AER 4.3

Arrhythmia & Electrophysiology Review Volume 4 • Issue 3 • Winter 2015

www.AERjournal.com

Volume 4 • Issue 3 • Winter 2015

The Role of MicroRNAs in Antiarrhythmic Therapy for Atrial Fibrillation Sebastian Clauss, Moritz F Sinner, Stefan Kääb and Reza Wakili

Nature and Nurture in Arrhythmogenic Right Ventricular Cardiomyopathy – A Clinical Perspective Cynthia A James

Body Surface Mapping to Guide Atrial Fibrillation Ablation Seigo Yamashita, Ashok J Shah, Saagar Mahida, Jean-Marc Sellal, Benjamin Berte, Darren Hooks, Antonio Frontera, Nora Al Jefairi, Jean-Yves Wielandts, Han S Lim, Sana Amraoui, Arnaud Denis, Nicolas Derval, Frédéric Sacher, Hubert Cochet, Mélèze Hocini, Pierre Jaïs and Michel Haïssaguerre

Syncope in Patients with Pacemakers

Electrical remodelling

Richard Sutton

Ca

DADs

2+

Depolarisation

NCX

Potential therapeutic interventions modulating AF-relevant miRNAs

Na+ Na+ Na+

Diastolic Ca2+ leak

Ca2+

Intramuscular or systemic injection

P

P

MiR-133

Hyp e MiR-1 phosprhory latio n B56α

RYR2

Antagomirs, LNAs, miRNA sponges/ erasers, miR-masks, miRNA mimics

PP2A B56δ

SR

APD shortening Structural remodelling

Atrial fibrosis

MiR-133 MiR-590

MiR-133

MiR-21

Spry1

MAK/ERK signaling

Y

ISK

KCNN3

MiR-499

PTEN

MMP2

Enhanced EMC turnover

IKs/IKr

SK3 channel

FBN1

MiR-29b

MiR-26

TRPC3 channel

TR

N

COL1A2

REE

Extracellular matrix EMC deposition

AT1 receptor TGFβ receptor profibrotic profibrotic signalling signalling COL1A1

AF begets AF

MiR-30 CTGF

TGFβ

TOPY EC

MiR-133

Angiotensin II

IK1

IcaL

Inward rectifier K+ channels

L-Type CA2+ channels

KCNE1 KCNJ2 KCNB2 KCNH2

CACNA1C CACNAB1

MiR-1

MiR-1 MiR-133

MiR-328

MiR-26

Reduced conduction velocity

MiR-21

Fibroblast

ISSN - 2050-3369

proliferation Potential Therapeutic Atrial Fibrillation Cx43 Interventions Modulating Termination After MiR-1 Cx40 miRNAs RepeatMiR-208a Mapping

Decreased miRNAand enhancing Voltage Mapping target protein expression Intramural Scar Increased miRNA inhibiting target protein expression

Gap junctions

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

AER4.3_FC+spine2.indd All Pages

29/11/2015 23:10

Quadra Assura MP™ CRT-D with MultiPoint™ Pacing

18%

Relative reduction in all-cause mortality1

53% Lower risk of hospitalization 87% Lower hospitalization costs compared to Bipolar LV leads 26% Absolute improvement in CRT response rate 2

3

4

SJMprofessional.com

1. Turakhia, M. P., Cao, M., Fischer, A., Arnold, E., Sloman, L. S., Dalal, N. & Gold, M. R., (2014). Reduced Mortality with Quadripolar Versus Bipolar Left Ventricular Leads in Cardiac Resynchronization Therapy. Presented at Heart Rhythm Society (HRS) 2014, San Francisco CA. PO01-51. This data is from a retrospective data analysis and has limitations.

2. Forleo, G. B., Panattoni, G., Bharmi R., Dalal, N., Pollastrelli, A., Rocca, D. D.,…Romeo, F., (2014). Hospitalization Rates and Associated Cost Analysis of Quadripolar versus Bipolar CRT-D: a comparative analysis of single-center prospective Italian registry. Presented at Heart Rhythm Society (HRS) 2014, San Francisco CA. AB39-02.

3. Corbisiero, R., Armbruster, R. & Muller, D., (2014). Reduced Costs Post CRT with Quadripolar LV leads compared to Bipolar LV leads. Heart Rhythm Society (HRS) 2014, San Francisco CA. PO01-195.

4. Pappone C., Calovic, Z., Culo, A., McSpadden, L. C., Ryu, K., Baldi, M.,…Santinelli, V. (2013). Multisite Left Ventricular Pacing in a Single Coronary Sinus Branch Improves 3-Month Echocardiographic and Clinical Response to Cardiac Resynchronization Therapy. Journal of Cardiac Failure, 19(8), S26.

Rx Only Brief Summary: Prior to using these devices, please review the Instructions for Use for a complete listing of indications, contraindications, warnings, precautions, potential adverse events and directions for use.

Unless otherwise noted, ™ indicates that the name is a trademark of, or licensed to, St. Jude Medical or one of its subsidiaries. ST. JUDE MEDICAL and the nine-squares symbol are trademarks and service marks of St. Jude Medical, Inc. and its related companies. © 2015 St. Jude Medical, Inc. All Rights Reserved.

SJM-QD-1115-0036a | Item approved for international use only.

Untitled-2 1

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Volume 4 • Issue 3 • Winter 2015

Editor-in-Chief Demosthenes Katritsis Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

Section Editor – Arrhythmia Mechanisms / Basic Science

Section Editor – Clinical Electrophysiology and Ablation

Section Editor – Implantable Devices

Andrew Grace

Karl-Heinz Kuck

Angelo Auricchio

University of Cambridge, UK

Asklepios Klinik St Georg, Hamburg, Germany

Fondazione Cardiocentro Ticino, Lugano, Switzerland

Etienne Aliot

Warren Jackman

Christopher Piorkowski

University Hospital of Nancy, France

University of Oklahoma Health Sciences Center, Oklahoma City, US

University of Dresden, Germany

University Hospital Uppsal, Sweden

Mark Josephson

Johannes Brachmann

Beth Israel Deaconess Medical Center, Boston, US

ALFA – Alliance to Fight Atrial Fibrillation, Venice-Mestre, Italy

Klinikum Coburg, II Med Klinik, Germany

Josef Kautzner

Frédéric Sacher

Pedro Brugada

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Bordeaux University Hospital, LIRYC Institute, France

Samuel Lévy

Richard Schilling

Carina Blomström-Lundqvist

University of Brussels, UZ-Brussel-VUB, Belgium

Hugh Calkins Johns Hopkins Medical Institutions, Baltimore, US

A John Camm St George’s University of London, UK

Riccardo Cappato IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

Ken Ellenbogen Virginia Commonwealth University School of Medicine, US

Sabine Ernst Royal Brompton and Harefield NHS Foundation Trust, UK

Andreas Götte

Aix-Marseille Université, France

Antonio Raviele

Cecilia Linde

Barts Health NHS Trust, London Bridge Hospital, London, UK

Karolinska University, Stockholm, Sweden

William Stevenson

Gregory YH Lip University of Birmingham Centre for Cardiovascular Sciences, UK

Francis Marchlinski University of Pennsylvania Health System, Philadelphia, US

Jose Merino Hospital Universitario La Paz, Spain

Fred Morady Cardiovascular Center, University of Michigan, US

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

Richard Sutton National Heart and Lung Institute, Imperial College, London, UK

Juan Luis Tamargo University Complutense, Madrid, Spain

Sotirios Tsimikas University of California San Diego, US

Panos Vardas

St Vincenz-Hospital Paderborn and University Hospital Magdeburg, Germany

Sanjiv M Narayan Stanford University Medical Center, US

Hein Heidbuchel

Marc A Vos

Mark O’Neill

Hasselt University and Heart Center, Jessa Hospital, Hasselt, Belgium

King’s College, London, UK

University Medical Center Utrecht, The Netherlands

Gerhard Hindricks

Carlo Pappone

Katja Zeppenfeld

Maria Cecilia Hospital, Italy

Leiden University Medical Center, The Netherlands

University of Leipzig, Germany

Carsten W Israel JW Goethe University, Germany

Sunny Po Heart Rhythm Institute, University of Oklahoma Health Sciences Center, US

Heraklion University Hospital, Greece

Douglas P Zipes Krannert Institute of Cardiology, Indianapolis, US

Design & Production Tatiana Losinska • Digital Commercial Manager Ben Sullivan Account Executive Ryan Challis • Publishing Director Liam O’Neill Managing Director David Ramsey • Commercial Director Mark Watson • Managing Editor Becki Davies | managingeditor@radcliffecardiology.com Circulation & Commercial Contact Mark Watson | mark.watson@radcliffecardiology.com • Cover image | shutterstock.com • Cover design Tatiana Losinska

In partnership with

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

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Lifelong Learning for Cardiovascular Professionals

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 there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology.

Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice.

Radcliffe Cardiology, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. © 2015 All rights reserved © RADCLIFFE CARDIOLOGY 2015

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Established: October 2012

Aims and Scope • Arrhythmia & Electrophysiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in the arrhythmia and electrophysiology sphere.

• Arrhythmia & Electrophysiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field.

• Arrhythmia & Electrophysiology Review provides comprehensive updates on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-today clinical practice.

• The journal endeavours, through its timely teaching reviews, to support the continuous medical education of both specialist and general cardiologists, and disseminate knowledge of the field to the wider cardiovascular community.

Structure and Format • Arrhythmia & Electrophysiology Review is a tri-annual journal comprising review articles and 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 Arrhythmia & Electrophysiology Review is replicated in full online at www.AERjournal.com

Frequency: Tri-annual

Current Issue: Winter 2015

• Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is returned to the reviewers to ensure the revised version meets their quality expectations.

Once approved, the manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Submissions and Instructions to Authors • 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, formalise the working title and scope of the article.

• Subsequently, the Managing Editor provides an ‘Instructions to Authors’ document and additional submission details.

• The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the Managing Editor for further details: managingeditor@radcliffecardiology.com. The ‘Instructions to Authors’ information is available for download at www.AERjournal.com

Reprints All articles included in Arrhythmia & Electrophysiology Review are available as reprints (minimum order 1,000). Please contact Liam O’Neill at liam.oneill@radcliffecardiology.com

Editorial Expertise

Distribution and Readership

Arrhythmia & Electrophysiology 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 members of the journal’s Peer Review Board as well as other experts appointed for their experience and knowledge of a specific topic.

• An experienced team of Editors and Technical Editors.

Arrhythmia & Electrophysiology Review is distributed tri-annually through controlled circulation to general and specialist senior cardiovascular professionals in Europe. All manuscripts published in the journal are free-to-access online at www.AERjournal.com and www.radcliffecardiology.com

Abstracting and Indexing Arrhythmia & Electrophysiology Review is abstracted, indexed and listed in Embase, Scopus, Google Scholar and Summon by Serial Solutions.

Copyright and Permission Peer Review • On submission, all articles are assessed by the Editor-in-Chief or Managing Editor to determine their suitability for inclusion.

• The Managing Editor, following consultation with the Editor-in-Chief, Section Editors and/or a member of the Editorial Board, sends the manuscript to members of the Peer Review Board, who are selected on the basis of their specialist knowledge in the relevant area.

All peer review is conducted double-blind.

• Following review, manuscripts are either accepted without modification, accepted pending modification, in which case the manuscripts are returned to the author(s) to incorporate required changes, or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments.

Radcliffe Cardiology is the sole owner of all articles and other materials that appear in Arrhythmia & Electrophysiology Review unless otherwise stated. Permission to reproduce an article, either in full or in part, should be sought from the journal’s Managing Editor.

Online All manuscripts published in Arrhythmia & Electrophysiology Review are available free-to-view at www.AERjournal.com and www.radcliffecardiology.com.

Also available at www.radcliffecardiology.com are other journals within Radcliffe Cardiology’s portfolio: Interventional Cardiology Review, Cardiac Faiilure Review and European Cardiology Review. n

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138

AER4.3_Aims-Scope.indd 138

© RADCLIFFE CARDIOLOGY 2015

28/11/2015 11:45

ALL IT TAKES IS ONE. ONE bacterial cluster in a CIED patient can create an infection.

ONE out of every two patients with a CIED Infection may not survive beyond three years.1

S aureus

ONE CIED Infection may cost your hospital in excess of $100,000 USD.2 ONE TYRX™ Absorbable Antibacterial Envelope can help.3-9 . Stabilize CIED Placement . Help Prevent CIED Infection (Associated with 70% to 100% fewer infections compared to patients without them)

For more information visit TYRX.com & HeartDeviceInfection.com.

Copyright © 2015, Medtronic, Inc. UC201504005cEN

2015_TYRX_AER_MECH.indd 139

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Contents

Foreword

144

Widening our Circle of Influence Demosthenes Katritsis, Editor-in-Chief Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, US

Editorial

145

Clinical Electrophysiology and Precision Medicine Initiatives Andrew Grace, Section Editor – Arrhythmia Mechanisms/ Basic Science University of Cambridge, Cambridge, UK

Arrhythmia Mechanisms 146

The Role of MicroRNAs in Antiarrhythmic Therapy for Atrial Fibrillation Sebastian Clauss, 1,2,3 Moritz F Sinner, 2 Stefan Kääb, 2,3 and Reza Wakili 2,3 1. Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, US; 2. University Hospital Munich, Ludwig-Maximilians University Munich; 3. DZHK (German Centre for Cardiovascular Research), Partner site Munich, Germany

Clinical Arrhythmias

156

Nature and Nurture in Arrhythmogenic Right Ventricular Cardiomyopathy – A Clinical Perspective Cynthia A James Division of Cardiology, Johns Hopkins University, Baltimore, Maryland, US

163

Upstream Treatment of Atrial Fibrillation with n-3 Polyunsaturated Fatty Acids: Myth or Reality?

Francesco Orso, 1,2 Gianna Fabbri 2 and Aldo Pietro Maggioni 2 1. Azienda Ospedaliero-Universitaria Careggi, Section of Geriatric Medicine and Cardiology, Florence, Italy; 2. ANMCO Research Center, Florence, Italy

TYRX™ ABSORBABLE ANTIBACTERIAL ENVELOPE REFERENCES: 1. Sohail MR et al. PACE. 2015;38(2):231-239. 2. Sohail MR et al. Arch Intern Med. 2011;171(20):1821-1828. 3. Huntingdon Life Sciences Study TR-2011-054. 4. Hirsh J. EP Lab Digest. July 2012;12(7). 5. Shariff N et al. J Cardio Electrophysiol. 2015. Online publication. 6. Kolek et al. J Cardio Electrophysiol.

2015. Efficacy of Bio-Absorbable Antibacterial Envelope. Online publication. 7. Bloom HL et al. Pacing Clin Electrophysiol. 2011;34(2):133-142. 8. Mittal S et al. Heart Rhythm. 2014;11(4):595-601. 9. Henrikson CA, Citadel and Centurion Study Results: Use of Antibacterial Envelope is Associated with Low 12-Month CIED Infection Rates. Oral presentation at European Heart Rhythm Association (EHRA) EUROPACE-CARDIOSTIM 2015.

BRIEF STATEMENT: The TYRX TM Absorbable Antibacterial Envelope is NOT indicated for use in patients with contaminated or infected wounds; Systemic Lupus Erythematosus (SLE); who have an allergy or history of allergies to tetracyclines, Rifampicin, or an allergy to absorbable sutures.The use of these products in patients with compromised hepatic and renal function, or in the presence of hepatotoxic or renal toxic medications, should be considered carefully, because Minocycline and Rifampicin can cause additional stress on the hepatic and renal systems. Patients who receive the TYRX TM Absorbable Antibacterial Envelope and who are also taking methoxyflurane should be monitored carefully for signs of renal toxicity.

2015_11_13_TYRX_Refernces_ArrhythmiaElectrophysReview.indd 1 MECHANICAL FILE NAME AER 4.3_contents_Winter2015.indd 140

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2015_11_13_TYRX_Refernces_ArrhythmiaElectrophysReview_MECH.pdf

TYRX

INCLUDED FONTS

DATE

EFFRA: Light,Regular, Medium, Bold, Italic

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Contents

Clinical Arrhythmias 169

Early Repolarisation Syndrome – New Concepts Demosthenes G Katritsis, 1 Bernard J Gersh 2 and A John Camm 3 1. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, US; 2. Mayo Medical School, Rochester, Minnesota, US; 3. St George’s University of London, UK

172

Body Surface Mapping to Guide Atrial Fibrillation Ablation Seigo Yamashita, 1 Ashok J Shah, 1 Saagar Mahida, 1 Jean-Marc Sellal, 1 Benjamin Berte, 1 Darren Hooks, 1 Antonio Frontera, 1 Nora Al Jefairi, 1 Jean-Yves Wielandts, 1 Han S Lim, 1 Sana Amraoui, 1 Arnaud Denis, 1 Nicolas Derval, 1,2 Frédéric Sacher, 1,2 Hubert Cochet, 2,3 Mélèze Hocini, 1,2 Pierre Jaïs 1,2 and Michel Haïssaguerre 1,2 1. Hôpital Cardiologique du Haut-Lévêque, CHU de Bordeaux, Pessac, France; 2. Institut Liryc/Equipex Music, Université de Bordeaux-Inserm U1045, Pessac, France; 3. Hôpital Cardiologique du Haut-Lévêque, CHU de Bordeaux, Pessac, France

Diagnostic Electrophysiology & Ablation

177

Long-term Outcomes of Ventricular Tachycardia Ablation in Different Types of Structural Heart Disease Jackson J Liang, Pasquale Santangeli and David J Callans Electrophysiology Section, Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, US

184

Selecting the Appropriate Ablation Strategy: the Role of Endocardial and/or Epicardial Access Mario Njeim and Frank Bogun University of Michigan, Ann Arbor, MI, USA

Device Therapy

189

Syncope in Patients with Pacemakers Richard Sutton National Heart & Lung Institute, Imperial College, London, UK

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© RADCLIFFE CARDIOLOGY 2015

29/11/2015 23:18

INFECTION +DEVICE

=REMOVAL

Cardiac device infections can be deadly. They’re also tricky to identify. It’s why more than 6 in 10 infected devices are undertreated or not treated at all. The key to reversing this trend is vigilance—and prompt action.

Complete system removal, including leads, is a safe and effective solution. CIED patients with infection symptoms should be referred to an extracting physician for further evaluation.

Infection + Device = Removal.

Join the cause. Visit www.deviceinfection.com

THIS EDUCATIONAL CONTENT IS INTENDED FOR HEALTHCARE PROFESSIONALS ONLY. CARDIAC DEVICE REMOVAL MAY NOT BE APPROPRIATE FOR SOME PATIENTS DEPENDING ON INDIVIDUAL HEALTH FACTORS. TREATMENT DECISIONS SHOULD ALWAYS BE BASED ON THE JUDGMENT AND EXPERTISE OF A HEALTHCARE PROFESSIONAL. IF YOU ARE A PATIENT WITH QUESTIONS OR CONCERNS ABOUT AN IMPLATED CARDIAC DEVICE, PLEASE CONSULT WITH YOUR PHYSICIAN. ©2014 Spectranetics All rights reserved. Approved for external distribution. D021873-01 042014

infection Ad.indd 143

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28/11/2015 12:03

Foreword

Widening our Circle of Influence

W

e are delighted to announce that all Arrhythmia & Electrophysiology Review articles, from our first issue back in 2012, to this issue and all future issues going forward, will soon be available in full on

PubMed Central (PMC) and indexed on PubMed. Indexing of Arrhythmia & Electrophysiology Review on PubMed and PMC will increase awareness of the journal itself as well as raising the profile of authors among the wider cardiology community.

PMC is a web-based repository of biomedical and life science journal literature operated by the US National Institutes of Health (NIH). In order to be accepted onto PMC, our articles have had to undergo a rigorous scientific quality evaluation, followed by a technical evaluation. It is testament to the efforts of authors, peer reviewers and editorial board that the journal has been successful in this process, and our thanks goes out to all of you who have been involved in one way or another.

In the meantime, we will need to beware of complacency, and will be maintaining our efforts to ensure

the quality of the journal throughout 2016. We would welcome your input into this process, so if you would be interested in submitting a review article or opinion piece for consideration, we look forward to hearing from you.

Demosthenes Katritsis Editor-in-Chief, Arrhythmia & Electrophysiology Review Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, US

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AER Foreword 4.3.indd 144

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

28/11/2015 12:16

Editorial

Clinical Electrophysiology and Precision Medicine Initiatives

T

he principal aim of Arrhythmia & Electrophysiology Review is to provide concise, timely articles highlighting clinical advances relevant to the management of those with arrhythmias. The Editors have

also from the outset1 emphasised the substantial gaps in our capacity inter alia to predict those at risk of

sudden death, understand atrial fibrillation mechanisms and provide effective and safe drug treatment.

In these and other areas of clinical practice many of our efforts will in hindsight be seen, despite all our best efforts, to have been primitive.2 We are however fortunate in that the characteristics of the diseases that provide our daily bread are most open to quantification amongst any of the sub-specialities.2 Precision medicine, ‘an approach to disease treatment and prevention that seeks to maximise effectiveness by taking into account individual variability in genes, environment and lifestyle’,3 and a term coined for inclusion in a US National Research Council report4 has achieved recent prominence following the announcement by President Obama of enhanced, targeted funding in his State of the Union Address on 20 January 2015.3,5–7 As an exemplar excitable tissue the heart differs from the brain8 in being accessible, relatively simple and in many aspects experimentally tractable.2 In the coming issues this journal will continue to address genetic, epigenetic and phenotypic aspects determining individual variability to clinical presentation. The whole community should contribute to national and international research programs that through deeper phenotyping,9–11 extended data gathering and an analysis of ever-larger datasets promise to provide contemporary templates for effective, efficient clinical care.

Andrew Grace, Section Editor – Arrhythmia Mechanisms / Basic Science University of Cambridge, Cambridge, United Kingdom

1.

2.

3.

4.

Katritsis D. Arrhythmia & Electrophysiology Review – do we need another journal? Arrhythmia & Electrophysiology Review 2012;1:6.

Grace AA, Roden DM. Systems biology and cardiac arrhythmias. Lancet 2012;380:1498–508.

Jameson JL, Longo DL. Precision medicine – personalised, problematic, and promising. N Engl J Med 2015;372:2229–34.

Desmond-Hellmann S. Toward precision medicine: A new social contract? Sci Transl Med 2012;4:129ed3.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

AER 4.3_Editorial - Grace.indd 145

5.

6.

7.

8.

Aronson SJ, Rehm HL. Building the foundation for genomics in precision medicine. Nature 2015;526:336–42.

Hawgood S, Hook-Barnard IG, O’Brien TC, Yamamoto KR. Precision medicine: Beyond the inflection point. Sci Transl Med 2015;7:300ps317.

Iyengar R, Altman RB, Troyanskya O, FitzGerald GA. Medicine.

Personalization in practice. Science 2015;350:282–3.

Alivisatos AP, Chun M, Church GM, et al. A national network of neurotechnology centers for the brain initiative. Neuron

2015;88:445–8.

Delude CM. Deep phenotyping: The details of disease. Nature 2015;527:S14–15.

10. Grace AA. Prophylactic implantable defibrillators for hypertrophic cardiomyopathy: Disarray in the era of precision medicine. Circ Arrhythm Electrophysiol 2015;8:763–6.

11. MacRae CA, Pollak MR. Effect size does matter: The long road to mechanistic insight from genome wide association.

Circulation 2015;132:1943–5.

9.

145

28/11/2015 12:20

Arrhythmia Mechanisms

The Role of MicroRNAs in Antiarrhythmic Therapy for Atrial Fibrillation Sebastian Clauss, 1,2,3 Moritz F Sinner, 2 Stefan Kääb, 2,3 and Reza Wakili 2,3 1. Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, US; 2. University Hospital Munich, Ludwig-Maximilians University Munich; 3. DZHK (German Centre for Cardiovascular Research), Partner Site Munich, Germany

Abstract Atrial fibrillation (AF) is the most common arrhythmia worldwide and has an enormous impact on our healthcare system as it is a major contributor of morbidity and mortality. Although there are several therapeutic options available, treatment of AF still remains challenging.

AF pathophysiology is complex and still incompletely understood. In general, our understanding of AF is based on two mechanistic paradigms as functional hallmarks of AF: ectopic activity and reentry. Both ectopic activity and reentry are the result of remodelling processes. Functional and/or expressional changes in ion channels, connexins or calcium-handling proteins are important factors in electrical remodelling, whereas signalling processes leading to atrial dilatation and atrial fibrosis are key factors of structural remodelling.

In recent years, new intriguing key players in AF pathophysiology have been identified: microRNAs (miRNAs). MiRNAs are short, non-coding RNA fragments that can regulate gene expression and have been demonstrated as important modifiers in signalling cascades leading to electrical and structural remodelling. In this article we review the miRNA-mediated molecular mechanisms underlying AF with special emphasis on the perspective of miRNAs as potential therapeutic targets for AF treatment.

Keywords Atrial fibrillation, arrhythmia, microRNA, remodelling, therapeutics, antagomiR, miRNA-sponge, miRNA-eraser, miR-mask, miR-mimic Disclosure: The authors have no conflicts of interest to declare.

Received: 13 July 2015 Accepted: 23 October 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(3):146–55. Access at: www.AERjournal.com Correspondence: Reza Wakili, Marchionistraße 15, 81377 München, Germany; E-mail: reza.wakili@med.uni-muenchen.de

Support: Dr Clauss has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement No PIOF-GA-2012-328352. Dr Clauss, Dr Wakili and Dr Kääb were supported by the German Centre for Cardiovascular Research (DZHK). Dr Wakili, Dr Sinner and Dr Kääb received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 633193” [CATCH ME].

Atrial fibrillation (AF) is the most common arrhythmia experienced in clinical practice, and is responsible for significant morbidity and mortality.1 It affects more than 6 million people in Europe.1 The lifetime risk of developing AF after the age of 40 is approximately 25 %.1 AF is a major public health burden as it is associated with an increased risk of stroke by fivefold, dementia by twofold, heart failure by threefold and mortality by twofold.1,2 Current therapeutic options include non-invasive treatment using antiarrhythmic agents and invasive methods using catheter ablation.3,4 Although several improvements have been achieved, challenges still remain. Pulmonary vein isolation is now an established treatment, especially for patients with paroxysmal AF, but success rates (freedom from AF) in persistent AF are still insufficient.3,5,6 To further improve AF treatment, mechanisms underlying AF initiation and maintenance have to be further elucidated to better enable identification of the most suitable treatment strategy for each individual patient (in terms of drug toxicity, freedom of AF symptoms and improved quality of life) and recognition of patients at high risk for AF. In recent years our understanding of AF pathophysiology has markedly improved by the identification of key players in cardiovascular signalling: microRNAs (miRNAs).7 We will provide a comprehensive overview of the role of miRNAs in AF and their potential therapeutic implications.

146

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Pathophysiology of Atrial Fibrillation The pathophysiological basis of AF is multifactorial and complex.8,9 Electrophysiological hallmarks of AF are ectopic activity and reentry as the functional surrogates for trigger and susceptible substrate.

Underlying molecular mechanisms include changes in expression and function of ion channels, altered calcium homeostasis, enhanced atrial automaticity, alterations in gap junction distribution, and adverse effects on atrial integrity such as dilatation, fibrosis or inflammation.

These mechanisms are summarised as electrical and structural remodelling, and will be described here briefly.

Three main mechanisms causing focal ectopic activity are: enhanced atrial automaticity, early afterdepolarisations and delayed afterdepolarisations. Under normal physiological conditions, generation and conduction of electrical impulses in the heart is implemented by a characteristic sequence of voltage changes driven by depolarising and repolarising ion currents. Cardiomyocytes display a resting membrane potential of around -80 mV. An electrical impulse causes a swift depolarisation by rapidly activated sodium channels with subsequent influx of sodium ions. Following this, potassium ions exit the cell through potassium channels, initiating the repolarisation of the cell (re-establishing the resting membrane potential). Simultaneously, calcium ions enter the cell leading to cell contraction (excitation– contraction coupling) and slowing of the repolarisation.

© RADCLIFFE CARDIOLOGY 2015

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The Role of MicroRNAs in Antiarrhythmic Therapy for Atrial Fibrillation

In healthy hearts the sinus node dominates the generation of electrical signals. However, it is possible that a cell outside the sinus node reaches the threshold potential earlier resulting in ectopic firing at a more rapid rate, potentially leading to atrial tachycardia. In this regard alterations of the cellular calcium homeostasis may play an important role as has been demonstrated in animal models and patients with AF.9 Delayed afterdepolarisations result from an abnormal calcium leak from the sarcoplasmatic reticulum (SR). Physiologically, cellular calcium is removed by the SR Ca2+ATPase (SERCA) and the Na+–Ca2+ exchanger (NCX) during diastole to re-establish ionic homeostasis at the end of the cardiac cycle. During atrial tachycardia, however, calcium is progressively accumulated in the cell because of repetitive activation of the L-type Ca2+ channel. This Ca2+ overload leads to multiple maladaptive alteration, for example, a Ca2+ overload of the SR with concomitant dysfunction of the ryanodine receptor (SR calciumrelease channel). This distribution of the SR regulation can cause spontaneous diastolic Ca2+ release from the SR during diastole, which then can activate the electrogenic NCX (Ca2+ versus 3 Na+) causing a depolarising inward current (delayed afterdepolarisation). This leads to a progressive depolarisation of the cell and ectopic firing (when the threshold potential is reached; so-called triggered activity).10–12 Early afterdepolarisations occur when the action potential duration (APD) is excessively prolonged, for example, in the context of arrhythmia syndromes such as long-QT syndrome.9,11,12 In this setting, another phenomenon called dispersion of repolarisation has been described.

In healthy myocardia, a more or less homogeneous-organised repolarisation prevents onset of arrhythmia; in diseased myocardium, however, a vulnerable substrate can be created by heterogeneous electrophysiological properties due to remodelling processes. This may be caused by transmural APD variations within the 3D myocardial structure. These changes causing electrophysiological heterogeneity can result in proarrhythmic repolarisation differences predisposing to the initiation of arrhythmias. Pacemaker cells express specific ion channels (funny channels) that are responsible for the so-called automaticity (i.e. the progressive diastolic depolarisation). Therefore, an upregulation of these ion channels, as seen in heart failure, could be a possible mechanism leading to enhanced automaticity.13 Another hallmark of AF is reentry that can occur when at least two (functionally or anatomically) distinct pathways, a unidirectional block in one of the pathways and a slowed conduction, are present. In this case the conduction time along the unblocked pathway must exceed the refractory period of the blocked pathway (conduction time x reentry circle length > refractory period). In healthy myocardia, the electrical properties are relatively homogeneous without slow conduction areas preventing the occurrence of reentry. In diseased myocardia, however, two mechanisms are important: altered electrical properties that cause a shortening of the refractory period or conduction slowing, and structural changes (e.g. atrial fibrosis) that disturb the uniform and homogeneous excitation and thereby provide an anatomical substrate for reentry. In a healthy heart, reentry cannot occur because cardiomyocytes display a certain refractory period that prevents premature stimuli to conduct. When the refractory period is shortened, however, the cell is excitable earlier, ectopic activity can be conducted and reentry can be initiated. Additionally, slowed conduction velocity can also allow reentry because cells are excitable again when the impulse arrives. Structural changes in the atrium such as dilatation and fibrosis extend conduction pathways, slow conduction and create conduction barriers favouring initiation and maintenance of reentry circuits. Interestingly, some of the electro-

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anatomical changes implicated in AF pathophysiology initially act as a protective mechanism of the cell, but finally result in a fixed substrate for AF maintenance. Atrial tachycardia (as seen in AF) causes a cellular calcium overload. To reduce the calcium influx and to antagonise the calcium overload, the calcium current is reduced (by inactivation of calcium channels (short-term effect) and reduced gene expression of the calcium channels (long-term effects), leading to a shortening of the action potential. This favours reentry and therefore contributes to AF maintenance (‘AF begets AF’).14

MicroRNAs as Novel Regulators of Cardiac Arrhythmogenic Remodelling In 1993 it was discovered that development of Caenorhabditis elegans is regulated by a short RNA fragment named Lin-4 that inhibits the expression of lin-14 by binding to the 3’ untranslated region of its mRNA.15,16 In the following years, these miRNAs were identified as key players in molecular signalling leading to disease. Although other noncoding RNA species have been discovered so far,17,18 we will focus on miRNAs in this review.

