AER 5.3 by Radcliffe Cardiology

Arrhythmia & Electrophysiology Review Volume 5 • Issue 3 • Winter 2016

Volume 5 • Issue 3 • Winter 2016

www.AERjournal.com

Anatomical Consideration in Catheter Ablation of Idiopathic Ventricular Arrhythmias Takumi Yamada and G Neal Kay

Management of Cardiac Electronic Device Infections: Challenges and Outcomes Rikke Esberg Kirkfeldt, Jens Brock Johansen and Jens Cosedis Nielsen

Pharmacological Tests in Atrial Fibrillation Ablation Jean-Baptiste Gourraud, Jason G Andrade, Laurent Macle and Blandine Mondésert

Executive Summary: European Heart Rhythm Association Consensus Document on the Management of Supraventricular Arrhythmias Demosthenes G Katritsis, Giuseppe Francisco G Cosio, Pierre Jais, Gerhard Hindricks, Mark E Josephson, Roberto Keegan, Bradley P Knight, Karl-Heinz Kuck, Deirdre A Lane, Gregory YH Lip, Helena Malmborg, Hakan Oral, Carlo Pappone, Sakis Themistoclakis, Kathryn A Wood, Kim Young-Hoon and Carina Blomström Lundqvist

ISSN - 2050-3369

Autopsy Hearts Exhibiting the Right Ventricular Papillary Muscles and Moderator Band

Subcutaneous Implantable Cardioverter-Defibrillator in the Left Lateral Thoracic

Triggers of Atrial Fibrillation During Second Catheter Ablation

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Volume 5 • Issue 3 • Winter 2016

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

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

Charles Antzelevitch

Carsten W Israel

Carlo Pappone

JW Goethe University, Germany

Lankenau Institute for Medical Research, Wynnewood, US

IRCCS Policlinico San Donato, Milan, Italy

Warren Jackman

University of Oklahoma Health Sciences Center, Oklahoma City, US

Sunny Po

University Hospital Uppsala, Sweden

Johannes Brachmann

Pierre Jaïs

Antonio Raviele

Carina Blomström-Lundqvist

Klinikum Coburg, II Med Klinik, Germany

Bordeaux University Hospital, Electrophysiology and Heart Modelling Institute (LIRYC), France

Pedro Brugada

University of Brussels, UZ-Brussel-VUB, Belgium

Mark Josephson

Beth Israel Deaconess Medical Center, Boston, US

Alfred Buxton

Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, US ALFA – Alliance to Fight Atrial Fibrillation, Venice-Mestre, Italy

Frédéric Sacher Bordeaux University Hospital, Electrophysiology and Heart Modelling Institute (LIRYC), France

Beth Israel Deaconess Medical Center, Boston, US

Josef Kautzner

Hugh Calkins

John Hopkins Medical Institution, Baltimore, US

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

A John Camm

Samuel Lévy

St George’s University of London, UK

Aix-Marseille University, France

Riccardo Cappato

Cecilia Linde

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

Gregory YH Lip

Richard Sutton

IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

Karolinska University, Stockholm, Sweden

Ken Ellenbogen

University of Birmingham, UK

Virginia Commonwealth University School of Medicine, US

Francis Marchlinski

University of Pennsylvania Health System, Philadelphia, US

Sabine Ernst

Royal Brompton and Harefield NHS Foundation Trust, London, UK

Andreas Götte

St Vincenz-Hospital Paderborn and University Hospital Magdeburg, Germany

Hein Heidbuchel

Richard Schilling

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

William Stevenson

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

Juan Luis Tamargo

University Complutense, Madrid, Spain

Jose Merino

Panos Vardas

Hospital Universitario La Paz, Madrid, Spain

Heraklion University Hospital, Greece

Fred Morady

Marc A Vos

Cardiovascular Center, University of Michigan, US

University Medical Center Utrecht, Netherlands

Sanjiv M Narayan

Katja Zeppenfeld

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

Stanford University Medical Center, US

Leiden University Medical Center, Netherlands

Gerhard Hindricks

Mark O’Neill

St. Thomas’ Hospital and King’s College London, London, UK

Douglas P Zipes

University of Leipzig, Germany

Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, US

Managing Editor Becki Davies • Production Jennifer Lucy Digital Commercial Manager Ben Sullivan • New Business & Partnership Director Rob Barclay Publishing Director Liam O’Neill • Managing Director David Ramsey • Commercial Director Mark Watson •

In partnership with

• •

Editorial Contact Becki Davies managingeditor@radcliffecardiology.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffecardiology.com •

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Cover image www.istockphoto.com

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use 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, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS © 2016 All rights reserved ISSN: 2050-3369 • eISSN: 2050–3377 © RADCLIFFE CARDIOLOGY 2016

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Established: October 2012

Aims and Scope • Arrhythmia & Electrophysiology Review aims to assist time-pressured physicians to keep 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 2016

• 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

Distribution and Readership Editorial Expertise 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 PubMed, Embase, Scopus, Google Scholar and Summon by Serial Solutions. All articles are published in full on PubMed Central one month after publication.

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 Failure Review, European Cardiology Review and US Cardiology Review. n

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Contents

Foreword

158

Closer Scientific Collaboration with the European Heart Rhythm Association Demosthenes Katritsis, Editor-in-Chief Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

EHRA Editorial

160

Time to Connect with Europe’s Strongest Heart Rhythm Network Gerhard Hindricks, EHRA President

Guest Editorial

162

Atrial Fibrillation and Heart Failure: How Should We Manage Our Patients? Farhan Shahid1 and Gregory Y H Lip1,2 1. University of Birmingham Institute of Cardiovascular Sciences, City Hospital, Birmingham, UK; 2. Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

Clinical Arrhythmias

164

Brugada Syndrome: Defining the Risk in Asymptomatic Patients Juan Sieira and Pedro Brugada Heart Rhythm Management Centre, Universitair Ziekenhuis Brussel-Vrije Universiteit Brussel, Brussels, Belgium

170

Pharmacological Tests in Atrial Fibrillation Ablation Jean-Baptiste Gourraud, Jason G Andrade, Laurent Macle and Blandine Mondésert Electrophysiology Service, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada

177

A Clinical Perspective on Sudden Cardiac Death Demosthenes G Katritsis,1 Bernard J Gersh,2 and A John Camm3 1. Athens Euroclinic, Greece, and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; 2. Mayo Medical School, Rochester, MN, USA; 3. St George’s University of London, UK

Device Therapy

183

Management of Cardiac Electronic Device Infections: Challenges and Outcomes Rikke Esberg Kirkfeldt,1 Jens Brock Johansen2 and Jens Cosedis Nielsen1 1. Department of Cardiology, Aarhus University Hospital, Skejby, Denmark; 2. Department of Cardiology, Odense University Hospital, Odense, Denmark

188

ICD Therapy for Primary Prevention in Hypertrophic Cardiomyopathy Amar Trivedi and Bradley P Knight Division of Cardiology, Department of Medicine, Northwestern University, Chicago, IL, USA

Diagnostic Electrophysiology & Ablation

197

The Role of Cardiac MRI in the Diagnosis and Risk Stratification of Hypertrophic Cardiomyopathy Ethan J Rowin and Martin S Maron Hypertrophic Cardiomyopathy Institute, Division of Cardiology, Tufts Medical Center, Boston, MA; Chanin T. Mast Center for Hypertrophic Cardiomyopathy, Morristown Medical Center, Morristown, NJ, USA

203

Anatomical Consideration in Catheter Ablation of Idiopathic Ventricular Arrhythmias Takumi Yamada and G Neal Kay Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama, USA

EHRA Consensus

210

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Supporting life-long learning for arrhythmologists Arrhythmia & Electrophysiology Review, led by Editor-in-Chief Demosthenes Katritsis and underpinned by an editorial board of world-renowned physicians, comprises peer-reviewed articles that aim to provide timely update on the most pertinent issues in the field. Available in print and online, Arrhythmia & Electrophysiology Reviewâ&#x20AC;&#x2122;s articles are free-to-access, and aim to support continuous learning for physicians within the field.

Call for Submissions Arrhythmia & Electrophysiology Review publishes invited contributions from prominent experts, but also welcomes speculative submissions of a superior quality. For further information on submitting an article, or for free online

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access to the journal, please visit:

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Radcliffe Cardiology Arrhythmia & Electrophysiology Review is part of the Radcliffe Cardiology family. For further information, including free access to thousands of educational reviews from across the speciality, visit:

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Foreword

Closer Scientific Collaboration with the European Heart Rhythm Association

elcome to our final issue of 2016. This year has been a busy one for Arrhythmia & Electrophysiology Review: the start of the year saw the journalâ&#x20AC;&#x2122;s launch on PubMed Central with indexing of all articles on PubMed, increasing visibility of articles to the global cardiology community.

Our ongoing partnership with the European Heart Rhythm Association (EHRA) has been strengthened with the publication of a regular EHRA editorial in the journal, updating readers on new initiatives, and in this issue, for the first time, we include an executive summary of the latest EHRA consensus document on management of supraventricular arrhythmias. The journalâ&#x20AC;&#x2122;s online portal, www.AERjournal.com has just been re-launched with a clean new design, providing an improved user experience and more intuitive structure that should prove easier to navigate. We would welcome your feedback on the changes. We would like to extend thanks to all the contributors, peer reviewers and readers, for your continued support of Arrhythmia & Electrophysiology Review during 2016. We look forward to bringing you more high-quality clinical reviews, editorials and opinion pieces in 2017. Demosthenes Katritsis, Editor-in-Chief, Arrhythmia & Electrophysiology Review Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

DOI: 10.15420/AER.2016.5.3.ED1

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EHRA Editorial

Time to Connect with Europe’s Strongest Heart Rhythm Network

ith 2016’s last quarter upon us, the Board of the European Heart Rhythm Association (EHRA) and I are happy to be sharing the latest updates and insights from this busy and fruitful year with the readers

of Arrhythmia & Electrophysiology Review. The EHRA has intensified its involvement in clinical trials. Following our longstanding support of the Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST, www.easttrial.org) comparing early intervention strategies for atrial fibrillation, we are now entering the field of sudden cardiac death. The Restoration of Chronotropic Competence in Heart Failure Patients with Normal Ejection Fraction – Sudden Cardiac Death (REVISIt SCD) trial, a multinational

EHRA President – Gerhard Hindricks

randomised trial to re-evaluate the need for implantation of a defibrillator for the primary prevention of sudden cardiac death in patients with ischaemic cardiomyopathy and reduced left ventricular ejection fraction, is in the final stage of preparation. With a consortium of strong partners, we are planning to randomise 3,500 patients with reduced ejection fraction after myocardial infarction to optimal medical therapy with and without an implantable cardioverter-defibrillator. We hope this important trial will be approved and started in 2017. The preparations for the EHRA EUROPACE–CARDIOSTIM 2017 have started. This 4-day congress, to be held from 18 to 21 June in Vienna, Austria, promises to be another huge milestone in the history of our association. The EHRA Scientific Programme Committee has developed a compelling programme designed to provide attendees with the latest in science and education in the field of cardiac rhythm disorders and therapies. Registration is now open, with early registration fees applying until 17 April 2017, and abstracts can be submitted during this period. Log on to www.escardio.org/EUROPACE for more information. EHRA members are entitled to a special discount when registering, so make sure your membership is valid when registering or renew it to benefit from this discount. Please note that we currently offer special discounts on membership fees; see www.escardio.org/EHRA-membership EHRA Recognised Training Centres (ERTCs) are one of the many initiatives that EHRA has launched this year. We encourage you to put your centre forward and join this exclusive club. This quality label will verify the uniformity of educational tools and attract fellows and practitioners, as well as standardising and facilitating teaching. ERTCs will host trainees for the new EHRA Observational Training Programme, which will offer EHRA members a 2–4-week educational visit to an ERTC to gain experience in a specific area. This programme is just one more good reason to join or to renew your membership. The EHRA educational calendar has been packed during 2016. There have been live courses with more than 560 participants, and great results from the certification exams held in English, and additionally translated into Italian, German and Dutch for allied professionals. Several new webinars are expected before the end of the year. EHRA is moving forward. Join us and connect to Europe’s strongest rhythm network! On behalf of the EHRA Board, I wish you a warm and productive winter season. Gerhard Hindricks, EHRA President 2015–2017 www.escardio.org/EHRA DOI: 10.15420/AER.2016.5.3.ED2

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Guest Editorial

Atrial Fibrillation and Heart Failure: How Should We Manage Our Patients?

trial fibrillation (AF) and heart failure (HF) are global epidemics that began more than a century ago, and their association with an ageing general population has brought about an increase in cardiovascular morbidity and rising healthcare costs.1,2 More than 50 % of patients with permanent AF have a concurrent diagnosis of HF and this proportion is expected to rise.3

It is well established that the detrimental impact of AF in patients with HF results in a greater number of hospital admissions, longer hospital stays and an overall increase in mortality in HF patients with AF.4,5

Pathophysiology of AF and HF: A Brief Overview The pathophysiology of AF and HF are closely interlinked. Patients with HF develop an increase in left ventricular filling pressure secondary to either systolic or diastolic dysfunction.6 Such changes lead to a remodelling of the left atrium, which in turn can act as a substrate for AF. HF patients also demonstrate altered calcium handling leading to calcium overload, which in turn can alter depolarisation patterns, resulting in arrhythmias. AF itself can alter the efficiency by which systole and diastole take place, the end result being a shortened left ventricular filling time. This, along with suboptimal rate control, reduces myocardial contractility resulting in systolic HF. With regards to the complications of thromboembolism, both AF and HF confer a prothrombotic state, by fulfilment of Virchowâ&#x20AC;&#x2122;s triad for thrombogenesis.7,8 Hence, the risk of stroke and thromboembolism is increased with either AF or HF, and accentuated when both conditions are present concomitantly.

What Should We Do? Whilst AF and HF are intimately related, which develops first? The Framingham Study suggested that patients were more likely to develop HF first rather than AF (41 % versus 38 %), while in 21 % of patients, both conditions occurred simultaneously.9 Asymptomatic AF is common, and would often be first diagnosed when the onset of AF leads to decompensated HF. Conversely, prolonged AF with poorly controlled ventricular rates may lead to presentation with HF, sometimes related to progressive left ventricular impairment and dilatation (the so-called tachycardia-induced cardiomyopathy).10 Treatment with HF therapies may modulate the onset of AF. The use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor inhibitors (ARBs) reduces the risk of developing AF by nearly 30 % overall, with an even greater risk reduction in HF patients.11 The Candesartan in Heart Failure Assessment of Reduction in Morbidity and Mortality Program (CHARM) suggests a benefit for ARBs in the primary prevention of AF, whether with left ventricular systolic or diastolic dysfunction.12 The benefit of beta-blockers (BBs) in patients with HF and AF versus those with sinus rhythm is less well established. Both European and US guidelines recommend the use of BBs in patients with HF and concomitant AF.13,14 This is in keeping with a meta-analysis of registry data including over 200,000 patients showing that patients with AF and concomitant HF had lower all-cause mortality when treated with BBs.15 Nonetheless, an individual patient analysis of trial data showed less prognostic benefit of BBs in HF with associated AF,16 but this may be due in part to the fact that ventricular rates <70 beats/min have been associated with poorer outcomes in these patients leading to no prognostic benefit.17 Conflicting evidence is also apparent for the use of mineralocorticoid receptor antagonists (MRAs) in patients with left ventricular systolic dysfunction and AF. Sub-analyses from the Atrial Fibrillation and Congestive Heart Failure trial (AF-CHF) showed an increase in mortality in such patient cohorts (HR 1.4; 95 % CI 1.1â&#x20AC;&#x201C;1.8); however, patients receiving MRA therapy were probably more unwell and this may have been a confounding factor in this analysis.18 In the Eplerenone in Mild Patients Hospitalization and Survival Study

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Guest Editorial in Heart Failure (EMPHASIS-HF) study, the use of eplerenone reduced new-onset AF and improved prognosis in HF due to systolic impairment, whether or not AF was present.19 In summary, there are some data suggesting a beneficial effect of ACEIs, ARBs, BBs and MRAs in patients with HF with reduced ejection fraction (HFrEF) and AF compared with sinus rhythm (SR). Such therapy has the potential to aid favourable left ventricular remodelling and limiting cardiac fibrosis, leading to a reduction in new onset AF and improved prognosis.13

Role of Anticoagulation With NOACs versus Warfarin All patients with HF and AF are at increased risk of stroke and thromboembolism, and should be considered for stroke prevention with oral anticoagulation (OAC). Such patients should be assessed using the CHA2DS2VASc score (congestive heart failure, hypertension with blood pressure [BP] >140/90, age 65–74 or age ≥75, diabetes mellitus, previous stroke/transient ischaemic attack or thromboembolism, vascular disease) and the HAS-BLED score (hypertension [systolic BP >160 mmHg], abnormal liver/renal function [with creatinine ≥200 μmol/L], stroke, bleeding history or predisposition, labile international normalised ratio [INR] in range <60 % of the time, elderly [>65], concomitant drugs/alcohol) to help decision making when balancing the benefits and risks of stroke prevention against bleeding.20 The non-vitamin K oral anticoagulants (NOACs) have gained preferential use over warfarin in patients with HF and AF in guidelines, and a recent meta-analysis points to the superiority of NOACs in AF patients with associated HF.13,21 The vitamin K antagonists (VKAs), eg. warfarin, are alternative OACs, but attention to quality of anticoagulation control with a high (>70 %) time in therapeutic range (TTR) between 2.0 and 3.0 is needed.

Conclusion New-onset HF in patients with established AF is often benign,22 but AF in a patient with established HF is associated with a worse outcome.23,24 The management of HF with concomitant AF requires optimisation of HF medical therapy as per evidence-based guidelines. Appropriate thromboprophylaxis is also needed, whether with a NOAC or VKA with well-managed anticoagulation control.

Farhan Shahid1 and Gregory Y H Lip1,2 1. University of Birmingham Institute of Cardiovascular Sciences, City Hospital, Birmingham, UK; 2. Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

1. 2. 3.

8. 9.

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Wodchis WP, Bhatia RS, Leblanc K, et al. A review of the cost of atrial fibrillation. Value Health 2012;15:240–8. DOI: 10.1016/j.jval.2011.09.009; PMID: 22433754 Braunschweig F, Cowie MR, Auricchio A. What are the costs of heart failure? Europace 2011;13(Suppl 2):ii13–7. DOI: 10.1093/europace/eur081; PMID: 21518742 Chiang CE, Naditch-Brule L, Murin J, et al. Distribution and risk profile of paroxysmal, persistent, and permanent atrial fibrillation in routine clinical practice: insight from the reallife global survey evaluating patients with atrial fibrillation international registry. Circ Arrhythm Electrophysiol 2012;5:632– 9. DOI: 10.1161/CIRCEP.112.970749; PMID: 22787011 Rivero-Ayerza M, Scholte Op, Reimer W, et al. New-onset atrial fibrillation is an independent predictor of in-hospital mortality in hospitalized heart failure patients: results of the EuroHeart Failure Survey. Eur Heart J 2008;29:1618–24. DOI: 10.1093/eurheartj/ehn217; PMID: 18515809 Khazanie P, Liang L, Qualls LG, et al. Outcomes of medicare beneficiaries with heart failure and atrial fibrillation. JACC Heart Fail 2014;2:41–8. DOI: 10.1016/j.jchf.2013.11.002; PMID: 24622118; PMCID: PMC4174273 Mills RW, Narayan SM, McCulloch AD. Mechanisms of conduction slowing during myocardial stretch by ventricular volume loading in the rabbit. Am J Physiol Heart Circ Physiol 2008;295:H1270–8. DOI: 10.1152/ajpheart.00350.2008; PMID: 18660447; PMCID: PMC2544493 Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow's triad revisited. Lancet 2009;373:155–66. DOI: 10.1016/S0140-6736(09)600404; PMID: 19135613 Lip GY, Gibbs CR. Does heart failure confer a hypercoagulable state? Virchow's triad revisited. J Am Coll Cardiol 1999;33:1424–6. PMID: 10193748 Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation 2003;107:2920–5. DOI: 10.1161/01. CIR.0000072767.89944.6E; PMID: 12771006 Lip GY, Fauchier L, Freedman SB, et al. Atrial fibrillation. Nat Rev Dis Primers 2016;2:16016. DOI: 10.1038/nrdp.2016.16; PMID: 27159789

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Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. J Am Coll Cardiol 2005;45:1832–9. DOI: 10.1016/j.jacc.2004.11.070; PMID: 15936615 Ducharme A, Swedberg K, Pfeffer MA, et al. Prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. Am Heart J 2006;152:86–92. PMID: 16838426 Ponikowski P, Voors AA, Authors/Task Force M, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. DOI: 10.1093/ eurheartj/ehw128; PMID: 27206819 Yancy CW, Jessup M, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239. DOI: 10.1016/j.jacc.2013.05.019; PMID: 23747642 Nielsen PB, Larsen TB, Gorst-Rasmussen A, et al. Betablockers in atrial fibrillation patients with or without heart failure: association with mortality in a nationwide cohort study. Circ Heart Fail 2016;9:e002597. DOI: 10.1161/ CIRCHEARTFAILURE.115.002597; PMID: 26823497 Kotecha D, Holmes J, Krum H, et al. Efficacy of beta-blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet 2014;384:2235–43. DOI: 10.1016/S0140-6736(14)61373-8; PMID: 25193873 Mareev Y, Cleland JG. Should beta-blockers be used in patients with heart failure and atrial fibrillation? Clin Ther 2015;37:2215–24. DOI: 10.1016/j.clinthera.2015.08.017; PMID: 26391145 O'Meara E, Khairy P, Blanchet MC, et al. Mineralocorticoid receptor antagonists and cardiovascular mortality

19.

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in patients with atrial fibrillation and left ventricular dysfunction: insights from the Atrial Fibrillation and Congestive Heart Failure Trial. Circ Heart Fail 2012;5:586– 93. DOI: 10.1161/CIRCHEARTFAILURE.111.965160; PMID:22798522 Swedberg K, Zannad F, McMurray JJ, et al. Eplerenone and atrial fibrillation in mild systolic heart failure: results from the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) study. J Am Coll Cardiol 2012;59:1598–603. DOI: 10.1016/j. jacc.2011.11.063; PMID: 22538330 Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS: The Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Endorsed by the European Stroke Organisation (ESO). Europace 2016;pii:euw295. [Epub ahead of print]; DOI: 10.1093/europace/euw295; PMID: 27567465 Xiong Q, Lau YC, Senoo K, et al. Non-vitamin K antagonist oral anticoagulants (NOACs) in patients with concomitant atrial fibrillation and heart failure: a systemic review and meta-analysis of randomized trials. Eur J Heart Fail 2015;17:1192–200. Epub 2015 Sep 3; DOI: 10.1002/ejhf.343; PMID: 26335355 Smit MD, Moes ML, Maass AH, et al. The importance of whether atrial fibrillation or heart failure develops first. Eur J Heart Fail 2012;14:1030–40. DOI: 10.1093/eurjhf/hfs097; PMID: 22733981 Kotecha D, Chudasama R, Lane DA, et al. Atrial fibrillation and heart failure due to reduced versus preserved ejection fraction: A systematic review and meta-analysis of death and adverse outcomes. Int J Cardiol 2016;203:660–6. Epub 2015 Oct 28; DOI: 10.1016/j.ijcard.2015.10.220; PMID: 26580351 Swedberg K, Olsson LG, Charlesworth A, et al. Prognostic relevance of atrial fibrillation in patients with chronic heart failure on long-term treatment with beta-blockers: results from COMET. Eur Heart J 2005;26:1303–8. DOI: 10.1093/ eurheartj/ehi166; PMID: 15767288

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Abstract Since the first description of the Brugada syndrome (BS) in 1992, scientific progress in the understanding of this disease has been enormous; at the same time more and more individuals with the disease have been diagnosed. The profile of patients with BS has changed with more asymptomatic individuals and less expressive clinical features. Asymptomatic BS individuals are at lower arrhythmic risk than those presenting with syncope or sudden cardiac death (SCD). The event incidence rate is around 0.5 % per year; this figure is relevant due to the fact that individuals have a long life expectancy and are otherwise healthy. As a result of the risk of SCD, risk stratification is of utmost importance. As the implantation of a cardioverter defibrillator is the main treatment for those patients at higher risk, benefits and long-term potential risks have to be adequately considered. Some risk factors, such as spontaneous type 1 electrocardiogram (ECG) pattern, are widely accepted, whilst for others contradictory data are present. Furthermore, novel risk factors are now available that might help in the management of BS. The presence of a spontaneous type 1 ECG pattern, history of sinus node dysfunction and inducible ventricular arrhythmias during programmed electrical stimulation of the heart allow us to risk stratify these patients.

Keywords Brugada syndrome, prognosis, risk stratification, sudden cardiac death, Implantable cardioverter-defibrillator, electrophysiological study Disclosure: Prof Brugada has been a consultant to Biotronik and has received speakers’ fees from Medtronic and Biotronik. Dr Sieira has no conflicts of interest to declare. Received: 20 June 2016 Accepted: 26 September 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(3):164–9 DOI: 10.15420/aer.2016:22:3 Correspondence: Juan Sieira, Heart Rhythm Management Centre, UZ Brussel-VUB, Laarbeeklaan 101, 1090 Brussels, Belgium. E: jasieira@gmail.com

Brugada syndrome (BS) is an inherited disease characterised by coved-type ST-segment elevation in the right precordial leads (V1–V3) and an increased risk of sudden cardiac death (SCD) in the absence of structural heart disease.1 It typically affects otherwise healthy individuals in their forties.2 SCD is the most dramatic presentation, but many patients are asymptomatic at the time of diagnosis.3 As SCD can be the first manifestation of the disease, recognising those patients at risk for future events is of utmost importance. Furthermore, history of warning symptoms might not be present and predisposing factors can be absent prior to the event.4 Asymptomatic patients are at a lower risk of developing SCD, but arrhythmic events are not negligible.2.5 Clinical presentation has evolved since the first description of the syndrome. From the more expressive patients presented in the first reports, nowadays patients are frequently asymptomatic with a nonspontaneous type 1 electrocardiogram (ECG) pattern at diagnosis.6,7 Even after great scientific progress, identifying those patients at risk remains challenging and controversial. Few studies have directly addressed this issue and most available registries are limited to a relative short follow-up period, which makes it impossible to evaluate the whole BS spectrum. As patients remain at risk lifelong, studies with a long follow-up are necessary. Clinical practice guidelines are focused on those patients at higher risk and do not offer specific recommendations concerning the management of individuals who have never suffered an aborted SCD.

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Specifically, the guidelines only state that an electrophysiological (EP) test might be useful in the management of BS patients with a class IIb recommendation level.8 The placement of an implantable cardioverter-defibrillator (ICD) remains the therapy with the most proven efficacy to prevent SCD in patients with BS. Considering that BS patients have a long life expectancy, device-related complications have to be carefully considered, and the risks and benefits of implantation should be adequately weighed.9

Incidence of Arrhythmic Events In our experience, 67 % of patients with BS are asymptomatic. Similar figures are found in other registries: 64 % in the France, Italy, Netherlands, Germany (FINGER) registry10 and 79 % in the Programmed Electrical Stimulation Predictive Value (PRELUDE) registry.11 As expected, an asymptomatic status is less frequently found in ICD registries; between 44 and 26 % of patients.2,12 Quantification of arrhythmic events is crucial to offer solid management recommendations. Initial reports showed an event rate of 2.7 % per year in asymptomatic patients.13 This figure has dropped over the years, probably due to selection bias, as initial reports may have included patients at higher risk. Recent registries show an annual incidence of 0.5 % during a mean follow-up of 32–73 months.3,10 In our experience, arrhythmic risk of asymptomatic patients is 3.8 % at 5 years and 4.6 % at 10 and 15 years.3 This might seem relatively low, but when considering the long life expectancy of these patients and the lack of other conditions, this figure becomes very relevant. It should also be

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noted that the risk of SCD in the general population without BS and at 40 years of age is, at the most, 1:10.000 per year, which is about 100 times less than that for asymptomatic BS patients. Interestingly, when selecting a high-risk asymptomatic population, in whom an ICD has been placed, the rate of events is similar to patients presenting with syncope, underscoring the fact that accurate risk stratification is critical.2 BS has been classically considered a disease that affects mainly men. We have recently reported that BS is not as uncommon in women as previously thought.14 Women represent more than 40Â % of our database, with a less severe presentation and more benign course. In asymptomatic women, the event rate is 0.27 % per year, significantly less than men but still significantly more than in the general population without BS. Nevertheless, as will be discussed later, there are no clear risk factors that can help to stratify the risk in women.

Risk Stratification More than 20 years after the first description of BS, risk stratification remains challenging and controversial. Evidence from big registries and longer follow-ups are now available. Some risk factors have been repeatedly reported and are widely accepted, whilst others remain controversial, with contradictory reports. Furthermore, novel risk markers have emerged and might help when facing an asymptomatic patient with BS. Current practical guidelines and consensus recommend implantation of an ICD in patients surviving a SCD (class I) and those with syncope and spontaneous type 1 electrocardiogram (ECG) class IIa.8 No specific statement is made for asymptomatic patients. These guidelines do not refer to newly described risk factors and lack recommendations for the low risk, but otherwise frequent, groups. We will hereafter review the risk factors of importance in asymptomatic patients: both those factors that are widely accepted as well as those that are still controversial or reported less frequently.

did not present any arrhythmic events during follow-up17 or were attributed to ischaemic heart disease.18 In this context, decision for implanting or replacing an ICD in elderly patients must be done individually. Available literature is limited to a small number of patients and further evidence is needed. Nevertheless, we believe that establishing the diagnosis is important, as it has family implications. As a familial disease, it is well known that when a patient is diagnosed, a family is diagnosed.

Sex BS has usually been considered a condition that affects mainly men. We have recently reported that females are not uncommon amongst patients with BS.14 BS in women presents specific differences in comparison with men. Clinical presentation is more benign, with fewer spontaneous type 1 ECG patients and usually presenting as asymptomatic.19 Prognosis is also more favourable, with an annual event rate of 0.25 %. Nevertheless, events can occur during followup,20 and what is even more worrisome is that we lack specific risk factors to stratify this population.14 Few studies have addressed this issue. Benito et al. reported that the history of atrial fibrillation and longer PR interval were associated with arrhythmic events in women with BS.19 We recently found that a previous history of sinus node dysfunction (SND) was related to this prognosis. Interestingly, a spontaneous type 1 ECG is not associated with more frequent events. Furthermore, in our series all the events in asymptomatic women occurred in patients with a drug-induced BS ECG pattern.14

Family History Previously, the presence of a family history of SCD was not associated with a worse prognosis.3 Our group found that multiple antecedents of SCD in first-degree relatives younger than 35 years of age were associated with further arrhythmic events, but this condition was uncommon and it lost significance when adjusted with other variables.21 When follow-up is expanded over more years, early SCD in first-degree relatives is associated with outcomes of a similar magnitude as spontaneous type 1 ECG pattern (unpublished data).

Age Patients with BS are typically diagnosed during their fourth decade.3 Despite age not being related to prognosis, two subgroups merit special consideration: paediatric and elderly patients. Fortunately, prevalence of BS in the paediatric age group is low. Nevertheless, amongst the eight patients that constituted the initial BS report, three were children. Paediatric BS patients who present symptoms have an especially bad prognosis.4 Conversely, asymptomatic patients appear to have good outcomes, even more so when they do not show the type 1 pattern spontaneously; however, they are not risk free.15 Therefore, individual evaluation is needed and those patients at higher risk should undergo an ICD implantation. Furthermore, the decision to perform a drug challenge (and electrophysiological [EP] study) has to be individualised, balancing risks and benefits.16 However, we believe that it is important to achieve the diagnosis of BS in the paediatric population, to recommend general measures and identify patients at high risk. Importantly, we recommend repetition of the test after puberty, as in our experience, up to 25 % of patients with an initially negative drug test become positive.15 Conversely, BS diagnosed in elderly patients appears to have a benign prognosis.17,18 Furthermore, diagnosis of BS in this age group is infrequent. Amongst all BS patients, those over 70 years of age

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Genetics Mutations can be identified in approximately 20â&#x20AC;&#x201C;30 % of patients with BS. Some recent reports show a higher proportion. 4,22 The presence of an identifiable mutation has not been clearly linked to a worse prognosis; this being particularly true amongst asymptomatic patients.10 Nevertheless, some studies suggest a possible relationship.23 One report showed that certain mutations were associated with the presence of symptoms or longer PR,24 factors known to be related to a worse outcome. One recent study shows a non-significant borderline association between positive genetic testing and arrhythmic events. Interestingly, none of the negative genotype patients suffered an event. This is an important finding but more evidence is needed as the relationship was non-significant and the population of this study was relatively small.4

Electrocardiogram Pattern The hallmark of the BS diagnosis is the characteristic ST-segment elevation (see Figure 1). Since the first BS reports, the ECG pattern has shown a clear prognostic value. Patients displaying the spontaneous pattern have a worse prognosis, with a hazard ratio (HR) of 4.0 for events.3 Although patients diagnosed after a drug challenge have a better outcome, they are still at risk.

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Clinical Arrhythmias Figure 1: Electrocardiographic Findings in Brugada Syndrome

displaying early repolarisation in the inferior leads, a type 1 Brugada pattern could be recorded in high intercostal leads.38 Other ECG parameters that might be associated with a worse prognosis are T-peak T-end interval, T-wave alternans, the aVR sign and a prominent S-wave in lead I.39--43 Evidence regarding their value is driven by studies involving a small number of patients that were mainly symptomatic. Therefore, their usefulness in asymptomatic patients is yet to be confirmed.

Atrial Fibrillation

A: Electrocardiogram displaying a spontaneous type 1 pattern. B: Electrocardiogram displaying a QRS with fragmentation

Furthermore, most asymptomatic patients do not display the spontaneous type 1 pattern. Typical ECG changes might experience spontaneous variations, in both morphology and ST elevation.25,26 In addition to spontaneous fluctuation, many factors and drugs influence ST-segment elevation.27,28 Patients initially considered to have druginduced BS can display the type 1 ECG spontaneous pattern during follow-up. In our experience it can happen in around 20 % of patients.2 A fever-induced type 1 ECG pattern merits a special consideration. Though evidence regarding its value and prognosis is sparse, a recent report shows an arrhythmic incidence rate of 0.9 % per year, an intermediate risk between that of patients with a drug-induced type 1 ECG pattern and those displaying it spontaneously.29 Due to the lower risk of these patients and potential long-term complications of ICD implantation, risk stratification in the drug-induced BS subgroup needs to be precise. Recent reports have questioned the value of drug-induced BS and the drug challenge itself.30,31 To date, drug challenge remains the best available tool for diagnosis. This value was first reported in 2000.32 Unfortunately, the presence or absence of a mutation cannot be considered as the diagnostic gold standard. Furthermore, within the same family, individuals with the same mutation may exhibit different responses during the drug challenge.

Electrocardiogram Parameters Great effort has been made to find ECG characteristics other than the typical type 1 ECG pattern to identify patients at higher risk. Interesting findings have been reported. The presence of QRS fragmentation has been associated with a worse prognosis and a more expressive clinical presentation of the BS (see Figure 1).11,33,34 Around one-third of asymptomatic patients might present fragmentation but none suffered arrhythmic events.33 Further reports, however, suggest that it is an independent risk marker and therefore can be useful in asymptomatic patients.34 Together with QRS fragmentation, repolarisation anomalies appear to have value to stratify patients. It has been shown that they can be present in around 10 % of BS patients and might co-exist with fragmented QRS.35 They are associated with a more severe clinical presentation and also have an independent prognosis value. A combination of both parameters might confer patients with an especially high risk.36,37 Interestingly, it has recently been reported that in around 16 % of patients with idiopathic ventricular fibrillation (VF)

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Atrial fibrillation is more common in patients with BS than in the general population.44 Furthermore, it can raise clinical suspicion leading to BS diagnosis in a young patient.45 Its presence is related to a higher risk patient, with a more expressive clinical presentation and worse long-term outcome.46 As with other parameters, value in asymptomatic patients is not clear. It can just be a marker of a more severe disease and not independently associated with prognosis. In our experience, it has a borderline association with events that are lost in asymptomatic patients.

