AER 5.2 by Radcliffe Cardiology

Arrhythmia & Electrophysiology Review Volume 5 • Issue 2 • Autumn 2016

Volume 5 • Issue 2 • Autumn 2016

www.AERjournal.com

Brugada Syndrome and Early Repolarisation: Distinct Clinical Entities or Different Phenotypes of the Same Genetic Disease? Giulio Conte, Maria Luce Caputo, François Regoli, Tiziano Moccetti, Pedro Brugada and Angelo Auricchio

The Significance of Shocks in Implantable Cardioverter Defibrillator Recipients Anthony Li, Amit Kaura, Nicholas Sunderland, Paramdeep S Dhillon and Paul A Scott

Management of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia and Vasovagal Syncope Satish Raj and Robert Sheldon

Anatomical Substrates and Ablation of Reentrant Atrial and Ventricular Tachycardias in Repaired Congenital Heart Disease Charlotte Brouwer, Mark G Hazekamp and Katja Zeppenfeld

B Ablation Catheter

Typical AVNRT S/AAT LI

RI CS

Atypical AVNRT

Lasso Catheter ISSN - 2050-3369

Proposed Circuit of Atrioventricular Nodal Reentrant Tachycardia

CARTO 3D Map of the Left Atrium During Ablation

Schematic Overview of Classic Fontan Anatomy

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Volume 5 • Issue 2 • Autumn 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 •

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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: Autumn 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.

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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

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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

Cardiac Resynchronisation Therapy: The Optimal QRS Duration Revisited Demosthenes Katritsis, Editor-in-Chief

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, US

EHRA Editorial

The European Heart Rhythm Association: A Myriad of Benefits and Privileges Gerhard Hindricks, EHRA President

Arrhythmia Mechanisms rugada Syndrome and Early Repolarisation: Distinct Clinical Entities B or Different Phenotypes of the Same Genetic Disease?

Giulio Conte, 1 Maria Luce Caputo, 1 François Regoli, 1 Tiziano Moccetti, 1 Pedro Brugada 2 and Angelo Auricchio 1

1. Cardiocentro Ticino, Lugano, Switzerland; 2. Heart Rhythm Management Centre, Brussels, Belgium

Clinical Arrhythmias

Arrhythmogenic Cardiomyopathy: Electrical and Structural Phenotypes

Deniz Akdis, 1 Corinna Brunckhorst, 1 Firat Duru, 1,2 Ardan M Saguner 1

1. Department of Cardiology, University Heart Center, Zurich, Switzerland; 2. Center for Integrative Human Physiology, University of Zurich, Switzerland

102

Individualising Anticoagulant Therapy in Atrial Fibrillation Patients

Marco Alings

Amphia Ziekenhuis, Breda, The Netherlands; Julius Clinical Research; University Medical Centre (UMC) Utrecht, Utrecht, The Netherlands

110

The Significance of Shocks in Implantable Cardioverter Defibrillator Recipients

Anthony Li, Amit Kaura, Nicholas Sunderland, Paramdeep S Dhillon and Paul A Scott

Department of Cardiology, King’s College Hospital NHS Foundation Trust, London, UK

117

Antiarrhythmic Drug Therapy to Avoid Implantable Cardioverter Defibrillator Shocks

Jaber Abboud and Joachim R Ehrlich

St. Josefs-Hospital, Wiesbaden, Germany

122

Management of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia and Vasovagal Syncope

Satish Raj and Robert Sheldon

Libin Cardiovascular Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada

130

Classification, Electrophysiological Features and Therapy of Atrioventricular Nodal Reentrant Tachycardia

Demosthenes G Katritsis and Mark E Josephson

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

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Contents

136

Diagnostic Electrophysiology & Ablation Holter Monitoring and Loop Recorders: From Research to Clinical Practice

Alessio Galli, Francesco Ambrosini and Federico Lombardi

Cardiovascular Diseases Unit, Fondazione IRCCS Caâ&#x20AC;&#x2122; Granda Ospedale Maggiore Policlinico, Department of Clinical and Community Sciences, University of Milan, Milan, Italy

144

Reduction of Fluoroscopy Time and Radiation Dosage During Catheter Ablation for Atrial Fibrillation

Kenichiro Yamagata, Bashar Aldhoon, Josef Kautzner

Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic

150

Anatomical Substrates and Ablation of Reentrant Atrial and Ventricular Tachycardias in Repaired Congenital Heart Disease

Charlotte Brouwer, 1 Mark G Hazekamp 2 and Katja Zeppenfeld 1

1. Department of Cardiology, Leiden University Medical Centre, The Netherlands; 2. Department of Cardiothoracic Surgery, Leiden University Medical Centre, The Netherlands

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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

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Foreword

Cardiac Resynchronisation Therapy: The Optimal QRS Duration Revisited

echanical dyssynchrony, ie nonsynchronous contraction of the wall segments of the left ventricle (intraventricular) or between the left and right ventricles (interventricular), impairs systolic function and ventricular filling, increases wall stress and worsens mitral regurgitation. It is most readily defined by the

presence of QRS widening and left bundle branch block (LBBB) configuration on the electrocardiogram. Biventricular pacing by atrial-synchronised pacing of the right ventricle and left ventricle via the coronary sinus to the basal or midventricular left ventricle region accomplishes reverse remodelling of the left ventricle, and this mode of therapy is now recommended by both European and US guidelines. Still, however, the precise indications for implementation of cardiac resynchronisation therapy (CRT) are not established. The optimum QRS duration, in particular, is a matter of ongoing debate. LBBB and QRS >150 s, female gender and non-ischaemic aetiology are established predictors of response. There was initial evidence that CRT may be beneficial even in mildly symptomatic patients (NYHA I or II) and a QRS >120 ms, especially in presence of LBBB morphology.1–3 However, we know now that a QRS duration <120 ms (LESSER-EARTH trial),4 or even <130 ms (EchoCRT),5 may be

Table 1: Recommendations of Guidelines for Cardiac Resynchronisation Therapy 8–11 ACCF/AHA 2013 Guideline on Heart Failure SR, LVEF ≤35 %, LBBB, QRS ≥150 ms, NYHA III/IV SR, LVEF ≤35 %, LBBB, QRS ≥150 ms, NYHA II SR, LVEF ≤35 %, LBBB, QRS 120–149 ms, NYHA II/III/IV SR, LVEF ≤35 %, non-LBBB, QRS ≥150 ms, NYHA III/IV SR, LVEF ≤35 %, non-LBBB, QRS 120–149 ms, NYHA III/IV SR, LVEF ≤35 %, non-LBBB, QRS ≥150 ms, NYHA II SR, LVEF ≤30 %, non-LBBB, QRS ≥150 ms, NYHA I

ESC 2015 Guideline on Ventricular Arrhythmias and SCD I-A I-B IIa-B IIa-A IIb-B IIb-B IIb-C

ESC 2013 Guideline on Cardiac Pacing and CRT Sinus rhythm LVEF <35%, QRS >150 ms, LBBB, NYHA II-IV LVEF <35%, QRS 120–150 ms, LBBB, NYHA II-IV LVEF <35%, QRS >150 ms, non-LBBB, NYHA II-IV LVEF <35%, QRS 120–150 ms, LBBB, NYHA II-IV QRS <120 ms

I-A I-B IIa-B IIb-B III-B

Atrial fibrillation LVEF ≤35%, QRS ≥120, NYHA III/IV provided that a biventricular pacing as close to 100 % as possible can be achieved. CRT = cardiac resynchronisation therapy; SR = sinus rhythm; LVEF = left ventricular ejection fraction; LBBB = left bundle branch block ; NYHA = New York Heart Association; SCD = sudden cardiac death

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IIa-B

Sinus rhythm and NYHA III/ambulatory IV LVEF LVEF LVEF LVEF

≤35 ≤35 ≤35 ≤35

%, LBBB, QRS >150 ms I-A %, LBBB, QRS 120–150 ms I-B %, no LBBB, QRS >150 ms IIa-B %, no LBBB, QRS 120–150 ms IIb-B

Atrial fibrillation and NYHA III/ambulatory IV LVEF ≤35 %, QRS >120–150 ms and 100 % biventricular pacing achievable

I-B

Sinus rhythm with mild (NYHA II) heart failure LVEF ≤30 %, LBBB, QRS >130 ms LVEF ≤35%, QRS ≥150 ms

I-A IIb-A

ESC 2016 Guideline on Heart Failure CRT to reduce morbidity and mortality: SR, LVEF ≤35%, LBBB,QRS ≥150 ms I-A SR, LVEF ≤35%, LBBB,QRS 130–149 ms I-A SR, LVEF ≤35%, non-LBBB,QRS ≥150 ms IIa-B SR, LVEF ≤35%, non- LBBB,QRS 130–149 ms IIb-B AF, LVEF ≤35%, NYHA III-IVa,QRS ≥130 ms I-A provided a strategy to ensure biventricular capture is in place or the patient is expected to return to sinus rhythm. CRT is contraindicated in patients with III-A a QRS duration <130 ms

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Foreword

detrimental. In patients with mild heart failure, CRT defibrillators (CRT-D) may also be beneficial in non-LBBB patients with PR interval prolongation and left ventricular ejection fraction (LVEF) <30 %, but with a QRS duration ≥130 ms.6 Patients with QRS >130 ms may also respond to CRT even if LVEF >30 %.7 These data are reflected in the recently published ESC guidelines on heart failure.8 In contrast to previous ESC as well as US guidelines,9–11 a minimal QRS duration of 130 ms is now required for recommendation of CRT (Table 1).8–11 Perhaps, this is a reasonable step towards a more rational use of our resources: CRT may be beneficial in certain clinical settings, but as the BLOCK-HF trial has taught us, the potential of increased LV lead-related complications should always be considered.12 CRT is a valuable therapeutic mode, but cautious use is necessary to ensure its continuing efficiency in both medical and socio-economic terms. Demosthenes Katritsis, Editor-in-Chief, Arrhythmia & Electrophysiology Review Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, US

Goldenberg I, Kutyifa V, Klein HU, et al. Survival with cardiac-resynchronisation therapy in mild heart failure. N Engl J Med 2014;370:1694–701. DOI: 10.1056/ NEJMoa1401426; PMID: 24678999 Linde C, Abraham WT, Gold MR, et al. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol 2008;52:1834–43. DOI: 10.1016/j. jacc.2008.08.027; PMID: 19038680 Abraham WT, Young JB, León AR, et al. Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator, and mildly symptomatic chronic heart failure. Circulation 2004;110:2864–8. DOI: 10.1161/01.CIR.0000146336.92331.D1; PMID:15505095 Thibault B, Harel F, Ducharme A, et al. Cardiac resynchronization therapy in patients with heart failure and a QRS complex <120 milliseconds: the Evaluation of Resynchronization Therapy for Heart Failure (LESSEREARTH) trial. Circulation 2013;127:873–81. DOI: 10.1161/ CIRCULATIONAHA.112.001239; PMID: 23388213 Steffel J, Robertson M, Singh JP, et al. The effect of QRS duration on cardiac resynchronization therapy in patients with a narrow QRS complex: a subgroup analysis of the

EchoCRT trial. Eur Heart J 2015;36:1983–9. DOI: 10.1093/ eurheartj/ehv242; PMID: 26009595 Kutyifa V, Stockburger M, Daubert JP, et al. PR interval identifies clinical response in patients with non-left bundle branch block: a Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy substudy. Circ Arrhythm Electrophysiol 2014;7:645–51. DOI: 10.1161/CIRCEP.113.001299; PMID: 24963007 Kutyifa V, Kloppe A, Zareba W, et al. The influence of left ventricular ejection fraction on the effectiveness of cardiac resynchronization therapy MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). J Am Coll Cardiol 2013;61:936–44. DOI: 10.1016/j.jacc.2012.11.051; PMID: 23449428 Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129– 200. DOI: 10.1093/eurheartj/ehw128; PMID: 27206819 Yancy CW, Jessup M, Bozkurt B, et al. ACCF/AHA 2013 Guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.

10.

11.

12.

J Am Coll Cardiol 2013;62:e147–e239. DOI: 10.1016/j. jacc.2013.05.019; PMID: 23747642 Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace 2013;15:1070–118. DOI: 10.1093/europace/eut206; PMID: 23801827 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). Europace 2015;17:1601–87. DOI: 10.1093/europace/euv319; PMID: 26318695 Curtis AB Worley SJ, Adamson PB, et al; Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK HF) Trial Investigators. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med 2013;368:1585–93. DOI: 10.1056/ NEJMoa1210356; PMID: 23614585

DOI: 10.15420/AER.2016.5.2.ED1

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EHRA Editorial

The European Heart Rhythm Association: A Myriad of Benefits and Privileges

he Board of the European Heart Rhythm Association (EHRA) extends its best wishes for a well deserved summer break to the readers of Arrhythmia & Electrophysiology Review and expresses great pleasure about the

continuation of the co-operation between the journal and our Association. We are happy to share information from EHRA and keep the readership of Arrhythmia & Electrophysiology Review in the loop of our activities and updates. Today, at EHRA, the leading network of European Cardiac Rhythm Management, we aim to improve the quality of life of the population by reducing the impact of cardiac rhythm disturbances and reduce sudden cardiac death. Together with more than 1,600 members across 85 countries we convene and connect with our

EHRA President – Gerhard Hindricks

members to share insights, science, best practice and resources. EHRA has developed tremendously over the last decade and has continuously enlarged the scope of educational and career development activities. Looking towards the last two quarters of this year, I have the pleasure of announcing the launch of a couple of new initiatives. To start with, the Fellow of EHRA (FEHRA): while the term ‘fellowship’ is used to focus on the professional development of the fellow, we at EHRA seek not only to provide short-term learning and training opportunities to our young community but also to reward and extend a range of privileges to a group of select professionals. The call for 2017 applications is now open until 30 October 2016. Log on to www.escardio.org/FEHRA to learn more about the application process and requirements. In parallel, the EHRA Recognised Training Centres (ERTC) is a quality label that will verify the uniformity of educational tools, and attract fellows and practitioners to these recognised centres, as well as standardise and facilitate teaching. Please consider putting forward your centre to join this exclusive club of certified high-quality education and training centres. The highlight of this season will be encouraging all non-EHRA members to join us; spread the word among your colleagues as we have put in place an exceptional incentive plan to be announced during the annual ESC Congress in Rome, 27–31 August 2016. Stop by the ESC Membership Stand at the ESC Plaza or check our membership page on www.escardio.org/EHRA-membership On behalf of the EHRA Board and the EHRA staff at the European Heart House I wish you a sunny and enjoyable summer season and look forward to seeing you all at the annual ESC Congress in Rome, Village 4. Gerhard Hindricks EHRA President 2015–2017 www.escardio.org/EHRA

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DOI: 10.15420/AER.2016.5.2.ED2

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Be part of the leading network of European Cardiac Rhythm Management, connect with EHRA and access all these benefits: Registration discount on EHRA annual congresses: • CARDIOSTIM-EHRA EUROPACE 2016 & EHRA EUROPACE-CARDIOSTIM 2017

Reduced fee for the EP Europace Journal

•

Discounted fee for EHRA educational courses

• •

•

EHRA monthly webinars

•

ESC elearning platform

• • •

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Exclusivity to EHRA Training Fellowship Programmes

EHRA quarterly e-newsletter Automatic ESC Membership Voting rights*

15/08/2016 22:03

Arrhythmia Mechanisms

Brugada Syndrome and Early Repolarisation: Distinct Clinical Entities or Different Phenotypes of the Same Genetic Disease? Giulio Conte, 1 Maria Luce Caputo, 1 François Regoli, 1 Tiziano Moccetti, 1 Pedro Brugada 2 and Angelo Auricchio 1 1. Cardiocentro Ticino, Lugano, Switzerland; 2. Heart Rhythm Management Centre, Brussels, Belgium

Abstract Brugada and early repolarisation (ER) syndromes are currently considered two distinct inherited electrical disorders with overlapping clinical and electrocardiographic features. A considerable number of patients diagnosed with ER syndrome have a genetic mutation related to Brugada syndrome (BrS). Due to the high variable phenotypic manifestation, patients with BrS may present with inferolateral repolarisation abnormalities only, resembling the ER pattern. Moreover, the complex genotype–phenotype interaction in BrS can lead to the occurrence of mixed phenotypes with ER syndrome. The first part of this review focuses on specific clinical and electrocardiographic features of BrS and ER syndrome, highlighting the similarity shared by the two primary electrical disorders. The genetic background, with emphasis on the complexity of genotype–phenotype interaction, is explored in the second part of this review.

Keywords Brugada syndrome, early repolarisation, sudden cardiac death, genotype, phenotype, electrocardiogram, ventricular arrhythmias Disclosure: Prof Brugada has been a consultant to Biotronik and has received speakers’ fees from Medtronic and Biotronik; Prof Auricchio has been a consultant to Medtronic, Boston Scientific, LivaNova and St. Jude, and has received speakers’ fees from Medtronic, Boston Scientific and LivaNova. The other authors have no conflicts of interest to declare Received: 11 April 2016 Accepted: 25 July 2016 Citation: Arrhythmia & Electrophysiology Review 2016;2016;5(2):84–9 DOI: 10.15420/AER.2016.23.2 Correspondence: Giulio Conte MD, PhD, Cardiocentro Ticino, Lugano, Switzerland. E: giulio.conte@cardiocentro.org

General understanding of early repolarisation (ER) has dramatically changed in the last decade. For several years, ER has been considered a benign electrocardiographic (ECG) finding with high prevalence in the general population. Recently different studies have challenged this view and showed a significant association with life-threatening arrhythmias.1–5 In 2008 Haïssaguerre et al. first reported an increased prevalence of a particular pattern of ER on the resting 12-lead ECG of patients with history of idiopathic ventricular fibrillation (VF) (see Figure 1).2 In these patients, ER was characterised by elevation of the QRS-ST segment junction of at least 0.1 mV above the baseline level, manifesting as QRS slurring (a smooth transition from the QRS complex to the ST segment) or notching (a positive J deflection of at least 1 mm inscribed on the S wave) in two adjacent inferior (II, III and aVF), lateral (I, aVL, and V4–V6), or infero-lateral leads. The ER pattern was observed in 31 % of patients with idiopathic VF and in 5 % of healthy control subjects. Moreover, patients with idiopathic VF and ER pattern presented a higher risk of experiencing an arrhythmic recurrence during a 5-year follow-up.2 This observation was confirmed by a case-control study showing that J-point elevation in the inferior and lateral leads is more frequent in patients with idiopathic VF than in matched control subjects (27 % versus 8 % in inferior leads; 13 % versus 1 % in lateral leads).3 Conversely, ER localised exclusively in V4 to V6 occurs with similar frequency among patients and healthy subjects.3 ER pattern has been shown to be an arrhythmic marker even in the general population of healthy subjects. Tikkanen et al. observed ER pattern in 5.8 % of community-based general population of middle-

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aged subjects.4 Interestingly, healthy individuals with an ER pattern of more than 0.2 mV in inferior leads presented a significantly increased risk of death from cardiac causes and had a higher risk of fatal arrhythmic events.4 A recently published study by Siebermair et al. confirmed that ER pattern in patients with idiopathic VF remains a strong risk factor for arrhythmia recurrence during a very long-term follow-up. Over time, appropriate implantable cardioverter-defibrillator (ICD) interventions can occur in up to 43 % of these patients with idiopathic VF and are observed more often and earlier in patients with ER pattern.5 Based on these findings, when associated with ER pattern, idiopathic VF is considered a distinct clinical entity and has been included in the group of inherited primary arrhythmia syndromes as ER syndrome.6 Notably, ECG definition of ER varies considerably among studies. A recent expert consensus paper has attempted a systematic definition of ER.7 It can be misinterpreted as fragmentation of the QRS complex.7,8 To be considered ‘true ER’, an end-QRS notch or slur should occur on the final 50 % of the downslope of an R-wave. In contrast, fragmentation of QRS complex consists of a notch midway on the downslope of an R-wave. Moreover, ER can present with an ascending ST segment (if amplitude of the ST segment 100 ms after J point termination is greater than amplitude at J termination) or with a descending or horizontal ST segment (if ST-segment amplitude 100 ms after J point termination is less than or equal to the amplitude at J point termination). ER with high amplitude (>0.2 mV) in the inferior leads, associated with a horizontal or descending ST

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segment, confers the highest arrhythmic risk. Conversely, ascending ST segment has not been found associated with a higher risk of lifethreatening arrhythmias. Finally, ST segment in the absence of a slur or a notch should be considered as nonspecific ST-segment elevation rather than ER pattern.7

Figure 1: Early Repolarisation Pattern A

aVR

aVL

III

aVF

aVR

aVL

III

aVF

Brugada Syndrome and Early Repolarisation Brugada syndrome (BrS) is an inheritable syndrome characterised by an increased risk of sudden cardiac death (SCD) in patients without overt structural cardiac abnormalities.6,9 The Brugada brothers first described the disease as a new distinct clinical and electrocardiographic entity in 1992.9 The initial report included a series of eight patients presenting with incomplete right bundle branch block, ST-segment elevation on 12-lead ECG and susceptibility to sustained ventricular arrhythmias. All the patients had no electrolytic or ischaemic disturbances nor obvious structural heart disease that could explain the ECG findings.9 Interestingly, an ECG pattern similar to coved-type ST-segment elevation was previously reported as a normal variant in the healthy population or related to VF in patients with structural cardiac abnormality.10,11 Subsequently, a group of Italian researchers considered it as a form of arrhythmogenic right ventricular cardiomyopathy.12 The identification of the first putative casual gene mutation in 1998 clarified the controversy confirming the genetic nature of the disease.13 Over the past two decades a considerable number of studies, including reports of two consensus conferences, contributed to definition of the clinical characteristics, and of cellular and molecular features associated with the disease.14–18 Three different ECG patterns have been identified in patients with BrS (see Table 1). Although all three patterns can be present in BrS and even in the same patient at different times, only type 1 ECG is considered diagnostic of the syndrome.17–20 In fact, according to the last expert consensus document on inherited primary arrhythmia syndromes, BrS is definitively diagnosed when a type 1 ST-segment elevation is observed either spontaneously or after intravenous administration of a sodium channel blocking agent in at least one right precordial lead (V1 and V2), placed in a standard or a superior position (up to the second intercostal space).6 Moreover, in 2012 a group of experts produced a consensus document on ECG criteria outlining a number of new features that can help to identify the Brugada type 1 ECG. According to this document, the ECG pattern, to be considered as type 1, has to display: • • •

• • • • •

ST-segment elevation with the highest point of QRS-ST of at least 2 mm in lead V1; Coved-type morphology (concave or rectilinear, followed by a negative and symmetrical T-wave); Progressive decline of the ST-segment morphology (the high take-off is always higher than 40 ms later and this is, in turn, higher than after 80 ms); Slow ST-segment descent after the QRS peak (<0.4 mV at 40 ms); Ratio of peak height of QRS-ST: peak of ST segment after 80 ms >1 Greater duration of QRS complex in V1 and V2 than in middle and left precordial leads; Location in V1 or V2 but never exclusively in V3; Absence of a wide S-wave in lead I and V6.

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Panel A: Baseline ECG of a patient with QRS slurring in inferior leads; Panel B: patient with J waves in inferior leads.

Moreover, given the minimal morphological differences between type 2 and type 3 and the lack of impact on prognosis, both patterns have been unified in the type 2 ECG.19 The heterogeneity of BrS can lead some patients to present with additional repolarisation abnormalities such as ER signs in the inferolateral leads (see Figure 2).21,22 Up to 12 % of patients with BrS have the infero-lateral ER pattern. It is more frequently associated with type 1 ECG and previous symptoms, although no significant association with a worse outcome was reported, as shown by a multicentre study.21,22 Patients with BrS experiencing electrical storms have a higher prevalence of ER pattern.23 Moreover, Kawata et al. reported ER pattern in up to 63 % of patients with BrS and documented VF and a worse outcome when ER pattern was persistent.24 It is worth noting that previous studies on ER syndrome have potentially included patients with BrS and nondiagnostic baseline ECG. A very recent study has, in fact, shown that up to 30 % with an initial diagnosis of ER syndrome display spontaneous Brugada type 1 in the high intercostal right precordial leads only, and most VF recurrences occur in patients with ER pattern and Brugada type 1 ECG documented in any of the right precordial leads.25 Based on such findings, sodium channel blocker challenge and ECG recording in high intercostal spaces should be performed in any case of unexplained VF and documented ER pattern in order to exclude the presence of a channelopathy. In BrS, repolarisation signs can coexist with depolarisation abnormalities and a combination of such findings seems to confer an even higher risk of further arrhythmic events.26,27 Tokioka et al. reported a combination of ER pattern and fragmented QRS in 3.6 % of patients with BrS. Both ER pattern and fragmented QRS were identified as independent predictors of further arrhythmic events, and patients with both ERP and fragmented QRS had a significantly higher frequency of arrhythmic events than did those who had neither ER nor fragmented QRS.27

Overlapping Features of Brugada and Early Repolarisation Syndromes Brugada and ER syndromes are two primary electrical disorders named J-wave syndromes by some investigators.28 Both clinical entities present with distinct ECG abnormalities affecting the junction between the terminal portion of the QRS complex and the beginning of the ST segment. In addition, the two syndromes seem to share a common channelopathy asset that leads to an increased risk of SCD (see Table 1). Antzelevitch and Yan revealed that the presence of an outward

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Arrhythmia Mechanisms Table 1: ECG, Clinical and Genetic Features of Brugada Syndrome and Early Repolarisation Syndrome

Brugada Syndrome

ER Syndrome

Diagnostic pattern

Type 1 ECG*

ER pattern¥

Additional ECG

Type 2 ECG**, type 3***

abnormalities

ECG, ER pattern¥, f-QRS§

Dynamicity of ECG

Yes

ECG Features

Yes

pattern over time Induction of ECG pattern

Yes

Unknown

Male predominance

Yes

Mean age of first

35–40

Controversial

Rest/sleep/fever

Rest

Inheritance

Autosomal

dominant

Sporadic cases

Yes

Association with

Yes (myopathies)

Not established

SCN5A, KNCJ8, CACNA1C, CACNA2D1, CACNB2b, ABCC9, SCN10A, GpD1L, SCN1B, KCNE3, SCN3B, KCND3, RANGFR, SLMAP, SCN2B, PKP2, FGF12, HEY2,SEMA3A

SCN5A, KNCJ8, CACNA1C, CACNA2D1, CACNB2b, ABCC9, SCN10A

by sodium channel blockers Vagal-mediated accentuation of ECG pattern Age-dependent manifestation of ECG pattern Clinical Features

arrhythmic event Prognostic value of VA inducibility at

prominent ECG changes appear just before the onset of ventricular arrhythmias.2,32 An additional characteristic shared by patients with Brugada and ER pattern is related to the intermittent nature and dynamicity of the ECG pattern over time. Moreover, the ECG phenotype can differ with gender and age categories of patients.33,34 Even the response to ajmaline in BrS can be age dependent.35 The clinical value of repeating ajmaline challenge after puberty in asymptomatic family members with prepubertal negative drug test was recently reported.35 Apart from the ECG, BrS and ER syndrome have several clinical similarities. They present both a highly variable clinical expressivity ranging from a lifelong course to sudden death even in the first months of life.36 Male predominance is a common characteristic.2,33 Moreover, sudden death usually occurs in the third or fourth decade of life.2,36 Ventricular fibrillation is triggered by short-coupled premature ventricular complexes and arrhythmic episodes occur at rest or during sleep. Additionally, they both respond well to quinidine, isoproterenol and cilostazol, explained by the effect of these agents on inhibition of potassium currents or increase of calcium currents.37 Apart from the similar ECG and clinical phenotype, some differences can be also appreciated between the two entities. They include: •

EP study Circumstances of arrhythmic episodes Genetic Features

•

extra-cardiac diseases Gene mutations

*Type 1 ECG is characterised by a coved-type ST-segment elevation ≥2 mm in at least one right precordial lead (V1–V3), followed by symmetric negative T waves, with little or no isoelectric separation. **Type 2 ECG displays a ST-segment elevation of >2 mm in right precordial leads followed by positive or biphasic T waves, resulting in a saddleback configuration. ***Type 3 ECG is defined as any of the two previous types if ST-segment elevation is ≤1 mm. ¥ ER pattern is characterised by a notch or slur ≥1 mm, occurring on the final 50 % of the downslope of an R-wave, in two adjacent inferior (II, III and aVF), lateral (I, aVL and V4–V6), or infero-lateral leads. § f-QRS (fragmented QRS) presents as a notch midway on the downslope of an R-wave. BrS = Brugada syndrome; ER syndrome = early repolarisation syndrome.