For a detailed description, especially of miRNA biogenesis we refer to previously published reviews.19–22 Briefly, miRNAs are short (approximately 22 base pairs), single-stranded, non-coding RNAs that regulate post-transcriptional gene expression. MiRNAs can induce down- and upregulation of genes either by direct inhibition of their target mRNA (causing direct downregulation of their target gene) or inhibition of an endogenous antagonist of another gene (causing indirect upregulation of a gene dependent on the miRNA’s target gene). MiRNAs are broadly conserved among species; to date, thousands of miRNAs have been discovered in plants, insects and mammals. According to the latest release of the online database miRBase (version 21.0, June 2014) 2,588 mature miRNAs have been identified in humans.23 Each miRNA can act on several target genes and each gene can be affected by several miRNAs. This complex regulatory network results in up- and downregulation of agonists and antagonists at the same time leading to the idea of miRNAs as fine tuners of gene expression.24 Experiments on genetic ablation of the enzyme dicer that is one of the key enzymes in miRNA biogenesis, revealed the crucial role for miRNAs in normal development as mice and zebrafish with dicer knockout are not viable.25 A cardiac-specific knockout of dicer in mice also resulted in premature lethality due to cardiac dilatation and heart failure.26 Finally, dicer is essential even in the adult organism as shown by da Costa Martins et al., who demonstrated that a reduced cardiac dicer activity leads to increased incidence of sudden cardiac death, cardiac hypertrophy and expressional switch from an adult to a fetal gene expression programme.27 These studies offered compelling evidence that microRNAs play an important role in normal cardiac development and disease.26,27 Therefore, a growing number of studies has been published evaluating the role of miRNAs in cardiac electrical and structural remodeling, potentially contributing to the initiation and maintenance of AF pathophysiology. 7,9

miRNAs Involved in Electrical Remodelling MiRNAs involved in cardiac electrical remodelling are miR-1, miR-26, miR-208a, miR-328 and miR-499 (Table 1, Figure 1). Their target genes are encoding ion channels, connexins or proteins involved in calcium

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Arrhythmia Mechanisms Table 1: MiRNAs Involved in Cardiac Electrical Remodelling MiRNA

Up- /

Species

Model/tissue

Target

downregulation Mir-1

Downregulation

Potential arrhythmogenic effect

References

Upregulation of Kir2.1 (subunit of IK1) => APD

29

gene(s) Human

KCNJ2

AF patients; left atrial tissue

shortening Upregulation

Human

KCNJ2

Ventricular tissue from explanted hearts

Downregulation of Kir2.1 (subunit of IK1) => APD

30

prolongation => early afterdepolarisations

Upregulation

Rat

Myocardial infarction model;

Upregulation

Rat

Neonatal ventricular cardiomyocytes

Upregulation

Human

Ventricular tissue from explanted

ventricular tissue

GJA1

hearts Upregulation

Rat

Downregulation of Cx43 => atrial conduction

30

slowing

Myocardial infarction model; ventricular tissue

Upregulation

Rat

Neonatal ventricular cardiomyocytes

Upregulation

Guinea pig

Treatment with arsenic trioxide for

KCNJ2

7 days Upregulation

Rat

Downregulation of Kir2.1 (subunit of IK1) => APD

37

prolongation => early afterdepolarisations B56a

Ventricular cardiomyocytes

Downregulation of PP2A =>

32,33

hyperphosphorylation of ryanodine receptors Upregulation

Dog

Chronic heart failure model (ventricular tachypacing); cardiomyocytes

Upregulation Mir-26

Downregulation

Rabbit Dog

Right atrial tachypacing

KCNE1,

Downregulation of potassium channel subunits

KCNB2

=> shortening of the atrial ERP

KCNJ2

Chronic heart failure model (ventricular tachypacing); atrial tissue

Downregulation

Human

AF patients; right atrial tissue

Mir-106b-25 Downregulation

Human

AF patients; right atrial tissue

35

shortening

RYR2

cluster

Mir-133

Upregulation of Kir2.1 (subunit of IK1) => APD

31

Increased activity of ryanodine receptors =>

36

calcium leak Downregulation

Mouse

MiR-106b-25-knockout model

Upregulation

Guinea pig

Treatment with arsenic trioxide for

ERG

Downregulation of ether-a-go-go (subunit

37

of IKr) => APD prolongation => early

7 days

afterdepolarisations Upregulation

Dog

B56d

Chronic heart failure model (ventricular tachypacing);

Downregulation of PP2A =>

33

hyperphosphorylation of ryanodine receptors

cardiomyocytes Mir-208

Upregulation

Mouse

GJA5

Transgenic overexpression model

Downregulation of Cx40 => atrial conduction

40

slowing Mir-328

Upregulation

Dog Human

Right atrial tachypacing model; left

CACNA1A, Downregulation of the L-type calcium

atrial tissue

CACNB1

channel => APD shortening

KCNN3

Unknown mechanism

42

AF patients; rheumatic heart disease; atrial tissue

Mir-499

Upregulation

Human

AF patients; right atrial tissue

44

APD = action potential duration; Cx43 = connexin-43; Cx40 = connexin-40; ERP = effective refractory period; miRNA = microRNA; PP2A = protein phosphatase 2A.

signalling resulting in conduction slowing or shortening of the action potential duration, which are hallmarks of AF pathophysiology.

miR-1

tachystimulation of atrial tissue resulted in downregulation of miR-1 and upregulation of Kir2.1 protein and IK1 density. An increased IK1 density is associated with a shortening of the APD and could therefore enable reentry and AF maintenance.

MiR-1 and miR-133 are muscle-specific (skeletal and heart) miRNAs that are expressed from bicistronic clusters and, therefore, are among the most abundant miRNAs in the heart.28 Girmatsion et al. showed that miR-1 is downregulated in the heart of patients with persistent AF compared with patients with sinus rhythm.29 They demonstrated that this downregulation of miR-1 is accompanied by a significant upregulation of its target gene KCNJ2 that encodes Kir2.1, the subunit of the inward rectifier potassium channel IK1. Additionally, they showed that an ex vivo

Yang et al. indicated another role for miR-1 in arrhythmogenesis as they confirmed KCNJ2 as an miR-1 target gene, but also identified GJA1 as an additional target gene that encodes connexin-43.30 They performed a miR-1 overexpression in an ischaemic rat model (which is in contrast to the miR-1 downregulation in patients with AF).

Overexpressing miR-1 in the rat model led to downregulation of KCNJ2 and GJA1 resulting in APD prolongation and conduction slowing.

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Figure 1: Schematic Overview of Potential Therapeutic Interventions Modulating miRNAs Involved in AF Pathophysiology.

Electrical remodelling Ca

DADs

2+

Depolarisation

NCX

Potential therapeutic interventions modulating AF-relevant miRNAs

Na+ Na+ Na+

Diastolic Ca2+ leak

Ca2+

Intramuscular or systemic injection

P

P

MiR-133

Hyp e MiR-1 phos rphory latio n B56α

RYR2

AntagomiRs, LNAs, miRNA sponges/ erasers, miR-masks, miRNA mimics

PP2A B56δ

SR

APD shortening Structural remodelling

Atrial fibrosis

Angiotensin II

MiR-590

MiR-133

MiR-21

Spry1

MAK/ERK signaling

ISK

KCNN3

FBN1

MiR-499

PTEN

MMP2

IKs/IKr

SK3 channel

Y

MiR-29b

MiR-26

TRPC3 channel

TR

N

COL1A2

REE

Extracellular matrix ECM deposition

AT1 receptor TGFβ receptor profibrotic profibrotic signalling signalling COL1A1

AF begets AF

MiR-30 CTGF

TGFβ

TOPY EC

MiR-133 MiR-133

Enhanced ECM turnover

IK1

IcaL

Inward rectifier K+ channels

L-Type CA2+ channels

KCNE1 KCNJ2 KCNB2 KCNH2

CACNA1C CACNAB1

MiR-1

MiR-1 MiR-133

MiR-328

MiR-26

Reduced conduction velocity

MiR-21

Fibroblast proliferation MiR-1 MiR-208a

Decreased miRNA enhancing target protein expression

Cx43

Increased miRNA inhibiting target protein expression

Cx40

Gap junctions APD = action potential duration; DAD = delayed afterdepolarisation; ECM = extracellular matrix; LNA = locked nucleic acid; miRNA = microRNA; SR = sarcoplasmatic reticulum. Figure shows key aspects of structural and electrical remodelling resulting in ectopy and reentry and ultimately leading to a vicious circle of ‘AF begets AF’. Syringes illustrate miRNAs that were targeted in vivo by antagomiRs, LNAs, miRNA sponges/erasers, miR-masks or miRNA mimics.

In 2013, Jia and colleagues published a study evaluating the role of miR-1 in rabbits.31 They performed right atrial tachypacing in rabbits for 1 week resulting in increased inducibility of AF due to a shortening of the atrial effective refractory period and an increase in the slowly activating delayed rectifier potassium current (IKs). They found an upregulation of miR-1 paralleled by a downregulation of KCNE1 (coding for the voltage-gated potassium channel subfamily E member 1, minK) and KCNB2 (coding for the voltage-gated potassium channel subfamily B member 2, Kv2.2). Using anti-miR-1 inhibitor oligonucleotides, they rescued the phenotype and prevented expressional changes of miR-1, KCNE1 or KCNB2.

reduced/enhanced AF vulnerability was observed in miR-26 overexpression/knockdown.

Additionally, miR-1 is implicated in playing a role in calcium homeostasis.

In rat cardiomyocytes, Terentyev et al. induced an overexpression of miR-1 resulting in downregulation of its target B56a, a regulatory subunit of the protein phosphatase 2A (PP2A).32 PP2A now dissociates from the ryanodine receptor leading to hyperphosphorylation of this calcium channel. Hyperphosphorylated ryanodine receptors show arrhythmogenic spontaneous calcium release that can cause afterdepolarisations.32,33

miR-133

miR-26 MiR-26 has also been shown to regulate gene expression of KCNJ2.34,35 In a canine AF model and in human atrial samples, miR26 is downregulated while Kir2.1 is upregulated. Overexpression of miR-26 resulted in suppressed KCNJ2 expression, miR-26 knockdown resulted in enhanced KCNJ2 expression. These results were confirmed in a mouse model performing virus-induced miR-26 overexpression and miR-mask induced miR-26 knockdown:35

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miR-106b-25 cluster Recently, Chiang and colleagues identified the miR-106b-25 cluster (miR-25, miR-93 and miR-106b) as mediators of electrical remodelling.36 They showed a downregulation in the atria of patients with AF and found an increased susceptibility for AF in miR-106b-25-knockout mice due to increased SR calcium release (SR calcium leak) mediated by an enhanced ryanodine receptor expression (which is the confirmed target gene of miR-93).

Shan and colleagues evaluated the role of miR-133 on the QT interval in a guinea pig model.37 An upregulation of miR-133 resulted in significantly decreased protein levels of ERG, a subunit of the potassium channel responsible for the delayed rectifier potassium current Ikr, accompanied by a prolonged QTc interval and increased mortality rates. These findings were reproduced by direct application of miR-133 while miR-133 blockade using an antisense inhibitor abolished the effects. Interestingly, they also confirmed previous results of miR-1 in their model (upregulation of miR-1, downregulation of Kir2.1 protein).37 Matkovich et al. generated a miR-133 overexpressing mouse that displayed QT/APD prolongation and a reduced outward potassium current Ito,f.38 Although they could measure a reduced expression of the Ito,f subunit KCNIP2, they did not validate this gene as a miR-133 target.

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Up- /

Species

Model/tissue

Target gene(s)

Potential arrhythmogenic effect

References

Mouse

3 heart failure models (b1-adrenergic

spry1

Sprouty-1 ↓ => reduced antagonism

46

downregulation Mir-21

Upregulation

receptor transgenic; TAC;

against ERK–MAP kinase => fibroblast

isoproterenol treated); LV tissue

survival ↑ => cardiac fibrosis

Upregulation

Rat

Neonatal cardiac fibroblasts

Upregulation

Human

AF patients, left atrial tissue

spry1

Sprouty-1 ↓ => reduced antagonism

48

against ERK–MAP kinase => fibroblast survival ↑ => cardiac fibrosis Upregulation

Rat

Neonatal fibroblasts treated with

Upregulation

Mouse

Rac1 knockout (developing AF);

Upregulation

Rat

Ischaemic heart failure model;

Ang II /CTGF atrial tissue spry1

Dog

49

survival ↑ => cardiac fibrosis

left atrial tissue Upregulation

Sprouty-1 ↓ => reduced antagonism against ERK–MAP kinase => fibroblast

induction of AF during EP study; Ventricular tachypacing model;

COL1A1,

Extracellular matrix proteins ↑, matrix

left atrial tissue

COL3A1,

metalloproteinases ↓ => atrial fibrosis

51

FBN1, MMP2 Upregulation

Dog

Ventricular tachypacing model; atrial fibroblasts

Upregulation

Pig

Ischaemic heart failure model;

Not

induction of AF during EP study;

evaluated

Not yet evaluated

52

PTEN ↓ => MMP2 ↑ => enhanced matrix

47

right atrial tissue Upregulation

Mouse

Ischaemic heart failure model;

PTEN

ventricular tissue Mir-26

Downregulation

Dog

Ventricular tachypacing model;

turnover TRPC3

left atrial tissue

TRPC3 ↑ in fibroblasts => fibroblast

34

proliferation/differentiation ↑, extracellular matrix ↑

Mir-29b

Downregulation

Dog

Isolated atrial fibroblasts

Downregulation

Mouse

Ischaemic heart failure model;

COL1A1,

LV tissue

COL1A2,

Extracellular matrix proteins ↑

53

Extracellular matrix proteins ↑

54

Suggesting a fine-tuning effect to attenuate

52

COL3A1, FBN1, ELN1 Downregulation

Dog

Ventricular tachypacing model;

COL1A1,

left atrial tissue

COL1A2, COL3A1, FBN1

Downregulation

Human

AF patients, right atrial tissue

Downregulation

Human

AF patients, plasma

Upregulation

Pig

Ischaemic heart failure model;

Not evaluated

the effects of other upregulated profibrotic

induction of AF during EP study;

miRNAs

right atrial tissue Downregulation

Rat

LV hypertrophy model (Ang II

COL1A1

Collagen ↑ => fibrosis

56

CTGF

Profibrotic CTGF ↑ => extracellular matrix

55

treatment 4 weeks) Mir-30

Downregulation

Rat

Transgenic Ren-2 model; ventricular tissue

Downregulation

Mouse

TAC model; ventricular tissue

Downregulation

Human

Patients with aortic stenosis

proteins ↑ => fibrosis

and LV hypertrophy; left ventricular tissue Downregulation

Rat

Transgenic Ren-2 model; ventricular cells

Downregulation Downregulation

Dog Dog

Ventricular tachypacing model;

COL1A1, COL3A1, Extracellular matrix proteins ↑ =>

left atrial tissue

FBN1, MMP2

atrial fibrosis

Not evaluated

Atrial fibrosis

51

Ventricular tachypacing model; atrial fibroblasts

Downregulation

Dog

LSPV tachypacing model;

57

atrial tissue

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Table 2 continued: MiRNAs Involved in Cardiac Structural Remodelling MiRNA

Up- /

Species

Model/tissue

Target gene(s)

Potential arrhythmogenic effect

References

COL1A1

Collagen ↑ => fibrosis

56

downregulation Downregulation

Mouse

TAC model; ventricular tissue

Downregulation

Human

Patients with aortic stenosis and

Downregulation

Rat

Transgenic Ren-2 model; ventricular

Downregulation

Rat

LV hypertrophy model (Ang II

LV hypertrophy; LV tissue cells treatment 4 weeks) Downregulation Downregulation

Dog Dog

Ventricular tachypacing model;

COL1A1, COL3A1, Extracellular matrix proteins ↑ => atrial

left atrial tissue

FBN1, MMP2

fibrosis

TGF-β1

Profibrotic TGF-β1 ↑ => collagen ↑ => atrial

51

Ventricular tachypacing model; atrial fibroblasts

Downregulation

Dog

Nicotine treatment for 30 days;

37

fibrosis

induction of AF during EP study; right atrial tissue Downregulation

Dog

Cardiac fibroblasts isolated from right atrium after nicotine treatment

Downregulation

Human

AF patients; smokers versus nonsmokers; right atrial tissue

Downregulation

Dog

LSPV tachypacing model;

Not evaluated

Atrial fibrosis

57

Myocardial infarction model;

PPP3CA,

Collagen content ↑ => fibrosis

58

ventricular tissue

PPP3CB

Nicotine treatment for 30 days;

TGF-βRII

atrial tissue Mir-499 Mir-590

Downregulation Downregulation

Mouse Dog

Profibrotic TGF-βRII ↑ => collagen ↑ => atrial 37 fibrosis

induction of AF during EP study; right atrial tissue Downregulation

Dog

Nicotine treatment for 30 days; induction of AF during EP study; cardiac fibroblasts isolated from right atrium

Downregulation

Human

AF patients; smokers versus nonsmokers; right atrial tissue

Ang II = angiotensin II; CTGF = connective tissue growth factor; EP = electrophysiology; LSPV = left superior pulmonary vein; LV = left ventricular; miRNA = microRNA; MMP2 = matrix metalloproteinase 2; PTEN = phosphatase and tensin homologue; Rac1 = Ras-related C3 botulinum toxin substrate 1; TAC = transaortic banding; TGF-b1 = transforming growth factor b1; TRPC3 = transient receptor potential cation channel, subfamily C, member 3.

Belevych et al. recently published a study in a canine model of heart failure.33 They demonstrated that miR-133 is upregulated leading to downregulation of its target gene B56d, a catalytic subunit of PP2A with similar effects as B56a (that is downregulated as a target gene of miR-1, see above).

miR-208a MiR-208 is an interesting miRNA as the two isoforms (miR-208a and miR-208b) are differentially expressed during cardiogenesis.39 MiR208a is encoded within an intron of the α-cardiac muscle myosin heavy chain gene MYH6 (adult isoform), whereas miR-208b is encoded within an intron of the β-cardiac muscle myosin heavy chain gene MYH7 (fetal isoform). MiR-208 isoforms are expressed along with their host genes: miR-208b is expressed during cardiogenesis while miR208a is expressed in adult hearts. Interestingly, pathological cardiac remodelling is associated with the induction of a fetal gene expression pattern with re-expression of MYH7 and, therefore, miR-208b.40,41 To evaluate miR-208 in cardiac remodeling, Callis et al. performed an overexpression of miR-208a in a mouse model and observed an increased vulnerability towards arrhythmias. 40 They demonstrated that miR-208 targets GJA5 encoding the cardiac gap junction protein

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connexin-40 and therefore mediates pro-arrhythmogenic remodelling by altering gap junction expression.

miR-328 Another miRNA involved in calcium signalling is miR-328. It is upregulated in atrial tissue of patients with AF and in a canine AF model.42 CACNA1C and CACNB1, subunits of the L-type calcium channel, were identified as target genes of miR-328. In the canine model, an adenovirus-induced miR-328 overexpression caused reduced L-type calcium current and APD shortening and increased AF vulnerability. Knockdown of miR-328 with an antagomiR reversed these effects suggesting a potential role for miR-328 in cardiac electrical remodelling via the L-type calcium channel.

miR-499 KCNN3 encodes the calcium-activated potassium channel 3 (SK3) and is potentially involved in AF pathophysiology as common genetic variants within this gene are associated with AF.43 Recently, Ling and co-workers reported that miR-499 was elevated in human atrial tissue; SK3 protein expression, however, was downregulated.44 Finally, they provided evidence of a direct interaction between miR-499 and KCNN3

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Arrhythmia Mechanisms Table 3: In Vivo miRNA Manipulation in the Context of AF MiRNA

Species/model

MiRNA manipulation

Mir-1

Rabbit ± RA tachypacing

Overexpression: lentivirus construct containing mir-1 precursor sequence Direct i.m. Injection into RA

Route of administration

Knockdown: lentivirus construct containing anti-mir-1 oligonucleotide

References 31

Direct i.m. Injection into RA

sequence Mir-21

Rat ± myocardial infarction

Mir-21 Mir-26

Knockdown: mir-21 antagomiR

Direct i.m. Injection into LA

49

Mouse ± myocardial infarction Knockdown: mir-21 antagomiR

Intravenous

48

Mouse (wild type)

Overexpression: adeno-associated virus containing mir-26a mimic

Intravenous

35

Knockdown: adeno-associated virus containing anti-mir-26a sequence

Intravenous

Target protection: adeno-associated virus containing KCNJ2 mask

Intravenous

Mir-29b

Mouse (wild type)

Knockdown: adeno-associated virus containing anti-mir-29b sponge

Intravenous

54

Mir-328

Dog ± RA tachypacing

Overexpression: adeno-associated virus containing mir-328 precursor

Direct i.m. Injection into RA

42

sequence Dog ± RA tachypacing

Knockdown: coinjection of mir-328 antagomiR

Direct i.m. Injection into RA

Mouse (wild type)

Knockdown: mir-328 antagomiR

Intravenous

i.m. = intramuscular; LA = left atrium; RA = right atrium.

by in vitro overexpression and knockdown experiments. However, the authors analysed only eight patients (four with AF, four without AF [controls]) and did not report any enhanced arrhythmogenity in vitro or in vivo. Thus, the functional role of SK3 channels in AF pathophysiology still remains unclear as overexpression of SK3 channels in mice did not result in development of AF, but in an increased incidence of sudden death due to bradyarrhythmias and heart block.45

MiRNAs Involved in Structural Remodelling MiRNAs involved in cardiac structural remodelling are miR-21, miR26, miR-29b, miR-30, miR-133 and miR-590 (Table 2, Figure 1). These miRNAs regulate genes encoding proteins that are involved in extracellular matrix turnover and pro- or antifibrotic signalling cascades leading to atrial fibrosis as the anatomical substrate for reentry.

miR-21 A first report of miR-21 being involved in profibrotic signalling was published by Thum et al. in 2008.46 In a murine heart failure model, they showed that miR-21 is upregulated mostly in cardiac fibroblasts.

By targeting sprouty homologue 1 (Spry1) miR-21 regulated the profibrotic ERK–MAP kinase signalling pathway. In vivo knockdown of miR-attenuates cardiac fibrosis and improves cardiac function.

In a mouse model of myocardial infarction (MI), miR-21 was upregulated leading to repression of the transcription factor phosphatase and tensin homologue (PTEN).47 This blockade results in an upregulation of matrix metalloproteinase 2 (MMP2) and an enhanced matrix turnover suggesting a role for miR-21 in ventricular remodelling.

Finally, miR-21 was detected to be upregulated in left atrial tissue of patients with AF.48 This was associated with reduced expression of Spry1 and increased expression of the profibrotic connective tissue growth factor (CTGF), lysyl oxidase and Rac1-GTPase, resulting in increased collagen content. Additionally, it could be shown in vitro that CTGF and angiotensin II induce an upregulation of miR-21. Finally, Adam and co-workers generated a Rac1-GTPase-knockout mouse and confirmed their previous results in that animal model suggesting a potential mechanism on the profibrotic action of angiotensin II via miR-21.

Cardin et al. showed that miR-21 is upregulated in an ischaemic heart failure model in rats.49 Again, Spry1 was confirmed as the miR-21

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target gene being downregulated. They injected a miR-21 antagonist directly into the left atria resulting in significant knockdown of miR-21, upregulation of Spry1, improvement of myocardial function, reduction of atrial fibrosis and, finally, reduced AF duration.

Our group evaluated the role of several miRNAs in atrial remodelling in a canine AF model, in which heart failure is induced by ventricular tachypacing, leading to a subsequent atrial remodelling with increased susceptibility for AF.50 We showed that tachycardiomyopathy is associated with a significant upregulation of extracellular matrix proteins (collagen-1, collagen-3 and fibrillin) and a downregulation of MMP2 in left atrial tissue as well as in cardiac fibroblasts.51 These changes were accompanied by increased atrial fibrosis and an upregulation of miR-21. Other miRNAs that are discussed in detail below (miR-29b, miR-30a, miR-133a) were decreased in our model.

Because tachycardiomyopathy is rare in humans we also established an ischaemic heart failure model in pigs to evaluate proarrhythmogenic atrial remodelling processes.52 We induced MI by balloon occlusion of the left anterior descending artery. After 4 weeks of reperfusion, pigs showed a significant heart failure phenotype (left ventricular [LV] pressure increased, LV ejection fraction reduced, LV angiography reduced), significant atrial fibrosis (left and right atria) and were more prone to AF than healthy control pigs (AF inducibility increased, AF burden increased, AF duration/induction increased). In our first analysis, we demonstrated a significant upregulation of miR-21, which accompanied the fibrotic remodelling of the atria.52 In summary, several reports provide consistent evidence regarding a potential role of miR-21 on atrial structural remodelling and AF pathophysiology.

miR-26 Besides its role in electrical remodelling (described above), miR-26 is also reported to be involved in structural remodelling.34 In the canine ventricular tachypacing (VTP) model, miR-26 was downregulated in fibrillating atria causing an upregulation of transient receptor potential cation 3 (TRPC3) channels. These TRPC3 channels have been shown to be expressed in cardiac fibroblasts regulating calcium influx, cell proliferation, extracellular signal-regulated kinase phosphorylation

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and α-smooth muscle actin protein expression. In vivo blockade of TRPC3 channels prevented the development of an AF substrate in the canine VTP model.

miR-29b In 2008 van Rooij et al. reported a downregulation of miR-29b in a mouse model of MI that was accompanied with increased fibrosis and an upregulation of extracellular matrix proteins as collagen, fibrillin and elastin.53 They could reproduced their results in vitro by miR-29b overexpression and knockdown, respectively.

Our group evaluated the role of miR-29b in atrial remodelling in the canine VTP model.50 After 24 hours of tachypacing, miR-29b was significantly downregulated in atrial tissue as well as in atrial fibroblasts and remained decreased throughout the time course (up to 2 weeks of ventricular pacing).54 Extracellular matrix proteins (collagen, fibrillin) were upregulated, atrial fibrosis was enhanced and the induced AF duration was significantly prolonged. Lentiviral miR-29b manipulation in fibroblasts mimicked the effects seen in the canine model: overexpression of miR-29b led to a downregulation and miR29b knockdown led to an upregulation of extracellular matrix proteins.

Interestingly, we confirmed these changes (miR-29b downregulation) in right atrial tissue of patients with AF.

Other miRNAs Involved in Structural Remodelling Duisters et al. analysed ventricular tissue from rats (hypertensioninduced heart failure model) and mice (transaortic banding [TAC] model), rat cardiac cells and human ventricular biopsy samples (patients suffering from aortic stenosis with LV hypertrophy versus patients who have had coronary artery bypass grafting without LV hypertrophy).55 Their results were consistent over species: miR30c and miR-133 were downregulated, whereas their target gene CTGF, a profibrotic mediator, was upregulated. In vitro manipulation achieving miRNA overexpression/knockdown confirmed their results and provided evidence for a potential role of these miRNAs in structural remodelling.

increased atrial fibrosis and AF vulnerability compared with healthy dogs. The profibrotic mediator transforming growth factor b 1 (TGFβ1) and the TGF-β receptor-II (TGF-βRII) were significantly upregulated, whereas miR-133 and miR-590 were downregulated in the right atrium.

They identified TGF-β1 as the target gene of miR-133 and TGF-βRII as the target gene of miR-590. In vitro manipulation confirmed their in vivo results (up-/downregulation of miR-133/miR-590 resulted in down-/ upregulation of TGF-β1/TGF-βRII/collagen). Finally, they examined right atrial tissue of AF patients and could show that miR-133/miR-590 were downregulated in smokers, suggesting a potential mechanism of the increased risk of AF in smokers.

MiRNAs as Potential Therapeutics The findings described above demonstrate compelling evidence that miRNAs are powerful factors in AF pathophysiology suggesting in vivo manipulation for AF treatment. So far, several options to agonise or antagonise miRNA effects were developed and successfully evaluated in vivo in AF-related animal models, as described above and summarised in Table 3.31,35,42,48,49,54 Overexpression of a miRNA that is downregulated in disease can be achieved by miRNA mimics. Mimics are synthetic double-stranded RNAs that are incorporated and processed by the cell-like endogenous miRNAs and therefore ‘mimic’ their effects.59 However, mimics are not tissue- or cell-type specific and can therefore create undesirable offtarget effects. This can be avoided by using cardiotropic adenoassociated virus-mediated miRNA transfer that has been shown for the treatment of heart failure in mice60 and cardiac hypertrophy in rats.61

Castoldi et al. injected angiotensin II in rats for 4 weeks resulting in significant hypertrophy and fibrosis.56 They showed a downregulation of miR-133 and miR-29b paralleled by upregulation of collagen-1. All the effects were abolished when rats were treated with irbesartan, suggesting a role for miR-133/miR-29b in angiotensin-II induced cardiac remodelling.

For antagonising a pathological miRNA upregulation, several knockdown approaches are available including anti-miRNA oligonucleotides (antagomiRs)62 or locked nucleic acid,63 miRNA sponges, erasers or masks. AntagomiRs are synthetic oligonucleotides with miRNAcomplementary sequences that bind to endogenous miRNAs competitively inhibit them to bind to their target genes. MiRNA sponges64,65 and erasers62 are sequences of multiple miRNA sequences incorporated into a vector (e.g. a [cardiotropic] virus). While sponges contain only the seed sequence and might therefore inhibit various miRNAs, erasers are complementary to specific miRNAs. MiR-masks, however, are single-stranded oligonucleotides that are complementary to a miRNA target sequence and can therefore specifically block single miRNA–mRNA interactions.35,66

Besides these studies on ventricular hypertrophy, our group identified an atrial downregulation of miR-30 and miR-133 in the canine VTP model accompanied by increased atrial fibrosis.51 This finding was confirmed by Li et al. who induced AF (without heart failure) in dogs by rapid pacing of the left superior pulmonary vein for 5 weeks.57

All potential therapeutic interventions are currently based on an intramuscular or systemic application of these agents in vivo. Figure 1 summarises the suspected mechanisms of miRNAs being involved in AF pathophysiology and illustrates potential interventions in order to interrupt the vicious circle of AF begets AF.