Sinus Node Dysfunction SND can be associated with mutations in the sodium channels.47,48 Not surprisingly, it can be present in BS patients. The underlying mechanism is not clear; a more expressive form of the disease might be involved. SND is usually related to a more severe and early disease, and patients are frequently symptomatic. Nevertheless, we have recently described that in asymptomatic BS patients, concomitant SND has a worse prognosis that might justify a more aggressive therapeutic attitude.3

Electrophysiological Testing Deep controversy still exists around the prognostic value of an electrophysiological study (EPS). The first data initially suggesting that it might help to identify subjects at higher risk were reported 15 years ago.49 Since then several groups have communicated contradictory results.50,51 In 2010 the FINGER registry was published.10 It pooled data from 11 European centres, 1,029 patients with a median followup of 32 months. Interestingly, they performed a specific analysis of the asymptomatic population. The only variable associated with events was the EPS (performed in 369 patients). When introduced in the multivariable analysis, it lost statistical association (p=0.09), but the number of events in the asymptomatic population was 10 and therefore a lack of statistical power might have been responsible for this result. Shortly after the FINGER registry the PRELUDE registry was published.11 This study was specifically designed to evaluate the role of EPS in BS. A total of 308 individuals were followed during a median of 34 months. Kaplan-Meier event curves were practically identical in patients with and without induced ventricular arrhythmias (VAs). We have recently published our experience in this field.6 Four hundred and four individuals underwent an EPS, after a mean follow-up of 74 months; the EPS was independently associated with a worse outcome (HR 8.3). When restricted to an asymptomatic population it remained predictive for events. Our data suggest that the EPS is useful in both patients presenting type 1 ECG spontaneously or after a drug challenge. Interestingly, the EPS had a high negative predictive value (98.3 %), suggesting that asymptomatic patients with no induced VAs have an excellent prognosis (see Figure 2).

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Some considerations should be made around the value of inducible VAs. First, the EPS protocols vary widely throughout the literature. Our protocol has remained unchanged since the first reports. It includes only one stimulation site, the right ventricle apex, and it does not include repetition of extrastimuli. It might be one of the less aggressive in the literature and the fact that our inducibility rate is one of the lowest reflects this. A more aggressive protocol might decrease the specificity of the test and might be the reason for the divergent results found in the literature. The PRELUDE registry used two stimulation sites, and the FINGER and the recently published pooled analysis do not have a homogenous protocol. Furthermore, our population has a more benign profile compared with other studies, with a less spontaneous type 1 ECG pattern; this might explain the difference in the arrhythmic event rate. The second consideration is that we must not forget that the EPS is not a diagnostic test, but rather a tool that helps us to stratify our patients. An inducible VA does not mean that a patient will present arrhythmic events, but only that he (she) might be at a higher risk of sudden death.

Figure 2: Risk of Arrhythmic Events by Inducible Ventricular Arrhythmias According to Kaplan-Meier Method Higher risk

Inducible Ventricular Arrhythmias

Sinus node dysfunction

High risk characteristics Spontaneous type 1

Lower risk

Novel risk factors ECG parameters Family history of SCD Fragmentation / ERP Sex

Less proven features

ECG = electrocardiogram; ERP = early repolarisation pattern; SCD = sudden cardiac death.

Figure 3: Risk Factors Associated with Arrhythmic Events in Brugada Syndrome 1.0

0.8 Event Probability

A pooled analysis of the EPS in BS has recently been published.52 It pooled the data from eight registries with 1,312 patients with a median follow-up of 38 months and heterogeneous stimulation protocols. The overall conclusion is that EPS predicts future arrhythmic events with a HR of 2.7. Importantly, inducibility was significantly associated with events when adjusted to a number of variables that included the ECG pattern and symptoms, and was limited to stimulation with up to two extrastimuli. In this study, 53 % of the patients presented a spontaneous type 1 ECG pattern, significantly higher than our cohort. An interesting remark is that this study did not include any data coming from the groups that actively defended the prognostic value of the EPS based on their results. Should those results have been pooled together, the value of the EPS would have been even more significant.

0.6

0.4 EPS inducible 0.2

General Management Recommendations An ICD is the most accepted therapy for high-risk patients. Clinical guidelines recommend an ICD in patients that have suffered a SCD (class Ia), patients with syncope and a spontaneous type 1 ECG pattern (class IIa), and those with inducible arrhythmias (class IIb).8,53 Few recommendations are offered for asymptomatic patients. Risk stratification in BS remains under active investigation. Besides classical risk factors, such as spontaneous type 1 ECG or symptoms, big effort is being made to identify new factors that could help to manage patients. Unfortunately, as previously shown, these new markers are mainly found in patients with a more severe clinical presentation and therefore are easily recognisable as being at high risk. In our experience, three variables should be taken into special consideration in asymptomatic patients: a spontaneous type 1 ECG, the presence of SND and inducible VAs during programmed stimulation of the heart (see Figure 3). Inducible VAs demonstrated a HR of 9, the highest amongst the others, and was the only one independently associated with events. Furthermore, recent reports are underscoring its value of the EPS.52 SND should also be considered with special caution. In our experience, a BS patient displaying this condition is at a particularly high risk. Fortunately, it is uncommon, but it is invariably associated with a more severe disease. Most patients with SND are symptomatic and they

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p<0.01

EPS non-inducible

0.0 0.0

100

150

200

250

Time (months) EPS = electrophysiological study.

present at a younger age. When adjusted by other factors, SND loses the statistical relationship with events; however, this might be due to a lack of power.3 ECG findings are also important. Nevertheless, a spontaneous type 1 ECG pattern does not justify on its own an ICD implantation.8 Each patient should be evaluated individually, paying special consideration to other risk factors; such as sex, other ECG characteristics and family history of SCD. In this context a normal EPS is reassuring. A negative predictive value of the test is 98 %, making a patient very unlikely to present future events. In our experience, amongst 289 asymptomatic patients with no inducible VAs, only two presented an event during the EPS.3 ICD implantation should be considered only after a careful evaluation of the risks and benefits. In our experience, around 20 % of patients had inappropriate shocks and 15 % suffered device-related complications.2 These latter complications were found mostly in patients younger than 40 years. Of note, no complication was fatal (though one patient died of a urinary sepsis shortly after a device revision). Similar rates are reported by other groups.9,12 In a study from

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Clinical Arrhythmias our group, complications affected up to 33 % of children with ICDs.16 In this particularly active category of patients, lead fracture occurred more frequently. Moreover, the long life expectancy leads to multiple generator change procedures, with a potential increased rate of device-related complications. Subcutaneous ICDs (S-ICDs) are a promising option in the BS population. Of note, the dynamic ECG pattern that can occur in BS patients might lead to inappropriate shocks.54,55 Furthermore, a small percentage of BS patients might need atrial or ventricular pacing. We have demonstrated that a small percentage of BS patients might have concomitant SND,3 which has prognostic importance and can appear in a paediatric age. Furthermore, monomorphic ventricular tachycardia (VT) might happen in BS and effectively respond to antitachycardia pacing.56 Consequently, S-ICD implantation in BS should be considered after taking into account these facts.

quinidine does not completely suppress arrhythmic events in patients with BS,58 and quinidine is not recommended as an alternative to ICD in all high-risk patients. Quinidine acts mainly to inhibit the transient outward potassium current. Given that the mechanisms underlying the development of BS are multifaceted and quinidine’s actions are limited to the inhibition of the transient outward potassium current, drug therapy does not guarantee complete protection. Epicardial radiofrequency substrate ablation has emerged as a promising tool for the management of BS. First described by Nademanee and colleagues in 2011, radiofrequency ablation of the anterior aspect of the right ventricular outflow tract (RVOT) rendered arrhythmias during electrophysiological testing noninducible, normalised ECG patterns, and had an excellent prognosis at 20 months.59 Similar results have also been reported by others.60 Further experience and evidence is needed as a prophylactic measure in high-risk asymptomatic patients.

Non-device-based Therapeutic Tools Quinidine is widely accepted as a treatment for electrical storm or frequent ICD shocks in patients with BS,8 or as an alternative for patients contraindicated for ICD implantation. Quinidine has been shown to be effective as an alternative to ICD, even in high-risk patients. An EP-based drug therapy involves an aggressive electrophysiological stimulation protocol, with repetition of the test under the drug and regularly follow-up. No arrhythmic events have been reported during follow-up in these patients.57 However, other reports showed that

Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol 1992;20(6):1391–6. PMID: 1309182 2. Conte G, Sieira J, Ciconte G, et al. Implantable cardioverterdefibrillator therapy in Brugada syndrome: a 20-year single-center experience. J Am Coll Cardiol 2015;65(9):879–88. DOI: 10.1016/j.jacc.2014.12.031; PMID: 25744005 3. Sieira J, Ciconte G, Conte G, et al. Asymptomatic Brugada syndrome: Clinical characterization and long-term prognosis. Circ Arrhythm Electrophysiol 2015;8(5):1144–50. DOI: 10.1161/ CIRCEP.114.003044; PMID: 26215662 4. Andorin A, Behr ER, Denjoy I, et al. Impact of clinical and genetic findings on the management of young patients with Brugada syndrome. Heart Rhythm 2016;13(6):1274–82. DOI: 10.1016/j.hrthm.2016.02.013; PMID: 26921764 5. Priori SG, Napolitano C, Gasparini M, et al. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation 2002;105(11):1342–7. PMID: 11901046 6. Sieira J, Conte G, Ciconte G, et al. Prognostic value of programmed electrical stimulation in Brugada syndrome: 20 years experience. Circ Arrhythm Electrophysiol 2015;8(4):777–84. DOI: 10.1161/CIRCEP.114.002647; PMID: 25904495 7. Casado-Arroyo R, Berne P, Rao JY, et al. Long-term trends in newly diagnosed Brugada syndrome: implications for risk stratification. J Am Coll Cardiol 2016;68(6):614–23. DOI: 10.1016/ j.jacc.2016.05.073; PMID: 27491905 8. Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015;36(41):2793–867. DOI: 10.1093/eurheartj/ehv316; PMID: 26320108 9. Olde Nordkamp LR, Postema PG, Knops RE, et al. Implantable cardioverter-defibrillator harm in young patients with inherited arrhythmia syndromes: A systematic review and metaanalysis of inappropriate shocks and complications. Heart Rhythm 2016;13(2):443–54. DOI: 10.1016/j.hrthm.2015.09.010; PMID: 26385533 10. Probst V, Veltmann C, Eckardt L, et al. Long-term prognosis of patients diagnosed with Brugada syndrome: Results from the FINGER Brugada syndrome registry. Circulation 2010;121(5):635–43. DOI: 10.1161/ CIRCULATIONAHA.109.887026; PMID: 20100972 11. Priori SG, Gasparini M, Napolitano C, et al. Risk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) registry. J Am Coll Cardiol 2012;59(1):37–45. DOI: 10.1016/j.jacc.2011.08.064; PMID: 22192666 12. Sacher F, Probst V, Maury P, et al. Outcome after implantation of a cardioverter-defibrillator in patients

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24.

Conclusion Nowadays most patients diagnosed with BS are asymptomatic. Prognosis is more favourable than in symptomatic patients but arrhythmic events happen. Clinical guidelines lack specific recommendations for these patients. Risk stratification remains challenging and sometimes controversial. Spontaneous type 1 ECG, inducible VAs during an EPS and presence of SND can identify patients at a higher risk. Novel risk markers might help in their management. ■

with Brugada syndrome: a multicenter study-part 2. Circulation 2013;128(16):1739–47. DOI: 10.1161/ CIRCULATIONAHA.113.001941; PMID: 23995538 Brugada J, Brugada R, Antzelevitch C, et al. Long-term followup of individuals with the electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V1 to V3. Circulation 2002;105(1):73–8. PMID: 11772879 Sieira J, Conte G, Ciconte G, et al. Clinical characterisation and long-term prognosis of women with Brugada syndrome. Heart 2016;102(6):452–8. DOI: 10.1136/heartjnl-2015-308556; PMID: 26740482 Conte G, de Asmundis C, Ciconte G, et al. Follow-up from childhood to adulthood of individuals with family history of Brugada syndrome and normal electrocardiograms. JAMA 2014;312(19):2039–41. DOI: 10.1001/jama.2014.13752; PMID: 25399282 Conte G, Dewals W, Sieira J, et al. Drug-induced Brugada syndrome in children: clinical features, device-based management, and long-term follow-up. J Am Coll Cardiol 2014;63(21):2272–9. DOI: 10.1016/j.jacc.2014.02.574; PMID: 24681144 Conte G, DE Asmundis C, Sieira J, et al. Clinical characteristics, management, and prognosis of elderly patients with Brugada syndrome. J Cardiovasc Electrophysiol 2014;25(5):514–9. DOI: 10.1111/jce.12359; PMID: 24400668 Kamakura T, Wada M, Nakajima I, et al. Evaluation of the necessity for cardioverter-defibrillator implantation in elderly patients with Brugada syndrome. Circ Arrhythm Electrophysiol 2015;8(4):785–91. DOI: 10.1161/CIRCEP.114.002705; PMID: 26067668 Benito B, Sarkozy A, Mont L, et al. Gender differences in clinical manifestations of Brugada syndrome. J Am Coll Cardiol 2008;52(19):1567–73. DOI: 10.1016/j.jacc.2008.07.052; PMID: 19007594 Sacher F, Meregalli P, Veltmann C, et al. Are women with severely symptomatic Brugada syndrome different from men? J Cardiovasc Electrophysiol 2008;19(11):1181–5. DOI: 10.1111/j.1540-8167.2008.01223.x; PMID: 18554195 Sarkozy A, Sorgente A, Boussy T, et al. The value of a family history of sudden death in patients with diagnostic type I Brugada ECG pattern. Eur Heart J 2011;32(17):2153–60. DOI: 10.1093/eurheartj/ehr129; PMID: 21727093 Hasdemir C, Payzin S, Kocabas U, et al. High prevalence of concealed Brugada syndrome in patients with atrioventricular nodal reentrant tachycardia. Heart Rhythm 2015;12(7): 1584–94. DOI: 10.1016/j.hrthm.2015.03.015; PMID: 25998140 Sommariva E, Pappone C, Martinelli Boneschi F, et al. Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification. Eur J Hum Genet 2013;21(9):911–7. DOI: 10.1038/ejhg.2012.289; PMID: 23321620; PMCID:PMC3746265 Meregalli PG, Tan HL, Probst V, et al. Type of SCN5A mutation determines clinical severity and degree of conduction

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slowing in loss-of-function sodium channelopathies. Heart Rhythm 2009;6(3):341–8. DOI: 10.1016/j.hrthm.2008.11.009; PMID: 19251209 Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005;111(5):659–70. DOI: 10.1161/01.CIR.0000152479.54298.51; PMID: 15655131 Alings M, Wilde A. “Brugada” syndrome: clinical data and suggested pathophysiological mechanism. Circulation 1999;99(5):666–73. PMID: 9950665 Miyazaki T, Mitamura H, Miyoshi S, et al. Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome. J Am Coll Cardiol 1996;27(5):1061–70. DOI: 10.1016/0735-1097(95)00613-3; PMID: 8609322 Mizumaki K, Fujiki A, Tsuneda T, et al. Vagal activity modulates spontaneous augmentation of ST elevation in the daily life of patients with Brugada syndrome. J Cardiovasc Electrophysiol 2004;15(6):667–73. DOI: 10.1046/j.1540-8167.2004.03601.x; PMID: 15175062 Mizusawa Y, Morita H, Adler A, et al. The prognostic significance of fever-induced Brugada syndrome. Heart Rhythm 2016;13(7):1515–20. DOI: 10.1016/j.hrthm.2016.03.044; PMID: 27033637 Viskin S, Rosso R, Friedensohn L, et al. Everybody has Brugada syndrome until proven otherwise? Heart Rhythm 2015;12(7):1595–8. DOI: 10.1016/j.hrthm.2015.04.017; PMID: 25998201 Havakuk O, Viskin S. A tale of 2 diseases: The History of Long-QT Syndrome and Brugada Syndrome. J Am Coll Cardiol 2016;67(1):100–8. DOI: 10.1016/j.jacc.2015.10.020; PMID: 26764071 Brugada R, Brugada J, Antzelevitch C, et al. Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. Circulation 2000;101(5):510–5. PMID: 10662748 Morita H, Kusano KF, Miura D, et al. Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome. Circulation 2008;118(17): 1697–704. DOI: 10.1161/CIRCULATIONAHA.108.770917; PMID: 18838563 Kawata H, Morita H, Yamada Y, et al. Prognostic significance of early repolarization in inferolateral leads in Brugada patients with documented ventricular fibrillation: a novel risk factor for Brugada syndrome with ventricular fibrillation. Heart Rhythm 2013;10(8):1161–8. DOI: 10.1016/j.hrthm.2013.04.009; PMID: 23587501 Sarkozy A, Chierchia GB, Paparella G, et al. Inferior and lateral electrocardiographic repolarization abnormalities in Brugada syndrome. Circ Arrhythm Electrophysiol 2009;2(2):154–61. DOI: 10.1161/CIRCEP.108.795153; PMID: 19808460 Tokioka K, Kusano KF, Morita H, et al. Electrocardiographic

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parameters and fatal arrhythmic events in patients with Brugada syndrome: combination of depolarization and repolarization abnormalities. J Am Coll Cardiol 2014;63(20): 2131–8. DOI: 10.1016/j.jacc.2014.01.072; PMID: 24703917 Conte G, de Asmundis C, Sieira J, et al. Prevalence and clinical impact of early repolarization pattern and QRS-fragmentation in high-risk patients with Brugada syndrome. Circ J 2016; DOI: 10.1253/circj.CJ-16-0370; PMID: 27558008: epub ahead of print. Kamakura T, Wada M, Nakajima I, et al. Significance of electrocardiogram recording in high intercostal spaces in patients with early repolarization syndrome. Eur Heart J 2016;37(7):630–7. DOI: 10.1093/eurheartj/ehv369; PMID: 26261291 Zumhagen S, Zeidler EM, Stallmeyer B, et al. Tpeak-Tend interval and Tpeak-Tend/QT ratio in patients with Brugada syndrome. Europace 2016; DOI: 10.1093/europace/euw033; PMID: 26941339: epub ahead of print. Castro Hevia J, Antzelevitch C, Tornes Barzaga F, et al. TpeakTend and Tpeak-Tend dispersion as risk factors for ventricular tachycardia/ventricular fibrillation in patients with the Brugada syndrome. J Am Coll Cardiol 2006;47(9):1828–34. DOI: 10.1016/j.jacc.2005.12.049; PMCID: PMC1474075 Babai Bigi MA, Aslani A, Shahrzad S. aVR sign as a risk factor for life-threatening arrhythmic events in patients with Brugada syndrome. Heart Rhythm 2007;4(8):1009–12. DOI: 10.1016/j.hrthm.2007.04.017; PMID: 17675073 Uchimura-Makita Y, Nakano Y, Tokuyama T, et al. Time-domain T-wave alternans is strongly associated with a history of ventricular fibrillation in patients with Brugada syndrome. J Cardiovasc Electrophysiol 2014;25(9):1021–7. DOI: 10.1111/ jce.12441; PMID: 24761970 Calò L, Giustetto C, Martino A, et al. A new electrocardiographic marker of sudden death in Brugada syndrome: The S-Wave in lead I. J Am Coll Cardiol 2016;67(12):1427–40. DOI: 10.1016/j.jacc.2016.01.024; PMID: 27012403 Morita H, Kusano-Fukushima K, Nagase S, et al. Atrial fibrillation and atrial vulnerability in patients with Brugada

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syndrome. J Am Coll Cardiol 2002;40(8):1437–44. PMID: 12392834 45. Rodríguez-Mañero M, Namdar M, Sarkozy A, et al. Prevalence, clinical characteristics and management of atrial fibrillation in patients with Brugada syndrome. Am J Cardiol 2013;111(3): 362–7. DOI: 10.1016/j.amjcard.2012.10.012; PMID: 23206922 46. Giustetto C, Cerrato N, Gribaudo E, et al. Atrial fibrillation in a large population with Brugada electrocardiographic pattern: prevalence, management, and correlation with prognosis. Heart Rhythm 2014;11(2):259–65. DOI: 10.1016/ j.hrthm.2013.10.043; PMID: 24513919 47. Morita H, Fukushima-Kusano K, Nagase S, et al. Sinus node function in patients with Brugada-type ECG. Circ J 2004;68(5):473–6. PMID: 15118291 48. Letsas KP, Korantzopoulos P, Efremidis M, et al. Sinus node disease in subjects with type 1 ECG pattern of Brugada syndrome. J Cardiol 2013;61(3):227–31. DOI: 10.1016/ j.jjcc.2012.12.006; PMID: 23403368 49. Brugada P, Geelen P, Brugada R, et al. Prognostic value of electrophysiologic investigations in Brugada syndrome. J Cardiovasc Electrophysiol 2001;12(9):1004–7. PMID: 11573688 50. Eckardt L. Electrophysiologic investigation in Brugada syndrome; yield of programmed ventricular stimulation at two ventricular sites with up to three premature beats. Eur Heart J 2002;23(17):1394–401. PMID: 12191751 51. Delise P, Allocca G, Marras E, et al. Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach. Eur Heart J 2011;32(2): 169–76. DOI: 10.1093/eurheartj/ehq381; PMID: 20978016; PMCID:PMC3021386 52. Sroubek J, Probst V, Mazzanti A, et al. Programmed ventricular stimulation for risk stratification in the Brugada syndrome: A pooled analysis. Circulation 2016;133(7):622–30. DOI: 10.1161/CIRCULATIONAHA.115.017885; PMID: 26797467; PMCID:PMC4758872 53. 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

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2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;10(12):1932–63. DOI: 10.1016/ j.hrthm.2013.05.014; PMID: 24011539 Conte G, Regoli F, Moccetti T, Auricchio A. Subcutaneous implantable cardioverter-defibrillator and druginduced Brugada syndrome: the importance of repeat morphology analysis during ajmaline challenge. Eur Heart J 2016;37(19):1498. DOI: 10.1093/eurheartj/ehv572; PMID: 26530106 Olde Nordkamp LR, Conte G, Rosenmöller BR, et al. Brugada syndrome and the subcutaneous implantable cardioverterdefibrillator. J Am Coll Cardiol 2016;68(6):665–6. DOI: 10.1016/ j.jacc.2016.05.058; PMID: 27491911 Rodríguez-Mañero M, Sacher F, de Asmundis C, et al. Monomorphic ventricular tachycardia in patients with Brugada syndrome: A multicenter retrospective study. Heart Rhythm 2016;13(3):669–82. DOI: 10.1016/j.hrthm.2015.10.038; PMID: 26538325 Belhassen B, Rahkovich M, Michowitz Y, et al. Management of Brugada syndrome: thirty-three-year experience using electrophysiologically guided therapy with class 1A antiarrhythmic drugs. Circ Arrhythm Electrophysiol 2015;8(6):1393–402. DOI: 10.1161/CIRCEP.115.003109; PMID: 26354972 Anguera I, García-Alberola A, Dallaglio P, et al. Shock reduction with long-term quinidine in patients with Brugada syndrome and malignant ventricular arrhythmia episodes. J Am Coll Cardiol 2016;67(13):1653–4. DOI: 10.1016/ j.jacc.2016.01.042; PMID: 27150692 Nademanee K, Veerakul G, Chandanamattha P, et al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation 2011;123(12):1270–9. DOI: 10.1161/ CIRCULATIONAHA.110.972612; PMID: 21403098 Brugada J, Pappone C, Berruezo A, et al. Brugada syndrome phenotype elimination by epicardial substrate ablation. Circ Arrhythm Electrophysiol 2015;8(6):1373–81. DOI: 10.1161/ CIRCEP.115.003220; PMID: 26291334

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Abstract The invasive management of atrial fibrillation (AF) has been considerably changed by the identification of major sites of AF initiation and/ or maintenance within the pulmonary vein antra. Percutaneous catheter ablation of these targets has become the standard of care for sustained maintenance of sinus rhythm. Long-term failure of ablation is related to an inability to create a durable transmural lesion or to identify all of the non-pulmonary vein arrhythmia triggers. Pharmacological challenges during catheter ablation have been suggested to improve outcomes in both paroxysmal and persistent AF. Herein we review the mechanism and evidence for the use of pharmacological adjuncts during the catheter ablation of AF.

Keywords atrial fibrillation, catheter ablation, adenosine, isoproterenol, ibutilide, pulmonary vein isolation Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: Jean-Baptiste Gourraud has received student support from the Fédération Francaise de Cardiologie. Dr Andrade is supported by a Michael Smith Foundation Clinical Scholar award. Received: 21 August 2016 Accepted: 6 October 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(3):170–6. DOI: 10.15420/aer.2016:27:2 Correspondence: Dr Blandine Mondesert, Institut de Cardiologie de Montréal, 5000 rue Bélanger, H1T1C8 Montréal, QC, Canada; E: Blandine.Mondesert@icm-mhi.org

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia observed in clinical practice, occurring in approximately 2 % of the general population.1–3 A progressive increase in both the prevalence and incidence of AF has been demonstrated in recent years, defining AF as a major economic and public health issue.1 The identification of sites of AF initiation and/or maintenance within the pulmonary veins (PVs) has led to the development of percutaneous procedures to electrically isolate the PVs from the left atrium (LA).4 Large observational studies and multiple randomised-controlled trials have demonstrated that catheter ablation is universally superior to anti-arrhythmic drugs (AADs) for the maintenance of sinus rhythm (66–89 % versus 9–58 %, respectively) and results in a greater improvement in arrhythmia-related symptoms, exercise capacity and quality of life.1,2,5–8 As a result, catheter ablation has become the ‘standard of care’ for the maintenance of sinus rhythm in symptomatic patients in whom drugs are ineffective or poorly tolerated. While the results of ablation are unequivocally superior to medical therapy, they are unfortunately not flawless: approximately 30 % of paroxysmal AF patients will experience arrhythmia recurrence after a single ablation procedure.8 As most recurrences are in association with PV reconnection or as a result of non-PV triggers, several pharmacological challenges have been proposed to improve outcomes.9–12 This article reviews the pathophysiological background and evidence for the use of pharmacological challenges during catheter ablation procedures.

Pathophysiology of Atrial Fibrillation and Atrial Fibrillation Catheter Ablation Despite decades of progress, there is no comprehensive pathophysiological explanation of AF. Early hypotheses postulated that

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AF resulted from the co-existence of multiple independent wavelets propagating randomly throughout the left and right atria (the ‘multiple wavelet hypothesis’).13,14 This hypothesis suggested that as long as the atria had a sufficient electrical mass, and an adequately short refractory period, AF could be initiated and indefinitely perpetuated.15 Based on this theory, the early surgical interventions for AF were designed to reduce the excitable mass of atrial tissue by compartmentalising the atria into smaller regions incapable of sustaining a critical number of circulating wavelets.16 Unfortunately this strategy has proved to be of limited efficacy and has been associated with a substantial risk of major complications.17 In the late 1990s, Haïssaguerre and colleagues demonstrated that AF is a triggered arrhythmia initiated by rapid repetitive discharges, predominantly from the proximal aspect of the PVs.4 This discovery led to the development of percutaneous procedures to directly eliminate spontaneous focal ectopic activity within the PVs. However, early AF recurrences from the targeted and other nontargeted PVs led to modification of the ablation strategy to electrically isolate all of the PVs.18,19 Over the past 17 years, the recognition that sites of AF initiation and/or maintenance (e.g. triggered activity and micro re-entry) are frequently located within the PV antrum has shifted the ablation target more proximally.20–22 As such, the contemporary AF ablation procedure is a hybrid approach whereby circumferential ablative lesions are placed within the peri-venous left atrial myocardium, i.e. outside of the tubular veins with the goal of electrical pulmonary vein isolation (PVI). Successful electrical PVI is defined as a bidirectional conduction block documented using a circular mapping catheter placed at the PV ostia. Ablation is able to target both the initiating triggers, as well as the mass of electrically-active LA tissue capable of sustaining the fibrillatory

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Figure 1: Triggers of Atrial Fibrillation During Second Catheter Ablation

Prevalence (%)

p=0.67 100 90 80 70 60 50 40 30 20 10 0

RAA

LAA

0.32 %/0.2 %/0

SVC 1.6 %/2.0 %/2.1 %

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0.33 %/0.4 %/0

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CT/ER 3.7 %/4.8 %/2.8 %

IVC

PAF (n=1,531) Paroxysmal

Persistent

Longstanding Persistent

LLAP

0.33 %/0.20 %/0 LIPV

AVNRT 2.6 %/1.2 %/1.4 %*

CS/MV/LOM 1.4 %/2.2 %/2.8 %

PERS (n=496) LS PERS (n=141)

(A) Prevalence of pulmonary vein reconnection in paroxysmal (PAF), persistent (PERS) and longstanding persistent (LS PERS) atrial fibrillation (AF). (B) Prevalence of right and left nonpulmonary vein triggers. * = 2 patients with long-standing persistent AF; AVNRT = AV node reentrant tachycardia; CS = coronary sinus; CT = crista terminalis; ER = eustacian ridge; LAA = left atrial appendage; LLAP = left lateral accessory pathway; LOM = ligament of Marshall; MV = mitral valve; PW = posterior wall; RAA = right atrial appendage; SVC = superior vena cava; TV = tricuspid valve. Modified from Singh et al, 2016.101

wavelets responsible for AF perpetuation.3 It also has the advantage of limiting PV stenosis.23 While isolation of the PV antra has become the cornerstone of all contemporary AF ablation procedures, patients with more advanced forms of AF, e.g. persistent rather than paroxysmal AF, are known to be less dependent on the PV antra for arrhythmia initiation and perpetuation. 24–26 As the disease progresses, electrical and structural remodelling of the atrial substrate shifts the sites of AF perpetuation to regions outside the PV–LA junction and results in the emergence of non-PV triggers.27–29 The ablation of these ‘fibrotic atrial’ forms of AF often requires adjunctive strategies targeting the abnormal LA substrate, such as linear LA ablation with the goal of compartmentalising the LA into smaller regions incapable of sustaining micro re-entry, or the ablation of complex fractionated atrial electrograms (CFAEs, or areas of abnormal substrate representing areas of slow conduction, conduction block or local ‘pivot’ points) that perpetuate AF re-entry.20,30–33 However, the addition of such substrate-based ablation (either linear ablation or CFAE elimination) does not appear to reduce AF recurrence after PVI in patients with persistent AF.34 It has been suggested that ganglionated plexi may have a role in the initiation and maintenance of both paroxysmal and non-paroxysmal AF.35–41 Localisation is usually performed on the endocardium either anatomically, by vagal response following high-frequency stimulation, or by Fourier transform in sinus rhythm.35,37 Although ganglionated plexi ablation significantly reduces AF recurrence, the long-term success rate is lower than after PVI.35–41 Interestingly, in addition to PVI, the suppression of ganglionated plexi response – particularly that observed during cryoablation – may reduce AF recurrence.40,41

is important to recognise that the reasons for long-term failure are largely centred on the relative inability to create a lasting transmural lesion using the contemporary ablation toolset. While electrical PVI may be achieved acutely, the combination of inadequate electrode– tissue contact, insufficient power delivery and tissue oedema may prevent radiofrequency (RF)-induced heating of the myocardium to lethal temperatures.27,42–44 As the transient injury induced at the time of index ablation resolves, gaps in the initial line of ablation may emerge, allowing PV triggers to excite the adjacent LA and induce AF.27 This is highlighted by the observation that >90 % of patients requiring a second catheter ablation procedure demonstrate one (or more) PV reconnections (see Figure 1A).26,45 For patients with more advanced forms of AF, recurrences may be due to the persistence of LA substrate abnormality as well as non-PV triggers (see Figure 1B). These triggers can be found in about 50 % of patients and originate in the superior vena cava, left atrial free wall or appendage, coronary sinus, crista terminalis or right atrial free wall.27 Targeted ablation of these non-PV triggers has been shown to improve outcomes, but unfortunately is limited by non-inducibility at the time of the ablation procedure, as well as unreliable long-term behaviour over time.9,33,46

Pharmacological Challenges in Catheter Ablation of Atrial Fibrillation Four pharmacological adjuncts have been proposed to improve the outcomes of AF ablation. These four agents – isoproterenol, adenosine, amiodarone and ibutilide – are mechanistically disparate and are used for different purposes: unmasking dormant conduction (DC), inducing non-PV triggers or identifying abnormal substrate for ablation.

Although many authors believe that additional ablations are required for non-paroxysmal AF or some paroxysmal AF, no randomised studies have consistently shown which strategy to use.

Adenosine

Mechanism of Atrial Fibrillation Recurrence After Ablation

Mechanism of Action

Unfortunately, the results of ablation can be unsatisfactory. In the case of paroxysmal AF, only about 70 % of patients will remain arrhythmiafree after a single ablation procedure without the use of AADs.1,2,5–8 It

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Adenosine is predominantly used to differentiate permanent PV-atrial conduction block from DC (i.e. viable but latently non-conducting tissue).