shift of balance in repolarising currents in canine wedge preparations, caused by a decrease in sodium or calcium channel currents or an increase in outward potassium currents, creates a notch in the action potential of the epicardium, resulting in a transmural voltage gradient.29 Accentuation of such condition in the right ventricular outflow tract gives rise to BrS coved-type ECG in the right precordial leads; whereas if the infero-lateral ventricle is affected, a J-point elevation, distinct J-wave or end-QRS slur can manifest in the inferior and/or lateral leads. Brugada and ER pattern can manifest spontaneously or be concealed, becoming apparent only under certain conditions such as fever, high vagal tone, sodium channel blocker challenge (for BrS) or Valsalva manoeuvre (for ER syndrome).30,31 For both syndromes, most

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•

The cardiac region of origin of the ECG phenomena (right ventricular outflow tract in BrS versus inferolateral ventricle in ER syndrome); Low-voltage areas (<1.5 mV) with abnormal electrograms present exclusively in the right ventricle of patients with BrS; The pro-arrhythmic effect of flecainide in BrS and its effect in attenuating the degree of J-point elevation in patients with ER syndrome; The different prognostic role of inducible ventricular arrhythmias at EP study.38–40

In a multicentre study of patients with ER syndrome and aborted sudden death, inducibility of sustained VF during electrophysiology study was relatively infrequent in idiopathic VF survivors (22 %) and did not predict any further arrhythmia during the long-term follow-up.41 In BrS there are many controversies regarding the prognostic role of EP study.42 Although large studies agree that electrophysiological study inducibility is greatest among BrS patients, there has been no consensus on the value of the EP study in predicting outcome.6,43,44 Several consensus documents have addressed this issue and the current recommendation is to implant an ICD in inducible patients (Class IIb indication).6 However, two recent meta-analyses have shown that in BrS, ventricular arrhythmias induced by programmed ventricular stimulation are associated with future arrhythmic events, independently from the symptom status of patients.45,46

One Phenotype: Different Genes Apart from displaying several clinical similarities, BrS and ER syndrome share a very complex genetic architecture and a far from understood genotype–phenotype interaction. Brugada and ER syndromes are both genetically heterogeneous and have a considerable allelic heterogeneity: mutations in different genes can lead to the same clinical manifestation and different mutations within each gene can cause the same disease. In addition, different gene mutations and variants can coexist and affect one or more

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subunits of the potassium, calcium and sodium channel structures.47 BrS has been associated with mutations in 19 different genes, whereas ER syndrome has been associated with mutations in seven genes. The first gene associated with ER syndrome was KCNJ8, which encodes a pore-forming subunit of the ATP-sensitive potassium channel (Kir6.1-IkATP). The KCNJ8-S422L variant mutation was first described in a young female with ER pattern and frequent episodes of VF.48 Subsequently, loss of function mutations was found in the SCN5A gene and L-type calcium channel genes (LTCC, CACNA1C, CACNB2, CACNA2D1) in patients with idiopathic VF and ER.49,50 Moreover, genetic variants have been identified in the ABCC9 gene, encoding the ATP-binding cassette transporters of ATP-sensitive potassium channels.51 All these gene mutations associated to ER syndrome might enhance the underlying inwardâ&#x20AC;&#x201C;outward current imbalance responsible for accelerated epicardial repolarisation. Known genes only account for a small proportion of patients. Only a small fraction of identified genetic variants has been examined by use of functional expression studies to establish causality or the potential contribution to the pathogenesis of the disease. BrS and ER syndromes can present as familial or isolated cases.53 Malignant familial forms of ER have been reported to be transmitted as an autosomal dominant trait in three large French families.54 Similarly, inheritance in BrS occurs via an autosomal dominant mode of transmission with incomplete penetrance. Most individuals diagnosed with BrS have an affected parent. The proportion of sporadic cases caused by de novo mutation is lower.53 52

Moreover, the yield of DNA testing in BrS is higher in familial cases (44 %) as compared with isolated cases (21 %).52 After the identification in 1998 of the first gene linked to BrS, the SCN5A gene encoding for the alpha subunit of the cardiac sodium channel, other responsible genes have been reported.13,55 In all genotypes, either a decrease in the inward sodium or calcium current, or an increase of the outward potassium currents has been shown to be associated with the BrS phenotype. Genetic abnormalities are found in up to onethird of genotyped patients, and for the SCN5A gene alone more than 300 mutations have been described.56 Reported mutations include missense mutation, nonsense mutation, nucleotide insertion/deletion and splice site mutation. Loss of function of the sodium channel, which impairs the fast upstroke in phase 0 of the action potential, occurs because of decreased expression of Nav1.5 proteins in the sarcolemma, expression of non-functional channels, or altered gating properties (delayed activation, earlier inactivation, faster inactivation, enhanced slow inactivation and delayed recovery from inactivation).57 The specific type of SCN5A mutation may affect the phenotype. In fact it has been reported that mutations leading to a stop codon, where no sodium channel is created, or missense mutation with >90 % peak sodium current reduction seem to be associated with a poorer prognosis compared with mutations resulting in loss-of-function.58 Reduced sodium current and BrS phenotype can also be due to sodium and calcium channel-associated proteins: GPD1-L, SCN1B and SCN3B. Moreover, lossof-function mutations in the l-type calcium channel (LTCC) genes encoding for the a and b subunits of the cardiac calcium channel can cause BrS. Putative casual mutations have been also found in genes that regulate transient outward potassium current (KCNJ8, KCNE3, KCND3, KCNE5). A recent comprehensive mutational analysis of 12 known BrSsusceptibility genes in a large cohort of unrelated BrS patients

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Figure 2: Ajmaline-induced Brugada Type 1 ECG in a Patient with Inferior ER Pattern, Presenting with Sudden Cardiac Arrest I

III

aVR

aVL

aVF

Baseline

V1 V2

Ajmaline (1 mg/kg) V1

III

aVR

aVL

aVF

Panel A: Baseline ECG showing early repolarisation pattern in inferior leads (*). Panel B: ECG during ajmaline challenge (dose of 1 mg/kg) showing appearance of Brugada type 1 ECG in right precordial and inferior leads (arrows).

identified SCN5A mutations in 16 %, with the other genes accounting for <5 % of patients.55 The lack of familial segregation data of many susceptibility genes, the relatively frequent association of BrS with common genetic variants and the lack of functional studies remain a major limitation of the genetic testing in BrS. According to the last consensus document on channelopathies, genetic testing in BrS is not recommended in the absence of a diagnostic ECG. On the other hand, it may be useful and is recommended for family members of a successfully genotyped proband. Sequence analysis of SCN5A should be completed first. If no pathogenic variant is identified, sequence analysis of SCN1B, SCN2B, SCN3B, GPD1L, CACNA1C, CACNB2, CACNA2D1, KCNE3, KCNE1L, KCNJ8, HCN4, RANGRF, SLMAP and TRPM4 may be considered.6

One Gene: Different Phenotypes Interestingly, all genes related to and potentially involved in the pathogenesis of ER syndrome have been described as associated with BrS. It has been reported that mutations in the same gene can lead to different phenotypes. As well as BrS, SCN5A mutations may lead to other diseases. SCN5A mutations are implicated in long-QT syndrome type 3, progressive cardiac conduction disease, sick sinus syndrome (or a combination of these), congenital atrial standstill, dilated cardiomyopathy or ER syndrome. A single mutation of SCN5A can lead to several phenotypes in the same family or in a single patient such as BrS, long-QT syndrome type 3, sick sinus syndrome and a variable degree of conduction disturbances (first-degree to complete AV block) known as overlap syndrome.59,60 KCNJ8, LTCC, SCN5A and SCN10A gene mutations have been shown to underline both ER syndrome and BrS. Meideros-Domingo et al. genetically screened 87 probands with BrS and 14 with ER syndrome and found 1 BrS and ER syndrome proband with a S422L-KCNJ8 mutation; the variation was absent in 600 controls.61 Similarly, Barajas-

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Arrhythmia Mechanisms Martinez et al. reported the same missense mutation, p.Ser4222Leu in KCNJ8 in 3 BrS and 1 ER syndrome proband.62 Cases of ER syndrome are often associated with electrical storms in which defects in genes traditionally causing BrS, such as SCN5A, are involved and in combination with mutations in IkATP genes.51 A SCN5A mutation can lead to varying degrees of the Brugada ECG phenotype in members of the same family: in some of them repolarisation abnormalities can occur in the inferior leads only, whereas in others the right precordial leads are characteristically affected.63 This might be related to a different or additional spatial localisation of the affected cardiomyocyte within the heart, other than the right ventricular outflow tract. A complex genetic inheritance known as the oligogenic model has been recently hypothesised to explain particular clinical presentation of inherited cardiac diseases.47 In contrast to the monogenic paradigm, where a strong monogenic component is responsible of the disease susceptibility, for other diseases such as BrS or ER syndrome inheritance of many genetic risk variants can occur. In addition, the presence of modulating factors may contribute to the manifestation of the disease with a mixed phenotype.64

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Conclusion Brugada and ER syndromes are considered to be two distinct, inherited electrical disorders with overlapping clinical and electrocardiographic features. A considerable number of patients diagnosed with ER syndrome have a genetic mutation related to BrS. Due to its highly variable phenotypic expressivity, patients with BrS may present exclusively with inferolateral repolarisation abnormalities, such as the ER pattern. Moreover, the complex genotype–phenotype interaction in BrS can lead to the occurrence of mixed phenotypes with ER syndrome. Significant progress in understanding BrS has been achieved since its first description. More than two decades of extensive research on the syndrome have revealed part of its genetic background and electrophysiological and clinical characteristics. The remaining unresolved questions on the genotype–phenotype interaction in BrS provide a stimulus for ongoing active research into the condition. Further functional expression and computational studies will help to elucidate the pathogenic nature and the exact functional consequences of many genetic variants associated with these inherited electrical disorders. ■

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44.

ST-segment elevation and right bundle branch block but structurally normal hearts. Circulation 2000;101:510–5. PMID: 10662748 Gourraud JB, Le Scouarnec S, Sacher F, et al. Identification of large families in early repolarization syndrome. J Am Coll Cardiol 2013;61:164–72. DOI: 10.1016/j.jacc.2012.09.040; PMID: 23273290 Conte G, Sieira J, Sarkozy A, et al. Life-threatening ventricular arrhythmias during ajmaline challenge in patients with Brugada syndrome: incidence, clinical features, and prognosis. Heart Rhythm 2013;10:1869–74. DOI: 10.1016/ j.hrthm.2013.09.060; PMID: 24055942 Benito B, Sarkozy A, Mont L, et al. Gender differences in clinical manifestations of Brugada syndrome. J Am Coll Cardiol 2008;52:1567–73. DOI: 10.1016/j.jacc.2008.07.052; PMID: 19007594 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;63:2272–9. DOI: 10.1016/j.jacc.2014.02.574; PMID: 24681144 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;312:2039–41. DOI: 10.1001/jama.2014.13752; PMID: 25399282 Priori SG, Napolitano C, Gasparini M, et al. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation 2002;105:1342–7. PMID: 11901046 Hermida JS, Denjoy I, Clerc J, et al. Hydroquinidine therapy in Brugada syndrome. J Am Coll Cardiol 2004;43:1853–60. DOI: 10.1016/j.jacc.2003.12.046; PMID: 15145111 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;123:1270–9. 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;8:1373–81. DOI: 10.1161/ CIRCEP.115.003220; PMID: 26291334 Ahn J, Roh SY, Lee DI, et al. Effect of flecainide on suppression of ventricular fibrillation in a patient with early repolarization syndrome. Heart Rhythm 2016;13:1724–8. DOI: 10.1016/j.hrthm.2016.03.051; PMID: 27033341 Mahida S, Derval N, Sacher F, et al. Role of electrophysiological studies in predicting risk of ventricular arrhythmia in early repolarization syndrome. J Am Coll Cardiol 2015;65:151–9. DOI: 10.1016/j.jacc.2014.10.043; PMID: 25593056 Belhassen B, Michovitz Y. Arrhythmic risk stratification by programmed ventricular stimulation in Brugada syndrome: the end of the debate? Circ Arrhythm Electrophysiol 2015;8: 757–9. DOI: 10.1161/CIRCEP.115.003138; PMID: 26286299 Sieira J, Conte G, Ciconte G, et al. Prognostic value of programmed electrical stimulation in Brugada syndrome: 20 years experience. Circ Arrhythm Electrophysiol 2015;8:777–84. DOI: 10.1161/CIRCEP.114.002647; PMID: 25904495 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

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Cardiol 2012;59:37–45. DOI: 10.1016/j.jacc.2011.08.064; PMID: 22192666 45. Sroubek J, Probst V, Mazzanti A, et al. Programmed ventricular stimulation for risk stratification in the Brugada syndrome: a pooled analysis. Circulation 2016;133:622–30. DOI: 10.1161/CIRCULATIONAHA.115.017885; PMID: 26797467; PMCID: PMC4758872 46. Letsas KP, Liu T, Shao Q, et al. Meta-analysis on risk stratification of asymptomatic individuals with the Brugada phenotype. Am J Cardiol 2015;116:98–103. DOI: 10.1016/ j.amjcard.2015.03.044; PMID: 25933735 47. Bezzina CR, Lahrouchi N, Priori SG. Genetics of sudden cardiac death. Circ Res 2015;116:1919–36. DOI: 10.1161/ CIRCRESAHA.116.304030; PMID: 26044248 48. Haïssaguerre M1, Chatel S, Sacher F, et al. Ventricular fibrillation with prominent early repolarization associated with a rare variant of KCNJ8/KATP channel. J Cardiovasc Electrophysiol 2009;20:93–8. DOI: 10.1111/j.15408167.2008.01326.x; PMID: 19120683 49. Watanabe H, Nogami A, Ohkubo K, et al. Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization. Circ Arrhythm Electrophysiol 2011;4:874–81. DOI: 10.1161/CIRCEP.111.963983; PMID: 22028457 50. Burashnikov E, Pfeiffer R, Barajas-Martinez H, et al. Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm 2010;7:1872–82. DOI: 10.1016/j.hrthm.2010.08.026; PMID: 20817017; PMCID: PMC2999985 51. Hu D, Barajas-Martínez H, Terzic A, et al. ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene. Int J Cardiol 2014;171:431–42. DOI: 10.1016/j.ijcard. 2013.12.084; PMID: 24439875; PMCID: PMC3947869

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52. Hofman N, Tan HL, Alders M, et al. Yield of molecular and clinical testing for arrhythmia syndromes: report of 15 years’ experience. Circulation 2013;128:1513–21. DOI: 10.1161/CIRCULATIONAHA.112.000091; PMID: 23963746 53. Schulze-Bahr E, Eckardt L, Breithardt G, et al. Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: different incidences in familial and sporadic disease. Hum Mutat 2003;21:65–12. DOI: 10.1002/humu.9144; PMID: 14961552 54. Gourraud JB, Le Scouarnec S, Sacher F, et al. Identification of large families in early repolarization syndrome. J Am Coll Cardiol 2013;61:164–72. DOI: 10.1016/j.jacc.2012.09.040; PMID: 23273290 55. Crotti L, Marcou CA, Tester DJ, et al. Spectrum and prevalence of mutations involving BrS1- through BrS12susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing: implications for genetic testing. J Am Coll Cardiol 2012;60:1410–8. DOI: 10.1016/j.jacc.2012.04.037; PMID: 22840528; PMCID: PMC3624764 56. Kapplinger JD, Tester DJ, Alders M, et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm 2010;7:33–46. DOI: 10.1016/j.hrthm.2009.09.069; PMID: 20129283; PMCID: PMC2822446 57. Dumaine R, Towbin JA, Brugada P, et al. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res 1999;85:803–9. PMID: 10532948 58. Meregalli PG, Tan HL, Probst V, et al. Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. Heart

Rhythm 2009;6:341–8. DOI: 10.1016/j.hrthm.2008.11.009; PMID: 19251209 59. Bezzina CR, Rook MB, Groenewegen WA, et al. Compound heterozygosity for mutations (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system. Circ Res 2003;92:159–68. PMID: 12574143 60. Wang DW, Yazawa K, George AL Jr., et al. Characterization of human cardiac Na+ channel mutations in the congenital long QT syndrome. Proc Natl Acad Sci USA 1996;93:13200–5. PMID: 8917568; PMCID: PMC24070 61. Medeiros-Domingo A, Tan BH, Crotti L, et al. Gain-offunction mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes. Heart Rhythm 2010;7:1466–71. DOI: 10.1016/j.hrthm.2010.06.016; PMID: 20558321; PMCID: PMC3049900 62. Barajas-Martínez H, Hu D, Ferrer T, et al. Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8. Heart Rhythm 2012;9:548–55. DOI: 10.1016/j. hrthm.2011.10.035; PMID: 22056721; PMCID: PMC3288170 63. Potet F, Mabo P, Le Coq G, et al. Novel Brugada SCN5A mutation leading to ST segment elevation in the inferior or the right precordial leads. J Cardiovasc Electrophysiol 2003;14:200–3. PMID: 12693506 64. Kolder I, Tanck M, Bezzina CR. Common genetic variation modulating cardiac ECG parameters and susceptibility to sudden cardiac death. J Mol Cell Cardiol 2012;52:620–9. DOI: 10.1016/j.yjmcc.2011.12.014; PMID: 22248531

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Arrhythmogenic Cardiomyopathy: Electrical and Structural Phenotypes Deniz Akdis, 1 Corinna Brunckhorst, 1 Firat Duru, 1,2 Ardan M Saguner 1 1. Department of Cardiology, University Heart Center, Zurich, Switzerland; 2. Center for Integrative Human Physiology, University of Zurich, Switzerland

Abstract This overview gives an update on the molecular mechanisms, clinical manifestations, diagnosis and therapy of arrhythmogenic cardiomyopathy (ACM). ACM is mostly hereditary and associated with mutations in genes encoding proteins of the intercalated disc. Three subtypes have been proposed: the classical right-dominant subtype generally referred to as ARVC/D, biventricular forms with early biventricular involvement and left-dominant subtypes with predominant LV involvement. Typical symptoms include palpitations, arrhythmic (pre)syncope and sudden cardiac arrest due to ventricular arrhythmias, which typically occur in athletes. At later stages, heart failure may occur. Diagnosis is established with the 2010 Task Force Criteria (TFC). Modern imaging tools are crucial for ACM diagnosis, including both echocardiography and cardiac magnetic resonance imaging for detecting functional and structural alternations. Of note, structural findings often become visible after electrical alterations, such as premature ventricular beats, ventricular fibrillation (VF) and ventricular tachycardia (VT). 12-lead ECG is important to assess for depolarisation and repolarisation abnormalities, including T-wave inversions as the most common ECG abnormality. Family history and the detection of causative mutations, mostly affecting the desmosome, have been incorporated in the TFC, and stress the importance of cascade family screening. Differential diagnoses include idiopathic right ventricular outflow tract (RVOT) VT, sarcoidosis, congenital heart disease, myocarditis, dilated cardiomyopathy, athlete´s heart, Brugada syndrome and RV infarction. Therapeutic strategies include restriction from endurance and competitive sports, b-blockers, antiarrhythmic drugs, heart failure medication, implantable cardioverter-defibrillators and endocardial/epicardial catheter ablation.

Keywords Arrhythmogenic right ventricular dysplasia/cardiomyopathy, arrhythmias, ventricular tachycardia, sudden cardiac death, implantable cardioverter defibrillator Disclosure: The authors have no conflicts of interest to declare. Acknowledgements: This work and the Zurich ARVC Program are supported by grants from the Georg and Bertha Schwyzer-Winiker Foundation, Zurich, the Baugarten Foundation, Zurich, filling the gap grant, University of Zurich and the Swiss National Science Foundation, Switzerland. Received: 13 January 2016 Accepted: 3 August 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(2):90–101 DOI: 10.15420/AER.2016.4.3 Access at: www.AERjournal.com Correspondence: Dr Ardan M Saguner, Department of Cardiology, University Heart Center Zurich Rämistrasse 100, CH-8091 Zurich, Switzerland. E: ardan.saguner@usz.ch

Arrhythmogenic cardiomyopathy (ACM) is usually referred to as arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D).1 A first historical description was made in 1736, whereas its first modern description dates back to 1982.2 Initially, ACM was thought to be an embryological malformation.3 Yet in recent years it became evident that the pathophysiology of an ongoing genetically determined myocardial atrophy did not fit the theory of a congenital myocardial aplasia. Genetic and pathological studies have been crucial to understand ACM. From autoptic studies we know that atrophy of the ventricular myocardium due to progressive myocyte loss and infiltration by fibrofatty tissue are key findings.4 These studies led to the assignment of ARVC/D as a primary cardiomyopathy by the World Health Organization in 1995.5 In its most typical form, the right ventricle (RV) is primarily affected, which is then referred to as ARVC/D.6 As the disease progresses, the left ventricle (LV) may also be involved.7 Molecular studies have identified causative mutations in genes encoding proteins of the intercalated disc, desmosomes in particular.8 These mutations impair the electrical and mechanical stability of the ventricular

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myocardium9,10 with subsequent inflammation, apoptosis, necrosis and fibrofatty infiltration, which usually begins after puberty.11,12 In a minority of patients non-desmosomal mutations in calcium regulating genes, growth factors and other structural genes have been associated with ACM. Nonetheless, genetic mutations cannot entirely account for phenotypic expression and disease progression, and genetic mutations cannot be identified in up to 50 % of the ACM population studied. Therefore, epigenetic and environmental factors such as exercise seem to play a pivotal role as disease modifiers. 1,13,14 Increased workload for the myocardium during physical activity enhances this adverse remodelling, and the thinner RV is particularly prone.15 Due to the multiple facets of the disease, the term ARVC/D is somewhat misleading. Since biventricular involvement and LV involvement may be present,1,16 a broader term such as arrhythmogenic cardiomyopathy has been recently proposed by the Heart Rhythm Society/European Heart Rhythm Association (HRS/EHRA).1,16,17 Together with novel genetic evidence that further expanded the pathophysiology of this heterogeneous disease beyond desmosomal mutations, the term ACM is now commonly being used to describe a hereditary form of non-hypertrophic cardiomyopathy

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that primarily manifests with ventricular arrhythmias due to fibrofatty infiltration of the ventricular myocardium.1,18,19

Epidemiology Phenotypic expression is more common in males (2–3:1).14 ACM usually manifests during adolescence, but can also emerge in the elderly.20 With a general prevalence of 1:2,000–1:5,000 ARVC/D is a rare disease, which is defined as a prevalence of ≤1:2,000 according to the European definition.21 However, in some endemic areas the prevalence may be higher.22 ACM is a leading cause of sudden cardiac death (SCD) due to ventricular tachyarrhythmias, particularly in young athletes ≤35 years of age.23,24 In one Italian study, ACM accounted for up to 22 % of SCD in young adults.6,25,26 Generally, ACM first manifests with ventricular arrhythmias. In classical ARVC/D, ventricular arrhythmias arise from the RV.27

Table 1: Genetic Mutations Associated With Arrhythmogenic Right Ventricular Cardiomyopathy/ Dysplasia 19,32,59 Involved Structure

Gene

Reported Incidence

Plakophilin 2

25–40 %

Desmocollin 2

2–7 %

Desmoglein 2

5–10 %

Desmoplakin

2–12 %

Plakoglobin Unknown

Desmosome

Non-desmosomal proteins Cytoplasmatic molecules

α-T-catenin Unknown

Calcium/sodium channels

Ryanodine

receptor 2

Unknown

Phospholamban Unknown

Genetics and Disease Modulation

Nuclear envelope proteins/

Lamin A/C

ARVC/D is usually inherited as an autosomal dominant trait. Recessive forms with additional phenotypic characteristics exist.28 Recessive mutations of desmosomal genes can cause severe forms of ARVC/D, such as Naxos disease and Carvajal syndrome, some with skin and hair involvement, since both alleles are involved.29,30 Moreover, it has been shown that in up to 18 % of patients with ARVC/D, compound or digenic heterozygosity is present, indicating that in some cases more than one pathogenic allele may be involved.31 Currently 13 different genetic loci have been reported to be associated with ARVC/D. The most common genes encode for desmosomal proteins.32,33 Recent studies have shown that non-desmosomal genes can also lead to an ARVC/D phenotype (see Table 1). However, in cardiomyopathies – similar to other genetic diseases – it is very important to use rigorous criteria when calling a genetic variant or mutation pathogenic, since many variants may only constitute innocent bystanders.

Transmembrane proteins

Transmembrane

protein 43

Cytoskeletal proteins

Desmin

A recent transatlantic collaboration with ACM registries from the Netherlands and the US has suggested rigorous criteria on how to classify genetic variants/mutations in ACM, which are now widely accepted in this field.32 Another recent large-scale trial on long QT and Brugada syndromes from the US has revealed that even among laboratories experienced in genetic testing for cardiac arrhythmia disorders, there was low concordance in designating variants as pathogenic. In an unselected population, the putatively pathogenic genetic variants were not associated with phenotypic abnormalities, which raises questions about the implications of notifying patients of incidental genetic findings.1,34,35 Thus, it is important to consider whether the genetic finding is present in a symptomatic patient or family member with a rather high pre-test probability, or in an asymptomatic patient as an incidental finding, who as a matter of course has a low pre-test probability.35 The American College of Medical Genetics and Genomics has published recommendations on how to report incidental findings in clinical exome and genome sequencing.36 Genetically affected relatives demonstrate variable, and often milder phenotypes, which has been attributed to incomplete disease penetrance. Therefore, the prevalence of familial disease is probably underestimated.32 Nonetheless, an important reason why index patients usually present with more severe phenotypes than their family members is so-called ascertainment bias. The clinician should bear in mind that relatives due to ascertainment alone will likely have milder phenotypes since they were not the ones to initially present. As opposed to this, index patients (probands) by

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Unknown

Titin Unknown Membrane receptors/

Transforming

cytokines

growth factor β3

Unknown

default are always the most affected, which is an important reason why some genetics literature would exclude probands in analyses to offset ascertainment bias. This sort of bias is inherent to genetic diseases and has to be considered when performing genetic testing of index patients and family cascade screening.37 Desmosomes provide cell-to-cell adhesion and consist of three major groups of proteins:38 a) the transmembrane proteins (cadherins) desmocollin-2 (DSC2) and desmoglein-2 (DSG2), b) desmoplakin (DSP) and c) the linker armadillo proteins plakoglobin (JUP) and plakophillin-2 (PKP2), which are mediators between the cadherins and DSP.9,39 In about 80 % of cases with confirmed pathogenic mutations, mutations in PKP2, DSP, and DSG2 are identified,8 with the most common mutations involving PKP2. Several mutations have been described in these desmosomal genes. Besides unambiguous pathogenic splice site and truncating mutations, it is crucial to also identify pathogenic missense mutations in patients with ACM, as they have been reported to have the same impact on disease outcome as other mutations.32,40 Yet, the variability of genotype–phenotype correlations and the heterogeneity of genetic mutations pose a great challenge for ACM diagnosis and risk stratification. Some mutations have been associated with specific clinical outcomes. For instance, truncating mutations in DSP or digenic/ compound heterozygosity of desmosomal genes are associated with more aggressive phenotypes and can be considered as risk factors of SCD and heart failure.32,41,42 Further studies with larger patient cohorts and rigorous genetic criteria are needed in order to improve our understanding of genotype–phenotype correlations in ACM. In a minority of cases, mutations can be detected in non-desmosomal genes. Mutations in the ryanodine receptor, which releases calcium from the sarcoplasmic reticulum during muscle contraction,43 and in the key calcium regulating protein phospholamban (PLN) may also lead to ACM phenotypes, and although these patients may present at an older age, their long-term prognosis might be worse.32,44 Mutations in transforming growth factor b 3 (TGFb3) have also been reported, resulting in its overexpression inducing myocardial fibrosis by stimulation of mesenchymal proliferation.