In an MI model in mice, Wang and co-workers observed a downregulation of miR-499 in the area at risk after ischaemia.58 For a further analysis, they produced a miR-499 transgenic mouse and observed improved cardiac function and reduced collagen content after MI. The catalytic subunits of calcineurin (PPP3CA, PPP3CB) were identified as target genes of miR-499. Further analysis revealed alterations in mitochondrial fission and apoptosis signalling as the potential mechanism underlying the miR-499 actions.

Future Directions and Clinical Perspective

Atrial remodelling was further investigated by Shan et al.37 They administered nicotine in dogs for 30 days resulting in significant

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MiRNA manipulation in animal models has been demonstrated as a potential therapeutic approach. A first clinical trial used miravirsen, an antagomiR of miR-122, on patients with chronic hepatitis C infection (HCV).67 In this Phase IIa multicentre trial the use of miravirsen was shown to safe and effective in 36 patients: 5 weekly injections resulted in a dose-dependent reduction of HCV RNA levels for 14 weeks without evidence of viral resistance. A follow-up study on their patient cohort could confirm the safety and effectivity of miravirsen.68 Furthermore, upcoming clinical trials targeting miRNAs have been announced in the context of kidney fibrosis and coronary artery disease.69,70

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Arrhythmia Mechanisms These initial data and upcoming trials in humans are promising and justify further evaluation of miRNA therapeutics in AF, too. Based on the available data and suggested mechanisms of atrial fibrosis by miRNA action one focus could be the prevention or inhibition of progression of atrial fibrosis by targeting extracellular matrix-relevant miRNAs (e.g. miR-21 or miR-29b).

However, several challenges remain including more detailed evaluation of underlying pathophysiological mechanisms, chemical optimisation of miRNA agents or refinement of drug delivery. Furthermore, miRNAs might also serve as diagnostic biomarkers for AF as shown in our study on miR-29b. We demonstrated a significant downregulation of miR-29b in the plasma of patients with persistent AF that was further aggravated in patients with AF and concomitant congestive heart failure.54 In case miRNAs could provide a representative biomarker for the existing structural changes or the predominant underlying pathophysiological mechanism this information could guide the choice of therapy in the individual patient.

In summary, progress in miRNA research has opened a window for establishing a new potential therapeutic intervention in the context of

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translational medicine. The future will show whether miRNAs can help to close the translational gap between underlying causes and specific treatment, which is currently thought to be one major problem in AF disease management.71 n

Clinical Perspective • MicroRNAs are mediators of electrical and structural remodelling leading to AF. • MicroRNA-related mechanisms can be targeted in vivo by antagomiRs, locked nucleic acids, miRNA-sponges/ erasers, miR-masks (inhibiting miRNA effects) or miR mimics (enhancing miRNA effects).

• A first clinical phase IIa trial using an antagomiR for treatment of hepatitis C demonstrated it to be safe and effective for treatment of human patients.

• Upcoming clinical trials will be targeting miRNAs in the context of kidney fibrosis and coronary artery disease.

• Targeting miRNAs in patients might be a novel therapeutic option for treatment of AF.

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30. Yang B, Lin H, Xiao J, et al. The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nature Med 2007;13:486–91.

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33. Belevych AE, Sansom SE, Terentyeva R, et al. MicroRNA-1 and -133 increase arrhythmogenesis in heart failure by dissociating phosphatase activity from RyR2 complex. PloS One 2011;6:e28324.

34. Harada M, Luo X, Qi XY, et al. Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation. Circulation 2012;126:2051–64.

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Clinical Arrhythmias

Nature and Nurture in Arrhythmogenic Right Ventricular Cardiomyopathy – A Clinical Perspective Cynthia A James Division of Cardiology, Johns Hopkins University, Baltimore, Maryland, US

Abstract Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterised by frequent ventricular arrhythmias and slowly progressive predominant RV dysfunction. Up to two-thirds of ARVD/C patients have mutations in genes encoding the cardiac desmosome. Mutations in other genes are increasingly recognised. Inheritance of ARVD/C is generally autosomal dominant with reduced age-related penetrance and significant variable expressivity. While the full explanation for this phenotypic heterogeneity remains unclear, there is increasing evidence that exercise plays a major role in disease penetrance and arrhythmic risk.

The disproportionate representation of athletes among ARVD/C patients has long been noted. Recently, the association of exercise with earlier onset and more severe arrhythmic and structural disease has been documented. This article reviews current evidence regarding the association of genotype, exercise and clinical outcomes and discusses the emerging paradigm in which genetic predisposition and environmental factors (exercise) interact around a threshold for phenotypic expression of ARVD/C.

Keywords Arrhythmogenic right ventricular dysplasia, exercise, desmosome, arrhythmogenic right ventricular cardiomyopathy, arrhythmia, genetics Disclosure: Cynthia A James receives salary support from investigator-initiated research grants from St Jude Medical and Boston Scientific Corp.

Acknowledgements: We are grateful to the ARVD/C patients and families who make this work possible.

Received: 16 September 2015 Accepted: 5 October 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(3):156–62. Access at: www.AERjournal.com Correspondence: Cynthia A James, Johns Hopkins ARVD Program, Carnegie 568D, 600 N Wolfe Street, Baltimore, Maryland, US 21287. E: cjames7@jhmi.edu

Support: Cynthia A James holds grants sponsored by the National Society of Genetic Counselors and the Barth Syndrome Foundation. The Johns Hopkins ARVD/C Program is supported by the Dr Francis P Chiaramonte Private Foundation, the Leyla Erkan Family Fund for ARVD Research, the Dr Satish Rupal and Robin Shah ARVD Fund at Johns Hopkins, the Bogle Foundation, the Healing Hearts Foundation, the Campanella family, the Patrick J Harrison Family, the Peter French Memorial Foundation and the Wilmerding Endowments.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a rare heritable cardiomyopathy characterised by fibro-fatty replacement of the myocardium, which predisposes patients to frequent lifethreatening ventricular arrhythmias and slowly progressive ventricular dysfunction.1,2 Structural involvement of the right ventricle (RV) generally predominates,3,4 although left dominant forms of ARVD/C are increasingly well-recognised.5 Patients typically present in their second to fifth decade with symptoms associated with ventricular arrhythmias and go on to have an arrhythmic disease course.6,7 Sudden cardiac death may be the first manifestation in up to 50 % of index cases.8 ARVD/C was first described in the modern scientific literature in 1982 in the seminal work of Frank Marcus and colleagues.9 In this initial description of 24 patients with ventricular arrhythmias and RV dysfunction from a French tertiary care centre, the authors speculated that ARVD/C resulted from a developmental abnormality of the RV musculature. Indeed, the original name – arrhythmogenic RV dysplasia – reflects this early interpretation. However, soon afterwards, threads of evidence implicating both inherited factors (nature) and exercise (nurture) in ARVD/C pathogenesis emerged. Clustering of ARVD/C within families was appreciated early.10 Investigators recognised the cardiac phenotype of a rare familial cardio-cutaneous condition, Naxos disease, overlapped with ARVD/C.11 The major discovery that

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homozygous mutations in junctional plakoglobin (JUP) were the genetic basis of Naxos disease in 2000,12 led to rapid identification of mutations in each of the desmosomal genes among ARVD/C patients.

Simultaneously, articles began appearing calling attention to the fact that many patients with ARVD/C were elite athletes13 and that athletic ARVD/C patients appeared to have a particularly high risk of sudden cardiac death.14,15 These early observations set the stage for research exploring the genetic basis of ARVD/C (nature) and the role of endurance exercise (nurture) in ARVD/C pathogenesis and clinical course. This article will review current evidence regarding the association of genotype, endurance exercise and clinical phenotype of ARVD/C patients and at-risk family members and discuss the emerging paradigm in which genetic predisposition and environmental factors (exercise) interact around a threshold for phenotypic expression of ARVD/C. Excellent reviews have recently been published describing current understanding of the molecular mechanism through which ARVD/C-associated mutations lead to disease.16,17 Thus, this paper will focus on evidence from clinical research and address three questions: 1) To what extent does genotype predict ARVD/C phenotype? 2) How is endurance exercise associated with ARVD/C phenotype and clinical course?

3) How do exercise and genotype interact in disease pathogenesis?

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Nature and Nurture in Arrhythmogenic Right Ventricular Cardiomyopathy

Nature – To what Extent does Genotype Predict ARVD/C Phenotype?

Genetic Basis of ARVD/C Following the landmark discovery in 2000 that mutations in JUP, which encodes plakoglobin, was the cause of Naxos disease,12 there was rapid discovery of ARVD/C-associated mutations in each of the desmosomal genes including DSP encoding desmoplakin,18 PKP2 encoding plakophilin-2,19 DSG2 encoding desmoglein-220 and DSC2 encoding desmocollin-2.21 Cardiac desmosomes are specialised adhesion junctions composed of a symmetrical group of proteins – the cadherins, the armadillo proteins and the plakins – that provide a mechanical connection between cardiac myocytes. It is now known that up to two-thirds of ARVD/C patients have mutations in genes encoding the cardiac desmosome,22 with heterozygous radical mutations in PKP2 most prevalent among the North American and most European populations.22,23 Inheritance of desmosomal mutations typically follows an autosomal dominant pattern with incomplete penetrance and variable expressivity. However, patients with multiple mutations (compound heterozygosity and digenic) are not uncommon.24 Cases with homozygous mutations and pedigrees more reminiscent of autosomal recessive disease also occur.25,26 The reported proportion of ARVD/C patients with multiple mutations ranges widely (4–21 %)23,27 and is likely related to how stringently missense variants are adjudicated.28 Although the vast majority of reported ARVD/C-associated mutations are desmosomal (95.5 % of mutations reported in the ARVD/C Genetic Variant Database),29 extradesmosomal mutations are being identified in an increasing minority of patients. The first of these was a founder mutation in transmembrane protein 43 (TMEM43) S358L discovered among families in Newfoundland, Canada.30 More recently, mutations have been reported in genes previously associated with other cardiomyopathies and arrhythmia syndromes including desmin (DES),31 titin (TTN),32 lamin A/C (LMNA),33 phospholamban (PLN)34 and Nav1.5 (SCN5A),35 the pore-forming subunit of the voltage-gated cardiac sodium channel. These findings likely reflect clinical overlap of ARVD/C with dilated cardiomyopathy at one phenotypic extreme36 and with arrhythmia syndromes associated with sodium channel dysfunction, particularly Brugada syndrome, at the other.17 Mutations in the CTNNA3 gene coding for α T-catenin protein in the ‘area composita’, (composed of both desmosomal and adherens junctional proteins), have also recently been shown to be associated with ARVD/C.37 Finally, mutations in transforming growth factor β3 (TGFβ3)38 and the cardiac ryanodine receptor-2 (RYR2)39 have been described, although the association of mutations in these genes with an ARVD/C phenotype have not been confirmed.

The increasing recognition of mutations in extradesmosomal genes among ARVD/C patients is largely the result of advances in geneticsequencing technology (next-generation sequencing). This technology allows for comprehensive sequencing at low cost with rapid turnaround. While identification of mutations in novel ARVD/C genes is useful for both scientific discovery and clinical management, it comes with challenges associated with interpretation of sequence results.

As increasing numbers of genes are sequenced in ARVD/C patients, increasing numbers of genetic variants with uncertain pathogenicity are revealed. Missense variants are a significant interpretive challenge.

It is important to realise that assessing pathogenicity of genetic variants should be performed with knowledge of the background ‘genetic noise’ in a healthy population. A study by Kapplinger et al.40

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focusing only on the desmosomal genes highlights the complexity.

In this study of 427 putatively healthy individuals, 16 % were found to carry a rare missense variant in the desmosomal genes. (In this study the authors considered each variant exclusively observed in ARVD/C patients but absent in a large, ethnically matched, control cohort a ‘mutation’.) A recently updated ARVD/C-specific genetic variant database (http://www.arvcdatabase.info) encompassing more than 1,400 variants collating published evidence is useful for interpretation.29 Recent recommendations for adjudication of genetic variants suggest increasingly stringent criteria be used.41 Finally, there remain many ARVD/C cases with no identifiable mutation. In the largest study of ARVD/C families to date, among 439 index cases ascertained through the Johns Hopkins and Dutch Interuniversity Cardiology Institute of the Netherlands (ICIN) ARVD/C Registries, 37 % had no identifiable mutation in the desmosomal genes, PLN or TMEM43.7 Of interest, among these cases without mutations, clear evidence of familial disease (meeting ARVD/C 2010 Family History Task Force Criteria)42 was present in only one-fifth.

This raises the question of whether the remaining 80 % of cases had ARVD/C caused primarily by genetic factors, a question we will return to in the latter part of the paper.

Association of Genotype with Clinical Characteristics Studies of the association of genotype with clinical ARVD/C phenotype are challenging due to broad clinical variability even within families who share both genotype and environment. However, clinically useful patterns of genotype/phenotype associations have begun to emerge. Broadly, the clinical course of ARVD/C does not differ substantially between ARVD/C index patients with and without identifiable mutations.7 As shown in Figure 1, regardless of mutation status, ARVD/C is a highly arrhythmic condition. Most index patients experience symptoms and sustained ventricular arrhythmias, but only a minority heart failure or transplant. The single exception to this pattern of overall similarity was that index patients with mutations had a significantly younger age of symptom onset and first ventricular arrhythmias than patients without mutations. This pattern of earlier onset is commonly seen when comparing strongly genetic forms of diseases with those with complex multifactorial inheritance.

In a pattern also observed among many genetic diseases, several groups of investigators have found that ARVD/C patients with more than one desmosomal mutation have worse phenotypes than patients with a single or no mutation. Rigato et al. observed increased penetrance and worse arrhythmic outcomes in 21 Italian carriers of multiple mutations in comparison to 113 carriers of single-desmosomal mutations.43 They showed that being a carrier of more than one mutation was the most significant risk factor for malignant arrhythmic events and sudden death in their population. In another study, a higher incidence of cardiogenic syncopal events occurred in multiple mutations carriers among a Chinese population of ARVD/C patients.27 Finally, in an analysis of 577 desmosomal, PLN and TMEM43 mutation carriers drawn from the Johns Hopkins and Dutch ARVD/C Registries, the 4 % of patients with multiple mutations had significantly earlier occurrence of sustained ventricular tachycardia/ventricular fibrillation, a lower rate of survival free from sustained ventricular arrhythmias and more frequent left ventricular (LV) dysfunction, Class C heart failure and cardiac transplantation.23 Taken together, these data suggest an effect of gene dosage on ARVD/C phenotype. Based on these data, more aggressive management of carriers of multiple mutations is indicated.

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Clinical Arrhythmias Figure 1: Survival Free from Any Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C)–related Symptoms, Sustained Ventricular Arrhythmias, Cardiac Death and Cardiac Transplantation in 439 ARVD/C Index patients (A) with Pathogenic and (B) without Identified Mutations 100

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Symptoms (p=0.005) and sustained ventricular arrhythmia (p=0.020) occurred significantly more often at younger age in index-patients with mutations. Survival free from cardiac death (p=0.644) and transplantation (p=0.704) was similar in both groups. Overall clinical course was similar. From Groeneweg et al., 2015.7 with permission.

There are also several clinically relevant associations between mutations in specific desmosomal genes and ARVD/C characteristics.

A higher prevalence of LV involvement occurs among carriers of DSP mutations. This association was initially recognised by Norman et al. among a British population of ARVD/C patients in 2005.44 Defects in the C-terminal of the protein were associated with early and predominant involvement of the LV and a high occurrence of sudden death.45 In a large study by Bhonsale et al.,23 DSP carriers experienced more than fourfold more LV dysfunction (40 %) and Class C heart failure (13 %) than their large group of PKP2 carriers. LV involvement is also more likely among cases with PLN mutations. (Most PLN carriers have the Dutch founder mutation c.40_42delAGA that has been identified in 13 % of ARVD/C index patients in the Netherlands).1 The TMEM43 S358L founder mutation most prevalent in Newfoundland is associated with very high disease penetrance and arrhythmic risk among male carriers in comparison to other ARVD/C patients.46

Incomplete Penetrance and Variable Expressivity While improved understanding of the genetic basis of ARVD/C has been helpful in diagnosing and managing patients, familial ARVD/C remains a clinically heterogeneous disorder characterised

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Nurture – How is Exercise Associated with Disease Onset and Clinical Course?

Influence of Exercise on Disease Expression The appreciation of the association of exercise and ARVD/C began with the twin observations that ARVD/C patients were frequently athletes and that arrhythmias occurred disproportionately during athletic activity in ARVD/C patients.13,15 A review of autopsies in the Veneto region of Italy showed participation in competitive athletics resulted in a more than fivefold increase in sudden cardiac death risk among young patients with ARVD/C.14 Consistent with

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by incomplete age-related penetrance and significant variable expressivity.47 With the expansion of genetic testing for ARVD/C and integration of genetic test results into the diagnostic criteria,42 clinicians are increasingly confronted with caring for at-risk mutation carriers. While the literature reports up to 83 % penetrance of desmosmal mutations (in Spanish carriers of a DSP c1339C>T mutation),48 this likely is an overestimate, or at least a ceiling. Families initially ascertained and enrolled in genetic research will have higher than typical penetrance as this is what makes them attractive for genetic studies. In the large report by Bhonsale et al. of over 500 desmosomal mutation carriers,23 roughly one-third met ARVD/C 2010 Diagnostic Task Force Criteria (TFC). When family members are diagnosed, they often have a milder course than probands.7 While the full explanation for this phenotypic heterogenity remains unclear, there is increasing evidence that exercise plays a major role in disease penetrance and arrhythmic risk.

this observation, implementation of a pre-participation screening programme resulted in a sharp decline in such deaths.49 The first observation that athletic involvement correlated with disease characteristics among living patients was by Sen-Chowdhry and colleagues who found that among a group of 116 ARVD/C patients, the 11 patients who participated in long-term endurance training had more severe RV dysfunction.45 During the past 2 years, research has accelerated with four clinical studies focused on addressing the extent to which exercise influences ARVD/C onset and disease course. These studies, reviewed below, make a compelling case that there is a dose-dependent relationship between exercise intensity and duration and disease severity.

The first study, published by James et al.,50 collected exercise history by interview from 87 carriers of heterozygous desmosomal mutations ascertained from the Johns Hopkins ARVD/C Registry. Endurance athletes were defined as participants in a sport with a high dynamic demand (>70 % Max O2), based on the 36th Bethesda Conference Classification of Sports (Task Force 8),51 for at least 50 hours/year at vigorous intensity.

The results of the study showed that both participation in vigorous endurance (aerobic) athletics and greater duration of annual exercise were associated with an increased likelihood of ARVD/C diagnosis in a dose-dependent fashion. Similarly, as shown in Figure 2, survival from first sustained ventricular arrhythmia and onset of Class C heart failure was worse among athletes. Furthermore, the study suggested that modifications in exercise following clinical presentation could alter clinical course. Mutation carriers who continued to participate in high duration exercise after clinical presentation had worse survival from first ventricular arrhythmia compared with individuals who reduced their exercise. Taken together these data suggested an important link between exercise and the outcomes of desmosomal mutation positive ARVD/C patients and family members.

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Next, the Johns Hopkins group confirmed the association of exercise with clinical course among 43 ARVD/C index patients without desmosomal, PLN or TMEM43 mutations. Patients were categorised as athletes using the same criteria previously described. Sawant et al.52 found that those participating in the highest intensity (MET-hours/ year) exercise prior to clinical presentation had earlier onset, worse RV structural abnormalities and poorer survival from ventricular arrhythmias in follow-up.

Finally, Ruwald et al. recently reported data from 108 probands ascertained in the North American ARVC registry.53 For this study patients self-reported whether they were inactive, recreational athletes or competitive athletes both prior to diagnosis and in follow-up. Similar to the findings of James et al., Sawant et al. and Saberniak et al., competitive athletes had a worse clinical profile with earlier symptom onset, and a worse survival from a combined ventricular tachyarrhythmia/death endpoint. They also noted that individuals who continued competitive exercise had a significantly worse arrhythmic course following diagnosis compared with those who reduced exercise, validating the initial findings of James et al.50 By contrast, the authors detected no differences in age of onset or risk of ventricular arrhythmias/death between patients who rated themselves as inactive versus recreational athletes. While these data are somewhat reassuring, some caution is warranted as close examination of the data shows recreational athletes had somewhat worse LV function than inactive patients. Additionally, age of symptom onset and survival from sustained ventricular arrhythmia among recreational athletes appears to be midway between the competitive athletes and inactive patients, albeit not significantly different.

Recent studies from model systems have also implicated exercise in ARVD/C pathogenesis. Murine ARVD/C models with abnormal expression of two different desmosomal proteins (plakoglobin and plakophilin-2)54,55 have both shown evidence of earlier development of disease and worse structural abnormalities when exposed to endurance training. The molecular mechanism of this process remains unclear. Recent evidence suggests while reduction of desmosomal protein expression causes decreased cell–cell adhesion, expression of mutant protein results in cells with typical mechanical properties but abnormal signalling responses to stress.56

Implications for Exercise Recommendations for ARVD/C Patients and Family Members Taken together these data convincingly argue that participation in vigorous or competitive endurance exercise leads to poor outcomes

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Figure 2: Cumulative Lifetime Survival Free from Sustained Ventricular Arrhythmia and Class C Heart Failure among 87 Desmosomal Mutation Carriers 1.0

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These findings were subsequently confirmed in both European and multicentre North American populations and in ARVD/C patients without desmosomal mutations. Saberniak and colleagues investigated the impact of exercise on myocardial function among 110 Scandanavian ARVD/C patients (both with and without desmosomal mutations) and mutation carrier family members.22 Data were again collected by interview. Exercise participation was measured by metabolic equivalent (MET)-minutes per week with patients participating in vigorous (≥6 METs) physical activity for ≥4 hours/week classified as athletes. The authors showed that athletes were more likely to meet diagnostic criteria, experience ventricular arrhythmias and progress to cardiac transplant.

Furthermore, they found that both RV and LV function were significantly reduced in athletes and that intensity of exercise was correlated with the extent of structural dysfunction in a dose-dependent fashion.

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Cumulative lifetime survival free of sustained ventricular arrhythmias (A) and stage C heart failure (B) stratified by participation in endurance athletics. Event-free survival from sustained arrhythmias and stage C heart failure is significantly lower among endurance athletes.

HF = heart failure; VT/VF = ventricular tachycardia/ventricular fibrillation (sustained ventricular arrhythmia). From: James et al., 201350 with permission.

in ARVD/C patients. A recent international expert consensus statement on the treatment of ARVD/C57 integrated these data and recommended that ARVD/C patients be restricted from competitive and/or endurance sports (Class I recommendation). Restriction from other athletic activities with the possible exception of recreational low-intensity sports was also recommended (Class IIa). These recommendations are generally concordant with existing professional recommendations from Europe and North America.58–60

ARVD/C Pathogenesis – How do Exercise and Genotype Interact in Disease Pathogenesis?

The research described establishes the role of both genetic predisposition and exercise in ARVD/C pathogenesis and course. Our understanding of how these factors interact remains incomplete. An emerging paradigm suggests there is a threshold for phenotypic expression of ARVD/C with the relative amount of exercise necessary to reach the threshold varying based on genotype.52,61 As shown in the schematic (see Figure 3), we hypothesise that individuals born with very high genetic risk, such as carriers of multiple mutations, require little (or perhaps no) exercise to promote ARVD/C onset. At the other end of the spectrum, a series of studies by Heidbüchel et al. suggests ultra-endurance athletes exposed to massive amounts of exercise may develop a predominantly exercise-induced form of ARVD/C.62 This hypothesis, first proposed in 2003, 63 was developed based on a clinical pattern of a high prevalence of RV arrhythmias and predominant RV dysfunction among high-level

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Clinical Arrhythmias Figure 3: Model of the Relative Influence of Exercise and Genetics in the Pathogenesis of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Desmosomal mutations-, FH+

Desmosomal mutations-, FH-

Ultraendurance athlete

Arrhythmia right ventricular dysplasia/cardiomyopathy Genetic

Exercise

FH: Meeting 2010 family history task force criteria

From: Sawant et al., 2014.52

endurance athletes referred for evaluation of palpitations and other arrhythmia-associated symptoms. Further support for this concept came from their observation that among 41 athletes with definite or probable ARVD/C, only six had a definite or possible desmosomal mutation and few had a family history of disease. 64 Furthermore, their mutation carriers had done significantly less exercise than the remaining cases suggesting less exercise was required for disease onset in the setting of a genetic predisposition.

Sawant et al. recently confirmed and extended these findings via a study of 82 index cases, half of whom carried a desmosomal mutation.52 All the patients without desmosomal mutations were athletes (≥50 hours/year participation in a sport with high dynamic demand at vigorous intensity) in comparison to two-thirds of mutation carriers.

Additionally, similar to the findings of Heidbüchel and colleagues, the patients without a desmosomal mutation had done considerably more intense exercise prior to clinical presentation. Sawant also found a relatively low prevalence of familial disease among cases without desmosomal mutations. Furthermore, as presented in Figure 4, gene-elusive cases with familial disease had performed exercise indistinguishable from that of desmosomal mutation carriers while the ARVD/C patients with neither a mutation nor a family history had done by far the most intense exercise.

While these studies suggest exercise plays a disproportionate role in the pathogenesis of ARVD/C cases without an apparent genetic predisposition, it is premature to conclude that this group of ARVD/C patients has an entirely acquired disease. In the study by Sawant et al., 10 % of cases with no identifiable mutation in the desmosomal genes, PLN or TMEM43 had clear evidence of familial disease by TFC. Second, ARVD/C is a rare disease (prevalence is estimated at 1/5,000)2 suggesting only a relatively small proportion of athletes are susceptible. One could speculate that this susceptibility stems from mutations in novel genes with lower penetrance or by combinations of rather low penetrant variants in both desmosomal and other genes. Other environmental factors as well as patient sex may also play a role.

Is there a Threshold for Safe Exercise for Desmosomal Mutation Carriers?

If, as the model suggests, exercise and genetic predisposition have an additive effect towards a threshold for ARVD/C pathogenesis, there may be a level of exercise at least some at-risk mutation carriers can participate in without triggering ARVD/C onset. Based on their finding of

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p=0.004 Median MET-hours/year before presentation

Desmosomal mutations+

Figure 4: Exercise Intensity Among 82 ARVD/C Index Patients Stratified by Genotype and 2010 Family History Task Force Criteria

6,000

6,711 n=39

4,000

3,041 n=4

2,000

0 Gene-elusive, no family history

3,184 n=15 2,424 n=23

Gene-elusive with Desmosomal, family history no family history

Desmosomal with family history

Gene‐elusive, non‐familial patients participated in significantly higher‐intensity exercise than those with family history or desmosomal mutations (p=0.004, Kruskal‐Wallis one‐way analysis of variance). MET = metabolic equivalent. From: Sawant et al., 2014.52

a dose–response relationship of exercise with the extent of LV and RV dysfunction, Saberniak and colleagues22 postulated that there may be no threshold value for recommendations for physical activity in at-risk mutation carriers to prevent negative effects on myocardial function.

However, given the indisputable benefits of exercise for overall health, complete exercise restriction in young, otherwise healthy mutation carriers is not without risk. Unfortunately, there are few clinical recommendations for appropriate exercise for at-risk carriers. The recent ARVD/C treatment consensus statement concludes only that restriction from competitive sports may be considered in healthy gene carriers (Class IIa).57 Therefore, we recently completed a study65 assessing a threshold for disease onset based on the American Heart Association (AHA) minimum recommended exercise (450–750 MET-minutes weekly)66 for maintenance of overall health in adults. In this study we interviewed members of families segregating heterozygous radical mutations in plakophilin-2. This study design allowed us to control for genotype and other genetic and environmental variables clustering in families as the interaction of exercise and genetic predisposition likely differs based on genotype.

Unsurprisingly, probands had done more exercise than family members and athletic family members had poor outcomes. However, family members who restricted exercise at or below the upper bound of the AHA minimum were significantly less likely to be diagnosed and had no sustained ventricular arrhythmias. (These family members were not sedentary; their median exercise was 80 % of the lower AHA bound.) Furthermore, when family members were diagnosed and had a first sustained ventricular arrhythmia they had accumulated 2.8and 3.5-fold, respectively, greater MET-hours exercise (from age 10) than the AHA-recommended minimum. By contrast, median exercise for family members who did not develop disease was close to the AHA recommended levels across the lifespan.

These results suggest that at least for many unaffected PKP2 carriers, the AHA-recommended minimum exercise level may fall below the

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threshold required to promote disease onset. This points to restricting these carriers from endurance and high-intensity athletics, but potentially not from AHA-minimum recommended levels of exercise for healthy adults. It is likely the threshold for healthy versus risky exercise will differ based on genotype and will almost certainly be much lower for carriers of multiple mutations. The findings also support the concept of the additive model of genetic predisposition and exercise intensity in ARVD/C pathogenesis. Future research to improve understanding of the interaction of genotype and exercise ‘dose’ as well as other environmental factors in triggering disease onset is key to improving care for families affected with ARVD/C. Additionally, improved understanding of the molecular mechanism through which exercise interacts with expression of abnormal protein or reduced protein expression to cause the pathological features of ARVD/C is critical. n

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Clinical Perspective • Carriers of multiple mutations typically have a more severe ARVD/C phenotype with more frequent and earlier onset arrhythmias, structural dysfunction, heart failure and need for transplant.

• DSP and PLN carriers are at significant risk of developing LV dysfunction.

Their risk is significantly higher than that of the large proportion of ARVD/C patients with PKP2 mutations for whom the risk is relatively low.

• The data support restricting ARVD/C patients from competitive, frequent, high-intensity exercise regardless of genotype.

• Unaffected PKP2 carriers of heterozygous mutations may be able to participate in exercise based on AHA-minimum guidelines for exercise in healthy adults, thus avoiding risks of a sedentary lifestyle so long as they are complying with regular ongoing clinical follow-up to detect any early signs of ARVD/C onset.

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Hariharan V, Asimaki A, Michaelson JE, et al. Arrhythmogenic right ventricular cardiomyopathy mutations alter shear response without changes in cell–cell adhesion. Cardiovasc Res 2014;104:280–9.

Corrado D, Wichter T, Link MS, et al. Treatment of arrhythmogenic right ventricular cardiomyopathy/dysplasia: An international task force consensus statement. Circulation 2015;132:441–53.

Maron BJ, Ackerman MJ, Nishimura RA, et al. Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome. J Am Coll Cardiol 2005;45:1340–5.

Pelliccia A, Corrado D, Bjornstad HH, et al. Recommendations for participation in competitive sport and leisure-time physical activity in individuals with cardiomyopathies, myocarditis and pericarditis. Eur J Cardiovasc Prev Rehabil 2006;13:876–85.

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Clinical Arrhythmias 60. Maron BJ, Chaitman BR, Ackerman MJ, et al. Working groups of the American Heart Association Committee on Exercise CR, Prevention, Councils on Clinical C and Cardiovascular Disease in the Y. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation 2004;109:2807–16.