Following ablation, the resting membrane potential (RMP) of the targeted left atrial myocardial cells becomes depolarised due to cell membrane injury. This depolarisation of the RMP results in sodiumchannel inactivation (when >−60mV), leading to inexcitability and

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Clinical Arrhythmias Figure 2: Effect of Pharmacological Challenge on Pulmonary Vein Potentials and Dormant Conduction After Pulmonary Vein Isolation Adenosine without DC

Isoproterenol with DC

Pre-ablation

Membrane potential (mV)

+25

Pre-ablation Post-ablation

+25

Post-ablation S

S –25

–50

Isoproterenol S

–25 –50

–75

Time (ms) 0

Adenosine with DC Pre-ablation +25

Time (ms) 0

1000

Membrane potential (mV)

Adenosine

1000 Isoproterenol+Adenosine

D Pre-ablation

Adenosine Post-ablation

+25

Post-ablation S

0 S

–25

–50

Iso+Ado

–25 –50

–75

Time (ms) 0

1000

Time (ms) 0

1000

Pulmonary vein potentials are recorded immediately above the ablation line in the perfused heart of a dog. (A) After adding adenosine without dormant conduction (DC). (B) After adding adenosine in a case with DC. (C) After adding isoproterenol in a case with DC. (D) After adding isoproterenol plus adenosine (Iso+Ado) in a case with DC. S = stimulus artefacts without action potential responses. Modified from Datino et al., 2011. 50

functional conduction block.47,48 After a waiting period of 30–60 minutes, a slow hyperpolarisation can be observed leading to spontaneous PV reconnection, called DC.49 The difference between dormant and nondormant PVs lies primarily in the degree of RF-induced depolarisation. Non-dormant PVs are depolarised more severely (post-ablation RMPs positive to −50 mV) than dormant PVs (post-ablation RMPs of −50 to −60 mV).49 Adenosine has been proposed as a useful test of DC due to its differential effect on PV cells and LA cells.50 In both the PV and LA cells adenosine is able to shorten the action potential duration, however it selectively hyperpolarises the RMP by about 10 mV and increases dV/dt (max) by selectively activating IKAdo in PV cells (leading to an increase in the transient outward potassium currents; see Figure 1).49,51,52 Moreover adenosine’s effect on the PV sodium channel removes voltage-dependent INa inactivation, and further increases the dV/dt (maximum velocity of phase 0 of the action potential; see Figure 2).49,51,52 Taken together, in the event of incomplete membrane damage after RF ablation, adenosine can facilitate membrane hyperpolarisation, restoring the excitability threshold see (Figure 1). Conversely, those cells that have sustained irreversible damage will not respond to adenosine infusion, i.e. the membrane will remain depolarised and unexcitable. Additionally, adenosine may reveal nonPV triggers secondary to post-bradycardia adrenergic simulation.9,49

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Clinical Value In 2004, Arentz et al. demonstrated that adenosine could be used to reveal DC.53 Subsequent observational studies have demonstrated DC in 25–51 % of cases after PVI using RF. These studies have suggested that ablation guided by adenosine triphosphate (ATP)/adenosine administration can reduce AF recurrences at 1 year by 32–50 % (relative risk reduction).53–57 Despite a lower incidence of DC (13–40 %), a similar effect has been suggested after cryoablation of the PV.58,59 The recently-published randomised Adenosine Following Pulmonary Vein Isolation to Target Dormant Conduction Elimination (ADVICE) study was the first to prospectively evaluate the impact of adenosine testing on clinical outcomes after AF ablation.60 After PV isolation using an irrigated-tip RF catheter, adenosine revealed DC in 53 % of patients. Those with DC were randomised to additional adenosineguided RF ablation until DC was eliminated or no further ablation. In this study a 56 % relative-risk reduction (27 % absolute risk reduction) in the recurrence of atrial tachyarrhythmias was observed with the elimination of DC. In contrast, the Unmasking Dormant Electrical Reconduction by Adenosine Triphosphate (UNDER-ATP) study and the study by Ghanbari et al. failed to demonstrate a significant difference in the reduction of AF recurrence between adenosine-guided PVI and conventional PVI (1-year event-free survival of 68.7 % with ATP-guided versus 67.1 % without ATP, p=0.25 in UNDER-ATP; and 61 % with

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Figure 3: Evolution of the Resting Membrane Potential of the Pulmonary Vein After Ablation Control (n=6)

Adenosine (n=9)

2-hour recordings

–70

–70 ***

RMP (mV)

***

†

***

–35

0 0–15

15–30

30–45

45–60

60–120

0–15

no drug

15–30 ADO

Minutes after ablation

30–45

45–60

60–120

no drug (washout)

Minutes after ablation

(A) Spontaneous evolution of resting membrane potential. ***p<0.001 versus 0–15 minutes. (B) Evolution with adenosine: †p<0.001 for adenosine versus 0–15 minutes by Bonferroni-adjusted t-tests; §p<0.001 for adenosine versus washout period of 30–45 minutes by Bonferroni-adjusted t-tests; ¥p <0.001 for washout period of 30–45 versus washout period of 60–120 minutes by Bonferroni-adjusted t-tests. ADO = adenosine, RMP = resting membrane potential. Modified from Datino et al., 2010. 49

adenosine plus isoproterenol versus 66 % with isoproterenol alone, p=0.83 in Ghanbari et al.).61,62 Differences in the studies’ methodology and approach may explain these results. First, the endpoint of adenosine testing in the ADVICE study and Ghanbari et al. was based on titration of the adenosine dose until the intended electrophysiological effect (transient AV block or sinus arrest) was observed. Conversely, in the UNDER-ATP study the dose of adenosine was predetermined (0.4 mg/kg) and was not altered regardless of the observed effect. Given the lack of documentation of adenosine effect, it is possible that patients in the UNDER-ATP study were underdosed. Second, the waiting period between the achievement of index PVI and adenosine test varied between the studies. In the ADVICE study it was 20 minutes after isolation of the last PV, while in Ghanbari et al. it was 60 minutes, and in UNDER-ATP there was no specific protocol regarding the timing of adenosine administration. In effect this resulted in a median waiting period in UNDER-ATP and Ghanbari et al. that was more than double that of the ADVICE trial. This is relevant given the knowledge that spontaneous recovery of PV–LA conduction is a time-dependent process, with spontaneous RMP hyperpolarisation occurring approximately 30 minutes after ablation.49,50 Mechanistically the administration of adenosine results in a more rapid hyperpolarisation, effectively predicting the spontaneous reconnections that occur between 20 and 60 minutes post-PVI (Figure 3).60,63–66 Taken together it is not surprising that the UNDER-ATP trial and Ghanbari et al. had a higher rate of spontaneous PV reconnection (42.6 % in UNDER-ATP versus 27 % in ADVICE) and a lower rate of DC (27.6 % versus 53 % in the ADVICE study and 37 % in the Ghanbari et al study).53–57,60 Third, as a result of the low prevalence of DC the UNDER-ATP trial was underpowered. Lastly, The ADVICE study only included patients with paroxysmal AF treated with PVI alone, while the UNDER-ATP study included patients with persistent AF (32.8 %) treated with PVI accompanied by additional linear lesions or complex electrogram ablation. While adenosine testing lacks substantial effect in the case of additional linear lesions

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or the ablation of non-PV triggers, the delivery of additional substrateguided ablation (roof line, mitral isthmus line, superior vena cava isolation and CFAE elimination) would have conferred an even longer waiting period. Thus the pathophysiology of persistent AF, the longer post-PVI waiting period and the relative underdosing of adenosine could all explain the low rate of DC revealed with adenosine testing in the UNDER-ATP study. As such, we can conclude the use of adenosine testing for DC is useful in paroxysmal AF patients when an adequate adenosine dose (titrated to clinical effect) is administered after a fixed waiting period (20 minutes). Concomitant use of dipyridamole has been suggested to prolong the transient effect of adenosine in DC and to reduce AF recurrence by facilitating the elimination of DC.67,68 The global outcome of such a strategy, however, remains to be assessed.

Isoproterenol Isoproterenol is used predominantly to identify non-PV triggers that have been associated with AF recurrence, particularly in those with persistent AF.69–74 These triggers may originate from the superior vena cava, coronary sinus, interatrial septum, crista terminalis, Eustachian ridge, inferior mitral annulus, atrial appendages, persistent left superior vena cava and ligament of Marshall. When present, nonPV triggers have been associated with AF recurrence and a worse outcome after ablation.69–74 Fortunately these sites can be revealed in patients with paroxysmal and persistent AF with the infusion of highdose isoproterenol.9,11,75

Mechanism of Action Isoproterenol is a cardiac beta1 and beta2 adrenoreceptor agonist with positive chronotropic, dromotropic and inotropic effects. Via the cyclic adenosine monophosphate mechanism, isoproterenol results in an increase in diastolic [Ca2+]i and intracellular Ca2+, decreasing the action potential duration and atrial refractory periods while facilitating slow diastolic depolarisation (abnormal automaticity) and triggered

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procedure was significantly worse with the addition of CFAE (29 %) when compared with PVI plus non-PV triggers alone (49 %, p<0.040) and PVI plus non-PV triggers plus empirical trigger-site ablation (58 %, p<0.004). Last, the relevance of targeting non-PV triggers remains a matter of debate. Most studies considered repetitive premature atrial contraction as the target for ablation.9,33, 81–87 Several repetitive premature atrial contractions, however, will never induce AF. As such, an increased success rate has been achieved when targeting only the premature atrial contractions that induce AF.9 Thus, non-PV AF trigger could explain the variation observed in the prevalence and outcomes in different groups.

Clinical Value Observational studies have suggested that PVI accompanied by the ablation of non-PV triggers unmasked by isoproterenol infusion could improve the success rate of catheter ablation.69–74,81–83 Non-PV triggerablation protocols generally involve burst-pacing protocols with isoproterenol infusion to induce the triggers, followed by mapping and elimination. Unfortunately the utility of non-PV trigger elimination is limited by the difficulty in inducing, identifying and eliminating these non-PV triggers. In different cohorts the prevalence of non-PV triggers varies between 9 and 19 % (9 % in Inoue et al.’s study of 263 persistent AF patients, 11 % in Santangelli et al.’s study of 2,168 patients with paroxysmal and persistent AF, and 19 % in Lin et al.’s study of 130 patients with long-standing persistent AF).33,84,85 This incidence seems to increase with age, worse atrial substrate and in the presence of cardiomyopathy.81,86 Despite the identification of non-PV trigger sites, however, only 30 % of these can be eliminated due to difficulties in localising them.85 That said, a better arrhythmia-free outcome has been observed in patients in whom all PV and non-PV triggers are eliminated when compared with those in whom triggers are identified but cannot be eliminated (86 % versus 37 %; p=0.09).85 It is not clear whether current protocols are able to reliably identify all relevant non-PV trigger sites. As such, it has been postulated that empiric ablation of common non-PV trigger sites may improve outcomes. This has been examined in the Randomized Ablation Strategies for the Treatment of Persistent Atrial Fibrillation (RASTA) study, which compares: circumferential PVI plus ablation of nonPV triggers; circumferential PVI plus ablation of non-PV triggers plus empirical ablation at common non-PV trigger sites; and circumferential PVI plus ablation of non-PV triggers plus CFAE ablation.87 The freedom from atrial arrhythmias after a single ablation

Amiodarone and ibutilide Amiodarone and ibutilide are used to organise persistent AF.

Mechanism of Action In advanced forms of AF, the abnormal atrial substrate is thought to act as a driver of arrhythmia perpetuation.88,89 Although PVI can reduce the amount of substrate required for atrial re-entry, persistent AF seems to be less dependent on the PV antral region for arrhythmia initiation and perpetuation, relying more on perpetuating regions outside the PV–LA junction. It has been postulated that these CFAEs (local signals during AF that are either at a very short cycle length, or are fractionated with two or more components and/or a continuous perturbation of the baseline) represent areas of slow conduction, conduction block or ‘pivot’ points for AF perpetuating re-entry. It is thought that complete elimination of these abnormal substrate areas may improve outcomes.90–92 Extensive ablation of atrial substrate may result in prolonged procedures, however, and increased risk of complications.93,94 Moreover, while fractionation may be recorded close to the core of an AF-perpetuating rotor, it may also be recorded at sites not actively participating in the AF process, i.e. bystander sites of passive wavelet collision. It is postulated that the co-administration of amiodarone and ibutilide (both class III AADs) might facilitate the identification of CFAE sites critical to AF maintenance by eliminating areas of passive atrial activation. Mechanistically these agents differentiate active from passive CFAEs by lengthening the effective refractory period (e.g. global AF cycle length). Pre-treatment with amiodarone or the administration of ibutilide during catheter ablation to reduce active CFAE sites has been shown to reduce the amount of ablation in persistent AF without adversely affecting longerterm outcomes.95,96

Clinical Value

Clinical Perspective • Adenosine can prevent the need for a long observational time to identify dormant conduction that will increase the recurrence of AF after pulmonary vein isolation (PVI). • The role of adenosine in a second ablation procedure for the treatment of paroxysmal AF and in the catheter ablation of persistent AF remains to be assessed. • In patients with paroxysmal and persistent AF, the use of isoproterenol should be considered in appropriate cases as its ability to reveal non-PV triggers has been demonstrated. • Amiodarone and ibutilide allow the organisation of electrical substrates in persistent AF but they do not appear to be efficient in reducing AF recurrence.

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The Substrate Trigger Ablation for Reduction of Atrial Fibrillation II (STAR-AF II) study recently demonstrated that the addition of substrate-base ablation (either linear ablation or CFAE elimination) did not reduce AF recurrence after PVI in patients with persistent AF.34 These negative results could be explained by the amount of ablation that increases the iatrogenic arrhythmia rate.87,97–99 To reduce this arrhythmia rate, two recent randomised studies have investigated the effect of ibutilide and amiodarone with respect to PVI and CFAE ablation. Mohanty et al. described a 112-patient population treated with amiodarone for persistent AF.100 Patients were randomised to either amiodarone continuation or amiodarone discontinuation 4 months prior to catheter ablation. The authors observed a higher organisation rate of AF, and a lower amount of RF energy required terminate AF in the amiodarone continuation group. Despite this, they observed an increase in AF recurrence with amiodarone continuation. In the

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Modified Ablation Guided by Ibutilide Use in Chronic Atrial Fibrillation (MAGIC-AF) study, Singh et al. randomly assigned 200 patients with persistent AF to receive ibutilide during catheter ablation.101 A higher AF organisation rate, a reduction in the number of CFAE sites and a higher rate of AF termination were observed during catheter ablation in the ibutilide group, similar to the study by Mohanty et al.101 Likewise the clinical outcomes were unchanged. These results once again suggest the limited role of substrate ablation instead of PVI.

Conclusion PVI remains the cornerstone of catheter ablation for the treatment of both paroxysmal and persistent AF, but the durability of electrical

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isolation remains a challenge. Both longer observational time (>30 minutes) and adenosine testing (>20 minutes after successful PVI with dose titration to achieve transient atrioventricular conduction block) are efficient and should be considered after PVI to decrease long-term PV reconnection and AF recurrences in paroxysmal AF. Isoproterenol may unmask non-PV triggers in appropriate cases. The benefit seems to be relatively greater during a second ablation procedure, particularly if one or more PVs have reconnected. Limited data are available to support the use of amiodarone and ibutilide; despite their role in substrate organisation, the lack of impact on clinical outcome does not suggest a relevant use in catheter ablation of AF. ■

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pulmonary vein ectopic beats initiating paroxysmal atrial fibrillation: implication for catheter ablation. J Am Coll Cardiol 2005;46:1054–9. DOI: 10.1016/j.jacc.2005.06.016; PMID: 16168291 Arruda M, Mlcochova H, Prasad SK, et al. Electrical isolation of the superior vena cava: an adjunctive strategy to pulmonary vein antrum isolation improving the outcome of AF ablation. J Cardiovasc Electrophysiol 2007;18:1261–6. DOI: 10.1111/j.1540-8167.2007.00953.x; PMID: 17850288 Johnson N, Danilo P, Wit AL, et al. Characteristics of initiation and termination of catecholamine-induced triggered activity in atrial fibers of the coronary sinus. Circulation 1986;74: 1168–79. PMID: 3769174 Elayi CS, Fahmy TS, Wazni OM, et al. Left superior vena cava isolation in patients undergoing pulmonary vein antrum isolation: impact on atrial fibrillation recurrence. Heart Rhythm 2006;3:1019–23. DOI: 10.1016/j.hrthm.2006.05.024; PMID: 16945794 Biase LD, Burkhardt JD, Mohanty P, et al. Left atrial appendage: an underrecognized trigger site of atrial fibrillation. Circulation 2010;122:109–18. DOI: 10.1161/ CIRCULATIONAHA.109.928903; PMID: 20606120 Tsai C-F, Tai C-T, Hsieh M-H, et al. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava electrophysiological characteristics and results of radiofrequency ablation. Circulation 2000;102:67–74. DOI: 10.1161/01.CIR.102.1.67; PMID: 10880417 Kurotobi T, Iwakura K, Inoue K, et al. Multiple arrhythmogenic foci associated with the development of perpetuation of atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:39–45. DOI: 10.1161/CIRCEP.109.885095; PMID: 19996379 Liang BT, Frame LH, Molinoff PB. Beta 2-adrenergic receptors contribute to catecholamine-stimulated shortening of action potential duration in dog atrial muscle. Proc Natl Acad Sci 1985;82:4521–5. PMID: 2989829 Chen P-S, Maruyama M, Lin S-F. Arrhythmogenic foci and the mechanisms of atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:7–9. DOI: 10.1161/CIRCEP.110.936385 Chen Y-J, Chen Y-C, Yeh H-I, et al. Electrophysiology and arrhythmogenic activity of single cardiomyocytes from canine superior vena cava. Circulation 2002;105:2679–85. DOI: 10.1161/01.CIR.0000016822.96362.26; PMID: 12045176 Wit AL, Boyden PA. Triggered activity and atrial fibrillation. Heart Rhythm 2007;4:S17–S23. DOI: 10.1016/ j.hrthm.2006.12.021; PMID: 17336878 Wang T-M, Luk H-N, Sheu J-R, et al. Inducibility of abnormal automaticity and triggered activity in myocardial sleeves of canine pulmonary veins. Int J Cardiol 2005;104:59–66. DOI: 10.1016/j.ijcard.2004.10.016; PMID: 16137511 Zhao Y, Di Biase L, Trivedi C, et al. Importance of nonpulmonary vein triggers ablation to achieve long-term freedom from paroxysmal atrial fibrillation in patients with low ejection fraction. Heart Rhythm 2016;13:141–9. DOI: 10.1016/j.hrthm.2015.08.029; PMID: 26304713 Hayashi K, An Y, Nagashima M, et al. Importance of nonpulmonary vein foci in catheter ablation for paroxysmal atrial fibrillation. Heart Rhythm 2015;12:1918–24. DOI: 10.1016/ j.hrthm.2015.05.003; PMID: 25962801 Hsu L-F, Jaïs P, Keane D, et al. Atrial fibrillation originating from persistent left superior vena cava. Circulation 2004;109:828–32. DOI: 10.1161/01.CIR.0000116753.56467.BC; PMID: 14757689 Lin D, Frankel DS, Zado ES, et al. Pulmonary vein antral isolation and nonpulmonary vein trigger ablation without additional substrate modification for treating longstanding persistent atrial fibrillation. J Cardiovasc Electrophysiol 2012;23:806–13. DOI: 10.1111/j.1540-8167.2012.02307.x; PMID: 22509772 Inoue K, Kurotobi T, Kimura R, et al. Trigger-based mechanism of the persistence of atrial fibrillation and its impact on the efficacy of catheter ablation. Circ Arrhythm Electrophysiol 2012;5:295–301. DOI: 10.1161/CIRCEP.111.964080 Santangeli P, Di Biase L, Mohanty P, et al. Catheter ablation of atrial fibrillation in octogenarians: safety and outcomes. J Cardiovasc Electrophysiol 2012;23:687–93. DOI: 10.1111/ j.1540-8167.2012.02293.x; PMID: 22494628 Dixit S, Marchlinski FE, Lin D, et al. Randomized ablation strategies for the treatment of persistent atrial fibrillation: RASTA study. Circ Arrhythm Electrophysiol 2012;5:287–94.

DOI: 10.1161/CIRCEP.111.966226; PMID: 22139886 88. Roux J-F, Gojraty S, Bala R, et al. Complex fractionated electrogram distribution and temporal stability in patients undergoing atrial fibrillation ablation. J Cardiovasc Electrophysiol 2008;19:815–20. DOI: 10.1111/j.1540-8167.2008.01133.x; PMID: 18373601 89. Hunter RJ, Diab I, Tayebjee M, et al. Characterization of fractionated atrial electrograms critical for maintenance of atrial fibrillation: a randomized, controlled trial of ablation strategies (the CFAE AF trial). Circ Arrhythm Electrophysiol 2011;4:622–9. DOI: 10.1161/CIRCEP.111.962928; PMID: 21844156 90. 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. DOI: 10.1016/j.jacc.2013.03.081; PMID: 23727084 91. Rostock T, Rotter M, Sanders P, et al. High-density activation mapping of fractionated electrograms in the atria of patients with paroxysmal atrial fibrillation. Heart Rhythm 2006;3:27–34. DOI: 10.1016/j.hrthm.2005.09.019; PMID: 16399048 92. Viles-Gonzalez JF, Gomes JA, Miller MA, et al. Areas with complex fractionated atrial electrograms recorded after pulmonary vein isolation represent normal voltage and conduction velocity in sinus rhythm. Europace 2013;15: 339–46. DOI: 10.1093/europace/eus321; PMID: 23148118 93. Roux J-F, Gojraty S, Bala R, et al. Effect of pulmonary vein isolation on the distribution of complex fractionated electrograms in humans. Heart Rhythm 2009;6:156–60. DOI: 10.1016/j.hrthm.2008.10.046; PMID: 19187903 94. Lin Y-J, Chang S-L, Lo L-W, et al. A prospective and randomized comparison of limited versus extensive atrial substrate modification after circumferential pulmonary vein isolation in nonparoxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2014;25:803–12. DOI: 10.1111/jce.12407; PMID: 24628987 95. Miwa Y, Minamiguchi H, Bhandari AK, et al. Amiodarone reduces the amount of ablation during catheter ablation for persistent atrial fibrillation. Europace 2014;16:1007–14. DOI: 10.1093/europace/eut399; PMID: 24446509 96. Singh SM, D’Avila A, Kim SJ, et al. Intraprocedural use of ibutilide to organize and guide ablation of complex fractionated atrial electrograms: preliminary assessment of a modified step-wise approach to ablation of persistent atrial fibrillation. J Cardiovasc Electrophysiol 2010;21:608–16. DOI: 10.1111/j.1540-8167.2009.01671.x; PMID: 20039991 97. Providência R, Lambiase PD, Srinivasan N, et al. Is There Still a Role for Complex Fractionated Atrial Electrogram Ablation in Addition to Pulmonary Vein Isolation in Patients With Paroxysmal and Persistent Atrial Fibrillation? Meta-Analysis of 1415 Patients. Circ Arrhythm Electrophysiol 2015;8:1017–29. DOI: 10.1161/CIRCEP.115.003019; PMID: 26082515 98. Sawhney N, Anousheh R, Chen W, et al. Circumferential pulmonary vein ablation with additional linear ablation results in an increased incidence of left atrial flutter compared with segmental pulmonary vein isolation as an initial approach to ablation of paroxysmal atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:243–8. DOI: 10.1161/CIRCEP.109.924878; PMID: 20339034 99. Oral H, Chugh A, Yoshida K, et al. A randomized assessment of the incremental role of ablation of complex fractionated atrial electrograms after antral pulmonary vein isolation for long-lasting persistent atrial fibrillation. J Am Coll Cardiol 2009;53:782–9. DOI: 10.1016/j.jacc.2008.10.054; PMID: 19245970 100. Mohanty S, Di Biase L, Mohanty P, et al. Effect of periprocedural amiodarone on procedure outcome in patients with longstanding persistent atrial fibrillation undergoing extended pulmonary vein antrum isolation: results from a randomized study (SPECULATE). Heart Rhythm 2015;12:477–83. DOI: 10.1016/j.hrthm.2014.11.016; PMID: 25460855 101. Singh SM, d’Avila A, Kim Y-H, et al. The modified stepwise ablation guided by low-dose ibutilide in chronic atrial fibrillation trial (The MAGIC-AF Study). Eur Heart J 2016;37:1614–21. DOI: 10.1093/eurheartj/ehw003.

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A Clinical Perspective on Sudden Cardiac Death Demosthenes G Katritsis, 1 Bernard J Gersh, 2 and A John Camm 3 1. Athens Euroclinic, Greece, and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; 2. Mayo Medical School, Rochester, MN, USA; 3. St George’s University of London, UK

Abstract This article presents the epidemiology, aetiology and pathophysiology of sudden cardiac death. The modern management of survivors as well as of family members of victims is discussed, as are the relevant recommendations of guidelines prepared by learned societies.

Keywords Out-of-hospital cardiac arrest, sports-related sudden death, sudden cardiac death, sudden unexplained death syndrome 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 a modified excerpt from Ch.68: Sudden Cardiac Death from ‘Clinical Cardiology: Current Practice Guidelines’ edited by Katritsis, Gersh, & Camm (2016): Oxford University Press, with kind permission. © Oxford University Press, 2016. Received: 1 December 2015 Accepted: 28 October 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(3):177–82. DOI: 10.15420/aer.2016:11:2 Correspondence: Dr D Katritsis, Athens Euroclinic, 9 Athanassiadou Street, Athens 11521, Greece; E: dkatrits@dgkatritsis.gr and dkatrits@bidmc.harvard.edu

Sudden cardiac death (SCD) is usually defined as death due to cardiac causes occurring within 1 hour of the onset of symptoms. Unexplained sudden death occurring in an individual older than 1 year of age is known as 'sudden unexplained death syndrome'. Unexplained sudden death occurring in an individual younger than 1 year of age is known as 'sudden unexplained death in infancy'. SCD with negative pathological and toxicological assessment is termed 'sudden arrhythmic death syndrome'.1

Epidemiology In 2011, approximately 365,500 people (approximately 0.1 % of the population) experienced emergency medical services-assessed out-of-hospital cardiac arrests in the United States.2,3 Of the 19,300 bystander-witnessed out-of-hospital cardiac arrests that year, 31.4 % of victims survived. The annual incidence of SCD increases as a function of advancing age, being 100-fold less frequent in individuals <30 years of age (0.001 %) than it is in adults >35 years.4,5 There is a similar incidence in Europe, with reports of out-of-hospital cardiac arrest ranging from 0.04 % to 0.1 %.6–8 When the aetiological definition is limited to coronary artery disease (CAD) and its tachyarrhythmic burden, the estimate is <200,000 events per year.9 Approximately 50 % of all cardiac deaths are sudden, and this proportion has remained unchanged despite the overall decrease in cardiovascular mortality in recent decades. The proportion of all natural deaths due to SCD is 13 %; if a definition of 24 hours from onset of symptoms is used, it increases to 18.5 %.9 Analysis of data from the Department of Defense Cardiovascular Death Registry in the United States reveals that the incidence of sudden unexplained death per 100,000 person-years is 1.2 for persons aged 18–35 years and 2.0 for those >35 years of age.10 The numbers are higher in the King County (Washington) Cardiac Arrest Database, being 2.1 for infants of 0–2 years, 0.61 for children aged 3–13 years, 1.44 for young people aged

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14–24 years and 4.4 for 25–35-year-olds, respectively.11 In the Oregon Sudden Unexpected Death Study, the annual incidence of sudden cardiac arrest among blacks was more than twofold higher than in whites for both men and women.12 In Denmark, the annual incidence of SCD is 2.3 for people aged 1–35 years and 21.7 for people aged 36–49 years.6 Population movement, and especially major train stations, are associated with a higher risk of SCD.13 The main problem with SCD is that the majority of out-of-hospital sudden cardiac arrests occur among patients in whom cardiac arrest is the first clinical expression of the underlying disease or those in whom disease has previously been identified but classified as low risk.9 There is an inverse relationship between incidence and absolute numbers of events, indicating that a large portion of the total population burden emerges from subgroups with lower risk indexes,9 thus making the identification and prevention of future events particularly difficult. The incidence of sports-related sudden death from any cause in the general population is 0.5–2.1 per 100,000 per year.8,14–16 Although the vast majority of such cases occur during middle age, they represent a relatively small proportion (5 %) of overall sudden cardiac arrest cases.17 The sports-related sudden death rate is higher in elite athletes, with a reported incidence of 1:8,253 participants per year in the National Collegiate Athletic Association (NCAA). Among NCAA division I male basketball players, the incidence is 1:5,200 per year.16 In other studies, the reported incidence of SCD ranges from 0.24 to 3.8 per 100,000, with higher rates seen in African and Afro-Caribbean athletes.18–20,21

Aetiology CAD is the most common underlying cause of SCD in the Western world, being responsible for 75–80 % of cases; cardiomyopathies

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Clinical Arrhythmias Table 1: Common Causes of Sudden Cardiac Arrest Ischaemic Heart Disease Myocardial infarction (including non-ST segment elevation myocardial infarction) Anomalous coronary origin Coronary spasm Inherited Channelopathies Long QT syndrome Short QT syndrome Brugada syndrome Early repolarisation syndrome Catecholaminergic polymorphic ventricular tachycardia Cardiomyopathies Alcoholic Hypertrophic Idiopathic Obesity-related Fibrotic Arrhythmogenic right ventricular cardiomyopathy Myocarditis Heart Failure Especially with left ventricular ejection fraction <35 % Valve disease Aortic stenosis Congenital diseases Tetralogy of Fallot Other causes Severe electrolyte disturbances Massive pulmonary embolus Vigorous activity in sedentary individuals Acute psychosocial and economic stress

and genetic channelopathies account for most of the remainder (see Table 1).6,22 SCD accounts for 50 % of all CAD-related deaths.9 The incidence of SCD-related atherosclerotic CAD is 0.7 per 100,000 person-years in 18–35-year-olds, increasing to 13.7 per 100,000 in those >35 years of age.10 Female survivors of cardiac arrest are less likely to have underlying CAD (45 %); valve disease and dilated or arrhythmogenic cardiomyopathy are more common.23 Following acute myocardial infarction there is increased risk of SCD during the first months due to tachyarrhythmias or other complications such as re-infarction or myocardial rupture,24 and myocardial scar predisposes to monomorphic ventricular tachycardia (VT). Apart from patients with ST-segment elevation, patients resuscitated from a shockable rhythm should be subjected to coronary angiography.25–27 Although most patients with a cardiac arrest have demonstrable CAD, however, less than half seem to have suffered an acute myocardial infarction.28,29 Only 38 % of cardiac arrest survivors develop evidence of myocardial infarction,22 and the use of tenecteplase during advanced life support for out-of-hospital cardiac arrest does not improve outcomes.30 The most common causes of non-ischaemic SCD are currently cardiomyopathy related to obesity or alcoholism and fibrotic cardiomyopathy.31

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In patients with preserved ejection fraction in the Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER), an aetiological diagnosis was possible in approximately half of cardiac arrest survivors, the rest being considered cases of idiopathic ventricular fibrillation (VF), presumably due to intrinsic electric abnormalities such as early repolarisation.32 A resuscitated cardiac arrest victim, preferably with documentation of VF, in whom known cardiac, respiratory, metabolic and toxicological aetiologies have been excluded through clinical evaluation is considered to have idiopathic VF.1 Several ion-channel and gene-coding mutations have been associated with idiopathic VF.33 Genetic testing diagnoses an inherited arrhythmia (genetic channelopathy) in up to 29 % of families where a relative has died due to SCD.34 Several studies have also demonstrated a familial predisposition to SCD that may or may not be related to genetic channelopathies.35–37 Coronary spasm is also a cause of cardiac arrest, particularly in male smokers with minimal or no pre-existing CAD.38 Mitral valve prolapse in female patients with ECG repolarisation abnormalities, and frequent complex ventricular ectopy, has also been associated with out-of-hospital cardiac arrest.39,40 An association between air pollution (fine particulate matter with an aerodynamic diameter <2.5 µm and ozone) and out-of-hospital cardiac arrest has recently been demonstrated.41 SCDs account for most cardiac and many non-AIDS-related natural deaths in HIV-infected patients.42 Lower socioeconomic status, depression, anxiety, social isolation and acute emotional stress have all been linked to increased SCD risk.43,44 There is a circadian variation in SCD. The peak incidence of SCD occurs between 6 am and noon (and is blunted by beta-blockers), with a smaller peak occurring in the late afternoon for out-of-hospital VF arrests. The incidence is highest on Mondays.45,46 In the young (<35 years), the most common cause of SCD is arrhythmia, mostly in the context of an apparently normal heart.11,47 The most common causes of SCD are congenital abnormalities in those aged 0–13 years, primary arrhythmia in the 14–24-year age group, and CAD in those >25 years.11 In 5–20 % of cases no significant cardiac abnormality is found at autopsy.10,47 In a recent Danish registry report on individuals aged <50 years, sudden death was caused by noncardiac diseases, such as pulmonary embolism, meningitis and cerebrovascular bleeding, in 28 % of cases.48 In sports-related sudden death in the general population, a clear diagnosis is made in <25 % of cases, but the cause is usually an acute coronary syndrome (75 %).14 In professional athletes, a diagnosis is usually made in up to 65 % of cases and hypertrophic cardiomyopathy (HCM) is considered the main cause, at least in the United States, followed by arrhythmogenic right ventricular cardiomyopathy (ARVC, especially in the Veneto region of Italy), congenital coronary anomalies, genetic channelopathies, myocarditis, Wolff–Parkinson–White syndrome and Marfan syndrome, with blunt trauma, commotio cordis and heat stroke being less frequent causes.19,49,50 There is evidence, however, that HCM may not be the major cause of SCD in athletes.16,20 Autopsies in deceased NCAA athletes most often reveal a structurally normal heart (25 %), followed by coronary artery anomalies (11 %), myocarditis (9 %), ARVC (5 %) and aortic dissection (5 %), with HCM only demonstrated in 8 % of individuals.16 Findings from the Race Associated Cardiac Arrest Event Registry (RACER) indicate that marathons and half-

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Sudden Cardiac Death

Table 2: Recommendations following Idiopathic Ventricular Fibrillation and Sudden Adult Death Syndrome Recommendation

Class

Idiopathic Ventricular Fibrillation (IVF) Evaluation Genetic testing in IVF when there is suspicion of a specific genetic disease following

IIa

clinical evaluation of the patient and/or family members Genetic screening of a large panel of genes in patients in whom there is no suspicion of an inherited

III

arrhythmogenic disease after clinical evaluation Therapeutic Interventions ICD implantation in patients with the diagnosis of IVF

Antiarrhythmic therapy with quinidine, guided or empirical programmed electrical stimulation in patients with a diagnosis of IVF

IIb

in conjunction with ICD implantation or when ICD implantation is contraindicated or refused Ablation of Purkinje potentials in patients with a diagnosis of IVF presenting with uniform morphology premature ventricular

IIb

contractions in conjunction with ICD implantation or when ICD implantation is contraindicated or refused. If a first-degree relative of an IVF victim presents with unexplained syncope and no identifiable phenotype

IIb

following thorough investigation, then after careful counselling an ICD implant may be considered Evaluation of Family Members Evaluation of the first-degree relatives of all IVF victims with resting ECG, exercise stress testing and echocardiography.

Assessment of first-degree relatives with a history of palpitations, arrhythmias or syncope should be prioritised Follow up clinical assessment in young family members of IVF victims who may manifest symptoms and /or signs

of the disease at an older age and in all family members whenever additional SUDS or SUDI events occur Evaluation of first-degree relatives of IVF victims with Holter and signal averaged ECGs, cardiac MRI and

IIa

provocative testing with Class Ic antiarrhythmic drugs Evaluation of first-degree relatives of IVF victims with epinephrine infusion

IIb

Sudden Adult Death Syndrome (SUDS) Evaluation For all SUDS victims: Collect personal/family history and circumstances of the sudden death

Expert cardiac pathology to rule out the presence of microscopic indicators of structural heart disease

Collect blood and/or suitable tissue for molecular autopsy/post-mortem genetic testing

Carry out an arrhythmia syndrome-focused molecular autopsy/post-mortem genetic testing

IIa

Therapeutic interventions Genetic screening of ﬁrst-degree relatives of a SUDS victim whenever a pathogenic mutation in a gene associated with

an increased risk of sudden death is identiﬁed by molecular autopsy in the SUDS victim Evaluation of ﬁrst-degree blood relatives of all SUDS victims with resting ECG with high right ventricular leads, exercise stress

testing and echocardiography. Assessment of obligate carriers and relatives with a history of palpitations, arrhythmias, or syncope should be prioritised Follow-up clinical assessment in young family members of SUDS victims who may manifest symptoms and/or signs of the disease

at an older age and in all family members whenever additional SUDS or SUDI events occur Evaluation of ﬁrst-degree relatives of SUDS victims with ambulatory and signal-averaged ECGs, cardiac MRI, and provocative

IIa

testing with Class Ic antiarrhythmic drugs Evaluation of ﬁrst-degree relatives of SUDS victims with epinephrine infusion

IIb

ICD = implantable cardioverter-defibrillator; IVF = idiopathic ventricular fibrillation; SUDI = sudden unexplained death of an infant; SUDS = sudden unexplained death syndrome. Adapted from Priori et al., 2013.1

marathons are associated with a low overall risk of cardiac arrest or sudden death (1:100,000), with deaths most commonly attributable to HCM (26 %) or atherosclerotic coronary disease (16 %).45 Some of these cardiac arrests might, however, have been provoked by heat stroke.51 CAD is the predominant cause of SCD in older athletes.52 Vigorous exertion can trigger cardiac arrest or SCD, especially in untrained persons, but habitual vigorous exercise diminishes the risk of sudden death during vigorous exertion.53 Most studies have found inverse associations between regular physical activity and SCD.22

Pathophysiology VT or VF was thought to be the most common cause of out-of-hospital cardiac arrest, accounting for approximately three-quarters of cases,

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the remaining 25 % being caused by bradyarrhythmias or asystole.54,55 More recent studies, however, suggest that the incidence of VF or pulseless VT as the first recorded rhythm in out-of-hospital cardiac arrest has declined to <30 % in the past few decades.56–58 Pulseless electrical activity (electromechanical dissociation) and asystole are proportionally more frequent mechanisms than VT/VF. Recent data demonstrate a pulseless electrical activity incidence of 19–23 %, with approximately 50 % of patients initially having asystole.59 However, the majority of survivors are in the subgroup whose initial rhythm is VF or pulseless VT.57 VF is a cause of cardiac arrest, and if untreated the arrhythmia is usually fatal. Spontaneous reversions to sinus rhythm have, however, been recorded. Non-arrhythmic mechanisms, such as myocardial rupture or aortic aneurysm rupture, may also result in SCD.