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Clinical Arrhythmias TGFb3 modulates desmosomal expression as well, so mutations can alter desmosomal distribution and influence cellâ&#x20AC;&#x201C;cell stability.45 A mutation in the transmembrane protein 43 (TMEM43) leads to a severe and highly lethal form of ARVC/D. This mutation was identified as a founder mutation in Newfoundland. Although this mutation is not located on the heterosomes, the phenotype is gender-specific with males having lower life expectancy than females, and carrying a higher risk for SCD.46 Although the pathophysiological role of TMEM43 remains uncertain, studies have proposed that it may interact within the adipogenic pathway and also lead to nuclear structural changes.47 The TMEM43 p.S358L (Newfoundland) mutation has been shown to be fully penetrant.48 In this subgroup, it is important to screen large pedigrees since this mutation can be highly lethal and often presents with SCD as a first symptom.49 Newer data shows that further proteins are associated with ACM. The intracellular filament protein desmin, Îą-T catenin (a cytoplasmic protein), lamin A/C (a nuclear protein) and titin (a large sarcomeric protein) have been associated with ACM and phenocopies.1,34,50 Various genetic mutations have been associated with ACM, but these cannot account for the entire spectrum of disease expression. Therefore, epigenetic and environmental factors may act as disease modulators. First evidence for this hypothesis arose from monozygotic twin studies, where differences were reported in symptom onset, disease severity and arrhythmic risk.51 A male predominance of disease expression has been generally described in ACM, with male gender constituting an independent risk factor for adverse outcome.52,53 Recent data of compound and digenic heterozygosity indicates that modifier genes may account for residual variation and disease severity.31,54 Most importantly, strenuous physical activity, particularly endurance sports, plays an important role for early disease manifestation, disease severity and progression.13,55,56 Understanding the relationship between genotype and phenotype is challenging. Although ACM is mostly inherited as an autosomal dominant trait, this is likely an oversimplification since disease expressivity and penetrance are generally low. Clinical presentation and disease course can substantially differ within the same affected family due to the complex genetic and epigenetic background. Yet, it should be noted that variable phenotypic expression is seen in almost all genetic diseases, and is not only encountered in ACM. Using genetic testing as a diagnostic tool can be challenging. This particularly holds true for next-generation sequencing (NGS) methods, by which an abundancy of genetic variants of unknown significance can be detected, which is particularly challenging when it comes to the interpretation of borderline or overlapping phenotypes.34,57 Therefore, as previously mentioned, rigorous criteria to label a mutation as pathogenic should be used. Data from exome sequencing projects and in silico predictive programs can be helpful in this regard, especially for missense mutations and variants in order to avoid 'genetic' overdiagnosis.1,32 Nevertheless, genetic testing may be very helpful to verify ACM in the index patient and in identifying affected relatives and subclinical/ concealed phases. It is hoped that NGS will facilitate the identification of new disease modifiers or causative mutations, particularly in patients in whom a desmosomal mutation is present, but disease penetrance is not complete in family members harbouring this particular desmosomal mutation, and the real genetic culprit is yet to be found.58,59

desmosome can result in a loss of cardiomyocytes accompanied by fibro-fatty tissue replacement.9,60,61 Desmosomal proteins interact with other junctional molecules such as other cadherins, catenins, ion channels, e.g. the sodium channel Nav1.5, and gap junction molecules.62 A functional link between desmosomes, gap junctions and Nav1.5 has been described, and recently named connexome.63 Several mechanisms are being discussed in the pathogenesis of ACM. Reduced cell-to-cell adhesion by desmosomal dysfunction due to genetic mutations is thought to be a key mechanism.39,64 Mutations in desmosomes change the 3D structure, their length and the total amount of desmosomes.65,66 This can trigger intercalated disc remodelling, which does not only alter mechanical stability, but also electrical coupling between cells, and intra/intercellular signal transduction affecting apoptosis and lipid metabolism.39,61,67,68 A decrease of JUP at the intercalated disc with its nuclear translocation and suppression of the canonical Wnt signalling pathway has been reported, even in individuals with other desmosomal mutations.65 Early histology and electron microscopy studies revealed that fibrofatty replacement of the RV goes along with inflammation and apoptosis.4,69,70 Induced pluripotent stem cell models from patients harbouring a pathogenic PKP2 mutation have highlighted that enhanced mitochondrial fatty acid uptake may lead to changes in fatty acid oxidation and promote fatty infiltration.61 Further experimental and clinical data suggest that non-desmosomal structures such as Nav1.5, PLN, desmin, titin and TMEM43 also interact with desmosomes and that mutations in these genes may change intracellular signalling pathways (see Figure 1).71,72 PLN knockout has been associated with calcium channel modulation leading to VT.73 Furthermore, PLN phosphorylation has been reported to be upregulated in patients with ARVC/D72 in analogy to the pathophysiology of heart failure, which can be the endstage clinical presentation of ACM.74 Regarding titin mutations it has been shown that certain mutations may lead to a reduced structural stability and increased susceptibility for undergoing proteolysis.75 TMEM43 has also been associated with the intercalated disc and the adipogenic pathway.47,48 It has been shown that the TMEM43 p.S358L (Newfoundland) mutation may affect the localisation of proteins involved in cellular conduction and reduce conduction velocity in cardiac tissue.76 Yet, the role of non-desmosomal genetic mutations in the disease pathogenesis has not been fully elucidated, and there is a need for further experimental and clinical studies. Patient specific induced pluripotent stem cell models may play an important role in the discovery of novel disease mechanisms.61 Furthermore, volume overload and mechanical stress have also been suggested to enhance desmosomal dysfunction, which may explain why vigorous exercise has a negative impact on ACM phenotype, and why endurance athletes are particularly prone to adverse remodelling.77 In mice with PKP2 mutations, exercise leads to RV dilation and dysfunction.78,79 Clinical studies underscore the negative impact of sports, particularly high-intensity endurance training on ACM phenotype.13,80 Myocarditis has also been associated with ACM, especially in genotype elusive patients, since cardiotropic viruses and bacteria have been found in cardiac tissue of these patients.11,81 Yet, the role of cardiotropic agents in the pathogenesis of ACM needs further investigation.

Phenotypic Expression Pathogenesis The desmosomal complex is crucial for cellular adhesion, tissue strength and stability. It is located at the cardiac intercalated disc. A defective

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Classification of ACM into three different subtypes has been suggested. Right-dominant ARVC/D is considered as the classical form. Nonclassical forms were recently described.38,82,83 LV involvement is

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reported with a prevalence of up to 70 % of cases,84 which may be attributed to improved diagnostic methods.85 Yet, the proposed classification below is simplistic. It is important to keep in mind that due to genetic heterogeneity, epigenetic and environmental modifying factors and ascertainment bias there is a phenotypic continuum with the right- and left-dominant subtypes at opposite ends. Some mutations have been described to confer all described phenotypes.46 With regard to the important issue of ascertainment bias, individuals seeking medical attention often present with symptoms and advanced phenotypes. This can cause a selection bias in registries, and studies investigating ACM and genotype–phenotype correlations derived from these studies may not apply to a general ACM population. Such a bias is difficult to avoid in rare diseases such as ACM but has to be considered when interpreting study results.37 In right-dominant ARVC/D, a dilated RV with regional wall motion abnormalities with no or minimal LV involvement is observed (see Figure 2A). Myocardial remodelling starts in the subepicardial layers and may become transmural later on.17 Myocardial wall thinning can be seen on macroscopic examination.22,86 The subtricuspid region and RVOT are particularly prone to this remodelling process, leading to aneurysm formation.17 The concept of RV apical involvement and the term 'triangle of dysplasia' have recently been questioned.87 If an affected region is accessible for histological evaluation, inflammation, fibrosis and/or fatty infiltration can be visible.18,88 Biventricular arrhythmogenic cardiomyopathy is characterised by early involvement of both ventricles (see Figure 2B).89,90 Disease progression is characterised by systolic impairment and biventricular dilation with clinical features of global congestive heart failure. In contrast to dilated cardiomyopathy (DCM) with biventricular involvement, ventricular arrhythmias of both, right bundle branch block (RBBB) configuration – originating in the LV – and left bundle branch block (LBBB) configuration are present at an early stage.

Figure 1: Phospolamban Protein Expression and Localisation PLN

pPLN

ARVC/D

DCM

Control

Expression and distribution of total and phosphorylated phospholamban (PLN) in the right ventricular myocardium of patients with ARVC/D as compared with patients with non-ischaemic dilated cardiomyopathy (DCM) and healthy controls. Representative immunohistochemistry with Alexa Fluor® 488 dye as secondary antibody and 6-Diamidino-2-phenylindole as nucleus staining. ARVC/D = Arrhythmogenic right ventricular cardiomyopathy/dysplasia; pPLN = phosphorylated phospholamban. Modified with permission from Akdis et al., 2015.72

• • • • •

been introduced.18 It is important to distinguish syndromes leading to ventricular arrhythmias and SCD from benign forms and those forms primarily leading to heart failure.26,42,93 A high clinical suspicion should be raised if symptoms correlate with premature ventricular beats or VT, particularly LBBB morphology with a superior axis. However, left ventricular forms or biventricular disease can also present with VT with RBBB morphology. Monomorphic VT is associated with more advanced disease stages, although gross structural abnormalities are not always required for maintaining re-entry circuits.93,94 Up to onequarter of patients present with atrial arrhythmias, most frequently atrial fibrillation.95,96 This is associated with inappropriate implantable cardioverter defibrillator (ICD) shocks and an increased risk of both death and heart failure.97 It is not exceptional for ACM to manifest with SCD (annual incidence up to 9 %),98 both during strenuous physical activity99 and in the sedentary state.15 In ARVC/D caused by TMEM43 mutations, enhanced sympathetic activity has been shown as a trigger for lethal arrhythmias, particularly in males.47

Although palpitations and (pre)syncope are the most frequent symptoms,91 they also occur in many other arrhythmic syndromes such as cardiac sarcoidosis, channelopathies and other cardiomyopathies.92 Since there is a considerable overlap between ARVC/D and 'arrhythmic forms' of idiopathic DCM, the broader term ACM has

T-wave inversions in V1–3 are benign until puberty, and their prevalence among athletes and controls seems to be similar thereafter.100 If T-wave inversions in V1–3 are detected after puberty, transthoracic echocardiography (TTE) can be performed to rule out structural heart disease. Dyspnoea and signs of right-sided heart failure are rare. Congestive heart failure may occur with progressive LV involvement. The treating physician should keep in mind that ACM cannot be excluded by the absence of structural abnormalities, as arrhythmias

Left-dominant arrhythmogenic cardiomyopathy (ALVC) has been proposed as a distinct form of ACM. It is characterised by the early occurrence of LV involvement (arrhythmias precede gross structural alterations), when global RV function is preserved. Electrocardiographic (ECG) and structural findings are left-sided analogues to those observed in ARVC/D (see Table 2).89

Clinical Presentation ACM should be suspected if the following symptoms occur, particularly in young athletes: Palpitations Arrhythmic (pre)syncope Aborted SCD Chest pain ± rise in cardiac biomarkers Presumed DCM with early onset and frequent ventricular arrhythmias • Precordial T-wave inversions beyond V1 after puberty (see Table 2, Figure 3).

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Clinical Arrhythmias Table 2: Clinical Characteristics of Arrhythmogenic Ventricular Cardiomyopathy 89

Classic Right Dominant Left Dominant Form Form (ARVC/D)

12-lead surface ECG

QRS prolongation V1–3

Slurred S-wave upstroke

Early precordial R wave

V1–3

transition

ε wave in V1–3

ε-like waves in inferior or

Leftward QRS axis (<0°)

lateral leads

(Incomplete) RBBB

LBBB

Inverted T waves in V1–3

Inverted T waves in

inferolateral leads

Inverted T waves in V1–6

Inverted T waves V1–6

with biventricular

involvement

Poor R wave progression

Signal-averaged ECG

Late potentials

Arrhythmia

PVC of LBBB configuration PVC of RBBB configuration

VT of LBBB configuration

– VT of RBBB configuration

Ventricular volumes

Mild to severe RV-dilation Mild to severe LV dilation

± dysfunction

RV/LV volume ratio

≥1.2, increases with

<1.0

disease expression

Other imaging

Regional wall motion

abnormalities

abnormalities in RV

abnormalities in LV

Fat/LGE in RV

Non-compacted

myocardium

appearance

LGE in the subepicardial

and midwall LV

myocardium Genetics and

Desmosomal mutations

Association with TMEM43

environmental factors

frequent; endurance

(Newfoundland)

athletes typically affected

mutation, DSP mutations and PLN mutations

ARVC/D = arrhythmogenic right ventricular cardiomyopathy/dysplasia; ECG = electrocardiogram; e = epsilon; LBBB = left bundle branch block; LGE = late gadolinium enhancement; LV = left ventricle; PVC = premature ventricular contraction; RBBB = right bundle branch block; RV = right ventricle; VT = ventricular tachycardia.

often occur in the early – so called 'concealed phase' – preceding structural abnormalities. In a study evaluating 37 ARVC/D families, <50 % of family members had overt disease and 17 family members did not display the phenotype despite harbouring the pathogenic mutation.101 Of note, during the concealed phase and in subtypes primarily presenting with heart failure, palpitations and (pre)syncope do not have a great diagnostic value. Therefore, it is important to combine several tools for diagnosis and risk stratification, including genetics whenever possible and reasonable. In certain subgroups a positive mutation status, particularly in males, may play a role in diagnosis and risk stratification,35,58,102 for example in families harbouring the TMEM43 p.S358L (Newfoundland) mutation – a fully penetrant, sex-influenced, highly lethal form of ARVC/D.48

Diagnosis Revised 2010 Task Force Criteria In 2010, the original 1994 TFC by McKenna et al.103 were revised to increase diagnostic sensitivity, particularly in affected asymptomatic family members.102 Pathogenic mutations were included, and cut-off values for imaging and histology were provided. The impact of these changes has been recently evaluated. Some investigators reported an increased diagnostic yield,104 whereas others did not.105,106 The clinician should bear in mind that the 2010 TFC only apply to ARVC/D,

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but not left-dominant ACM. For most forms of ACM there is only weak evidence supporting pre-symptomatic diagnosis by genetic testing.1,32 However, in the case of the TMEM43 p.S358L mutation, presymptomatic diagnosis can be made by a positive genotype only.48,49 For most subforms of ACM we have to rely on the 2010 TFC to establish the diagnosis. The current gold standard for diagnosis of ARVC/D are the 2010 TFC, at least until these criteria can be be further improved.102 The revised TFC consist of six diagnostic categories (see Table 3): • Global and/or regional myocardial dysfunction and structural abnormalities • Histological characterisation • Repolarisation abnormalities on 12-lead surface ECG • Depolarisation abnormalities on 12-lead surface ECG • Arrhythmias • Family history and genetics. A definite diagnosis can be made with two major criteria, one major and two minor criteria, or four minor criteria from different categories; 'borderline' diagnosis with one major and one minor criterion, or three minor criteria and a 'possible' diagnosis if one major criterion or two minor criteria are present. Comprehensive non-invasive evaluation is mandatory, which includes a thorough clinical history, pedigree analysis, 12-lead surface ECG, TTE with detailed assessment of the RV, CMR, stress testing and Holter ECG. Event recorders and invasive diagnostics may be necessary if suspicion remains high and symptoms are rare. The revised TFC define quantitative criteria and abnormalities mainly based on comparison between adult index patients with ARVC/D and healthy controls. This approach has some limitations that should be taken into account. First, reference values of patients with ARVC/D and healthy subjects were derived from selected populations from tertiary care centres specialised in applying this particular diagnostic modality. Therefore, these reference values are prone to a substantial selection and ascertainment bias, and thus may not apply to the general ACM population, family members and individuals younger than 12 years. Moreover, they do not apply to patients with left-dominant forms.102

12-lead Surface ECG and Signal-averaged ECG 12-lead surface ECG will be abnormal in about 50 % of patients. This will include T-wave inversions in the right precordial leads, sometimes also involving V4–6, slurred S-wave upstroke in V1–3 ≥55 ms (see Figure 3), and with more advanced stages e waves.107 The interpretation of e waves significantly varies among observers. Furthermore, e waves occur at more advanced stages, when the vast majority of patients already fulfils other TFC for definite diagnosis. Thus, e waves in the absence of other diagnostic criteria should be interpreted with caution.108 T-wave inversions can be found in healthy individuals, patients with anterior ischaemia or RV hypertrophy.108,109 A recent study highlighted the importance of serial ECG evaluations, since dynamic ECG changes may occur.110 Delay of ventricular depolarisation due to scar (zig-zag pathways) may be visible as QRS fragmentation,108 e waves111 or late potentials recorded by signal-averaged ECG (SAECG).112 SAECG may not be sensitive enough to detect early forms of ACM.112 Over recent years, the role of SAECG for ARVC/D diagnosis has diminished due to major advances in imaging and genetics.

Stress Testing Ventricular arrhythmias in patients with ACM are often triggered by sympathetic activation. Thus, treadmill testing can reveal VT/

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VF or increase premature ventricular contractions with different morphologies. In a recent study, exercise testing revealed typical ECG abnormalities in a considerable number of patients with latent ARVC/D.113 In another study, the evaluation of the arrhythmic potential during very high dose isoproterenol infusion was sensitive for diagnosis of early forms of ARVC/D.114

Figure 2: Structural Phenotypes of Arrhythmogenic Cardiomyopathy A

1 cm

Transthoracic Echocardiography TTE is readily available in most centres and rapidly informative. Thus, TTE is considered as the initial imaging tool for suspected ACM and for screening family members. It may show RV enlargement and regional contraction abnormalities, most commonly in the subtricuspid region and RVOT.115 RVOT dimensions are crucial for diagnosis according to the 2010 TFC.116 The LV can be affected in up to 70 % of patients with ARVC/D displaying hypokinesia and a reduced ejection fraction. Frequently, LV structural abnormalities are localised in the posterolateral region.87,117,118 Novel technologies such as strain imaging allow for better quantification of regional wall motion, thereby allowing earlier disease detection and LV involvement.84

Cardiac Magnetic Resonance Tomography Cardiac magnetic resonance tomography (CMR) has emerged as the non-invasive gold standard for assessing the RV over the past 20 years.119 Assessment of right-sided volumes and ejection fraction is highly accurate. Late-gadolinium enhanced (LGE) CMR can reveal myocardial fibrosis.120 Yet, myocardial fibrosis and fat as potential diagnostic features were not integrated in the TFC, because of their limited specificity, high intra-and inter-observer variability and the need for highly specialised interpreters.121,122 This owes to the fact that the RV is very thin and epicardial fat cannot reliably be distinguished from intramyocardial fat. However, CMR plays an important role for ARVC/D diagnosis (see Figure 2A). Consensus documents for nonclassic forms are awaited. The advent of novel technologies such as CMR tagging may facilitate early diagnosis of ARVC.123–127

RV Angiography RV angiography is considered very useful to diagnose ARVC/D128 and thus is equivalent to TTE and CMR in the 2010 TFC. It has a positive predictive value of ∼85 %, with a negative predictive value of 95 %.129 High quality images allow assessment of RV morphology and wall motion. Yet, clinicians want to apply non-invasive diagnostic strategies without ionising radiation, particularly in young patients. Serial followup angiographies for monitoring disease progression are not feasible. Of note, hypokinesia is not considered diagnostic in the 2010 TFC, since akinesia or dyskinesia are required.

Electrophysiological Study and Electroanatomical Voltage Mapping The goal of an electrophysiological study (EPS) in patients with ACM is the induction of sustained ventricular arrhythmias for making the diagnosis, risk stratification and to guide ablation. Moreover, the susceptibility for arrhythmias ± sympathetic challenge with isoproterenol, ICD treatment algorithms and efficacy of antiarrhythmic drugs (AAD) can be assessed. Electroanatomical voltage mapping (EAM) is a technique using electrophysiological catheters to measure myocardial voltages. After obtaining several hundred to thousands of points, a voltage map can be reconstructed. Normal myocardium generally displays bipolar voltages >1.5 mV.130,131 In diseased myocardium, lower voltages with a longer duration, splitting and fractionation of signals can be recorded. Myocardial voltage maps

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IVS

Left panel (A): Classical ARVC/D – Regional right ventricular (RV) dyskinesia in the subtricuspid area (red arrow) during systole detected by cardiac magnetic resonance imaging (4-chamber view). The RV is dilated (RV end-diastolic volume index 121 ml/m2, norm 65–102) and RV ejection fraction is reduced (RV–EF 42 %, norm >45 %). Regional RV dyskinesia in conjunction with RV dilation is considered a major criterion for ARVC/D diagnosis. Note that there is no left ventricular involvement in this patient. Right panel (B): Biventricular ACM – This explanted heart during heart transplantation from a patient (fulfilling a definite diagnosis according to the 2010 Task Force Criteria) harbouring a pathogenic desmoplakin mutation shows biventricular dilation and fatty infiltration of both ventricles including the interventricular septum (IVS). Cardiac sarcoidosis was ruled out in this patient by histology.

can be obtained both from the endocardium and epicardium. EAM is generally safe, and improves outcomes of VT ablation.132–135 The diagnostic and prognostic utility of EAM has not been implemented in the current TFC, but recent data indicate that it can be useful for diagnosis and risk stratification.136

Endomyocardial Biopsy Endomyocardial biopsy (EMB) has, for a long time, been considered the diagnostic gold standard for ACM diagnosis. Indeed, histological examination and immunostaining may allow confirmation of ACM, and exclude differential diagnoses, e.g. sarcoidosis, Chagas disease or other forms of myocarditis. Yet, biopsies are usually taken from the RV septum for safety reasons. Since the process of fibro-fatty infiltration spares the septum, EMB often yields false-negative results.137,138 EMB from diseased regions is problematic, as these regions are very thin, and sampling carries an increased risk of perforation. As ACM is patchy, several biopsies should be obtained. EAM-guided biopsies taken from low-voltage areas may improve diagnostic yield and better distinguish between myocarditis or sarcoidosis.130,139

Genetic Testing When performing genetic testing, rigorous criteria to ascertain whether a mutation or variant is pathogenic should be used. An HRS/EHRA consensus statement for genetic testing in ACM was published recently.1 Genetic testing is performed to confirm ACM in individuals with a high (Class IIa) or intermediate (at least one major or two minor criteria; Class IIb) clinical suspicion and to identify genetically-affected relatives harbouring the pathogenic mutation (Class I). Genetic testing in cases fulfilling only one minor criterion is not recommended.8,42,58 A negative genetic test does not exclude ACM, since other unknown causal mutations and environmental factors may also cause the disease.60,140 With the exception of TMEM43 p.S358L mutation carriers48 and autosomal-recessive forms, genotype does not provide a diagnosis of ACM by itself.1,8,102 Yet, the identification of pathogenic mutations may be useful in the differential diagnosis of ACM and phenocopies, such as myocarditis, idiopathic RVOT tachycardia, DCM, muscular dystrophies or sarcoidosis.1,32,141 Genetic testing should not be seen as the only diagnostic tool, but may be very helpful especially in identifying affected relatives and subclinical/ concealed phases. 58,59 Genetic cascade screening of relatives offers an alternative strategy to serial clinical evaluation. In this regard, the absence of a clear pathogenic mutation in a family member

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Clinical Arrhythmias Table 3: Revised (2010) Task Force Criteria for Diagnosis of ARVC/D I. Global or regional dysfunction/structural alterations Major

2D TTE

Regional RV akinesia, dyskinesia or aneurysm and 1 of the following criteria (end diastole):

- PLAX RVOT ≥32 mm (PLAX/BSA] ≥19 mm/m2)

- PSAX RVOT ≥36 mm (PSAX/BSA] ≥21 mm/m2)

or RV fractional area change ≤33 %

CMR

Regional RV akinesia, dyskinesia, or dyssynchronous RV contraction and 1 of the following criteria (end diastole):

- RV end-diastolic volume /BSA ≥110 mL/m2 (male) or ≥100 mL/m2 (female)

or RV ejection fraction ≤40 %

RV Angiography

Regional RV akinesia, dyskinesia or aneurysm

Minor

2D TTE

Regional RV akinesia, or dyskinesia and 1 of the following criteria (end diastole):

- PLAX RVOT ≥29–31 mm ([PLAX/BSA] ≥16–18 mm/m2)

- PSAX RVOT ≥32–35 mm ([PSAX/BSA] ≥18–20 mm/m2)

- RV fractional area change >33–39 %

CMR

R egional RV akinesia, dyskinesia or dyssynchronous RV contraction and 1 of the following criteria (end diastolic):

- RV end-diastolic volume/BSA ≥100–109 mL/m2 (male) or ≥90–99 mL/m2 (female) or RV ejection fraction >40–44 %

II. Histopathology (endomyocardial biopsy) Major Residual myocytes <60 % by morphometric analysis (or <50 % if estimated), with fibrous replacement of the RV free wall myocardium

≥1 sample, with or without fatty replacement

Minor Residual myocytes 60–75 % by morphometric analysis (or 50–65 % if estimated), with fibrous replacement of the RV free wall ≥1 sample, with or without fatty replacement III. Repolarisation abnormalities (>14 years of age) Major T-wave inversions V1–3 or beyond (in absence of complete RBBB) Minor

T-wave inversions V1–2 or V4–6 (in absence of complete RBBB)

T-wave inversions V1–4, if complete RBBB present

IV. Depolarisation abnormalities Major

e wave (reproducible low-amplitude signals between end of QRS complex to onset of the T wave) in V1–3

Minor Signal-averaged ECG with late potentials (if QRS on standard surface ECG <110 ms) V. Arrhythmias Major

Non-sustained or sustained ventricular tachycardia (VT) of LBBB morphology with superior axis

Minor

Non-sustained or sustained VT of RVOT configuration, LBBB morphology with inferior axis or of unknown axis

>500 VES per 24 h (Holter)

VI. Family history Major

ARVC/D in a first-degree relative who meets current Task Force Criteria

ARVC/D confirmed pathologically at autopsy or surgery in a first-degree relative

Identification of a pathogenic mutation categorised as associated with ARVC/D in index patient

Minor

Suspected ARVC/D in a first-degree relative (current Task Force criteria can not be determined)

Premature SCD (<35 years of age) due to suspected ARVC/D in a first-degree relative

ARVC/D confirmed pathologically or by current Task Force Criteria in second-degree relatives Definite diagnosis: two major or one major and two minor criteria or four minor from different categories; Borderline diagnosis: one major and one minor or three minor criteria from different categories; Possible diagnosis: one major or two minor criteria from different categories. BSA = body surface area; CMR = cardiac magnetic resonance tomography; ECG = electrocardiogram; LV = left ventricle; PLAX = parasternal long-axis view; PSAX = parasternal short-axis view; RBBB = right bundle branch block; RVOT = RV outflow tract; RV = right ventricle; TTE = transthoracic echocardiogram; VES = ventricular extrasystole; VT = ventricular tachycardia.102

causing the disease in the index patient obviates the need for serial clinical evaluation in this family member. Current guidelines102 do not recommend genetic testing for risk stratification and therapeutic decision-making in ACM due to conflicting study results.8,142–144 Recent studies showed an association between positive genotype and earlier disease onset in index patients harbouring a known genetic mutation as compared with index patients without a known genetic mutation. However, ascertainment bias has to be considered in such

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a comparison.32 Moreover, these results can be biased by the fact that ACM is almost never fully penetrant, >40 % of ACM patients are genotype elusive, and the pathogenic mechanism in these patients is not clear. Yet, the results of genotype–phenotype correlation studies can be clinically helpful for some genetic mutations. For instance, truncating mutations in DSP, digenic or compound heterozygous mutations and mutations in the non-desmosomal gene TMEM43 are associated with more severe phenotypes and therefore, may be considered as risk factors of SCD.8,32,41,42,102 For TMEM43 p.S358L

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carriers, a diagnosis of ARVC/D can be made only by the presence of this genetic mutation, and clinical screening of family members is strongly recommended.49

Figure 3: Electrical Phenotypes of Arrhythmogenic Cardiomyopathy

Differential Diagnosis A common differential diagnosis is idiopathic right ventricular outflow tract VT (RVOT-VT), particularly in early stages of ARVC/D lacking gross structural abnormalities.145 RVOT-VT is not associated with structural heart disease, and thus has a more benign course. In RVOT-VT, 12-lead surface ECG and SAECG are normal during sinus rhythm. A single VT morphology with LBBB pattern and an inferior axis is recorded in most of the cases, although slightly different morphologies (all with an inferior axis) can occur if VT origin is above the pulmonary cusps.146 ECG scoring systems to differentiate idiopathic RVOT-VT and ARVC/D have been suggested.147 In ARVC/D, QRS duration during VT was longer (≥120 ms in lead I).148 Notching of the QRS and precordial transition in lead V6 were exclusively seen in ARVC/D. Idiopathic RVOT-VT is difficult to induce by programmed ventricular stimulation.148,149 Idiopathic RVOTVT responds well to verapamil. Endocardial ablation is feasible and curative, whereas in ARVC/D, ablation is not curative and an epicardial approach may be necessary to eliminate the clinical VT. Genetic testing, a positive family history, EAM and EMB can help to differentiate ACM and localised forms of myocarditis.150 Cardiac sarcoid can mimic ARVC/D, and the current TFC do not reliably distinguish between these two. In a study of patients with suspected ARVC/D also being evaluated by EMB, a high incidence (15 %) of cardiac sarcoid was identified.151 Cardiac sarcoid should be considered if respiratory and systemic symptoms, high-grade atrioventricular conduction block and septal involvement are present, and familial disease is absent. Diagnosis is confirmed by EMB and thoracic CT scans.151 DCM is particularly difficult to distinguish from non-classic forms of ACM, and these two entities can significantly overlap and harbour similar mutations. Palpitations, (pre)syncope and ventricular arrhythmias are present at an early stage in ACM, often in the absence of gross structural abnormalities, which is the opposite in DCM.18 Atrioventricular conduction block is more common in DCM, but mutations in lamin A/C can lead to ACM with conduction defects, as well.152 Brugada syndrome can mimic ACM, as RV conduction delay has been demonstrated in both entities. The presence of structural abnormalities favours ACM. Recently, a genetic overlap between these two has been suggested. In vitro studies have shown a cellular interaction between desmosomes and ion channels. Mutations associated with Brugada syndrome were found in ACM patients and vice versa.153 Titin mutations have also been associated with a phenotypic overlap between ACM and DCM. The same holds true for PLN mutations.44 However, the genetic interpretation of the large titin molecule and its variants is particularly challenging.75 Treatment of these patients and their arrhythmogenic risk has not been established yet, which has to be addressed in future studies. Other common differential diagnoses include right ventricular infarction, congenital left-to-right shunts, Chagas disease and Uhl’s disease.22 Finally, adaptation of the RV to increased workload in endurance athletes can mimic ARVC/D, and there is a debatable grey zone of what is considered physiological adaptation.154

A 12-lead surface ECG (25 mm/s, 10 mm mV) showing typical depolarisation abnormalities (prolonged terminal activation duration in V1–3 ≥55 ms, a minor criterion according to the 2010 Task Force criteria, thin arrows) and repolarisation abnormalities (T-wave inversions in V1–4 in the absence of complete right bundle branch block, a major criterion according to the 2010 Task Force criteria, bold arrows) and a premature ventricular beat with left bundle branch block morphology and inferior axis (bold arrow).