61. La Gerche A. Defining the interaction between exercise and arrhythmogenic right ventricular cardiomyopathy.

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62. Heidbüchel H, Prior DL, La Gerche A. Ventricular arrhythmias associated with long-term endurance sports: what is the evidence? Br J Sports Med 2012;46(Suppl. 1):i44–50.

63. Heidbüchel H, Hoogsteen J, Fagard R, et al. High prevalence of right ventricular involvement in endurance athletes with ventricular arrhythmias. Role of an electrophysiologic study in risk stratification. Eur Heart J 2003;24:1473–80.

64. La Gerche A, Robberecht C, Kuiperi C, et al. Lower than expected desmsomal gene mutation prevalence in endurance athletes with complex ventricular arrhythmias

of right ventricular origin. Heart 2010;96:1268–74.

65. Sawant AC, Te Riele AS, Tichnell C,et al. Safety of American Heart Association Minimum Recommended Exercise for Desmosomal Mutation Carriers. Heart Rhythm 2015 doi: 10.1016/j.hrthm.2015.08.035 [Epub ahead of print].

66. Haskell WL, Lee IM, Pate RR, et al. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Med Sci Sports Exerc 2007;39:1423–34.

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Clinical Arrhythmias

Upstream Treatment of Atrial Fibrillation with n-3 Polyunsaturated Fatty Acids: Myth or Reality?

Fra nc esc o Ors o, 1 ,2 G i a n n a Fa b b r i 2 a n d A l d o P i e t r o M a g g i o n i 2 1. Azienda Ospedaliero-Universitaria Careggi, Section of Geriatric Medicine and Cardiology, Florence, Italy; 2. ANMCO Research Center, Florence, Italy

Abstract Atrial fibrillation (AF) is the most common sustained arrhythmia in adults and is associated with an increased risk of fatal and non-fatal events. Antiarrhythmic drugs provide limited protection against AF recurrence and have a poor safety profile. Several mechanisms have been proven to be involved in AF, e.g. inflammation, oxidative stress, fibrosis and ischaemia. Prevention of AF with interventions that target these mechanisms has emerged as a result of experimental studies suggesting the use of upstream therapies. Long chain n-3 polyunsaturated fatty acids (n-3 PUFA) have multiple effects on cardiac electrophysiology, and epidemiological studies on fish oil suggest a possible use of n-3 PUFA in AF prevention. Several randomised clinical trials have been designed to evaluate the efficacy of n-3 PUFA in preventing AF. In this review, we report the conflicting results of these trials in two different clinical settings: recurrence in patients with history of AF and development of post-operative AF in patient undergoing cardiac surgery.

Keywords Arrhythmias, atrial fibrillation, post-operative atrial fibrillation, n-3 PUFA, prevention Disclosure: The authors have no conficts of interest to declare.

Received: 8 October 2015 Accepted: 5 November 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(3):163–8. Access at: www.AERjournal.com Correspondence: Aldo P Maggioni, ANMCO Research Center, Via La Marmora 34, 50121 Florence, Italy. E: maggioni@anmco.it, centrostudi@anmco.it

Atrial fibrillation (AF) is the most common sustained arrhythmia in adults and confers increased risk of death,1 thromboembolism and impaired quality of life.2 Current pharmacological antiarrhythmic drugs provide limited protection against AF recurrence and have poor safety profiles, while invasive ablation treatments are associated with significant risks and limited long-term success rates. Moreover, neither of these treatments has been documented to reduce adverse outcomes associated with AF.3,4 Several pathophysiological processes have been proved to be involved in AF, such as inflammation, oxidative stress, endothelial dysfunction, initiating triggers (often from pulmonary veins), changes in autonomic tone in addition to fibrosis and ischaemia. Prevention of AF with interventions that modify these substrates or target specific mechanisms for AF has emerged as a result of recent experimental studies suggesting the use of upstream therapies. Non-antiarrhythmic drugs that have been tested in prevention of AF include angiotensin-converting-enzyme inhibitors, angiotensin receptor blockers, statins and long chain-3 polyunsaturated fatty acids (n-3 PUFA). n-3 PUFA have multiple effects on cardiac electrophysiology,5–10 such as membrane stabilisation in the myocardial cell by prolonged inactivation of the fast sodium outward channel, resulting in a longer refractory time and provide protection from ventricular arrhythmias and sudden death,11–13 but also have antifibrotic, anti-inflammatory and antioxidant characteristics that might influence the mechanisms involved in the initiation and maintenance of AF.14 In several experimental animal models, pre-treatment with n-3 PUFA decreased the development and progression of atrial fibrosis, reduced the abundance of collagen in atrial appendage and the duration of

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induced episodes of AF.15,16 They also prevented, in this kind of model, significant shortening of the atrial effective refractory period associated with AF, reduced inducibility of AF and sustainability of induced AF and attenuated structural changes in the atrial myocardium.16 Results of epidemiological studies have been controversial: In the Cardiovascular Health Study, the consumption of boiled or baked fish one to four times per week was associated with a 30 % lower risk of incident AF at 12 years compared with fish consumption less than once a week.17 However, in other population-based studies no association was found between n-3 PUFA intake and incident AF. Both the Danish Study and the Physicians’ Health Study showed that the patients with higher fish intake were more likely to develop AF: in the Danish study adjusting hazard ratios (HRs) for incident AF at 5.7 years, in quintiles 2–5, were 0.86, 1.08, 1.01 and 1.34 (p for trend = 0.006) compared with the lowest quintile and in the Physicians’ Health Study patients with the highest fish intake (≥5 meals per week) were more likely to develop AF compared with those eating fish <1 time per month (RR 1.46; 95 % CI 0.94–2.28).18,19 Finally, no association between development of AF at 3 years and fish intake was found in the Women’s Health Initiative study, which was carried out in more than 45,000 women.20 All these studies were based on food frequency questionnaires to assess fish intake and none provided data on serum n-3 PUFA content and its relationship with development of AF. In the Kuopio Ischaemic Heart Disease Risk Factors Study, designed to investigate risk factors for cardiovascular diseases, atherosclerosis and related outcomes in middle-aged men from eastern Finland, the serum concentration of n-3 PUFA was

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Clinical Arrhythmias Figure 1: Prevalence of Atrial Fibrillation at Study Entry by Circulating Levels of n-3 PUFA in 1,203 patients (GISSI-HF Trial) 25 p=0.012 20 19.1

Prevalent AF (%)

15 14.3 10

10.3

5

0

≤4.32

4.33–5.43

>5.43

Plasma n–3 PUFA (mol %) AF = atrial fibrillation; PUFA = polyunsaturated fatty acids.

measured in 2,174 men. Only high docosahexanaeoic (DHA) acid but not eicosapentaenoic (EPA) acid content was associated with reduced risk of incident AF (HR 0.62; 95 % CI 0.42–0.92; p=0.02) suggesting that the preventive effect may depend on the use of a specific acid.21 These results are consistent with other studies in which DHA has been shown to be able to inhibit cardiac arrhythmias in rats and to have a beneficial effect on heart rate variability in humans.22,23 In this context, the focus of several randomised clinical trials in n-3 PUFA has been on two AF populations: patient for whom the objective was to maintain normal sinus rhythm after cardioversion or spontaneous restoration of sinus rhythm and patients in whom the objective was to prevent AF after cardiac surgery. The aim of this paper is to give an up-to-date review of the results of these trials and of recently published meta-analyses on this topic, trying to explain the conflicting results that have emerged by focusing on methodological aspects and on possible pathophysiological mechanisms, such as the role of inflammation and oxidative stress, as suggested by more recent studies and from biohumoral subanalysis of these trials.

Effects of n-3 Fatty Acids on Prevention of Recurrent Atrial Fibrillation Several trials have been designed to evaluate the effect of n-3 PUFA in the prevention of AF recurrence (see Table 1). In FORWARD (Randomised Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation), 586 patients with previous symptomatic episodes of AF were randomised to receive 1 g/day n-3 PUFA or placebo in a double-blind fashion; the primary efficacy endpoint was the time to first recurrence of AF; the follow-up duration was 12 months. At the end of the study, 18.9 % in placebo group and 24.0 % in n-3 PUFA had recurrent AF (HR 1.28 95 % CI 0.90–1.83) and the lack of statistical differences between randomised patients to placebo or n-3 PUFA were observed for all the other study outcomes (composite of all-cause mortality, non-fatal stroke, non-fatal acute MI, systemic embolism, heart failure development and severe bleeding).24 In a post hoc analysis of the GISSI HF trial (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico Prevenzione), the effect on new episodes of AF of n-3 PUFA daily supplementation was examined in 5,835 patients with heart failure.25 In this trial, fish consumption at study

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entry was estimated through a self-administered questionnaire and circulating levels of n-3 PUFA were measured in a subgroup of 1,203 patients. More frequent fish consumption with diet was associated, in univariate analysis, with a lower prevalence of AF but after the adjusted analysis fish intake was not associated with AF prevalence while, among patients with measured serum levels of n-3 PUFA, those in the lowest tertile (≤4.32 mmol %) had a twofold higher risk of AF than those in highest tertile (>5.43 mmol %) (OR 1.84; 95 % CI 1.15–2.95; p=0.012) (see Figure 1).25 During the follow-up period of 3.9 years, 15.2 % of the patients allocated to n-3 PUFA and 14.6 % of those randomised to placebo developed AF (unadjusted HR 1.10; 95 % CI 0.96–1.25; p=0.19).

The efficacy of n-3 PUFA supplementation in the prevention of AF was assessed in a randomised trial of 663 outpatients carried out in the US. Patients had symptomatic paroxysmal (542 patients) or persistent AF (121 patients) without structural heart disease and they were treated with 8 g/day of n-3 PUFA for the first 7 days and with 4 g/day thereafter for through 24 weeks. At the end of the study, there were no differences between treatment groups for recurrence of symptomatic AF in both paroxysmal (HR 1.15; 95 % CI 0.90–1.46; p=0.26) and persistent stratum (HR 1.64; 95 % CI 0.92–2.92; p=0.09).26 Several studies have been conducted in the clinical setting of postcardioversion recurrence of AF. The preliminary results of a randomised trial showed that therapy with 1 g/day of n-3 PUFA in 199 patients with recurrent persistent AF was associated with a significantly lower incidence of recurrence compared with placebo at 1 year (40 % versus 72 %; p=0.007).27 These results were not supported by the results of other randomised trials. In the study by Bianconi et al., 204 patients with persistent AF were randomised to receive 3g/day of n-3 PUFA until electrical cardioversion and 2g/day thereafter for 6 months.28 AF relapsed in 58.9 % of the n-3 PUFA and in 51.1 % of the placebo patients (p=0.28). Similarly, no favourable effects of 4 weeks’ pretreatment with n-3 PUFA on recurrence of AF after cardioversion were shown in 108 patients.29 Systematic reviews published in the last few years did not provide a definitive answer on the role of n-3 PUFA in prevention of AF probably because the number of patients was relatively small;30–32 in a recent meta-analysis including 16 studies, the analyses were conducted separately for persistent or post-operative AF, eight studies (1,990 patients) evaluated the effect of n-3 PUFA on reverted persistent or paroxysmal AF with a follow-up ranging from 6 to 12 months.33 Treatment had no effect on AF recurrence (RR 0.95; 95 % CI 0.79–1.13) and there were no statistical differences in the overall death rate (RR 0.85; 95 % CI 0.26–2.77). In 2014, a new randomised placebo controlled trial was published: 337 patients with symptomatic paroxysmal or persistent AF, documented within 6 months from enrolment, were randomised to high doses of fish oils (4 g/day) or placebo and followedup on average for 271±129 days. The primary endpoint was time to first AF recurrence lasting at least 30 second and it did not differ between groups (64 % in fish oil group versus 63 % in placebo group; p=0.5).

Results were consistent across all pre-specified subgroups such as diabetic, hypertensive, paroxysmal or persistent AF patients, except for a significantly higher AF recurrence for fish oil users with ischaemic heart disease (HR 2.6; 95 % CI 1.1–6.1).34 These data, in combination with those from previous trials, do not recommend the use of n-3 PUFA to prevent recurrent or incident AF (see Table 1).

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Table 1: Effect of n-3 Polyunsaturated Fatty Acids on Atrial Fibrillation Study

Patients

Design (Dose), Comparator

Follow-up

End Point

Results

12 months

Symptomatic AF

HR (95 % CI)

recurrences

1.28 (0.90–1.83)

Relapse of AF

RR* (95 % CI)

Persistent or Paroxysmal Atrial Fibrillation FORWARD24 (2012) Erdogan et

al.29

(2007)

586 108

Double blind (1 g day), placebo Triple blind (N/A), placebo

12 months

0.89 (0.74–1.07) Margos et

al.53

(2007)

40

Open label (N/A)

6 months

Persistent AF

RR* (95 % CI) 0.88 (0.39–1.95)

Bianconi et

al.28

(2011)

204

Double blind (1.7 g mean daily), placebo

6 months

AF recurrences

51.1 % pl versus 58.9 %

Kowey et al.26 (2010)

663

Double blind (3.4 g mean daily), placebo

6 months

Symptomatic AF/flutter HR (95 % CI)

Özaydin et al.54 (2011)

47

Open label (N/A)

12 months

n-3 PUFA; p=0.28

Nodari et al.27 (2011) Kumar et al.55 (2011) Nigam et al.34 (2014)

205 182 337

Double blind (1.7 g mean daily), placebo Open label (1.74 g day) Double blind (4 g day), placebo

12 months 12 months 6 months

recurrences

1.22 (0.98–1.52)

AF recurrences >10

37.5 % pl versus 39.1 %

minutes

n-3 PUFA; p=1

Sinus rhythm

HR (95 % CI)

maintenance

0.62 (0.52–0.72)

Persistent AF

HR (95 % CI)

recurrences

0.385 (0.27–0.56)

AF recurrences >30

HR (95 % CI)

seconds

1.10 (0.84–1.45)

AF >5 minutes or

OR (95 % CI)

requiring intervention

0.35 (0.16–0.76)

AF >15 minutes

RR* (95 % CI)

Post–operative Atrial Fibrillation Calò et al.38 (2005) Heidt et al.39 (2009)

160 102

Open label (1.7 g mean daily)

In hospital

Double blind (100 mg/kg per day intravenous), ICU stay placebo

Saravanan et al.41 (2010) 103

0.58 (0.28–1.20)

Double blind (2 g day), placebo

In hospital

AF ≥30 seconds

35 % pl vs 42 % n-3 PUFA, χ2=0.60

Heidarsdottir et al.40

168

Double blind (2.2 g day), placebo

(2010)

AF >5 minutes

2 weeks)

Sorice et al.43 (2011) Farquharson et al.44

201 194

Open label (2 g day)

In hospital

Double blind (4.5 g day), placebo

(2011) Sandesara et al.

OPERA45

In hospital (maximum

42

(2012) 243

(2012)

1,516

Double blind (2 g day), placebo Double blind (2 g day), placebo

54.2 % pl versus 54.1 % n-PUFA; p=0.99

AF >5 minutes or

OR (95 % CI)

requiring intervention

0.43 (0.20–0.95)

In hospital (maximum

AF/flutter ≥10 minutes OR (95 % CI)

6 days)

or requiring intervention 0.70 (0.39–1.28)

2 weeks

Documented AF

OR (95 % CI)

requiring intervention

0.89 (0.52–1.53)

AF ≥30 seconds (ECG

OR (95 % CI)

or rhythm strips)

0.96 (0.77–1.20)

In hospital

*Data on relative risk (RR) are taken from a meta-analysis of Mariani et al. AF = atrial fibrillation; CI = confidence interval; ECG = electrocardiogram; HR = hazard ratio; ICU = intensive care unit; OR = odds ratio; pl = placebo; PUFA = polyunsaturated fatty acids.

33

However, many secondary prevention trials had a short follow-up duration and, for this reason, important benefits from n-3 PUFA could be missed. The Vitamin D and Omega-3 Trial (VITAL) rhythm substudy is examining the impact of the administration of 1 g/day of n-3 PUFA on incident AF 25,875 men and women without cardiovascular disease over 5 years of follow up. It is possible that with a more prolonged duration of treatment a potential benefit could emerge.35

Effects of n-3 Fatty Acids on Post-operative Atrial Fibrillation Prevention Cardiac surgery is often complicated by the occurrence of supraventricular arrhythmias and particularly AF (post-operative AF [POAF]). Almost 30–40 % of patients undergoing coronary artery bypass grafting (CABG) surgery develop POAF, most frequently between the second and the third post-operative day.36 This percentage rises nearly to 70 % in patients undergoing concomitant valve surgery. The risk of developing this arrhythmia is related to the presence of several clinical risk factors (e.g.

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prior history of AF, heart failure, left atrial enlargement, left ventricular systolic dysfunction, post-operative withdrawal of beta-adrenergic receptor blockers and chronic obstructive pulmonary disease), but the stronger predictor is advancing age.37 POAF has both clinical and economic implications: patients who develop POAF are at increased risk of cerebrovascular events, haemodynamic instability and congestive heart failure. Furthermore, POAF is associated with increased length of stay in the intensive care unit and prolonged hospitalisations and is therefore responsible for significant patient morbidity and healthcare costs.36 Several drugs (e.g. amiodarone, sotalol and beta-adrenergic receptor blockers) have proved effective in reducing the risk of POAF. As multiple acute factors contribute to the development of AF after cardiac surgery (enhanced sympathetic and parasympathetic tone, atrial stretch, fluid and electrolyte abnormalities, metabolic abnormalities, oxidative stress, myocardial and pericardial inflammation) other treatments have been tested and are currently under evaluation. Based on the evidence

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Clinical Arrhythmias of anti-inflammatory and antioxidant proprieties of n-3 PUFA several studies have been designed to prove their efficacy on POAF prevention (see Table 1).

Calò and colleagues evaluated the efficacy of n-3 PUFA for the prevention of POAF in 160 patients randomised to polyunsaturated fatty acids (n-3 PUFA 2 g/day) and to a control group. Treatment was initiated at least 5 days preoperatively and continued until hospital discharge. Patients randomised to n-3 PUFA had a significantly lower incidence of POAF compared with the control group (15.2 % versus 33.3 %; p=0.013) and a mean shorter hospital stay (7.3 [2.1] versus 8.2 [2.6] days; p=0.017).38 Heidth et al. randomised 102 patients to n-3 PUFA (100 mg fish oil/kg body weight/day) given intravenously or free fatty acids (100 mg soya oil/kg body weight/day) starting on admission to hospital and ending at discharge from intensive care. POAF (primary endpoint) occurred in 15 patients (30.6 %) in the control and in 9 (17.3 %) in the n-3 PUFA group (p<0.05). Furthermore, patients allocated to a n-3 PUFA treatment had to be treated in the intensive care unit for a shorter period of time than the control patients.39 Based on these promising results, Heidarsdottir and colleagues conducted a prospective, double-blinded, placebo-controlled trial randomising 168 patients admitted for CABG and/or valvular repair surgery to receive n-3 PUFA capsules (1,240 mg EPA and 1,000 mg DHA) or olive oil capsules for 5–7 days prior to surgery and postoperatively until hospital discharge. Unlike previous studies, the authors found no difference in the incidence of POAF (54.2 versus 54.1 %; p=0.99) and in the length of stay.40 Similar disappointing results were found by Saravanan et al. who failed to demonstrate the efficacy of n-3 PUFA, 2 g/day administered orally (versus olive oil, placebo) in reducing the incidence of POAF in 103 patients undergoing CABG surgery. Despite higher n-3 PUFA levels in serum and right atrial tissue in the active treatment group, there was no significant difference between groups in the primary outcome of POAF (placebo versus n-3 PUFA; 43 % versus 56 %; p=0.28).41 Sandesara et al. in the Fish Oil for Reduction of Atrial Fibrillation After Cardiac Surgery (FISH) trial randomised patients undergoing CABG to pharmaceutical-grade n3 PUFAs 2 g orally twice daily (minimum of 6 g) or a matched placebo ≥24 hours before surgery. Despite a higher n-3 PUFA dose, a longer time of treatment (2 weeks after surgery) and larger sample size (260 patients) compared with previous similar studies, the rate of POAF was similar in both groups (30 % n-3 PUFAs versus 33 % placebo; p=0.67).42 Sorice and colleagues randomised 201 patients undergoing CABG to n-3 PUFA 2 g/day or placebo for at least 5 days before surgery and until hospital discharge. The authors found a significant reduction in the incidence of POAF in the n-3 PUFA group. Interestingly, subgroup analysis showed a significant reduction of POAF only in the group including patients treated with n-3 PUFA undergoing ‘on-pump’ CABG surgery, with no effect on those who underwent ‘off-pump’ cardiac surgery. Notably, therapy with n-3 PUFA had no effect on length of post-operative hospital stay.43 Farquharson and colleagues undertook a double-blind randomised controlled trial to examine the effectiveness of fish oil supplementation

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on POAF after CABG and valve procedures in 200 patients randomised to receive fish oil (providing 4.6 g/day of n-3 PUFA) or a control oil starting 3 weeks before surgery. The longer period of pre-treatment did not have the expected results: 194 subjects completed the study, with 47 of 97 subjects in the control group and 36 of 97 subjects in the fish oil group developing POAF in the first 6 days after surgery (primary endpoint, OR 0.63; 95 % CI 0.35–1.11). Notably there was a significant decrease in mean length of stay in the ICU in the fish oil group (ratio of means 0.71; 95 % CI 0.56–0.90).44 The conflicting results of all these previous trials gave the impulse for the organisation of an international multicentre double-blind, placebocontrolled, randomised clinical trial, the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) trial, with the enrolment of 1,516 patients scheduled for cardiac surgery. Patients were randomised to receive n-3 PUFA (1 g capsules containing ≥840 mg n-3 PUFA as ethyl esters) or placebo, with preoperative loading of 10 g over 3 to 5 days (or 8 g over 2 days) followed postoperatively by 2 g/day until hospital discharge or post-operative day 10, whichever came first. The primary endpoint (POAF lasting longer than 30 seconds) occurred in 233 (30.7 %) patients assigned to placebo and 227 (30.0 %) assigned to n-3 PUFAs (OR 0.96; 95 % CI 0.77–1.20; p=0.74). Furthermore, no significant differences between the two groups were observed for any of the secondary endpoints: post-operative AF lasting longer than 1 hour, resulting in symptoms, or treated with cardioversion; post-operative AF excluding atrial flutter; time to first postoperative AF; number of AF episodes per patient; hospital utilisation; and major adverse cardiovascular events, 30-day mortality. Treatment was safe in terms of bleeding and other adverse events.45 Two interesting analyses46–7 on biohumoral data from the OPERA trial have recently been published confirming the limited influence of mechanical and haemodynamic factors and reinforcing the role of oxidative stress in the pathogenesis of POAF. N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) or high-sensitivity cardiac troponin T (hs-cTnT) on the morning of surgery, or changes in their levels between morning of surgery and post-surgery, were not significantly associated with POAF after adjustment for clinical and surgical characteristics.46 On the contrary a relatively linear association with incident POAF of validated, fatty acid-derived oxidative stress biomarkers (F2-isoprostanes, isofurans and F3-isoprostanes) measured in plasma and urine on the day of surgery and on the second post-operative day could be described.47 Two metanalyses,33,48 which included the same eight38–45 clinical trials discussed above, on POAF prevention with n-3 PUFA have recently been published. Interestingly, the authors obtained opposite results: Mariani et al.33 found no significant benefit, whereas Costanzo and colleagues48 found that preoperative supplementation with n-3 PUFA significantly prevented the occurrence of POAF in patients undergoing cardiac surgery. The difference in results of the two studies can be explained by the different adjudication of events in the trial of Saravanan and colleagues.41 Costanzo and colleagues48 used the primary outcome measure of any AF >30 seconds in the monitor recordings (number of events with n-3 PUFA versus control, 22 versus 18) whereas Mariani and colleagues33 considered clinical AF (29 events in the n-3 PUFA group versus 22 in the controls). Costanzo and colleagues conducted a subgroup analysis showing particular benefit in patients undergoing CABG surgery.

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Upstream Treatment of Atrial Fibrillation with n-3 Polyunsaturated Fatty Acids

In accordance with the results of the biohumoral analysis in the OPERA trial,46,47 and following the hypothesis of a strong involvement of oxidative stress in the development of POAF, Rodrigo and colleagues49 designed a controlled trial to assess whether the reinforcement of the antioxidant system, through n-3 PUFA plus antioxidant vitamin supplementation, could reduce the incidence of POAF. A total of 203 patients scheduled for on-pump cardiac surgery were randomised to placebo or supplementation with n-3 PUFA (2 g/day) (EPA:DHA ratio 1:2), vitamin C (1 g/day) and vitamin E (400 IU/day). POAF occurred in 10 of 103 patients (9.7 %) in the supplemented group versus 32 of 100 patients (32 %) in the placebo group (p<0.001). The efficacy of antioxidant therapy with vitamin C in preventing POAF as well as reducing in hospital stay was confirmed in a recently published metanalysis.50 The results of trials discussed do not support the routine use of n-3 PUFA in POAF prevention, but their combination with other drugs with antioxidant proprieties seem to have promising perspectives that should be confirmed in larger adequately powered controlled trials.

Conclusions The efficacy of n-3 PUFA in preventing AF has been tested, with conflicting results, in several randomised clinical trials conducted both in patients with a history of AF and in those undergoing cardiac surgery (the so-called POAF). The results of these trials do not support the routine use of n-3 PUFA in AF prevention in both settings.

Accordingly, both European51 and US guidelines52 do not recommend their systematic use in clinical practice. The promising results of the combination of n-3 PUFA with other drugs with antioxidant proprieties

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Marchioli R, Barzi F, Bomba E, et al. GISSI-Prevenzione Investigators. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: timecourse analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) Prevenzione. Circulation 2002;105:1897–903.

Mozzaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol 2011;58:2047–67.

Sakabe M, Shiroshita-Takeshita A, Maguy A, et al. Omega-3 polyunsaturated fatty acids prevent atrial fibrillation associated with heart failure but not atrial tachycardia remodeling Circulation 2007;116:2101–9.

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need to be confirmed, providing interesting pathophysiological explanation of the conflicting results of the studies by pointing out the importance of oxidative stress over inflammation in the pathogenesis of AF and particularly of POAF. n

Clinical Perspective • Atrial fibrillation (AF) is associated with an increased risk of fatal and nonfatal events and current antiarrhythmic drugs provide limited protection against AF recurrence and have poor safety profile.

• Understanding of the pathophysiological mechanisms that underlie AF has led to the development of upstream strategies for AF prevention.

• n-3 polyunsaturated fatty acids (n-3 PUFA) are safe, well tolerated and have multiple effects on cardiac electrophysiology and both clinical and preclinical studies have shown ‘antiarrhythmic properties’.

• The efficacy of n-3 PUFA in preventing AF has been tested, with conflicting results, in several randomised clinical trials conducted both in patients with history of AF and in those undergoing cardiac surgery (so-called post-operative AF).

• The results of these trials do not support the routine use of n-3 PUFA in AF prevention, but their combination with other drugs with antioxidant proprieties seem to have promising perspectives.

15. Ramadeen A, Connelly KA, Leong-Poi H, et al. N-3 polyunsaturated fatty acid supplementation does not reduce vulnerability to atrial fibrillation in remodeling atria. Heart Rhythm 2012;9:1115–22.

16. Savelieva I, Kakouros N, Kourliouros A, et al. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part I: primary prevention. Europace 2011;13:308–28.

17. Mozaffarian D, Psaty BM, Rimm EB, et al. Fish intake and risk of incident atrial fibrillation Circulation 2004;110:368–73.

18. Forst L, Vestergaard P. n-3 Fatty acids consumed form fish and risk of atrial fibrillation or flutter: the Danish Diet, Cancer and Health Study. Am J Clin Nutr 2005;81:50–4.

19. Alzer A, Gaziano JM, Manson JE, et al. Relationship between fish consumption and the development of atrial fibrillation in men. Heart Rhythm 2006;3:55 (abstract).

20. Berry JD, Prineas RJ; van Horn L, et al. Dietary fish intake and incident atrial fibrillation (from the Women’s Health Initiative).

Am J Cardiol 2010;105:844–8.

21. Virtanen JK, Mursu J, Voutilainen S, et al. Serum long-chain n-3 polyunsaturated fatty acid and risk of hospital diagnosis of atrial fibrillation in men. Circulation 2009;120:2315–21.

22. McLeman P, Howe P, AbeywardenaM, et al. The cardiovascular protective role of docosahexaenoic acid. Eur J Pharmacol 1996;300:83–98.

23. Christensen JH, Christensen MS, Dyerberg J, et al. Heart rate variability and fatty acid content of blood cell membranes: a dose-response study with n-3 fatty acids. Am J Clini Nutr 1999;70:331–7.

24. Macchia A, Grancelli H, Varini S, et al. on behalf of the GESICA Investigators. Omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: results of the FORWARD (Randomized Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation) trial. J Am Coll Cardiol 2013;61:463–8.

25. Aleksova A, Masson S, Maggioni AP, et al. n-3 polyunsaturated fatty acids and atrial fibrillation in patients with chronic heart failure: the GISSI HF trial. Eur J Heart Fail 2013;15:1289–95.

26. Kowey PR, Reiffel JA, Ellenbogen KA, et al. for the OM-8 Clinical Trial Investigators. Efficacy and safety of Prescription Omega-3 fatty acids (POM-3) for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial.

JAMA 2010;304:2363–72.

27. Nodari S, Triggiani M, Foresti A, et al. Use of n-3 polyunsaturated fatty acids to maintain sinus rhythm after cardioversion from persistent atrial fibrillation: a prospective randomized study. Circulation 2011;124:1100–6.

28. Bianconi L, Calò L, Mennuni S, et al. Polyunsaturated fatty acids for the prevention of atrial fibrillation recurrence after electrical cardioversion of chronic persistent atrial fibrillation: a randomized double-blind, multicentre study. Europace 2011;13:174–81.

29. Erdogan A, Bayer M, Kollath D, et al. Omega AF study: Polyunsaturated fatty acids (N-3 PUFA) for prevention of atrial fibrillation relapse after successful external cardioversion.

Heart Rhythm 2007;4:S185–6 Abstract.

30. Liu T, Korantzopoulos P, Shehata M, et al. Prevention of atrial fibrillation with omega-3 fatty acids: a meta-analysis of randomized clinical trials. Heart 2011;97:1034–40.

31. Khawaja O, Graziano JM, Djoussè L. A meta-analysis of omega-3 fatty acids and incidence of atrial fibrillation. J Am Coll Nutr 2012;31:4–13.

32. He Z, Yang L, Tian J, et al. Efficacy and safety of omega-3 fatty acids for the prevention of atrial fibrillation: a meta-analysis.

Can J Cardiol 2013;29:196–203.

33. Mariani J, Doval HC, Nul D, et al. N-3 poliunsaturated fatty acids to prevent atrial fibrillation: updated systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc 2013;2:e005033.

34. Nigam A, Talajic M, Roy D, et al. for the AFFORD Investigators.

Fish Oil for the reduction of Atrial Fibrillation Recurrence, Inflammation and Oxidative Stress. J Am Coll Cardiol 2014;64:1441–8.