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Clinical Arrhythmias Table 3: Indications for Autopsy and Molecular Autopsy in Sudden Death Victims An autopsy to investigate the causes of sudden

I-C

death and to define whether sudden cardiac death is secondary to arrhythmic or non-arrhythmic mechanisms (e.g. rupture of an aortic aneurysm) A standard histological examination of the heart

I-C

including mapped labelled blocks of myocardium from representative transverse slices of both ventricles, whenever an autopsy is performed Analysis of blood and other adequately-collected

I-C

body fluids for toxicology and molecular pathology in all victims of unexplained sudden death Targeted post-mortem genetic analysis of

IIa-C

potentially disease-causing genes in all sudden death victims in whom a specific inheritable channelopathy or cardiomyopathy is suspected Adapted from Priori et al., 2015.75

Table 4: Guidelines on Public-access Defibrillation Public access defibrillation should be established at sites

I-B

where cardiac arrest is relatively common and suitable storage is available (e.g. schools, sports stadiums, large stations, casinos, etc.) or at sites where no other access to defibrillation is available (e.g. trains, cruise ships, aeroplanes, etc.) Teach basic life support to the families of patients

IIb-C

at high risk of sudden cardiac death Adapted from Priori et al., 2015.75

Investigations in Survivors Overall survival after out-of-hospital cardiac arrest remains low, at approximately 7.6 %,60 but survivors’ quality of life is good for at least for the next 12 months.61 Early coronary angiography in patients resuscitated as a result of a shockable rhythm with immediate percutaneous coronary intervention improves survival.26,27 A full cardiac assessment is needed in cardiac arrest survivors.38 Patients presenting with VF or sustained monomorphic VT are at a considerable risk of recurrence, particularly in the presence of reduced left ventricular function. Studies of out-of-hospital cardiac arrest survivors as well as of patients with sustained VT have shown that the actuarial incidence of sudden death 2 years after the presenting arrhythmia varies from 15 % to 30 %. Up to 74 % of patients with out-of-hospital cardiac arrest have VF recurrence during prehospital care, and the time in VF is associated with a worse outcome.62 Long-term survival among patients who have undergone rapid defibrillation after out-of-hospital cardiac arrest, however, is similar to that among age-, sex- and disease-matched patients who have not had out-of-hospital cardiac arrest, although only 40 % of survivors had an implantable cardioverter defibrillator implanted.63 Family members of young SCD victims are at increased risk for ventricular arrhythmias and ischaemic heart disease. Screening of first-degree relatives, especially those <35 years old, is important.64 When findings suggest cardiomyopathy or genetic channelopathy, the evaluation of other family members is also necessary. The examination of relatives (cascade family screening) may have a significant diagnostic yield.65 It should be noted, however, that no reported history of sudden death among the relatives of most young (<35 years) decedents may be identified.47 Investigation into the

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genetic basis of SCD, such as the candidate gene approach, has explored the potential association between SCD in CAD and genes associated with genetic channelopathies. Genome-wide association studies are promising but of limited clinical value.9 The following tests are useful for establishing a diagnosis in SCD survivors:38 • ECG (ischaemia, myocardial infarction, inherited channelopathies). • Echocardiography (heart failure, cardiomyopathies, valve disease, congenital heart disease). • Coronary angiography (CAD, congenital coronary anomalies, coronary spasm). • Exercise test (ischaemia, long QT syndrome [LQTS], catecholaminergic polymorphic ventricular tachycardia [CPVT]). • Electrophysiology testing (induction of arrhythmia, pharmacological provocation for Brugada syndrome, LQTS, CPVT). Procainamide testing may provoke a Brugada pattern irrespective of the baseline ECG and should be considered in the workup of SCD.66 • Cardiac MRI (ARVC, sarcoidosis, myocarditis, myocardial injury from coronary spasm). • Genetic testing is indicated when an inherited phenotype is detected (ARVC, Brugada syndrome, CPVT, LQTS). Its role in phenotypicallyambiguous or -negative patients is not established, since it is not always possible to differentiate between disease-causing mutations and irrelevant genetic variants. The recommendations for genetic testing are presented in Table 2. • Cardiac biopsy may also be needed in elusive cases. A molecular autopsy may also be considered as part of the community forensic investigation to enhance SCD prevention for other family members (see Table 3). Thus, in cases of documented SCD without an obvious cause, collection of post-mortem blood in ethylenediaminetetraacetic acid, i.e. the purple-top tube to enable DNA extraction, for subsequent DNA analysis may identify a cause of death in up to 30 % of cases.67 A forensic examination, including a toxicology screen, may establish the diagnosis in cases of traumatic, toxic or cardiac causes. A negative pathological examination suggests a genetic channelopathy.68 Post-mortem MRI is also a valuable tool for non-invasively documenting pathological findings, such as myocardial infarction or severe myocardial hypertrophy,69 and post-mortem computed tomography coronary angiography is now possible.70 Despite every effort, however, nearly half of the causes of cardiac arrest will remain unexplained.32

Management of Cardiac Arrest A population-based cohort study on out-of-hospital cardiac arrest survivors in Ontario, Canada, detected an improved 30-day survival from 9.4 % in 2002 to 13.6 % in 2011.71 Survival is better in places with facilities for bystander resuscitation.15 Defibrillators in public locations (Table 4), such as train stations,13 however, only reduce the incidence of SCD when the local population is trained to use them.72 Recent data from the United States Cardiac Arrest Registry to Enhance Survival (CARES) suggest that rates of survival following out-of-hospital cardiac arrest have improved among sites participating in a performanceimprovement registry.73 Improved survival rates are more prominent in patients aged 18–80 years.74

Clinical Implications The annual incidence of SCD increases as a function of advancing age. CAD is the most common cause, and cardiomyopathies and

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genetic channelopathies account for most of the remaining cases. In the young (<35 years), the most common cause of SCD is arrhythmias, mostly in the context of an apparently normal heart. In sports-related sudden death in the general population, a clear

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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. Europace 2013;10:1932–63. DOI: 10.1016/j.hrthm.2013.05.014; PMID: 24011539 Fishman GI CS, Dimarco JP, Albert CM, et al. Sudden cardiac death prediction and prevention: Report from a National Heart, Lung, and Blood Institute and Heart Rhythm Society workshop. Circulation 2010;122:2335–48. DOI: 10.1161/ CIRCULATIONAHA.110.976092; PMID: 21147730 Mozaffarian D, Benjamin EJ, Go AS, et al.; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics – 2015 update: A report from the American Heart Association. Circulation 2015;131:e29–322 DOI: 10.1161/ CIR.0000000000000152; PMID: 25520374 Stecker EC, Reinier K, Marijon E, et al. Public health burden of sudden cardiac death in the United States. Circ Arrhythm Electrophysiol 2014;7:212–7. DOI: 10.1161/CIRCEP.113.001034; PMID: 24610738 Kong MH, Fonarow GC, Peterson ED, et al. Systematic review of the incidence of sudden cardiac death in the United States. J Am Coll Cardiol 2011;57:794–801 DOI: 10.1016/ j.jacc.2010.09.064; PMID: 21310315 Risgaard B, Winkel BG, Jabbari R, et al. Burden of sudden cardiac death in persons aged 1 to 49 years: Nationwide study in Denmark. Circ Arrhythm Electrophysiol 2014;7:205–11. DOI: 10.1161/CIRCEP.113.001421; PMID: 24604905 de Vreede-Swagemakers JJ, Gorgels AP, Dubois-Arbouw WI, et al. Out-of-hospital cardiac arrest in the 1990’s: A populationbased study in the Maastricht area on incidence, characteristics and survival. J Am Coll Cardiol 1997;30:1500–5. PMID: 9362408 Berdowski J,. de Beus MF, Blom M, et al. Exercise-related outof-hospital cardiac arrest in the general population: incidence and prognosis. Eur Heart J 2013;34:3616–23. DOI: 10.1093/ eurheartj/eht401 Myerburg RJ, Junttila MJ. Sudden cardiac death caused by coronary heart disease. Circulation 2012;125:1043–52. DOI: 10.1161/CIRCULATIONAHA.111.023846; PMID: 22371442 Eckart RE, Shry EA, Burke AP, et al,. Sudden death in young adults: an autopsy-based series of a population undergoing active surveillance. J Am Coll Cardiol 2011;58:1254–61. DOI: 10.1016/j.jacc.2011.01.049; PMID: 21903060 Meyer L, Stubbs B, Fahrenbruch C, et al. Incidence, causes, and survival trends from cardiovascular-related sudden cardiac arrest in children and young adults 0 to 35 years of age: a 30-year review. Circulation 2012;126:1363–72. DOI: 10.1161/CIRCULATIONAHA.111.076810; PMID: 22887927 Reinier K NG, Huertas-Vazquez A, Uy-Evanado A, et al. Distinctive clinical profile of blacks versus whites presenting with sudden cardiac arrest. Circulation.2015;132:380–7. DOI: 10.1161/CIRCULATIONAHA.115.015673; PMID: 26240262 Marijon E, Bougouin W, Tafflet M, et al. Population movement and sudden cardiac arrest location. Circulation 2015;131:1546–54. DOI: 10.1161/CIRCULATIONAHA.114.010498; PMID: 25762061 Marijon E, Tafflet M, Celermajer DS, et al. Sports-related sudden death in the general population. Circulation 2011;124:672–81. DOI: 10.1161/CIRCULATIONAHA.110. 008979; PMID: 21788587 Marijon E, Bougouin B, Celermajer DS, et al. Major regional disparities in outcomes after sudden cardiac arrest during sports. Eur Heart J 2013;34:3632–40. DOI: 10.1093/eurheartj/ eht282; PMID: 23918760 Harmon KG, Asif IM, Maleszewski JJ, et al. Incidence, etiology, and comparative frequency of sudden cardiac death in NCAA athletes: a decade in review. Circulation 2016;134. DOI: 10.1161/CIRCULATIONAHA.115.015431 Marijon E, Uy-Evanado A, Reinier K, et al. Sudden cardiac arrest during sports activity in middle age. Circulation 2015;131:1384–91. DOI: 10.1161/ CIRCULATIONAHA.114.011988; PMC4406826 Maron BJ, Haas TS, Murphy CJ, et al. Incidence and causes of sudden death in U.S. College athletes J Am Coll Cardiol 2014;63:1636–43. DOI: 10.1016/j.jacc.2014.01.041; PMID: 24583295 Chandra N, Bastiaenen R, Papadakis M, et al. Sudden cardiac death in young athletes: practical challenges and diagnostic dilemmas. J Am Coll Cardiol 2013;61:1027–40. DOI: 10.1016/ j.jacc.2012.08.1032; PMID: 23473408 Holst AG, Winkel BG, Theilade J, et al. Incidence and etiology of sports-related sudden cardiac death in Denmark – implications for preparticipation screening. Heart Rhythm 2010;7:1365–71. DOI: 10.1016/j.hrthm.2010.05.021; PMID: 20580680 Roberts WO, Stovitz SD. Incidence of sudden cardiac death in Minnesota high school athletes 1993-2012 screened with a standardized preparticipation evaluation. J Am Coll Cardiol 2013;62:1298–1. DOI: 10.1016/j.jacc.2013.05.080 Deo R, Albert CM. Epidemiology and genetics of sudden cardiac death. Circulation 2012;125:620–37. DOI: 10.1161/

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diagnosis is made in <25 % of cases, but the cause is usually an acute coronary syndrome (75 %). Examination of relatives (cascade family screening) may have a significant diagnostic yield and is strongly recommended. ■

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Arrhythmic mitral valve prolapse and sudden cardiac death. Circulation 2015;132:556–66. DOI: 10.1161/CIRCULATIONAHA.115.016291; PMID: 26160859 41. Ensor KB, Raun LH, Persse D. A case-crossover analysis of out-of-hospital cardiac arrest and air pollution. Circulation 2013;127:1192–9. DOI: 10.1161/CIRCULATIONAHA.113.000027; PMID: 23406673 42. Tseng ZH, Secemsky EA, Dowdy D, et al. Sudden cardiac death in patients with human immunodeficiency virus infection. J Am Coll Cardiol 2012;59:1891–6. DOI: 10.1016/ j.jacc.2012.02.024; PMID: 22595409 43. Empana JP, Jouven X, Lemaitre RN, et al. Clinical depression and risk of out-of-hospital cardiac arrest. Arch Intern Med. 2006;166: 195–200. DOI: 10.1001/archinte.166.2.195; PMID: 16432088 44. Leor J, Poole WK, Kloner RA. Sudden cardiac death triggered by an earthquake. N Engl J Med. 1996;334:413–9. DOI: 10.1056/ NEJM199602153340701; PMID: 8552142 45. Kim JH, Malhotra R, Chiampas G, et al. Cardiac arrest during long-distance running races. 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Device Therapy

Management of Cardiac Electronic Device Infections: Challenges and Outcomes Rikke Esberg Kirkfeldt, 1 Jens Brock Johansen 2 and Jens Cosedis Nielsen 1 1. Department of Cardiology, Aarhus University Hospital, Skejby, Denmark; 2. Department of Cardiology, Odense University Hospital, Odense, Denmark

Abstract Cardiac implantable electronic device (CIED) infection is an increasing problem. Reasons for this are uncertain, but likely relate to an increasing proportion of implantable cardioverter defibrillator (ICD) and cardiac resynchronisation therapy (CRT) devices implanted, as well as implantations in ’higher risk‘ candidates, i.e. patients with heart failure, diabetes and renal failure. Challenges within the field of CIED infections are multiple with prevention being the most important challenge. Careful prescription of CIED treatment and careful patient preparation before implantation is important. Diagnosis is often difficult and delayed by subtle signs of infection. Treatment of CIED infection includes complete system removal in centres experienced in CIED extraction and prolonged antibiotic therapy. Meticulous planning and preparation before system extraction and later CIED re-implantation is essential for better patient outcome. Future strategies for reducing CIED infection should be tested in sufficiently powered, multicentre, randomised controlled trials.

Keywords Cardiac implantable electronic device, infection, pacemaker, implantable cardioverter defibrillator, predictors, prevention, management, outcomes Disclosure: The authors have no conflicts of interest to declare Received: 10 April 2016 Accepted: 17 October 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(3):183–7. DOI: 10.15420.aer.2016:21:2 Correspondence: Rikke Esberg Kirkfeldt, Department of Cardiology, Aarhus University Hospital, Skejby, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus N, Denmark. E: reki@svf.au.dk

Cardiac implantable electronic device (CIED) therapy is effective and safe. However, infections related to CIED treatment may have devastating consequences, causing significant morbidity, mortality and generating considerable healthcare costs.1–6 Temporal trends in CIED treatment indicate a disproportional increase in CIED infections relative to implantation rates.1,7,8 Reasons for this trend are uncertain, but likely relate to increasing proportions of implantable cardioverter defibrillator (ICD) and cardiac resynchronisation therapy (CRT) devices implanted, as well as implantations in ’higher risk’ patients, i.e. patients with diabetes, heart failure and renal failure.1 Challenges within the field of CIED infections are multiple with prevention being the most important one. Diagnosis also poses a challenge with many patients exhibiting only vague symptoms.9–12 No international guidelines exist for management of CIED infections; however, an expert consensus statement on lead extractions,13 an American Heart Association scientific statement14 and a British guideline paper15 are useful for guiding decisions. This review aims to present available data along with identification of challenges and outcomes within the field of CIED infection.

Pathogenesis Bacterial inoculation often occurs as a result of bacterial colonisation of the operative site at time of CIED implantation. Staphylococcus species from the skin, especially, may contaminate the wound, likely during pocket formation, and later cause pocket infection and/or erosion.16 Most investigators concur that the majority of infections seen within the first year are attributed to this early colonisation and the formation of biofilm on device surfaces. Later, pocket erosion may

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also be caused by operative contamination and biofilm formation. Bacteria in biofilm are protected from killing by host defences and antimicrobial agents.17 Secondary seeding of the CIED may also occur, especially in Staphylococcus aureus bacteraemia. Thus, removal of the entire device is necessary when treating CIED infections.

Incidence of Cardiac Implantable Electronic Device Infection CIED infection rates vary widely depending on definition and followup duration. In a large, Danish cohort study, the estimated incidence was 1.82/1,000 device-years and higher within the first 12 months in pacemaker (PM) patients.18 Infection risk after PM implant is 0.5–1.0 % within the first 6–12 months.18–20 With more complex CIED types, infection rates are higher; 0.7–1.2 % in ICD recipients21–23 and 1.7–9.5 % in CRT recipients especially with defibrillators (CRT-D).24–26 After CIED replacement and system upgrade procedures, infection rates are 2–4 fold higher than after first implant.18–21,27–30

Presentation and Diagnosis Presentation of CIED infection demonstrates a wide spectrum from subtle complaints of pocket pain to septic shock.9,11,12,19,31 The most common presentation of CIED infection is pocket infection, most often seen within the first year.4,25,32 Pocket infection, however, may present years later, and any symptom from the CIED pocket should raise suspicion of infection and cause patient referral to a CIED specialist for evaluation. Typical signs are local erythema, warmth, pain and swelling, adherence of skin to device, and erosion of skin with a draining sinus (see Figure 1).33 Erosion is de facto infection. Early postoperatively, it may be difficult to distinguish a superficial

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Device Therapy Figure 1: Manifestations of Pocket Infections: Adherence Between Skin and Generator (A), Adherence and Perforation (B) and Overt Erosion (C,D)

vegetation,15 and in some cases 18-fluorodeoxyglucose positron emission tomography (FDG-PET).34,35

Prevention of Cardiac Implantable Electronic Device Infection CIED infection is a serious and potentially fatal complication for the patient, and in general necessitates complete CIED system removal. Thus, prevention of CIED infection is the most important issue.

Before Implantation

Table 1: Factors Associated with Increased Cardiac Implantable Electronic Device Infection Risk and Associated Relative Risk Early CIED re-intervention19,21 2.7–15.0 Pocket haematoma21,40 4.0–6.7 CIED replacement18 2.7 More complex CIED4,18,21 1.3–5.4 Temporary pacing4,19 2.5–5.0 Number of prior CIED procedures18 2.7–8.7

Careful CIED prescription (i.e. evaluation of indication for CIED implantation including appropriate type of CIED) is essential with assessment of risks and benefits, accounting for individual patient characteristics and comorbidities.36 Several patient-related factors are associated with heightened risk of CIED infection, such as age, gender, renal failure, diabetes, respiratory failure, corticosteroid treatment, chronic skin conditions and higher comorbidity index (see Table 1). Since these conditions are largely unavoidable, attention should focus on optimisation before CIED implantation. More complex systems have a higher infection risk and potential benefits from these systems should be weighed against lower infection risk with more simple systems.4,18,21 Meticulous pre-operative preparation is necessary. Fever within 24 hours before implant is associated with a 5–6 fold infection risk, and diagnosis and treatment of ongoing infection before implantation is therefore important.36 It is unsettled whether infected patients who need acute cardiac pacing are best managed with initial temporary transvenous pacing or primary permanent CIED implantation. In most cases, temporary pacing is chosen; however, presence of a temporary pacing lead is also associated with a higher infection risk.19,37

Prior CIED infection37 11.3 Fever/systemic infection19 5.8 Renal failure21,37 1.3 Haemodialysis32 8.6 Chronic skin disease37 10.6 Corticosteroid treatment4 13.9 Chronic obstructive pulmonary disorder21,37 1.2–9.8 Diabetes85 2.3 Higher Charlson comorbidity index37 2.7–3.0 Male gender18 1.5 Younger age18

1.4–4.5

Low operator experience54,55,86 NA Longer procedure duration24 NA

Indwelling lines (e.g. central venous catheters and chest tubes) should be removed before CIED implantation. Most operators prefer >24 hours. Chronic skin conditions are associated with a higher infection risk37 and should be appropriately treated before implant.

Peri-operative General recommendations for reducing surgical site infections should be applied, including antiseptic skin preparation. Use of chlorhexidinealcohol as an antiseptic reduces surgical site infections compared with povidone-iodine in clean surgery.36,38,39 This effect is thought to be related to a faster and more persistent activity despite exposure to bodily fluids during surgery. Use of transparent films, diathermia or substances to prevent bleeding have not proven beneficial.15

CIED = cardiac implantable electronic device.

wound infection from a pocket infection. Percutaneous puncture with pocket fluid aspiration should be avoided in all cases. Infection may track along the leads and cause bloodstream infection and/or endocarditis. In any CIED patient with systemic infection without obvious focus, CIED infection should be suspected. Blood cultures should be obtained before initiating antibiotic treatment. Cultures should be taken of the pocket and leads when the device is removed. Bacteria typical for CIED infections include staphylococcal species, corynebacteria or propionibacteria, and growth of these supports the diagnosis of CIED infection. Cultures are negative in 15 % of these cases.15 Supplementary diagnostics should include transoesophageal echocardiography to visualise leads, valvular involvement and

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Pre-operative, systemic antibiotic prophylaxis prior to CIED procedures is mandatory. One randomised controlled trial found infection risk reduced to 0.64 % within 6 months with antibiotic prophylaxis versus 3.28 % with placebo.40 Observational data and meta-analyses support this finding.4,18,19,41,42 Supporting evidence for using topical antibiotics is lacking;43 however, recently a promising development has been introduced. The TYRXTM Envelope is an antibacterial envelope releasing minocycline and rifampin in the generator pocket after CIED implantation. This envelope eliminates staphylococcal species and prevents biofilm formation on implanted pacing devices in animal studies,44 and reduces CIED infections in high-risk patients in observational studies.45–47 The most recent version is bio-absorbable and disappears within 9 weeks after implantation. In a single-centre observational study including 1,124 high-risk patients, infection

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Choice of antibiotic prophylaxis differs widely, influenced by local burden of methicillin-resistant staphylococci, local preference and tradition. An ongoing randomised trial enrolling 10,800 patients compares single-dose pre-operative antibiotics (cefazolin or vancomycin) with an antibiotic strategy adding intraoperative wound pocket wash (bacitracin) and post-operative cefalexin/cefadroxil/ clindamycin for two days.49

Figure 2: Association Between Number of Prior Device Procedures and Infection Risk

Adjusted Hazard Ratio

risk was 0.0 % for the bio-absorbable envelope, 0.3 % for the non-absorbable envelope and 3.1 % for controls with minimum follow-up time of 300 days.48 The effect of the bio-absorbable envelope is currently investigated in the Worldwide Randomized Antibiotic Envelope Infection Prevention Trial (WRAP-IT NCT02277990, commenced 2015), aiming to enrol 7,764 patients undergoing a highrisk CIED procedure. Widespread use of this envelope should await the results of this ongoing trial.

9 8 7 6 5 4 3 2 1

Prevention of tissue damage with a meticulous surgical technique assuring haemostasis is important. Some authors advocate capsulectomy during CIED replacement procedures to remove avascular tissue. This strategy has, however, not been tested in controlled studies, and capsulectomy may increase haematoma risk, which is associated with a higher infection risk.24,36,40 In anticoagulated patients, continued warfarin use is preferred to heparin bridging because of a lower risk of haematoma (odds ratio [OR] 0.19).50 Use of clopidogrel and aspirin increases risk, however, treatment is rarely discontinued. How to handle patients treated with one of the new oral anticoagulants is less clear. A conservative approach when managing haematoma is often advisable, unless particularly tense or painful. Even large haematomas gradually soften and resorb over a few weeks.

Re-operation Early re-operation is probably the strongest risk factor for later CIED infection.19,21,24 In a large, Danish cohort study, number of prior CIED procedures was strongly associated with a higher infection risk (see Figure 2).18 Careful CIED prescription is important to avoid early need for system upgrade, and should include estimation of left ventricular function prior to implantation. Attention should be given to reduce anticipated generator replacements with selection of generators with best reported longevity,51 and with careful programming to increase generator longevity. Evaluation of change in CIED indication at time of generator replacement is advisable (e.g. development of permanent atrial fibrillation or chronic heart failure). Need for CIED upgrade should be evaluated extremely carefully, given the high infection risk.21 Use of active fixation leads should be advocated – with due consideration for a suspected minor increased risk of cardiac perforation – to reduce risk of lead dislodgement and need for re-operation.52 Appropriate education and reasonable implant volume for each operator should be assured to decrease risk of lead dislodgements, and complications in general, requiring early re-operations.20,52–57

New Advances The recently introduced leadless PMs58 are likely to bear a lower risk of infection than transvenous systems; however, in the event of infection, extraction risk is unknown especially years after implantation. Confirmation of long-term efficacy and safety that is at least non-inferior to traditional PMs in randomised controlled trials is needed before advocating for their widespread utilisation. Currently, no such studies are underway.

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Number of prior procedures Adapted from Johansen, et al., 2011.18

Subcutaneous ICD systems59 do not bear the risk of blood-stream infection or endocarditis seen with traditional transvenous ICD systems. They could be attractive for patients not needing bradycardia or antitachycardia pacing and at particularly high risk of CIED infection. It is unlikely that the pocket infection rate is much lower than for traditional PMs. Again, documentation of at least non-inferiority compared with transvenous ICD systems is needed before expanding this treatment to larger patient-groups. The extraction risk, though, is negligible.

Treatment of Cardiac Implantable Electronic Device Infection Confirmation of CIED infection regardless of systemic or localised to pocket mandates prompt removal of all CIED hardware, and a prolonged course of intravenous antibiotics. Furthermore, a strategy for re-implantation is warranted. However, in cases of minor incisional abscesses, a few days after implantation, a course of antibiotics and careful follow-up may be sufficient.15

Planning of Treatment Planning of timely, correct and complete treatment is of the highest importance for better patient prognosis. Partial procedures such as generator removal and capping of leads are associated with an almost invariable relapse10,33,60,61 regardless of clinical presentation. General consensus favours percutaneous removal in centres with procedural volume sufficient to maintain operator skills, and with immediate surgical backup.13,14,62 Management of CIED infection is a multidisciplinary task, and may involve many specialists and various imaging techniques.63 Strategy for antibiotic treatment is often directed by an infection disease specialist. Few data exist in this field, but generally, antibiotics are recommended for 10–14 days after pocket infection, 14 days for bacteraemia and 4–6 weeks for endocarditis.14 Pacemaker-dependent patients pose a particular challenge, and temporary pacing needs careful planning. Heart failure teams should be involved after CRT device removal when anticipating haemodynamic support. All CIED hardware, including abandoned leads, even if contralateral to infected system, must be removed. In preparation, a chest X-ray is important and computerised

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Device Therapy tomography (CT)-scans may be used to visualise suspected perforated leads. Transoesophageal or intracardiac64,65 echocardiography is an important part of the evaluation.14 Large vegetations exceeding 2 cm may indicate surgical explants.13,31

endocarditis is reported between 24.5 % and 29.0 %,31,71,77 and CIED infections with endocarditis have a higher mortality than pocket infection.3,78 One study found a 6-month mortality of 10.1 % after system removal in patients with small lead vegetations and 18.4 % in patients with large lead vegetations.31

Extraction methodology is beyond the scope of this article.

Re-implantation Plan for re-implantation is advisable before system extraction. CIED indication must be re-evaluated because some arrhythmia problems may have resolved. Observational studies found that 20–40 % of patients were discharged without CIED re-implantation.32,66,67 Some patients have developed indication for more complex CIED treatment while others will need no re-implantation at all (e.g. malignancy in patients with prophylactic ICD). When re-implantation is necessary, this should be done on the opposite side of the chest. Timing of re-implantation must be individualised, with careful attention to an adequate period of antibiotic therapy. Epicardial placement of PM leads may be considered for those at high risk of re-infection or with limited vascular access. Leadless PM and subcutaneous ICD implantation could also be considered for selected patients. A continued dialogue, beginning pre-operatively, among the electrophysiologist, the surgeon and the infection disease specialist, is critical to ensure individual management plans.

Outcomes of Cardiac Implantable Electronic Device Infection In general, extraction of all CIED hardware is needed for successful treatment of CIED infections. A series without complete device removal have shown that over half of patients demonstrate relapse.10,68,69 In a recent study, it was found that the rate of CIED infection after CIED extraction was higher in patients with incomplete lead removal, 13.5 % versus 3.0 %.70 In addition, mortality appears higher without complete removal.71–73 One study indicated a threefold higher mortality without system removal.74 All-cause mortality following CIED infection is considerable, ranging from 6 % to 35 % at 2 years or longer follow-up, although many deaths are not infection-related.10,66,70,74–76 In most of these studies, more than 90 % of patients underwent complete CIED removal. Mortality with

Greenspon AJ, Patel JD, Lau E, et al. 16-year trends in the infection burden for pacemakers and implantable cardioverter-defibrillators in the United States 1993 to 2008. J Am Coll Cardiol 2011;58(10):1001–6. DOI: 10.1016/j. jacc.2011.04.033; PMID: 21867833 Baman TS, Gupta SK, Valle JA, Yamada E. Risk factors for mortality in patients with cardiac device-related infection. Circ Arrhythm Electrophysiol 2009;2(2):129–34. DOI: 10.1161/ CIRCEP.108.816868; PMID: 19808457 LE KY, Sohail MR, Friedman PA, et al. Clinical predictors of cardiovascular implantable electronic device-related infective endocarditis. Pacing Clin Electrophysiol 2011;34(4):450–9. DOI: 10.1111/j.1540-8159.2010.02991.x; PMID: 21208230 Sohail MR, Uslan DZ, Khan AH, et al. Risk factor analysis of permanent pacemaker infection. Clin Infect Dis 2007;45(2): 166–73. DOI: 10.1086/518889; PMID: 17578774 Sohail MR, Henrikson CA, Braid-Forbes MJ, et al. Mortality and cost associated with cardiovascular implantable electronic device infections. Arch Intern Med 2011;171(20): 1821–8. DOI: 10.1001/archinternmed.2011.441; PMID: 21911623 Kuehn C, Graf K, Heuer W, et al. Economic implications of infections of implantable cardiac devices in a single institution. Eur J Cardiothorac Surg 2010;37(4):875–9. DOI: 10.1016/j.ejcts.2009.10.018; PMID: 19939696 Cabell CH, Heidenreich PA, Chu VH, et al. Increasing rates of cardiac device infections among Medicare beneficiaries: 1990-1999. Am Heart J 2004;147(4):582–6. DOI: 10.1016/j. ahj.2003.06.005; PMID: 15077071

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System extraction is associated with a small risk of major complications, particularly vascular lacerations causing haemothorax and death.32,70,79–82 Extraction-related mortality rates are 0.1–0.8 % in large experienced centres.70,83 In one large, single-centre study, including more than 5,000 lead extractions, 43 % of which were due to infection, risk of major complications was 1.8 %, and minor complications 3.6 %. A total of 11 patients died as a result of the procedure.84 Complications are typically more frequent in surgical extractions with open heart surgery.31

Conclusion CIED infection is an increasing problem due to rising absolute numbers of CIED procedures and increasing patient comorbidity. The key challenge in the management of CIED infection is prevention. Careful prescription of CIED treatment and careful patient preparation before implantation is important. Diagnosis is often difficult and delayed by subtle signs of infection. Treatment of CIED infection includes complete system removal in centres experienced in CIED extraction and prolonged antibiotic therapy. Meticulous planning and preparation before system extraction and later CIED re-implantation is essential for better patient outcome. Future strategies for reducing CIED infection should be tested in sufficiently powered and welldesigned, multicentre, randomised controlled trials. ■

Clinical Perspective • Cardiac implantable device (CIED) infection is an increasing problem. • The key challenge in management of CIED infection is prevention. • Careful CIED prescription and preparation before implantation is important. • Diagnosis of CIED infection often is difficult due to subtle signs of infection. • Treatment of CIED infection includes complete system removal and often prolonged antibiotic therapy.

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The relation between patients’ outcomes and the volume of cardioverter-defibrillator implantation procedures performed by physicians treating medicare beneficiaries. J Am Coll Cardiol 2005;46(8):1536–40. DOI: 10.1016/j.jacc.2005.04.063; PMID: 16226180 55. Al-Khatib SM, Greiner MA, Peterson ED, et al. Patient and implanting physician factors associated with mortality and complications after implantable cardioverter-defibrillator implantation, 2002-2005. Circ Arrhythm Electrophysiol 2008;1(4):240–9. DOI: 10.1161/CIRCEP.108.777888; PMID: 19169382; PMCID: PMC2630252 56. Tobin K, Stewart J, Westveer D, Frumin H. Acute complications of permanent pacemaker implantation: their financial implication and relation to volume and operator experience. Am J Cardiol 2000;85(6):774–6, A9. PMID: 12000060 57. Eberhardt F, Bode F, Bonnemeier H, et al. Long term complications in single and dual chamber pacing are influenced by surgical experience and patient morbidity. Heart 2005;91(4):500–6. DOI: 10.1136/hrt.2003.025411; PMCID: PMC1768857 58. Reddy VY, Knops RE, Sperzel J, et al. Permanent leadless cardiac pacing: results of the LEADLESS trial. Circulation 2014;129(14):1466–71. DOI: 10.1161/ CIRCULATIONAHA.113.006987; PMID: 24664277 59. Lambiase PD, Barr C, Theuns DA, et al. Worldwide experience with a totally subcutaneous implantable defibrillator: early results from the EFFORTLESS S-ICD Registry. Eur Heart J 2014;35(25):1657–65. DOI: 10.1093/eurheartj/ehu112; PMID: 24670710; PMCID: PMC4076663 60. Sohail MR, Uslan DZ, Khan AH, et al. Management and outcome of permanent pacemaker and implantable cardioverterdefibrillator infections. J Am Coll Cardiol 2007;49(18):1851–9. DOI: 10.1016/j.jacc.2007.01.072; PMID: 17481444 61. Pichlmaier M, Knigina L, Kutschka I, et al. Complete removal as a routine treatment for any cardiovascular implantable electronic device-associated infection. J Thorac Cardiovasc Surg 2011;142(6):1482–90. DOI: 10.1016/j.jtcvs.2010.11.059; PMID: 21570093 62. Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015;36(44):3075–128. DOI: 10.1093/eurheartj/ehv319; PMID: 26320109 63. Rizkallah J, Kent W, Kuriachan V, et al. Troubleshooting during a challenging high-risk pacemaker lead extraction: a case report and review of the literature. BMC Res Notes 2015;8:94. DOI: 10.1186/s13104-015-1034-y

64. Narducci ML, Di Monaco A, Pelargonio G, et al. Presence of ‘ghosts’ and mortality after transvenous lead extraction. Europace 2016; DOI: 10.1093/europace/euw045; PMID: 27025772: epub ahead of press. 65. Narducci ML, Pelargonio G, Russo E, et al. Usefulness of intracardiac echocardiography for the diagnosis of cardiovascular implantable electronic device-related endocarditis. J Am Coll Cardiol 2013;61(13):1398–405. DOI: 10.1016/j.jacc.2012.12.041; PMID: 23500279 66. Deharo JC, Quatre A, Mancini J, et al. Long-term outcomes following infection of cardiac implantable electronic devices: a prospective matched cohort study. Heart 2012;98(9):724–31. DOI: 10.1136/heartjnl-2012-301627; PMID: 22523057 67. Bracke FA, Meijer A, van Gelder LM. Lead extraction for device related infections: a single-centre experience. Europace 2004;6(3):243–7. DOI: 10.1016/j.eupc.2004.01.007; PMID: 15121078 68. Margey R, McCann H, Blake G, et al. Contemporary management of and outcomes from cardiac device related infections. Europace 2010;12(1):64–70. DOI: 10.1093/europace/ eup362; PMID: 19910314 69. del Rio A, Anguera I, Miro JM, et al. Surgical treatment of pacemaker and defibrillator lead endocarditis: the impact of electrode lead extraction on outcome. Chest 2003;124(4):1451–9. PMID: 14555579 70. Gomes S, Cranney G, Bennett M, Giles R. Long-Term Outcomes Following Transvenous Lead Extraction. Pacing Clin Electrophysiol 2016;39(4):345–51. DOI: 10.1111/pace.12812; PMID: 26768807 71. Athan E, Chu VH, Tattevin P, et al. Clinical characteristics and outcome of infective endocarditis involving implantable cardiac devices. JAMA 2012;307(16):1727–35. DOI: 10.1001/ jama.2012.497; PMID: 22535857 72. Habib A, Le KY, Baddour LM, et al. Predictors of mortality in patients with cardiovascular implantable electronic device infections. Am J Cardiol 2013;111(6):874–9. DOI: 10.1016/j. amjcard.2012.11.052; PMID: 23276467 73. Massoure PL, Reuter S, Lafitte S, et al. Pacemaker endocarditis: clinical features and management of 60 consecutive cases. Pacing Clin Electrophysiol 2007;30(1):12–9. DOI: 10.1111/j.1540-8159.2007.00574.x; PMID: 17241309 74. Le KY, Sohail MR, Friedman PA, et al. Impact of timing of device removal on mortality in patients with cardiovascular implantable electronic device infections. Heart Rhythm 2011;8(11):1678–85. DOI: 10.1016/j.hrthm.2011.05.015; PMID: 21699855 75. Knigina L, Kühn C, Kutschka I, et al. Treatment of patients with recurrent or persistent infection of cardiac implantable electronic devices. Europace 2010;12(9):1275–81. DOI: 10.1093/ europace/euq192; PMID: 20621894 76. Hamid S, Arujuna A, Ginks M, et al. Pacemaker and defibrillator lead extraction: predictors of mortality during follow-up. Pacing Clin Electrophysiol 2010;33(2):209–16. DOI: 10.1111/j.1540-8159.2009.02601.x; PMID: 19889182 77. Grammes JA, Schulze CM, Al-Bataineh M, et al. Percutaneous pacemaker and implantable cardioverter-defibrillator lead extraction in 100 patients with intracardiac vegetations defined by transesophageal echocardiogram. J Am Coll Cardiol 2010;55(9):886–94. DOI: 10.1016/j.jacc.2009.11.034; PMID: 20185039 78. Viganego F, O’Donoghue S, Eldadah Z, et al. Effect of early diagnosis and treatment with percutaneous lead extraction on survival in patients with cardiac device infections. Am J Cardiol 2012;109(10):1466–71. DOI: 10.1016/j. amjcard.2012.01.360; PMID: 22356796 79. Byrd CL, Wilkoff BL, Love CJ, et al. Intravascular extraction of problematic or infected permanent pacemaker leads: 1994-1996. U.S. Extraction Database, MED Institute. Pacing Clin Electrophysiol 1999;22(9):1348–57. PMID: 10527016 80. Kennergren C, Bucknall CA, Butter C, et al. Laser-assisted lead extraction: the European experience. Europace 2007;9(8): 651–6. DOI: 10.1093/europace/eum098; PMID: 17597078 81. Maus TM, Shurter J, Nguyen L, et al. Multidisciplinary approach to transvenous lead extraction: a single center’s experience. J Cardiothorac Vasc Anesth 2015;29(2):265–70. DOI: 10.1053/j.jvca.2014.11.010; PMID: 25649700 82. Brunner MP, Cronin EM, Wazni O, et al. Outcomes of patients requiring emergent surgical or endovascular intervention for catastrophic complications during transvenous lead extraction. Heart Rhythm 2014;11(3):419–25. DOI: 10.1016/j. hrthm.2013.12.004; PMID: 24315967 83. Wazni O, Epstein LM, Carrillo RG, et al. Lead extraction in the contemporary setting: the LExICon study: an observational retrospective study of consecutive laser lead extractions. J Am Coll Cardiol 2010;55(6):579–86. DOI: 10.1016/j.jacc.2009.08.070; PMID: 20152562 84. Brunner MP, Cronin EM, Duarte VE, et al. Clinical predictors of adverse patient outcomes in an experience of more than 5000 chronic endovascular pacemaker and defibrillator lead extractions. Heart Rhythm 2014;11(5):799–805. DOI: 10.1016/j. hrthm.2014.01.016; PMID: 24444444 85. Qintar M, Zardkoohi O, Hammadah M, et al. The impact of changing antiseptic skin preparation agent used for cardiac implantable electronic device (CIED) procedures on the risk of infection. Pacing Clin Electrophysiol 2015;38(2):240–6. DOI: 10.1111/pace.12514; PMID: 25224666 86. Freeman JV, Wang Y, Curtis JP, et al. The Relation Between Hospital Procedure Volume and Complications of CardioverterDefibrillator Implantation From the Implantable CardioverterDefibrillator Registry. J Am Coll Cardiol 2010;56(14):1133–9. DOI: 10.1016/j.jacc.2010.07.007; PMID: 20863954

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ICD Therapy for Primary Prevention in Hypertrophic Cardiomyopathy Amar Trivedi and Bradley P Knight Division of Cardiology, Department of Medicine, Northwestern University, Chicago, IL, USA

Abstract Hypertrophic cardiomyopathy (HCM) is a common and heterogeneous disorder that increases an individual’s risk of sudden cardiac death (SCD). This review article discusses the relevant factors that are involved in the challenge of preventing SCD in patients with HCM. The epidemiology of SCD in patients is reviewed as well as the structural and genetic basis behind ventricular arrhythmias in HCM. The primary prevention of SCD with implantable cardioverter-defibrillator (ICD) therapy is the cornerstone of modern treatment for individuals at high risk of SCD. The focus here is on the current and emerging predictors of SCD as well as risk stratification recommendations from both North American and European guidelines. Issues related to ICD implantation, such as programming, complications and inappropriate therapies, are discussed. The emerging role of the fully subcutaneous ICD and the data regarding its implantation are reviewed.