1. Concealed phase: patients are asymptomatic and structural abnormalities are absent. SCD due to VF can be the primary manifestation in this phase. 2. Occurrence of symptomatic arrhythmias 3. Early heart failure symptoms 4. End-stage heart failure. Diagnosis and risk stratification during the concealed phase can be very challenging. Genetic testing with rigorous criteria and pre-participation screening of young athletes might help to identify affected individuals and prevent SCD.1,26,156 In one study, 7 % of ACM patients received cardiac transplantation after a mean follow-up of 10 years, mostly due to severe LV involvement.7 Physical activity promotes earlier disease manifestation and more rapid disease progression. Identification of affected athletes by pre-participation screening seems to substantially reduce mortality in this cohort.143,156

Therapy Recently, an international consensus statement on the treatment of ARVC/D has been published.144 Data on non-classic ACM subtypes is scarce.

Physical Activity Restriction

Disease Course ACM is a progressive disease however individual disease course can vary. Cardiac mortality is currently estimated ∼0.9 % per year. Most patients die of progressive heart failure or ventricular tachyarrhythmias.155 Four disease phases have been proposed:65

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Competitive athletes with ACM have up-to five-fold increased risk of SCD compared with sedentary individuals with ACM. Other studies have confirmed that high-level physical activity, particularly endurance sports, promotes disease onset, progression and adverse outcome.13,55 Thus, it is recommended that patients with a definite diagnosis of

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Clinical Arrhythmias ARVC/D do not participate in competitive and/or endurance sports (Class I). Furthermore, they should be restricted from participation in athletic activities, with the possible exception of recreational lowintensity sports (Class IIa).56,157

the TMEM43 p.S358L mutation is known to be fully penetrant and highly lethal, an ICD for primary prevention is indicated in all patients and family members harbouring this mutation (males immediately post-puberty and females ≥30 years) in order to improve survival in this subpopulation.49

Pharmacological Therapy Pharmacological options consist of antiarrhythmic drugs (AAD), e.g. sotalol, amiodarone and mexiletine, b-blockers and heart failure drugs. AADs are recommended as an adjunct to ICD therapy in patients with frequent discharges (class I).158 Moreover, they should be considered to improve symptoms due to frequent premature ventricular beats or non-sustained VT (class IIa), and may be considered as an adjunct to catheter ablation in selected patients with haemodynamically stable VT without an ICD (class IIb). Of note, cardioselective b-blockers should be considered in all patients with the ARVC/D phenotype irrespective of arrhythmias (class IIa), but their prophylactic use in healthy gene carriers is not recommended.158

Catheter Ablation Catheter ablation of VT is recommended in patients with incessant VT or frequent appropriate ICD interventions for VT despite AAD (on amiodarone: class I, off amiodarone: class IIa).144 If ≥1 endocardial ablation procedure fails, an epicardial approach is recommended (class I).135 ARVC/D begins in the subepicardial layers. Thus, in experienced hands, a combined endocardial/epicardial approach can be followed as an initial ablation strategy (class IIa). Since catheter ablation is not curative, it is not recommended as an alternative to ICD for prevention of SCD.144

Conclusion Implantable Cardioverter Defibrillator According to the most recent guidelines by the American College of Cardiology (ACC)/American Heart Association (AHA), the European Society of Cardiology (ESC) and the most recent international task force consensus statement on the treatment of ARVC/D, an ICD is recommended in patients with aborted SCD, haemodynamically unstable VT or VF (class I), and according to the consensus statement in those with severe systolic dysfunction of the RV, LV or both, irrespective of arrhythmias (class I).144,159–161 An ICD is generally indicated in ARVC/D patients who have experienced an episode of haemodynamically stable, sustained VT. If major risk factors such as unexplained syncope, moderate ventricular dysfunction, or non-sustained VTs are present, ICD implantation should be considered. Nonetheless, there is no clear consensus regarding primary prevention of SCD in ACM patients without documented sustained ventricular arrhythmia (VA). The AHA recommends an ICD in patients with a familial cardiomyopathy associated with SCD (class IIb, level of evidence C).161 The ESC states that in patients without documented VA or syncope, an ICD may be considered after detailed clinical assessment including family history, severity of RV and LV function and other factors such as psychological health and socioeconomic status.160 According to the international consensus statement, ICD implantation may be considered in patients with minor risk factors such as gender, age and ECG abnormalities and these patients should be evaluated on an individual basis. A single-chamber device is generally preferred in order to minimise the incidence of lead-related complications in this relatively young cohort. Since many patients benefit from antitachycardia pacing, there is currently no role for subcutaneous ICDs. Importantly, prophylactic ICD implantation is not recommended in asymptomatic patients without risk factors and most healthy gene carriers (class III).144 However, since

Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Europace 2011;13:1077–9. DOI: 10.1093/europace/ eur245; PMID: 21810866 Marcus FI, Fontaine GH, Guiraudon G, et al. Right ventricular dysplasia: a report of 24 adult cases. Circulation 1982;65: 384–98. PMID: 7053899 Angelini A, Basso C, Nava A, Thiene G. Endomyocardial biopsy in arrhythmogenic right ventricular cardiomyopathy. Am Heart J 1996;132:203–6. PMID: 8701870 Basso C, Thiene G, Corrado D, et al. Arrhythmogenic right ventricular cardiomyopathy. Dysplasia, dystrophy,

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Discoveries within the last decade have substantially improved our understanding of ACM from a purely RV dysplasia to an inherited polygenic disease with a broad phenotypic spectrum. Although ACM predominantly affects the RV, atypical forms also affecting the LV are encountered. Emerging technologies in imaging, genetics and device therapy have facilitated diagnosis and prevention of SCD. Future challenges comprise early identification of asymptomatic patients and family members, improved risk stratification, and causal therapies to cure this challenging disease. ■

Clinical Perspective •

• • •

• • • •

Arrhythmogenic cardiomyopathy (ACM) is a hereditary cardiomyopathy characterised by ventricular arrhythmias and structural/functional abnormalities of the ventricles. The most common arrhythmogenic right ventricular cardiomyopathy is generally referred to as ARVC/D. Causative mutations are detected in genes encoding the intercalated disc. Non-desmosomal mutations (e.g. TMEM43) have also been associated with ARVC/D and can cause malignant phenotypes. Exercise can promote disease onset, progression and adverse outcome. ACM is a common cause of sudden cardiac death in young athletes. The current gold standard for diagnosis are the 2010 TFC. Therapeutic strategies include restriction from endurance and competitive sports, b-blockers, antiarrhythmic drugs, heart failure medication, implantable cardioverterdefibrillators and endocardial/epicardial catheter ablation.

or myocarditis? Circulation 1996;94:983–91. PMID: 8790036 Richardson P, McKenna W, Bristow M, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation 1996;93:841–2. PMID: 8598070 Basso C, Calabrese F, Corrado D, Thiene G. Postmortem diagnosis in sudden cardiac death victims: macroscopic, microscopic and molecular findings. Cardiovasc Res 2001;50:290–300. PMID: 11334833 Pinamonti B, Dragos AM, Pyxaras SA, et al. Prognostic predictors in arrhythmogenic right ventricular cardiomyopathy: results from a 10-year registry. Eur Heart J 2011;32:1105–13. DOI: 10.1093/eurheartj/ehr040;

PMID: 21362707 Fressart V, Duthoit G, Donal E, et al. Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/ cardiomyopathy: spectrum of mutations and clinical impact in practice. Europace 2010;12:861–8. DOI: 10.1093/europace/ euq104; PMID: 20400443 9. Delmar M, McKenna WJ. The cardiac desmosome and arrhythmogenic cardiomyopathies: from gene to disease. Circ Res 2010;107:700–14. DOI: 10.1161/CIRCRESAHA.110.223412; PMID: 20847325 10. Sato PY, Coombs W, Lin X, et al. Interactions between ankyrin-G, Plakophilin-2, and Connexin43 at the cardiac intercalated disc. Circ Res 2011;109:193–201. DOI: 10.1161/ CIRCRESAHA.111.247023; PMID: 21617128; PMCID: PMC3139453 8.

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1998;98:1943–5. PMID: 9799217 118. Lindstrom L, Nylander E, Larsson H, Wranne B. Left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy – a scintigraphic and echocardiographic study. Clin Physiol Funct Imaging 2005;25:171–7. DOI: 10.1111/j.1475-097X.2005.00607.x; MID: 15888098 119. Pennell D, Casolo G. Right ventricular arrhythmia: emergence of magnetic resonance imaging as an investigative tool. Eur Heart J 1997;18:1843–5. PMID: 9447306 120. Dalal D, Tandri H, Judge DP, et al. Morphologic variants of familial arrhythmogenic right ventricular dysplasia/ cardiomyopathy a genetics-magnetic resonance imaging correlation study. J Am Coll Cardiol 2009;53:1289–99. DOI: 10.1016/j.jacc.2008.12.045; PMID: 19358943 121. Tandri H, Calkins H, Marcus FI. Controversial role of magnetic resonance imaging in the diagnosis of arrhythmogenic right ventricular dysplasia. Am J Cardiol 2003;92:649. PMID: 12943901 122. Bluemke DA, Krupinski EA, Ovitt T, et al. MR Imaging of arrhythmogenic right ventricular cardiomyopathy: morphologic findings and interobserver reliability. Cardiology 2003;99:153–62. DOI: 70672; PMID: 12824723 123. Prakasa KR, Wang J, Tandri H, et al. Utility of tissue Doppler and strain echocardiography in arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am J Cardiol 2007;100:507–12. DOI: 10.1016/j.amjcard.2007.03.053; PMID: 17659937 124. Teske AJ, Cox MG, De Boeck BW, et al. Echocardiographic tissue deformation imaging quantifies abnormal regional right ventricular function in arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Soc Echocardiogr 2009;22:920–7. DOI: 10.1016/j.echo.2009.05.014; PMID: 19553080 125. Jain A, Shehata ML, Stuber M, et al. Prevalence of left ventricular regional dysfunction in arrhythmogenic right ventricular dysplasia: a tagged MRI study. Circulation Cardiovascular imaging 2010;3:290–7. DOI: 10.1161/ CIRCIMAGING.109.911313; PMID: 20197508; PMCID: PMC3036009 126. Teske AJ, Cox MG, Te Riele AS, et al. Early detection of regional functional abnormalities in asymptomatic ARVD/C gene carriers. J Am Soc Echocardiogr 2012;25:997–1006. DOI: 10.1161/CIRCIMAGING.109.911313; PMID: 20197508; PMCID: PMC3036009 127. Vitarelli A, Cortes Morichetti M, Capotosto L, et al. Utility of strain echocardiography at rest and after stress testing in arrhythmogenic right ventricular dysplasia. Am J Cardiol 2013;111:1344–50. DOI: 10.1016/j.amjcard.2013.01.279; PMID: 23411103 128. Indik JH, Dallas WJ, Gear K, et al. Right ventricular volume analysis by angiography in right ventricular cardiomyopathy. Int J Cardiovasc Imaging 2011;28:995–1001. DOI: 10.1007/s10554011-9915-1; PMID: 21706146; PMCID: PMC3488440 129. Francés RJ. Arrhythmogenic right ventricular dysplasia/ cardiomyopathy. A review and update. Int J Cardiol 2006;110:279–87. DOI: 10.1016/j.ijcard.2005.07.004; PMID: 16099519 130. Corrado D, Basso C, Leoni L, et al. Three-dimensional electroanatomic voltage mapping increases accuracy of diagnosing arrhythmogenic right ventricular cardiomyopathy/ dysplasia. Circulation 2005;111:3042–50. DOI: 10.1161/ CIRCULATIONAHA.104.486977; PMID: 15939822 131. Ejima K, Shoda M, Manaka T, Hagiwara N. Targeted endomyocardial biopsy using electroanatomical voltage mapping in the early stage of arrhythmogenic right ventricular cardiomyopathy. Europace 2009;11:388–9. DOI: 10.1093/europace/eun357; PMID: 19168858 132. Marchlinski FE, Callans DJ, Gottlieb CD, Zado E. Linear ablation lesions for control of unmappable ventricular tachycardia in patients with ischemic and nonischemic cardiomyopathy. Circulation 2000;101:1288–96. PMID: 10725289 133. Sosa E, Scanavacca M, d›Avila A, Pilleggi F. A new technique to perform epicardial mapping in the electrophysiology laboratory. J Cardiovasc Electrophysiol 1996;7:531–6. PMID: 8743758 134. Bai R, Di Biase L, Shivkumar K, et al. Ablation of ventricular arrhythmias in arrhythmogenic right ventricular dysplasia/ cardiomyopathy: arrhythmia-free survival after endoepicardial substrate based mapping and ablation. Circ Arrhythm Electrophysiol 2011;4:478–85. DOI: 10.1161/CIRCEP.111.963066; PMID: 21665983 135. Garcia FC, Bazan V, Zado ES, et al. Epicardial substrate and outcome with epicardial ablation of ventricular tachycardia in arrhythmogenic right ventricular cardiomyopathy/ dysplasia. Circulation 2009;120:366–75. DOI: 10.1161/ CIRCULATIONAHA.108.834903; PMID: 19620503 136. Migliore F, Zorzi A, Silvano M, et al. Prognostic value of endocardial voltage mapping in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circ Arrhythm Electrophysiol 2013;6:167–76. DOI: 10.1161/CIRCEP.111.974881; PMID: 23392584 137. Asimaki A, Saffitz JE. The role of endomyocardial biopsy in ARVC: looking beyond histology in search of new diagnostic markers. J Cardiovasc Electrophysiol 2011;22:111–7. DOI: 10.1111/j.1540-8167.2010.01960.x; PMID: 21235662; PMCID: PMC3058333 138. Basso C, Ronco F, Marcus F, et al. Quantitative assessment of endomyocardial biopsy in arrhythmogenic right ventricular cardiomyopathy/dysplasia: an in vitro validation of diagnostic criteria. Eur Heart J 2008;29:2760–71. DOI: 10.1093/eurheartj/ ehn415; PMID: 18819962

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139. Avella A, d›Amati G, Pappalardo A, et al. Diagnostic value of endomyocardial biopsy guided by electroanatomic voltage mapping in arrhythmogenic right ventricular cardiomyopathy/dysplasia. J Cardiovasc Electrophysiol 2008;19:1127–34. DOI: 10.1111/j.1540-8167.2008.01228.x; PMID: 18554207 140. Bauce B, Rampazzo A, Basso C, et al. Clinical Phenotype and Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy in Paediatric Patients Carrying Desmosomal Gene Mutations. Heart Rhythm 2011;8:1686–95. DOI: 10.1016/j. hrthm.2011.06.026; PMID: 21723241; PMCID: PMC3205183 141. Sen-Chowdhry S, Syrris P, McKenna WJ. Role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol 2007;50:1813–21. DOI: 10.1016/j.jacc.2007.08.008; PMID: 17980246 142. Basso C, Carturan E, Pilichou K, et al. Sudden cardiac death with normal heart: molecular autopsy. Cardiovasc Pathol 2010;19:321–5. DOI: 10.1016/j.carpath.2010.02.003; PMID: 20381381 143. Basso C, Wichter T, Danieli GA, et al. Arrhythmogenic right ventricular cardiomyopathy: clinical registry and database, evaluation of therapies, pathology registry, DNA banking. Eur Heart J 2004;25:531–4. DOI: 10.1016/j.ehj.2003.12.025; PMID: 15039134 144. Corrado D, Wichter T, Link MS, et al. Treatment of arrhythmogenic right ventricular cardiomyopathy/dysplasia: an international task force consensus statement. Eur Heart J 2015;36:3227–37. DOI: 10.1093/eurheartj/ehv162; PMID: 26216920; PMCID: PMC4670964 145. O, Donnell D, Cox D, Bourke J, et al. Clinical and electrophysiological differences between patients with arrhythmogenic right ventricular dysplasia and right ventricular outflow tract tachycardia. Eur Heart J 2003;24: 801–10. PMID: 12727147 146. Liao Z, Zhan X, Wu S, et al. Idiopathic Ventricular Arrhythmias Originating From the Pulmonary Sinus Cusp: Prevalence, Electrocardiographic/Electrophysiological Characteristics, and Catheter Ablation. J Am Coll Cardiol 2015;66:2633–44. DOI: 10.1016/j.jacc.2015.09.094; PMID: 26670064 147. Hoffmayer KS, Bhave PD, Marcus GM, et al. An electrocardiographic scoring system for distinguishing

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right ventricular outflow tract arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy from idiopathic ventricular tachycardia. Heart Rhythm 2013;10: 477–82. DOI: 10.1016/j.hrthm.2012.12.009; PMID: 23246596 148. Ainsworth CD, Skanes AC, Klein GJ, et al. Differentiating arrhythmogenic right ventricular cardiomyopathy from right ventricular outflow tract ventricular tachycardia using multilead QRS duration and axis. Heart Rhythm 2006;3:416–23. DOI: 10.1016/j.hrthm.2005.12.024; PMID: 16567288 149. Hoffmayer KS, Machado ON, Marcus GM, et al. Electrocardiographic comparison of ventricular arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy and right ventricular outflow tract tachycardia. J Am Coll Cardiol 2011;58:831–8. DOI: 10.1016/j. jacc.2011.05.017; PMID: 21835319 150. Pieroni M, Dello Russo A, Marzo F, et al. High prevalence of myocarditis mimicking arrhythmogenic right ventricular cardiomyopathy differential diagnosis by electroanatomic mapping-guided endomyocardial biopsy. J Am Coll Cardiol 2009;53:681–9. DOI: 10.1016/j.jacc.2008.11.017; PMID: 19232901 151. Vasaiwala SC, Finn C, Delpriore J, et al. Prospective study of cardiac sarcoid mimicking arrhythmogenic right ventricular dysplasia. J Cardiovasc Electrophysiol 2009;20:473–6. DOI: 10.1111/j.1540-8167.2008.01351.x; PMID: 19017339 152. Quarta G, Syrris P, Ashworth M, et al. Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy. Eur Heart J 2012;33:1128–36. DOI: 10.1093/ eurheartj/ehr451; PMID: 22199124 153. Cerrone M, Lin X, Zhang M, et al. Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype. Circulation 2014;129:1092–103. DOI: 10.1161/CIRCULATIONAHA. 113.003077; PMID: 24352520; PMCID: PMC3954430 154. Heidbüchel H, La Gerche A. The right heart in athletes. Evidence for exercise-induced arrhythmogenic right ventricular cardiomyopathy. Herzschrittmacherther Elektrophysiol 2012;23:82–6. DOI: 10.1007/s00399-012-0180-3; PMID: 22782727 155. Hulot JS, Jouven X, Empana JP, et al. Natural history and risk stratification of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation 2004;110:1879–84. DOI:

10.1161/01.CIR.0000143375.93288.82; PMID: 15451782 156. Corrado D, Basso C, Pavei A, et al. Trends in sudden cardiovascular death in young competitive athletes after implementation of a preparticipation screening program. JAMA 2006;296:1593–601. DOI: 10.1001/jama.296.13.1593; PMID: 17018804 157. Sawant AC, Te Riele AS, Tichnell C, et al. Safety of American Heart Association-recommended minimum exercise for desmosomal mutation carriers. Heart Rhythm 2016;13: 199–207. DOI: 10.1016/j.hrthm.2015.08.035; PMID: 26321091 158. Rigato I, Corrado D, Basso C, et al. Pharmacotherapy and other therapeutic modalities for managing Arrhythmogenic Right Ventricular Cardiomyopathy. Cardiovasc Drugs Ther 2015;29:171–7. DOI: 10.1007/s10557-015-6583-8; PMID: 25894016 159. Corrado D, Leoni L, Link MS, et al. Implantable cardioverterdefibrillator therapy for prevention of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation 2003;108:3084–91. DOI: 10.1161/01.CIR.0000103130.33451.D2; PMID: 14638546 160. 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;36:2793–867. DOI: 10.1093/eurheartj/ehv316; PMID: 26320108 161. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/ AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation 2008;117:e350–408. DOI: 10.1161/ CIRCUALTIONAHA.108.189742; PMID: 18483207

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Individualising Anticoagulant Therapy in Atrial Fibrillation Patients Marco Alings Amphia Ziekenhuis, Breda, The Netherlands; Julius Clinical Research; University Medical Centre (UMC) Utrecht, Utrecht, The Netherlands

Abstract Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have emerged as alternatives to VKAs for the prevention of stroke in patients with non-valvular atrial fibrillation. Four NOACs: dabigatran, apixaban, rivaroxaban and edoxaban, have received regulatory approval in Europe from the European Medicines Agency. Numerous factors can influence the decision to prescribe a NOAC, the most important of which are assessment of stroke and bleeding risks. Given the variation in design of the pivotal phase III clinical trials investigating the efficacy and safety of NOACs, and in the absence of head-to-head comparative data, it is impossible to recommend one NOAC over the other. However, NOACs offer the opportunity for individualised therapy based on factors such as renal function, age or patient/doctor preference for once- or twice-daily dosing regimens. Dose reduction of some NOACs should be considered in at-risk patient populations.

Keywords Atrial fibrillation, stroke reduction, non-vitamin K antagonist oral anticoagulants, dabigatran, apixaban, rivaroxaban, edoxaban Disclosure: Dr Alings has served as an advisor and/or speaker for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Merck Sharp and Dohme, and Sanofi-Aventis. Acknowledgements: Katrina Mountfort, employed by Medical Media Communications (Scientific) Ltd, provided medical writing and editorial support to the author, which was funded by Daiichi Sankyo Europe GmbH. Received: 8 March 2016 Accepted: 24 May 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(2):102–9 DOI: 10.15420/AER.20.3. Access at: www.AERjournal.com Correspondence: Marco Alings, Department of Cardiology, Amphia Ziekenhuis, Molengracht 21, 4818 CK Breda, Netherlands E: marco@alings.org

Atrial fibrillation (AF) is the most common cardiac arrhythmia, with the highest prevalence in elderly patients, and is characterised by an irregular heart rhythm that may result in clots in the heart that can spread throughout the circulatory system. It is seen in approximately 2 % of the European adult population and is a significant cause of increasing healthcare costs in developed countries.1 Its frequency is projected to more than double by mid-century, reflecting the growing proportion of elderly individuals.2 AF influences quality of life significantly and is associated with permanent disability, cognitive disturbance, hospitalisation and absence from work, as well as a fivefold increased incidence of stroke.3 Up to one-quarter of all strokes are attributable to documented AF.4 The aims of AF management are therefore twofold: rate/rhythm control and anticoagulation. In patients with AF, aspirin reduces stroke by 22 % compared with placebo. However, patients treated with aspirin have an increased bleeding risk similar to that of vitamin K antagonist (VKA)-treated patients.5,6 The use of aspirin for stroke prevention has been superseded by VKAs, and aspirin is not recommended for this indication.7 The efficacy of oral anticoagulant (OAC) therapy for stroke prevention in AF (SPAF) has been well-established;8 anticoagulation using VKAs such as warfarin has been the mainstay of AF treatment for many years.9 A metaanalysis of six placebo-controlled trials showed that warfarin significantly reduced stroke risk by 64 %.10 However, in the last decade, the limitations of VKAs have led to the development of non-VKA oral anticoagulants (NOACs), including dabigatran11 (a direct thrombin inhibitor), apixaban,12 rivaroxaban13 and edoxaban14 (factor Xa inhibitors). In clinical trials, all NOACs have proved non-inferiority, and some superiority to warfarin in terms of stroke prevention and bleeding risk.11–14 Several guidelines

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worldwide recommend the use of OACs in patients with AF and ≥1 additional risk factor for stroke (for a risk score of 1, the European and US guidelines issue a Class IIa recommendation, whereas the Canadian guideline issues a Class IIb recommendation).7,15,16 However, the benefit– risk ratio of OAC therapy, i.e. the net benefit of risk reduction of embolic ischaemic events versus the increased risk for bleeding, should be assessed on a case-by-case basis. This enables therapy to be tailored to the specific requirements and risk factors of an individual. This article will discuss individualising anticoagulant therapy in AF patients.