35. Manson JE, Bassuk SS, Lee IM, et al. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acids supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials 2012;33:159–71.

36. Mathew JP, Fontes ML, Tudor IC, et al. A multicenter risk index for atrial fibrillation after cardiac surgery. JAMA 2004;291:1720–9.

37. Zaman AG, Archbold A, Helft G, et al. Atrial fibrillation after coronary artery bypass surgery: a model for preoperative risk stratification. Circulation 2000;101:1403–8.

38. Calò L, Bianconi L, Colivicchi F, et al. N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial. J Am Coll Cardiol 2005;45:1723–8.

39. Heidt MC, Vician M, Stracke SK, et al. Beneficial effects of intravenously administered N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a prospective randomized study. Thorac Cardiovasc Surg 2009;57:276–80.

40. Heidarsdottir R, Arnar DO, Skuladottir GV, et al. Does treatment with n-3 polyunsaturated fatty acids prevent atrial fibrillation after open heart surgery? Europace 2010;12:356–63.

41. Saravanan P, Bridgewater B, West AL, et al. Omega-3 fatty acid supplementation does not reduce risk of atrial fibrillation after coronary artery bypass surgery: a randomized, doubleblind, placebo-controlled clinical trial. Circ Arrhythm Electrophysiol 2010;3:46–53.

42. Sandesara CM, Chung M, Van Wagoner D, et al. on behalf of the FISH Trial Investigators. A randomized, placebo-controlled trial of omega-3 fatty acids for inhibition of supraventricular

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arrhythmias after cardiac surgery: the FISH trial. J Am Heart Assoc 2012;1:e000547.

Sorice M, Tritto FP, Sordelli C, et al. N-3 polyunsaturated fatty acids reduces post-operative atrial fibrillation incidence in patients undergoing “on-pump” coronary artery bypass graft surgery. Monaldi Arch Chest Dis 2011;76:93–8.

Farquharson AL, Metcalf RG, Sanders P, et al. Effect of dietary fish oil on atrial fibrillation after cardiac surgery. Am J Cardiol 2011;108:851–6.

Mozaffarian D, Marchioli R, Macchia A, et al. for the OPERA Investigators. Fish oil and postoperative atrial fibrillation: the omega-3 fatty acids for prevention of post-operative atrial fibrillation (OPERA) randomized trial. JAMA 2012;308:2001–11.

Masson S, Wu JH, Simon C, et al. Circulating cardiac biomarkers and postoperative atrial fibrillation in the OPERA trial. Eur J Clin Invest 2015;45:170–8.

Wu JH, Marchioli R, Silletta MG, et al. Oxidative stress biomarkers and incidence of postoperative atrial fibrillation in the omega-3 fatty acids for prevention of postoperative

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Costanzo S, di Niro V, Di Castelnuovo A, et al. Prevention of postoperative atrial fibrillation in open heart surgery patients by preoperative supplementation of n-3 polyunsaturated fatty acids: an updated meta-analysis. J Thorac Cardiovasc Surg 2013;146:906–11.

Rodrigo R, Korantzopoulos P, Cereceda M, et al. A randomized controlled trial to prevent post-operative atrial fibrillation by antioxidant reinforcement. J Am Coll Cardiol 2013;62:1457–65.

Ali-Hassan-Sayegh S, Mirhosseini SJ, Rezaeisadrabadi M, et al. Antioxidant supplementations for prevention of atrial fibrillation after cardiac surgery: an updated comprehensive systematic review and meta-analysis of 23 randomized controlled trials. Interact Cardiovasc Thorac Surg 2014;18:646–54.

Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation:An update of the 2010 ESC Guidelines for the

management of atrial fibrillation. Europace 2012;14:1385–1413.

52. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1–76.

53. Margos P, Leftheriotis D, Katsouras G, et al. Influence of n-3 fatty acids intake on secondary prevention after cardioversion of persistent atrial fibrillation to sinus rhythm.

Europace 2007;9(Suppl. 3):iii51 (abstract).

54. Özaydin M, Erdogan D, Tayyar S, et al. N-3 polyunsaturated fatty acids administration does not reduce the recurrence rates of atrial fibrillation and inflammation after electrical cardioversion: a prospective randomized study. Anadolu Kardiyol Derg 2011;11:305–9.

55. Kumar S, Sutherland F, Morton JB, et al. Long-term omega-3 polyunsaturated fatty acid supplementation reduces the recurrence of persistent atrial fibrillation after electrical cardioversion. Heart Rhythm 2012;9:483–91.

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Early Repolarisation Syndrome – New Concepts Demosthenes G. K a t r i t s i s, 1 B e r n a r d J. G e r s h , 2 A J o h n Ca m m 3 1. Athens Euroclinic, Athens, Greece, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, US, 2. Mayo Medical School, Rochester, MN, US, 3. St George’s University of London, UK

Abstract New concepts regarding early repolarisation syndrome are presented. Genetics and epidemiology data, as well as new evidence on the potential clinical significance of early repolarisation patterns, are discussed.

Keywords Early repolarisation syndromes, J-wave syndromes Disclosure: The authors have no conflicts of interest to declare.

Acknowledgements: Andrew Grace, Section Editor– Arrhythmia Mechanisms/Basic Science acted as Editor for this article. This article is adapted from pp.530-533 Ch.61 Early repolarization syndromes: New Concepts, (updated) from ‘Clinical Cardiology: Current Practice Guidelines’ edited by Katritsis, Gersh, & Camm (2013): Oxford University Press, with kind permission. © Oxford University Press, 2013.

Received: 9 November 2015 Accepted: 25 November 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(3):169–71. Access at: www.AERjournal.com Correspondence: Dr D Katritsis, Division of Cardiology, Beth Israel Deaconess Medical Center, 185 Pilgrim Rd, Baker 4, Boston, MA 02215. E: dkatrits@bidmc.harvard.edu

Early repolarisation pattern is defined electrocardiographically by a distinct J wave or J-point elevation that is either a notch or a slur of the terminal part of the QRS entirely above the baseline, with or without ST-segment elevation. The peak of the notch or slur (Jp) should be ≥0.1 mV in two or more contiguous leads, excluding leads V1 to V2 (see Figure 1).1,2 Early repolarisation syndromes (ERS) refer to sudden cardiac death or documented VT/VF in individuals with an early repolarisation pattern.

A prominent J wave has been long observed in cases of hypothermia hypercalcaemia and ischaemia.3 The term J-wave syndromes usually denotes inherited conditions such as ERS and the Brugada syndrome,4 which are due to mutations affecting calcium, potassium and sodium channels and may contribute to overlap syndromes.4,5

Genetics and Pathophysiology The J-wave deflection occurring at the QRS–ST junction (also known as the Osborn wave) was first described in 1953 and is seen in many conditions such as acute ischaemia (especially in true posterior myocardial infarction), hypothermia, hypercalcaemia, brain injury, acidosis and early repolarisation syndromes. An increase in net repolarising current, due to either a decrease of inward Na+ or Ca2+ currents (INa, and ICa,L), or augmentation of outward currents, such as Ito, IK–ATP, and IK–ACh, lead to augmentation of the J wave or the appearance of ST-segment elevation that is more prominent during slow heart rates.

Overlap with other syndromes may be seen. Mutations in the SCN10A gene may produce patterns of Brugada, early repolarisation and conduction disease,5 and a high prevalence of early repolarisation in short QT syndrome has also been reported.6 Physiological heterogeneity of electrical properties and transmural gradients in ion channel distribution in the endocardial, midmyocardial (M cells) and epicardial layers result in regional differences in electrophysiological properties.

Ventricular epicardial (particularly RV) and M cells, but not endocardial action potentials, display a prominent phase 1 due to a large transient outward potassium current (Ito) giving rise to the typical spike and dome

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or notched configuration of the action potential and inscription of the J wave in the ECG. The degree of accentuation of action potential notch leading to loss of the dome depends on the magnitude of Ito. When Ito is prominent, as it is in the right ventricular epicardium, an outward shift of current causes phase 1 of the action potential to progress to more negative potentials at which the L-type calcium current (ICa,L) fails to activate, leading to all-or-none repolarisation and loss of the dome. Loss of the action potential dome usually is heterogeneous, resulting in marked abbreviation of the action potential at some sites but not at others. The dome then can propagate from regions where it is maintained to regions where it is lost, giving rise to local transmural reentry and closely coupled extrasystoles (phase 2 reentry). When the extrasystole occurs on the preceding T wave, it results in an R on T phenomenon that initiates polymorphic VT or VF.

Clinical Significance The early repolarisation pattern has long been considered to be a benign ECG manifestation (6–13 % in the general population), that is seen more commonly in young healthy men and athletes (22–44 %) and its clinical significance has been questioned.7 In a recent report on professional athletes, a correlation between J-point elevation and interventricular septum thickness was observed, suggesting a possible mechanistic role of exercise-induced left ventricular hypertrophy as the basis for J-point elevation, and no cardiac death was observed in a median of 13 years follow-up.8 Similarly, in the CARDIA study, the presence of early repolarisation in young adults was not associated with higher risk of death during long-term follow-up.9 The possibility that false tendons, e.g. discrete, fibromuscular structures that transverse the LV cavity, are related to the genesis of J waves has also been raised.10 However, there has been evidence suggesting that the early repolarisation pattern may be associated with a risk for VF, depending on the location of early repolarisation, magnitude of the J wave

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A

D

E

C

A. ‘Classic’ early repolarisation without J wave. B. Notched J wave with ascending ST segment. C. Notched J wave with horizontal/descending ST segment. D. Slurred J wave with ascending ST segment. E. Slurred J wave with horizontal/descending ST segment. With permission from Biasco, et al., 2013.

Figure 2: Rapidly Ascending (A) and Horizontal (B) ST Segment in the Leads Deploying J Waves A

ERS is diagnosed in:

1mV

J waves marked with arrowhead. ‘Concave/rapidly ascending’ – when there is 0.1 mV elevation of the ST segment within 100 ms after the J point and the ST segment merged gradually with the T wave. ‘Horizontal/descending’ – when the ST-segment elevation is 0.1 mV within 100 ms after the J point and continues as a flat ST segment until the onset of the T wave. With permission from Rosso, et al., 2012.

and degree of ST elevation.2,11,12 In a large study on a communitybased general population of 10,864 middle-aged subjects, an early repolarisation pattern with J-point elevation of at least 0.1 mV in the inferior leads of a resting ECG was associated with an increased risk of death from cardiac causes.13 In addition, among patients with a history of idiopathic ventricular fibrillation, an increased prevalence of early repolarisation, (up to 23 %), defined as an elevation of the QRS– ST junction of at least 0.1 mV from baseline in the inferior or lateral lead, manifested as QRS slurring or notching, has been detected.11,14 A higher prevalence of J-wave and/or QRS slurring (but not of ST elevation) has been found among athletes with cardiac arrest/sudden death than in controls.15 A horizontal/descending type (defined as ≤0.1 mV elevation of the ST segment within 100 ms after the J point) in the inferior leads, as opposed to a rapidly ascending ST segment type, may help to identify those individuals who are clearly at risk (see Figure 2).16,17 Coexistence of an anterior early repolarisation pattern (e.g. in leads V1–V3),18 and early repolarisation in the inferior leads, especially in cases without other QRS complex abnormalities, predict the occurrence of VT/VF.19 Still, several obscure points remain with this syndrome. An early repolarisation pattern in the inferolateral leads occurs in 5 % of apparently healthy individuals;13,14 it may not be consistently seen, and even the horizontal/descending ST type was seen in 3 % of controls.16,17 In the Atherosclerosis Risk in Communities (ARIC) study, J-point elevation was associated with an increased risk of sudden

1.

2.

3.

Macfarlane PW, Haissaguerre M, Huikuri HV, et al. The early repolarization pattern: a consensus paper. J Am Coll Cardiol 2015;66:470.

Obeyesekere MN, Klein GJ, Nattel S, et al. A clinical approach to early repolarization. Circulation 2013;127:1620–9.

Demidova MM, Martín-Yebra A, van der Pals J, et al. Transient

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Diagnosis Specific diagnostic criteria for early repolarisation pattern and ERS were presented by the Heart Rhythm Society (HRS), European Heart Rhythm Association (EHRA) and Asia Pacific Heart Rhythm Society (APHRS) in 2013, as follows.24

B

1mV

cardiac death (SCD) in whites and in women, but not in blacks or men.20 A pattern of J-wave and/or QRS slurring (but not of ST elevation) has been associated with cardiac arrest/sudden death in athletes,15 but many healthy athletes have early repolarisation with a rapidly ascending pattern. Inferolateral early repolarisation pattern is seen in 25–35 % of competitive athletes, and inferior only in 4 %, and is considered a dynamic phenomenon related to physical activity.8,21,22 Finally, a large genome-wide association study has been unable to identify genetic variants associated with the pattern, possibly reflecting the phenotypic heterogeneity that exists among these individuals.23 It seems, therefore, that the majority of individuals with early repolarisation are at no or minimal risk for arrhythmic events.2

4.

5.

1. T he presence of J-point elevation ≥1 mm in ≥2 contiguous inferior and/or lateral leads of a standard 12-lead ECG in a patient resuscitated from otherwise unexplained VF/ polymorphic VT; 2. A SCD victim with a negative autopsy and medical chart review with a previous ECG demonstrating J-point elevation ≥1 mm in ≥2 contiguous inferior and/or lateral leads of a standard 12-lead ECG; and 3. The presence of J-point elevation ≥1 mm in ≥2 contiguous inferior and/or lateral leads of a standard 12-lead ECG. In addition, specific repolarisation patterns that have been previously discussed should be also taken into account. The Brugada syndrome is characterised by J-point or ST-segment elevation in the right precordial leads, and approximately 12 % of patients display typical early repolarisation abnormalities. However, it is typical that the ST-segment elevation is augmented in the right precordial leads by sodium-channel blockers; whereas in ERS, the early repolarisation pattern is usually attenuated.25

Therapy The risk stratification and optimum management of these patients are not well defined and the recognition of the truly malignant forms is difficult. Electrophysiology testing does not appear useful for risk stratification. VF is infrequently induced (22 %) and has no predictive value for ICD therapy.26 Patients with aborted sudden death in the absence of identifiable cause (idiopathic VF) are treated with ICD. Ablation of idiopathic VF, targeted to short coupled ventricular premature beats that originate predominantly from the Purkinje system and the right ventricular outflow track and trigger VF, has also been reported.27 According to the 2013 HRS/EHRA/APHRS statement, ICD is indicated only in patients who have survived a cardiac arrest (I) and it might be considered (IIb) in symptomatic family members of ER syndrome patients with a history of syncope in the presence of ST segment elevation >1 mm in 2 or more inferior or lateral leads. Quinidine may also be used in addition to ICD (IIa), as well as isoproterenol to suppress electrical storms (IIa).24 n

and rapid QRS-widening associated with a J-wave pattern predicts impending ventricular fibrillation in experimental myocardial infarction. Heart Rhythm 2014;11:1195–201.

Antzelevitch C, Yan GX. J-wave syndromes: Brugada and early repolarization syndromes. Heart Rhythm 2015;12:1852–66.

Hu D, Barajas-Martínez H, Pfeiffer R, et al. Mutations in

6.

7.

SCN10A are responsible for a large fraction of cases of Brugada syndrome. J Am Coll Cardiol 2014;64:66.

Watanabe H, Makiyama T, Koyama T, et al. High prevalence of early repolarization in short QT syndrome Heart Rhythm 2010;7:647–52.

Surawicz B, Macfarlane PW. Inappropriate and confusing

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8.

9.

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12.

13.

electrocardiographic terms: J-wave syndromes and early repolarization. J Am Coll Cardiol 2011;57:1584–6.

Biasco L, Cristoforetti Y, Castagno D, et al. Clinical, electrocardiographic, echocardiographic characteristics and long term follow up of elite soccer players with J-point elevation. Circ Arrhythm Electrophysiol 2013;6:1178–84.

Ilkhanoff L, Soliman EZ, Prineas RJ, et al. Clinical characteristics and outcomes associated with the natural history of early repolarization in a young, biracial cohort followed to middle age: the coronary artery risk development in young adults (CARDIA) study. Circ Arrhythm Electrophysiol 2014;7:392–9.

Nakagawa M, Ezaki K, Miyazaki H, et al. Electrocardiographic characteristics of patients with false tendon: possible association of false tendon with J waves. Heart Rhythm 2012;9:782–8.

Derval N, Simpson CS, Birnie DH, et al. Prevalence and characteristics of early repolarization in the CASPER registry: cardiac arrest survivors with preserved ejection fraction registry. J Am Coll Cardiol 2011;58:722–8.

Wu SH, Lin XX, Cheng YJ, et al. Early repolarization pattern and risk for arrhythmia death: a meta-analysis. J Am Coll Cardiol 2013;61;645–50.

Tikkanen JT, Anttonen O, Junttila MJ, et al. Long-term outcome associated with early repolarization on electrocardiography.

N Engl J Med 2009;361:2529–37.

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14. Haissaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008;358:2016–23.

15. Cappato R, Furlanello F, Giovinazzo V, et al. J wave, QRS slurring, and ST elevation in athletes with cardiac arrest in the absence of heart disease: marker of risk or innocent bystander? Circ Arrhythm Electrophysiol 2010;3:305–11.

16. Rosso R, Glikson E, Belhassen B, et al. Distinguishing ‘benign’ from ‘malignant early repolarization’: the value of the ST-segment morphology. Heart Rhythm 2012;9:225–9.

17. Tikkanen JT, Junttila MJ, Anttonen O, et al. Early repolarization: electrocardiographic phenotypes associated with favorable long-term outcome. Circulation 2011;123:2666–73.

18. Kamakura T, Kawata H, Nakajima I, et al. Significance of non-type 1 anterior early repolarization in patients with inferolateral early repolarization syndrome. J Am Coll Cardiol 2013;62:1610–8.

19. Junttila MJ, Tikkanen JT, Kenttä T, et al. Early repolarization as a predictor of arrhythmic and nonarrhythmic cardiac events in middle-aged subjects. Heart Rhythm 2014;11:1701–6.

20. Olson KA, Viera AJ, Soliman EZ, et al. Long-term prognosis associated with J-point elevation in a large middle-aged biracial cohort: the ARIC study. Eur Heart J 2011;32:3098–106.

21. Noseworthy PA, Weiner R, Kim J, et al. Early repolarization pattern in competitive athletes: clinical correlates and the effects of exercise training. Circ Arrhthm Electrophysiol

2011;4:432–40.

22. Quattrini FM, Pelliccia A, Assorgi R, et al. Benign clinical significance of J-wave pattern (early repolarization) in highly trained athletes. Heart Rhythm 2014;11:1974–82.

23. Sinner MF, Porthan K, Noseworthy PA, et al. A metaanalysis of genome-wide association studies of the electrocardiographic early repolarization pattern. Heart Rhythm 2012;9:1627–34.

24. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;10:1932–63.

25. Kawata H, Noda T, Yamada Y, et al. Effect of sodium-channel blockade on early repolarization in inferior/lateral leads in patients with idiopathic ventricular fibrillation and Brugada syndrome. Heart Rhythm 2012;9:77–83.

26. Mahida S, Derval N, Sacher F, et al. Role of electrophysiological studies in predicting risk of ventricular arrhythmia in early repolarization syndrome. J Am Coll Cardiol 2015;65:151–9.

27. Knecht S, Sacher F, Wright M, et al. Long-term follow-up of idiopathic ventricular fibrillation ablation: a multicenter study, J Am Coll Cardiol 2009;54:522–8.

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Body Surface Mapping to Guide Atrial Fibrillation Ablation Seigo Yamashita, 1 Ashok J Shah, 1 Saagar Mahida, 1 Jean-Marc Sellal, 1 Benjamin Berte, 1 Darren Hooks, 1 Antonio Frontera, 1 Nora Al Jefairi, 1 Jean-Yves Wielandts, 1 Han S Lim, 1 Sana Amraoui, 1 Arnaud Denis, 1 Nicolas Derval, 1,2 Frédéric Sacher, 1,2 Hubert Cochet, 2,3 Mélèze Hocini, 1,2 Pierre Jaïs 1,2 and Michel Haïssaguerre 1,2 1. Hôpital Cardiologique du Haut-Lévêque, CHU de Bordeaux, Pessac, France; 2. Institut Liryc/Equipex Music, Université de Bordeaux-Inserm U1045, Pessac, France; 3. Hôpital Cardiologique du Haut-Lévêque, CHU de Bordeaux, Pessac, France

Abstract Atrial fibrillation (AF) is the most common rhythm disorder, and is strongly associated with thromboembolic events and heart failure. Over the past decade, catheter ablation of AF has advanced considerably with progressive improvement in success rates.

However, interventional treatment is still challenging, especially for persistent and long-standing persistent AF. Recently, AF analysis using a non-invasive body surface mapping technique has been shown to identify localised reentrant and focal sources, which play an important role in driving and perpetuating AF. Non-invasive mapping-guided ablation has also been reported to be effective for persistent AF. In this review, we describe new clinical insights obtained from non-invasive mapping of persistent AF to guide catheter ablation.

Keywords Ablation, atrial fibrillation, body surface mapping, driver, non-invasive Disclosure: Michel Haïssaguerre, Pierre Jaïs and Mélèze Hocini are stockholders in CardioInsight Inc and Ashok J Shah is a paid consultant to CardioInsight Inc. The remaining authors have no conflicts of interest to declare.

Received: 21 July 2015 Accepted: 18 November 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(3):172–6. Access at: www.AERjournal.com Correspondence: Michel Haïssaguerre, Hôpital Cardiologique du Haut-Lévêque Avenue de Magellan, Bordeaux-Pessac, 33604, France.

E: michel.haissaguerre@chu-bordeaux.fr

Catheter ablation therapy has been widely used for rhythm control in patients with atrial fibrillation (AF).1 Since the first report in 1994,2 several interventional techniques have been proposed for AF, including replication of the surgical Maze,2 targeting pulmonary vein (PV) foci,3 segmental ostial and circumferential PV isolation,4,5 ganglionated plexi ablation,6 linear lesions in the left atrium (LA),7 complex fractionated atrial electrogram (CFAE)-based ablation8 and a stepwise approach.9 PV isolation remains the cornerstone of paroxysmal AF ablation and has a high success rate. In persistent AF, its role is limited because of the additional involvement of LA substrate due to extensive electrical and anatomical remodelling. The understanding of the substrate maintaining AF leads to the concept of pre-existing specific fibrotic atrial cardiomyopathy. The presence of fibrosis causing changes in cellular coupling results in spatial nonuniform anisotropic impulse propagation, which is a potential cause of abnormal atrial activation underlying the initiation and perpetuation of reentrant arrhythmia-like AF.10,11 In view of these changes underlying persistent AF, several ablation strategies have been attempted to modify the atrial substrate. While there has been some improvement in clinical outcomes,6–9 factors such as undue radiofrequency (RF) application, long procedural duration and high incidence of post-procedural atrial tachycardia (AT) remain.12 Recently, AF mapping using activation13 or phase-based14 analysis of body surface potentials, has allowed potential visualisation of AF-driving substrate in the form of multiple wavelets and reentrant drivers. Prior knowledge of the main AF-driving regions has been shown to facilitate the ablation procedure in patients with persistent AF.14

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Non-invasive Body Surface Mapping Analysis for Atrial Fibrillation From the previous investigations, multiple atrial wavelets, macroreentries and localised sources (focal or reentry) have been reported to lead to maintenance of AF.15,16 Electrical activities in the myocardium during AF can be mapped with electrode arrays in the in situ heart17 and voltage-sensitive fluorescent dyes in the isolated heart,18 which demonstrate complex and often irregular activity. A study involving epicardial mapping of induced human AF demonstrated multiple dynamic wave fronts interacting with changing arcs of conduction block and slow conduction.19 Another recent study mapping chronic AF intraoperatively demonstrated short regular cycle length that could be consistent with a driver with irregular activation of the rest of the atrium.20 Although it is now well accepted that the irregular waveform is seen from an irregular and constantly changing activation sequence on the surface electrogram during AF, these drivers are practically difficult to detect with conventional techniques because of the continuous and intermittent spatiotemporal dynamicity of underlying sources.21,22 To assess driver activities, phase analysis has been applied to these signals. Due to the wavefront interactions leading to constant fractionation and collision, phase mapping provides an amplitudeindependent manner to characterise and visualise dynamic data.23 Non-invasive mapping enables panoramic beat-to-beat mapping of this dynamic rhythm using phase analysis.9,14 Electrocardiographic imaging, which non-invasively images cardiac electrical activity in the heart, has been developed recently.24–26 This novel modality can demonstrate reconstructed unipolar electrical potentials, electrograms and isochrones on the epicardium by using

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Figure 1: Processing of Body Surface Mapping

Figure 2: Significance of Number of Driver Regions 8

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Pe rs ist in ent S Pe R rs (1 iste –3 n m t Pe ) rs (4 iste –6 n m t Pe ) rs (7 iste –9 n m t ) P (1 ersi 0– st 12 en m t Lo ) ng - la st in g

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(A) After acquiring CT scan with the 252 electrode vest; (B) multiple atrial fibrillation (AF) windows with subtraction of QRST are analysed to identify consistent drivers by using phase map analysis. (C) The cumulative epicardial driver map is composed on the reconstructed biatrial shell from CT. Density of the driver map is based on the prevalence and trajectory of the reentrant driver core. AP = anterior–posterior ; PA = posterior–anterior

are acquired during a long ventricular pause – spontaneous or diltiazem-provoked. QRST is subtracted and AF maps are created using specific algorithms combining wavelet transform and phase mapping applied to the reconstructed epicardial potentials. Activation maps are computed using traditional unipolar electrogram intrinsic deflectionbased (dV/dT)max method. The AF drivers can be classified into two categories: (i) focal activation with centrifugal propagation from a point and (ii) reentry/rotor demonstrating rotated wave with full-phase propagation around a functional or anatomical centrepoint. The core and trajectory of reentrant drivers and focal sources are depicted on the patient-specific biatrial geometry (see Figure 1A–C).28,32 The number of foci and reentry through the total duration of all AF windows are displayed on cumulative driver-density maps.

Distribution and Characteristics of Localised Driver Non-invasive mapping reveals multiple locations of drivers in persistent AF. These drivers demonstrate abrupt appearance at single or multiple sites and reproducibly rotate few times, often showing meandering motion spatiotemporally. In our previous report,14 repetitive reentrant activities (>1 rotation) were observed in 73 % of reentrant drivers with median 2.6 (interquartile range 2.3–3.3) repetitive rotations.

The trajectory of reentrant driver core was spread over mean 7±2 cm2; accordingly the map displays driver location not at a discrete site, but over a certain area with variable density (see Figure 1C).

The drivers were located in PVs and their respective antra in about 90 % patients in paroxysmal AF where approximately 50 % of patients demonstrated non-PV foci and reentry.33 In persistent AF left PV-appendage (ridge), right PV/septum and inferior LA were most common locations of reentrant driver. Focal driver originated from PV ostium and right or left appendages with a median of four regions.14 The prevalence and distribution of drivers depend on the clinical duration of AF such that the total number of driver regions and

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geometrical information from computed tomography (CT) and an inverse mathematical algorithm.27 Based on the inverse principle, the clinical utility of non-invasive body surface mapping in atrial and ventricular arrhythmias has been reported.28–31 Body surface mapping is undertaken by using a commercially available system (ECVUETM, Cardioinsight Technologies). After acquiring 64 section multi-detector CT images with a vest of 252 body-surface electrodes positioned on the thorax and upper abdomen, epicardial unipolar electrograms are reconstructed on a patient-specific biatrial geometry.27 AF electrograms

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76 years, female AF duration: 36 m LA surface: 20 cm2 LAA/RAA-CL: 222/231 No of reentries/10s: 11 SR: 6 min RF

67 years, male AF duration: 5 m LA surface: 25 cm2 LAA/RAA-CL: 175/196 No of reentries/10s: 11 SR: 11 min RF

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77 years, male AF duration: 3 m LA surface: 27 cm2 LAA/RAA-CL: 176/209 No of reentries/10s: 19

47 years, male AF duration: 11 m LA surface: 24.1 cm2 LAA/RAA-CL: 160/159 No of reentries/10s: 17

(A) The median number of driver regions. (B) Relationship between radiofrequency (RF) time for atrial fibrillation (AF) termination and number of driver regions (upper). RF time for AF termination significantly correlated to number of driver regions (p<0.001). While RF time inversely collated to cycle length of left atrial appendage (r=0.52; p<0.001) (lower).

(C) Typical examples of driver map in patients with and without acute success. The cases with AF termination demonstrated a fewer number of reentrant drivers, smaller left atrium and longer cycle length of left/right atrial appendage compared with non-AF termination cases. CL = cycle length; LA = left atrium; LAA = left atrial appendage; LSPV = left superior pulmonary vein; RF = radiofrequency.

activities increase with the length of continuous AF (see Figure 2A), indicating that the driver characteristics are associated with the extent of atrial remodelling. Previous reports demonstrated that longstanding AF had a larger LA surface with a greater amount of total scar (delayed enhancement area on magnetic resonance imaging [MRI]) and more continuous CFAE surface area than persistent AF.34 The relationship between CFAE sites and localised drivers is not clear. In our study, prolonged fractionated electrograms were more frequently ob-served at the reentrant driver regions compared with non-driver regions (62 % versus 40 %; p=0.04). Additionally electrograms recorded on a multielectrode catheter covered most of the AF cycle length at the driver regions, which indicate towards the possibility of localised reentry.14 Of note, multi-electrode endocardial mapping was not performed simultaneously with the body surface mapping. Of note, 50 % of CFAE sites

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Clinical Arrhythmias Figure 3: Driver-based Ablation

(A) Targeted signal and endpoint of local radiofrequency (RF) application. The rapid and fragmented potentials in the driver area are targeted. The endpoint of RF application is organisation of the local fragmented signals and slowing of the local AF cycle length at the RF site. (B) A typical example of driver-based ablation. In this case, based on the body surface mapping result, left atrial inferior was targeted at first because of high density of reentrant drivers and the fact that fragmented activities were observed in the coronary sinus, left atrial septum; ridge and anterior were then followed. Finally atrial fibrillation terminated at left atrial anterior (blue spot).