Keywords Hypertrophic cardiomyopathy, sudden cardiac death, implantable cardioverter defibrillator, subcutaneous implantable cardioverter-defibrillator Disclosure: Dr Trivedi has no conflicts of interest to declare. Dr Knight has been a consultant to manufacturers of implantable defibrillators and participated in clinical trials sponsored by Medtronic, Boston Scientific, St Jude and Biotronik. Received: 12 September 2016 Accepted: 2 December 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(3):188–96. DOI: 10.15420/aer.2016:30:2 Correspondence: Bradley P Knight, Medical Director, Center for Heart Rhythm Disorders, Bluhm Cardiovascular Institute, Northwestern Memorial Hospital, Cooley Professor of Medicine, Northwestern University, Feinberg School of Medicine, 676 St. Clair, Suite 600, Chicago, IL 60611, USA. E: bknight@nm.org

Hypertrophic cardiomyopathy (HCM), a genetic sarcomeric disorder associated with myocyte disarray and scar deposition, is intimately linked to sudden cardiac death (SCD) due to malignant ventricular arrhythmias. In the first modern published description of the disease in 1958, Dr Donald Teare describes the case of a 14-year-old male who collapsed while being chased around his school’s playground.1 He was reported to have been having ‘blackout episodes’ for months. He had seen physicians and the only abnormal finding elicited was a third heart sound and a soft systolic murmur. As there was no evidence of seizure activity, he was advised to continue his daily activities without restriction. After collapsing while playing, he was pronounced dead on arrival at the hospital and his autopsy was remarkable for massive septal hypertrophy. Dr Teare’s report described seven more cases of young adults all who suddenly collapsed without warning with similar findings on autopsy. Since 1958 our understanding of HCM has markedly improved, but up to the 1980s little progress had been made in preventing SCD. The advent of the implantable cardioverter-defibrillator (ICD) has drastically changed our ability to prevent SCD. In this review we discuss our current epidemiological, genetic and structural understanding of the link between HCM and SCD. We also discuss the role of modern ICD therapy in the primary prevention of sudden death in patients with HCM.

Epidemiology of Hypertrophic Cardiomyopathy and Sudden Cardiac Death HCM is the most common form of genetically inherited cardiovascular disease, with a prevalence of one in 500 individuals.2,3 Patients with HCM make up 1 % of cardiology practice. Many patients with HCM

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interact with the healthcare system from young adulthood onwards.4 The mortality rates in early studies were as high as 5–7 % per year.5,6 With the advent of ICDs and early detection of the disease, modern cohorts have mortality rates of under 1 %.7,8 SCD due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) is still the most common cause of mortality, however, accounting for 51 % of all HCM-related deaths.8 Sudden death in patients with HCM is one of the leading causes of death in individuals under the age of 40.9 While there appears to be no difference in SCD rates based on gender, age is an important factor:10 SCD is more common in younger patients, especially those under the age of 35; however, up to 20 % of SCDs have been reported to occur in patients over the age of 65.8 Identifying patients within this heterogeneous disorder who are at high risk of sudden death is a challenge.

Genetics of Hypertrophic Cardiomyopathy and Sudden Cardiac Death HCM is a heterogeneous disease that is classically transmitted in an autosomal dominant fashion. HCM often arises from mutations in genes responsible for the formation of cardiac sarcomeres. Sarcomeric mutations, initially discovered in the 1980s, are found in up to 70 % of patients with a family history of HCM.11 The most common mutations are in the myosin heavy chain (MYH7 gene) and myosin binding protein C (MYBPC3 gene).12 There is marked heterogeneity in penetrance, however, and a poor understanding of how the different genotypes manifest as HCM phenotypes. Currently, there is minimal evidence to support the use of genetic testing to identify patients who are at high risk of SCD. Small studies have found that patients with a more malignant inheritance of their mutations (i.e. homozygous mutations) as well as the presence of a MYH7 gene mutation have

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increased rates of heart failure.13 Emerging data suggest that rarer forms of the MYH7 mutation increase the risk of SCD.13,14 At this time, however, routine genetic testing cannot reliably be used to identify patients with HCM who are at elevated risk of SCD.

Structural Predisposition Towards Sudden Cardiac Death Myocardial fibrosis, microvascular ischaemia and cellular disarray predispose patients with HCM to re-entrant ventricular arrhythmias. Histological findings in HCM are consistent with myocardial fibrosis due to scarring and disruption of the normal cellular architecture.15,16 Fibrosed and disrupted cellular architecture is often found throughout the heart, but is mostly concentrated in the densest area of hypertrophy.17 Silent low-grade myocardial ischaemia and altered coronary blood flow are common in HCM and help create the conditions needed for scar formation and arrhythmogenesis.18 Fibrosis can be evaluated noninvasively with advanced imaging techniques. Currently cardiac magnetic resonance imaging (cMRI) is being used to better understand the role of fibrosis and how it relates to disease progression and risk of SCD. Late gadolinium contrast enhancement (LGE) visualised on cMRI is being studied as a surrogate for the degree and distribution of fibrosis. An association between the presence of LGE and nonsustained ventricular tachycardia (NSVT) has been recorded by outpatient ambulatory monitoring.19 While no clear link between LGE and SCD has been established, a recent metaanalysis found that the risk of SCD increased in the presence of LGE (odds ratio (OR) 2.52; 95 % confidence interval (CI) [1.44–4.40]).20

Primary Prevention of Sudden Cardiac Death While uncommon, SCD is the most devastating consequence of HCM. Prior to the advent of ICD therapy, pharmacological therapy was used in an attempt to reduce the risk of sudden death. The initial strategies involved beta-blockers and calcium-channel blockers, as well as antiarrhythmic agents such as quinidine, procainamide, sotalol and amiodarone. In a retrospective study prior to the widespread use of ICDs, the authors studied 293 patients who were considered to be at high risk for SCD.21 They compared the risk of SCD between patients who were prescribed medications (beta-blockers, verapamil, sotalol and amiodarone) for the prevention of SCD or relief of HCM symptoms versus those on no medical therapy. Patients on medical therapy had similar rates of sudden death to those receiving medications.21 It appears that pharmacological therapy alone is not sufficient to prevent SCD. In the current era of ICD implantation there are many patients on antiarrhythmic therapy who still receive appropriate ICD discharges to terminate VT/VF.22 Current and previous guidelines have found that there is no evidence for the use of medical therapy alone in the prevention of SCD.23,24 The advent of the transvenous ICD has markedly changed our ability to prevent SCD. It is of historical interest that two of the first individuals who had an ICD implanted were patients with HCM and frequent ventricular arrhythmias.25 The efficacy of ICD implantation specifically for the prevention of SCD in the HCM population was first studied in a group of 128 high-risk patients. In these patients, the rate of ICD therapy to terminate VT or VF was 7 % per year.22 Since then, several large multicentre studies have been completed that support the findings that ICDs are effective at terminating malignant arrhythmias with rates of therapy between 4 and 6 % per year.26–29 A multicentre international ICD registry consisting of 500 patients with HCM and ICD

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implants revealed that ICD interventions successfully terminated lifethreatening arrhythmias in 103 out of 104 patients who developed VT or VF.26 The one patient who was not successfully treated was found to have a faulty device. Another modern cohort study followed 1,000 patients under the age of 60 for 20 years.8 The authors found that the overall mortality rate for patients with HCM was similar to that of the general population, at nearly 1 %. While the mortality rates were similar, the cause of death was very different in both groups, with SCD being the major cause of mortality in the HCM group. Eighty per cent of the patients who suffered SCD had either declined ICD implantation or had been evaluated prior to the widespread use of ICD therapy. It is postulated that nine ICDs need to be implanted to treat one episode of malignant arrhythmia or SCD. This is comparable to high-risk patients with an ischaemic cardiomyopathy.30 There is no doubt that the ICD is efficacious in preventing SCD. The primary difficulty for the clinician arises when trying to select patients for whom the risks are outweighed by the benefits of ICD implantation.

Risk Stratification Although the current mortality rate of HCM is low, there are groups of patients with an elevated risk of SCD who would benefit from ICD placement. The current American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidelines from 2011 focus on the clinical factors that increase the risk of SCD.24 It is important to note that our current understanding is still incomplete. As always, one must tailor the decision to the needs and desires of the individual patient. The guidelines recommend that all patients should undergo SCD risk stratification at their initial evaluation, as well as periodic re-evaluation to determine whether their risk of SCD has changed.24 The clinical variables are grouped into two categories (see Table 1). The first category includes established risk markers. Some of these markers are individually sufficient to prompt ICD placement, while others prompt ICD placement when they are found in conjunction with other high-risk features. The second category includes risk modifiers. These serve as additional markers to help identify high-risk patients; alone they are not sufficient to promote ICD placement. Established risk markers carry more weight, as the evidence linking them to SCD is more robust; however, our understanding of risk modifiers has continued to develop since the guidelines were produced in 2011.

Established Risk Markers Prior Personal History of Ventricular Fibrillation, Sudden Cardiac Death or Sustained Ventricular Tachycardia Patients who have already experienced and survived an episode of SCD or malignant ventricular arrhythmia represent the highest risk group. The annual rate of subsequent events in this secondary prevention group is 10 % per year.31–33 This is the only risk marker with an excellent positive predictive value.

Family History of Sudden Cardiac Death Prior to our understanding that HCM is a genetic disease, authors made the observation that SCD disproportionately affects certain families.34 The first patient clinically diagnosed with HCM came to medical attention due to several siblings dying suddenly at a young age.35 Despite this, the lack of clear associated genetic markers has led some authors to argue that a family history should not be an established risk factor.36 Another complicating factor is the various definitions of family history used by investigators. Some studies use an age cut-off

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Device Therapy Table 1: Established Risk Factors and Risk Modifiers for Sudden Cardiac Death (SCD) in Patients with Hypertrophic Cardiomyopathy (HCM) Risk

Details

Established Factor* Prior SCD event due to ventricular tachycardia

This is the highest-risk group

or ventricular fibrillation Unexplained syncope

A history of unexplained syncope occurring 6 months prior to clinical

evaluation is associated with an increased risk of SCD

Maximal left ventricular-wall thickness

There is a linear relationship between left ventricular-wall thickness and SCD.

A thickness ≥30 mm is an independent risk factor for SCD, with a 20 % increase in

the relative risk of death at 10 years compared to the general HCM population

Nonsustained ventricular tachycardia

In select patients, especially young patients, a history of nonsustained

ventricular tachycardia on ambulatory monitoring is a marker for increased

risk of SCD. There may be value in longer-term monitoring to assess the

burden of nonsustained ventricular tachycardia in unclear cases

Abnormal blood pressure response to exercise

Many patients with HCM have an abnormal blood pressure response to

exercise, defined as a decrease in systolic pressure of 20 mmHg or a failure

to increase systolic blood pressure by 20 mmHg while exercising. A normal

response to exercise has a high negative predictive value. An abnormal

response to exercise is useful in conjugation with other risk factors

Family history of SCD

A history of documented SCD in at least one first-degree family member is

associated with an increased risk of SCD. There is currently no conclusive

evidence that a history of SCD in second-degree and more distantly-related

family members should influence the decision to place an implantable

cardioverter-defibrillator

Modifier§ Late gadolinium enhancement on cardiac magnetic

This is a marker of cardiac fibrosis and recent data have supported its role in

resonance imaging

identifying patients at elevated for SCD. Any late gadolinium enhancement

places patients at increased risk of SCD. If found, a thorough evaluation for

other risk factors should be performed

Apical aneurysm

While rare, a dilated and thinned left ventricular apex is associated with

significant scarring. Patients with HCM and apical aneurysms often present

with monomorphic ventricular tachycardia

Genetic mutations

Genetic mutations targeting the myosin heavy chain (MYH7 gene) appear

to increase the risk of SCD, however the mutation has poor positive

predictive value

*These six risk markers are the best-studied predictors of SCD in patients with HCM. They are the cornerstone in determining a patient’s risk of SCD. §These clinical markers should be used in conjunction with established risk markers. If a risk modifier is found on routine testing, thorough investigation should be undertaken by testing for established risk markers. HCM: hypertrophic cardiomyopathy; SCD: sudden cardiac death. Adapted from Gersh et al., 2011.24

of 50 years when determining whether a SCD event was due to HCM, while others consider having had two first-degree relatives die from SCD as an indication of a positive family history.31,37 Recent studies define a positive family history as SCD in any first-degree relative of a patient with HCM.38 The totality of evidence appears to favour using a carefully elucidated family history as a risk factor for SCD. Cohort studies demonstrate that family history is independently associated with a 20 % increase in the relative risk of SCD.35 The ACCF/AHA guidelines define family history as an established risk marker if one or more first-degree family members have suffered SCD, irrespective of the family member’s age or whether he or she had a documented history of HCM.24

Unexplained Syncope Syncope in HCM can originate from either a haemodynamic- or arrhythmia-mediated cause. Haemodynamic mechanisms include left ventricular outflow tract (LVOT) obstruction and abnormal vagal tone. A large series of 1,511 patients found that a history of unexplained syncope occurring 6 months prior to clinical evaluation led to a fivefold increase in the relative risk of SCD (adjusted hazard ratio: 4.89; 95 % CI [2.19–10.94]).39 A remote history of unexplained syncope

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(greater than 5 years prior to evaluation), however, did not increase the risk of SCD.39 The current guidelines consider any unexplained recent syncopal event identified after a careful history-taking to be a risk factor, and one that has occurred within the past 6 months to be particularly concerning.

Maximal Left Ventricular-Wall Thickness There is a linear relationship between left ventricular hypertrophy (LVH) and the risk of SCD. An increase in LV mass leads to myocardial remodelling and fibrosis, which predispose patients to re-entrant arrhythmias.40 Studies have demonstrated that a LV-wall thickness ≥30 mm is an independent risk factor for SCD, with a 20 % increase in the relative risk of death at 10 years compared to the general HCM population.41 Based on these studies, the guidelines recommend a LV-wall diameter ≥30 mm be considered an established risk marker. It is important to note that LVH appears to increase the risk of SCD in younger patients to a greater extent. The guidelines recommend individualised decision-making when a younger patient begins to demonstrate LVH.41 Young patients (<30 years), even those with moderate LVH (LV-wall thickness >16 mm), should undergo further risk stratification.42 If one identifies other high-risk features such as

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NSVT, abnormal blood pressure response to exercise or fibrosis on MRI, then ICD implantation should be considered.

Nonsustained Ventricular Tachycardia NSVT is defined as three or more consecutive ventricular beats of <30 s in duration at a heart rate ≥120 beats/min. It is most often found during ambulatory monitoring. Early studies failed to show NSVT as a clear, independently-associated risk factor for SCD.43 However, a much larger contemporary study of 531 patients demonstrated that those who developed NSVT of any duration were more likely to die from SCD, especially younger patients. The OR for patients under the age of 30 with NSVT was 4.35 (95 % CI [1.54–12.28]); the OR for those >30 years was 2.16 (96 % CI [0.82–5.69]).44 There are conflicting reports on whether the duration and frequency of NSVT have any prognostic implications. The current ACCF/AHA guidelines suggest that there may be value in longer-term monitoring to help assess the burden of NSVT in unclear cases.24 This approach is reasonable. If non-invasive ambulatory monitoring is unrevealing, implantable loop recorders should be considered. Implantable loop recorders may be most useful when a patient has risk factors of unclear clinical significance, such as infrequent symptoms suggestive of an arrhythmia, malignant genetic mutations or imaging findings concerning for fibrosis.

Abnormal Blood Pressure Response to Exercise As much as 33 % of patients with HCM have an abnormal blood pressure response to exercise.45 An abnormal blood pressure response is a failure to augment or sustain blood pressure while exercising. This is defined as a decrease in systolic pressure from baseline by 20 mmHg during exercise, or a failure to increase systolic pressure by 20 mmHg while exercising. Studies have demonstrated that an abnormal blood pressure response has a very low positive predictive value of 15 %, but a high negative predictive value of 95 % in determining risk of SCD.45,46 If a patient has a dynamic obstruction causing an abnormal response to exercise, the guidelines suggest re-assessing any abnormal blood pressure response after treatment to relieve the obstruction.

Potential Risk Modifiers Risk modifiers can be used in conjunction with established risk markers to determine a patient’s risk of SCD.24 The risk modifiers are LGE on cMRI, LV apical aneurysm and genetic mutations. LGE is a maker of cardiac fibrosis that is strongly associated with increased ventricular ectopy and NSVT,47,48 and since the guidelines have been written more data have emerged supporting the use of LGE in risk stratification.17,20 Apical aneurysm formation is a rare finding in patients with HCM. The LV apex is dilated and thin-walled with significant scarring, which predisposes these patients to malignant arrhythmias.49 The documented incidence of SCD in these patient is as high as 5 % a year.50 Often these patients present with sustained monomorphic VT, rather than VF, caused by the large apical scar. While ‘malignant’ genetic mutations of the cardiac sarcomere are discussed in the ACCF/AHA guidelines, the authors suggest that the evidence is poor and routine screening would be of limited value in risk stratification.51

ACCF/AHA Recommendations for Implantable Cardioverter-defibrillator Implantation The current ACCF/AHA guidelines on ICD implantation are an evolution of the shared ACCF and European Society of Cardiology

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(ESC) guidelines written in 2003.23 The risk factors listed above were described in the 2003 guidelines, and are used systematically to risk stratify patients in the 2011 ACCF/AHA HCM guidelines. The guidelines also stress the importance of individualised decision-making in determining the need for ICD therapy, as HCM is a heterogeneous disorder with varied phenotypes. Nonetheless, the use of established risk factors as well as risk modifiers can help guide clinicians in selecting patients who would benefit from ICD therapy. The difficulty in using our existing knowledge of SCD in HCM is that our current established risk markers have a low positive predictive value (10–20 %).24,30,52 To improve the predictive value, the guidelines combine certain risk markers with risk modifiers. It should be noted that simply adding risk factors does not always result in a cumulative increase in the risk of SCD.29 A recent study found no increase in ICD intervention rate in patients with multiple risk factors compared to patients with one risk factor.29,52 The current ACCF/AHA recommendations for ICD implantation are summarised below.24

Class I Recommendation ICD therapy should be recommended to individuals with a documented history of cardiac arrest, VF or haemodynamically-significant VT. There is strong expert consensus that secondary prevention of SCD with ICD implantation is appropriate.24,53 As discussed, this is the highest-risk cohort and will benefit the most from ICD therapy. This recommendation is supported by B level evidence (data derived from non-randomised studies or a single randomised trial).

Class IIa Recommendations ICD implantation is considered reasonable when patients have any of the following established risk markers: sudden death in one or more first-degree relatives; maximal LV wall thickness ≥30 mm; or a recent and unexplained syncopal event. It is also reasonable in select patients with NSVT, especially those under the age of 30 who have other established risk markers or risk modifiers. ICD implantation can also be considered in patients with an abnormal blood pressure response to exercise in the presence other risk factors or modifiers. The above indications also apply to children. These recommendations are based on C level evidence (consensus opinion of experts, case studies and standard of care).

Class IIb Recommendations The usefulness of ICD implantation is unknown when patients have only NSVT or an abnormal blood pressure response to exercise in the absence of any other risk marker or modifier.

Class III Recommendations ICD placement should not be performed in the following scenarios: routine implantation regardless of SCD risk; to allow patients with HCM to participate in competitive sports; and in patients with an identified HCM genotype but no clinical manifestation of HCM.24

European Society of Cardiology’s Hypertrophic Cardiomyopathy Risk Calculator Historically the North American and European cardiovascular societies have issued a shared guideline regarding ICD implantation for HCM.23 This has recently changed with the 2014 update to the ESC guidelines.53 Unlike the previous shared guidelines and the current ACCF/AHA guidelines, the ESC guidelines advocate the use of a risk calculator to determine an individual patient’s risk of SCD. The scoring model that the ESC risk calculator uses is derived from

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Device Therapy a large European multicentre cohort of 3,675 patients with HCM.54 In the study, statistical modelling was employed to find clinical variables that were associated with SCD at ≥15 % significance. In the ESC risk calculator, these variables are weighted and produce a score that is expressed as the risk of SCD over 5 years. A score of greater than 6 % over 5 years is considered high risk and indicates that an ICD is recommended; a score of less than 4 % over 5 years is considered low risk and ICD placement is unlikely to be indicated. Unlike the ACCF/AHA guidelines, the ESC risk-scoring algorithm does not treat clinical variables as binary; it assigns relative weight to different variables. This approach may be preferable, as most clinical variables used to determine the risk of SCD have at most modest positive predictive value when evaluated in isolation. The seven clinical variables that the ESC risk score incorporates are: age, maximum LV-wall thickness, LVOT gradient, left atrial size, NSVT, family history of SCD and unexplained syncope. Some of these variables are not part of the ACCF/AHA guidelines (age, LVOT obstruction and left atrial size). In contrast, some of the risk modifiers that the ACCF/AHA guidelines use, including an abnormal blood pressure response to exercise, are not included in the ESC risk calculator. The performance of the risk calculator is currently under debate. There is currently evidence favouring and opposing the use of the risk ESC risk calculator when compared to the ACCF/AHA guidelines. The initial external validation studies performed with a cohort of 706 patients found that the ESC model is theoretically better at discriminating low- from high-risk patients.55 A group of 502 patients with HCM in Argentina where studied in a similar fashion. The authors concluded that the ESC risk score accurately categorised all patients who experienced an ICD shock or SCD as either intermediate or high risk.56 There are, however, concerns that the risk calculator has poor sensitivity compared to the ACCF/AHA guidelines. A recent study designed to determine the calibration of the calculator used a cohort of 1,629 patients previously risk-stratified according to the ACCF/AHA guidelines.57 The authors found that the ESC calculator had adequate specificity but poor sensitivity compared to the ACCF/AHA guidelines. Fifty-nine per cent of patients who were stratified as high-risk by the ACCF/AHA guidelines and went on to have an appropriate ICD intervention or SCD would have been classified as low-risk if the ESC calculator had been used. Given the heterogeneity in the molecular and structural abnormalities that characterise HCM, it is especially important that an algorithmic score is validated in diverse populations with varying genotypes and phenotypes. Further validation or revision of the ESC risk calculator will be needed before it can fully supplement the current ACCF/AHA guidelines in North America.

Invasive Testing in Risk Stratification for Implantable Cardioverter-defibrillator Implantation The use of electrophysiological (EP) testing to risk stratify patients with HCM is controversial. The largest study, performed in the late 1980s, demonstrated a decrease in 5-year survival in patients when VT – either polymorphic or monomorphic – was induced with aggressive programmed ventricular stimulation.58 Studies from this period in time are difficult to apply as most of the patients studied with EP testing would be considered high risk by current guidelines and already have an indication for ICD therapy. The study also required the use of aggressive stimulation protocols requiring right and left ventricular sites in 71 % of all inducible patients. Polymorphic VT was the most

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commonly induced arrhythmia, occurring in 76 % of inducible patients. Polymorphic VT is a less sensitive marker, as up to one-third of individuals without structural heart disease can develop polymorphic VT with similar stimulation protocols.58,59 Given the unclear indication, as well as potential risk, there is no clear consensus on when to perform EP testing in patients with HCM. There are reported cases of fascicular VT amenable to ablation in patients with HCM. One appropriate use of EP study would be to diagnose and possibly treat patients who present with sustained monomorphic VT and may have a fascicular or bundle branch re-entrant VT mechanism.60,61 Acknowledging the unclear role of EP testing, the AHA/ACC/ESC 2006 guidelines for the management of patients with ventricular arrhythmias issues a class IIb level of evidence (C) for the use of routine EP testing in patients with HCM for the purpose of risk stratification.62

Issues Related to Implantable Cardioverterdefibrillator Implantation Once a patient is deemed to potentially benefit from ICD therapy, there are several issues to resolve prior to the implantation. They include discussing the risks of ICD-related complications and determining the type of defibrillator system to implant. ICD-related complications are an important factor to consider in patients with HCM, as many are young and will have a device in place for much of their adult lives. There are two particular risks to discuss in depth with the patient: the risk of device-related complications/ malfunction; and the risk of inappropriate ICD therapy. Given the variability of age and other comorbid conditions, the risk of ICD complications varies depending on the patient. For example, children and teenagers appear to have a higher incidence of lead fractures due to the strain placed on leads by their growth and development.63 Younger patients will also require multiple ICD generator changes throughout their life, which increases the risk of device-related complications. The published rate of mechanical complications due to ICD implantation is between 4 and 6 % a year in the HCM population.29,64 This includes immediate device complications, such as pneumothorax, pericardial effusion and haematoma or pocket infection. It also includes long-term consequences such as endocarditis and upper extremity venous thrombosis.65 Knowledge of ICD lead performance is growing. Studies suggest that 60–72 % of ICD leads are functioning at 8 years, and that patients who undergo revision have a markedly higher incidence of repeat lead failure or revision.66 This is of particular importance as many HCM patients will require dependable functioning transvenous leads for decades. Inappropriate ICD therapy, defined as any defibrillation or antitachycardia pacing (ATP) delivered by the device for events other than sustained VT or VF, is another complication related to ICD implantation. A recent analysis described the rate of inappropriate device therapy in a cohort of adult patients with HCM who underwent ICD implantation. 29 The authors hypothesised that modern ICD programming, with prolonged detection zones and better supraventricular tachycardia (SVT) discrimination, could lead to a reduction in inappropriate ICD therapy. The authors found that 20 % of patients in the cohort were treated inappropriately despite modern ICD programming. The inappropriate therapy was

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initiated by atrial fibrillation (39 %), T-wave oversensing (24 %), sinus tachycardia (16 %), atrioventricular nodal re-entrant tachycardia (8 %) and lead fracture (8 %). The rate of appropriate therapy was similar for all patients, regardless of whether they received any inappropriate shock (3.2–3.4 % per year). These findings are similar to other observational studies and mark an avenue for further improvement in current implantation techniques and programming or new device placement strategies.

Figure 1: The Subcutaneous Implantable CardioverterDefibrillator is Implanted in the Left Lateral Thoracic around the Fifth and Sixth Intercostal Space and Near the Mid-axillary Line. The Defibrillation Coil is Positioned Parallel to the Sternum and Should Ideally be in Contact with the Deep Fascia

Implantable Cardioverter-defibrillator Device Selection Single- or dual-chamber transvenous ICDs are the most common devices that are implanted for primary and secondary prevention of SCD. Single-chamber ICDs are the current guideline-based recommendation for patients with HCM who are at high risk for SCD, but without other compelling reasons for dual-chamber pacing. This is especially true in young patients, who will be exposed to the risks of intra-cardiac leads for an extended period of time. Dual-chamber devices are recommended for patients with other indications for dualchamber pacing, such as pre-existing paroxysmal atrial fibrillation with rapid rates or sinus bradycardia.24 For instance, the older patient with heart failure symptoms and elevated resting outflow gradients (>50 mmHg) may benefit from a dual-chamber system to potentially reduce his or her gradient and heart failure symptoms.24 When compared with single-chamber ICDs, there are no consistent data that dual-chamber devices reduce the likelihood of receiving an inappropriate shock.67 The advent of the fully subcutaneous ICD (S-ICD), see Figure 1, has provided a valuable alternative for certain patients with HCM. It avoids the need for transvenous leads with the entire device implanted below the subcutaneous layer of the chest. The S-ICD allows patients without a need for pacing to have the benefits of arrhythmia protection without the risks of intravascular lead infection or failure. This is particularly useful in young patients with HCM who could avoid the complications associated with transvenous leads as well as the potential procedural risks related to the removal of existing transvenous leads. To qualify for S-ICD placement, patients undergo a screening procedure to ensure that their QRS and T-wave morphology and amplitude are analysed in various positions. If the T-wave is too large or delayed in relation to the QRS complex, then there is a risk of T-wave oversensing and double counting of the heart rate, which can cause inappropriate therapy.68 The S-ICD appears to be effective in safely terminating VT/VF in patients with HCM. In a single-centre study of 16 patients with HCM, the S-ICD appropriately terminated VF in every patient with 65 J of energy and in 80 % of patients with 50 J. A body mass index >34 was the only baseline characteristic that was associated with an unsuccessful 50 J shock.69 This early success led to long-term followup studies that also appear promising.70 A recent publication of a large pooled S-ICD cohort of 872 patients, including 100 patients with HCM, indicates that the S-ICD can effectively terminate spontaneous life-threatening arrhythmias.71 When examining patients with HCM and S-ICDs, the authors found that 3 % had received appropriate and successful therapies for monomorphic VT. No patient had an episode of VF during the study

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period. The complication rate of the S-ICD in patients with HCM was low: one patient developed a haematoma, one patient had electrode movement during the procedure, two patients were found to have suboptimal positioning of either their leads or the generator, and two patients developed an infection that required device explantation. The overall infection rate in the HCM subgroup was 1.6 % per year. There were no lead malfunctions in this cohort. The safety data demonstrate low rates of infection and lead disruption in the S-ICD. It is also important to note that, unlike transvenous systems, extraction does not carry the risk of intravascular perforation. Inappropriate therapy occurred in 12.5 % of patients with HCM who

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had an S-ICD, similar to the non-HCM cohort. T-wave oversensing was the cause of inappropriate therapy in 83 % of HCM patients. This is in contrast to studies of patients with transvenous leads, which have shown SVT to be the main cause of inappropriate therapy.29 SVTs such as atrial fibrillation and flutter are common arrhythmias in patients with HCM.72 In a large study examining the outcomes of transvenous ICD systems, atrial fibrillation/flutter was responsible for 51 % of all inappropriate ICD shocks in patients with transvenous devices.64 In the S-ICD pooled cohort, SVTs (including atrial fibrillation/flutter) were responsible for only 17 % of all inappropriate ICD shocks. Prolonged tachycardia detection time and the S-ICD specific discrimination algorithm may explain why fewer patients with S-ICDs appear to receive inappropriate shocks for SVT. Avoiding inappropriate device therapy with the S-ICD requires discrimination between VT and a narrow complex tachycardia with a small QRS:T ratio. The advent of dual zone programming is reported to reduce the rates of inappropriate sensing by up to 40 %.73 Patients with HCM may provide a special challenge in avoiding inappropriate shocks due to the progressive nature of hypertrophy and the activity level of younger patients. Both the QRS complex and T-wave may change in amplitude and morphology as the ventricle hypertrophies in HCM.74 This can lead to a mismatch between the template stored at implant and the QRS and T-wave sensed by the device during tachycardia. Young patients with HCM may also exercise vigorously and develop rate-related aberrancy in conduction that can lead to failed SVT discrimination. One option is to have active patients with HCM perform an exercise test prior to implantation in order to apply the ECG template to the ECG during exercise to screen for patients who should not receive the device. It is also helpful for patients who qualify and undergo successful implantation to undergo stress testing after implantation. This will allow the device to store a morphology that can be used when the patient is achieving high

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heart rates with exercise. It is important to note that while the rate of inappropriate therapy with S-ICD systems needs improvement, it is well within observed rates of transvenous leads.29 Sensing algorithms in the S-ICD have been modified recently to reduce the risk of T-wave oversensing by the device. The problem will likely improve with time as further algorithm refinements are made to avoid T-wave oversensing. There is concern by some that S-ICDs may not be appropriate for patients with HCM due to the lack of ATP. Monomorphic VT is a common finding in HCM, and ATP therapy has been shown to be modestly successful in terminating monomorphic VT in certain instances.75 Data from Multicentre Automatic Defibrillator Implantation Trial to Reduce Inappropriate Therapy (MADIT RIT) patients who received appropriate ATP therapy showed no reduction in the number of appropriate ICD shocks.76 The modest, if any, benefit of ATP availability does not appear to outweigh the significant risks of complications from transvenous systems. Current data suggest that an S-ICD is as effective at terminating VT/VF in patients with HCM (see Figure 2) as transvenous systems, with a similar rate of inappropriate therapy. A recent, large retrospective trial comparing the clinical outcomes of the S-ICD to transvenous systems in a heterogeneous group of 1,160 patients demonstrated similar trade-offs between the two systems as discussed earlier.77 The authors’ analysis demonstrated that the S-ICD system was more likely to deliver inappropriate therapy due to t-wave oversensing while the transvenous systems were more likely to deliver inappropriate therapy due to SVTs. S-ICD patients had more non-lead related complications which included pocket erosion, defibrillation testing failure and device failure (9.9 % versus. 2.2 % in the transvenous group). The study once again demonstrated a major advantage of the S-ICD: a decrease in lead complications which were defined as replacement or repositioning of the leads (0.8 % vs 11.5 % over 5 years) in the S-ICD group. It is likely that, as S-ICD technology matures and implanters become more comfortable with the device, non-lead related complications will be reduced. The totality of evidence suggests that an S-ICD may be the optimal option in many patients with HCM, especially in young patients who should not be subjected to the risk of transvenous lead failure if it can be avoided.