Assessment of Stroke Risk Various reviews have identified the most consistent independent risk factors for AF-related stroke.17,18 However, risk stratification schemes based on these risk factors have modest predictive value for identifying high-risk patients,18 therefore the focus has shifted towards identifying low-risk patients who do not need anticoagulation therapy.7 Across international guidelines, the CHA2DS2-VASc risk score (congestive heart failure [e.g. left ventricular ejection fraction (LVEF) <40 %], hypertension, diabetes, vascular disease [e.g. prior myocardial infarction (MI), peripheral arterial disease (PAD)], age 65–75, female sex all 1 point; age ≥75, stroke/transient ischaemic attack (TIA) each 2 points) is used to identify low-risk patients, i.e. a CHA2DS2-VASc score of 0 for men or 1 for women, for whom the absolute risk of stroke is less than 1 % per year.19 A 2011 model showed the threshold for ischaemic stroke above which OAC therapy should be considered to be >0.9 %/year for NOAC therapy and >1.7 %/year for warfarin therapy.20 Recently, the stroke risk of patients with a CHA2DS2-VASc score of 1 has become the focus of discussion. Among different studies, annual

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Table 1: Pharmacokinetic Characteristics of the Non-vitamin K Antagonist Oral Anticoagulants and Recommended Dosing

Dabigatran

Apixaban Edoxaban

Rivaroxaban

Drug form

Dabigatran etexilate is a prodrug that is

Not a prodrug

Mode of action

Thrombin inhibitor

FXa inhibitor

Bioavailability

3–7 %

50 %

62 %

66 % (with food ~100 %)

Renal clearance

85 %

27 %

50 %

35 %

Half-life (t½)

12–17 hr

12 hr

10–14 hr

9–13 hr

Plasma peak → trough level

2 hr → 12 hr

1–4 hr →12 hr

1–2 hr → 24 hr

2–4 hr → 24 hr

Liver metabolism CYP3A4

Not involved

Moderate

6–22 %

>39 %

Dosing NOAC

150 mg/110 mg twice daily

5 mg twice daily

60 mg once daily

20 mg once daily

Dose adjustment

None in phase III trial

2.5 mg twice daily

30 mg once daily if:

15 mg once daily if:

• SPC recommends 110 mg twice

if two of:

• CrCl 30–50 ml/min or

• CrCl 15–49 ml/min

converted to active dabigatran

daily when CrCl 30–49 ml/min and

• creatinine ≥1.5 mg/dL • <60 kg or (≥133 μMol/L)

high risk of bleeding • 75 mg twice daily if CrCl 30–49 ml/ min approved in US only, and not

(cyclosporin, dronedarone,

• <60 kg

erythromycin or ketoconazole)

tested in phase III trial NOAC not recommended (SPC)

CrCl <30 ml/min

• use of P-gp inhibitors

• age ≥80 year

CrCl <15 ml/min

CrCl = creatinine clearance; NOAC = non-vitamin K antagonist oral anticoagulant; P-gp = permeability glycoprotein; SPC = summary of product characteristics. Adapted from Heidbuchel et al., 2015.33

stroke risk for AF patients with a CHA2DS2-VASc score of 1 not on OAC therapy, varies from 0.6 % to >2.0 %. In a large retrospective study of Swedish health registries of AF patients with a CHA2DS2-VASc score of 1, and who were not exposed to OAC therapy at any time during follow up, the annual ischaemic stroke risk was 0.1–0.2 % for women and 0.5–0.7 % for men. Using a wider definition of ischaemic embolic events, including TIA and pulmonary embolism, the annual event rate was 1.3 % in men.21 In a large retrospective study of Danish Health registries of AF patients, in untreated patients with a CHA2DS2-VASc score of 0 (male) or 1 (female), the annual stroke event rate was 0.49 %. In this study, the annual stroke risk increased to 1.55 % in patients with one additional risk factor.22 There has been debate as to whether in all patients a CHA2DS2-VASc score of 1 supersedes the threshold for ischaemic stroke above which OAC therapy should be considered.22–24 However, not all risk factors in the CHA2DS2-VASc score carry an equal risk. Higher age is the risk factor associated with the highest stroke risk. In a large Taiwanese population-based study of AF patients with CHA2DS2-VASc score of 1 (male) or 2 (female) and not receiving anticoagulation therapy, ischaemic stroke risk in men ranged from 1.96 %/year for men with a CHA2DS2-VASc score of 1 based on the presence of vascular disease to 3.50 %/year for men with a CHA2DS2-VASc score of 1 based on an age of 65–74 years. Ischaemic stroke risk in women ranged from 1.91 %/year for women with a CHA2DS2-VASc score of 2 based on the presence of hypertension to 3.34 %/year for women with a CHA2DS2VASc score of 2 based on an age of 65–74 years.24 Based on these data, in line with international guidelines, oral anticoagulation should be considered in AF patients with one additional stroke risk factor.7,15,16,24

Assessment of Bleeding Risk Bleeding is the most feared complication of OAC therapy. Warfarinrelated bleeding is responsible for one-third of all hospitalisations for adverse drug events.25 Most risk factors for stroke are also risk factors for bleeding. Even though AF patients with a higher bleeding risk have a greater net clinical benefit with OAC therapy (the absolute reduction

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in stroke risk outweighs the absolute increase in bleeding events),5 bleeding risk is the most important barrier to initiating OAC therapy.26 Three bleeding risk scores have been validated in AF populations: the HEMORR2HAGES, HAS-BLED and ATRIA risk scores.27–29 However, only HAS-BLED has been validated in large real-world populations and offers better prediction accuracy than the others.30 Bleeding risk assessment using the HAS-BLED risk score is therefore recommended for all patients with AF.7,31 The HAS-BLED risk score assigns 1 point for each of the following: hypertension (>160 mmHg); abnormal renal/ liver function; previous stroke; bleeding history or predisposition, labile international normalised ratio (INR), elderly, concomitant drugs/ alcohol excess. HAS-BLED scores ≥3 indicate a high risk of bleeding.28 The HAS-BLED score should not be used to exclude patients from OAC therapy, but to address modifiable bleeding risks.32 In summary, initiation of OAC therapy should be based on the individual assessment of stroke risk. According to the European Society of Cardiology (ESC) guidelines, in AF patients with a CHA2DS2VASc score of 0 in males or 1 in females (annual stroke risk <1 %/year), initiation of OAC therapy is not recommended. In AF patients with one additional CHA2DS2-VASc risk, OAC may be considered. Regardless of the HAS-BLED score, in AF patients with CHA2DS2-VASc score ≥2 there is an obvious net clinical benefit for OAC therapy.7

Non-vitamin K Antagonist Oral Anticoagulants: Pharmacokinetics and Clinical Trial Design All NOACs share a relative short elimination half-life of approximately 12 hours. Edoxaban and rivaroxaban are administered once daily, dabigatran and apixaban twice daily (see Table 1). Renal clearance shows marked differences among the NOACs, ranging from 27 to 50 % for the factor Xa (FXa) inhibitors to 85 % for dabigatran.11–14,33 NOACs exhibit little potential for drug-drug interactions, and do not require dose adjustment on the basis of coagulation tests like VKAs. However, dose adjustment may be indicated depending on clinical characteristics of the patient and use of concomitant medication. Intestinal absorption of NOACs is dependent on a permeability glycoprotein (P-gp) transporter. Therefore, co-medication that is

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Clinical Arrhythmias Table 2: Phase III Clinical Trial Design of the Four Non-vitamin K Antagonist Oral Anticoagulants ARISTOTLE • Apixaban 5 mg twice daily (2.5 mg*) Twice daily

≥1 risk factor

• Double-blind, doubledummy • Comparator: warfarin,

RE-LY • Dabigatran 110 or 150 mg twice daily • PROBE • Comparator: warfarin, INR 2.0–3.0

INR 2.0–3.0 * dose reduction to 2.5 mg twice daily if two of: creatinine ≥1.5 mg/dL (≥133 μmol/L), age ≥80 year or <60 kg

ROCKET-AF • Rivaroxaban 20 mg once

Once daily

≥2 risk factors

daily (15 mg)* • Double-blind, doubledummy • Comparator: warfarin, INR 2.0–3.0 * dose reduction to 15 mg

ENGAGE AF-TIMI 48 • Edoxaban 30 or 60 mg once daily (15 or 30 mg)* • Double-blind, doubledummy • Comparator: warfarin, INR 2.0–3.0 * half dose if CrCl 30–50 ml/min

once daily if CrCl 30–49 ml/

or <60 kg or P-gp inhibitors

min

(verapamil, quinidine)

ARISTOTLE = Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation; CrCl = creatinine clearance; ENGAGE AF-TIMI 48 = Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-TIMI 48; INR = international normalised ratio; P-gp = permeability glycoprotein; PROBE = prospective randomised open blinded endpoint; RE-LY = Randomized Evaluation of Long-term Anticoagulant Therapy; ROCKET AF = Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.

competing with the P-gp transporter will increase NOAC plasma levels. P-gp inhibitors commonly used in AF patients include verapamil, dronedarone and quinidine. As dabigatran has a much lower bioavailability than the other NOACs (approximately 7 % versus ≥50 %), P-gp inhibitors will especially affect dabigatran levels. Conversely, P-gp inducers such as rifampicin will reduce the NOAC plasma level. Cytochrome P450 (CYP3A4) is involved in the hepatic clearance of rivaroxaban and, to a lesser extent, of apixaban and edoxaban, but not of dabigatran. Strong CYP3A4 inducers or inhibitors have the potential to influence their plasma levels, especially rivaroxaban levels. However, these do not require routine monitoring. In real-life settings, in patients with a high bleeding risk, dose reduction of NOACs has been suggested when higher plasma levels can be expected. The European Heart Rhythm Association (EHRA) has published a practical guide to the use of NOACs.33 This provides recommendations on: initiating therapy; monitoring the anticoagulant effect; drugdrug interactions; switching between anticoagulant regimens; ensuring compliance; dealing with dosing errors; managing bleeding complications; and special indications in patients undergoing surgical interventions or cardioversion; as well as patients with chronic kidney disease, acute stroke, coronary artery disease and malignancies.33

Phase III Clinical Trials The efficacy and safety of NOACs for SPAF have been established in four pivotal phase III trials. Dabigatran, apixaban, rivaroxaban and edoxaban were studied in the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial, the Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation (ARISTOTLE) trial, the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for

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Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) and the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial, respectively.11–14 Among these clinical trials, distinct similarities and differences can be discerned (see Table 1 and 2). In all of the phase III NOAC trials in patients with AF, dose-adjusted warfarin with a target INR of 2–3 was used as the comparator arm (see Table 1 and 2). The primary endpoint in all of these trials was the reduction in stroke and systemic embolism,11–14 and the safety endpoint was reduction in major bleeding according to the definition of the International Society on Thrombosis and Haemostasis (ISTH).11–14 However, in ROCKET AF, the principal safety endpoint was a composite of major and non-major clinically relevant bleeding events.13 In the RE-LY trial, a prospective randomised open blinded endpoint (PROBE) design was used. In contrast, in the FXa inhibitor studies a doubleblind, double-dummy design was used. A non-inferiority design was used in all studies, with hierarchical statistical testing for superiority once the non-inferiority margin was met. The choice for non-inferiority designs is based on the proven efficacy of warfarin in SPAF. The non-inferiority boundary, which is set to ensure that the study drug preserves a pre-specified portion of the benefit of warfarin over placebo, was set between <1.38 and <1.46, i.e. the study drug would be declared non-inferior if the confidence interval excluded that the primary outcome rate with study drug was >1.38 to >1.46 times higher than with warfarin.11–14 Once the non-inferiority criterion was satisfied, superiority for the primary efficacy endpoint could be tested. In the RE-LY trial, two different doses of dabigatran, 110 mg or 150 mg twice daily, were evaluated, without dose reduction.11 In the ARISTOTLE trial, apixaban 5 mg twice daily was used, with dose reduction to 2.5 mg twice daily for subjects who at baseline fulfilled two out of three criteria (age ≥80 years, body weight ≤60 kg and serum creatinine level ≥1.5 mg/dL [133 μmol/L]).12 In the ROCKET AF, rivaroxaban 20 mg Once daily was tested, with dose reduction to 15 mg Once daily for subjects with a reduced creatinine clearance (CrCl) of 30–49 mL/min.13 In the ENGAGE AF-TIMI 48 trial, two doses of edoxaban, 30 mg or 60 mg Once daily, were evaluated, with a 50 % dose reduction to 15 mg or 30 mg Once daily, respectively, for subjects with a CrCl 30–50 mL/min, a body weight ≤60 kg, or concomitant administration of verapamil, quinidine or dronedarone (strong P-gp inhibitors).14 Patients with AF and ≥1 additional stroke risk factor were included in the RE-LY and the ARISTOTLE trials, and with ≥2 additional stroke risk factors in the ROCKET-AF and the ENGAGE AF-TIMI 48 trial, i.e. patients in the ROCKET-AF and the ENGAGE AF-TIMI 48 trial were at higher risk of stroke compared with the patient populations in the RE-LY and ARISTOTLE trials. Consequently, the underlying risk for stroke differed significantly across the trials, with mean CHADS2 scores ranging from 2.1 to 3.5.11–14 In summary, when interpreting efficacy and safety data, it is important to realise that there are distinct differences between these phase III NOAC trials. Given the heterogeneity of the different trials and in the absence of head-to-head studies, a comparative efficacy of the individual four NOACs cannot be assessed. In a meta-analysis of the four phase III trials, compared with warfarin, NOACs significantly reduced the risk of stroke (HR 0.81; 95 % CI 0.73–0.91), intracranial haemorrhage (HR 0.48; 95 % CI 0.39–0.59) and mortality, with a similar risk for major bleeding (HR 0.86; 95 % CI 0.73–1.00), but increased gastrointestinal bleeding (HR 1.25; 95 % CI 1.01–1.55).34 The 19 % risk

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reduction in stroke or systemic embolism was mainly driven by a 51 % reduction in haemorrhagic stroke (HR 0.49; 95 % CI 0.38–0.64). NOACs were similar to warfarin in prevention of ischaemic stroke (HR 0.92; 95 % CI 0.83–1.02) and myocardial infarction (0.97; 95 % CI 0.78–1.20). The benefits of reduction in stroke or systemic embolism and reduction in bleeding were consistent across multiple subgroups examined, with no interaction for age, CrCl and time in therapeutic range for warfarin.34 Based on their favourable benefit–risk ratio, regulatory agencies have approved the use of NOACs for reduction of risk of stroke in patients with non-valvular AF. Furthermore, international guidelines on the treatment of AF have now issued a class I recommendation for the use of NOACs for stroke prevention in patients with AF and a CHA2DS2VASc score ≥2,7,15 and a class IIa recommendation for the preferred use of NOACs over VKA.7,16

Real World Effectiveness Data of Non-vitamin K Antagonist Oral Anticoagulants The efficacy of NOACs has been established within the setting of wellcontrolled phase III trials, with strict inclusion and exclusion criteria, and control of therapy adherence and use of concomitant medication. However, the safety profile of NOACs demonstrated in controlled trial settings may be different in a real life setting. The comparative effectiveness of dabigatran versus warfarin was studied in a large cohort of 134,414 propensity score-matched Medicare beneficiaries. Compared with warfarin, dabigatran reduced the risk of ischaemic stroke (HR 0.80 [0.67–0.96]), intracranial haemorrhage (HR 0.34 [0.26–0.46]) and death (HR 0.86 [0.77–0.96]); there were no differences between cohorts in risk of major bleeding (HR 0.97 (0.88–1.07) or acute MI (HR 0.92 [0.78–1.08]), and there was an increased risk of gastro-intestinal bleeding (HR 1.28 [1.14–1.44]).35 In the RE-LY trial, patients were randomised to dabigatran 150 mg twice daily or 110 mg twice daily. In this US cohort study, however, 16 % of the patients used dabigatran 75 mg twice daily. In the subgroup treated with dabigatran 150 mg twice daily, the magnitude of effect for the above reported outcomes was greater. In the subgroup treated with dabigatran 110 mg twice daily, none of the outcome comparisons were statistically significantly different from warfarin except for a lower risk of bleeding. In a prospective, non-interventional oral anticoagulation registry of 1,776 daily-care patients (Dresden NOAC registry), rivaroxaban-related major bleeding (3.1 %/year) compared well to major bleeding in the ROCKET-AF (3.4 %).36 In an observational pharmacovigilance study of 27,467 rivaroxaban users, incidence of major bleeding was 2.86 %/ year, consistent with the phase III trial results.37 To date, no real world registry data are yet available for apixaban and edoxaban. Data for edoxaban are currently being accrued through the Edoxaban Treatment in Routine Clinical Practice – Atrial Fibrillation – Europe (ETNA-AF-Europe) registry, which recently commenced enrolment and aims to recruit approximately 13,000 patients from 1,450 sites across 12 countries.38 Despite the more favourable safety profile of NOACs, the initial absence of specific antidotes to reverse the anticoagulant effect of NOACs may, rightly or wrongly, have formed an obstacle to their use in daily care. For rapid reversal of life-threatening warfarin-associated bleeding, in addition to general measures such as discontinuation of the anticoagulant and supportive measurements, the administration of four-factor prothrombin complex concentrates (PCC) is recommended,

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together with vitamin K to allow for de novo synthesis of coagulation factors.39 However, despite rapid normalisation of the INR, the prognosis of warfarin-associated major bleeding remains poor. For rapid reversal of life-threatening NOAC-associated bleeding, the administration of PCC may be considered in addition to general measures.33 Recently, data on specific reversal agents have been published. Idarucizumab, a monoclonal antibody fragment, was designed to specifically reverse the anticoagulant effect of dabigatran. The Reversal Effects of Idarucizumab on Active Dabigatran (REVERSEAD) trial included patients with serious bleeding or those requiring urgent surgical procedure. An interim analysis after 90 patients were recruited showed that 5 g IV idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes.40 The trial, however, was not designed to compare clinical outcome data. Based on these data, in patients presenting with dabigatran-associated lifethreatening bleeding, idarucizumab, a monoclonal antibody fragment, is the preferred reversal agent33 and has been shown to be safe in initial clinical trials.41,42 Andexanet alfa, a recombinant modified human factor Xa decoy protein, was designed to specifically reverse the anticoagulant effects of factor Xa inhibitors. In the Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity (ANNEXA) trials, 101 healthy older volunteers were given either apixaban or rivaroxaban and then randomised to andexanet or placebo. Administration of an andexanet bolus followed by a 2-hour infusion of andexanet reduced anti-FXa activity by 92 % and 94 %, respectively.43 The availability of NOACspecific antidotes may take away possible concerns about reversal of NOAC activity, but these agents should be reserved for life-threatening bleeding or for urgent surgical procedures or thrombolysis. A detailed description of the management of bleeding complications can be found in Heidbuchel et al.33 In conclusion, the effectiveness of two NOACs in real world registry studies compares well to their phase III clinical trial results. More observational data on real life effectiveness of NOACs will emerge from on-going large registries with all four NOACs.44

Individual Factors Affecting Treatment Choice Since the introduction of NOACs, a range of questions relating to their use has emerged, which may affect treatment choice.45,46 There are no published trials comparing NOACs head-to-head, and it is unlikely that any will be conducted in the near future. It is essential to select the appropriate patients for treatment with NOACs to reduce the risk of adverse events and ensure optimal outcomes. A comprehensive guide on the practical use of NOACs has been published by Heidbuchel et al.,33 and is available online at www.NOACforAF.eu. A thorough patient history should be taken, including concomitant prescription and over-the-counter medications and assessment of kidney function. Dose reduction may be indicated in at-risk patient populations: • F or dabigatran, it is recommended to reduce the dosage to 110 mg twice daily in patients ≥80 years or in patients receiving concomitant verapamil. In patients aged 75–80 years and in patients with moderate renal impairment, dose reduction may be considered according to physician discretion in patients at high bleeding risk.47 • For apixaban, it is recommended to halve the dosage to 2.5 mg twice daily in patients with at least two of the following characteristics: age ≥80 years, body weight ≤60 kg or serum creatinine ≥1.5 mg/dL.48 • For rivaroxaban, dose adjustment to 15 mg once daily is recommended in patients with moderate to severe renal impairment (CrCl 15–49

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Clinical Arrhythmias Table 3: Increased NOAC Plasma Levels and Recommendations Towards Dosing Antiarrhythmic

Drug Amiodarone

Mode of interaction P-gp competition

Dabigatran 1*

Apixaban 1

Edoxaban 1

Rivaroxaban 1

drugs

Digoxin

P-gp competition

Diltiazem

P-gp and CYP3A4

Dronedarone

P-gp and CYP3A4

Quinidine

P-gp competition

Verapamil

P-gp competition

Antibiotics

Clarithromycin, P-gp and CYP3A4

Erythromycin Fungostatic

~conazoles

Age

≥75 years

P-gp and CYP3A4

≥80 years

1**

Weight

≤60 kg

1**

GFR 30–49 mL/min

creatinine

GFR 15–30 mL/min

Renal function

>133 μmol/L**

GFR <30 mL/min

GFR <15 mL/min

↑bleeding risk (HAS-BLED 3, NSAIDs, systemic steroids)

A score of ≥3 (red flag): use of non-vitamin K antagonist oral anticoagulants (NOAC) contraindicated/not recommended. A score of 2 (two yellow or one orange flag): reduce dose (from 150 to 110 mg twice daily for dabigatran; from 20 to 15 mg once daily for rivaroxaban; from 5.0 to 2.5 mg twice daily for apixaban). *Dose reduction of dabigatran to 110 mg twice daily if weight <60 kg is expert opinion,33 which deviates from the summary of product characteristics (SPC) for dabigatran, which recommends clinical surveillance if weight <50 kg. **Dose reduction of apixaban to 2.5 mg twice daily if two of the following criteria are met: creatinine ≥1.5 mg/dL (≥133 μMol/L), age ≥80 year or <60 kg. Rifampicin, carbamazepine, phenobarbital and phenytoin reduce NOAC plasma levels through P-gp and CYP3A4 induction. Concomitant use should be avoided. GFR = glomerular filtration rate; NSAIDs = nonsteroidal anti-inflammatory drugs; P-gp = permeability glycoprotein. Adapted from Heidbuchel et al., 2015.33

mL/min), but no dose adjustment is recommended for body weight or elderly age.49 • For edoxaban, dose adjustment to 30 mg once daily is recommended in patients with moderate to severe renal impairment (CrCl 15–50 mL/min), and/or body weight ≤60 kg and/or concomitant use of strong P-gp inhibitors (cyclosporin, dronedarone, erythromycin, ketoconazole; see Table 3).50

Adherence to Dosing Regimen As a first step, patients taking NOACs should be well-informed about the importance of adherence to the scheduled dosing regimen. Depending on the patient’s preference, once daily or twice daily dosing may be chosen. Medication possession ratio (MPR; number of days of medication supplied between first prescription and subsequent 365 days, divided by 365) is used as a surrogate parameter for medication intake. In a retrospective Medicare cohort of 1,440,254 patients taking an antidiabetic, antihyperlipidemic, antiplatelet, or cardiac agent with once daily or twice daily dosing, compared with twice daily, once daily dosing increased overall MPR from 57 % to 66 %, respectively (+15.8 %). However, no difference was seen in the MPR for cardiac agents (0.63 in both groups).51 In a retrospective cohort study of 10,697 patients with AF initiated on oral once daily or twice daily regimens of antidiabetic or antihypertensive medications, the MPR was 75.3 % and 70.4 % for once daily and twice daily regimens, respectively. Notably, adherence as represented by the MPR was highest in patients >65 years of age, with a similar MPR for once daily dosing versus twice daily dosing (87 versus 85 %).52 In a Danish cohort study of 2,960 AF patients using dabigatran twice daily, after one year the overall proportion of days covered (PDC; sum of days of supply of medication, divided by the number of days evaluated) was 83.9 %, with 76.8 % of the patients having a one year PDC >80 %. Patients with increased risk for stroke (CHA2DS2-VASc scores ≥2), regular users of cardiovascular drugs and patients with a history of stroke/TIA all showed more adherence than the reference group with a CHA2DS2-VASc score of 1.53 There is considerable debate about the benefits of once daily administration over twice daily. Several studies suggest that once

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daily dosing may increase adherence.44,46–48 In two studies of insurance claims database (n=10,697 and 16,014, respectively), patients with AF treated with once daily dosing regimens for long-term medications were associated with significantly higher adherence compared with subjects on twice daily regimens.52,54 A systematic review and metaanalysis of four randomised control trials (a total of 2,557 patients) involving patients with chronic cardiovascular disease found a significant 56 % reduction in the risk of non-adherence to drug therapy.55 However, there is a disproportionately greater impact on drug action of missing a dose of a once daily than a twice daily NOAC.56

Concomitant Medications Assessment of concomitant medication is an important consideration when initiating OAC therapy. The elderly AF population often uses many concomitant medications. For example, in the ROCKET AF, at baseline, 51 % of patients were on 5–9 concomitant medications and 13 % were on ≥10 concomitant medications.57 To assist with self-administration and compliance with multiple dosage instructions, dispensed drugs may be repackaged into smaller, ready to dispense quantities from larger bulk containers. Dabigatran capsules, however, can only be dispensed and stored in the manufacturer’s original packaging to protect from moisture, and therefore are not suitable for repackaging.47 The EHRA has proposed that patients taking NOACs carry a patient information card that provides information both for the patient (instructions on correct intake) and healthcare workers (renal function, concomitant medication, etc.).33 Over-the-counter drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), antiplatelet therapy (APT) or drugs that compete with the P-gp transporter (e.g. verapamil) and/or CYP3A4 (like fungostatics) can increase bleeding risk.58 The occurrence of drug-drug interactions should be avoided as much as possible, and not be used as an argument to refrain from OAC therapy. If higher NOAC plasma levels are expected, dose reduction should be considered. For an extensive overview of drug-drug interaction and recommendations for dose reduction, see Heidbuchel et al.33

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Patients with AF receiving oral anticoagulants are often treated with concomitant APT, mostly aspirin, even in the absence of cardiovascular disease. However, concomitant use of aspirin and warfarin significantly increases the risk for major bleeding.59 In the RE-LY trial, 38.4 % of the enrolled patients received concomitant APT at some time during the study. Dabigatran 110 mg twice daily was non-inferior to warfarin in reducing stroke, without an interaction for APT (with APT: HR 0.93; [0.70–1.25]; without APT: HR, 0.87 [0.66–1.15]).60 Dabigatran 150 mg twice daily was superior to warfarin in reducing stroke in the overall patient population; however, this effect seemed attenuated among patients who used APT (with APT: HR 0.80 [0.59–1.08], without APT: HR 0.52 [0.38–0.72]). Concomitant use of APT increased the risk of major bleeding; however, the relative advantage of dabigatran over warfarin in reducing major bleeds showed no interaction for aspirin use.60 In the ARISTOTLE trial, 24 % of the enrolled patients were using aspirin at baseline. The benefits of apixaban in stroke prevention (with aspirin: apixaban 1.12 %/year versus warfarin 1.91 %/year, HR 0.58 [0.39–0.85] versus without aspirin: apixaban 1.11 %/year versus warfarin 1.32 %/year, HR 0.84 [0.66–1.07]) and the reduction in major bleeding (with aspirin: apixaban 3.10 %/year versus warfarin 3.92 %/ year, HR 0.77 [0.60–0.99] versus without aspirin: apixaban 1.82 %/year versus warfarin 2.78 %/year, HR 0.65, [0.55–0.78]) showed no interaction for aspirin use.61 In the ROCKET AF, 35 % of the enrolled patients were using concomitant aspirin therapy. Aspirin use was associated with increased risk of major bleeding (with aspirin use: rivaroxaban 4.52 %/ year versus warfarin 4.12 %/year, without aspirin use: rivaroxaban 3.11 %/year versus warfarin 3.11 %/year).13 Rivaroxaban was noninferior to warfarin for the occurrence of major bleed, without an interaction for APT use (with aspirin use: HR 1.10 (0.89–1.36), without aspirin use: HR 1.0 (0.83–1.20). In the ENGAGE AF-TIMI 48 trial, 23 % of the enrolled patients were using concomitant APT, mostly aspirin, at 3 months. Relative efficacy in stroke prevention and reduction in major bleeding showed no interaction with concomitant antiplatelet use.62,63 In conclusion, concomitant use of antiplatelet drugs increases the absolute risk for major bleeding, without affecting the relative benefits of NOACs over warfarin. Recommendations are given in the individual summary of product characteristics (SPC) for the administration of NOACs with APT and/or aspirin.

a pre-specified secondary analysis of the ROCKET-AF, patients were stratified into age categories: <75 (n=8,021) and ≥75 (n=6,215) years. The risk of major bleeding and the risk of stroke/SEE increased with age. The efficacy of rivaroxaban in stroke prevention and the occurrence of bleeding showed a consistent treatment effect across age groups.66 In a pre-specified secondary analysis of the ENGAGE AF-TIMI 48 trial, patients were stratified into age categories: <65 (n=5,497), 65–74 (n=7,134) and ≥75 (n=8,474) years. The risk of major bleeding and stroke/SEE increased with age, but more markedly so for major bleeding. The treatment effects of edoxaban seen in the overall patient population were consistent in different age subgroups, with a major impact on absolute risk reduction for major bleeding, without an interaction for age. In addition, the absolute benefits of edoxaban tended to be greater in the elderly.67 These observations were supported in a recent systematic review and meta-analysis of 19 NOAC trials conducted in patients with AF or venous thromboembolism (VTE).68 In summary, in phase III trials, when compared to warfarin, in terms of efficacy and safety the benefits of NOAC therapy are consistent regardless of age. A 2015 ESC consensus document that focused on age-specific risks and benefits of antithrombotic drugs tested in phase III trials, provided recommendations on dose reduction in the elderly.69 For dabigatran a dose reduction to 110 mg twice daily for age 75–79 years is recommended,70 which is the European Medicines Agency (EMA)-approved dose for patients ≥80 years. For apixaban a dose reduction to 2.5 mg twice daily is recommended if age ≥80 years and body weight is 60 kg or serum creatinine is ≥1.5 mg/dL, similar to the EMA approval. No age specific dose adjustments for rivaroxaban and edoxaban are recommended in this consensus document.