Figure 4: Typical Examples of Repeat Mapping

The results of repeat mapping after ablation showed three different patterns: (1) Elimination of the targeted driver by effective ablation (red dotted circle); (2) persistence of the targeted driver indicating insufficient local ablation and requiring additional RF applica-tions at the same region (blue dotted circle); and (3) new driver appearance at a contigu-ous or completely different region (yellow dotted circle). ABL = .ablation

have been reported to be passive bystanders due to non-local signal or wave collisions.35,36 Non-invasive mapping may be considered to reveal critical CFAE sites harbouring localised AF drivers. Interestingly, a previous report showed that 89 % of CFAE sites were located at non-scar and patchy scar areas (41 % at patchy fibrosis area; 48 % at healthy area).34 Another study demonstrated that localised reentrant drivers are located at the border of fibrotic areas,37 with the good correlation between LA fibrosis burden and the number of localised reentrant driver regions (r=0.42; p=0.04). It suggested that the border zone of fibrosis allows formation of a substrate favourable for slow conduction and reentry of wavelets (reentrant driver) capable of perpetuating AF.37

Non-invasive Mapping-guided Ablation The order of ablation is determined based on the cumulative driver map (see Figure 1C). After acquiring atrial geometry on 3D-electroanatomical mapping system (CARTO3; Biosense Webster Inc), the region having the highest density of reentrant drivers is targeted first followed by the region with the second-highest driver density and so on. Within the driver area, rapid and continuous fragmented signals and the activation gradient between proximal and distal electrodes are locally

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mapped and targeted for ablation.38 The endpoint of RF application is elimination of fragmented potential and slowing of the AF cycle length at the local site (see Figure 3A). Each RF application targets dominant clusters of AF driver at 30–40 W (25 W in posterior wall) using an irrigated-tip catheter with temperature cut-off set at 45°C. If AF persists after ablation of the first targeted region, the second-highest density area of driver is subsequently ablated in the same way (see Figure 3B).

The endpoint of the procedure is AF termination (sinus rhythm [SR] or AT) or completion of RF applications targeting all driver areas. If the drivers are found to be present around PVs, ipsilateral PV isolation is routinely performed. Reentrant drivers are more preferentially targeted than focal drivers because of the fact that sites harbouring atrial focal activities during AF were not found to be strongly associated with AF termination.32 Also, stable drivers with good quality signals on the non-invasive map are targeted regardless of their type. AF sustained after driver-based ablation is electrocardioverted.

Acute and Long-term Clinical Outcome After Driver-guided Ablation In our series of 103 persistent AF patients who underwent driverbased ablation,14 AF terminated during the procedure in 82 (80 %) patients with RF duration of 35±21 minutes. The mode of termination was SR in 28 (34 %) and AT in 54 (66 %) patients. AF termination with only driver ablation without linear lesions was achieved in 65 (63 %) patients. The number of targeted region for AF termination increased with AF duration (three in AF lasting <3 months, four in AF lasting 4–6 months and six in AF lasting >6 months). Inversely, the termination rate decreased with AF duration (85 % in AF lasting <3 months, 82 % in AF lasting 4–6 months, 67 % in AF lasting 7–9 months, 36 % in AF lasting 10–12 months and 15 % in AF lasting >12 months). Moreover, the patients with SR at the beginning of the procedure demonstrated the highest termination rate of 88 %. An impressive finding of driverbased ablation is that high AF-termination rate was achieved with re-duced RF-time compared with the stepwise approach (28±17 versus 65±33; p<0.0001). At 12 months post ablation, 64 % of patients maintained SR and 22 % were in AT. In this study, 85 % patients with AF termination were free from AF at 1 year after the procedure, which was comparable to stepwise ablation strategy. Also, the AF-free survival rate was higher in patients with acute AF termination than non-termination (85 % versus 63 %; p=0.045). In another population, RF time for AF termination increased with the number of driver regions and correlated to cycle length of left and right atrial appendages (see Figure 2B).39 Continuous AF duration, left appendage cycle length, number of reentrant drives and surface area of LA were independent predictors of AF termination on multivariable analysis (see Figure 2C).

These results suggest that driver-based ablation is feasible and effective in patients with persistent AF and those having progressed atrial remodelling with extended fibrosis (AF duration >12 months) continue to pose a challenge.

Recently, a prospective multicentre study (non-invasive mapping of atrial fibrillation study [AFACART]) demonstrated feasibility and utility of body surface mapping in persistent AF.40 In this study, 118 persistent AF patients (AF duration <1 year) were enrolled among eight European centres that had no prior experience using noninvasive system for driver-guided ablation to evaluate its acute success rate, RF time and clinical outcome at 12 months. Acute success (AF termination) was achieved in 64 % patients by driverbased ablation with 46±28 minutes of RF time. During 6±3 months’ follow-up, 83 % of patients were free from AF including recurrent AT

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in 38 % patients. These results indicate that driver-guided ablation of persistent AF is feasible and its outcomes reproducible in centres with no prior experience.

Figure 5: Typical Example of AF Termination After Repeat Mapping

Limitation and Prospects of Body Surface Mapping Non-invasive body surface mapping of AF drivers have some limitations: 1) Assessment of the drivers in the septal area is difficult. It is projected posteriorly on right atrium or anteriorly in the interatrial groove from right/left septum. These areas are close to each other and located under the epicardium making it difficult to identify driver area from body surface signals. 2) Agreement between driver areas and ablation sites may not be perfect because the body surface mapping system (ECVUE) does not have 3D-mapping navigation system. Although image integration with CARTO3 is possible, it may not be performed in all cases. 3) Accuracy of detection of small amplitude and very short cycle length (very rapid drivers) signals is not reliable because of the preset limits on the range of acceptable signal/noise ratio and window of analysable AF cycle length (4–8 Hz). The sensitivity is low in the case of far-field and small signals (<0.15 mV), particularly in scar tissue where they may not be detected correctly. In such areas, global activation can be used as a surrogate, yet it may be difficult to distinguish reentrant activity from focal activity. 4) Reconstructed epicardial electrogram signals may be affected by tissues between the epicardium and body surface and specific anatomical conditions (high/low BMI, lung disease, limited coverage of the vest due to body habitus). 5) Transformation of data to phase-based analysis may demonstrate false reentrant activity because of interpolation of incomplete wave curvatures. To resolve this matter, local raw electrograms need to be checked manually to ascertain sequential propagation of regional waves. 6) Finally, reentrant and focal drivers detected by non-invasive body surface mapping were not validated by concurrent endocardial mapping, AF substrates are dynamic 3D structures with a range of discordance between the endocardial and epicardial tissue.41 Hence further examinations will be needed to validate AF mechanisms including reentrant and focal drivers.

The non-invasive technique has been recently used to remap AF immediately after driver ablation. In fact, the critical point of driverbased ablation is to assess elimination of drivers after ablation.

Moreover, incomplete RF application may not impact drivers or generate new AF substrate via slow conduction in the heterogenous region. In a small number of patients, we have shown the results of repeat mapping with different patterns (elimination, persistence and new appearance of driver) (see Figure 4).42 Figure 5 demonstrates a typical example of AF termination after repeat body surface mapping.

A new reentrant driver appeared at the posterior of left superior PV on remapping AF persisting post driver ablation, AF was terminated by ablation in this area. Repeat non-invasive mapping provides important information on the dynamics of driver domains during ablation. Repeat

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Calkins H, Kuck KH, Cappato R, et al. 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. Europace 2012;14:528–606.

Swartz JF, Pellersels G, Silvers J, et al. A catheter-based curative approach to atrial fi-brillation in humans. Circulation 1994;90:I–335.

Haïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ec-topic beats originating in the pulmonary veins. N Engl J Med 1998;339:659–66.

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Persistent atrial fibrillation (AF) (54-year-old male) with maximum AF duration of 5 months.

AF persisted after ablation for all driver regions (left atrial septum, inferior, appendage, left superior pulmonary vein [PV]). Repeat mapping with body surface mapping revealed new reentrant driver region at the posterior of left superior PV (red dotted circle), AF terminated to sinus rhythm 20 seconds after RF application at this area (blue spot). LA = left atrium; LAA = left atrial appendage; LSPV = left superior pulmonary vein; RF = radiofrequency; SCI = shortest complex interval.

mapping can reveal residual and new drivers, which have the potential to increase the AF termination rate and improve clinical outcomes.

Conclusion Non-invasive AF mapping is feasible and guides ablation by providing panoramic beat-to-beat mapping to understand dynamic AF mechanisms. Driver-guided ablation promises equivalent clinical results with less RF time compared with stepwise ablation. Repeat AF mapping post-ablation may provide insights into the impact of ablation on drivers, emergence of residual or possibly new drivers and thereby improve this strategy of AF management. ■

Clinical Perspective • Localised reentrant and focal drivers play an important role in perpetuating atrial fibrillation (AF).

• Non-invasive body surface mapping visualises AF drivers in panoramic beat-to-beat mapping and enables understanding of dynamic AF mechanisms.

• Driver-guided ablation achieves similar AF termination rate with a relatively lesser ex-tent of ablation than the stepwise approach, which may improve the clinical outcome in persistent AF. • When AF persists after driver ablation, repeat mapping allows assessment of the impact of ablation on the drivers and detection of emerging or previously subdued drivers, which continue to maintain AF.

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6. 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.

7. Jaïs P, Hocini M, Hsu LF, et al. Technique and results of linear ablation at the mitral isthmus. Circulation 2004;110:2996–3002.

8. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: Mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044–53.

9. Haïssaguerre M, Sanders P, Hocini M, et al. Catheter ablation of long-lasting persistent atrial fibrillation: critical structures for termination. J Cardiovasc Electrophysiol 2005;16:1125–37.

10. Spach MS, Dolber PC. Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic

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Rostock T, Drewitz I, Steven D, et al. Characterization, mapping, and catheter ablation of recurrent atrial tachycardias after stepwise ablation of long-lasting persistent atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:160–9.

Cuculich PS, Wang Y, Lindsay BD, et al. Noninvasive characterization of epicardial activation in humans with diverse atrial fibrillation patterns. Circulation 2010;122:1364–72.

Haïssaguerre M, Hocini M, Denis A, et al. Driver domains in persistent atrial fibrillation. Circulation 2014;130:530–8.

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16. Haïssaguerre M, Hocini M, Sanders P, et al. Localized sources maintaining atrial fibrillation organized by prior ablation.

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17. Narayan SM, Krummen DE, Enyeart MW, et al. Computational mapping identifies localized mechanisms for ablation of atrial fibrillation. PLoS One 2012;7:e46034.

18. Efimov IR, Nikolski VP, Salama G. Optical imaging of the heart. Circ Res 2004;95:21–33.

19. Cox JL, Canavan TE, Schuessler RB, et al. The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation.

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20. Sahadevan J, Ryu K, Peltz L, et al. Epicardial mapping of chronic atrial fibrillation in patients: preliminary observations. Circulation 2004;110:3293–9.

21. Schuessler RB, Kawamoto T, Hand DE, et al. Simultaneous epicardial and endocardial activation sequence mapping in the isolated canine right atrium. Circulation 1993;88:250–63.

22. Kneller J, Zou R, Vigmond EJ, et al. Cholinergic atrial fibrillation in a computer model of a two-dimensional sheet of canine atrial cells with realistic ionic properties. Circ Res 2002;90:E73–E87.

23. Umapathy K, Nair K, Masse S, et al. Phase mapping of cardiac fibrillation. Circ Arrhythm Electrophysiol 2010;3:105–14.

24. Rudy Y, Burnes JE. Noninvasive electrocardiographic imaging.

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25. Spach MS, Barr RC, Lanning CF, et al. Origin of body surface QRS and T wave potentials from epicardial

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potential distributions in the intact chimpanzee. Circulation 1977;55:268–8.

26. Durrer D, van Dam RT, Freud GE, et al. Total excitation of the isolated human heart. Circulation 1970;41:899–912.

27. Ramanathan C, Ghanem RN, Jia P, et al. Noninvasive electrocardiographic imaging for cardiac electrophysiology and arrhythmia. Nat Med 2004;10:422–8.

28. Haïssaguerre M, Hocini M, Shah AJ, et al. Noninvasive panoramic mapping of human atrial fibrillation mechanisms: a feasibility report. J Cardiovasc Electrophysiol 2013;24:711–7.

29. Shah AJ, Hocini M, Xhaet O, et al. Validation of novel 3-dimensional electrocardio-graphic mapping of atrial tachycardias by invasive mapping and ablation: a multicenter study. J Am Coll Cardiol 2013;62:889–97.

30. Hocini M, Shah AJ, Denis A, et al. Noninvasive 3D mapping system guided ablation of anteroseptal pathway below the aortic cusp. Heart Rhythm 2013;10:139–41.

31. Wang Y, Cuculich PS, Zhang J, et al. Noninvasive electroanatomic mapping of human ventricular arrhythmias with electrocardiographic imaging. Sci Transl Med 2011;3:98ra84.

32. Takahashi Y, Hocini M, O’Neill MD, et al. Sites of focal atrial activity characterized by endocardial mapping during atrial fibrillation. J Am Coll Cardiol 2006;47:2005–12.

33. Zellerhoff S, Hocini M, Dubois R, et al. Mechanisms driving paroxysmal AF displayed by noninvasive panoramic imaging (AB 35-05). Heart Rhythm 2013;10:S41–95.

34. Jadidi AS, Cochet H, Shah AJ, et al. Inverse relationship between fractionated electrograms and atrial fibrosis in persistent atrial fibrillation: combined magnetic resonance imaging and high-density mapping. J Am Coll Cardiol 2013;62:802–12.

35. Jadidi AS, Duncan E, Miyazaki S, et al. Functional nature of electrogram fractionation demonstrated by left atrial highdensity mapping. Circ Arrhythm Electrophysiol 2012;5:32–42.

36. Narayan SM, Wright M, Derval N, et al. Classifying fractionated electrograms in human atrial fibrillation using monophasic action potentials and activation mapping: evidence for localized drivers, rate acceleration, and nonlocal signal etiologies. Heart Rhythm 2011;8:244–53.

37. Cochet H, Dubois R, Relan J, et al. Relationship between rotor activity and fibrosis in persistent atrial fibrillation: a combined noninvasive mapping and MRI study (PO 06-61).

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Diagnostic Electrophysiology & Ablation

Long-term Outcomes of Ventricular Tachycardia Ablation in Different Types of Structural Heart Disease Jackson J Liang, Pasquale Santangeli and David J Callans Electrophysiology Section, Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, US

Abstract Ventricular tachycardia (VT) often occurs in the setting of structural heart disease and can affect patients with ischaemic or nonischaemic cardiomyopathies. Implantable cardioverter-defibrillators (ICDs) provide mortality benefit and are therefore indicated for secondary prevention in patients with sustained VT, but they do not reduce arrhythmia burden. ICD shocks are associated with increased morbidity and mortality, and antiarrhythmic medications are often used to prevent recurrent episodes. Catheter ablation is an effective treatment option for patients with VT in the setting of structural heart disease and, when successful, can reduce the number of ICD shocks. However, whether VT ablation results in a mortality benefit remains unclear. We aim to review the long-term outcomes in patients with different types of structural heart disease treated with VT ablation.

Keywords Ventricular tachycardia, catheter ablation, outcomes, survival, cardiomyopathy Disclosure: Jackson Liang and Pasquale Santangeli have no conflicts of interest to declare. David J Callans has received honoraria for consulting and/or lectures from Biosense Webster, Biotronik, Boston Scientific, Medtronic and St Jude Medical.

Received: 10 June 2015 Accepted: 19 October 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(3):177–83. Access at: www.AERjournal.com Correspondence: David J Callans, Hospital of the University of Pennsylvania, 9 Founders Pavilion – Cardiology, 3400 Spruce St, Philadelphia, PA, 19104, US. E: david.callans@uphs.upenn.edu

Ventricular tachycardia (VT) is a significant cause of morbidity and mortality in patients with structural heart disease (SHD). While implantable cardioverter-defibrillators (ICDs) have been shown to be effective in preventing sudden death due to ventricular arrhythmias, they are not able to prevent recurrent VT episodes. Antiarrhythmic drugs (AADs) have some demonstrated efficacy in preventing VT episodes, although options remain limited in patients with SHD and the degree of benefit is suboptimal. Amiodarone is the most effective AAD, but is associated with significant side-effects with long-term use, and many patients are unable to tolerate the medication.

In this article, we will summarise the available data on long-term outcomes following VT ablation in patients with different types of SHD.

Heterogeneity of Ventricular Tachycardia Ablation Studies – Impact on Long-term Outcomes

With the advances in technology over the past two decades, catheter ablation has become an increasingly utilised adjunctive treatment modality for patients with VT. Catheter ablation has been clearly shown to be effective in decreasing the number of VT episodes, including antitachycardia pacing (ATP) therapies and shocks. While catheter ablation reduces long-term VT recurrences, it has not been shown to provide mortality benefit in patients with SHD.1 In this regard, patients still tend to be referred for ablation late in their disease course. Two prior studies have shown that early referral for ablation in patients with ischaemic and non-ischaemic cardiomyopathy (ICM and NICM) is associated with improved long-term VT suppression.2,3

The 2009 VT ablation guidelines have proposed standards for reporting long-term outcomes after VT ablation for clinical trials (see Table 1).4 However, the outcomes in previous smaller retrospective studies have been quite variable. The patient populations in different studies may vary significantly with regards to the number of VT episodes, haemodynamic stability of VTs, presence of back-up ICD, etc. Additionally, ablation strategies (i.e. endocardial versus endocardial/epicardial approach; mapping and ablation approaches) may differ between studies, based on investigator and institutional preferences. Substrate-based ablation approaches, which are often used in patients with haemodynamically unstable VT, may differ greatly between VT ablation centres (i.e. late potential ablation, local abnormal ventricular activity ablation, scar homogenisation, scar dechannelling, linear ablation strategies and core isolation).5–12 When VT recurs after an initial ablation procedure, repeat ablation may be necessary to achieve long-term suppression.13 While some studies

There have been limited data published from prospective randomised controlled trials examining the long-term outcomes of VT ablation.

Most outcome studies have been single or multicentre retrospective observational experiences, and case series with limited sample sizes, so are subject to a variety of biases and confounding factors.

report long-term outcomes following the index ablation procedure, others have referred to long-term outcomes following the last ablation procedure in patients requiring multiple procedures. Therefore, it is of utmost importantance that providers carefully review the methods of each study, particularly inclusion and exclusion criteria, prior to extrapolating results to individual patients in clinical practice.

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Diagnostic Electrophysiology & Ablation Table 1: Proposed Standards for Reporting Long-term Outcomes after VT Ablation For Clinical Trials Required Follow-up Duration • VT recurrence* (minimum follow-up duration of 6–12 months) • Mortality (minimum follow-up duration of 1 year) Efficacy Endpoints • Spontaneous recurrence of any sustained VT • Freedom from VT in absence of antiarrhythmic drug use (follow-up begins 5 half-lives after drug discontinuation, or 3 months after stopping amiodarone) • Death Other Outcomes that should be Reported if Possible • Number of VT recurrences during follow-up period • Recurrence of monomorphic VT (as opposed to VF or polymorphic VT) • Freedom from VT with previously ineffective antiarrhythmic therapy • Improvement in VT frequency (i.e. >75 % decrease in VT frequency for 6-month monitoring period before and after ablation) • Quality of life • Cost-effectiveness *Ventricular tachycardia (VT) recurrence = any VT episode lasting >30 s or requiring implantable cardioverter-defibrillator intervention.

Table 2: Long-term VT Recurrence Rates after Catheter Ablation in Patients with Ischaemic Cardiomyopathy Author

Year

Number

Follow-up VT

of

(Months)

Patients Morady et

al.29

Kim et al.22

Recurrence

9 13

1994 21

13 45

Gonska et al.23

1994

Rothman et al.25

1997 35

14 31 18 31

24

20

Stevenson et al.26

1998 52

Ortiz et al.30

1999 34

26 38

El-Shalakany et al.31

1999 15

15 27

Calkins et al.18

2000 119

Borger van der Burg et al.32 2002

89

8 46 34

23

Della Bella et al.27

2002 124

41 28

O’Donnell et al.33

2002 109

61 23

Segal et al.34

2005 40

36 57

Verma et al.35

2005 46

16 37

Stevenson et al.19

2008 231

6 47

Tanner et al.20

2010 63

12 49

Dinov et al.36

2014 164

27 57

Prioretti et al.28

2015 87

21 26

Reddy et al. (SMASH-VT)14 2007 128

23

Kuck et al. (VTACH)15

23 53

2010 107

Al-Khatib et al. (CALYPSO)16 2015

27

6

12 62

*This study included 136 patients in total, only 72 of whom underwent radiofrequency ablation.

VT = ventricular tachycardia. Adapted with permission from: Santangeli et al., 2011.91

Ischaemic Cardiomyopathy There have been only three major prospective randomised clinical trials examining long-term outcomes after VT ablation in patients with ICM.14–16 The first large-scale prospective randomised controlled trial examining ablation versus medical therapy in patients with ICM was the Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular Tachycardia (SMASH-VT) study.14 This trial initially enrolled only patients with recently implanted ICDs for secondary prevention and later included those who underwent ICD implantation for primary prevention who had received an appropriate ICD therapy for a single VT or ventricular fibrillation (VF) episode. A total of 128 patients were

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The second landmark trial was the Ventricular Tachycardia Ablation in Coronary Heart Disease (VTACH) study: a prospective, open, randomised control trial involving 16 centres in four European countries.15 The investigators enrolled 110 patients with haemodynamically stable VT, prior MI and reduced left ventricular ejection fraction (LVEF), who were randomly assigned to catheter ablation and ICD versus ICD alone. The primary endpoint was time to first VT/VF recurrence. Of the 107 patients included in the analysis (52 ablation; 55 control), median time to VT/VF recurrence in the ablation group was longer than the control group (18.6 versus 5.9 months). After 2 years, those randomised to ablation had superior VT/VF-free survival (47 versus 29 %; HR 0.61; 95 % CI 0.37–0.99; p=0.045) and were more likely to be free from cardiac hospital readmission (67 versus 45 %; HR 0.55; 95 % CI 0.30–0.99; p=0.044). Additionally, those in the ablation group on average had significantly fewer appropriate ICD shocks per patient year (mean 0.6±2.1 versus 3.4±9.2 shocks; p=0.018).15

(%)

1993 15 72*

enrolled and randomly assigned to catheter ablation or medical therapy (64 in each arm). The primary endpoint was survival from any appropriate ICD therapy (ATP or shock), and secondary endpoints included freedom from inappropriate ICD shock, death and ICD storm (≥3 shocks in 24-hour period). Freedom from recurrent VT/VF resulting in appropriate ICD therapy after 2 years of follow-up was significantly higher in the ablation arm (88 versus 67 %; HR 0.35; 95 % CI 0.15–0.78; p=0.007) compared with controls.14

The Catheter Ablation for VT in Patients with Implantable Cardioverter Defibrillator (CALYPSO) trial was a small prospective randomised trial comparing a strategy of early catheter ablation versus AADs for VT in patients with ICM with ICDs who had received appropriate ICD therapies for VT.16 This multicentre pilot study enrolled a total of 27 patients (13 ablation; 14 AAD), only 17 (71 %) of whom completed 6 months of follow-up. Rates of VT recurrence in this population of patients with multiple prior appropriate ICD therapies were significantly higher than those previously reported in SMASH-VT and VTACH: 62 % had recurrent VT in the ablation arm at 6 months following the ablation procedure.16 The 2-year VT-free survival rates in SMASH-VT and VTACH were 88 % and 47 %, respectively, while the 6-month VT-free survival rate in the much smaller CALYPSO trial was significantly lower (38 %), probably due to the fact that the trial selectively enrolled higher-risk patients known to have recurrent VT requiring appropriate ICD therapies.

Prospective non-randomised studies examining patients with ICM and varying VT burden have reported a wide range of long-term VT-free survival following ablation.

In 1997, Strickberger et al. prospectively enrolled 21 patients with ICD and frequent ICD therapies (mean of 25±88 ICD therapies within 36±51 days preceding ablation). Acute abolition of the clinical VT occurred in 76 %.17 Although this study did not report overall long-term VT-free survival, they did report a decrease in frequency of ICD therapies and improvement in quality of life in those with acute ablation success over a follow-up period of 11.8±10 months.17 The Cooled RF Ablation System clinical trial (2000) was a prospective, observational trial that included 146 patients with SHD, the majority (82 %) of whom had ICM.18 All patients had ICD implanted with haemodynamically stable VT and had failed at least two AADs. Mean follow-up duration was 243±153 days. One year after ablation, the VT

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Long-term Outcomes of Ventricular Tachycardia Ablation in Different Types of Structural Heart Disease

recurrence rate was 56 %, while the 1-year mortality rate was 25 %.

Of the 122 patients with at least 2 months clinical follow-up, 81 % had >75 % reduction in VT frequency in the first 2 months after ablation.

The Multicenter Thermocool VT Ablation Trial was a prospective observational trial that enrolled 231 patients with recurrent monomorphic VT in setting of ICM treated with catheter ablation.19 This study was focused on evaluating the efficacy of VT ablation in very high-risk patients, and therefore included patients with haemodynamically unstable, unmappable and multiple VTs. After 6 months, 53 % of patients were free from recurrent incessant VT or intermittent VT and the mortality rate at 1 year was 18 %.19

Table 3: Long-term VT Recurrence Rates after Catheter Ablation in Patients with Dilated Non-ischaemic Cardiomyopathy

2006

8

The EURO-VT study was a multicentre, prospective, non-randomised observational study that enrolled 63 ICM patients with multiple (>4) episodes of symptomatic VT within 6 months (or VT storm) of randomisation.20 Over mean follow-up of 12 months, 49 % had VT recurrence, although the majority (79 %) of those with VT recurrence had reduction in ICD therapies.20

Cano et al.40

2009

22

Schmidt et al.41

2010

Retrospective observational studies examining VT ablation for patients with ICM published have reported varying long-term rates of VT recurrence ranging from 16 to 66 %. Table 2 summarises long-term outcomes of VT ablation in patients with ICM.10,14–16,18–36

Non-ischaemic Cardiomyopathy To date, there have been no prospective randomised trials describing outcomes following VT ablation in patients with NICM. Patients with NICM have higher rates of acute procedural failure and long-term VT recurrence following ablation compared with ICM.28,36 Unlike ICM, where the underlying substrate is relatively homogeneous, patients with NICM have heterogeneous substrates that reflect the variety of pathogenetic processes. However, the distribution of abnormal substrates in patients with non-ischaemic pathology has been shown fairly homogeneous, with a typical involvement of perivalvular regions and high prevalence of intramural and/or epicardial substrates. Table 3 summarises long-term outcomes of VT ablation in dilated NICM (DCM),6,10,37–44 and Table 4 summarises long-term outcomes of VT ablation in other forms of NICM.45–65 The Heart Center of Leipzig VT (HELP-VT) study was a prospective observational European single-centre study that enrolled 63 patients with NICM and 164 patients with ICM who were treated with VT ablation between 2008 and 2011.36 Activation mapping and ablation were performed in nearly half of patients, and substrate modification was not uniformly performed. Acute procedural success (defined as complete non-inducibility after ablation) was achieved in 66.7 % of those with NICM (versus 77.4 % in ICM; p=0.125). Long-term VT-free survival was significantly lower for NICM compared with ICM: cumulative VT-free survival after median follow-up periods of 20 and 27 months for NICM and ICM, respectively, were 23 % and 43 % (HR 1.62, 95 % CI 1.12–2.34; p=0.01). VT-free survival rates at 1 year were 40.5 % for NICM and 57 % for ICM.36 Proietti et al. recently reported their experience with a substrate-guided ablation approach in 55 NICM and 87 ICM patients.28 They showed lower rates of freedom from recurrent VT in those with NICM compared with ICM (49 % versus 74 %; p=0.03) over a follow-up period of 21.1 months.

They attributed their higher rates of long-term success (compared with previous reports) to the fact that higher rates of acute procedural success might have been achieved using a substrate-based approach.28

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Author

Year

Number of Patients

Epi Mapping/ Follow-up VT Ablation, (n) (Months) Recurrence (%)

Marchlinski et al.10 2000

7

0

8

43

Hsia et al.37

2003

19

3

22

74

2004

28

8

Endo = 29 Endo = 47

Soejima et

al.38

Cesario et

al.39

Nakahara et al.

42

Epi = 10

Epi = 43

8

12

25

22

18

29

16

15

12

47

2010

16

12

14

50

Kuhne et al.43

2010

24

7

18

If LP (+) = 33

Haqqani et al.44

2011

31

14

20

32

2012

14

Not reported

13

14

If LP (-) = 93

Vergara et

al.6

Endo = endocardial; Epi = epicardial; LP = late potentials; VT = ventricular tachycardia.

Table 4: Long-term VT Recurrence Rates after Catheter Ablation in Patients with NICM Different from DCM Author

Year

NICM Type

Number of Patients

Follow- VT up Recurrence (Months) (%)

Marchlinski et al.45

2004

ARVC

19

27

11

Verma et al.46

2005

ARVC

22

36

47

Yao et

al.47

2007

ARVC

32

29

19

Dalal et al.48

2007

ARVC

24

32

91

Garcia et al.49

2009

ARVC

13

18

23

2011

ARVC

49

40

31

2012

ARVC

87

88

85**

Bai et

al.50

Philips et al.51 al.52*

Mussigbrodt et

2015

ARVC

28

19

47

Santangeli et al.53

2010

HCM

22

20

27

Dukkipati et al.54

2011

HCM

10

38

30

Koplan et al.

55

2006

CS

8

6

75

Jefic et al.56

2009

CS

9

10

44

Naruse et al.57

2014

CS

14

33

43

Kumar et al.

58

2015

CS

21

58

86

Gonska et al.59

1996

CHD

16

16

0

Furushima et al.60

2006

CHD

7

61

0

al.61

2007

CHD

11

30

9

2007

CHD

8

35

25

Zeppenfeld et Kriebel et al.62 Kapel et

al.63

2015

CHD

34

46

12

Dello Russo et al.64

2012

Myocarditis 20

28

10

Maccabelli et al.65

2014

Myocarditis 26

23

23

*Long-term outcomes are following last ablation procedure. Of note, all 28 patients underwent index ablation due to ventricular tachycardia (VT) storm. **Cumulative freedom from VT after a single ablation procedure at 10 years was 15 %. Rates of freedom from VT at 1, 2 and 5 years were 47 %, 31 % and 21 %, respectively. ARVC = arrhythmogenic right ventricular cardiomyopathy; CHD = congenital heart disease; CS = cardiac sarcoidosis; HCM = hypertrophic cardiomyopathy; NICM = non-ischaemic cardiomyopathy.

One large single-centre retrospective observational study, which examined 226 patients with NICM treated with VT ablation, reported 29 % rate of death or transplant at long-term follow-up (4.4±3.3 years follow-up), while the secondary composite endpoint of death, heart

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Diagnostic Electrophysiology & Ablation transplantation or hospitalisation for VT recurrence at 1 year (after the last ablation) was 31 %.66

Dilated Cardiomyopathy Patients with DCM tend to have worse prognosis after VT ablation compared with arrhythmogenic right ventricular cardiomyopathy (ARVC) and congenital heart disease (CHD).66 Retrospective studies have demonstrated VT recurrence rates ranging between 46 and 61 % during long-term follow-up (mean 11–25 months for individual studies).38 Patterns of scar in non-ischaemic DCM have been previously described. Classically, there is involvement of the base of the heart along the perivalvular region, particularly around the basolateral LV.37,67 In this group of patients, the prevalence of intramural and epicardial substrates is high. At our institution, up to 11.3 % of all NICM patients had an isolated septal substrate. Haqqani et al. reported that this particular population frequently required multiple procedures to achieve VT control. VT recurred in 32 % of patients over mean follow-up of 20 months after ablation.44 Oloriz et al. later classified 87 NICM patients treated with ablation as having either predominantly anteroseptal versus inferolateral scar based on endocardial unipolar voltage mapping.68 Patients with inferolateral scar frequently had epicardial substrate, while those with anteroseptal scar more often had intramural septal substrate. They noted a higher VT recurrence rate in those with anteroseptal scar (74 vs 25 %; p<0.001), resulting in higher redo ablation rate (59 versus 7 %; p<0.001). Anteroseptal scar was an independent predictor of VT recurrence in the multivariate analysis (HR 5.5; p<0.001).