Clinical Perspective • Hypertrophic cardiomyopathy is a heterogeneous genetic disorder that increases the risk of sudden cardiac death (SCD). Implantable cardioverter-defibrillator (ICD) therapy is a safe and efficacious means of preventing sudden death in patients with an elevated risk of ventricular arrhythmias. • There are multiple clinical risk factors to help determine an individual’s risk of SCD. Most clinical variables have excellent negative predictive value but modest positive predictive value. Individualised decision-making is imperative in determining the risk of SCD. • Traditional transvenous ICD therapy is effective at preventing SCD; however, it is associated with risks such as device infection, lead complications and inappropriate therapy. • The fully subcutaneous ICD provides the benefits of preventing SCD with a completely extracardiac system. This may be ideal for hypertrophic cardiomyopathy patients, especially younger patients who may have an ICD for most of their adult life.

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Conclusion There has been significant progress in understanding the relationship between sudden death and HCM in the past 50 years. The implantation of an ICD in patients who are deemed to be at high risk of SCD has significantly altered the mortality rate. The

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current strategy of primary prevention relies on risk stratification based on clinical variables. To improve care for patients with HCM we will need to improve how we identify high-risk patients, perhaps with more refined genetic and imaging data, as well as continuing to refine our treatment options for HCM with devices such as the S-ICD. ■

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ventricular arrhythmias: what is the significance of induced arrhythmias and what is the correct stimulation protocol? Circulation 1985;72:1-7. PMID: 4006120 Behr ER, Elliott P, McKenna WJ. Role of invasive EP testing in the evaluation and management of hypertrophic cardiomyopathy. Card Electrophysiol Rev 2002;6:482-6. PMID: 12438832. Mittal S, Coyne RF, Herling IM, et al. Sustained bundle branch reentry in a patient with hypertrophic cardiomyopathy and nondilated left ventricle. J Interv Card Electrophysiol 1997;1:73-7. PMID: 9869954 Sonoda K, Okumura Y, Watanabe I, et al. Successful catheter ablation of premature ventricular contractions originating from the anterior fascicle of the left bundle branch in a patient with hypertrophic cardiomyopathy. J Arrhythmia 2013;29:232-4. DOI: 10.1016/j.joa.2012. 10.005 Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). Europace 2006;8:746-837. DOI: 10.1093/europace/eul108 Maron BJ. Risk stratification and role of implantable defibrillators for prevention of sudden death in patients with hypertrophic cardiomyopathy. Circ J 2010;74:2271-82. DOI: 10.1253/circj.cj-10-0921; PMID: 20962423 Oâ&#x20AC;&#x2122;Mahony C, Lambiase PD, Quarta G, et al. The longterm survival and the risks and benefits of implantable cardioverter defibrillators in patients with hypertrophic

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cardiomyopathy. Heart 2011;98:116-25. DOI: 10.1136/ hrt.2010.217182; PMID: 21757459 Lin G, Nishimura RA, Gersh BJ, et al. Device complications and inappropriate implantable cardioverter defibrillator shocks in patients with hypertrophic cardiomyopathy. Heart 2009;95:709-14. DOI: 10.1136/hrt.2008.150656; PMID: 19282314 Maisel WH, Kramer DB. Implantable cardioverter-defibrillator lead performance. Circulation 2008;117:2721-3. DOI: 10.1161/ circulationaha.108.776807; PMID: 18506015 Theuns DAMJ, Klootwijk APJ, Goedhart DM, et al. Prevention of inappropriate therapy in implantable cardioverterdefibrillators. Results of a prospective, randomized study of tachyarrhythmia detection algorithms. ACC Curr J Rev 2005;14:44-5. DOI: 10.1016/j.accreview.2005.03.038 Groh CA, Sharma S, Pelchovitz DJ, et al. Use of an electrocardiographic screening tool to determine candidacy for a subcutaneous implantable cardioverterdefibrillator. Heart Rhythm 2014;11:1361-6. DOI: 10.1016/ j.hrthm.2014.04.025; PMID: 24755323 Weinstock J, Bader YH, Maron MS, et al. Subcutaneous implantable cardioverter defibrillator in patients with hypertrophic cardiomyopathy: an initial experience. J Am Heart Assoc 2016;5:e002488. DOI: 10.1161/JAHA.115.002488; PMID: 26873684 Lewis GF, Gold MR. Safety and efficacy of the subcutaneous implantable defibrillator. J Am Coll Cardiol 2016;67:445â&#x20AC;&#x201C;54. DOI: 10.1016/j.jacc.2015.11.026; PMID: 26821634 Lambiase PD, Gold MR, Hood M, et al. Evaluation of subcutaneous ICD early performance in hypertrophic cardiomyopathy from the pooled EFFORTLESS and IDE cohorts. Heart Rhythm 2016;13:1066-74. DOI: 10.1016/ j.hrthm.2016.01.001; PMID: 26767422 Olivotto I, Cecchi F, Casey SA, et al. Impact of atrial fibrillation

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on the clinical course of hypertrophic cardiomyopathy. Circulation 2001;104:2517-24. PMID: 11714644 Brisben AJ, Burke MC, Knight BP, et al. A new algorithm to reduce inappropriate therapy in the S-ICD system. J Cardiovasc Electrophysiol 2015;26:417-23. DOI: 10.1111/jce.12612; PMID: 25581303 McKenna WJ, Borggrefe M, England D, et al. The natural history of left ventricular hypertrophy in hypertrophic cardiomyopathy: an electrocardiographic study. Circulation 1982;66:1233-40. DOI: 10.1161/01.cir.66.6.1233; PMID: 6128085 Wathen MS. Prospective randomized multicenter trial of empirical antitachycardia pacing versus shocks for spontaneous rapid ventricular tachycardia in patients with implantable cardioverter-defibrillators: Pacing Fast Ventricular Tachycardia Reduces Shock Therapies (PainFREE Rx II) trial results. Circulation 2004;110:2591-6. DOI: 10.1161/01. cir.0000145610.64014.e4; PMID: 15492306 Moss AJ, Schuger C, Beck CA, et al. Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med 2012;367:2275-83. DOI: 10.1056/ nejmoa1211107; PMID: 23131066 Brouwer TF, Yilmaz D, Lindeboom R, et al. Long-term clinical outcomes of subcutaneous versus transvenous implantable defibrillator therapy. J Am Coll Cardiol 2016;68:2047-55. DOI: 10.1016/j.jacc.2016.08.044; PMID: 27810043

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Diagnostic Electrophysiology & Ablation

Abstract Hypertrophic cardiomyopathy (HCM), the most common genetic cardiomyopathy, is a disease characterised by substantial heterogeneity. Although the majority of patients with HCM remain asymptomatic with near-normal longevity, a small, but important, subset remain at risk for a wide range of clinical outcomes including sudden death. Cardiovascular magnetic resonance (CMR), with its high spatial resolution and tomographic imaging capability, has emerged as an imaging modality particularly well suited to characterise the phenotypic expression of HCM. CMR helps in the diagnosis of HCM by identifying areas of hypertrophy not well visualised by echocardiography, providing more accurate wall thickness measurements and differentiating HCM from other causes of left ventricular (LV) hypertrophy. CMR has led to the identification of novel subgroups of patients with HCM, including those with LV apical aneurysms (a subgroup at increased risk for ventricular arrhythmias and thromboembolic stroke), as well as abnormalities that contribute to LV outflow obstruction. Additionally, contrast-enhanced CMR with late-gadolinium enhancement (LGE) has recognised patients with extensive LGE (≥15 % LV myocardium) as individuals who may be at increased risk of sudden death, independent of other high-risk features, with implications on management strategies including consideration for primary prevention implantable cardioverter defibrillator therapy. These observations justify an expanded role of CMR in the routine clinical assessment of patients with HCM.

Keywords hypertrophic cardiomyopathy, cardiovascular magnetic resonance, sudden death Disclosure: The authors have no conflicts of interest to declare Received: 13 January 2016 Accepted: 18 October 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(3):197–202. DOI: 10.15420/aer.2016:13:3 Correspondence: Ethan J Rowin, Tufts Medical Center, #70, 800 Washington Street, Boston, Massachusetts 02111, USA. E: erowin@tuftsmedialcenter.org

Hypertrophic cardiomyopathy (HCM), the most common genetic cardiomyopathy, is present in one in 500 of the general population and is caused by over 1,400 mutations in at least 11 genes encoding the cardiac sarcomere.1–4 Although the majority of patients with HCM remain asymptomatic with near-normal longevity, a small, but important, subset of patients are at increased risk for a wide range of clinical outcomes including development of advanced heart failure symptoms, atrial and ventricular arrhythmias, thromboembolic events, and even sudden death. 5–8 HCM is characterised by a heterogeneous phenotypic expression with diverse range of extent and pattern of hypertrophy (massive to minimal hypertrophy, that can occur at any location from the apex to the base), 4,9 outflow obstruction (resting, provocable or nonobstructive),10 and left ventricular (LV) systolic function (hyperdynamic to systolic dyfunction).1 Cardiovascular magnetic resonance (CMR), a highresolution 3D tomographic imaging technique that provides sharp contrast between the blood pool and myocardium, has emerged as an imaging technique that is particularly well suited to characterise the diverse morphological expression of this disease (see Figure 1), and is the imaging modality of choice when the diagnosis or morphological characteristic of HCM remains in doubt following echocardiography.1,2,11–13 In addition, contrast-enhanced CMR with late-gadolinium enhancement (LGE) has the capability to identify areas of myocardial fibrosis/scarring with novel data demonstrating that the extent of LGE by CMR may play an important role in risk

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stratification of patients with HCM.14–18 Thereby, it is timely to discuss the specific areas that CMR contributes in the clinical evaluation and risk assessment of patients with HCM.

Diagnosis A diagnosis of HCM is made when unexplained LV hypertrophy (range 13–60 mm; mean 22 mm) occurs in the absence of another disease capable of producing a similar magnitude of hypertrophy.5,6 Therefore, the clinical diagnosis is highly dependent on accurate non-invasive quantification of the LV wall thickness. Traditionally, 2D echocardiography has been the primary imaging modality used in evaluation; however, the echocardiographic examination may provide measurements that appear to fall within the non-diagnostic range (i.e. normal or borderline increase).9 By virtue of its high spatial resolution, CMR allows a more precise assessment of LV wall thickness and areas of hypertrophy. In fact, CMR has identified focal and segmental areas of hypertrophy within the LV that is not reliably identified by 2D echocardiogram, particularly in the anterolateral free wall, apex or posterior septum (see Figure 2).9,19 This is an important consideration as 20 % of patients with HCM have focal areas of hypertrophy, confined to one or two LV segments.4 For these reasons, when a clinical diagnosis of HCM is suspected due to clinical symptoms, electrocardiographic abnormalities or family history, and echocardiography is normal/non-diagnostic, additional testing with CMR should be performed.5

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Diagnostic Electrophysiology & Ablation Figure 1: Cardiovascular Magnetic Resonance Images in Six Patients with Hypertrophic Cardiomyopathy Demonstrating Diverse Phenotypic Expression A

C *

* *

A–C: Short-axis CMR images demonstrating: (A) massive LV hypertrophy (wall thickness of 31 mm) confined to the ventricular septum (asterisk), (B) massive LV hypertrophy (wall thickness of 30 mm) in the inferior septum and inferior wall (asterisk) and (C) mild asymmetric hypertrophy of the septum (asterisk; wall thickness of 16 mm) in a patient with a disease-causing sarcomere mutation in the myosin-binding protein C gene. D: Four-chamber long-axis view demonstrating hypertrophy localised to the LV apex (asterisks). E: Threechamber long-axis view demonstrating muscular midcavitary obstruction attributable to the insertion of anomalous anterolateral papillary muscle directly into anterior leaflet (arrow) contacting the midventricular septum in systole (arrowheads). F: A 24-year-old genotypepositive phenotype-negative man with two deep, narrow myocardial crypts (arrows) in the anterior septum, considered a morphological marker for affected status. Ao = aorta; CMR = cardiovascular magnetic resonance; HCM = hypertrophic cardiomyopathy; LA = left atrium; LV = left ventricle; RV = right ventricle.

Figure 2: Cardiovascular Magnetic Resonance for Hypertrophic Cardiomyopathy Diagnosis A

C RV

Similarly, an overestimation of LV wall thickness may also occur with echocardiography. For example, when the crista supraventricularis, a right ventricular muscle structure, is situated adjacent to the ventricular septum; this structure may be inappropriately included in the septal measurements by echocardiography, an overestimation of wall thickness that can be avoided using CMR.13

Assessment of Family Members with Hypertrophic Cardiomyopathy Screening of all first-degree relatives of patients with HCM is indicated to identify those individuals with potentially unrecognised disease.5,6 Screening should begin at the onset of adolescence, with repeat imaging performed annually (every 12–18 months) throughout adolescence, and then every 5 years until the fourth decade of life, as delayed-onset hypertrophy can also occur later in adulthood. While echocardiography has traditionally been the mainstay test used in screening, the realisation that CMR provides a more precise delineation of LV hypertrophy has led to the increased use as part of the screening evaluations.20,21 This not only allows for more accurate diagnosis, but also a benchmark for future studies to better define the potential progression of LV hypertrophy. The availability of genetic testing in clinical practice has resulted in the identification of family members with HCM who carry a diseasecausing sarcomere mutation (and therefore are at risk of developing phenotypic HCM), but without LV hypertrophy (i.e. genotype positive– phenotype negative [G+P−] patients).20–23 This led to the observation with echocardiography that abnormalities of myocardial function are present in G+P− patients, and the emerging principle that even in the absence of increased LV wall thickness these hearts may be abnormal.21–23 CMR has added to these insights by demonstrating that a number of additional morphological abnormalities may be present including myocardial crypts (see Figure 1F), elongated mitral valve leaflets, expanded extracellular space (with T1 mapping) and LGE.24–27 When genetic testing is negative or ambiguous (as in 60 % of patients), or when not pursued due to financial or personal preference, CMR can identify these abnormalities in the absence of LV hypertrophy, raising suspicion for genotype-positive status among family members.2,21 This should prompt continued close surveillance with serial CMR for development of LV hypertrophy and conversion to clinical disease.

Differentiation of Other Aetiologies of Left Ventricular Hypertrophy

Athlete’s Heart

An asymptomatic 36-year-old woman with a family history of HCM. A: Twelve-lead electrocardiogram was abnormal with incomplete right bundle branch block and anterior and inferior Q waves. B: 2D echocardiogram demonstrated normal LV wall thickness. C: Given abnormal ECG, patient underwent CMR, which reveals an area of segmental hypertrophy in the anterolateral LV wall (asterisk) consistent with a diagnosis of HCM. CMR = cardiovascular magnetic resonance; HCM = hypertrophic cardiomyopathy; LV = left ventricle; RV = right ventricle.

LV hypertrophy associated with systemic training (i.e. athlete’s heart) may be difficult to differentiate from HCM.28,29 The differentiation between athlete’s heart and HCM is critical as HCM is an important cause of sudden death in athletes, responsible for 6–36 % of events.30–32 A variety of different morphological features on CMR may help distinguish HCM from athlete’s heart. Additionally, CMR can evaluate for other structural abnormalities that are also frequently implicated in sudden death of athletes including arrhythmogenic right ventricular cardiomyopathy and myocarditis.30–32 Thereby, a normal CMR provides a further level of reassurance.

Areas of LV hypertrophy may similarly be underestimated by echocardiography, with more accurate measurements made by CMR. This has important management implications as massive hypertrophy (wall thickness ≥30 mm) is an independent risk factor for sudden death in HCM, and in some patients may only be recognised by CMR.2

CMR can help differentiate athlete’s heart from HCM by identification of focal pattern of hypertrophy, a finding supportive of a diagnosis of HCM. In addition, forced deconditioning of an athlete may serve as a useful strategy to resolve diagnosis, with CMR well suited to compare maximum LV wall thickness measurements before and after

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a period of systemic deconditioning. In this regard, a patient whose wall thickness regresses by more than 2 mm supports a diagnosis of athlete’s heart, while hypertrophy that remains present despite deconditioning supports a diagnosis of HCM.33

Figure 3: Cardiovascular Magnetic Resonance for Differentiation of Aetiology of Left Ventricular Hypertrophy Amyloid

Fabry’s Disease

Contrast-enhanced CMR with LGE, provides the opportunity to aid in the differentiation between HCM and athlete’s heart given the ability to non-invasively provide tissue characterisation by means of identifying focal areas of replacement fibrosis and expanded extracellular space. While LGE is present in about half of individuals with HCM, LV remodelling associated with athlete’s heart should not result in focal areas of myocardial scarring/fibrosis, especially in younger individuals.33 Therefore, in an athlete suspected to have HCM, the presence of LGE on contrast-enhanced CMR favours a diagnosis of HCM. In contrast, the absence of LGE cannot be used to reliably exclude the possibility of HCM as this is found in half of patients with a clinical diagnosis of HCM.13

LV RV

Danon Disease

Hypertensive Cardiomyopathy The differentiation of LV hypertrophy due to systemic hypertension from HCM has historically been challenging. CMR can help in differentiation by examining the pattern of hypertrophy, with longstanding systemic hypertension resulting in more concentric hypertrophy (near-identical hypertrophy in septum and lateral wall), while LV wall thickening in HCM is more commonly asymmetric.11–13 This asymmetric pattern favours a diagnosis of HCM over hypertension; however, it should be noted that in some patients with HCM the pattern of hypertrophy may also be symmetrical.11–13 Additionally, presence of LV outflow obstruction due to typical systolic anterior motion of the mitral valve will help sway a diagnosis towards HCM, as this finding is present in over two-thirds of patients with HCM and rarely seen in hypertensive cardiomyopathy.11–13 CMR can also be helpful in the detection of changes in serial measurements of LV wall thickness after aggressive treatment with antihypertensives, in which a regression of hypertrophy would favour a diagnosis of hypertensive cardiomyopathy.

Infiltrative Cardiomyopathy Infiltrative cardiomyopathies, including amyloidosis or glycogen/ lysosmal storage diseases (such as Fabry’s or Danon disease) can mimic clinical HCM as they can produce increased wall thickness as part of their phenotypic expression (see Figure 3).34–36 Although these diseases may have non-cardiac signs and symptoms, disease expression can also be confined only to the heart. The accurate differentiation of these ‘phenocopies’ is critical as treatment strategies and prognosis differs compared with HCM. In amyloidosis, CMR identification of increased LV wall thickness in both the lateral wall as well as the septum combined with global subendocardial LGE is suggestive of cardiac amyloidosis and not typical in HCM.34 Suspicion of Fabry’s disease, an X-linked storage disease in which mutations in the alpha-galactosidase A gene leads to cellular accumulation of glycosphingolipids in multiple organs including the heart, and potentially treatable with enzyme replacement therapy, can be raised by increased LV wall thickness in both the lateral wall and septum with LGE confined to the basal inferolateral wall.35 Danon disease, which is due to mutations in genes that encode the lysosomal-associated membrane protein 2, leads to accumulation of intracellular vacuoles and is a profound and accelerated disease process with rapid clinical deterioration leading commonly to advanced heart failure and sudden death at a young age (commonly <25 years old).36 CMR can be suggestive of the diagnosis in the setting of massive LV hypertrophy with extensive diffuse and often transmural LGE.37 T1 mapping, a novel

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Three different patients referred for evaluation of HCM; CMR in each raised concern for alternative aetiology of LV hypertrophy. A: Pre-contrast short-axis CMR image in a 64-yearold man with increased LV wall thickness in both septum and lateral wall (maximum wall thickness of 18 mm in septum and 14 mm in lateral wall). B: Post-contrast images in the same patient demonstrates early contrast washout with epicardial LGE in septum (arrows) and global subendocardial LGE (arrowheads) leading to concern for amyloidosis. Patient underwent cardiac biopsy confirming a diagnosis of amyloidosis. C: Pre-contrast short-axis CMR image in a 44-year-old woman with increased LV wall thickness in both septum and lateral wall (maximum wall thickness of 16 mm in septum and 13 mm in the lateral wall). D: Post-contrast images in the same patient demonstrate LGE confined to the basal inferolateral wall leading to concern for Fabry’s disease. Patient underwent genetic testing, which revealed a pathogenic mutation in the galactosidase alpha gene confirming the diagnosis. E: Pre-contrast short-axis CMR image in a 21-year-old man demonstrated massive LV hypertrophy (wall thickness of 32 mm) confined to the ventricular septum (asterisk). F: Postcontrast images in the same patient demonstrated transmural LGE throughout the anterior and lateral walls with mid-myocardial LGE throughout the septum in a pattern atypical for HCM and thereby raising concern for Danon Disease. Genetic testing was thereby sent and revealed a pathogenic mutation in the lysosomal-associated membrane protein 2 gene confirming the diagnosis. CMR = cardiovascular magnetic resonance; HCM = hypertrophic cardiomyopathy; LGE = late-gadolinium enhancement; LV = left ventricle; RV = right ventricle.

CMR sequences, has potential to help in the further differentiation of HCM from these infiltrative cardiomyopathies.38,39 Although CMR findings may be suggestive of a phenocopy in a patient undergoing evaluation for HCM, CMR findings in themselves are not diagnostic and must be considered within the clinical contest of an individual patient. Therefore. confirmation with either laboratory testing, molecular genetic analysis or biopsy (either cardiac or another affected tissue) is often ultimately required to make a definitive diagnosis.5,6

Phenotype Characterisation of HCM Left Ventricular Apical Aneurysms Increasing penetration of CMR into routine cardiovascular practice has resulted in more frequent identification of a subset of patients with an unusual phenotype of HCM with thin-walled, scarred LV apical aneurysms (see Figure 4). This important group of patients had been underdiagnosed prior to the application of CMR to HCM, largely based on small- to moderate-sized aneurysms not reliably identified by echocardiography.40 Contrast-enhanced CMR has demonstrated that the aneurysm rim in these patients is composed predominantly of fibrosis that extends from the aneurysm rim into the septum and free wall and serves as nidus for ventricular tachycardia. These changes may place in patients at increased risk of arrhythmic sudden death and thromboembolic stroke (secondary to LV thrombus formation in the aneurysmal cavity).40 Thereby, the identification of LV apical aneurysms may raise important management implications with consideration for implantable cardioverter defibrillator (ICD) therapy as well as systemic anticoagulation for stroke prevention.1,5

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Diagnostic Electrophysiology & Ablation Figure 4: Left Ventricular Scarring Associated with Apical Aneurysm Formation in a Patient with Hypertrophic Cardiomyopathy A

by echocardiography yet are critical as they potentially alter the septal reduction strategy in favour of surgical myectomy, as alcohol septal ablation is unable to address these additional abnormalities.43,44

Risk Stratification

Sudden Death LA

P D

A: Cine steady state-free precession non-contrast two-chamber long-axis CMR image in systole of a thin-walled LV apical aneurysm (arrowheads) with maximal LV wall thickness at midventricular level with muscular apposition of the septum and LV free wall producing distinct proximal (P) and distal (D) chambers. B: Two-chamber end-diastolic images from the same patient after injection of gadolinium contrast showing transmural LGE of the aneurysm rim (arrowheads) with extension into the contiguous anterior and inferior walls (thick arrows). A and B: The LV apical aneurysm contains a sizable intracavitary thrombus attached to the rim of the aneurysm (narrow arrow). CMR = cardiovascular magnetic resonance; HCM = hypertrophic cardiomyopathy; LGE = late-gadolinium enhancement; LA = left atrium; LV = left ventricle.

Figure 5: Pyramid Profile of Risk Stratification Model Currently Used to Identify Patients at the Highest Risk of Sudden Death Who May be Candidates for ICD for Sudden Death Prevention

2° Prevention: Cardiac arrest/sustained VT 1° Prevention: Familial history of HCM-SD Unexplained syncope Multiple-repetitive NSVT Abnormal exercise BP response Massive LVH ≥30 mm LGE ≥15 % of LV mass* Rare subgroups: LV apical aneurysms End-stage HCM (EF <50 %)

ICD Highest

Intermediate

B Lowest LV

RV Major risk markers appear in boxes at the upper left. *Extensive LGE is a potential novel primary risk marker that can also be used as an arbitrator when conventional risk assessment is ambiguous. B. Example of a patient with extensive LGE throughout the septum (arrows) occupying 17 % of LV mass, and without other traditional risk markers. Based on extensive LGE, the patient had ICD placed for primary prevention of sudden death with appropriate ICD discharge for VF 1 year later. EF = ejection fraction; HCM = hypertrophic cardiomyopathy; ICD = implantable cardioverter defibrillator; LGE = late gadolinium enhancement; LV = left ventricular; LVH = left ventricular hypertrophy; NSVT = non-sustained ventricular tachycardia; RV = right ventricle; SD = sudden death; VT = ventricular tachycardia.

Outflow Obstruction Mechanical impedance to LV outflow due to systolic anterior motion of the mitral valve is perhaps the most important cause of limiting heart failure symptoms in HCM.10 The identification of LV outflow obstruction in the setting of drug-refractory severe symptoms is critical as it alters management strategies towards invasive septal reduction therapy with either surgical myectomy or alcohol septal ablation.5,6 CMR allows for precise evaluation of the left ventricular outflow tract (LVOT) and anomalies contributing to outflow obstruction, including anomalous insertion of the anterior papillary muscle directed into the mitral leaflet (see Figure 1e), elongated mitral valve leaflet lengths and muscle bundles that extend from the apex and attach into the basal anterior septum.41,42 The identification of these features may be missed

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Since the initial descriptions of HCM, sudden death has been a highly visible and devastating disease consequence. Fortunately, sudden death is confined to a small subset of patients with HCM within the broad disease spectrum.7,8 Sudden death events occur unpredictable, often without warning signs or symptoms and is most common in young people through mid-life.1 The application of ICD for primary prevention of sudden death in HCM has created the opportunity to prevent these catastrophic events.45 This has placed increased importance on risk stratification to help identify individuals who may benefit from device therapy for primary prevention. The current American College of Cardiology (ACC) and American Heart Association (AHA)-based HCM risk stratification algorithm has relied on five major risk markers (see Figure 5) and has been highly effective in identifying many patients with HCM who will benefit from ICD therapy.5 While this has been instrumental in decreasing rates of sudden death and HCM-related mortality to 0.5 %/ year, some patients without conventional risk markers nevertheless remain at risk of sudden death.7,8 These limitations have led to an interest in additional strategies to improve the current risk model. In this regard, attention has focused on contrast-enhanced CMR with LGE to non-invasively identify myocardial fibrosis, the potential arrhythmogenic substrate in HCM.14–18 Early studies demonstrated that patients with HCM and evidence of LGE on CMR have increased rates of non-sustained ventricular tachycardia on ambulatory Holter monitoring compared with patients without LGE, raising the concept that LGE represents a substrate for generation of malignant ventricular arrhythmias.14 This notion led to several outcome studies, each with relatively small patient cohorts, evaluating the presence of LGE on CMR and demonstrating that patients with HCM with LGE were at increased risk of cardiovascular mortality.16–18 However, LGE is fairly common in patients with HCM, with a prevalence of >50 %, and thereby the use of presence of LGE alone as a sudden death risk marker would lead to over-implantation of ICD for primary prevention.2 Conversely, a large multicentre study with almost 1300 patients with HCM demonstrated that LGE extent is capable of identifying patients at increased sudden death risk and deserving of consideration of ICD placement.15 Extensive LGE, occupying ≥15 % of LV mass, is equivalent to a twofold sudden death risk as compared with no LGE. This increased sudden death risk is present even among patients without other established risk markers and who would otherwise be considered at low risk. Furthermore, when data from this study was pooled with data from a study by Ismail et al.,46 the only other study to report adjusted hazard ratio for the extent of LGE in HCM, the amount of LGE remains independently associated with sudden death risk (adjusted hazard ratio 1.4 for every 10 % increase in LGE of LV mass; and adjusted hazard ratio of 1.6 for 15 % LGE).47 Based on these data, it may be reasonable to consider that patients with HCM with extensive LGE (≥15 % LV myocardium) at increased risk, independent of other high-risk features, with implications on management strategies including consideration for primary prevention ICD therapy (see Figure 5).2,15 Extensive LGE also helps resolve decision making regarding ICD in complex situations when sudden death risk remains ambiguous after

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standard risk stratification, as it can serve as an arbitrator towards ICD placement.15 In contrast, the absence of LGE is associated with lower risk for sudden death and should provide a measure of reassurance.2,15 Therefore, LGE has emerged as a potentially powerful tool to strengthen the ACC/AHA risk stratification model.

Systolic Dysfunction Extensive LGE can also be predictive of progression to the end-stage phase of HCM, characterised by LV remodelling with ventricular cavity dilation, wall thinning secondary to scarring and systolic dysfunction (ejection fraction <50 %).48 Extensive LGE, comprising ≥15 % of total LV mass, also prospectively identifies patients with preserved systolic function who are at risk of heart failure progression due to systolic dysfunction and may require future heart transplantation.15 This recognition can alter management strategies including consideration for altered medical therapy, prophylactic ICD and timely evaluation for heart transplantation once symptoms develop.48

Future Direction: T1 Mapping T1 mapping is a novel and promising CMR technique that provides assessment of the total extent of expanded extracellular space, rather than the detection of regional areas of myocardial fibrosis identified by traditional LGE imaging.49 It has been postulated that T1 mapping may emerge as a diagnostic imaging marker in differentiating pathological cardiovascular diseases such as HCM from that of other forms of LV hypertrophy (such as Fabry’s disease39 or amyloidosis38) and that this technique may prove to be superior to LGE for risk stratification in HCM. However, to date, there has been no link between T1 mapping and cardiovascular outcomes within HCM. In addition, conflicting data exist regarding T1 mapping values in G+P– patients, and if this value can indeed differentiate G+P– patients to normal controls.24,50 Thereby, continued investigations applying T1 mapping to HCM is necessary to better to define the role of this technique.

Maron BJ, Ommen SR, Semsarian C, et al. Hypertrophic cardiomyopathy: present and future, with translation into contemporary cardiovascular medicine. J Am Coll Cardiol 2014;64:83–99. DOI: 10.1016/j.jacc.2014.05.003; PMID: 24998133. Maron MS, Maron BJ. Clinical impact of contemporary cardiovascular magnetic resonance imaging in hypertrophic cardiomyopathy. Circulation 2015;132:292–8. DOI: 10.1161/ CIRCULATIONAHA.114.014283; PMID: 26216086. Wigle ED, Rakowski H, Kimball BP, Williams WG. Hypertrophic cardiomyopathy. Clinical spectrum and treatment. Circulation 1995;92:1680–92. PMID: 7671349. Maron MS, Maron BJ, Harrigan C, et al. Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance. J Am Coll Cardiol 2009;54:220–8. DOI: 10.1016/j.jacc.2009.05.006; PMID: 19589434. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124:e783–831. DOI: 10.1161/CIR.0b013e318223e2bd; PMID: 22068434. Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:2733–79. DOI: 10.1093/eurheartj/ehu284; PMID: 25173338. Maron BJ, Rowin EJ, Casey SA, et al. Hypertrophic cardiomyopathy in children, adolescents, and young adults associated with low cardiovascular mortality with contemporary management strategies. Circulation 2016;133:62–73. DOI: 10.1161/CIRCULATIONAHA.115.017633; PMID: 26518766. Maron BJ, Rowin EJ, Casey SA, et al. Hypertrophic cardiomyopathy in adulthood associated with low cardiovascular mortality with contemporary management strategies. J Am Coll Cardiol 2015;65:1915–28. DOI: 10.1016/ j.jacc.2015.02.061; PMID: 25953744. Rickers C, Wilke NM, Jerosch-Herold M, et al. Utility of cardiac

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10.

11.

12.

13.

14.

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16.

17.