Renal Function Chronic kidney disease (CKD) is common in patients with AF, with a third of patients having stage III CKD (estimated glomerular filtration rate [eGFR] 30–60 mL/min).71 In patients with AF, renal failure is a risk factor for both stroke and bleeding.72 Among NOACs, the renal clearance varies considerably, from 27 % for apixaban48 to 85 % for dabigatran,47 and dose reductions may be indicated in patients with reduced renal function. Therefore, renal function should be monitored yearly, but more frequently in patients ≥75 years of age using dabigatran or edoxaban, i.e. at 6 months intervals.33 Quarterly monitoring of renal function is recommended in patients with CrCl 15–30 ml/min.

Age Approximately 15 % of patients with AF are <60 years of age, whereas more than one-third of patients with AF are ≥75 years of age.2 The risk of stroke and the risk of major bleeding increases with age. All anticoagulants will cause more bleedings in elderly patients, especially in the presence of other bleeding risk factors. In the RE-LY trial, 7,258 patients were ≥75 years of age. For the primary efficacy outcome of stroke or systemic embolism, the benefit of dabigatran versus warfarin was independent of age. The risk of major bleeding increased with age. With increasing age, the benefit in reducing major bleedings was attenuated with similar and higher bleeding rates compared with warfarin for dabigatran 110 mg twice daily and 150 mg twice daily, respectively.64 In a pre-specified secondary analysis of the ARISTOTLE trial, patients were stratified into age categories: <65 (n=5,471), 65–74 (n=7,052) and ≥75 (n=5,678) years. The risk of major bleeding and the risk of stroke/systemic embolic events (SEE) increased with age. The benefits of apixaban in stroke prevention showed no interaction with age. Apixaban reduced the rate of major bleeding compared with warfarin with a consistent treatment effect across age groups.65 In

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Patients with AF and mild-to-moderate renal failure (CrCl 30–50 mL/min) were enrolled in the phase III trials.11–14 As pre-specified per protocol, rivaroxaban, apixaban and edoxaban dosing was reduced in these patients, and dabigatran dosing was not. In the ENGAGE AF-TIMI 48 trial with edoxaban, the dosing was adjusted both at the time of randomisation and also during the trial, to resemble real world clinical practice.14 In a pre-specified secondary analysis of the ENGAGE AF-TIMI 48 trial, patients were stratified into eGFR categories ≤50 and >50 mL/min. The relative risk of stroke/systemic embolism with edoxaban vs warfarin in the pre-specified analysis in those with CrCl ≤50 (HR 0.87, 0.65–1.18) was similar to those with CrCl >50 (HR 0.87, 0.72–1.04; p-interaction = 0.94). While there is a trend towards decreasing efficacy with increasing CrCl for edoxaban compared with well-managed warfarin, the overall safety and net clinical benefit of edoxaban compared to warfarin is consistent across renal function groups.73 In a pre-specified secondary analysis of the ARISTOTLE trial, patients were stratified into eGFR categories: >80 (n=7,518), >50–80 (n=7,587)

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Clinical Arrhythmias and ≤50 (n=3,017) mL/min. The risk of stroke and the incidence of major bleeding increased with deteriorating renal function in the overall population irrespective of treatment. The benefits of apixaban in stroke prevention showed no interaction with renal function. The relative reduction in major bleeding with apixaban was significantly greater in patients with an eGFR ≤50 mL/min.74 In a pre-specified secondary analysis of the ROCKET-AF, patients were stratified into eGFR categories: ≥50 mL/min (n=11,277), randomised to rivaroxaban 20 mg or warfarin; and 30–49 mL/min (n=2950), randomized to rivaroxaban 15 mg or warfarin. The risk of stroke and the incidence of major bleeding increased with deteriorating renal function. The efficacy of rivaroxaban in stroke prevention showed no interaction with renal function. Rates of major bleeding were similar for rivaroxaban and warfarin, with no interaction for renal function.75 In a pre-specified secondary analysis of RE-LY, patients were stratified into eGFR categories: ≥80 (n=3,880), >50–80 (n=10,697) and ≤50 (n=3,374) mL/min. Again, the risk of stroke and major bleeding increased with deteriorating renal function in the overall population irrespective of treatment. The benefits of dabigatran in stroke prevention showed no significant interaction with renal function (consistent with the overall trial, a lower risk with high dose dabigatran and similar risk with low dose dabigatran compared with warfarin). There was, however, an interaction between treatment and renal function such that compared to warfarin with either doses of dabigatran the relative reduction in major bleeding was greater in patients with an eGFR ≥80 mL/min.76 These observations were supported in a recent systematic review and meta-analysis of five studies comprising 72,845 AF patients randomised to NOAC of warfarin, in which NOACs had similar efficacy and safety compared to warfarin across different levels of renal function.77 In summary, in patients with AF, renal impairment is associated with higher rates of stroke and bleeding. Compared to warfarin, in terms of efficacy and safety the benefits of NOACs are maintained regardless of renal function.78

8. 9.

Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol 2014;6:213–20. DOI: 10.2147/CLEP.S47385; PMID: 24966695 Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370–5. PMID: 11343485 Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation 2012;125:e2–220. DOI: 10.1161/ CIR.0b013e31823ac046; PMID: 22179539 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983–8. PMID: 1866765 Olesen JB, Lip GY, Lindhardsen J, et al. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: A net clinical benefit analysis using a ‘real world’ nationwide cohort study. Thromb Haemost 2011;106:739–49. DOI: 10.1160/TH11-05-0364; PMID: 21789337 Hansen ML, Sorensen R, Clausen MT, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010;170:1433–41. DOI: 10.1001/archinternmed.2010.271; PMID: 20837828 Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449– 57. PMID: 8018000 Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 1991;84:527–39. PMID: 1860198 Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–67. PMID: 17577005

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Conclusion In patients with AF and ≥1 stroke risk factor, phase III trials have demonstrated the favourable benefit–risk ratio in SPAF of NOACs compared with VKA. Real life data confirm the effectiveness and safety of NOACs, making NOACs the preferred choice over VKA for SPAF. Older age and CKD increase the risk of bleeding for both NOAC as well as for VKA. The benefits of NOACs, however, are maintained in subgroups of elderly patients and patients with CKD. Due to higher rates of stroke and major bleeding in these subgroups, the absolute benefits of NOACs are even greater in these subgroups. In the absence of head-to-head comparisons, there is no single NOAC that can be recommended above the other NOACs. Rather, the caregiver has the opportunity for personalised care, based on clinical factors such as renal function and age, practical factors such as those recommended by the EHRA guide,33 convenience of and likely adherence to the dosing regimen, potential need for dose reduction (for example, in the presence of CKD) and patient preference. Patient compliance is also an important factor to be taken into account when selecting NOACs. Concomitant medication may increase the risk of bleeding. Therefore, in line with the SPC of the individual NOACs, dose reduction of NOACs is to be considered in the presence of drugs that can be expected to increase the plasma level of NOACs. Although aspirin may be co-administered with all NOACs, in general to reduce the risk of major bleeding where possible, concomitant use of APT should be avoided.47–50 As the incidence of coronary artery disease and AF ranges between 24 and 46 %,79 management of patients treated with a NOAC and presenting with an acute coronary syndrome may deserve special care. Finally, patient education and knowledge transfer on SPAF are important tools to increase compliance. Resources for patients are available online with the international cardiology societies (e.g. at the ESC/EHRA website, see: www.afibmatters.org; at the AHA website, see: ’TheAFibFive‘ and myafibexperience.org; and patient information on the website of the AF Association: www.atrialfibrillation.org.uk).80 ■

10. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. DOI: 10.1056/NEJMoa0905561; PMID: 19717844 11. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. DOI: 10.1056/NEJMoa1107039; PMID: 21870978 12. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. DOI: 10.1056/NEJMoa1009638; PMID: 21830957 13. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104. DOI: 10.1056/NEJMoa1310907; PMID: 24251359 14. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719–47. DOI: 10.1093/eurheartj/ehs253; PMID: 22922413 15. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/ HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1–76. DOI:10.1016/j.jacc.2014.03.022 16. Verma A, Cairns JA, Mitchell LB, et al. 2014 focused update of the Canadian Cardiovascular Society Guidelines for the management of atrial fibrillation. Can J Cardiol 2014;30:1114– 30. DOI: 10.1016/j.cjca.2014.08.001; PMID: 25262857 17. Lip GY, Lane DA. Stroke prevention in atrial fibrillation: a systematic review. JAMA 2015;313:1950–62. DOI: 10.1001/ jama.2015.4369; PMID: 25988464

18. Lip GY. Stroke and bleeding risk assessment in atrial fibrillation: when, how, and why? Eur Heart J 2013;34:1041–9. DOI: 10.1093/eurheartj/ehs435; PMID: 23257951 19. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137:263–72. DOI: 10.1378/chest.09-1584; PMID: 19762550 20. Eckman MH, Singer DE, Rosand J, Greenberg SM. Moving the tipping point: the decision to anticoagulate patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2011;4:14–21. DOI: 10.1161/CIRCOUTCOMES.110.958108; PMID: 21139092 21. Friberg L, Skeppholm M, Terént A. Benefit of anticoagulation unlikely in patients with atrial fibrillation and a CHA2DS2VASc score of 1. J Am Coll Cardiol 2015;65:225–32. DOI: 10.1016/j.jacc.2014.10.052; PMID: 25614418 22. Lip GY, Skjøth F, Rasmussen LH, Larsen TB. Oral anticoagulation, aspirin, or no therapy in patients with nonvalvular AF with 0 or 1 stroke risk factor based on the CHA2DS2-VASc score. J Am Coll Cardiol 2015;65:1385–94. DOI: 10.1016/j.jacc.2015.01.044; PMID: 25770314 23. Lip GY, Lane DA. Modern management of atrial fibrillation requires initial identification of “low-risk” patients using the CHA2DS2-VASc score, and not focusing on “high-risk” prediction. Circ J 2014;78:1843–5. PMID: 25008366 24. Chao TF, Liu CJ, Wang KL, et al. Should atrial fibrillation patients with 1 additional risk factor of the CHA2DS2-VASc score (beyond sex) receive oral anticoagulation? J Am Coll Cardiol 2015;65:635–42. DOI: 10.1016/j.jacc.2014.11.046; PMID: 25677422; PMID: 25677422 25. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011;365:2002–12. DOI: 10.1056/ NEJMsa1103053; PMID: 22111719

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26. Pugh D, Pugh J, Mead GE. Attitudes of physicians regarding anticoagulation for atrial fibrillation: a systematic review. Age Ageing 2011;40:675–83. DOI: 10.1093/ageing/afr097; PMID: 21821732 27. Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J 2006;151:713–9. PMID: 16504638 28. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010;138:1093–100. DOI: 10.1378/chest.10-0134; PMID: 20299623 29. Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol 2011;58:395–401. DOI: 10.1016/j.jacc.2011.03.031; PMID: 21757117 30. Roldán V, Marin F, Fernández H, et al. Predictive value of the HAS-BLED and ATRIA bleeding scores for the risk of serious bleeding in a “real-world” population with atrial fibrillation receiving anticoagulant therapy. Chest 2013;143:179–84. PMID: 22722228 31. Skanes AC, Healey JS, Cairns JA, et al. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/ rhythm control. Can J Cardiol 2012;28:125–36. DOI: 10.1016/ j.cjca.2012.01.021; PMID: 22433576 32. Griffiths HR, Lip GY. New biomarkers and risk stratification in atrial fibrillation: simplicity and practicality matter. Circulation 2014;130:1837–9. DOI: 10.1161/CIRCULATIONAHA.114.012870; PMID: 25294785 33. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17:1467– 507. DOI: 10.1093/europace/euv309; PMID: 26324838 34. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955–62. DOI: 10.1016/ S0140-6736(13)62343-0; PMID: 24315724 35. Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 2015;131:157–64. DOI: 10.1161/ CIRCULATIONAHA.114.012061; PMID: 25359164 36. Beyer-Westendorf J, Förster K, Pannach S, et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 2014;124:955–62. DOI: 10.1182/blood-2014-03-563577; PMID: 24859362 37. Tamayo S, Frank Peacock W, Patel M, et al. Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol 2015;38:63–8. DOI: 10.1002/ clc.22373; PMID: 25588595 38. German Clinical Trials Register. Non-interventional study on Edoxaban treatment in routine clinical practice for patients with non valvular atrial fibrillation - ETNA-AF-Europe DRKS00007912. Available at: http://drks-neu.uniklinik-freiburg. de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ ID=DRKS00007912 (accessed 20 October 2015). 39. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e152S–84S. DOI: 10.1378/ chest.11-2295; PMID: 22315259; PMCID: PMC3278055. 40. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511–20. DOI: 10.1056/NEJMoa1502000; PMID: 26095746 41. Glund S, Stangier J, Schmohl M, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet 2015;386:680–90. DOI: 10.1016/S0140-6736(15)60732-2; PMID: 26088268 42. Eikelboom JW, Quinlan DJ, van Ryn J, Weitz JI. Idarucizumab: The Antidote for Reversal of Dabigatran. Circulation 2015;132:2412–22. DOI: 10.1161/ CIRCULATIONAHA.115.019628; PMID: 26700008 43. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015;373:2413–24. DOI: 10.1056/NEJMoa1510991. PMID: 26559317 44. Huisman MV, Lip GY, Diener HC, et al. Design and rationale of Global Registry on Long-Term Oral Antithrombotic Treatment

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patients with atrial fibrillation in the ENGAGE AF-TIMI 48 Trial. Circulation 2014;130:A19119. 64. Healey JS, Eikelboom J, Walletin L, et al. Effect of age and renal function on the risks of stroke and major bleeding with dabigatran compared to warfarin: an analysis from the RE-LY study. J Am Coll Cardiol 2010;55(10s1):A4.E37. DOI: 10.1016/ S0735-1097(10)60038-1 65. Halvorsen S, Atar D, Yang H, et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J 2014;35:1864–72. DOI: 10.1093/ eurheartj/ehu046; PMID: 24561548; PMCID: PMC4104493 66. Halperin JL, Hankey GJ, Wojdyla DM, et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation 2014;130:138–46. DOI: 10.1161/CIRCULATIONAHA.113.005008; PMID: 24895454 67. Kato ET, Guigliano RP, Ruff CT, et al. Abstract 16612: Efficacy and Safety of Edoxaban for the Management of Elderly Patients With Atrial Fibrillation: Engage AF-TIMI 48. Circulation 2014;130:A16612. 68. Sharma M, Cornelius VR, Patel JP, et al. Efficacy and Harms of Direct Oral Anticoagulants in the Elderly for Stroke Prevention in Atrial Fibrillation and Secondary Prevention of Venous Thromboembolism: Systematic Review and Meta-Analysis. Circulation 2015;132:194–204. DOI: 10.1161/ CIRCULATIONAHA.114.013267; PMID: 25995317 69. Andreotti F, Rocca B, Husted S, et al. Antithrombotic therapy in the elderly: expert position paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J 2015;36:3238–49. DOI: 10.1093/eurheartj/ehv304; PMID: 26163482 70. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011;123:2363–72. DOI: 10.1161/ CIRCULATIONAHA.110.004747; PMID: 21576658 71. Kooiman J, van de Peppel WR, van der Meer FJ, Huisman MV. Incidence of chronic kidney disease in patients with atrial fibrillation and its relevance for prescribing new oral antithrombotic drugs. J Thromb Haemost 2011;9:1652–3. DOI: 10.1111/j.1538-7836.2011.04347.x; PMID: 21585647 72. Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012;367:625–35. DOI: 10.1056/NEJMoa1105594; PMID: 22894575 73. Bohula EA, Giugliano RP, Ruff CT, et al. Abstract 17169: The Impact of Renal Function on Outcomes With Edoxaban in the ENGAGE AF-TIMI 48 Trial. Circulation 2015;132:A17169. 74. Hohnloser SH, Hijazi Z, Thomas L, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J 2012;33:2821–30. DOI: 10.1093/eurheartj/ ehs274; PMID: 22933567 75. Fox KA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 2011;32:2387–94. DOI: 10.1093/ eurheartj/ehr342; PMID: 21873708 76. Hijazi Z, Hohnloser SH, Oldgren J, et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation 2014;129:961–70. DOI: 10.1161/CIRCULATIONAHA.113.003628; PMID: 24323795 77. Nielsen PB, Lane DA, Rasmussen LH, et al. Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on safety and efficacy outcomes in atrial fibrillation patients: a systemic review and meta-regression analysis. Clin Res Cardiol 2015;104:418–29. DOI: 10.1007/s00392-0140797-9; PMID: 25416564 78. Hart RG, Eikelboom JW, Brimble KS, et al. Stroke prevention in atrial fibrillation patients with chronic kidney disease. Can J Cardiol 2013;29(7 Suppl):S71–8. DOI: 10.1016/j. cjca.2013.04.005; PMID: 23790601 79. Kralev S, Schneider K, Lang S, et al. Incidence and severity of coronary artery disease in patients with atrial fibrillation undergoing first-time coronary angiography. PLoS One 2011;6:e24964. DOI: 10.1371/journal.pone.0024964; PMID: 21957469; PMCID: PMC3177852 80. The AFibFive: 5 steps to your healthiest life with AFib. Available at: www.myvirtualpaper.com/doc/aha-publications/ atrial-fibrillation--your-healthiest-life/2012092701/5.html#4 (accessed 20 July 2015).

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The Significance of Shocks in Implantable Cardioverter Defibrillator Recipients Anthony Li, Amit Kaura, Nicholas Sunderland, Paramdeep S Dhillon and Paul A Scott Department of Cardiology, King’s College Hospital NHS Foundation Trust, London, UK

Abstract Large-scale implantable cardioverter defibrillator (ICD) trials have unequivocally shown a reduction in mortality in appropriately selected patients with heart failure and depressed left ventricular function. However, there is a strong association between shocks and increased mortality in ICD recipients. It is unclear if shocks are merely a marker of a more severe cardiovascular disease or directly contribute to the increase in mortality. The aim of this review is to examine the relationship between ICD shocks and mortality, and explore possible mechanisms. Data examining the effect of shocks in the absence of spontaneous arrhythmias as well as studies of non-shock therapy and strategies to reduce shocks are analysed to try and disentangle the shocks versus substrate debate.

Keywords Implantable cardioverter defibrillator shocks, mortality, inappropriate shocks, appropriate shocks, implantable cardioverter defibrillator programming Disclosure: The authors have no conflicts of interest to declare. Received: 4 January 2016 Accepted: 20 May 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(2):110–6 DOI: 10.15420/AER.2016.12.2 Access at: www.AERjournal.com Correspondence: Dr Paul A Scott, Department of Cardiology, King’s College Hospital NHS Foundation Trust, Denmark Hill, London, SE5 9RS, UK. E: paulscott3@nhs.net

Since the 1990s, the publication of several large randomised controlled trials (RCTs) have established the efficacy of implantable cardioverter defibrillator (ICD) therapy in reducing the risk of sudden cardiac death (SCD) in high-risk patients. Collectively these trials have demonstrated a significant all-cause mortality reduction compared with medical therapy alone, for both the primary and secondary prevention of SCD.1–9 The main life-saving therapy delivered by ICDs is shock therapy. In the largest cohort of real-world ICD recipients, totalling nearly 200,000 patients, 1-year shock occurrence post-implantation was 14 % and at 5 years 38 %.10 Rates of therapy are considerably higher in secondary prevention populations with nearly half receiving shocks at 1 year.11 However, although often life-saving, ICD shocks have a number of negative effects, including psychological morbidity and reduced quality of life, and are an economic burden. Data from both RCTs and observational studies have demonstrated significant reductions in measures of physical and mental wellbeing after a single shock that further decline with increasing numbers of shocks.12–17 ICD shocks also result in increased healthcare utilisation and a reduction in device longevity. Furthermore, more worryingly sub-analyses of the major ICD trials have suggested a subsequent increased risk of death in patients that receive shocks. Whether ICD shocks are merely markers of, or are directly contributing to, the poor prognosis observed in patients receiving them is unclear. The aim of this article is to review the current literature regarding this issue.

Relationship Between Shocks and Mortality The publication of the landmark primary prevention ICD trials, the Multicenter Automatic Defibrillator Implantation Trial (MADIT-II) and

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the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), over a decade ago, resulted in a widespread increase in ICD implantation worldwide.3,6 However, subsequent re-analysis of these trials raised concerns over an adverse prognosis in patients that received ICD shocks. The MADIT-II established the benefit of ICD implantation in postmyocardial infarction (MI) patients with a left ventricular ejection fraction (LVEF) ≤30 %, who had no history of sustained ventricular arrhythmias. However, there were initial concerns over a trend towards excess heart failure admissions in the ICD arm.3 In a subsequent analysis, the long-term follow-up data of the 720 defibrillator recipients in the trial were examined. Over a period of 21 months, 23 % of patients received device therapies for ventricular tachycardia (VT)/ventricular fibrillation (VF), which was associated with a 1-year mortality rate of 20 %. Furthermore, admissions for heart failure occurred in 26–31 % following device therapy versus 19 % in the therapy-free cohort. Hazard regression analysis demonstrated a threefold increase in mortality after a first therapy for VT (hazard ratio [HR] 3.4, 95 % confidence interval [CI] 1.9–5.9, p<0.001) or VF (HR 3.3, 95 % CI 1.3–8.1, p=0.01).18 In a further analysis of the MADIT II, inappropriate shocks were delivered in 83 (12 %) patients and associated with a twofold increase in mortality.19 In the SCD-HeFT, 2,521 patients with heart failure of any aetiology and LVEF ≤35 % were randomised to placebo, amiodarone or an ICD. Defibrillator therapy was associated with a significant 23 % reduction in all-cause mortality compared with placebo.6 Poole et al. examined the significance of shocks, both appropriate and inappropriate, in the 811 ICD recipients. During a follow-up of 46 months 33 % received at least one shock, of which only 47.6 % were solely for VT/VF,

15/08/2016 20:19

Significance of Shocks in Implantable Cardioverter Defibrillator Recipients

Figure 1: Forest Plot for Hazard Ratio of Mortality for (A) Appropriate Shock Versus No Shock and (B) Inappropriate Shock Versus No Shock

Weight (n)

Study

3.36 (204, 5.55)

7.24

719

5.68 (397, 8.12)

14.17

811

Year

HR (95 % CI)

Daubert

2006

Poole

2006

Study

Size

Year

HR (95 % CI)

Daubert

2008

2.29 (1.11, 4.71) 5.23

719

Poole

2008

1.98 (1.29, 3.05) 14.74

811

2010

1.84 (1.30, 2.61) 22.47

108,027

Weight (n)

Saxon-ICD 2010

2.05 (1.55, 2.71) 23.24

108027 Saxon-ICD

Saxon-CRT 2010

2.51 (2.01, 3.14) 36.46

77,751

Saxon-CRT 2010

1.60 (1.15, 2.23) 24.89

77,751

Streitner

2013

1.65 (0.95, 2.90) 5.82

561

van Rees

2011

1.40 (1.00, 2.00) 22.72

1,544

Sood

2014

2.28 (1.47, 3.54) 9.39

1,790

Sood

2014

1.28 (0.59, 2.77) 4.56

1,790

Ruwald

2014

6.32 (3.13, 12.75) 3.68

Ruwald

2014

2.61 (1.28, 5.31) 5.39

Overall

2.75 (240, 3.14)

0.5

Source: Meta-analysis from Proietti et al., 2015

100.00

1.71 (1.45, 2.02) 100.00

0.5

32.3 % for non-VT/VF and 20.1 % for both. In multivariate analysis, both inappropriate shocks (HR 1.98, 95 % CI 1.29–3.05, p=0.002) and appropriate shocks (HR 5.68, 95 % CI 3.97–8.12, p<0.001) were associated with mortality. The risk further increased with additional appropriate shocks, which was associated with an eightfold risk of death, and the occurrence of inappropriate shocks on top of this, increased this further to a nearly 16-fold risk.20 Proietti et al. performed a meta-analysis examining the size of the association between ICD shocks and mortality in major ICD trials. Data from 10 studies, including nearly 200,000 patients, were evaluated. In a pooled analysis, a significant association was found between ICD shocks and mortality. The association was stronger for appropriate (HR 2.95, 95 % CI 2.12–4.11, p<0.001) than inappropriate shocks (HR 1.71, 95 % CI 1.45–2.02, p<0.001) but both associations were significant. In keeping with prior studies, the combination of appropriate and inappropriate shocks was associated with a greater risk than the occurrence of just one type of shock (see Figure 1).21 These data conclusively demonstrate that the occurrence of ICD shocks is associated with a worse prognosis. The risk appears to be greater for appropriate than inappropriate shocks, though both are associated with impaired survival. Furthermore, multiple shocks are associated with worse outcomes.

Potential Mechanism of Increased Mortality with Shocks Evidence from human studies has shown that shocks increase serum biomarker levels of myocardial injury;22–24 however, translation to increased mortality has not been established. Experimental studies have also suggested that shock delivery may lead to direct myocardial stunning, the degree of which is related to the magnitude of the electrical shock. This is a mechanism that may be responsible for the post-shock pulseless electrical activity (PEA) seen frequently in the post-resuscitation setting.25,26 One study reviewed 320 deaths in ICD recipients enrolled in device trials to attempt to define the mode of death. Deaths were classified using data from medical notes, interviews of witnesses and ICD memory logs. In total, 317 deaths had sufficient data to assign a mode of death; 28 % were classified as sudden, 49 % non-sudden and 22 %

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Overall

non-cardiac. Of the sudden deaths, post-shock PEA was classified as the mechanism in 29 %.26 This potential importance of myocardial stunning is supported by data from Toh et al., who investigated the acute effects of ICD shocks on haemodynamics and myocardial function. Fifty patients undergoing ICD implantation and defibrillation testing (DFT) were evaluated by echocardiography, serum biomarker measurements before, immediately following and at 5 minutes and 4 hours after shock delivery, and had invasive arterial pressure monitoring during the procedure. Compared with patients with LVEF >45 %, those with poorer function experienced further transient depression of LVEF until 5 minutes post-DFT, which recovered to baseline by 4 hours, and significantly longer recovery time of mean arterial pressure to baseline.27 Examining the timing of death in relation to ICD shocks in RCTs may provide further insight. Of the 811 patients in the SCD-Heft who had an ICD implanted, 269 received at least one ICD shock. Of these 269 ICD recipients 77 died; progressive heart failure accounted for 43 % of deaths and sudden arrhythmic death 21 %. Median time to death following any shock was 204 days (interquartile range 1–630) and was longer for inappropriate compared with appropriate shocks. Postmortem data were available for 64 of the 173 patients that died with the device in situ. Of these, 20 were found to have died within 24 hours of a shock.20 While myocardial stunning may potentially account for death within the first 24 hours of a shock, it is unlikely to be an important factor in patients that died sometime after their device therapy.

Is It Shocks or Progression of the Substrate? As detailed above, there are a number of potential mechanisms by which shocks may directly increase the risk of death. However, equally there is a clear rationale for suggesting that shocks may be a marker of a higher risk patient. The occurrence of VT or VF that leads to appropriate shocks is increasingly likely in the presence of more advanced myocardial disease, which itself portends an adverse prognosis. Furthermore, the presence of atrial fibrillation (AF), the commonest cause of inappropriate therapy, is independently associated with an increased risk of death in patients with heart failure.28 Therefore, the association between ICD shocks and increased mortality may be explained by either the detrimental effects of the shocks

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Clinical Arrhythmias Figure 2: Risk of Death After First Shock Compared with No Shock Group in the ALTITUDE Study Variable: MVT and PMVT NSVT VF/PMVT MVT Atrial fibrillation/flutter Sinus tachycardla/SVT Noise/artifact/oversensing

95 % CI

2.77 2.17 2.10 1.65 1.61 0.97 0.91

(1.70 – 4.51) (0.82 – 5.70) (1.54 – 2.86) (1.36 – 2.01) (1.17 – 2.21) (0.68 – 1.37) (0.50 – 1.67) 1

MVT = monomorphic ventricular tachycardia; NSVT = non-sustained ventricular tachycardia; PMVT = polymorphic ventricular tachycardia; SVT = supraventricular tachycardia; VF = ventricular fibrillation.