Arrhythmogenic Right Ventricular Cardiomyopathy Long-term success rates of VT ablation in patients with ARVC have historically been quite variable and highly dependent on the specific ablation approach adopted.45–48,52 Over a decade ago, Marchlinski et al. reported a long-term VT suppression rate of 89 % in 19 patients who underwent endocardial VT ablation over a mean follow-up duration of 27 months.45 They identified that in these patients, certain areas such as the perivalvular tricuspid/pulmonary valve regions and the RV free wall and septum (but not the RV apex) were more likely to harbour areas with abnormal electrograms. Verma et al. showed 1, 2, and 3-year VT recurrence rates of 23 %, 27 %, and 47 %, respectively.46 Dalal et al. later reported much worse long-term outcomes in 24 patients treated with endocardial VT ablation at 29 centres across the country between 1999 and 2006.48 In their study, they reported VT recurrence rates after a single procedure of 64 %, 75 %, and 91 % after 1, 2, and 3 years, respectively. They hypothesised that the dismal long-term success was due to the fact that ARVC was an electrically progressive disease.48 Later, Riley et al. elegantly showed with serial electroanatomical voltage mapping that although the RV progressively dilates, only the minority of patients have progression of endocardial scar, suggesting that an aggressive substrate modification may be effective in long-term VT control.69 In fact, given the more extensive epicardial pathological substrate in ARVC, catheter ablation approaches using a combination of endoepicardial substrate based ablation have been recently shown to significantly improve VT-free survival at the short to mid-term followup.49–51,70 Garcia et al. reported a series of 13 ARVC patients with VT undergoing endo-epicardial mapping and ablation.49 The authors confirmed a more extensive epicardial involvement in these patients, with a reported success rate of 77 % over a mean follow-up time of 18

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months. Similar findings have been reported by Bai et al.50 in a multicentre series of 49 patients undergoing either endocardial-only ablation (n=23), or endo-epicardial ablation (n=26). After a follow-up of at least 3 years, VT-free survival achieved 52.2 % in the endocardial-only ablation group and 84.6 % in the endo-epicardial ablation group. Two other studies from different institutions across US and Europe have recently reported the same results.51,70 In conclusion, endo-epicardial ablation is significantly more effective that endocardial-only procedures in achieving VT-free survival in patients with ARVC, essentially due to the peculiar epicardial to endocardial progression of the disease.

Hypertrophic Cardiomyopathy Malignant ventricular arrhythmias in patients with hypertrophic cardiomyopathy (HCM) stem from pathological myocardial fibrosis, disruption of cellular architecture and hypertrophied myocytes,71,72 which constitute the substrate for reentrant VTs. Studies evaluating the pattern of myocardial tissue scarring in HCM reported a high prevalence of mid-myocardial and epicardial fibrotic areas.73,74 Remarkably, in a small subset of patients in whom the disease evolves to the end-stage leading to aneurysm formation, a transmural scar can be detected.75,76 Until recently, the clinical experience with catheter ablation of VT was limited to patients with end-stage forms of the disease with apical aneurysms.76,77 Two recent studies have reported the feasibility and safety of VT ablation in larger series of patients with HCM also without apical aneurysms.53,54 In a multi-centre observational study, Santangeli et al. evaluated the role of VT ablation in a series of 22 patients with multiple episodes of drug-refractory VTs.53 In this study, an endo-epicardial ablation was required in 59 % of cases, and no major procedural complication was observed.

After an average follow-up of 20 months, freedom from recurrent VT reached 73 %. In a subsequent study, Dukkipati et al. reported 10 patients with HCM-related monomorphic VT treated with combined endocardial and epicardial ablation.54 Epicardial scar was identified in 80 % of patients, endocardial scar in 60 % and no scar in 10 %.

Five patients had stable inducible monomorphic VT and were treated with combined endocardial and epicardial ablation. Four underwent combined endocardial and epicardial ablation with a substrate-based approach based on sites of late/fractionated potentials with good pace maps. The final patient was non-inducible and had no endocardial or epicardial scar, so no ablation was performed. During mean long-term follow-up of mean 37.4±16.9 months, only three (30 %) patients had ICD shocks for recurrent VT (including the lone patient who was noninducible and had no electroanatomic scar).54

Cardiac Sarcoidosis From a clinical standpoint, cardiac sarcoidosis (CS) may be difficult to differentiate from other forms of NICM, such as ARVC.78 However, patients with CS typically present with more-extensive LV scar and may have septal involvement (which is rare in ARVC), in addition to worse overall long-term ablation outcomes.58,79 In 2006, Koplan et al. reported a 75 % VT recurrence rate within 6 months of ablation in eight patients with CS treated with catheter ablation for incessant VT.55 Two small observational studies showed long-term VT recurrence rates of 43–44 % over median follow-up periods of 10 and 33 months after ablation.56,57 In another study of eight patients with CS, the clinical VTs were successfully abolished in five (63 %).79 While the authors did not specify the recurrence rate of those with failed ablation, only one (20 %) of the five patients with successful ablation had recurrent VT after 6 months of follow-up.79

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Long-term Outcomes of Ventricular Tachycardia Ablation in Different Types of Structural Heart Disease

The largest study of catheter ablation for VT in patients with CS included 21 patients, who tended to have multiple inducible VTs, which were consistent with scar-related reentry.58 Voltage mapping demonstrated confluent RV and patchy LV scarring with a predilection for the septum, anterior wall and perivalvular regions. While RV epicardial scar is usually overlaid RV endocardial scar, this was not the case with the LV. The rate of complete acute procedural success was relatively poor, and freedom from VT after 1 year after a single procedure was only 25 % (37 % after multiple procedures). Ablation was effective, however, in acutely terminating VT storm in seven (78 %) of the nine patients who were referred for incessant VT.58

The VANISH trial is a prospective observational trial that is aiming to compare ablation versus aggressive AAD therapy in patients with prior MI who present with recurrent VT.84 Included patients will have prior MI with ICD in place, and must have been treated with at least one appropriate ICD therapy, and have failed at least one AAD. Goal enrolment is 260 patients, and patients will be randomised to either ablation or aggressive AAD therapy (high-dose amiodarone or addition of mexilitine). Duration of follow-up is 5 years, and primary outcome is a composite of appropriate ICD shocks, VT storm and death. Secondary outcome is all-cause mortality. The trial has finished enrolling patients and has an estimated study completion date of March 2016.

Repaired Congenital Heart Disease

STAR-VT is an open-label, prospective randomised trial that aims to examine whether scar-based VT ablation results in superior outcomes compared with routine AAD therapy in patients with monomorphic VT in the setting of ICM or NICM.85 Goal enrolment is 1,453 patients, and inclusion criteria include implantation of a St Jude Medical ICD or cardiac resynchronisation therapy device, ≥1 documented monomorphic VT episode (either spontaneous or induced during electrophysiological study or non-invasive programmed stimulation).

Patients will be randomised to either substrate-guided ablation using the FlexAbility Ablation Catheter versus routine drug therapy and followed for 1 year. The primary outcome measure will be freedom from any ICD shock (appropriate or inappropriate) for recurrent sustained VT (>30 s) in one year, and secondary outcome measures include number of cardiovascular-related hospitalisations and emergency room visits. This trial is currently enrolling patients and has an estimated study completion date of May 2021.

Compared with other aetiologies of NICM, long-term outcomes in patients with repaired CHD are quite favourable.66 Smaller reports have shown rates of VT-free survival ranging between 75 and 100 % over long-term follow-up (mean follow-up durations ranging between 16–61 months).59–62 In the largest series to date, Kapel et al. reported outcomes in 34 patients with repaired CHD (82 % with repaired Tetralogy of Fallot) treated with catheter ablation targeting anatomic isthmuses containing reentrant VT circuits.63 During long-term followup (mean 46 months), VT recurred in only 11.7 % of cases (0 % in those with complete procedural success versus 44 % in those without complete success), and one patient with poor cardiac function received an ICD shock for VF after ablation.63

Viral Myocarditis Arrhythmias including VT often occur during the acute phase of viral myocarditis due to the presence of active inflammation. Later, the long-term sequelae of viral myocarditis including fibrosis and scar may predispose to reentrant VT. Imaging with MRI in patients with viral myocarditis has shown that different viruses tend to have different patterns of myocardial involvement.80 Due to the variability of the scar distribution, pre-procedural imaging (MRI or CT) may be helpful when performing VT ablation in these patients. Using an imaging-guided approach, Maccabelli et al. found that patients with myocarditisrelated VT very frequently have epicardial substrate.65 Long-term (median 23 months) freedom from recurrent VT after ablation in their cohort was 77 %. Dello Russo et al. subsequently studied 20 consecutive patients with biopsy-proven viral myocarditis and VT refractory to AADs referred for catheter ablation.64 During long-term follow-up (median 28 months), 90 % of the patients remained free of sustained VT and only two (10 %) patients died from non-arrhythmic cardiac causes.64

Ongoing Trials There are multiple major ongoing trials that will further examine the long-term outcomes of VT ablation, and others which have been terminated due to difficult enrolment. Four of these ongoing trials include VT ablation versus Enhanced Drug Therapy (VANISH), the Substrate Targeted Ablation Using the FlexAbility Ablation Catheter System for the Reduction of Ventricular Tachycardia (STAR-VT) trial, PARTITA and the BERLIN study. Additionally, several ongoing studies are analysing effects of sympathetic modulation, including bilateral cardiac sympathetectomy (Cardiac Denervation Surgery for Prevention of Ventricular Tacharrhythmias [PREVENT VT])81 and renal sympathetic denervation (Renal SympathetiC Denervation to Suppress Ventricular Tachyarrhythmias [RESCUE-VT] and Renal Sympathetic Denervation as an Adjunct to Catheter-based VT Ablation [RESET-VT])82,83 as adjunct measures to prevent recurrent VT.

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The third large ongoing trial is the PARTITA trial, which is a large multicentre European trial aiming to determine whether timing of VT ablation after appropriate ICD shock affects long-term prognosis.86 The estimated enrolment is 590 patients who have ICD for primary or secondary prevention. After enrolment, all patients will remain in Phase A until receiving appropriate ICD shock, at which point they enter Phase B in which they will be randomised to immediate VT ablation after appropriate shock versus waiting until VT storm. Followup duration in Phase B is 2 years, and the primary outcome measure in Phase B will be worsening heart failure hospitalisations or allcause mortality. Secondary outcome measures include cardiovascular mortality, electrical storm or VT recurrence during Phase B. This study is currently recruiting patients, and has an estimated study completion date of September 2018.

The BERLIN study is a prospective randomised controlled trial taking place in Germany, which is aiming to enrol 208 patients with prior MI and LVEF 30–50 % who have an ICD indication and documented VT.87 Patients are randomised to either early ablation (immediately following ICD implantation) versus late ablation (after third ICD shock).

Primary endpoints include all-cause mortality and hospital admission secondary to cardiac causes, while the secondary endpoint is time to first ICD shock.

Complications While catheter ablation is an effective treatment option in the management of VT, it is not without risk. A recent meta-analysis reported overall complication rates in 8–10 % of procedures.88 While the majority of complications are related to vascular access, more serious complications, such as stroke or transient ischaemic attack, pericardial effusion or cardiac tamponade and even death, may rarely

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Diagnostic Electrophysiology & Ablation occur. Furthermore, since VT ablation procedures may be prolonged and significant amounts of fluids may be given during the procedure (particularly when ablating with irrigated catheters), close monitoring of haemodynamic and fluid status is paramount. Acute periprocedural haemodynamic decompensation occurred in 11 % of patients undergoing VT ablation for scar-related VT in one series.89 As such, patients should be medically optimised prior to the ablation procedure, and prophylactic support with percutaneous LV assist devices may be beneficial to facilitate mapping and ablation in certain high-risk patients.90

Timing and Patient Selection Since ICD shocks are associated with increased mortality and morbidity, VT ablation should be considered in all patients with SHD and recurrent VT refractory to at least one AAD. Retrospective studies have demonstrated improved VT-free survival with an early ablation approach,2,3 and several prospective clinical trials examining timing of VT ablation are currently ongoing, as described above. VT ablation has been shown to have similar safety and efficacy in elderly patients so older age alone should not be a deterrent.21 The potential risks and benefits must be considered in each particular patient prior to deciding whether to proceed with VT

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Frankel DS, Mountantonakis SE, Robinson MR, et al.

Ventricular tachycardia ablation remains treatment of last resort in structural heart disease: argument for earlier intervention. J Cardiovasc Electrophysiol 2011;22:1123–8.

Dinov B, Arya A, Bertagnolli L, et al. Early referral for ablation of scar-related ventricular tachycardia is associated with improved acute and long-term outcomes: results from the Heart Center of Leipzig ventricular tachycardia registry.

Circ Arrhythm Electrophysiol 2014;7:1144–51.

Aliot EM, Stevenson WG, Almendral-Garrote JM, et al. EHRA/ HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias: developed in a partnership with the European Heart Rhythm Association (EHRA), a Registered Branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA).

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Arenal A, Glez-Torrecilla E, Ortiz M, et al. Ablation of electrograms with an isolated, delayed component as treatment of unmappable monomorphic ventricular tachycardias in patients with structural heart disease. J Am Coll Cardiol 2003;41:81–92.

Vergara P, Trevisi N, Ricco A et al. Late potentials abolition as an additional technique for reduction of arrhythmia recurrence in scar related ventricular tachycardia ablation.

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Jais P, Maury P, Khairy P, et al. Elimination of local abnormal ventricular activities: a new end point for substrate modification in patients with scar-related ventricular tachycardia. Circulation 2012;125:2184–96.

Di Biase L, Santangeli P, Burkhardt DJ, et al. Endo-epicardial homogenization of the scar versus limited substrate ablation for the treatment of electrical storms in patients with ischemic cardiomyopathy. J Am Coll Cardiol 2012;60:132–41.

Soejima K, Stevenson WG, Maisel WH, et al. Electrically unexcitable scar mapping based on pacing threshold for identification of the reentry circuit isthmus: feasibility for guiding ventricular tachycardia ablation. Circulation 2002;106:1678–83.

Marchlinski FE, Callans DJ, Gottlieb CD, Zado E. Linear ablation lesions for control of unmappable ventricular tachycardia in patients with ischemic and nonischemic cardiomyopathy.

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Tzou WS, Frankel DS, Hegeman T, et al. Core isolation of critical arrhythmia elements for treatment of multiple scarbased ventricular tachycardias. Circ Arrhythm Electrophysiol 2015;8:353–61.

Santangeli P, Marchlinski FE. Substrate mapping for unstable ventricular tachycardia. Heart Rhythm 2015; doi: 10.1016/j. hrthm.2015.09.023. epub ahead of print.

Kosmidou I, Inada K, Seiler J, et al. Role of repeat procedures for catheter ablation of postinfarction ventricular tachycardia.

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Reddy VY, Reynolds MR, Neuzil P, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med 2007;357:2657–65.

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ablation. In all patients with VT who have an appropriate periprocedural risk and in whom VT ablation is likely to be successful, we recommend consideration of ablation early in the course of treatment, especially in those who wish to avoid or are intolerant of AADs.

Conclusions While catheter ablation is an effective treatment option for VT suppression in patients with SHD, long-term VT suppression rates vary based on the underlying aetiology. Although prior studies have not demonstrated long-term mortality benefit, ablation is effective in reducing long-term VT recurrences, abolishing VT storm and preventing ICD shocks. The overall outcomes associated with catheter ablation are worse in patients with NICM compared with those with ischaemic substrates, which is likely the result of more complex substrates in NICM patients with a higher prevalence of intramural and/or epicardial substrates. In survivors of VT who do not yet have ICDs in place, an early ablation strategy in addition to ICD may reduce the incidence of future ICD therapies. Ongoing studies are further evaluating whether earlier catheter ablation of VT is associated with improved outcomes. n

16. Al-Khatib SM, Daubert JP, Anstrom KJ, et al. Catheter ablation for ventricular tachycardia in patients with an implantable cardioverter defibrillator (CALYPSO) pilot trial. J Cardiovasc Electrophysiol 2015;26:151–7.

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Selecting the Appropriate Ablation Strategy: the Role of Endocardial and/or Epicardial Access M a r i o N j e i m a n d Fra n k B o g u n University of Michigan, Ann Arbor, MI, USA

Abstract Percutaneous catheter ablation has emerged as an effective treatment modality for the management of ventricular tachycardia. Despite years of progress in this field, the role of epicardial mapping and ablation needs to be further refined. In this review, we discuss the relationship between the type of underlying heart disease and the location of the arrythmogenic substrate as it pertains to a procedural approach. We describe the contribution of preprocedural and intraprocedural diagnostic tools for the localisation of the arrhythmogenic substrate, with a special emphasis on cardiac MRI and electrophysiological mapping. In our opinion, the preferred approach to target ventricular tachycardia should depend on the patient’s underlying heart disease and the location of scar tissue, which can be best visualised using cardiac MRI.

Keywords Catheter ablation, delayed enhancement, endocardial, epicardial, MRI, ventricular tachycardia Disclosure: The authors have no conflicts of interest to declare.

Received: 15 February 2015 Accepted: 27 October 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(3):184–8. Access at: www.AERjournal.com Correspondence: Frank Bogun, Cardiovascular Center, The University of Michigan, 1500 East Medical Center Drive, SPC 5853, Ann Arbor, MI 48109, USA. E: fbogun@med.umich.edu

Percutaneous ablation for ventricular tachycardia (VT) was first attempted in 1983 and has rapidly evolved to become an important option for controlling recurrent VTs.1 Endocardial ablation remained the only percutaneous approach until epicardial access was introduced

by Sosa et al. in 1996 and thereafter became progressively more available as an adjunctive strategy for the treatment of challenging arrhythmias.2 The improved arsenal of percutaneous technologies, and the advances in understanding VT substrates, paved the way for consideration of catheter ablation early on in the treatment of patients with VT.3 Despite the progress made in the field, some key questions regarding the role of percutaneous epicardial mapping and ablation in the treatment of VT remain: When should an epicardial approach be used in the treatment of VT? Should this depend on the disease substrate? Should it be performed during an endocardial mapping procedure, or after an endocardial ablation has failed? We will discuss criteria for selecting an appropriate approach to map and ablate VT, focusing on location and imaging of the arrhythmogenic substrate, specific situations where an epicardial approach may be beneficial and situtations where it is not indicated.

circuit may also encompass the endocardium and extend into the epicardium, with critical components that can be reached from either the left ventricular endocardium or the epicardium. Although VTs originate from scar tissue in the majority of patients with structural heart disease,4 they may occasionally have a focal source and can arise from the outflow tract region, similar to patients with idiopathic ventricular arrhythmias.

Identification of the Arrhythmogenic Substrate and Ventricular Tachycardia Ablation – Patients With Structural Heart Disease

Delayed enhanced cardiac MRI is used as the gold standard for imaging of scar tissue. The location of scar tissue on preprocedural MRI determines the odds of reaching the circuit from the endocardium or the epicardial space in a given patient. The location of the scar predicts, to some extent, the location of the critical VT isthmus.5,6 In patients with ischaemic cardiomyopathy, the scar is located in the subendocardium and extends to the epicardium depending on the patient’s specific coronary artery distribution (Figure 1). Hence, in the majority of postinfarction patients, the arrhythmogenic tissue can be accessed from the endocardium. In a series of 98 patients with prior MI, only two patients required an epicardial ablation procedure for VT.7 Similar data have been described by Sarkozy et al. who reported a prevalence of only about 6 % of patients with prior infarctions in whom epicardial circuits were confirmed.8 Therefore, in these cases, an endocardial approach should be considered as first line.

Understanding the underlying arrhythmogenic substrate that leads to VT is essential for a successful ablation procedure. As a result of the 3D structure of the myocardium, critical components of the VT reentry circuit may be confined to locations deep in the subendocardium, the midmyocardium or the epicardium, and may be beyond the reach of current endocardial ablation techniques. On the other hand, a single

On the other hand, scars in patients with nonischaemic cardiomyopathy are most often located intramurally. An epicardial origin is the next most frequent scar location, followed by endocardial scarring.9 Often the scar has a basal periannular distribution.10 The scar distribution is particularly important with respect to procedural outcome.5 The

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lowest success rates were reported in patients in whom the majority of the scar had an intramural distribution (Figure 2).5 The value of a preprocedural MRI with respect to a planned epicardial procedure is highest in patients with nonischaemic cardiomyopathy, especially if the scar is located epicardially (Figure 3). An epicardial approach is also beneficial if the scar is located intramurally within the left ventricular free wall. An intramural septal location (Figure 2) cannot be reached from the epicardial space in most patients, and therefore this approach should not be used in such a scenario.

The disease process in arrhythmogenic right ventricular cardiomyopathy (ARVC) starts in the epicardium, and therefore the epicardium is usually involved in these patients. Furthermore, the epicardial scar has been found to be larger than the endocardial scar, and therefore an epicardial procedure is often required for patients with ARVC. If an endocardial ablation procedure fails to identify critical VT sites, an epicardial approach should be considered. Transmural activation of the epicardium from the endocardium may be delayed due to scar tissue that insulates the arrhythmogenic tissue in the epicardium.11 Often the paravalvular area of the tricuspid annulus harbours critical sites of VT circuits. Thick endocardial scarring has been described in the periannular area, and may contribute to the failure of endocardial ablation in targeting VT reentrant circuits.12 Involvement of the left ventricle is not uncommon, and is frequently subepicardial or intramural.13 Often, to render patients with ARVC

Figure 1: Delayed-enhanced MRI in a Patient with Prior Inferoseptal Myocardial Infarction

Stack of short axis views from a delayed-enhanced MRI study showing delayed enhancement in a patient with prior inferoseptal MI. The endocardial areas with delayed enhancement are delineated by the thick white line. Reproduced with permission from Desjardins et al., 2009.6

Figure 2: Delayed-enhanced MRI of Intramural Scar in a Patient with Nonischaemic Cardiomyopathy

non-inducible, both epicardial and endocardial ablation procedures are necessary.

In patients with cardiac sarcoidosis, the arrhythmogenic substrate originates intramurally, and reaches the endocardium or epicardium by extension of the disease process. In a series of patients with cardiac sarcoidosis in whom mapping and ablation of VT was performed, most VTs originated from a periannular area surrounding the tricuspid annulus and did not require epicardial access.14 However, if imaging shows predominant epicardial scarring, an epicardial approach should be considered.5 For other types of structural heart disease including hypertrophic cardiomyopathy15 or Chagas disease, an epicardial ablation is often necessary and should be considered early in the ablation procedure.16,17

Location of the Arrhythmogenic Substrate and Ventricular Tachycardia Ablation – Patients Without Structural Heart Disease The majority of idiopathic ventricular arrhythmias originate from the outflow tracts18 with the right ventricular outflow tract being the most common origin.19,20 Idiopathic ventricular arrhythmias can also originate in the left ventricular outflow tract, the aortic sinuses of Vasalva,21 the epicardium,3 the papillary muscles22 or any other location within the heart including the intramural myocardium.23 An endocardial approach is most successful for the majority of these arrhythmias. For epicardial idiopathic arrhythmias, a combined approach from the coronary venous system and adjacent anatomic sites has been most effective, with a success rate around 70 %.24 In some reports, a subxiphoid epicardial approach has been used to eliminate those arrhythmias.24–26 However, several groups have more recently demonstrated that this approach has a lower success rate due to epicardial fat and the proximity of coronary arteries, and given the higher potential for periprocedural complications,26–28 this approach should be reserved for selected cases only.

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Stack of three short-axis views from a delayed-enhanced MRI image (basal, left; apical, right) in a patient with nonischaemic cardiomyopathy. In light orange, area of intramural delayed enhancement; in light blue, endocardial delayed enhancement secondary to two prior failed ablation procedures. Reproduced with permission from Desjardins et al., 2013.39

Table 1: Factors favouring the need for an epicardial approach in the treatment of ventricular arrhythmia Factors predicting the need for an epicardial approach Underlying substrate • More commonly needed in NICM versus ICM • Commonly needed in ARVC, HCM, Chagas disease Preprocedural considerations • Delayed precordial maximal deflection index of ≥0.55, pseudo 'delta wave' of ≥34 ms, shortest RS complex ≥121 ms, presence of q wave in lead I • Epicardial or intramural (non septal) scar by MRI • Mobile intracavitary thrombus • Artificial aortic and mitral valves • Failed endocardial approach Intraprocedural considerations • Normal bipolar endocardial voltage combined with abnormal unipolar endocardial voltage • Late activation map and absence of matching pace maps in the endocardium ARVC = arrhythmogenic right ventricular cardiomyopathy; HCM = hypertrophic cardiomyopathy; ICM = ischaemic cardiomyopathy; NICM = nonischaemic cardiomyopathy.

In summary, the type of structural heart disease and the resulting location of arrhythmogenic substrate indicate in most patients whether an epicardial procedure is necessary at the outset.

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Diagnostic Electrophysiology & Ablation Figure 3: Delayed Enhanced MRI of an Epicardial Scar

A

B

D

C

A. Stack of short axis delayed-enhanced MRI views showing delayed enhancement in the epicardial left ventricular lateral wall (traced in dotted lines) in a patient with nonischaemic cardiomyopathy. Although the free wall is thinned, the endocardium is preserved. B. 3D display of scar tissue (grey) extracted from the MRI images. C. 3D display of scar (orange) and the surrounding epicardium (green) of the left ventricle. The heart is oriented in the same manner as in B. D. Merging of a voltage map with the 3D reconstruction of the scar seen on delayed enhanced MRI. The region of low voltage corresponds to the location of the delayed enhanced MRI scar. After a failed endocardial procedure, an epicardial ablation eliminated all inducible ventricular tachycardias in this patient. Modified with permission from Bogun et al., 2009.5

Figure 5: Voltage Mapping and Intramural Scar

Left: Polar view of the delayed enhanced MRI image of the same patient with intramural septal scar shown in Figure 2. Bipolar endocardial electroanatomical map (top; blue points, voltage ≥1.5 mV; red points, voltage <1.5 mV) as it projects on the polar map. Unipolar endocardial electroanatomical mapping points projecting on the polar map (bottom; blue points, voltage ≥6.8 mV; red points, voltage <6.8 mV). Right: Corresponding bipolar (top) map with a cut-off voltage of 1.55 mV and the corresponding unipolar (bottom) map with a cut-off voltage of 6.8 mV. Reproduced with permission from Desjardins et al., 2013.39

Figure 4: Epicardial VT and Pace-mapping

Twelve-lead ECG of an epicardial ventricular tachycardia (middle). Pacing at the site of origin within the great cardiac vein shows a morphology (right) similar to that of the clinical tachycardia. The pace map from the juxtaposed endocardial mitral annulus is shown (left).

Note the pseudo delta wave of the clinical tachycardia suggestive of an epicardial origin and the absence of a pseudo delta wave with endocardial pacing. Modified with permission from Yokokowa et al., 2011.50

Preprocedural Considerations A cardiac MRI with delayed enhancement should be obtained prior to an ablation procedure if at all possible. Post-processing of the images can be used to integrate the endocardial, epicardial and scar contours in 3D reconstruction images. There is a high degree of correlation between electroanatomical voltage mapping and the scar as characterised by MRI (Figure 3).6 Intraprocedural registration of the scar into the electroanatomic map helps to focus on an area of interest and facilitates the ablation procedure.29 The location of scar tissue has been correlated with the location of the arrhythmogenic substrate.5 A recent study demonstrated that preprocedural MRIs in patients with failed VT ablations also helped to localise the arrhythmogenic tissue and thereby indicated the likelihood of

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whether an epicardial ablation was necessary.30 In this study, patients with cardiac implanted electronic devices (CIEDs) were included.

With appropriate precautions and device programming no adverse events were noted in the patients with CIEDs. Artefact production by the ICD generator is a limitation of MRI, as it can obscure parts of the heart, and scarring cannot be excluded with certainty if this is the case. Reduction of artefact, however, has been described using a novel wideband late gadolinium enhancement imaging protocol.31 Although MRIs have been described to be safe in patients with CIEDs32–34 it needs to be pointed out that such an approach is not yet standard of care in most institutions. Most patients with structural heart disease and VT will already have a CIED in place and therefore imaging of these patients might be more difficult depending on institutional practices and protocols. To safely perform imaging in these patients, a protocol detailing specific programming steps of the CIED prior and after the MRI and monitoring of the patient throughout the MRI in addition to specific exclusion criteria are necessary.

A preprocedural echo should rule out an intracavitary thrombus prior to a planned endocardial ablation procedure. ECG criteria have also been used to distinguish endocardial from epicardial origins. 35 A delayed precordial maximal deflection index ≥0.55, 25 a pseudo ‘delta wave’ at QRS onset ≥34 ms, 36 a minimal RS interval ≥121 ms and the presence of a Q wave in lead I 35,37 suggest an epicardial VT origin (Figure 4). Those ECG criteria are readily available and should be considered when predicting the VT exit site. However, their accuracy is limited, especially in patients with structural heart disease, and can be improved when using a computerised algorithm focusing on the ECG slope of the initial part of the QRS complex. 38 It is essential to note that the QRS morphology solely reflects the VT exit site and cannot exclude the presence of endocardial components of the circuit, which may be eliminated using an endocardial approach.

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Selecting the Appropriate Ablation Strategy

Intraprocedural Considerations If endocardial mapping is performed first, in the absence of preprocedural imaging, unipolar mapping can be beneficial to indicate the presence of intramural or epicardial scar. While bipolar mapping is best in assessing local electrograms originating from tissue adjacent to the recording electrodes, unipolar mapping enables recording of deeper tissue layers. Unipolar signals are recorded between the distal tip of the ablation catheter and the Wilson central terminal during baseline rhythm. Unipolar endocardial mapping has been used for identification of nonendocardial scar that is located intramurally or epicardially. Different voltage cut-off values have been reported for identification of intramural scars in patients with nonischaemic cardiomyopathy (Figure 5),39 as well as epicardial scars in patients with ARVC40 and nonischaemic cardiomyopathy.41 In the presence of a normal endocardial bipolar voltage map combined with an abnormal unipolar voltage map an intramural or epicardial substrate needs to be considered and an epicardial approach may be warranted.

Identification of intramural septal scarring is of key importance, as an epicardial procedure is unlikely to reach the intramural septal substrate from the epicardial space. Transseptal conduction times have been found to be prolonged, and may indicate intramural septal scarring.42 In patients with prior MIs, but also in patients with other structural heart diseases and transmural scar, it is possible that parts of the reentrant circuit can be reached from sites other than the endocardium. A recent study pointed out that in approximately onethird of patients with prior infarctions, critical VT sites identified in the endocardium were non-exit sites (i.e. the VT exit in these patients was not confined to the endocardium and was located elsewhere, in the epicardium or intramurally), whereas the remaining critical sites had the exit within the endocardial myocardium.43 This further supports our contention that in patients with prior infarctions, an endocardial approach should be the preferred initial method.