Conclusion Over the last decade, contrast-enhanced CMR has emerged as a powerful imaging tool uniquely suited for the characterisation of the heterogeneous phenotypes in HCM.9–13 CMR provides relevant diagnostic and prognostic information not identifiable with traditional echocardiography.15–19 CMR impacts a variety of clinical management issues ranging from diagnosis and family screening to procedural planning for septal reduction therapy.20,25,38–41 Newer data demonstrate that extensive LGE, occupying ≥15 % LV myocardium, identifies patients at an increased sudden death risk and these patients may ultimately benefit from ICD placement for primary prevention.2,15 These observations help to justify an expanded role of CMR in the routine assessment of patients with HCM. ■

Clinical Perspective • Contrast-enhanced CMR has emerged as a power imaging tool uniquely suited for the characterisation of the heterogeneous phenotypes in HCM. • CMR helps to diagnose HCM given its abilities to identify areas of hypertrophy that is not well visualised by echocardiography, to provide more accurate wall thickness measurements and to differentiate other aetiologies of LV hypertrophy. • Contrast-enhanced CMR with LGE has identified patients with extensive LGE, occupying ≥15 % LV myocardium. Based on data from a recent large multicentre study, it may be reasonable to consider that these patients are at increased risk of sudden death, independent of other high-risk features, with implications on management strategies including consideration for primary prevention ICD therapy. • These observations help to justify an expanded role of CMR in the routine clinical assessment of patients with HCM.

magnetic resonance imaging in the diagnosis of hypertrophic cardiomyopathy. Circulation 2005;112:855–61. DOI: 10.1016/ j.jacc.2015.02.061; PMID: 25953744. Maron BJ, Maron MS, Wigle ED, Braunwald E. The 50-year history, controversy, and clinical implications of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy from idiopathic hypertrophic subaortic stenosis to hypertrophic cardiomyopathy: from idiopathic hypertrophic subaortic stenosis to hypertrophic cardiomyopathy. J Am Coll Cardiol 2009;54:191–200. DOI: 10.1016/j.jacc.2008.11.069; PMID: 19589431. Noureldin RA, Liu S, Nacif MS, et al. The diagnosis of hypertrophic cardiomyopathy by cardiovascular magnetic resonance. J Cardiovasc Mag Reson 2012;14:17. DOI: 10.1186/1532-429X-14-17; PMID: 22348519. To AC, Dhillon A and Desai MY. Cardiac magnetic resonance in hypertrophic cardiomyopathy. JACC Cardiovasc Imaging 2011;4:1123–37. DOI: 10.1016/j.jcmg.2011.06.022; PMID: 21999873. Maron MS. Clinical utility of cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J Cardiovasc Mag Reson 2012;14:13. DOI: 10.1186/1532-429X-14-13; PMID: 22296938. Adabag AS, Maron BJ, Appelbaum E, et al. Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic resonance. J Am Coll Cardiol 2008;51:1369–74. DOI: 10.1016/ j.jacc.2007.11.071; PMID: 18387438. Chan RH, Maron BJ, Olivotto I, et al. Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy. Circulation 2014;130:484–95. DOI: 10.1161/CIRCULATIONAHA.113.007094; PMID: 25092278. Bruder O, Wagner A, Jensen CJ, et al. Myocardial scar visualized by cardiovascular magnetic resonance imaging predicts major adverse events in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2010;56:875–87. DOI: 10.1016/j.jacc.2010.05.007; PMID: 20667520. Green JJ, Berger JS, Kramer CM, Salerno M. Prognostic value of late gadolinium enhancement in clinical outcomes for hypertrophic cardiomyopathy. JACC Cardiovasc Imaging 2012;5:370–7. DOI: 10.1016/j.jcmg.2011.11.021; PMID:

22498326. 18. O’Hanlon R, Grasso A, Roughton M, et al. Prognostic significance of myocardial fibrosis in hypertrophic cardiomyopathy. J Am Coll Cardiol 2010;56:867–74. DOI: 10.1016/j.jacc.2010.05.010; PMID: 20688032. 19. Moon JC, Fisher NG, McKenna WJ, Pennell DJ. Detection of apical hypertrophic cardiomyopathy by cardiovascular magnetic resonance in patients with non-diagnostic echocardiography. Heart 2004;90:645–9. PMID: 15145868. 20. Valente AM, Lakdawala NK, Powell AJ, et al. Comparison of echocardiographic and cardiac magnetic resonance imaging in hypertrophic cardiomyopathy sarcomere mutation carriers without left ventricular hypertrophy. Circ Cardiovasc Genet 2013;6:230–7. DOI: 10.1161/CIRCGENETICS.113.000037; PMID: 23690394. 21. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol 2012;60:705–15. DOI: 10.1016/j.jacc.2012.02.068; PMID: 22796258. 22. Seidman CE, Seidman JG. Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: a personal history. Circ Res 2011;108:743–50. DOI: 10.1161/ CIRCRESAHA.110.223834; PMID: 21415408. 23. Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J Am Coll Cardiol 2009;54: 201–11. DOI: 10.1016/j.jacc.2009.02.075; PMID: 19589432. 24. Ho CY, Abbasi SA, Neilan TG, et al. T1 measurements identify extracellular volume expansion in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy. Circ Cardiovasc Imaging 2013;6:415–22. DOI: 10.1161/CIRCIMAGING.112.000333; PMID: 23549607. 25. Rowin EJ, Maron MS, Lesser JR, Maron BJ. CMR with late gadolinium enhancement in genotype positive-phenotype negative hypertrophic cardiomyopathy. JACC Cardiovasc Imaging 2012;5:119–22. DOI: 10.1016/j.jcmg.2011.08.020; PMID: 22239901. 26. Maron MS, Rowin EJ, Lin D, et al. Prevalence and clinical profile of myocardial crypts in hypertrophic cardiomyopathy. Circ Cardiovasc Imaging 2012;5:441–7. DOI: 10.1161/

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Diagnostic Electrophysiology & Ablation CIRCIMAGING.112.972760; PMID: 22563033. 27. Brouwer WP, Germans T, Head MC, et al. Multiple myocardial crypts on modified long-axis view are a specific finding in pre-hypertrophic HCM mutation carriers. Eur Heart J Cardiovasc Imaging 2012;13:292–7. DOI: 10.1093/ehjci/jes005; PMID: 22277119. 28. Maron BJ, Udelson JE, Bonow RO, et al. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 3: Hypertrophic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy and Other Cardiomyopathies, and Myocarditis: A Scientific Statement From the American Heart Association and American College of Cardiology. Circulation 2015;132:e273–80. DOI: 10.1161/ CIR.0000000000000239; PMID: 26621644. 29. Pelliccia A, Maron MS, Maron BJ. Assessment of left ventricular hypertrophy in a trained athlete: differential diagnosis of physiologic athlete’s heart from pathologic hypertrophy. Prog Cardiovasc Dis 2012;54:387–96. DOI: 10.1016/ j.pcad.2012.01.003; PMID: 22386289. 30. Maron BJ, Doerer JJ, Haas TS, et al. Sudden deaths in young competitive athletes: Analysis of 1866 deaths in the united states, 1980-2006. Circulation 2009;119:1085–92. DOI: 10.1161/ CIRCULATIONAHA.108.804617; PMID: 19221222. 31. Harmon KG AI, Maleszewski JJ, Owens DS, et al. Incidence, etiology, and comparative frequency of sudden cardiac death in National Collegiate Athletic Associationathletes: A decade in review. Circulation 2015;132:10–9. DOI: 10.1161/ CIRCULATIONAHA.115.015431; PMID: 25977310. 32. Finocchiaro G, Papadakis M, Robertus JL, et al. Etiology of sudden death in sports: Insights from a United Kingdom regional registry. J Am Coll Cardiol 2016;67:2108–15. DOI: 10.1016/j.jacc.2016.02.062. PMID: 27151341. 33. Caselli S, Maron MS, Urbano-Moral JA, et al. Differentiating left ventricular hypertrophy in athletes from that in patients with hypertrophic cardiomyopathy. Am J Cardiol 2014;114:1383–9. DOI: 10.1016/j.amjcard.2014.07.070; PMID: 25217454. 34. Maceira AM, Joshi J, Prasad SK, et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005;111:186–93. DOI: 10.1161/01.CIR.0000152819.97857.9D; PMID: 15630027.

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35. Moon JC, Sachdev B, Elkington AG, et al. Gadolinium enhanced cardiovascular magnetic resonance in AndersonFabry disease. Evidence for a disease specific abnormality of the myocardial interstitium. Eur Heart J 2003;24:2151–5. PMID: 14643276. 36. Maron BJ, Roberts WC, Arad M, et al. Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy. JAMA 2009;301:1253–9. DOI: 10.1001/jama.2009.371; PMID: 19318653. 37. Piotrowska-Kownacka D, Kownacki L, Kuch M, et al. Cardiovascular magnetic resonance findings in a case of Danon disease. J Cardiovasc Mag Reson 2009;11:12. DOI: 10.1186/1532-429X-11-12; PMID: 19402899. 38. Sado DM, Flett AS, Banypersad SM, et al. Cardiovascular magnetic resonance measurement of myocardial extracellular volume in health and disease. Heart 2012;98:1436–41. DOI: 10.1136/heartjnl-2012-302346; PMID: 22936681. 39. Sado DM, White SK, Piechnik SK, et al. Identification and assessment of Anderson-Fabry disease by cardiovascular magnetic resonance noncontrast myocardial T1 mapping. Circ Cardiovasc Imaging 2013;6:392–8. DOI: 10.1161/ CIRCIMAGING.112.000070; PMID: 23564562. 40. Maron MS, Finley JJ, Bos JM, et al. Prevalence, clinical significance, and natural history of left ventricular apical aneurysms in hypertrophic cardiomyopathy. Circulation 2008;118:1541–9. DOI: 10.1161/CIRCULATIONAHA.108. 781401; PMID: 18809796. 41. Rowin EJ, Maron BJ, Lesser JR, et al. Papillary muscle insertion directly into the anterior mitral leaflet in hypertrophic cardiomyopathy, its identification and cause of outflow obstruction by cardiac magnetic resonance imaging, and its surgical management. Am J Cardiol 2013;111:1677–9. DOI: 10.1016/j.amjcard.2013.01.340; PMID: 23499271. 42. Maron MS, Olivotto I, Harrigan C, et al. Mitral valve abnormalities identified by cardiovascular magnetic resonance represent a primary phenotypic expression of hypertrophic cardiomyopathy. Circulation 2011;124:40–7. DOI: 10.1161/CIRCULATIONAHA.110.985812; PMID: 21670234. 43. Balaram SK, Ross RE, Sherrid MV, et al. Role of mitral valve

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plication in the surgical management of hypertrophic cardiomyopathy. Ann Thorac Surg 2012;94:1990–7. DOI: 10.1016/j.athoracsur.2012.06.008; PMID: 22858269. Patel P, Dhillon A, Popovic ZB, et al. Left ventricular outflow tract obstruction in hypertrophic cardiomyopathy patients without severe septal hypertrophy: implications of mitral valve and papillary muscle abnormalities assessed using cardiac magnetic resonance and echocardiography. Circ Cardiovasc Imaging 2015;8:e003132. DOI: 10.1161/ CIRCIMAGING.115.003132; PMID: 26082555. Maron BJ, Spirito P, Shen WK, et al. Implantable cardioverterdefibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA 2007;298:405–12. DOI: 10.1001/jama.298.4.405; PMID: 17652294. Ismail TF, Jabbour A, Gulati A, et al. Role of late gadolinium enhancement cardiovascular magnetic resonance in the risk stratification of hypertrophic cardiomyopathy. Heart 2014;100:1851–8. DOI: 10.1136/heartjnl-2013-305471; PMID: 24966307. Weng Z, Yao J, Chan RH, et al. Prognostic value of LGE-CMR in HCM: A Meta-Analysis. JACC Cardiovasc Imaging 2016;pii: S1936-878X(16)30406-5. DOI: 10.1016/j.jcmg.2016.02.031; PMID: 27450876. Harris KM, Spirito P, Maron MS, et al. Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation 2006;114:216–25. DOI: 10.1161/CIRCULATIONAHA.105.583500; PMID: 16831987. Moon JC, Messroghli DR, Kellman P, et al. Myocardial T1 mapping and extracellular volume quantification: a Society for Cardiovascular Magnetic Resonance (SCMR) and CMR Working Group of the European Society of Cardiology consensus statement. J Cardiovasc Mag Reson 2013;15:92. DOI: 10.1186/1532-429X-15-92; PMID: 24124732. Hinojar R, Varma N, Child N, et al. T1 mapping in discrimination of hypertrophic phenotypes: hypertensive heart disease and hypertrophic cardiomyopathy: Findings from the International T1 Multicenter Cardiovascular Magnetic Resonance Study. Circ Cardiovasc Imaging 2015;8: pii: e003285. DOI: 10.1161/CIRCIMAGING.115.003285; PMID: 26659373.

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Diagnostic Electrophysiology & Ablation

Abstract Idiopathic ventricular arrhythmias (VAs) are ventricular tachycardias (VTs) or premature ventricular contractions (PVCs) with a mechanism that is not related to myocardial scar. The sites of successful catheter ablation of idiopathic VA origins have been progressively elucidated and include both the endocardium and, less commonly, the epicardium. Idiopathic VAs usually originate from specific anatomical structures such as the ventricular outflow tracts, aortic root, atrioventricular (AV) annuli, papillary muscles, Purkinje network and so on, and exhibit characteristic electrocardiograms based on their anatomical background. Catheter ablation of idiopathic VAs is usually safe and highly successful, but can sometimes be challenging because of the anatomical obstacles such as the coronary arteries, epicardial fat pads, intramural and epicardial origins, AV conduction system and so on. Therefore, understanding the relevant anatomy is important to achieve a safe and successful catheter ablation of idiopathic VAs. This review describes the anatomical consideration in the catheter ablation of idiopathic VAs.

Keywords Anatomy, electrocardiogram, idiopathic, ventricular tachycardia, premature ventricular contraction, catheter ablation Disclosure: The authors have no conflicts of interest to declare. Received: 17 September 2016 Accepted: 01 November 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(3):203–9. DOI: 10.15420/aer.2016:31:2 Correspondence: Takumi Yamada, Division of Cardiovascular Disease, University of Alabama at Birmingham, FOT 930A, 510 20th Street South, Birmingham, AL 352940019, US. E: takumi-y@fb4.so-net.ne.jp

Idiopathic ventricular arrhythmias (IVAs) usually originate from the specific anatomical structures. For the past decade, major IVA origins from both endocardial and epicardial sites have been increasingly recognised (see Table 1).1–3 Catheter ablation of IVAs is usually safe and highly successful, but can sometimes be challenging because of the anatomical obstacles. Therefore, understanding the relevant anatomy is important to achieve a safe and successful catheter ablation of IVAs. This review describes the anatomical considerations in catheter ablation of IVAs.

Idiopathic Ventricular Arrhythmia Origins Relevant to the Anatomy The most common site of IVA origins is the ventricular outflow tract.3,4 IVAs originate more often from the right ventricular outflow tract (RVOT) than from the left ventricular outflow tract (LVOT). In the RVOT, the septum is a more common site of IVA origins than the free wall. The most common site of IVA origins in the LVOT is the aortic root followed by the sites underneath the aortic coronary cusps (see Figure 1A).5,6 Especially, the site underneath the left coronary cusp (LCC) is termed the aortomitral continuity (AMC). The mitral annulus is also one of the major sites of IVA origins.7,8 The anteromedial aspect of the mitral annulus continues to join the AMC. Anatomically, the aortic and mitral valves are in direct apposition and attach to the elliptical opening at the base of the left ventricle (LV) known as the LV ostium (see Figure 1A).9,10 As there is no myocardium between the aortic and mitral valves (fibrous trigone), LV IVAs usually originate from along the LV ostium. The LV myocardium comes in direct contact with the aorta at the base of the aortic coronary cusps (see Figure 1A).

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When IVAs arise from the most superior portion of the LV ostium (the aortic sinuses of Valsalva), they can be ablated at the base of the aortic coronary cusps. Some IVAs can be ablated from the junction (commissure) between the left and right coronary cusps (L-RCC).11 In these IVAs, catheter ablation from underneath the aortic coronary cusps is often required for their elimination. Anatomically, the superior end of the LV myocardium makes a semi-circular attachment to the aortic root at the bottom of the right and left coronary cusps. However, because of the semilunar nature of the attachments of the aortic coronary cusps, the superior end of the LV myocardium is located underneath the aortic valves at the L-RCC (see Figure 1A). Therefore, IVAs that can be ablated at the L-RCC should be classified into the same group as the IVAs that can be ablated within the aortic coronary cusps. In this setting, these IVAs may be defined as IVAs arising from the aortic root.6 IVAs can rarely be ablated from within the non-coronary cusp (NCC) of the aorta.6,12,13 Spatially, the aortic root occupies a central location within the heart, with the NCC anterior and superior to the paraseptal region of the atria close to the superior atrioventricular (AV) junctions (see Figure 1B).10 In normal human hearts, the NCC is adjacent to the atrial myocardium on the epicardial aspect and the NCC does not usually come into direct contact with the ventricular myocardium (see Figure 1B). Indeed, atrial tachycardias that can be ablated from within the NCC are far more common than ventricular arrhythmias (VAs). However, the clinical observation that a non-coronary sinus of Valsalva aneurysm can rupture into the right ventricle (RV) as well as the right atrium, supports the assumption that the NCC may be attached to the ventricular myocardium from which IVAs can arise.12 IVAs can arise from the pulmonary artery with

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Diagnostic Electrophysiology & Ablation Table 1: Idiopathic Ventricular Arrhythmia Origins

RV LV

Outflow tract region Supravalvular

Aorta*

Endocardial

RVOT

LVOT (AMC)*

Epicardial

LV summit*

(GCV, AIVV)

Annuli

MA*

TA (Peri-Hisian)

Fascicles

LPF >> LAF

Upper septum

Intracavital

PAM

PPAM >> APAM

Moderator band

Epicardium

Crux (MCV)

*LV ostium. AIVV = anterior interventricular vein; AMC = aortomitral continuity; APAM = anterolateral papillary muscle; GCV = great cardiac vein; LAF = left anterior fascicle; LPF = left posterior fascicle; LV = left ventricle; LVOT = LV outflow tract; MA = mitral annulus; MCV = mid-cardiac vein; PA = pulmonary artery; PAM = papillary muscle; PPAM = postero-medial papillary muscle; RV = right ventricle; RVOT = RV outflow tract; TA = tricuspid annulus. Modified with permission from Yamada, 2016.8

Figure 1: Computed Tomography Images Exhibiting the Anatomy Around the Aorta A

along the mitral annulus, but the anterolateral and postero-septal aspects of the mitral annulus are the most common and second most common sites of mitral annular IVA origins, respectively.7,8 Tricuspid annular IVAs can originate from any region along the tricuspid annulus, but more often originate from the septal aspect, especially in the anteroseptal or para-Hisian region than the free wall.15 IVAs can arise from intracavitary structures including the papillary muscles16–20 and moderator band.21 LV papillary muscle IVAs are known to arise more commonly from the postero-medial papillary muscle than the anterolateral papillary muscle.18 The sites of the papillary muscle IVA origins are limited to the base of the papillary muscles. IVAs can rarely originate from the papillary muscles in the RV (see Figure 2).20 IVAs can arise from all three RV papillary muscles, though half arise from the septal papillary muscle.20 Although more rare, the moderator band can be a source of IVAs including premature ventricular contractions (PVCs), ventricular tachycardias (VTs) and ventricular fibrillation.21 Anatomically, the moderator band is considered to be a part of the septomarginal trabeculation, crossing from the septum to the RV free wall and supporting the anterior papillary muscle of the tricuspid valve (see Figure 2).21 IVAs can arise from the Purkinje network, most commonly from the left posterior fascicle followed by the anterior and septal fascicles.19,22,23 The anterior fascicle runs along the mitral annulus, and the peripheral Purkinje network extends to the surface of the papillary muscles and moderator band. Therefore, these IVAs have to be differentiated from IVAs originating from the papillary muscles, moderator band and AV annuli. IVAs usually arise from the endocardium, but can also arise from the epicardium,24 and rarely from the intramural site.25 There are two

A: Two-dimensional computed tomography images showing the relationships between the ventricular myocardium and aortic sinus cusps. The arrowheads indicate the superior edge of the ventricular myocardium connecting with the left coronary cusp and right coronary cusp (RCC), and the dotted line indicates the ventriculo-arterial junction (the ostium of the left ventricle). Reproduced with permission from Yamada, et al., 2008.6 B: Two-dimensional (Right Panel) and three-dimensional (Left Panel) computed tomography images The dotted line indicates the tricuspid annulus and solid circle the right ventricular His bundle (HB) region. Reproduced with permission from Yamada, et al., 2008.13 Ant. = anterior; Ao = aorta; IAS = interatrial septum; L = left coronary cusp; LA = left atrium; LCA = left coronary artery; LV = left ventricle; MV = mitral valve; NCC/N = non-coronary cusp; R/RCC = right coronary cusp; RA = right atrium; RCA = right coronary artery; RV = right ventricle; SVC = superior vena cava.

major sites of epicardial IVA origins such as the crux of the heart26 and LV summit.27 Anatomically, the crux of the heart is formed by the junction of the AV groove and posterior interventricular groove, and corresponds roughly to the junction of the middle cardiac vein and coronary sinus (CS), near the origin of the posterior descending coronary artery (see Figure 3A).26 A region of the LV epicardial surface that occupies the most superior portion of the LV has been termed the LV summit by McAlpine (see Figure 3B).9,27 The LV summit is a triangular region bounded by the left anterior descending coronary artery anteriorly and left circumflex coronary artery posteriorly, and an imaginary arch sweeping from the first septal coronary artery across the lateral LV epicardium to the left AV groove. The great cardiac vein (GCV), which continues to become the anterior interventricular cardiac vein (AIVV) bisects the LV summit. The portion of the LV summit lateral to the GCV is accessible to epicardial catheter ablation (the accessible area). The region of the LV summit superior to the GCV is generally inaccessible to catheter ablation due to the close proximity of the coronary arteries and the thick layer of epicardial fat that overlies the proximal portion of these vessels (the inaccessible area).27

Mapping and Catheter Ablation of the Specific Idiopathic Ventricular Arrhythmia Origins Ventricular Outflow Tracts and Aortic Root

a ventricular myocardial extension from the RVOT.14 It should be noted that ventricular myocardial extensions never occur in the aorta.10 IVAs can originate from the AV annuli including the mitral annulus7,8 and tricuspid annulus.15 Mitral annular IVAs can originate from any regions

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Anatomically, the RVOT and LVOT are located next to each other, and it is often difficult to predict IVA origins from the RVOT or LVOT by the electrocardiograms prior to the procedure. Therefore, mapping in the RV should be first performed in all patients with IVAs exhibiting a left bundle branch block QRS morphology. Activation mapping seeking the

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Anatomical Consideration in Idiopathic Ventricular Arrhythmia Ablation

Figure 2: Autopsy Hearts Exhibiting the Right Ventricular Papillary Muscles and Moderator Band

Figure 3: The Sites of Epicardial Idiopathic Ventricular Arrhythmia Origins A

AMV = anterior mitral valve; Ao = aorta; APM = anterior papillary muscle; IPM = inferior papillary muscle; LV = left ventricle; MB = moderator band; RVOT = right ventricular outflow tract. Reproduced from McAlpine, 19759 with courtesy from the UCLA collection.

earliest bipolar activity and/or a local unipolar QS pattern during IVAs is most reliable for identifying a site of an IVA origin. Pace mapping is especially helpful for RVOT IVAs,1,2 but is less helpful for aortic root IVAs because pacing within the aortic coronary cusps may not exactly reproduce the QRS morphology of the IVAs due to preferential conduction across the ventricular septum28 or the inability to obtain myocardial capture despite the use of a high pacing current. When there are no suitable sites for ablation in the RV or when RV catheter ablation is unsuccessful, mapping in the aortic coronary cusps and LVOT should follow. As the posterior portion of the RVOT is in close apposition to the LV near the aortic root, when catheter ablation has not been successful in the LVOT, the RV should be carefully remapped before determining that an epicardial approach is required.

Before mapping and catheter ablation within the aortic coronary cusps, selective angiography of the coronary artery and aorta should be performed to carefully determine the coronary artery ostia in the aortic coronary cusps, to precisely define the location of the ablation catheter and to avoid arterial injury (see Figure 4).2,6,10 Calcifications of the coronary arteries in older patients may also facilitate delineation of the ostia of the coronary arteries. The three aortic coronary cusps can be readily identified during biplane aortography or coronary angiography. The LCC is most easily identified in the left anterior oblique (LAO) projection where this cusp is on the far lateral aspect of the aortic root, leftward and superior to the His bundle (HB) catheter (see Figure 4A). The RCC usually requires coronary angiography in both the right anterior oblique (RAO) and LAO projections for an accurate identification of the cusp relative to the right coronary artery (RCA) ostium (see Figure 4B). In the RAO projection, the ablation catheter is typically located anterior and inferior to the RCA ostium. In the LAO projection, the typical ablation site is more leftward in the RCC than the RCA ostium. The NCC is readily identified as the most inferior of the three cusps and by its close relation to the HB catheter (see Figure 4C). In the RAO projection, a catheter in the NCC is posterior and inferior to the RCA ostium, just above the HB catheter. In the LAO projection, the NCC is just superior to the HB catheter, well posterior to the RCA ostium. As the NCC overlies the atrial septum, the amplitude of an atrial electrogram is usually larger than that of the ventricular electrogram within the NCC. A ventricular pre-potential preceding the QRS onset is often recorded at the aortic root during IVAs and it may predict a successful ablation

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A: Autopsy heart exhibiting the crux of the heart. The dotted circle indicates the area where crux ventricular arrhythmias originate from. Reproduced with permission from McAlpine, 1975,9 with courtesy from the UCLA collection. B: Computed tomography (left panels) and fluoroscopic (right panels) images exhibiting the left ventricular summit. The left ventricular summit was defined based on the fluoroscopy and coronary angiography as the region on the epicardial surface of the left ventricle (LV) near the bifurcation of the left main coronary artery that is bounded by an arc (black dotted line) from the left anterior descending coronary artery (LAD) superior to the first septal perforating branch (black arrowheads) and anteriorly to the left circumflex coronary artery laterally. The great cardiac vein bisects the left ventricular summit into a superior portion surrounded by the white dotted line (the inaccessible area) and an inferior portion surrounded by the red dotted line (the accessible area). The white arrowheads indicate the first diagonal branch of the LAD. Reproduced with permission from Yamada, et al., 2010.27 ABL = ablation catheter; AIVV = anterior interventricular cardiac vein; Ao = aorta; CS = coronary sinus; GCV = great cardiac vein; HB = His bundle; LAA = left atrial appendage; LAD = left anterior descending coronary artery; LAO = left anterior oblique projection; LCA = left coronary artery; LCx = left circumflex coronary artery; LMCA = left main coronary artery; LV = left ventricle; MV = mitral valve; PA = pulmonary artery; PDA = posterior descending coronary artery; RAO = right anterior oblique; RCA = right coronary artery; RV = right ventricle; TV = tricuspid valve.

site.6,15 Pacing within the aortic coronary cusps often exhibits a long stimulus to QRS interval (more likely in the LCC than the RCC) whereas pacing below the aortic valves gives no latency between the pacing stimulus and QRS onset.6,10

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Diagnostic Electrophysiology & Ablation Figure 4: Coronary Angiograms and the Catheter Positions

anterior or posterior fascicle (posterior fascicle is more prevalent).22,23 It has been suggested that Purkinje tissue forms an important part of this reentrant VT circuit.22,23 Based on this anatomical and electrophysiological background, mapping for ablation is performed around the anatomical location of the involved fascicle seeking a discrete Purkinje potential that precedes the QRS complex during VT.22,23 Ablation at a basal site may be complicated with left bundle branch block. Therefore, catheter ablation should start from an apical site and shift toward a basal site until successful ablation is achieved. Catheter-induced trauma to the substrate may sometimes render the IVAs non-inducible, resulting in ablation failure. Left fascicular VTs are frequently not inducible or non-sustained at the time of the planned catheter ablation. In such a case, mapping and ablation targeting retrograde Purkinje potentials recorded at the mid-inferior septum during sinus rhythm may be an alternative approach.29 A linear RFCA strategy guided by the presence of Purkinje potentials during sinus rhythm, with pace mapping as an additional guide may also be effective.30 A linear radiofrequency lesion set is placed perpendicular to the long axis of the LV, approximately midway from the base to the apex in the region of the mid to mid-inferior septum. This approach may be complicated with left posterior fascicular block.

Papillary Muscles

A: The left main coronary angiogram. B: The right coronary angiograms. C: The right coronary angiograms with the ablation catheter within the non-coronary cusp. Note that the typical site of the successful catheter ablation within the left coronary cusp and right coronary cusp is at the nadir of those cusps. Ant. = anterior; CS = coronary sinus; HB = His bundle; LAD = left anterior descending coronary artery; LAO = left anterior oblique; LCC = left coronary cusp; LCx = left circumflex coronary artery; LMCA = left main coronary artery; NCC = non-coronary cusp; Post. = posterior; RAO = right anterior oblique; RCA = right coronary artery; RCC = right coronary cusp; RV = right ventricle; RVOT = right ventricular outflow tract. Reproduced with permission from Yamada, et al., 2008.10

In the aortic coronary cusps, radiofrequency catheter ablation (RFCA) is applied under continuous fluoroscopic observation with an angiographic catheter positioned within the ostium of the coronary artery. The outline of the aortic coronary cusps and flow in the coronary artery are intermittently observed by hand injections of contrast. RFCA should be avoided within 5 mm of the coronary artery. There is a potential risk of aortic insufficiency.

RFCA of papillary muscle IVAs is very challenging as compared with that of the other IVAs, probably because of the deep location of the origin relative to the endocardial surface of the papillary muscles, and the difficulty in maintaining stable contact of the catheter tip at the papillary muscles with the vigorous motion associated with normal contraction of the papillary muscles.16â&#x20AC;&#x201C;18 As a result of a deep origin of the papillary muscle IVAs, suppression of papillary muscle IVAs by a mechanical compression is rare, and instead, touching of a mapping catheter on the papillary muscles easily induces PVCs, which preclude activation mapping. A retrograde transaortic approach is usually used for mapping and catheter ablation of LV papillary muscle IVAs. A transseptal approach may be used to improve the contact and stability of the ablation catheter on the postero-medial papillary muscle during mapping of LV postero-medial papillary muscle IVAs,8 although that is not an option for mapping of LV anterolateral papillary muscle IVAs. For identifying the papillary muscle IVA origin, activation mapping is the most reliable method. Although pace mapping usually provides helpful clues in IVAs, a discrete radiofrequency lesion at the site with an excellent pace map is likely to fail to eliminate the papillary muscle IVAs. Instead, there is often a change in the QRS morphology after a radiofrequency application, probably because the site of the papillary muscle IVA origin may be located away from the breakout site, which can be recognised as the site with the best pace map. When the patient does not have an excellent pace map, further radiofrequency lesions will be required to completely eliminate the papillary muscle IVAs as compared with that in the patients with an excellent pace map because there should be no discrete breakout sites from a deeper IVA origin.

Purkinje System IVAs can originate from the Purkinje system with a focal or reentrant mechanism. When IVAs originate from the Purkinje network, a Purkinje potential always precedes the QRS onset during IVAs, and is also recorded during sinus rhythm at the successful ablation sites. Left fascicular VTs occur with a reentrant mechanism involving the left

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The creation of a deep radiofrequency lesion may be necessary for the long term success of the catheter ablation of papillary muscle IVAs because of the distance between the papillary muscle IVA origin and endocardial surface. Therefore, the use of high radiofrequency power settings delivered from an irrigated tip ablation catheter is

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strongly recommended in the catheter ablation of papillary muscle IVAs. Understanding the fluoroscopic location of the papillary muscles with an LV electrogram is helpful, but an intensive monitoring with transthoracic and intracardiac echocardiography and/or a three-dimensional mapping system should be used as a guide for mapping.16â&#x20AC;&#x201C;18,31

be attempted for mitral annular IVAs. At the successful ablation site of mitral annular and tricuspid annular IVAs, an atrial electrogram is usually recorded, and the ratio of the local atrial to ventricular electrograms should be <1.7,8,15 There is a potential risk of mitral and tricuspid insufficiency in the catheter ablation of mitral annular and tricuspid annular IVAs, respectively.

Patients with papillary muscle IVAs often exhibit variable QRS morphologies spontaneously and/or after the initial ablation lesions.18 The altered QRS morphologies of papillary muscle IVAs after the ablation may guide the following mapping and catheter ablation. Understanding the relationship between the changes in the QRS morphology and a shift in the breakout site to the opposite side of the papillary muscle may be helpful for determining the next target of the mapping and ablation. In these patients, radiofrequency lesions on both sides of the papillary muscles are often required to eliminate all variations in the QRS morphology. These differences in the QRS morphologies are compatible with the differences in the direction of the vector of the propagating wavefront from the successful ablation sites on both sides of the papillary muscles and can be reproduced by pacing from those sites. In these patients, a single IVA origin with preferential conduction to multiple exit sites is likely to operate with anisotropic conduction from the anatomic background that the LV papillary muscles are composed of a complex of myocardial strands with some separations between them on the basal and apical sides. Therefore, in some of these patients, radiofrequency lesions at a single site can eliminate all spontaneous QRS morphologies.

The earliest ventricular activation within the CS is usually pre-systolic during the mitral annular IVAs.7,8 Mapping should be performed underneath the mitral valve around the electrode of the CS catheter, recording the earliest ventricular activation with an ablation catheter through a retrograde transaortic approach. However, a transseptal approach may sometimes be required for better mapping in the posterior to postero-septal aspects of the mitral annulus. In either case, ablation should be performed with the ablation electrode in direct contact with the endocardium rather than through the mitral valve itself. Epicardial catheter ablation within the CS is rarely required for elimination of mitral annular IVAs, when endocardial catheter ablation is unsuccessful.

A low-amplitude ventricular pre-potential is often recorded at the successful ablation site. The mechanisms in the papillary muscle IVAs addressed above can also explain the presence of these pre-potentials and the possibility of isolating that pre-potential was demonstrated in one case study.32 Although a ventricular pre-potential is also often recorded at the successful ablation site of IVAs arising from the LV ostium,10 the mechanism of those ventricular pre-potentials is likely to differ between papillary muscle IVAs and LV ostial IVAs. In LV ostial IVAs, the first ventricular potential is a near-field electrogram representing the activation at the site of the IVA origin, while the second ventricular potential is a far-field electrogram representing the activation of the larger myocardial mass around the VA origin. On the other hand, for papillary muscle IVAs, the first ventricular potential is more likely a far-field electrogram representing the activation of the IVA origin deep under the surface of the papillary muscles, while the second ventricular potential is a near-field electrogram representing activation of the surface myocardium of the papillary muscle. Complications are rare in the catheter ablation of papillary muscle IVAs. However, frequent VTs originating from the papillary muscle of the ablation target often occur during the RFCA. The mechanism of these VTs is unclear, but an acceleration of the papillary muscle VTs resulting from a thermal effect or mechanical stimulation on the papillary muscles is likely to be its cause. It should be noted that these VTs can rarely lead to ventricular fibrillation.33 There is a potential risk of mitral insufficiency. In addition, the risk of recurrence after initially successful ablation is higher for papillary muscle IVAs than for the other IVAs.

Mitral and Tricuspid Annuli In order to identify the site of mitral annular and tricuspid annular IVA origins, activation mapping is the most reliable, but pace mapping is helpful when IVAs are infrequent. Pace mapping from the CS can

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As the mapping catheter approaches the tricuspid annulus from the right atrium, the tricuspid annulus is usually mapped on the tricuspid valve.8,15 Therefore, it is often challenging to achieve adequate contact and stability of the mapping catheter on the tricuspid annulus. In order to overcome such challenges, the use of long guiding sheaths may be recommended for mapping tricuspid annular IVAs. The use of high radiofrequency power settings delivered from an irrigated or non-irrigated 8 mm tip ablation catheter may also be recommended in the catheter ablation of tricuspid annular IVAs to create an effective radiofrequency lesion underneath the tricuspid valve. When catheter ablation on the tricuspid valve is unsuccessful, a catheter inversion technique should be attempted for mapping and catheter ablation underneath the tricuspid valve. RFCA may need to be abandoned when tricuspid annular IVA origins are located close to the AV conduction system. Anatomically, the RV near the HB is located next to the right and non-coronary sinuses of Valsalva, and the site near the membranous septum underneath those coronary cusps.8,13,34 Therefore, when RV mapping reveals the earliest ventricular activation near the HB region, mapping in the RCC and NCC, and the LV underneath these cusps should be added to identify the IVA origin and reduce the risk of damage to the AV conduction system. When it is assured that the IVA origin is located close to the HB in the RV, cryothermal ablation may be a viable alternative.2 RFCA is often unsuccessful for IVAs originating from the septal aspect of the tricuspid annulus.2 Junctional rhythm or mild impairment of the AV conduction can occur during RFCA delivered to this region, resulting in an inadequate radiofrequency lesion formation. On the other hand, RFCA of IVAs originating from the free wall of the tricuspid annulus is usually successful without any significant complications.

Moderator Band Guidance using realtime imaging with intracardiac echocardiography and three-dimensional electroanatomic mapping is necessary for an effective and safe mapping and catheter ablation of moderator band IVAs.8,21 Given the heterogeneous morphology of the moderator band, intracardiac echocardiographic imaging during the procedure is important to allow accurate mapping of the moderator band and ensure catheter contact during the ablation.

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Diagnostic Electrophysiology & Ablation The successful anatomic ablation sites along the moderator band are varied, including the septal insertion, body of the moderator band and free wall insertion.8,21 In challenging cases, changes in the QRS morphology can occur during the RFCA, suggesting a change in the exit site, with eventual PVC elimination after extensive ablation, particularly on the free wall insertion (subendocardial ventricular plexus). This might be explained by a deep origin within the moderator band with lateral exits that are modified progressively until all exits are eliminated. PVC termination can rarely be achievable with ablation of the right bundle branch. Despite an extensive ablation at the moderator band with adequate visualisation by intracardiac echocardiography, a repeat catheter ablation is often required, likely because of challenging catheter contact and stability leading to a low power delivery to the thick intracavitary structure.8,21

approaches, a simultaneous left coronary angiography should be performed intermittently to ensure the location of the ablation catheter relative to the left coronary arteries and to minimise the risk of thermal injury to these vessels (see Figure 3B). RFCA within 5 mm of the coronary artery should be avoided. In the catheter ablation of LV summit IVAs, the efficacy of the RFCA may be limited because of the inaccessibility, high impedance within the venous system, intramural IVA origins, close proximity to the coronary artery, or being epicardially underneath a fat pad. In some cases, RFCA within the LCC or at the AMC may allow elimination of IVAs originating from the inaccessible area of the LV summit. Cryothermal ablation may be a viable alternative to RFCA in cases with a high impedance within the venous system or when the origin is located close to a coronary artery.35

Intramural Sites Crux During crux IVAs, an early ventricular activation is recorded within the middle cardiac vein or proximal CS.8,26 If the local ventricular activation and pace map at that site is suitable for ablation, irrigated RFCA may be attempted. If it is unsuccessful, epicardial mapping via a subxiphoid pericardial approach should be performed. A prior coronary angiography is strongly recommended to determine a safer area for RFCA of crux IVAs, and RFCA within 5 mm of the coronary artery should be avoided. There is a potential risk of perforation of the CS or impairment of the coronary artery (posterior descending artery) when RFCA is performed within the CS or middle cardiac vein or on the epicardial surface.