Data on the prognostic implication of induced VF is provided by Bhavnani and colleagues who followed up a cohort of 1,327 patients undergoing ICD implantation from a single centre. All patients underwent ICD implantation with defibrillation testing after VF induction during the procedure. Patients were stratified into four groups according to shock type received: implantation shocks only, additional shocks for non-invasively stimulated VF, additional appropriate shocks only and additional inappropriate shocks only. A combined primary endpoint of all-cause mortality and hospitalisation for acute decompensated heart failure was used. When compared with implantation-only shocks, patients who underwent non-invasive VF induction with subsequent shocks had a similar risk of death and hospitalisation for heart failure. However, the occurrence of spontaneous arrhythmias requiring shocks carried a twofold risk of death and heart failure hospitalisation.30

Figure 3: Survival Rates by Rhythm and Implantable Cardioverter Defibrillator Therapy Type 1 0.95 0.9

Survival

0.85 0.8 0.75 0.7 0.65

No VT/VF

0.6

VT/VF, shocked

0.55 0.5

VT/VF, ATP, no shocks

Months Number at Risk No VT/VF (n=1,671)

1584

1,472

1,355

812

VT/VF, ATP, no shocks (n=253)

247

229

206

126

VT/VF, shocked (n=211)

201

186

172

ATP = antitachycardia pacing; VF = ventricular fibrillation; VT = ventricular tachycardia. Source: Sweeney et al., 2010.36

themselves, progression of the underlying disease process (with shocks merely a marker of disease progression) or a combination of the two. Several lines of evidence may be useful to disentangle this association. These include data from the occurrence of shocks in the absence of spontaneous arrhythmias, the effect of non-shock therapies (i.e. antitachycardia pacing [ATP]) in the treatment of ventricular arrhythmias and the impact of a range of strategies used to reduce the burden of shock therapy (strategic ICD programming, antiarrhythmic drugs and VT ablation).

The Impact of Shocks Without Spontaneous Arrhythmia There are a number of situations in which ICD shocks are delivered without the occurrence of spontaneous arrhythmias. These include defibrillation testing at implant, the induction of VF remote from the initial implant procedure and the occurrence of shocks for nonarrhythmic causes. Defibrillation testing in patients receiving ICDs provides an opportunity to examine the effect of shocks without acute arrhythmia. The Shockless Implant Evaluation (SIMPLE) trial was a randomised single-blind non-inferiority trial of defibrillation testing versus no defibrillation testing at the time of ICD implantation in 2,500 patients. A total of 1,253 patients were randomised to the defibrillation testing arm, of whom 74 % had primary prevention devices and 64 % an underlying ischaemic cardiomyopathy. The mean LVEF was 32 %. Overall, there was no difference in the composite primary endpoint of failed appropriate shock or arrhythmic death, and no difference

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in all-cause mortality between the groups. Analysis of secondary endpoints showed a non-significant trend towards an increase in adverse outcomes in the defibrillation testing group (4.5 % versus 3.2 %, p=0.08). Furthermore, in the defibrillation group there was a greater need for chest compressions (0.4 % versus 0.0 %, p=0.06) and emergency intubation (0.6 % versus 0.1 %, p=0.03) compared with the control arm.29 These data possibly suggest some detrimental effect of receiving shocks without spontaneous arrhythmia, though any potential effect is small and of uncertain clinical significance.

The ALTITUDE study aimed to differentiate the risk associated with shocks versus the underlying rhythm in patients receiving only inappropriate shocks. This was a prospective observational study of 127,134 patients who had either an ICD or cardiac resynchronisation therapy defibrillator (CRT-D) and were followed using a remote monitoring system. From this cohort, the investigators randomly sampled 3,809 (13 %) patients who received ≥1 shock. Over a 3-year follow up, 41 % of patients received shocks for non-VT/VF rhythms. Atrial arrhythmias were the commonest cause, accounting for 44 %, followed by other supraventricular arrhythmias (41 %) and noise or oversensing (11 %). In matched comparison to the no-shock group, the risk of death was no different if an inappropriate shock was delivered due to supraventricular arrhythmias (HR 0.97, 95 % CI 0.68–1.37, p=0.86) or noise/oversensing (HR 0.91, 95 % CI 0.50–1.67, p=0.76). In contrast, shocks delivered for AF/atrial flutter were associated with an increased risk of death (HR 1.61, 95 % CI 1.17–2.21, p=0.003) (see Figure 2).31 These findings were also replicated by a smaller prospective study of 1,411 patients.32 These data, evaluating the impact of shocks occurring in the absence of spontaneous arrhythmias, suggest that the risks associated with shocks are predominantly due to the underlying rhythm rather than the shocks themselves.

The Relationship Between Antitachycardia Pacing and Mortality ATP was developed as an alternative therapy to terminate VT to avoid shocks. Examining the association of mortality with ATP therapy may provide contributory evidence in the substrate versus shocks debate. However, data from individual studies are conflicting with some showing an increased risk of death and others not. Sweeney et al. published data from a meta-analysis of 2,135 patients enrolled in four trials that used ATP to reduce ICD shocks.33 Patients were predominantly male with ischaemic heart disease, and the majority received prophylactic devices. Over 11 months of follow-up,

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24.3 % patients received appropriate device therapy and 6.6 % died. Analysis of the differential effect of shocks versus ATP could only be ascertained for fast VTs, defined as 188–250 bpm, as slower VT were predominantly treated with ATP and VF with shocks. Shocks for fast VT were associated with an increased risk of death (HR 1.32, 95 % CI 1.23–1.41, p<0.0001), whereas ATP had no effect (see Figure 3). In a more recent study, Kleeman et al. prospectively followed 1,398 patients who underwent ICD implantation in a single centre. Patients were stratified into groups according to the mode of therapy: ATP only termination, appropriate shock termination or no appropriate therapy of any type. Over a 6-year follow-up, 54 % required therapies to terminate VT/VF. Of these, 74 % were terminated by ATP only. In multivariate analysis, an episode of first ATP was associated with a 2.6-fold increased risk of death (95 % CI 2.02–3.35). This association remained significant when excluding patients with appropriate shocks after prior ATP (HR 1.92, 95 % CI 1.38–2.67). However, the risk associated with ATP was still lower than that seen with shock therapy.34 A similar association with ATP-only therapy compared with no therapy was also demonstrated in the recently reported Assessing Therapies in Medtronic Pacemaker, Defibrillator and Cardiac Resynchronization Therapy Devices (OMNI) trial involving 2,255 patients over a 3-year follow-up (HR for death 1.45, 95 % CI 1.05–2.02, p=0.025).35 Overall, data regarding ATP and mortality risk are conflicting. Although analysis of RCTs with relatively short follow-up have found no association between ATP and mortality, evidence from cohorts with longer follow-up appear to indicate that ATP is associated with increased mortality, though with a lesser magnitude than the association with appropriate shocks. This may suggest that the arrhythmia itself has more of a bearing on mortality, though therapy type may also have an additional contribution to risk.

Table 1: Strategies to Reduce Implantable Cardioverter Defibrillator Therapies and Their Effect on Mortality Strategy to Reduce

Impact on

Implantable Cardioverter

Shock Reduction

Defibrillator Shocks Strategic ICD programming

50 % reduction in

30 % reduction

inappropriate therapy

in mortality

No difference in

appropriate shocks

Remote monitoring

ECOST RCT:

71 % reduction

No difference in

in all shocks and

mortality

52 % reduction

in inappropriate

shocks from the

ECOST trial

IN-TIME RCT

Reduction in all-

1-year results:

cause mortality

Shock occurrence

(HR 0.36)

not reported

Unclear impact of

reduced shocks

on mortality in

both trials

Antiarrhythmic drugs

48 % reduction in

No difference in

combined endpoint

mortality between

of mortality and first

sotalol versus

shock at 1-year with

placebo

sotalol in RCT

OPTIC RCT 1-year

No difference in

results: amiodarone

mortality between

plus b-blocker

Strategies to Reduce Implantable Cardioverter Defibrillator Shocks and Their Effect on Mortality Strategies that have been shown to reduce the burden of ICD shocks are summarised in Table 1, and their clinical impact on morbidity and mortality are discussed below.

Impact of Implantable Cardioverter Defibrillator Programming on Shock Reduction Strategic ICD programming can reduce the occurrence of ICD therapy without altering the underlying myocardial substrate, and has provided clear evidence implicating shocks as directly influencing

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groups

versus b-blocker

Interpretation of the relationship between ATP, shocks and mortality is further complicated by the fact that ventricular arrhythmias treated with ATP are typically different from those treated with shocks.18 Ventricular rates tend to be lower, arrhythmia onset to therapy delivery is typically shorter due to the absence of a charge time with ATP, and overall VT amenable to ATP may be a marker of a less diseased myocardium. Early studies of ATP testing for induced VT demonstrated lower success rates and higher rates of tachycardia acceleration for faster VTs.36 Furthermore, data reported by Moss and colleagues suggested that slower VTs, which are more frequently terminated by ATP, were associated with a better outcome than that of fast VTs.18 In another study, the rate of ICD shocks preceded by failed ATP was 18 times higher in patients who died at follow-up, further supporting the hypothesis that VT unresponsive to ATP could be a marker of substrate severity.33

Mortality Impact

(HR 0.27). Amiodarone

plus b-blocker

versus sotalol (HR 0.43)

Catheter ablation

SMASH-VT RCT 2-year No difference in

results: Reduction of

appropriate therapy

(HR 0.35)

VTACH RCT 2-year

No difference in

results: Higher

mortality

freedom from

VT/VF (HR 0.61)

mortality

ICD = implantable cardioverter defibrillator; ECOST = Effectiveness and Cost of ICDs Followup Schedule with Telecardiology; IN-TIME = The Influence of Home Monitoring on the Clinical Status of Heart Failure Patients With Impaired Left Ventricular Function; OPTIC = Optimal Pharmacological Therapy in Implantable Cardioverter Defibrillator Patients; RCT = randomised controlled trial; SMASH-VT = Substrate Mapping and Ablation in Sinus rhythm to Halt Ventricular Tachycardia; VF = ventricular fibrillation; VT = ventricular tachycardia; VTACH = Ventricular Tachycardia Ablation in Addition to Implantable Defibrillators in Coronary Heart Disease.

mortality risk.37 Two recent meta-analyses have examined the effect of ICD programming strategies on mortality reduction. Tan et al. sought to quantify the overall effect of ICD therapy reduction programming strategies on mortality from six major programming trials: Comparison of Empiric to Physician-tailored Programming of Implantable Cardioverter Defibrillators (EMPIRIC), Primary Prevention Parameters Evaluation (PREPARE), Role of Long Detection Window Programming in Patients With Left Ventricular Dysfunction, Non-ischemic Etiology in Primary Prevention Treated with a Biventricular ICD (RELEVANT), Multicenter Automatic Defibrillator

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Clinical Arrhythmias Figure 4: Meta-analysis of Therapy Reduction Versus Conventional Implantable Cardioverter Defibrillator Programming on Risk of Death A Weight % Relative Risk (95 % Confidence Interval) (random effects)

Study EMPIRIC

0.82 (0.49, 1.38)

11.01

PREPARE

0.56 (0.37, 0.84)

17.98

RELEVANT

0.98 (0.20, 4.76)

1.19

MADIT-RIT delay

0.65 (0.38, 1.11)

10.64

MADIT-RIT high rate

0.48 (0.27, 0.87)

8.83

ADVANCE III

0.87 (0.60, 1.25)

21.67

PROVIDE

0.75 (0.54, 1.03)

28.68

0.70 (0.59, 0.84)

100.00

2 Overall (I =0 % 95 % CI 0 % to 75 %)

0.1

B Study

Favours Therapy Reduction Programming

Favours Control

Weight % Relative Risk (95 % Confidence Interval) (random effects)

EMPIRIC

0.82 (0.49, 1.38)

14.51

MADIT-RIT combined

0.57 (0.36, 0.89)

19.14

ADVANCE III

0.87 (0.60, 1.25)

28.56

PROVIDE

0.75 (0.54, 1.03)

37.79

2 Overall (I =0 % 95 % CI 0 % to 79 %)

0.74 (0.61, 0.91)

100.00

0.1

Favours Therapy Reduction Programming

Favours Control

Panel A: all six studies; Panel B: only randomised controlled trials. ADVANCE III = Avoid Delivering Therapies for Nonsustained Arrhythmias in ICD Patients III; EMPIRIC = Comparison of Empiric to Physician-tailored Programming of Implantable Cardioverter Defibrillators; MADIT-RIT = Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy; PREPARE = Primary Prevention Parameters Evaluation; PROVIDE = Programming Implantable Cardioverter-Defibrillators in Patients with Primary Prevention Indication to Prolong Time to First Shock; RELEVANT = Role of Long Detection Window Programming in Patients With Left Ventricular Dysfunction, Non-ischemic Etiology in Primary Prevention Treated with a Biventricular ICD. Source: Tan et al., 2014.38

Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT), Avoid Delivering Therapies for Nonsustained Arrhythmias in ICD Patients III (ADVANCE III) and Programming Implantable CardioverterDefibrillators in Patients with Primary Prevention Indication to Prolong Time to First Shock (PROVIDE). In total 4,089 patients with therapy reduction programming were compared with 3,598 conventionally programmed patients. Therapy reduction programming involved using combinations of long detection times, high detection rates and SVT discriminators. Over a 1-year follow-up there was a 50 % reduction in inappropriate shocks in the strategic programming group, though appropriate shock rates were similar between groups. Therapy reduction programming was associated with a 30 % reduction in mortality (95 % CI 16–41 %, p<0.001) compared with the conventional arm (see Figure 4).38 The mortality benefit of programming long detection times was the focus of a meta-analysis by Scott and colleagues. Four studies enrolling 4,896 patients were included: RELEVANT, MADIT-RIT, ADVANCE III and PROVIDE. A mortality reduction of 23 % (RR 0.77, 95 % CI 0.62–0.96, p=0.02) was seen in the long detection arm. In keeping with the analysis of Tan et al. there was a 50 % reduction in inappropriate shocks, but no significant difference in the occurrence of appropriate shocks. Importantly, no increase in risk of syncope was seen. Data

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on ATP therapy was derived from two studies, which indicated a substantial reduction in both appropriate (RR 0.25, 95 % CI 0.15–0.41) and inappropriate ATP (RR 0.35, 95 % CI 0.19 – 0.64).39 The mortality reduction seen with strategic programming is compelling evidence that shock therapy and possibly ATP as well are not only markers of risk but have a direct and significant impact on mortality.

Remote Monitoring of Implantable Cardioverter Defibrillators Modern ICDs now have the ability to be remotely monitored. Data can be automatically transmitted from the device following a detected event or change in certain physiological parameters, which is then sent to a central database and onto the local device clinic, usually within 24 hours.40 Remote monitoring (RM) enables early detection of clinical or device-related problems and allows prompt intervention. Other potential benefits include reducing unnecessary face-to-face visits where a patient’s clinical status has remained stable, thus reducing the economic burden.41 The role of RM in reducing both appropriate and inappropriate shocks has been the subject of several studies. In a sub-analysis of the Effectiveness and Cost of ICDs Follow-up Schedule with Telecardiology (ECOST) trial involving 433 randomised patients, RM significantly reduced the number of shocks of any cause by 71 %, driven mainly by a 52 % reduction in inappropriate shocks and with a subsequent 72 % reduction in hospitalisation.42 Sensing problems arising as a result of lead failure, electromagnetic interference, T wave or myopotential oversensing contribute a small but important proportion of inappropriate shocks and can be preceded by detected events prior to any therapy administered. In one small single-centre cohort study of leads under advisory, RM patients experienced reduced shocks compared with those with standard clinic follow-ups (27 % versus 47 %).43 The ALTITUDE study, which compared nearly 70,000 patients under RM to 116,000 patients with device clinic only follow-up, provided compelling mortality data. The main finding of this study was a striking 50 % relative reduction in the risk of death in patients with RM (HR 0.56 for ICD, 0.45 for CRT-D). However, clinical data were lacking and as such differences in baseline characteristics that could have influenced survival could not be adjusted for between the groups.10 In the Influence of Home Monitoring on the Clinical Status of Heart Failure Patients With Impaired Left Ventricular Function (IN-TIME) multicentre RCT of automatic daily RM versus standard care in 664 patients, 1-year all-cause mortality was lower in the RM monitoring group (HR 0.36, p=0.004).44 Although mortality reduction was seen in both these trials, it is not possible to determine the contribution of shock reduction on overall mortality with these data.

The Impact of Antiarrhythmic Therapy on Shock Reduction and Mortality Therapy with antiarrhythmic drugs (AADs) aims to reduce the burden of arrhythmias associated with both appropriate and inappropriate therapy. As such AAD therapy may reduce device therapy by altering the electrophysiological properties of the myocardial substrate without significantly altering the underlying myocardial architecture. Two randomised trials have systematically examined the effect of AAD therapy in reducing ICD shocks. Sotalol was compared with

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a placebo in a double blind trial of 302 secondary prevention ICD patients. A combined primary endpoint of all-cause mortality and first shock therapy for any cause was used. At 1-year follow-up, sotalol was associated with a 48 % reduction in the primary endpoint compared with placebo, with a greater reduction in inappropriate versus appropriate shocks.45 There was no difference in mortality between the sotalol (four deaths) and placebo groups (seven deaths). The Optimal Pharmacological Therapy in Implantable Cardioverter Defibrillator Patients (OPTIC) trial randomised 412 patients with recently implanted ICDs, clinically documented VT/VF and a LVEF ≤40 % to a combination of amiodarone plus b-blocker, sotalol or b-blocker alone. At 1-year follow-up patients in the amiodarone plus b-blocker arm experienced fewer shocks compared with either sotalol (HR 0.43, 95 % CI 0.22–0.85) or b-blocker alone (HR 0.27 CI 0.14–0.52). There was a non-significant trend towards fewer shocks with sotalol compared with b-blockers alone (HR 0.61, 95 % CI 0.37–1.01, p=0.055). Rates of AAD discontinuation were higher with amiodarone (18 %) and sotalol (24 %) compared with b-blockers alone (5.3 %). Amiodarone was also associated with a high number of pulmonary (5.0 %) and thyroid (5.7 %) complications. Overall the mortality rate was low (3.1 % at 1-year) with no difference between treatment groups.46 The two studies taken together suggest that AADs significantly reduce the frequency of ICD shocks, without a significant mortality benefit. However the studies were not powered to demonstrate any mortality benefit. Furthermore, it is possible that any potential prognostic benefit from shock reduction may be offset by drug-related adverse events.47

Ventricular Tachycardia Ablation to Reduce Implantable Cardioverter Defibrillator Shocks Ablation has become increasingly important as an adjunctive therapy to reduce shocks in ICD recipients. There have been two RCTs of prophylactic VT ablation in patients with ICDs implanted after documented VT/VF due to ischaemic heart disease. The Substrate Mapping and Ablation in Sinus rhythm to Halt Ventricular Tachycardia (SMASH-VT) trial was a prospective, randomised, multicentre trial of catheter ablation versus medical therapy alone in 128 post-MI patients with a recently implanted secondary prevention ICD. The primary endpoint was freedom from any ICD therapy, either ATP or shocks. After a 2-year follow-up, catheter ablation reduced any appropriate therapy from 33 % to 12 % (HR 0.35, 95 % CI 0.15– 0.78, p=0.007) and appropriate shocks from 31 % to 9 % (p=0.003); however, mortality did not differ between the groups.48 The Ventricular Tachycardia Ablation in Addition to Implantable Defibrillators in Coronary Heart Disease (VTACH) trial was of a similar design to the SMASH-VT trial and enrolled 107 patients to catheter ablation plus ICD or ICD alone. In contrast to the SMASH-VT trial patients, those enrolled in the VTACH trial were a more homogenous group that required documented stable VT after baseline VT induction and had an ICD implanted post-ablation. At 2-year follow-up, time to VT/VF recurrence was longer in the ablation arm, 18.6 versus 5.9 months, and freedom from VT/VF was higher, 46 % versus 29 % (HR 0.61 95 % CI 0.37–0.99). Again, mortality did not differ between the two arms.49 To capture any possible effect of VT ablation on mortality, Mallidi et al. analysed data on 457 patients from five studies, including the SMASH-VT

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and VTACH populations, along with three observational studies. Catheter ablation was associated with a 35 % reduction in VT recurrence but with no effect on mortality. However, significant procedural complications occurred in 6 %, including death, stroke/transient ischaemic attack (TIA), cardiac perforation and atrioventricular (AV) block (approximately 1 % each), which may have offset any potential benefit on mortality seen due to a reduction in shocks.50 The results of ongoing VT ablation trials such as the Does Timing of VT Ablation Affect Prognosis in Patients With an Implantable Cardioverter-defibrillator? (PARTITA), Ventricular Tachycardia Ablation or Escalated Drug Therapy (VANISH)51 and Preventive Ablation of Ventricular Tachycardia in Patients with Myocardial Infarction (BERLIN) should provide further clarification on the relationship between reduction in ICD shocks and mortality.

The Relationship Between Left Ventricular Remodelling and Shocks Sood et al. examined the relationship between the degree of post-implant left ventricular remodelling, the occurrence of ICD shocks and mortality. The study population comprised 1,790 patients who received either an ICD or CRT-D as part of the MADIT-CRT study. Myocardial substrate progression was assessed by standard transthoracic echocardiography at baseline and at 1-year follow-up using LVEF and indexed LV volumes. Advanced myocardial structural disease, i.e. higher baseline echocardiographic volumes and lack of left ventricular remodelling at 1-year, was present in patients who received appropriate shocks but not in patients who received inappropriate shocks or no shocks. At 2-year follow-up, patients that received appropriate (HR 2.3, 95 % CI 1.47–3.54, p<0.001) but not inappropriate shocks (p=0.42) had an increased risk of mortality. This association remained significant when adjusted for echocardiographic remodelling at 1 year. This study suggests that the occurrence of shocks and the presence of advanced myocardial substrate remodelling are inextricably linked, and that the deleterious effects of shocks are most marked in the presence of a more diseased myocardial substrate.52

Conclusion It is clear that there is a strong and consistent association between increased mortality and both inappropriate and appropriate shocks. However, disentangling whether shocks are purely a marker of the severity of the underlying cardiac disease or whether they directly contribute to risk is challenging. Data supporting shocks as only a marker of risk include the neutral effect of shocks occurring in the absence of spontaneous arrhythmias, such as in defibrillation testing and inappropriate shocks for a nonarrhythmic cause. In contrast, data from trials examining the role of ICD programming to reduce shocks provide compelling evidence that shocks themselves contribute to risk. Overall the data are inconclusive. However, although it is not possible to draw definitive conclusions it is likely that both the substrate and the occurrence of shocks are important. It may be that while the occurrence of ICD shocks is a marker of more advanced cardiac disease, which itself portends a poor prognosis, the occurrence of shocks in the presence of a diseased substrate adds additional incremental risk that can be reduced by the avoidance of unnecessary

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Clinical Arrhythmias shocks. This hypothesis is supported by data from the MADIT-CRT study examining the relationship between mortality, shocks and substrate progression. However, what is incontrovertible is that ICD shocks are physically unpleasant and psychologically damaging, and so reducing them is important irrespective of their prognostic significance. Furthermore, the most common mode of death in ICD patients receiving a shock is pump failure, and the occurrence of any ICD therapy should prompt the re-evaluation and aggressive treatment of heart failure. ■

10.

11.

12.

13.

14.

15.

16.

17.

18.

Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996;335:1933–40. DOI: 10.1056/NEJM199612263352601; PMID: 8960472 Bigger JT Jr. Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. N Engl J Med 1997;337:1569–75. DOI: 10.1056/ NEJM199711273372201; PMID: 9371853 Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877–83. DOI: 10.1056/NEJMoa013474; PMID: 11907286 Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004;350:2151–8. DOI: 10.1056/ NEJMoa033088; PMID: 15152060 Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med 2004;351:2481–8. DOI: 10.1056/ NEJMoa041489; PMID: 15590950 Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37. DOI: 10.1056/ NEJMoa043399; PMID: 15659722 A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. N Engl J Med 1997;337:1576–83. DOI: 10.1056/NEJM199711273372202; PMID: 9411221 Kuck KH, Cappato R, Siebels J, Rüppel R. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH). Circulation 2000;102:748–54. PMID: 10942742 Connolly SJ, Gent M, Roberts RS, et al. Canadian implantable defibrillator study (CIDS) : a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation 2000;101:1297–302. PMID: 10725290 Saxon LA, Hayes DL, Gilliam FR, et al. Long-term outcome after ICD and CRT implantation and influence of remote device follow-up: the ALTITUDE survival study. Circulation 2010;122:2359–67. DOI: 10.1161/ CIRCULATIONAHA.110.960633; PMID: 21098452 Klein RC, Raitt MH, Wilkoff BL, et al. Analysis of implantable cardioverter defibrillator therapy in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. J Cardiovasc Electrophysiol 2003;14:940–8. PMID: 12950538 Sears SF, Todaro JF, Lewis TS, et al. Examining the psychosocial impact of implantable cardioverter defibrillators: a literature review. Clin Cardiol 1999;22:481–9. PMID: 10410293 Schulz SM, Massa C, Grzbiela A, et al. Implantable cardioverter defibrillator shocks are prospective predictors of anxiety. Heart Lung 2013;42:105–11. DOI: 10.1016/ j.hrtlng.2012.08.006; PMID: 23110854 Irvine J, Dorian P, Baker B, et al. Quality of life in the Canadian Implantable Defibrillator Study (CIDS). Am Heart J 2002;144:282–9. PMID: 12177646 Schron EB, Exner D V, Yao Q, et al. Quality of life in the antiarrhythmics versus implantable defibrillators trial: impact of therapy and influence of adverse symptoms and defibrillator shocks. Circulation 2002;105:589–94. PMID: 11827924 Mark DB, Anstrom KJ, Sun JL, et al. Quality of life with defibrillator therapy or amiodarone in heart failure. N Engl J Med 2008;359:999–1008. DOI: 10.1056/NEJMoa0706719; PMCID: PMC2823628 Noyes K, Corona E, Veazie P, et al. Examination of the effect of implantable cardioverter-defibrillators on healthrelated quality of life: based on results from the Multicenter Automatic Defibrillator Trial-II. Am J Cardiovasc Drugs 2009;9:393–400. DOI: 10.2165/11317980-000000000-00000; PMID: 19929037; PMCID: PMC4743243 Moss AJ, Greenberg H, Case RB, et al. Long-term clinical course of patients after termination of ventricular tachyarrhythmia by an implanted defibrillator. Circulation 2004;110:3760–5. DOI: 10.1161/01.CIR.0000150390.04704.B7; PMID: 15583079

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Clinical Perspective • ICD shocks are associated with increased mortality. • It is unclear whether shocks are merely a marker of a more severe disease or directly contribute to mortality. • Shocks in the absence of spontaneous arrhythmia have a neutral effect on mortality. • Reducing shocks by ICD programming reduces mortality. • Regardless of prognostic implication of shocks, they are painful, psychologically detrimental and should be avoided.

