressure vascular stiffness pre-load/-afterload congestion cardiac wall stress

tissular O2 delivery

cardiac efficiency

MACE HHF and improved HF outcomes

glomerular pressure albuminuria renal growth and inflammation Restores TG feedback Inhibits NHE3 activity

Preservation of renal function progression of albuminuria worsening of nephropathy

RENOPROTECTION

CARDIOPROTECTION BHOB = 3-beta-hydroxybutyrate; FA = fatty acid; HHF = hospitalisations for HF; MACE = major adverse cardiovascular events; NHE = Na+-H+ exchanger; P/O = ATP yield per oxygen atom consumed of oxidative phosphorylation; SGLT2 = sodium-glucose cotransporter 2; TG = tubuloglomerular.

Access at: www.ECRjournal.com

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IF EVERY DAY IS PRECIOUS, IS THE USUAL EVERYDAY CAD TREATMENT REALLY ENOUGH? Xarelto®. Saving More Lives of CAD Patients than Aspirin Alone1

Xarelto 2.5 mg film-coated tablets (Refer to full SmPC before prescribing.) This medicinal product is subject to additional monitoring. Composition: Active ingredient: 2.5 mg rivaroxaban. Excipients: Microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, hypromellose, sodium laurilsulfate, magnesium stearate, macrogol 3350, titanium dioxide (E171), iron oxide yellow (E172). Indication: Prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine. Prevention of atherothrombotic events in adult patients with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD) at high risk of ischaemic events, co-administered with ASA. Contraindications: Hypersensitivity to the active substance or any of the excipients; active clinically significant bleeding; lesion or condition considered a significant risk for major bleeding; concomitant treatment with any other anticoagulants except under specific circumstances of switching anticoagulant therapy or when unfractionated heparin is given at doses necessary to maintain an open central venous or arterial catheter; concomitant treatment of ACS with antiplatelet therapy in patients with a prior stroke or a transient ischaemic attack (TIA); concomitant treatment of CAD/PAD with ASA in patients with previous haemorrhagic or lacunar stroke, or any stroke within a month; hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C; pregnancy and breast feeding. Warnings and Precautions: Clinical surveillance in line with anticoagulation practice is recommended throughout treatment. Xarelto should be discontinued if severe haemorrhage occurs. Increasing age may increase haemorrhagic risk. Xarelto should be discontinued at the first appearance of a severe skin rash, or any other sign of hypersensitivity in conjunction with mucosal lesions. Not recommended: in patients with severe renal impairment (creatinine clearance <15 ml/min); in patients receiving concomitant systemic treatment with strong concurrent CYP3A4- and P-gp-inhibitors, i.e. azole-antimycotics or HIV protease inhibitors; in patients with increased bleeding risk; in patients receiving concomitant treatment with strong CYP3A4 inducers unless the patient is closely observed for signs and symptoms of thrombosis; for patients with a history of thrombosis diagnosed with antiphospholipid syndrome; Xarelto should not be used for thromboprophylaxis in patients having recently undergone transcatheter aortic valve replacement (TAVR); not recommended due to lack of data: treatment in combination with antiplatelet agents other than ASA and clopidogrel/ ticlopidine; in patients below 18 years of age; in patients concomitantly treated with dronedarone; in patients with prosthetic heart valves. Use with caution: in conditions with increased risk of haemorrhage; in patients with severe renal impairment (creatinine clearance 15 – 29 ml/min); in patients with moderate renal impairment (creatinine clearance 30 – 49 ml/min)

191004_02_AZ_XARE_CAD_210x297_RZ.indd 1

concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations; in patients treated concomitantly with medicinal products affecting haemostasis; in patients ≥ 75 years of age or with lower body weight; in CAD patients with severe symptomatic heart failure; when neuraxial anaesthesia or spinal/epidural puncture is employed. Patients on treatment with Xarelto and ASA or Xarelto and ASA plus clopidogrel/ticlopidine should only receive concomitant treatment with NSAIDs if the beneﬁt outweighs the bleeding risk. In patients at risk of ulcerative gastrointestinal disease prophylactic treatment may be considered. Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-Factor Xa assay may be useful in exceptional situations. Xarelto contains lactose. Undesirable effects: Common: anaemia, dizziness, headache, eye haemorrhage, hypotension, haematoma, epistaxis, haemoptysis, gingival bleeding, gastrointestinal tract haemorrhage, gastrointestinal and abdominal pains, dyspepsia, nausea, constipation, diarrhoea, vomiting, increase in transaminases, pruritus, rash, ecchymosis, cutaneous and subcutaneous haemorrhage, pain in extremity, urogenital tract haemorrhage, renal impairment, fever, peripheral oedema, decreased general strength and energy, post-procedural haemorrhage, contusion, wound secretion. Uncommon: thrombocytosis, thrombocytopenia, allergic reaction, dermatitis allergic, angioedema and allergic oedema, cerebral and intracranial haemorrhage, syncope, tachycardia, dry mouth, hepatic impairment, increases in bilirubin, blood alkaline phosphatase and GGT, urticaria, haemarthrosis, feeling unwell, increases in LDH, lipase, amylase. Rare: jaundice, bilirubin conjugated increased, cholestasis, hepatitis (incl hepatocellular injury), muscle haemorrhage, localised oedema, vascular pseudoaneurysm (uncommon in prevention therapy in ACS following percutaneous intervention). Very rare: anaphylactic reactions incl. shock, Stevens-Johnson syndrome/Toxic Epidermal Necrolysis, DRESS syndrome. Frequency not known: compartment syndrome or (acute) renal failure secondary to a bleeding. Classiﬁcation for supply: Medicinal product subject to medical prescription. Marketing Authorisation Holder: Bayer AG, 51368 Leverkusen, Germany Further information available from: xarelto.medinfo@bayer.com Version: EU/11 Find out more at Xarelto.com Reference: 1. Connolly S.J., Eikelboom J.W., Bosch J. et al. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018;391(10117):205–18. PP-XAR-ALL-1504-1. © Bayer AG, October 2019

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