In patients with idiopathic outflow tract arrhythmias, late activation times in the absence of matching endocardial pace maps at the sites of earliest activation suggests a deeper or epicardial focus.

Mapping within the aortic valve cusps and the coronary venous system is most helpful to identify an epicardial source. The subxiphoid epicardial approach, as mentioned above, is rarely successful in this scenario and should be limited to select cases given the higher risk of complications.26

Other Considerations A failed endocardial ablation procedure can suggest that the critical area might not be reachable from the endocardium. In these patients, preprocedural imaging is particularly helpful, especially if an intramural or epicardial substrate can be demonstrated.

Elimination of all inducible VTs should be the optimal goal for an ablation procedure if this can be safely achieved, as this approach has the best long-term outcome. If VTs after an endocardial approach remain inducible, an epicardial approach should be considered.44 This

1.

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3.

Hartzler GO. Electrode catheter ablation of refractory focal ventricular tachycardia. J Am Coll Cardiol 1983;2:1107–13.

Sosa E, Scanavacca M, d’Avila A, Pilleggi F. A new technique to perform epicardial mapping in the electrophysiology laboratory. J Cardiovasc Electrophysiol 1996;7:531–6.

Aliot EM, Stevenson WG, Almendral-Garrote JM, et al. EHRA/ HRS expert consensus on catheter ablation of ventricular arrhythmias: developed in a partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC), and the Heart Rhythm

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4.

approach has been beneficial in patients with prior MI, and also in patients with ARVC. Patients with a mobile intracavitary thrombus, and those with left ventricular scarring who have implanted artificial aortic and mitral valves are not candidates for extensive endocardial mapping procedures. Alternative approaches (i.e. epicardial ablation, transcoronary ethanol ablation45,46) can be considered in such settings Lesion depth is a major limitation for VTs originating from intramural sites. An epicardial procedure should be considered in the presence of intramural left ventricular free wall scarring. Bipolar ablation procedures from both aspects of the scar,47 ablation with an extendable needle catheter48,49 or simultaneous unipolar ablation49 have been described in this context. For these situations, epicardial access is helpful.

Conclusion In our opinion, the choice between an endocardial versus an epicardial approach to target VT should depend on the patient’s underlying disease substrate, and the location of the arrhythmogenic substrate within the myocardial wall, which can be best assessed with a cardiac MRI. Certain patient-specific characteristics including ECG criteria, previously failed ablations, the presence of intracardiac thrombi or intraprocedural mapping data may further impact on the decision to proceed with an epicardial mapping and ablation approach. In patients with idiopathic outflow tract arrhythmias, a transcutaneous subxiphoid approach is rarely needed, even if the arrhythmia has an epicardial origin. n

Clinical Perspective • Critical components of a ventricular tachycardia (VT) reentry circuit may be confined to locations deep in the subendocardium, the midmyocardium or the epciardium, and may be beyond the reach of current endocardial ablation techniques.

• ECG criteria suggesting an epicardial VT exit site include a delayed precordial maximal deflection index of ≥0.55, a pseudo ‘delta wave’ QRS of ≥34 ms, the shortest RS complex of ≥121 ms and the presence of q wave in lead I. While these criteria may be helpful in patients with idiopathic arrhythmias, their value in patients with structural heart disease has been debated.

• The type of structural heart disease and the resulting location of the arrhythmogenic substrate indicate, in most patients, whether an epicardial procedure will be necessary.

• The value of a preprocedural MRI with respect to a planned epicardial access is highest when an epicardial or intramural scar is identified within the left ventricular free wall, especially in patients with nonischaemic cardiomyopathy.

• For idiopathic outflow tract ventricular arrhythmias, a coronary venous approach combined with an endocardial method is most beneficial. The subxiphoid epicardial access is rarely beneficial in these patients.

Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA).

Heart Rhythm 2009;6:886–933.

Aliot EM, Stevenson WG, Almendral-Garrote JM, et al. EHRA/ HRS expert consensus on catheter ablation of ventricular arrhythmias: developed in a partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA).

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Desjardins B, Crawford T, Good E, et al. Infarct architecture and characteristics on delayed enhanced magnetic resonance imaging and electroanatomic mapping in patients with postinfarction ventricular arrhythmia. Heart Rhythm 2009;6:644–51.

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Neilan TG, Coelho-Filho OR, Danik SB, et al. CMR quantification of myocardial scar provides additive prognostic information in nonischemic cardiomyopathy. JACC Cardiovasc Imaging 2013;6:944–54.

Hsia HH, Callans DJ, Marchlinski FE. Characterization of endocardial electrophysiological substrate in patients with nonischemic cardiomyopathy and monomorphic ventricular tachycardia. Circulation 2003;108:704–10.

Haqqani HM, Tschabrunn CM, Betensky BP, et al.

Layered activation of epicardial scar in arrhythmogenic right ventricular dysplasia: possible substrate for confined epicardial circuits. Circ Arrhythm Electrophysiol 2012;5:796–803.

Garcia FC, Bazan V, Zado ES, et al. Epicardial substrate and outcome with epicardial ablation of ventricular tachycardia in arrhythmogenic right ventricular cardiomyopathy/ dysplasia. Circulation 2009;120:366–75.

Berte B, Denis A, Amraoui S, et al. Characterization of the left-sided substrate in arrhythmogenic right ventricular cardiomyopathy. Circ Arrhythm Electrophysiol 2015 [Epub ahead of print].

Jefic D, Joel B, Good E, et al. Role of radiofrequency catheter ablation of ventricular tachycardia in cardiac sarcoidosis: report from a multicenter registry. Heart Rhythm 2009;6:189–95.

Dukkipati SR, d’Avila A, Soejima K, et al. Long-term outcomes of combined epicardial and endocardial ablation of monomorphic ventricular tachycardia related to hypertrophic cardiomyopathy. Circ Arrhythm Electrophysiol 2011;4:185–94.

Sosa E, Scanavacca M, D’Avila A, et al. Endocardial and epicardial ablation guided by nonsurgical transthoracic epicardial mapping to treat recurrent ventricular tachycardia. J Cardiovasc Electrophysiol 1998;9:229–39.

D’Avila A, Splinter R, Svenson RH, et al. New perspectives on catheter-based ablation of ventricular tachycardia complicating Chagas’ disease: experimental evidence of the efficacy of near infrared lasers for catheter ablation of Chagas’ VT. J Interv Card Electrophysiol 2002;7:23–38.

Zipes DP, Jalife J. Cardiac electrophysiology from cell to bedside. Sixth edition. ed. Philadelphia, PA: Elsevier/ Saunders, 2014.

Iwai S, Cantillon DJ, Kim RJ, et al. Right and left ventricular outflow tract tachycardias: evidence for a common electrophysiologic mechanism. J Cardiovasc Electrophysiol 2006;17:1052–8.

Latchamsetty R, Bogun F. Premature ventricular complexes and premature ventricular complex induced cardiomyopathy. Curr Probl Cardiol 2015;40:379–422.

Ouyang F, Fotuhi P, Ho SY, et al. Repetitive monomorphic ventricular tachycardia originating from the aortic sinus

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Good E, Desjardins B, Jongnarangsin K, et al. Ventricular arrhythmias originating from a papillary muscle in patients without prior infarction: A comparison with fascicular arrhythmias. Heart Rhythm 2008;5:1530–7.

Yokokawa M, Good E, Chugh A, et al. Intramural idiopathic ventricular arrhythmias originating in the intraventricular septum: mapping and ablation. Circ Arrhythm Electrophysiol 2012;5:258–63.

Baman TS, Ilg KJ, Gupta SK et al. Mapping and ablation of epicardial idiopathic ventricular arrhythmias from within the coronary venous system. Circ Arrhythm Electrophysiol 2010;3:274–9.

Daniels DV, Lu YY, Morton JB, et al. Idiopathic epicardial left ventricular tachycardia originating remote from the sinus of Valsalva: electrophysiological characteristics, catheter ablation, and identification from the 12-lead electrocardiogram. Circulation 2006;113:1659–66.

Nagashima K, Choi EK, Lin KY, et al. Ventricular arrhythmias near the distal great cardiac vein: challenging arrhythmia for ablation. Circ Arrhythm Electrophysiol 2014;7:906–12.

Carrigan T, Patel S, Yokokawa M et al. Anatomic relationships between the coronary venous system, surrounding structures, and the site of origin of epicardial ventricular arrhythmias. J Cardiovasc Electrophysiol 2014;25:1336–42.

Santangeli P, Marchlinski FE, Zado ES, et al. Percutaneous epicardial ablation of ventricular arrhythmias arising from the left ventricular summit: outcomes and electrocardiogram correlates of success. Circ Arrhythm Electrophysiol 2015;8:337–43.

Gupta S, Desjardins B, Baman T, et al. Delayed-enhanced MR scar imaging and intraprocedural registration into an electroanatomical mapping system in post-infarction patients. JACC Cardiovasc Imaging 2012;5:207–10.

Njeim M, Yokokawa M, Frank L, et al. Value of cardiac magnetic resonance imaging in patients with failed ablation procedures for ventricular tachycardia. J Cardiovas Electrophysiol 2015 [Epub ahead of print].

Stevens SM, Tung R, Rashid S, et al. Device artifact reduction for magnetic resonance imaging of patients with implantable cardioverter-defibrillators and ventricular tachycardia: Late gadolinium enhancement correlation with electroanatomic mapping. Heart Rhythm 2014;11:289–98.

Nazarian S, Bluemke DA, Lardo AC, et al. Magnetic resonance assessment of the substrate for inducible ventricular tachycardia in nonischemic cardiomyopathy.

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Nazarian S, Hansford R, Roguin A, et al. A prospective evaluation of a protocol for magnetic resonance imaging of patients with implanted cardiac devices. Ann Intern Med 2011;155:415–24.

Dickfeld T, Tian J, Ahmad G, et al. MRI-Guided ventricular tachycardia ablation: integration of late gadoliniumenhanced 3D scar in patients with implantable cardioverterdefibrillators. Circ Arrhythm Electrophysiol 2011;4:172–84.

Valles E, Bazan V, Marchlinski FE. ECG criteria to identify epicardial ventricular tachycardia in nonischemic cardiomyopathy. Circ Arrhythm Electrophysiol 2010;3:63–71.

36. Rodriguez LM, Smeets JL, Timmermans C, Wellens HJ. Predictors for successful ablation of right- and left-sided idiopathic ventricular tachycardia. Am J Cardiol 1997;79:309–14.

37. Bazan V, Gerstenfeld EP, Garcia FC, et al. Site-specific twelve-lead ECG features to identify an epicardial origin for left ventricular tachycardia in the absence of myocardial infarction. Heart Rhythm 2007;4:1403–10.

38. Yokokawa M, Jung DY, Joseph KK, et al. Computerized analysis of the 12-lead electrocardiogram to identify epicardial ventricular tachycardia exit sites. Heart Rhythm 2014;11:1966–73.

39. Desjardins B, Yokokawa M, Good E, et al. Characteristics of intramural scar in patients with nonischemic cardiomyopathy and relation to intramural ventricular arrhythmias. Circ Arrhythm Electrophysiol 2013;6:891–7.

40. Polin GM, Haqqani H, Tzou W, et al. Endocardial unipolar voltage mapping to identify epicardial substrate in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

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41. Hutchinson MD, Gerstenfeld EP, Desjardins B, et al.

Endocardial unipolar voltage mapping to detect epicardial ventricular tachycardia substrate in patients with nonischemic left ventricular cardiomyopathy. Circ Arrhythm Electrophysiol 2011;4:49–55.

42. Betensky BP, Kapa S, Desjardins B, et al. Characterization of trans-septal activation during septal pacing: criteria for identification of intramural ventricular tachycardia substrate in nonischemic cardiomyopathy. Circ Arrhythm Electrophysiol 2013;6:1123–30.

43. Sinno MC, Yokokawa M, Good E et al. Endocardial ablation of postinfarction ventricular tachycardia with nonendocardial exit sites. Heart Rhythm 2013;10:794–9.

44. Di Biase L, Santangeli P, Burkhardt DJ, et al. Endo-epicardial homogenization of the scar versus limited substrate ablation for the treatment of electrical storms in patients with ischemic cardiomyopathy. J Am Coll Cardiol 2012;60:132–41.

45. Anh DJ, Hsia HH, Reitz B, Zei P. Epicardial ablation of postinfarction ventricular tachycardia with an externally irrigated catheter in a patient with mechanical aortic and mitral valves. Heart Rhythm 2007;4:651–4.

46. Berte B, Yamashita S, Sacher F, et al. Epicardial only mapping and ablation of ventricular tachycardia: a case series.

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47. Koruth JS, Dukkipati S, Miller MA, et al. Bipolar irrigated radiofrequency ablation: a therapeutic option for refractory intramural atrial and ventricular tachycardia circuits. Heart Rhythm 2012;9:1932–41.

48. Sapp JL, Beeckler C, Pike R, et al. Initial human feasibility of infusion needle catheter ablation for refractory ventricular tachycardia. Circulation 2013;128:2289–95.

49. Yamada T, Maddox WR, McElderry HT, et al. Radiofrequency catheter ablation of idiopathic ventricular arrhythmias originating from intramural foci in the left ventricular outflow tract: efficacy of sequential versus simultaneous unipolar catheter ablation. Circ Arrhythm Electrophysiol 2015;8:344–52.

50. Yokokawa M, Latchamsetty R, Good E, et al. Ablation of epicardial ventricular arrhythmias from nonepicardial sites.

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Device Therapy

Syncope in Patients with Pacemakers Ri c h a r d S u t t o n National Heart & Lung Institute, Imperial College, London, UK

Abstract Syncope in a pacemaker patient is a serious symptom but it is rarely due a pacemaker system malfunction. Syncope occurs in about 5 % of patients paced for atrioventricular (AV) block in 5 years, 18% in those paced for sinus node disease in 10 years, 20 % of those paced for carotid sinus syndrome in 5 years and 5–55 % of those older patients paced for vasovagal syncope in 2 years. The vastly different results in vasovagal syncope depend on the results of tilt testing, where those with negative tests approach results in pacing for AV block and those with a positive tilt test show no better results than with no pacemaker. The implication of tilt results is that a hypotensive tendency is clearly demonstrated by tilt positivity pointing to syncope recurrence with hypotension. This problem may be addressed by treatment with vasoconstrictor drugs in those who are suited or, more commonly, a reduction or cessation of hypotensive therapy in hypertensive patients. Other causes of syncope such as tachyarrhythmias are rare. The clinical approach to patients who report syncope is detailed.

Keywords Syncope, pacemaker, pacemaker malfunction, atrioventricular block, sinus node disease, carotid sinus syndrome, vasovagal syncope, tilt testing Disclosure: The author has no relevant conflicts of interest.

Received: 21 August 2015 Accepted: 3 November 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(3):189–92. Access at: www.AERjournal.com Correspondence: Richard Sutton DSc, Emeritus Professor of Clinical Cardiology, ICCH Building, St Mary’s Hospital Campus, 59–61 North Wharf Road, London W2 1LA, UK. E: r.sutton@imperial.ac.uk

Syncope in a patient with a pacemaker commands urgent action to ascertain its cause and provide appropriate treatment. This is a well accepted statement but the field has evolved in recent years and, strangely, has received little attention.

Many considerations bear on this issue. First, syncope in pacemaker patients is not common but may be more so than generally considered.

The lack of frequency may be attributed to better technology and greater expertise amongst practitioners but it should be modulated by the fact that more patients today receive pacemakers for other indications than syncope, rendering them unlikely to sustain syncope even if their pacemaker system fails. Second, we now live in an era of telemedicine where remote monitoring not only provides an opportunity to identify technological or arrhythmic causes of syncope in a pacemaker patient but also a chance for the patient very readily to report such an episode to hospital carers.1 Third, more patients today receive pacemakers for reflex syncope where the device is not expected to achieve the results in syncope prevention that pertain in atrioventricular block (AVB).2,3 Included with this aspect of syncope in pacemaker patients must also now be the realisation that syncope may be reflex in the largest group of patients worldwide that receive pacemakers, those with sino-atrial node disease.4

However, by 1991, Pavlovic et al., in a detailed analysis of 46 VVIpaced patients with recurrent syncope, found only two with exit block and an additional patient with sensing failure, which was unlikely to have been the cause of syncope.3 Thus, 4.3 % had pacing failure as the cause of syncope, while at the same time 8.6 % had orthostatic hypotension and 36.9 % were tilt positive. These tilt findings were invoked as explaining the syncope sustained by these patients but no explanation was found in another 30.4 %. They concluded that reflex syncope may be the most common cause of recurrent syncope in paced patients, with pacing hardware failure being quite rare.

Where We Were

This theme was reiterated by Sgarbossa et al. in a large series of 507 sick sinus syndrome patients from the Cleveland Clinic.4 In 62 ± 38 months of follow-up, they found syncope recurrence in 3 % at 1 year, 8 % at 5 years and 13 % predicted at 10 years. Their analysis of the causes of syncope indicated lead or pacemaker failure in 6.5 %, vasovagal in 18 %, orthostatic hypotension in 25.5 %, unexplained in 29.5 %, atrial tachyarrhythmias in 11.5 % and ventricular tachyarrhythmias in 5 %. They concluded that autonomic disturbances were the main contributors to syncope recurrence and pacing hardware failure was uncommon. Such conclusion was reached at a time when syncope in sick sinus syndrome was considered to be sinus arrest without effective escape mechanism rather than reflex in origin. However, Sgarbossa et al. noted that syncope prior to implant was the only reliable predictor of syncope post-implant.

In the late 1980s and early 1990s, we had already achieved a high standard of implant techniques and devices were well constructed with rare failure.2,3 Langenfeld et al. found a 3.5 % recurrence of syncope in AVB (Second and Third Degree) in 5 years; a question of reflex syncope did not arise.2

Helguera et al. focused on endocardial lead malfunction with a broad definition including exit block in 1,474 patients from the Cleveland Clinic.5 In 33 ± 32 months follow-up, only 54 patients had lead malfunction and 37 % had either syncope in 7 or pre-syncope

It is in these contexts that a review of this serious clinical problem is due.

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Device Therapy in 13 patients. These symptomatic lead malfunctions were more common in ventricular leads and in those who had severe symptoms pre-implant. No deaths were attributed to lead malfunction. The authors recommended closest attention to those patients with severe presenting symptoms and pacemaker dependency.

A PubMed search shows that little has been published on these issues between the mid-1990s and the recent past.

Where We Are Now New information on patients with sick sinus syndrome emerged from the DANPACE study, in which 1,415 patients were followed for 5.4 years.6 Syncope occurred in 17.5 % of patients after pacing; of those with AAIR pacing, 19 % had syncope whereas the figure was 15.8 % in DDDR-paced patients. Predictors for syncope were: for age 0–39 years, hazard ratio (HR) 2.9; >80 years, HR 1.4; and syncope pre-implant, HR 1.8. Patients with syncope after pacing suffered a higher mortality (HR 1.6). The authors of this highly regarded trial concluded that syncope after pacing in sick sinus syndrome is common, carries an increased mortality and is multifactorial. It would appear that reflex syncope may have been an important factor because syncope in the general population and in their paced group share a bimodal distribution curve with respect to age. Given the longer follow-up in these patients, they have confirmed the earlier findings in much smaller populations.

The increased mortality raises some anxiety, but may be explained by comorbidities rather than by a direct effect of syncope itself.

It is well known that vasovagal syncope recurs and risk of recurrence increases with more historical attacks, approaching 50 % after six lifetime events.7 It is therefore likely that a patient who has experienced many attacks in the past will have recurrences after pacing, even if the clear indication for pacing was not reflex syncope. Further, if the indication for pacing is reflex syncope, recurrence is highly likely. Much more has been learned recently in the latter group of patients. It is also necessary to restate, in this context, that reflex syncope has two components, bradycardia/asystole and vasodepression. The former of these may be well treated by a pacemaker but vasodepression is uninfluenced by pacing. Thus, the blood pressure may fall profoundly with a maintained heart rate by a pacemaker.

The ISSUE-3 study was to the first to demonstrate that pacing is significantly effective in older vasovagal syncope patients.8 However, the results were tempered by the recurrence of syncope within 2 years of 25 % in those paced versus 57 % in those unpaced (P< 0.04). Reassurance was garnered from the nearly 18 % syncope recurrence in sinus node disease reported from Denmark.6 Once the ISSUE-3 randomised controlled trial data were combined with the ISSUE-3 registry including patients (or physicians on their behalf) who refused pacing or the concept of randomisation at the point of randomisation, the importance of the tilt result was seen to be in terms of the outcome.9 Tilt-negative patients (with implantable loop recorder (ILR) showing asystole in a spontaneous attack and otherwise clinically identical to those who were tilt positive with the same ILR findings) did well with pacing – 5 % recurrence of syncope in 21 months.

Tilt-positive patients did no better than if they had no pacemaker, with 55 % recurrence rate of syncope.9 This finding at first appeared counter-intuitive, but analysis of the reported results of tilt testing over 28 years since the test was introduced for diagnosis of syncope pointed to an explanation.10,11

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The hypothesis suggests that tilt testing merely reveals a hypotensive or vasodepressive tendency and no longer should be termed diagnostic because this tendency is hidden by severe cardioinhibition. So a tilt-positive patient with severe cardioinhibition will not readily reveal accompanying vasodepression. Once paced, the pacemaker is expected to prevent cardioinhibition but cannot combat vasodepression, rendering recurrence of syncope likely.

The argument was strengthened by the literature on carotid sinus syndrome (CSS), a similar reflex syncope, where those CSS patients with a positive tilt test had 2.7 times the recurrence rate of those who were tilt negative.12 These data have been further supported by a later report from the same group, with more patients showing very similar findings.13 The Italian SUP-2 study, including 10 Italian centres, recently reported a decision algorithm for older patients presenting clinically likely reflex syncope.14 The decision-tree demanded carotid sinus massage (CSM) according to the ‘method of symptoms’ as a first test. Those who had positive CSM were paced, those negative proceeded to a tilt test and, if positive with asystole, were also paced.

Those who were tilt negative proceeded to ILR and, if positive with asystole in a spontaneous attack, were then paced. This algorithm permitted assessment of those who were tilt negative and ILR positive and it has been shown separately from the ISSUE-3 study that these patients do well with pacing with a very low syncope recurrence rate in 13 months of follow-up.

Thus, in reflex syncope, both vasovagal and CSS, recurrence of syncope can be predicted after pacing by the tilt test result. The hypothesis also addressed the frequent question in this age group of hypertension and its treatment.11 Hypertension in these patients is often aggressively treated, producing side effects of episodes of orthostatic hypotension.

It is considered likely that some of these patients, as a result, start to experience vasovagal syncope or it recurs (patients having sustained a few attacks in youth). Great care in administering hypotensive medication must now be the norm for these patients and randomised controlled trials are indicated. This group of patients should be considered at risk for syncope recurrence similarly to those who are tilt positive as in the ISSUE-38,9 and SUP-214 studies.

Syncope in paced patients has become much more clear now. It is either rarely due to pacing hardware malfunction or much more commonly due to reflex syncope occurring spontaneously or favoured by hypotensive treatment of hypertension.

How should Paced Patients who Report Syncope be Approached?

Syncope in the paced patient must be regarded as a serious symptom and be promptly investigated. The first consideration should be: was the correct diagnosis of the original syncope made? It is possible that syncope was reflex rather than conduction tissue disease. The second thought should be: are drugs playing a part? If the patient is hypertensive and on hypotensive treatment, this may be the cause of orthostatic hypotension or a rekindling of vasovagal syncope of youth.

The third matter to consider is whether the pacing mode is correct.

Patients with VVI pacing may have bouts of retrograde AV conduction that can precipitate syncope or, rarely, AAI mode has been selected for a patient with AVB. The fourth matter for thought is whether a tachyarrhythmia could be responsible for recurrence of syncope. In this instance, telemonitoring is extremely valuable for defining the arrhythmia. In such cases, assessment of left ventricular function by echocardiography may be helpful in showing deterioration of function

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Syncope in Patients with Pacemakers

that might be compatible with ventricular arrhythmias. Also, in the less likely possibility that atrial fibrillation is responsible for syncope, echocardiographic assessment of left atrial size is indicated.

Patients paced for AVB presenting syncope represent the most likely to have a pacing hardware fault as they are likely to be pacemaker dependent. First, it is necessary to make sure that the device is appropriate for the implanting indication and then consider the possibility of a technical fault. Always, it must be borne in mind that such faults may be difficult to identify in the clinic. In this instance, telemonitoring is much more effective.1 Early after implantation, the technical fault might be lead displacement or perforation or incomplete connection at the lead–pulse generator interface. Exit block may present early but also after the first month of implantation. The term ‘exit block’ implies that there is an excessive reaction by the endocardium at the site of the electrode, which has raised the stimulation threshold to a level above the output of the pacemaker. The pacemaker then fails to capture the heart. Some devices now measure the stimulation threshold and adjust output to address this problem. Later problems include lead insulation failure causing failure to capture heralded by low lead impedance, lead conductor fracture heralded by high lead impedance and possibly by oversensing. While these late problems are mostly lead related there could also be a pulse generator problem including normal or early battery depletion. Again, in all of these problems, telemonitoring is very important and must now be considered the standard of care.15 In patients with indications for pacing other than AVB, technical faults are also possible and must be excluded – telemonitoring is also ideal for this. After such a fault is considered very unlikely, a tilt test is advised to reveal a possible hypotensive tendency. If present, this may be the explanation for the patient’s problems but if absent hypotension could be considered unlikely. It should be borne in mind that a tilt test should no longer be taken as diagnostic but as a risk-ofsyncope-recurrence stratification tool.11 The patient needs to be seen and, if known to be pacemaker dependent, perhaps directly admitted to hospital (see Figure 1). In clinic, the usual assessments must be made, also including deep respiration and movement of the pulse generator to attempt to expose evidence of lead damage. A 12-lead ECG must be taken, which is something often not done in the pacemaker clinic. The pattern of depolarisation may have changed from that after implant, implying lead displacement. A chest X-ray may be needed and may show evidence of lead displacement, lead damage or twiddler’s syndrome. The evidence from remote monitoring must be set against the data collected in the clinic. Is the pacing mode and programme correct? The initial assessment for syncope, as in the European Society of Cardiology Guidelines,16 should be undertaken as this may not have been done at implant. Last, the patient

1.

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Varma N. Automatic home monitoring of patients with cardiac implantable electronic devices – the setting of a new standard. Europace 2013;15:Suppl 1.

Langenfeld H, Grimm W, Maisch B, et al. Course of symptoms and spontaneous ECG in pacemaker patients: a 5-year follow-up study. Pacing Clin Electrophysiol 1988;11:2198– 206.

Pavlovic SU, Kocovic D, Djordjevic M, et al. The etiology of syncope in pacemaker patients. Pacing Clin Electrophysiol 1991;14:2086–91.

Sgarbossa EB, Pinski SL, Jaeger FJ, et al. Incidence and predictors of syncope in paced patients with sick sinus syndrome. Pacing Clin Electrophysiol 1992;15:2055–60.

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Figure 1: Management of Patients with a Pacemaker Reporting Syncope

Exclude wrong diagnosis and role of drugs Attend pacemaker clinic Routine assessment 12-ECG + chest X-ray Syncope initial assessment Evidence from RM Pacemaker dependent

In-patient investigation ECG, Tilt, Re-operation Management

Not pacemaker dependent

Out-patient investigation Reprogramme RM ± Holter Management

PM = pacemaker; RM = remote monitoring

should be considered for admission to hospital – usually necessary for pacemaker-dependent patients, but unlikely to be necessary for patients not pacemaker dependent. For the non-dependent patient, remote monitoring should immediately be established if not already done. If remote monitoring is unavailable, prolonged Holter monitoring will often be required. Hospital admission is usually undertaken when a reoperation is needed rather than attempting therapy as a day case. It should be noted that diagnostic reoperation is now most unlikely to be needed because telemonitoring is so much more effective.

Patient management after diagnosis of the cause of syncope may be reoperation to correct the identified fault, lead repositioning, lead replacement, generator change or upgrading of the pacemaker system. In less serious problems, reprogramming may be sufficient. In reflex syncope cases, use of a rate-drop response type of pacemaker algorithm may help, especially making use of data from tilt testing to tune the program. A closed-loop pacemaker may be more effective than others in reflex syncope but no trial proof of this is currently available. For those who are tilt positive, attempting vasoconstrictor therapy with a drug such as midodrine may help. When it appears that sinus tachycardia is the trigger for syncope, antagonism of this by ivabradine or beta-blocker may help. These patients always need much reassurance because recurrence of pre-pacing symptoms does so much to undermine confidence.

In conclusion, syncope in a pacemaker patient is a serious symptom requiring action. It is quite rare for its explanation to be pacemaker hardware malfunction (around 5 % of cases) and it is much more commonly due to reflex syncope involving vasodepression, which may be iatrogenic by excessive hypotensive therapy. Syncope in pacemaker patients is not as rare as often thought, occurring in 18 % of sinus node disease patients in 10 years and 55 % of tilt positive vasovagal patients in 2 years. n

Helguera ME, Maloney JD, Fahy GJ, et al. Clinical presentation of endocardial lead malfunction. Am J Cardiol 1996;78:1297–9.

Chuen NK, Kirkfeldt RE, Andersen HR, et al. Syncope in paced patients with sick sinus syndrome from the DANPACE trial: incidence, predictors and prognostic implication. Heart 2014;100:842–7.

Rose MS, Koshman ML, Spreng S, et al. The relationship between health-related quality of life and the frequency of spells in patients with syncope. J Clin Epidemiol 2000;53:1209–16.

Brignole M, Menozzi C, Moya A, et al. Pacemaker therapy in patients with neurally-mediated syncope and documented asystole. Third international study on syncope of unknown etiology (ISSUE-3): a randomized trial. Circulation

2012;125:2566–71.

Brignole M, Donateo P, Tomaino M, et al. The benefit of pacemaker therapy in patients with presumed neurallymediated syncope and documented asystole is greater when tilt test is negative. An analysis from the third international study on syncope of uncertain etiology (ISSUE 3). Circ Arrhythm Electrophysiol 2014;7:10–6.

10. Kenny RA, Ingram A, Bayliss J, et al. Head-up tilt: a useful test for investigating unexplained syncope. Lancet 1986;1:1352–5.

11. Sutton R, Brignole M. Twenty-eight years of research permit reinterpretation of tilt-testing: hypotensive susceptibility rather than diagnosis. Eur Heart J 2014;35:2211–2.

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Am J Cardiol 1995;75:518–21.

13. Solari D, Maggi R, Oddone D, et al. Clinical context and outcome of carotid sinus symdrome diagnosed by means of the ‘method of symptoms’. Europace 2014;16:928–34.

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14. Brignole M, Ammirati F, Arabia F, et al. Assessment of a standardized algorithm for cardiac pacing in older patients affected by severe unpredictable reflex syncopes. Eur Heart J 2015;36:1529–35.

15. Sutton R. Remote monitoring as a key innovation in the management of cardiac patients including those with

implantable electronic devices. Europace 2013;15:i3–i5.

16. Moya, A, Sutton R, Ammirati F, et al. The Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC). Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J 2009;30:2631–71.

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