Left Ventricle Summit LV summit IVAs can be mapped and ablated through transvenous (the GCV or AIVV) or transpericardial approaches. Venography with an angiographic catheter or irrigated ablation catheter will be helpful as a guide for mapping within the GCV and AIVV.8,27 During mapping of LV summit IVAs, a mapping catheter within the GCV is helpful as a reference. Although LV summit IVA origins in the accessible area are usually amenable to ablation using an intrapericardial approach, catheter ablation of IVA origins in the inaccessible area is unlikely to be successful because of a thick layer of epicardial fat overlying the proximal coronary arteries and may be potentially hazardous to these vessels, although anatomic variations in some patients may allow catheter ablation even in this region. The left atrial appendage may sometimes override the accessible area (see Figure 3B) and cause a problem during mapping in this area. When a mapping catheter is placed on the left atrial appendage, a large atrial electrogram should be recorded at the mapping site, and catheter-induced premature atrial contractions may be observed. As the inaccessible area is covered with a thick fat pad, far-field electrograms are usually recorded, the local impedance is high and pacing even with a maximal output may not capture the ventricular myocardium in this area. In the accessible area with lesser fat pads, catheter ablation may be effective even at sites with far-field electrograms. In an epicardial catheter ablation using transvenous or percutaneous subxiphoid approaches, an externally irrigated ablation catheter is usually used. During the epicardial catheter ablation using transvenous and transpericardial

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Occasionally, mapping within the LV ostium will reveal the earliest but relatively late activation both endocardially and epicardially with a farfield electrogram morphology at both sites, suggesting intramural IVA origins. In such cases, pace maps from neither the endocardium nor epicardium typically achieve an excellent match to a QRS morphology of the IVAs. The most common intramural location is between the GCV epicardially and the AMC endocardially.25 Sequential ablation from the endocardial and epicardial sites often changes the QRS morphology but does not eliminate these IVAs. Although bipolar ablation between epicardial and endocardial electrodes may be effective, these intramural locations are best ablated by the use of simultaneous unipolar ablation at both sites. This approach using two generators allows the radiofrequency power to be individually titrated at both electrodes.

Conclusion IVAs usually originate from specific anatomical structures, commonly endocardial, but sometimes epicardial. Catheter ablation of IVAs is usually safe and highly successful, but sometimes can be challenging because of the anatomical obstacles. Understanding the relevant anatomy is helpful for achieving a safe and successful catheter ablation of IVAs. ■

Clinical Perspective • Idiopathic ventricular arrhythmias usually originate from specific anatomical structures. • One has to predict the site of an idiopathic ventricular arrhythmia origin by electrocardiograms, and choose the best equipment and strategy for the catheter ablation while considering the anatomical backgrounds. • One has to identify the site for a safe and successful catheter ablation of idiopathic ventricular arrhythmias by understanding the relevant anatomy and utilising imaging modalities. • Catheter ablation of idiopathic ventricular arrhythmias is usually safe and highly successful, but can sometimes be challenging because of the anatomical obstacles.

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9. 10.

11.

12.

13.

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aortic sinus cusp. Heart Rhythm 2008;5:37–42. DOI: 10.1016/ j.hrthm.2007.08.032; PMID: 18180020 14. Sekiguchi Y, Aonuma K, Takahashi A, et al. Electrocardiographic and electrophysiologic characteristics of ventricular tachycardia originating within the pulmonary artery. J Am Coll Cardiol 2005; 45:887–95. DOI: 10.1016/j.jacc.2004.10.071; PMID: 15766825 15. Tada H, Tadokoro K, Ito S, et al. Idiopathic ventricular arrhythmias originating from the tricuspid annulus: Prevalence, electrocardiographic characteristics, and results of radiofrequency catheter ablation. Heart Rhythm 2007; 4:7–16. DOI: 10.1016/j.hrthm.2006.09.025; PMID: 17198982 16. Doppalapudi H, Yamada T, McElderry HT, et al. Ventricular tachycardia originating from the posterior papillary muscle in the left ventricle: a distinct clinical syndrome. Circ Arrhythm Electrophysiol 2008;1:23–9. DOI: 10.1161/CIRCEP.107.742940; PMID: 19808390 17. Yamada T, McElderry HT, Okada T, et al. Idiopathic focal ventricular arrhythmias originating from the anterior papillary muscle in the left ventricle. J Cardiovasc Electrophysiol 2009;20:866–72. DOI: 10.1111/j.1540-8167.2009.01448.x; PMID: 19298560 18. Yamada T, Doppalapudi H, McElderry HT, et al. Electrocardiographic and electrophysiological characteristics in idiopathic ventricular arrhythmias originating from the papillary muscles in the left ventricle: relevance for catheter ablation. Circ Arrhythm Electrophysiol 2010;3:324–31. DOI: 10.1161/CIRCEP.109.922310; PMID: 20558848 19. Yamada T, Doppalapudi H, McElderry HT, et al. Idiopathic ventricular arrhythmias originating from the papillary muscles in the left ventricle: prevalence, electrocardiographic and electrophysiological characteristics, and results of the radiofrequency catheter ablation. J Cardiovasc Electrophysiol 2010;21:62–9. DOI: 10.1111/j.1540-8167.2009.01594.x; PMID: 19793147 20. Crawford T, Mueller G, Good E, et al. Ventricular arrhythmias originating from papillary muscles in the right ventricle. Heart Rhythm 2010;7:725–30. DOI: 10.1016/j.hrthm.2010.01.040; PMID: 20206325 21. Sadek MM, Benhayon D, Sureddi R, et al. Idiopathic ventricular arrhythmias originating from the moderator band: Electrocardiographic characteristics and treatment by catheter ablation. Heart Rhythm 2015;12:67–75. DOI: 10.1016/ j.hrthm.2014.08.029; PMID: 25240695 22. Tsuchiya T, Okumura K, Honda T, et al. Significance of late diastolic potential preceding Purkinje potential in verapamilsensitive idiopathic left ventricular tachycardia. Circulation 1999;99:2408–13. PMID: 10318662 23. Nogami A, Naito S, Tada H, et al. Demonstration of diastolic and presystolic Purkinje potentials as critical potentials in a macroreentry circuit of verapamil-sensitive idiopathic left ventricular tachycardia. J Am Coll Cardiol 2000;36:811–23. PMID: 10987604 24. Yamada T. Transthoracic epicardial catheter ablation: indications, techniques, and complications. Circ J

2013;77:1672–80. PMID: 23759656 25. 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. DOI: 10.1161/CIRCEP.114.002259; PMID: 25637597 26. Doppalapudi H, Yamada T, Ramaswamy K, et al. Idiopathic focal epicardial ventricular tachycardia originating from the crux of the heart. Heart Rhythm 2009;6:44–50. DOI: 10.1016/ j.hrthm.2008.09.029; PMID: 19121799 27. Yamada T, McElderry HT, Doppalapudi H, et al. Idiopathic ventricular arrhythmias originating from the left ventricular summit: anatomic concepts relevant to ablation. Circ Arrhythm Electrophysiol 2010;3:616–23. DOI: 10.1161/CIRCEP.110.939744; PMID: 20855374 28. Yamada T, Murakami Y, Yoshida N, et al. Preferential conduction across the ventricular outflow septum in ventricular arrhythmias originating from the aortic sinus cusp. J Am Coll Cardiol 2007;50:884–91. DOI: 10.1016/ j.jacc.2007.05.021; PMID: 17719476 29. Ouyang F, Cappato R, Ernst S, et al. Electroanatomic substrate of idiopathic left ventricular tachycardia: unidirectional block and macroreentry within the purkinje network. Circulation 2002;105:462–9. 30. Lin D, Hsia HH, Gerstenfeld EP, et al. Idiopathic fascicular left ventricular tachycardia: linear ablation lesion strategy for noninducible or nonsustained tachycardia. Heart Rhythm 2005;2:934–9. DOI: 10.1016/j.hrthm.2005.06.009; PMID: 16171747 31. Yamada T, McElderry HT, Doppalapudi H, Kay GN. Realtime integration of intracardiac echocardiography and electroanatomic mapping in PVCs arising from the LV anterior papillary muscle. Pacing Clin Electrophysiol 2009; 32:1240–3. DOI: 10.1111/j.1540-8159.2009.02472.x; PMID: 19719506 32. Liu XK, Barrett R, Packer DL, Asirvatham SJ. Successful management of recurrent ventricular tachycardia by electrical isolation of anterolateral papillary muscle. Heart Rhythm 2008;5:479–82. DOI: 10.1016/j.hrthm.2007.11.013; PMID: 18313610 33. Yamada T, McElderry HT, Allred JD, et al. Ventricular fibrillation induced by a radiofrequency energy delivery for idiopathic premature ventricular contractions arising from the left ventricular anterior papillary muscle. Europace 2009;11:1115–7. DOI: http://dx.doi.org/10.1093/europace/eup092 34. Yamada T, Plumb VJ, McElderry HT, et al. Focal ventricular arrhythmias originating from the left ventricle adjacent to the membranous septum. Europace 2010;12:1467–74. DOI: 10.1093/europace/euq259; PMID: 20682558 35. Obel OA, d’Avila A, Neuzil P, et al. Ablation of left ventricular epicardial outflow tract tachycardia from the distal great cardiac vein. J Am Coll Cardiol 2006;48:1813–7. DOI: 10.1016/ j.jacc.2006.06.006; PMID: 17084255

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EHRA Position Paper

Executive Summary: European Heart Rhythm Association Consensus Document on the Management of Supraventricular Arrhythmias Endorsed by Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulación Cardiaca y Electrofisiologia (SOLAECE) Demosthenes G Katritsis [Greece, Chair],1,2 Giuseppe Boriani [Italy],3 Francisco G Cosio [Spain],4 Pierre Jais [France],5 Gerhard Hindricks [Germany],6 Mark E Josephson [USA],2 Roberto Keegan [Argentina],7 Bradley P Knight [USA],8 Karl-Heinz Kuck [Germany],9 Deirdre A Lane [UK],10,11 Gregory YH Lip [UK],10,11 Helena Malmborg [Sweden],12 Hakan Oral [USA],13 Carlo Pappone [Italy],14 Sakis Themistoclakis [Italy],15 Kathryn A. Wood [USA],16 Kim Young-Hoon [South Korea],17 Carina Blomström Lundqvist [Sweden, Co-Chair] 12 1: Athens Euroclinic, Athens, Greece; 2: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; 3: Cardiology Department, Modena University Hospital, University of Modena and Reggio Emilia, Modena, Italy; 4: Hospital Universitario De Getafe, Madrid, Spain; 5: University of Bordeaux, CHU Bordeaux, LIRYC, France; 6: University of Leipzig, Heartcenter, Leipzig, Germany; 7: Hospital Privado del Sur y Hospital Espanol, Bahia Blanca, Argentina; 8: Northwestern Memorial Hospital, Chicago, IL, USA; 9: Asklepios Hospital St Georg, Hamburg, Germany; 10: University of Birmingham Institute of Cardiovascular Science, City Hospital, Birmingham, UK; 11: Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 12: Department of Cardiology and Medical Science, Uppsala University, Uppsala, Sweden; 13: University of Michigan, Ann Arbor, MI, USA; 14: IRCCS Policlinico San Donato, San Donato Milanese, Italy;15: Dell’Angelo Hosiptal, Venice-Mestre, Italy; 16: Emory University School of Nursing, Atlanta, USA; 17: Korea University Medical Center, Seoul, Republic of Korea

Abstract This paper is an executive summary of the full European Heart Rhythm Association (EHRA) consensus document on the management of supraventricular arrhythmias, published in Europace. It summarises developments in the field and provides recommendations for patient management, with particular emphasis on new advances since the previous European Society of Cardiology guidelines. The EHRA consensus document is available to read in full at http://europace.oxfordjournals.org

Keywords Supraventricular tachycardia, supraventricular arrhythmias, EHRA consensus Acknowledgement: This article is an abbreviated version of the full consensus document published in Europace DOI: 10.1093/europace/euw301. ©ESC 2016. Received: 20 October 2016 Accepted: 20 October 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(3):210–224. DOI: 10.15420/aer.2016:5.3.GL1

This is an executive summary of the full consensus document on the management of supraventricular tachycardia (SVT) patients published in Europace. The consensus document was prepared by a Task Force from the European Heart Rhythm Association (EHRA) with representation from the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulación Cardiaca y Electrofisiologia (SOLAECE). It summarises current developments in the field and provides recommendations for the management of patients with SVT based on the principles of evidence-based medicine, with focus on new advances since the last ESC guidelines.1 It does not cover atrial fibrillation, which is the subject of a separate clinical guideline. The process for evidence review has been described in the full document. Consensus statements are evidence-based, and derived primarily from published data. Current systems of ranking level of evidence are becoming complicated in a way that their practical utility might be compromised. We have, therefore, opted for an easier

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and, perhaps, more user-friendly system of ranking that should allow physicians to easily assess current status of evidence and consequent guidance (see Table 1). EHRA grading of consensus statements does not have separate definitions of Level of Evidence.

Diagnosis and Management of SVT The term supraventricular tachycardia literally indicates tachycardias (atrial and/or ventricular rates >100 bpm at rest), the mechanism of which involves tissue from the His bundle or above (see Table 2). Traditionally, however, SVT has been used to describe all kinds of tachycardias apart from ventricular tachycardias and atrial fibrillation (AF), the mechanisms of which are illustrated in Figure 1. The term narrow-QRS tachycardia indicates those with a QRS duration ≤ 120 ms. A wide-QRS tachycardia refers to one with a QRS duration >120 ms (see Table 3). In clinical practice, SVT may present as narrow- or wide-QRS tachycardias, and most of them usually, although not invariably, manifest as regular rhythms.

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Supraventricular Arrhythmias

Recommendations for the differential diagnosis of various forms of supraventricular tachycardias, as well as supporting references, are included in Figures 2–6. Recommendations for acute treatment preferences are given. Long-term treatment with antiarrhythmic drugs and/or catheter ablation are also presented and described for each type of SVT, with detailed recommendations given in Figure 7 and Tables 4–15. As compared with the previous SVT guideline from 2003, this consensus document contains several new recommendations

based on new trials and meta-analyses, such as the management of patients with asymptomatic Wolff-Parkinson-White syndrome, and the cautious use of certain antiarrhythmic drugs in adult congenital heart diseases. Some discrepancies with the corresponding American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines of 20152 may be related to new evidence that has emerged as well as differences in interpretation of studies and experts’ opinion. n

Table 1: Scientific Rationale of Recommendations

Table 2: Conventional Classification of Supraventricular Tachycardias

Scientific evidence that a treatment or

Recommended/

procedure is beneficial and effective.

indicated

Requires at least one randomised trial, or is

Atrial Tachycardias Sinus Tachycardia

supported by strong observational evidence

Physiological sinus tachycardia

and authors’ consensus General agreement and/or scientific

May be used or

evidence favour the usefulness/efficacy of a

recommended

Inappropriate sinus tachycardia Sinus node reentrant tachycardia Atrial Tachycardia

treatment or procedure. May be supported by randomised trials that are, however,

Focal atrial tachycardia

based on too small number of patients to

Multifocal atrial tachycardia

allow a green heart recommendation

Macro-reentrant tachycardia

Scientific evidence or general agreement

Should NOT be used

Cavotricuspid isthmus-dependent, counter-clockwise or clockwise (typical

not to use or recommend a treatment or

or recommended

atrial flutter)

procedure This categorisation for our consensus document should not be considered as being directly similar to that used for official society guideline recommendations which apply a classification (I-III) and level of evidence (A, B and C) to recommendations.

Non cavotricuspid isthmus–dependent, mitral isthmus-dependent, and other atypical left or right atrial flutters Atrioventricular Junctional Tachycardias Atrioventricular Nodal Reentrant Tachycardia Typical Atypical Non-reentrant Junctional Tachycardia Non-paroxysmal junctional tachycardia Focal junctional tachycardia Other non-reentrant variants Atrioventricular Tachycardias Atrioventricular reentrant tachycardia Orthodromic Antidromic (with retrograde conduction through the AV node or, rarely, through another pathway)

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EHRA Position Paper Table 3: Differential Diagnosis of Narrow and Wide QRS Tachycardias

Table 5: Therapy of Sinus Tachycardia

Narrow QRS (≤120 ms) Tachycardias

Inappropriate Sinus Tachycardia

Regular Physiological sinus tachycardia

Recommendation

Reference

Therapy is recommended mainly to control symptoms.

18, 19

Inappropriate sinus tachycardia

Ivabradine is recommended for symptomatic patients

Sinus nodal reentrant tachycardia

Beta-blockers and non-dihydropyridine calcium channel 19, 20

Focal atrial tachycardia

blockers are frequently ineffective or not tolerated at required doses. Therefore, may be considered as second-

Atrial flutter

and third-line therapy, respectively

Atrial fibrillation with very fast ventricular response

Catheter ablation should not be routinely considered

Atrioventricular nodal reentrant tachycardia

21-23

in patients with inappropriate sinus tachycardia. This

Non-paroxysmal or focal junctional tachycardia

treatment must be restricted to the most symptomatic

Orthodromic atrioventricular reentrant tachycardia

patients after the failure of other therapy and measures

Idiopathic ventricular tachycardia (especially high septal VT)

Sinus Nodal Reentrant Tachycardia

Irregular Atrial fibrillation Atrial focal tachycardia or atrial flutter with varying AV block

Recommendation

Reference

Catheter ablation may be used in patients with

symptomatic sinus nodal reentrant tachycardia Oral beta-blockers, diltiazem or verapamil may be

Multifocal atrial tachycardia

used in patients with symptomatic sinus nodal

Wide QRS (>120 ms) Tachycardias

19, 25

reentrant tachycardia

Regular Antidromic atrioventricular reentrant tachycardia Any regular atrial or junctional reentrant tachycardias with: aberration/bundle branch block

Table 6: Therapy of Focal Atrial Tachycardia

preexcitation/bystander accessory pathway Acute therapy

Ventricular tachycardia/flutter Irregular Atrial fibrillation or atrial tachycardia with varying block conducted

Recommendation

Reference

Synchronised DC cardioversion is recommended for

with aberration

haemodynamically unstable patients*

Antidromic atrioventricular reentrant tachycardia with a variable VA

Adenosine may be used in terminating a non-reentrant 26, 27

conduction

AT or diagnosing the tachycardia mechanism

Pre-excited AF

IV beta-blockers or verapamil or diltiazem may be used 9, 15, 28

Polymorphic VT

for pharmacologic cardioversion or rate control

Torsade de pointes

IV flecainide or propafenone may be used for

29, 30

pharmacologic cardioversion in the absence of structural

Ventricular fibrillation

or ischaemic heart disease IV amiodarone may be used for pharmacologic

Table 4: Acute Management of SVT without Established Diagnosis

31, 32

cardioversion or rate control IV ibutilide may be used for pharmacologic cardioversion 33 of micro-reentrant AT

Haemodynamically unstable SVT

* randomised data exist only for post-AF ablation AT. AT: atrial tachycardia.

Recommendation

Reference

Synchronised electrical cardioversion is

3, 4

recommended* Haemodynamically stable SVT

Chronic therapy Recommendation

Reference

Catheter ablation is recommended, especially for

34, 35

incessant AT*

Recommendation

Reference

Vagal manoeuvres, preferably in the supine position,

5-12

or adenosine are recommended

Beta-blockers or verapamil or diltiazem may be

36, 37

considered Flecainide or propafenone in the absence of structural

29, 30, 38

IV diltiazem or verapamil may be considered

9, 10, 13-15

or ischaemic heart disease may be considered

IV beta-blockers may be considered

13, 16, 17

* recommendations supported by strong observational evidence and authors’ consensus but no specific RCT.

* recommendation supported by strong observational evidence and authors’ consensus but no specific RCT.

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Table 7: Therapy of Multifocal Atrial Tachycardia Recommendation

Reference

Metoprolol is recommended in the absence of

28, 39

pulmonary disease Verapamil or diltiazem may be considered in the

presence of pulmonary disease

Table 8: Therapy of Atrial Flutter/ Macro-reentrant Tachycardia Acute Therapy Recommendation

Reference

Synchronised DC cardioversion is recommended for haemodynamically unstable patients with AFL/MRT*

40, 41

IV anticoagulation may be considered in case emergency cardioversion is necessary. Anticoagulation should be continued for

42, 43

4 weeks after sinus rhythm is established Intravenous beta-blockers, diltiazem or verapamil are recommended for acute rate control in patients with AFL who are

44-46

haemodynamically stable IV ibutilide or dofetilide, under close monitoring due to proarrhythmic risk, are recommended to cardiovert AFL

47-51

Amiodarone may be considered to control ventricular rate in the acute setting

52, 53

Atrial overdrive pacing (via oesophagus or endocardial) may be considered for conversion of AFL/MRT

54-57

Oral dofetilide may be considered to cardiovert AFL in non-urgent situations but only in hospitalised patients since there is a

proarrhythmic risk Class Ic antiarrhythmic drugs should not be used in the absence of AV blocking agents because of the risk of slowing atrial rate,

59, 60

and leading to 1:1 AV conduction Chronic Therapy Recommendation

Reference

One-time or repeated cardioversion associated with AAD are recommended as a long-term alternative for patients with infrequent AFL

61, 62

recurrences or refusing ablation In patients with recurrent or poorly tolerated typical AFL, CTI ablation is recommended for preventing recurrences with a low incidence

62, 63

of complications In patients with depressed LV systolic function, ablation may be considered to revert dysfunction due to tachycardiomyopathy and

64, 65

prevent recurrences Atypical AFL/MRT appearing early (3–6 months) after AF ablation may be initially treated by cardioversion and AAD, as it may not recur

66, 67

in the long term In patients with recurrent atypical or multiple ECG AFL patterns, catheter ablation may be considered after documentation of

68-73

mechanism Given the high incidence of AF after CTI ablation for typical AFL, correction of ‘AF risk factors’ may be considered after ablation

74-76

Oral anticoagulation may be considered for patients with episodes of atrial flutter

42, 43, 77-79

Stroke prevention is recommended with the same indications as in AF amongst patients with typical AFL and associated episodes of AF:* 42, 43 • ‘Low risk’ AFL patients, defined as CHA2DS2-VASc 0 in males or 1 in females, do not need antithrombotic therapy • Effective stroke prevention in patients with CHA2DS2-VASc score ≥1, is oral anticoagulation, whether with well controlled vitamin K antagonist (VKA) with a time in therapeutic range >70 %, or with a non-VKA oral anticoagulant (NOAC, either dabigatran, rivaroxaban, apixaban or edoxaban) • Bleeding risk should be assessed using the HAS-BLED score. Patients at high risk (score >3) should be identified for more regular review and follow-up, and the reversible bleeding risk factors addressed. A high HAS-BLED score is not a reason to withhold anticoagulation * recommendations supported by strong observational evidence and authors’ consensus but no specific RCT. AF: atrial fibrillation; AFL: atrial flutter;AV: atrioventricular; CTI: cavotricuspid isthmus; LV: left ventricular; MRT: macro-reentrant tachycardia.

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EHRA Position Paper Table 9: Therapy of Atrioventricular Nodal Reentrant Tachycardia

Table 11: Therapy of Atrioventricular Reentrant Tachycardias Due to Manifest or Concealed Accessory Pathways

Acute Therapy

Recommendation

Reference

Recommendation

Valsalva manoeuvre, preferably in the supine position,

5-8

Vagal manoeuvres (Valsalva and carotid sinus massage), 5-8

is recommended IV adenosine is recommended

Reference

preferably in the supine position, are recommended 9-12

as the first-line approach to achieve SVT termination. However, reversion rates range from 45.9% to 54.3%

Synchronised direct-current cardioversion is

recommended for haemodynamically unstable patients

Adenosine is recommended for conversion to sinus

10, 11, 102

rhythm but should be used with caution because it may precipitate AF with a rapid ventricular rate and even

in whom adenosine fails to terminate the tachycardia* IV verapamil or diltiazem may be considered in the absence

9, 10,

of hypotension or suspicion of VT or pre-excited AF

13-15, 81

IV beta-blockers (metoprolol or esmolol) may be

13, 16, 17

considered IV amiodarone may be considered

Single oral dose of diltiazem and propranolol may be

83, 84

considered

ventricular fibrillation Synchronised DC shock is recommended in manoeuvres or adenosine are ineffective or not feasible* IV ibutilide, procainamide, propafenone or flecainide in

103-105

antidromic AVRT may be considered IV beta-blockers, diltiazem, verapamil in orthodromic

16, 106, 107

AVRT may be considered IV digoxin, beta-blockers, diltiazem, verapamil and,

Chronic Therapy

haemodynamically unstable patients with AVRT if vagal

108-113

possibly, amiodarone are potentially harmful in patients

Recommendation

Reference

with pre-excited AF

Catheter ablation for slow pathway modification is

85-89

* recommendation supported by strong observational evidence and authors’ consensus but no specific RCT. AF: atrial fibrillation; AVRT: atrioventricular reentrant tachycardia; SVT: supraventricular tachycardia.

recommended in symptomatic patients or in patients with an ICD Diltiazem or verapamil may be considered

90-93

Beta-blockers may be considered

84, 92

No therapy for minimally symptomatic patients with

infrequent, short-lived episodes of tachycardia

Chronic Therapy Recommendation

Reference

Catheter ablation of the accessory pathway is

114-116

recommended in patients with symptomatic AVRT and/or pre-excited AF* Catheter ablation of concealed accessory pathways may 85, 86, 88, 89 be considered in symptomatic patients with frequent

* recommendation supported by strong observational evidence and authors’ consensus but no specific RCT. AF: atrial fibrillation; ICD: implantable cardioverter-defibrillator.

episodes of AVRT Oral flecainide or propafenone, preferably in combination

117-122

with a beta-blocker, may be considered in patients with

Table 10: Therapy of Focal Junctional Tachycardia

AVRT and/or pre-excited AF, and without structural or ischaemic heart disease Oral beta-blockers, diltiazem or verapamil may be

Acute Therapy Recommendation IV propranolol with or without procainamide, verapamil or flecainide may be considered for acute therapy

Reference 95-97

Oral amiodarone may be considered only among patient 123, 124 and catheter ablation is not an option

Reference

Beta-blockers, and in the absence of ischaemic or structural heart disease flecainide or propafenone,

pre-excitation sign on resting ECG are present in whom other AADs are ineffective or contraindicated,

Chronic Therapy Recommendation

90-93

considered for chronic management of AVRT if no

*: recommendation supported by strong observational evidence and authors’ consensus but no specific RCT. AAD: anti-arrhythmic drug; AF: atrial fibrillation; AVRT: atrioventricular reentrant tachycardia.

95, 98, 99

may be considered for chronic therapy Catheter ablation may be considered but at a risk of AV block

100, 101

AV: atrioventricular.

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Table 12: Management of Asymptomatic Pre-excitation Recommendation

Reference

Electrophysiological testing may be considered for risk

116,

stratification in subjects with asymptomatic ventricular

125-131

pre-excitation Catheter ablation of accessory pathways may be considered

116,

in asymptomatic patients with accessory pathways

128, 131

with antegrade refractory period <240 ms, inducible

Table 14: Chronic Therapy of Supraventricular Tachycardias in Adult Congenital Heart Disease Patients Recurrent symptomatic SVT Recommendation

Reference

Haemodynamic evaluation of structural defect for

134, 135

potential repair may be considered as initial evaluation of SVT Catheter ablation may be considered

136-142

Oral beta-blockers may be considered for recurrent AT

143

atrioventricular reentrant tachycardia triggering pre-excited atrial fibrillation, and multiple accessory pathways* Observation without treatment may be reasonable in

116, 127

asymptomatic WPW patients who are considered to be

Amiodarone may be considered for prevention, if other

at low risk following electrophysiology study or due to

144

medications and catheter ablation are ineffective or

intermittent preexcitation Screening programmes may be considered for risk

or atrial flutter

116, 127

stratification of asymptomatic subjects with pre-excited

contraindicated Antithrombotic therapy for AT or atrial flutter is the same 145, 146 as for patients with AF, since CHD patients with atrial

ECG

tachycardias and atrial flutter probably have similar risks

* recommendation supported by two randomised trials based on small numbers of patients. WPW: Wolff-Parkinson-White syndrome.

for thromboembolism as patients with AF Oral sotalol should not be used related to increased risk

Table 13: Acute Therapy of Supraventricular Tachycardias in Adult Congenital Heart Disease Patients

147

for proarrhythmias and mortality Flecainide should not be used in patients with ventricular 148 dysfunction related to increased risk for proarrhythmia and mortality

SVT Haemodynamically Unstable Recommendation

Reference

Electrical cardioversion is recommended (caution for sinus 132 node dysfunction and impaired ventricular function with

149

decrease recurrence of atrial tachycardia/flutter is not recommended Planned surgical repair and symptomatic SVT

need for chronotropic or inotropic support)* IV adenosine for conversion may be considered (caution

Implantation of a pacemaker for atrial-based pacing to

26, 27

for sinus node dysfunction and impaired ventricular

Recommendation

Surgical ablation of AT, atrial flutter or accessory pathway 150, 151

function with need for chronotropic or inotropic support)

may be considered

AVNRT/AVRT Haemodynamically Stable

In patients planned for surgical repair of Ebstein’s

Recommendation

Reference

IV adenosine may be considered

26, 27

Reference

152, 153

anomaly, preoperative electrophysiological study may be considered as a routine test In patients with SVT planned for surgical repair of

152-155

Ebstein’s anomaly, preoperative catheter ablation or Atrial overdrive pacing (via oesophagus or endocardial)

54-57

intraoperative surgical ablation of accessory pathways,

may be considered

flutter or AT may be considered.

Atrial flutter/AT haemodynamically stable

AF: atrial fibrillation; AT: atrial tachycardia; CHD: congenital heart disease; SVT: supraventricular tachycardia.

Recommendation

Reference

IV ibutilide for conversion of atrial flutter may be considered 133 (caution for pro-arrhythmia in patients with impaired ventricular function) IV metoprolol (caution for hypotension) may be considered 16, 39 for conversion and rate control Atrial overdrive pacing for conversion of atrial flutter

54-57

(via oesophagus or endocardial) may be considered *: recommendation supported by strong observational evidence and authors’ consensus but no specific RCT.

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EHRA Position Paper Table 15: Recommendations for Treatment of Supraventricular Tachycardias During Pregnancy Acute therapy Recommendation

Reference

DC cardioversion in patients with SVT causing haemodynamic instability*

156

Vagal manoeuvres, preferably in the supine position, may be considered as first line therapy Adenosine may be considered if vagal manoeuvres fail

157

IV metoprolol or propranolol may be considered as a second line drug if adenosine is ineffective

158

IV verapamil may be considered if adenosine and beta-blockers are ineffective or contraindicated

159

* recommendation supported by strong observational evidence and authorsâ&#x20AC;&#x2122; consensus but no specific RCT. DC: direct current; SVT: supraventricular tachycardias.

Chronic therapy Recommendation

Reference

No medical therapy may be considered in patients with tolerable symptoms Metoprolol, proprabolol or acebutolol may be considered in highly symptomatic patients*

158, 160

Verapamil may be reasonable in highly symptomatic patients when beta-blockers are ineffective or contraindicated*

161

Sotalol and flecainide may be reasonable in highly symptomatic patient when beta-blockers are ineffective

162, 163

or contraindicated* Catheter ablation may be considered in highly symptomatic, drug refractory SVT after the first trimester

164

Atenolol is not recommended

158, 165

* drugs should be avoided during the first trimester if possible. SVT: supraventricular tachycardias.

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Figure 1: Tachycardia Circuit and Typical 12-lead ECGs in Different Types of Narrow- and Wide-QRS Supraventricular Tachycardias

From left to right: typical (anti-clockwise) atrial flutter; left atrial tachycardia; typical AVNRT (slow-fast); orthodromic AVRT due to a left lateral accessory pathway; atypical AVNRT with LBBB aberration; antidromic AVRT due to an atriofascicular pathway (usually produces a horizontal or superior QRS axis, but normal axis may also occur, depending on the way of insertion into the right bundle and fusion over the left anterior fascicle). AVNRT: atrioventricular nodal reentrant tachycardia; AVRT: atrioventricular reentrant tachycardia; AP: accessory pathway, LBBB: left bundle branch reentry.

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EHRA Position Paper Figure 2: Differential Diagnosis of Narrow-QRS Tachycardia

a: rare causes; b: arbitrary number based on the VA interval for which data exist. An interval of 90 ms may also be used for surface ECG measurements if P waves are visible; c: it may also present with AV dissociation; d: it may also present with a short RP AVNRT: atrioventricular nodal reentrant tachycardia. AVRT: atrioventricular reentrant tachycardia; AP: accessory pathway.

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Figure 3: Responses of Narrow Complex Tachycardias to Adenosine

AVNRT: atrioventricular nodal reciprocating tachycardia; AVRT: atrioventricular reciprocating tachycardia; AT: atrial tachycardia; AV: atrioventricular; IV: intravenous; DAD: delayed afterdepolarisation; VT: ventricular tachycardia.

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EHRA Position Paper Figure 4: Differential Diagnosis of Wide QRS using the Brugada et al. Algorithm. The RS Interval (enlarged in the right panel) Measures 160 ms in lead V, and 70 ms in lead V6. Thus, the Longest RS Interval is More Than 100 ms and Diagnostic of Ventricular Tachycardia

Source: Brugada et al., 1991.166

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Figure 5: Differential Diagnosis of Wide-QRS Tachycardia using the Vereckei et al. Algorithm

Figure 6: Measurement of the R-wave Peak Time (RWPT) in Lead II

R-wave peak time (RWPT) measured from the isoelectric line to the point of first change in polarity is >50 ms (80 ms), thus indicating ventricular tachycardia. Source: Pava et al., 2010.168

Figure 7: Acute Treatment of Regular Tachycardia

In the lower panel, the crossing points of the vertical lines with the QRS contour in lead aVR show the onset and end of the QRS complex in lead aVR. The crossing points and initial and terminal 40 ms of the chosen QRS complex are marked by small crosses. vi /vt is the ventricular activation velocity ratio by measuring the vertical excursion in mV recorded on the ECG during the initial (vi ) and terminal (vt ) 40 ms of the QRS complex. Left: During the initial 40 ms of the QRS, the impulse traveled vertically 0.15 mV; therefore, vi = 0.15. During the terminal 40 ms of the QRS, the impulse traveled vertically 0.6 mV; therefore, vt = 0.6. Thus, vi /vt<1 yields a diagnosis of VT. Right: vi = 0.4 and vt = 0.2, determined the same way as in the left panel; thus, vi /vt >1 suggests a diagnosis of SVT. Source: Vereckei et al., 2008.167

Source: Pava et al., 2010.168

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20. 21.

22.

23.

24.

25.

26.

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tachyarrhythmias with digoxin, flecainide, and sotalol: Results of a nonrandomized multicenter study. Circulation 2011;124:1747–54. 164. Driver K, Chisholm CA, Darby AE, et al. Catheter ablation of arrhythmia during pregnancy. J Cardiovasc Electrophysiol 2015;26:698–702. 165. Lydakis C, Lip GY, Beevers M, Beevers DG. Atenolol and fetal growth in pregnancies complicated by hypertension. Am J Hypertens 1999;12:541–7.

166. Brugada P, Brugada J, Mont L, et al. A new approach to the differential diagnosis of a regular tachycardia with a wide QRS complex. Circulation. 1991;83:1649–59. 167. Vereckei A, Duray G, Szenasi G, et al. New algorithm using only lead aVR for differential diagnosis of wide QRS complex tachycardia. Heart Rhythm 2008;5:89–98. 168. Pava LF, Perafan P, Badiel M, et al. R-wave peak time at DII: a new criterion for differentiating between wide complex QRS tachycardias. Heart Rhythm 2010;7:922–6.

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