19. Daubert JP, Zareba W, Cannom DS, et al. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II. Frequency, mechanisms, predictors, and survival Impact. J Am Coll Cardiol 2008;51:1357–65. DOI: 10.1016/j.jacc.2007.09.073; PMID: 18387436 20. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008;359:1009–17. DOI: 10.1056/ NEJMoa071098; PMID: 18768944; PMCID: PMC2922510 21. Proietti R, Labos C, Davis M, et al. A systematic review and meta-analysis of the association between implantable cardioverter-defibrillator shocks and long-term mortality. Can J Cardiol 2015;31:270–7. DOI: 10.1016/j.cjca.2014.11.023; PMID: 25746019 22. Joglar JA, Kessler DJ, Welch PJ, et al. Effects of repeated electrical defibrillations on cardiac troponin I levels. Am J Cardiol 1999;83:270–2, A6. PMID: 10073835 23. Hurst TM, Hinrichs M, Breidenbach C, et al. Detection of myocardial injury during transvenous implantation of automatic cardioverter-defibrillators. J Am Coll Cardiol 1999;34:402–8. PMID: 10440152 24. Hasdemir C, Shah N, Rao AP, et al. Analysis of troponin I levels after spontaneous implantable cardioverter defibrillator shocks. J Cardiovasc Electrophysiol 2002;13:144–50. PMID: 11900289 25. Xie J, Weil MH, Sun S, et al. High-energy defibrillation increases the severity of postresuscitation myocardial dysfunction. Circulation 1997;96:683–8. PMID: 9244243 26. Mitchell LB, Pineda EA, Titus JL, et al. Sudden death in patients with implantable cardioverter defibrillators. the importance of post-shock electromechanical dissociation. J Am Coll Cardiol 2002;39:1323–8. PMID: 11955850 27. Toh N, Nishii N, Nakamura K, et al. Cardiac dysfunction and prolonged hemodynamic deterioration after implantable cardioverter-defibrillator shock in patients with systolic heart failure. Circ Arrhythm Electrophysiol 2012;5:898–905. DOI: 10.1161/CIRCEP.111.970285; PMID: 22837155 28. Borleffs CJW, van Rees JB, van Welsenes GH, et al. Prognostic importance of atrial fibrillation in implantable cardioverterdefibrillator patients. J Am Coll Cardiol 2010;55:879–85. DOI: 10.1016/j.jacc.2009.09.053; PMID: 20185038 29. Healey JS, Hohnloser SH, Glikson M, et al. Cardioverter defibrillator implantation without induction of ventricular fibrillation: a single-blind, non-inferiority, randomised controlled trial (SIMPLE). Lancet 2015;385:785–91. DOI: http:// dx.doi.org/10.1016/S0140-6736(14)61903-6 30. Bhavnani SP, Kluger J, Coleman CI, et al. The prognostic impact of shocks for clinical and induced arrhythmias on morbidity and mortality among patients with implantable cardioverter-defibrillators. Heart Rhythm 2010;7:755–60. DOI: 10.1016/j.hrthm.2010.02.039; PMID: 20211275 31. Powell BD, Saxon LA, Boehmer JP, et al. Survival After shock therapy in implantable cardioverter-defibrillator and cardiac resynchronization therapy-defibrillator recipients according to rhythm shocked. The ALTITUDE survival by rhythm study. J Am Coll Cardiol 2013;62:1674–9. DOI: 10.1016/j.jacc.2013.04.083; PMID: 23810882 32. Kleemann T, Hochadel M, Strauss M, et al. Comparison between atrial fibrillation-triggered implantable cardioverterdefibrillator (ICD) shocks and inappropriate shocks caused by lead failure: different impact on prognosis in clinical practice. J Cardiovasc Electrophysiol 2012;23:735–40. DOI: 10.1111/j.15408167.2011.02279.x; PMID: 22313314 33. Sweeney MO, Sherfesee L, DeGroot PJ, et al. Differences in effects of electrical therapy type for ventricular arrhythmias on mortality in implantable cardioverter-defibrillator patients. Heart Rhythm 2010;7:353–60. DOI: 10.1016/j.hrthm.2009.11.027; PMID: 20185109 34. Kleemann T, Strauss M, Kouraki K, Zahn R. Clinical course and prognostic relevance of antitachycardia pacing-terminated ventricular tachyarrhythmias in implantable cardioverterdefibrillator patients. Europace 2015;17:106875. DOI: 10.1093/ europace/euv007; PMID: 25687746 35. Sun S, Johnson J, DeGroot P, et al. Effect of ICD therapies on mortality in the OMNI trial. J Cardiovasc Electrophysiol 2016;27:192–9. DOI: 10.1111/jce.12860; PMID: 26501695 36. Hammill SC, Packer DL, Stanton MS, Fetter J. Termination and acceleration of ventricular tachycardia with autodecremental pacing, burst pacing, and cardioversion in patients with

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an implantable cardioverter defibrillator. Multicenter PCD Investigator Group. Pacing Clin Electrophysiol 1995;18:3–10. PMID: 7700828 Wilkoff BL, Fauchier L, Stiles MK, et al. 2015 HRS/EHRA/ APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. Heart Rhythm 2016;13:e50–86. DOI: 10.1016/j. hrthm.2015.11.018; PMID: 26607062 Tan VH, Wilton SB, Kuriachan V, et al. Impact of programming strategies aimed at reducing nonessential implantable cardioverter defibrillator therapies on mortality: a systematic review and meta-analysis. Circ Arrhythm Electrophysiol 2014;7:164–70. DOI: 10.1161/CIRCEP.113.001217; PMID: 24446023 Scott PA, Silberbauer J, McDonagh TA, Murgatroyd FD. Impact of prolonged implantable cardioverter-defibrillator arrhythmia detection times on outcomes: A meta-analysis. Heart Rhythm 2014;11:828–35. DOI: 10.1016/j.hrthm.2014.02.009; PMID: 24530622 Varma N, Epstein AE, Irimpen A, et al. Efficacy and safety of automatic remote monitoring for implantable cardioverterdefibrillator follow-up: the Lumos-T Safely Reduces Routine Office Device Follow-up (TRUST) trial. Circulation 2010;122:325– 32. DOI: 10.1161/CIRCULATIONAHA.110.937409; PMID: 20625110 Slotwiner D, Varma N, Akar JG, et al. HRS Expert Consensus Statement on remote interrogation and monitoring for cardiovascular implantable electronic devices. Heart Rhythm 2015;12:e69–100. DOI: 10.1016/j.hrthm.2015.05.008; PMID: 25981148 Guédon-Moreau L, Lacroix D, Sadoul N, et al. A randomized study of remote follow-up of implantable cardioverter defibrillators: safety and efficacy report of the ECOST trial. Eur Heart J 2013;34:605–14. DOI: 10.1093/eurheartj/ehs425; PMID: 23242192; PMCID: PMC3578267 Spencker S, Coban N, Koch L, et al. Potential role of home monitoring to reduce inappropriate shocks in implantable cardioverter-defibrillator patients due to lead failure. Europace 2009;11:483–8. DOI: 10.1093/europace/eun350; PMID: 19103654 Hindricks G, Taborsky M, Glikson M, et al. Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial. Lancet 2014;384:583– 90. DOI: http://dx.doi.org/10.1016/S0140-6736(14)61176-4 Pacifico A, Hohnloser SH, Williams JH, et al. Prevention of implantable-defibrillator shocks by treatment with sotalol. N Engl J Med 1999;340:1855–62. DOI: 10.1056/ NEJM199906173402402; PMID: 10369848 Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial. JAMA 2006;295:165–71. DOI: 10.1001/jama.295.2.165; PMID: 16403928 Van Herendael H, Pinter A, Ahmad K, et al. Role of antiarrhythmic drugs in patients with implantable cardioverter defibrillators. Europace 2010;12:618–25. DOI: 10.1093/europace/euq073; PMID: 20304841 Reddy VY, Reynolds MR, Neuzil P, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med 2007;357:2657–65. DOI: 10.1056/NEJMoa065457; PMID: 18160685; PMCID: PMC2390777 Kuck K-H, Schaumann A, Eckardt L, et al. Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): a multicentre randomised controlled trial. Lancet 2010;375:31– 40. DOI: 10.1016/S0140-6736(09)61755-4; PMID: 20109864 Mallidi J, Nadkarni GN, Berger RD, et al. Meta-analysis of catheter ablation as an adjunct to medical therapy for treatment of ventricular tachycardia in patients with structural heart disease. Heart Rhythm 2011;8:503–10. DOI: 10.1016/j.hrthm.2010.12.015; PMID: 21147263; PMCID: PMC3065522 Sapp JL, Wells GA, Parkash R, et al. Ventricular tachycardia ablation versus escalation of antiarrhythmic drugs. N Engl J Med 2016;375:111–21. DOI: 10.1056/NEJMoa1513614; PMID:27149033 Sood N, Ruwald A-CH, Solomon S, et al. Association between myocardial substrate, implantable cardioverter defibrillator shocks and mortality in MADIT-CRT. Eur Heart J 2014;35:106–15. DOI: 10.1093/eurheartj/eht451; PMID: 24179073

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Clinical Arrhythmias

Antiarrhythmic Drug Therapy to Avoid Implantable Cardioverter Defibrillator Shocks Jaber Abboud and Joachim R Ehrlich St. Josefs-Hospital, Wiesbaden, Germany

Abstract Implantable cardioverter defibrillators (ICDs) are effective in the prevention of arrhythmic sudden cardiac death. Many patients receiving an ICD are affected by heart failure and are at risk of ventricular arrhythmias, which may lead to appropriate shocks. On the other hand, in this population the incidence of atrial fibrillation, giving rise to inappropriate ICD shocks, is high. Accordingly, ICD discharges occur frequently and many patients with an ICD will need concomitant antiarrhythmic drug therapy to avoid or reduce the frequency of shocks. Therapeutic agents such as b-blockers, class I or class III antiarrhythmic drugs effectively suppress arrhythmias, but may have side-effects. Some drugs could eventually influence the function of ICDs by altering defibrillation or pacing threshold. Few prospective randomised trials are available, but current data suggest that amiodarone is most effective for prevention of appropriate or inappropriate ICD shocks. This review article summarises current knowledge regarding the antiarrhythmic management of patients with ICDs.

Keywords Implantable cardioverter defibrillator, autonomic tone, ventricular fibrillation, atrial fibrillation, pharmacological management, antiarrhythmic drugs, defibrillation threshold, pacing threshold, sudden cardiac death, resuscitation Disclosure: The authors have no conflicts of interest to declare Received: 23 December 2015 Accepted: 6 July 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(2):117â&#x20AC;&#x201C;21 DOI: 10.15420/AER.2016.10.2 Access at: www.AERjournal.com Correspondence: Joachim R. Ehrlich, Division of Cardiology, St. Josefs-Hospital, Beethovenstr. 20, 65189 Wiesbaden, Germany. E: joachimehrlich@t-online.de

Implantable cardioverter defibrillators (ICDs) have been used for over 30 years to prevent sudden cardiac death (SCD). The first indications for ICD placement were secondary prevention; later trials demonstrated a primary prevention benefit of ICD therapy in patients at risk of SCD. ICD therapy prolongs life in both patient populations.1 However, the efficacy of an ICD depends on its ability to correctly detect ventricular arrhythmia and deliver antitachycardia pacing or shocks. In cases of inadequate arrhythmia classification by the device, atrial fibrillation (AF) with rapid conduction to the ventricles can lead to inappropriate shocks. The ability of an ICD to correctly detect this arrhythmia is essential to avoid shock delivery. Furthermore, technical problems such as lead fractures, oversensing of myopotentials or external noise can lead to shock application. ICD shocks can be painful if experienced in the awake state and may reduce quality of life in affected patients.2 Shocks, whether appropriate or not, tend to occur frequently after the implantation of an ICD and avoiding shocks is a reasonable therapeutic target.3 Current evidence suggests that ICD shocks increase the risk of mortality.4 It remains a matter of debate if this finding depends on the context of a specific cardiac substrate or the shock per se.5 Of less controversy is the fact that patients who receive ICD shocks experience reduced quality of life. This has been a consistent finding in published studies that was already evident from data in the first available trials, such as the Antiarrhythmics Versus ICDs (AVID) trial.2 The occurrence of ICD shocks was associated with reduced physical functioning and decreased mental wellbeing. Another study reported that patients who experienced an ICD shock did not adapt well to

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living with an ICD and were generally more anxious than ICD recipients who received no shock.6 Accordingly, shock reduction by medical, interventional or technical means is a desirable goal.

General Measures Most patients receiving ICDs for primary prevention of SCD are affected by heart failure with reduced left ventricular ejection fraction (LVEF <35 %). Should these patients meet the criteria for cardiac resynchronisation therapy (CRT), implantation is indicated to achieve mortality and morbidity benefits.7 In addition, CRT responders exhibit fewer ventricular tachycardia/ventricular fibrillation (VT/VF) episodes after implantation than patients not receiving CRT.8 In general, care should be taken to keep these patients on optimal medical therapy including high-dose b-blockers, as these drugs lead to a reduction in rates of SCD and overall mortality in patients with ischaemic and non-ischaemic cardiomyopathy. If such treated patients develop arrhythmias despite b-blocker treatment, an additional anti-arrhythmic treatment will be necessary. In clinical practice, an adjunctive antiarrhythmic is administered to more than half of patients who have an ICD.9

Serum Potassium Levels Besides pharmacological interventions, simple methods aiming to normalise serum electrolyte levels could be of clinical value. Electrolyte imbalance is an important reversible cause for ventricular arrhythmias and often encountered clinically. In particular, hypokalaemia enhances cardiac electrical vulnerability.10 Conversely, where serum electrolyte levels are normalised, a stabilising effect in terms of arrhythmia

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Clinical Arrhythmias Table 1: Summary of Antiarrhythmic Drug Dosages Applied in Clinical Trials Dosage

Notes

Amiodarone 15,17–19

Antiarrhythmic Drug

References

200 mg once daily

Saturation dose 10–12 g

Sotalol 17–21

160 mg twice daily

Care should be taken to monitor for renal dysfunction

375 mg twice daily

Applied in addition to sotalol or amiodarone

Dofetilide 23–25

500 µg once daily

Care should be taken to monitor for renal dysfunction

Azimilide 15,22

175 mg once daily

Not clinically available

Dronedarone 26,27

400 mg twice daily

Contraindicated in patients with heart failure

Mexilitine 28–29

100 mg twice daily

Applied in addition to amiodarone

Ranolazine 32–35

incidence has been reported. For instance, a database study including >38,000 patients with acute MI showed the lowest risk of VF, cardiac arrest or death with potassium concentrations of 3.5–4.5 mmol/l.11 In contrast, hyperkalaemia may lead to intermittent or permanent loss of capture or T-wave oversensing. While the former may lead to arrhythmia induction, the latter could lead to double counting and inappropriate shock delivery.12 Accordingly, care should be taken to keep potassium levels within the normal range. While a high-tonormal range may be preferred, this certainly needs to be adjusted to account for the clinical characteristics of individual patients. Understanding the role of electrolyte imbalance for arrhythmia incidence is of particular importance as mineralocorticoid receptorblocker treatment is a guideline-recommended aspect of heart failure therapy.13 Care should be taken if patients receive such treatment as an increase in hyperkalaemia-associated deaths became evident after the publication of the Randomized Aldactone Evaluation Study (RALES).14

Adjunctive Antiarrhythmic Therapy to Reduce Shocks Although modern ICDs incorporate antitachycardia pacing to treat ventricular arrhythmias prior to shock application, the efficacy of such pacing therapy is sometimes limited. Furthermore, inaccurate classification of non-life-threatening tachyarrhythmia, such as supraventricular tachycardia (particularly AF) as ventricular in origin, increases the rate of inappropriate ICD shocks. These drawbacks associated with the use of ICDs raise questions of how and when to administer adjunctive anti-arrhythmic drug therapy in order to reduce the rate of ICD shocks and improve quality of life.15

Class III Antiarrhythmic Drugs Vaughan–Williams class III drugs that prolong cardiac action potential duration and thus refractoriness are indicated for suppressing atrial and ventricular arrhythmias. In general, antiarrhythmic drug treatment needs to be weighed against risks and potential side-effects. To date, there has been no study demonstrating a positive effect of antiarrhythmic drug therapy on mortality in patients with an ICD. In addition, in the light of reduced systolic left ventricle (LV) function one has to consider that antiarrhythmic drugs in general further suppress contractility. Only one study has demonstrated an increase in systolic LV function in patients with heart failure treated with amiodarone.16 This finding has not been replicated by other trials.

Amiodarone and Sotalol The Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients (OPTIC) study represents the largest randomised trial (n=412) comparing the antiarrhythmic drugs amiodarone, d,l-sotalol and b-blockers for ICD shock reduction.17 The OPTIC study included patients with a secondary prevention ICD indication and found

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that amiodarone in conjunction with a b-blocker greatly reduced the risk of both appropriate (HR 0.30, 95 % CI 0.14–0.68, p<0.05 versus b-blocker alone) and inappropriate (HR 0.22, 95 % CI 0.07–0.64, p<0.05 versus b-blocker alone) shocks. In addition to its direct antiarrhythmic effects on supraventricular and ventricular arrhythmias, amiodarone affects the atrioventricular node by slowing conduction and reducing heart rate, which also may help prevent inappropriate shocks due to supraventricular tachycardia.17 In the same study, d,l-sotalol when compared with b-blockers did not significantly reduce the frequency of ICD shocks; however, a numerical trend towards fewer shocks was evident (HR 0.61, 95 % CI 0.37–1.01, p=0.055 versus b-blocker alone).17 An earlier trial prospectively compared d,l-sotalol with placebo treatment and documented a significant benefit with sotalol in terms of shock reduction.18 Patients were included if they had a secondary prevention indication for an ICD and were stratified according to LVEF function below or above 30 %. In 302 patients with an ICD, d,l-sotalol was titrated up to 160 mg twice daily in addition to concomitant b-blocker therapy. In case of renal dysfunction (30–60 ml/min), one of the daily sotalol doses was skipped. In that trial, d,l-sotalol led to a 48 % relative risk reduction for any shock or death from any cause (HR 0.52, 95 % CI 0.37–0.74, p<0.05) compared with placebo. The incidence of inappropriate shocks for supraventricular arrhythmias was also significantly reduced (relative risk reduction by 64 %, p<0.05).18 The effectiveness of sotalol did not differ significantly in patients with a systolic LV function ≤30 % versus >30 %. AF with rapidly conducted ventricular activation is a common cause of inappropriate ICD shocks. Current AF guidelines recommend the use of amiodarone for AF relapse prevention in patients with relevant structural heart disease such as heart failure.19 In contrast, sotalol is not recommended for relapse prevention in the setting of heart failure as there is concern about the safety of sotalol in patients with AF.20 While heart failure patients may be particularly prone to sotalol-induced ventricular proarrhythmia, no increased mortality rate was observed in the specific population of patients with an ICD.18 It can be speculated that the ICD may protect patients from potential proarrhythmic events and, accordingly, sotalol could represent a therapeutic alternative in selected patients with an ICD, particularly those with normal renal function. The effectiveness of amiodarone to reduce the risk of inappropriate shocks is already evident even from small studies. In an observational study of 55 patients evaluating the incidence of inappropriate shocks after ICD implantation, amiodarone was most effective in reducing the rate of inappropriate shocks and was superior to b-blockers.21 The finding of amiodarone being the most potent antiarrhythmic drug for overall shock reduction is supported by a meta-analysis of 1889

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Antiarrhythmic Drug Therapy to Avoid ICD Shocks

patients in several trials.15 This report pooled data from the abovementioned prospective trials with several retrospective observational studies, and found that the risk of overall ICD shocks was reduced when comparing amiodarone plus b-blocker with b-blocker alone (HR 0.27, 95 % CI 0.14–0.52). Similarly, in that meta-analysis, sotalol was found to be superior to placebo (HR 0.55, 95 % CI 0.40–0.78), but not to other b-blockers (HR 0.61, 95 % CI 0.37–1.00]).15 This metaanalysis was largely supported by the results of the OPTIC study. Given the tendency towards a greater effect of sotalol over b-blockers in the OPTIC study and a statistically significant effect of sotalol in the trial by Pacifico et al., it appears reasonable to keep both substances in mind for shock prevention, realising that amiodarone is most effective (see Figure 1).

Azimilide and Dofetilide Azimilide is an experimental class III agent that is not clinically available. The meta-analysis by Ferreira-Gonzalez et al. looked at trials of patients treated with class III substances azimilide or dofetilide for shock reduction.15 It failed to document a relevant effect of these two drugs on shock reduction in comparison with placebo (azimilide: HR 0.78, 95 % CI 0.58–1.04, and dofetilide: HR 0.67, 95 % CI 0.43–1.04). In one prospective randomised study involving 633 patients with an ICD, two doses of azimilide were compared with placebo.22 This study documented a dose-dependent suppression of the incidence of ICD shocks by azimilide. However, after addition of data from several smaller dose-ranging studies these effects could no longer be observed.15 In contrast to azimilide, dofetilide is available in several countries. The Danish Investigations of Arrhythmia and Mortality on Dofetilide with Congestive Heart Failure (DIAMOND-CHF) trial suggested a mortality benefit for patients with heart failure with an LVEF <35 % who converted from AF to sinus rhythm on dofetilide.23 The trial was designed to study safety and efficacy of this class III antiarrhythmic drug in patients with heart failure and AF. In that study, ICD placement was an exclusion criterion, thus no data regarding incidence of shocks were available. One recent report suggests effectiveness of dofetilide in reducing the frequency of ventricular tachyarrhythmias in patients with an ICD even after failure of amiodarone. In that observational series 30 patients with symptomatic VT/VF episodes were treated with dofetilide and followed for over 2 years.24 In contrast, oral dofetilide was not effective for shock reduction (HR 0.67, 95 % CI 0.43–1.04, p=NS) in another small study.25 Accordingly, this substance holds some minor potential with an apparent safety profile. It needs to be studied in larger randomised trials.

Figure 1: Recommendations for Treating Inappropriate and Appropriate Implantable Cardioverter Defibrillator Shocks

ICD shock

Appropriate

Inappropriate

Programming adjustment necessary/possible?

AAD

First-line amiodarone

Second-line sotalol

SVT

Ablation/ AAD as indicated

AAD/ ablation (PVI)

Technical problems

Treat as indicated

AAD = antiarrhythmic drug; AF = atrial fibrillation; ICD = implantable cardioverter defibrillator; PVI = pulmonary vein isolation; SVT = supraventricular tachycardia.

Sodium Channel Blockers Although the sodium channel blockers are sometimes used as a last-resort therapy in patients with refractory ventricular tachyarrhythmias who fail or do not tolerate amiodarone, there are very limited clinical trial data available.28 In some patients with repetitive ventricular tachyarrhythmias a combination of class I and class III antiarrhythmic drugs – mostly amiodarone – is applied.29 Mexiletine is a Vaughan–Williams class Ib sodium channel blocker. In general, class I drugs should be avoided in patients with heart failure, but in an observational single-centre study, mexiletine given at a dose of 100 mg twice daily in addition to amiodarone 200 mg once daily was effective in reducing the rate of recurrent VT/VF episodes. A combination of mexiletine with sotalol did not have the same effect. However, this effect was only present at short-term follow-up (3 months). At 12 months no such effect remained. This drug may accordingly represent a short-term option for patients with refractory VT/VF episodes.28 Application of mexiletine in patients with long QT syndrome type 3 demonstrates a pathophysiological rationale for use. In this subtype of long QT syndrome a sodium channel gain-of-function mutation underlies QT prolongation and mexiletine shortens the QT interval in this context. It may accordingly reduce ventricular arrhythmias in these patients.30 The class Ic antiarrhythmic drug quinidine has a potential for treatment of arrhythmias in patients with Brugada syndrome.31 These substances may be used to prevent ICD shocks in specific patient populations.

Dronedarone Dronedarone was developed to circumvent the untoward side-effect profile of amiodarone, but it is contraindicated in patients with heart failure or permanent AF. The Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA) was initially designed to study a potential beneficial effect of dronedarone on the prognosis of patients with heart failure.26 The trial was stopped early as increased mortality rates were observed with the drug. There are no systematic studies of this substance for ICD shock reduction, but case reports suggest potential benefit in individual patients treated with the substance despite the presence of heart failure.27 The substance should not be used routinely, but may remain a ‘last-resort’ alternative in selected individual cases.

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Ranolazine Ranolazine inhibits the late sodium current that is increased in heart failure and leads to arrhythmia occurence.32 Late sodium current is also a target for AF therapy.33 However, ranolazine displayed only moderate efficacy in a prospective randomised trial of AF relapse prevention.34 In a multicentre observational series of 12 patients, ranolazine was added to sotalol, amiodarone or amiodarone/mexiletine and effectively reduced the rate of ICD shock recurrence.35 Beyond its observational nature, the trial was limited by the small sample size. Prospective randomised trial data are needed for a valid judgement regarding the use of ranolazine as adjunct therapy to reduce ICD shocks. Currently, this substance cannot be generally recommended for ICD shock reduction.

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Clinical Arrhythmias Potential Influences on Pacing and Defibrillation Thresholds Patients may die from arrhythmogenic causes despite the use of an ICD.36 Reasons for such ICD-unresponsive SCD may be patient or device related, including refractory electrical storm, asystole, pulseless electrical activity or technical defects of the implanted device and leads or potentially elevated defibrillation thresholds (DFTs).37 While there are several reports on changes of DFT by antiarrhythmic drugs in the literature (mostly historical studies and case reports from the 1980s and 1990s), there are few recent data regarding pacing threshold.

Pacing Threshold Chronic pacing threshold elevation with contemporary steroid-eluting electrode tips is much less of a problem than it was decades ago. However, chronic elevation of pacing thresholds may still occur with longer time since implantation, increasing age of the patient and disease progression. Antiarrhythmic drugs may alter the excitability of cardiac tissue. While loss of atrial capture has been reported after the application of flecainide and propafenone,38,39 data on ventricular pacing thresholds are highly controversial.40,41 Similarly, loss of atrial capture has been reported with amiodarone,42 whereas no such effect was seen on ventricular pacing thresholds.43 All of these studies were observational in nature. Loss of capture may develop over time in any implantable device. Whether this is truly related to drug administration in these observational patient series is difficult to judge owing to the lack of a control group. In summary, there is no evidence that any antiarrhythmic drug will consistently alter pacing thresholds in patients. Rather, a specific cardiac substrate may alter pacing thresholds by itself over time.

Defibrillation Threshold DFT is defined as the lowest amount of energy required to successfully defibrillate the heart and restore normal sinus rhythm. Optimal determination of DFT theoretically includes construction of a continuous dose–response curve between the energy delivered and the success of the defibrillation shock.44 Experimental data and early clinical studies indicate that antiarrhythmic drugs may alter defibrillation energy requirements, usually measured as the DFT.45 Routine ICD testing is no longer recommended as randomised trials evaluating DFT testing versus a non-testing strategy were neutral in terms of predicting effectiveness of ICD therapy.46 The Shockless Implant Evaluation (SIMPLE) study prospectively included patients with a left-sided ICD implant and a no-testing strategy was non-inferior to a testing strategy with respect to the endpoint of failed appropriate shock or death. Data from the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT) trial indicated no difference in survival if DFT was >20 J in comparison with ≤20 J.47 In a large retrospective analysis, Shukla et al. evaluated data from 968 patients who were enrolled in two separate clinical studies evaluating biphasic shock generators.48 In these uncontrolled studies, 11 % of patients had high DFTs defined as energy requirement ≥18 J. Several indices of advanced structural heart disease, such as NYHA functional class III/IV or low LVEF and the preoperative use of amiodarone, were predictive of higher DFTs.48

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The prospective randomised OPTIC trial provided an opportunity to obtain properly controlled data regarding effects of amiodarone, sotalol and b-blockers on DFT with contemporary ICDs. In patients exposed to 6–8 weeks of amiodarone therapy, a minor increase in defibrillation energy requirement of ∼1.3 J was observed, which was statistically significant when compared with a small decrease in DFT in the two other groups. However, a mean 1 J increase in DFT is unlikely to have any effect on outcomes, particularly in light of the potentially high energy delivery with modern ICD systems. Large increases in DFT with amiodarone were rare. In the sole case with a >10 J increase in DFT, an adequate safety margin of 10 J was maintained because of low DFT at baseline (2.5 J). This increase may be due in part to regression to the mean rather than only an effect of amiodarone. In the study, no significant delay in detection of VF on repeat DFT assessment was reported.49 The OPTIC study was the first randomised evaluation to demonstrate that effects of sotalol on DFT are similar to those of conventional b-blockers without class III antiarrhythmic properties.49 Accordingly, it appears generally safe to treat ICD patients with amiodarone and not necessary to perform DFT testing after drug application. Another study suggested that while oral therapy with amiodarone increased DFT during acute ischaemia in a closed-chest animal model, dronedarone in the same model had no effect on DFT either under basal state or after acute myocardial ischaemia.50 While DFT testing should not routinely be performed (neither at implant nor after administration of amiodarone), special situations – for instance if right-sided implants combined with amiodarone therapy or lead replacements – may still warrant such tests.

Summary and Future Direction Recent trials of ICD programming have shown a significant reduction of ICD shocks. The management of appropriate shocks is still challenging and may be optimised by assessment and treatment of the underlying ventricular arrhythmias and structural correlate in terms of revascularisation or ablation therapy. For current clinical practice, d,l-sotalol can be considered to reduce ICD shocks (appropriate or inappropriate) in patients without severe renal dysfunction. If sotalol is ineffective, amiodarone has a greater potential to reduce arrhythmia burden and subsequent shock delivery for a larger amount of potential side-effects. One has to keep in mind that both substances may suppress intrinsic sinus rate and accordingly atrial pacing may become necessary. Further clinical trials are needed to assess the long-term benefit of amiodarone to prevent ICD shocks in the context of potential side-effects. Whether other substances, such as ranolazine or dronedarone, will obtain a role in the management of arrhythmias in patients with an ICD is subject to future investigation. Patients with refractory VT/VF episodes despite amiodarone treatment may experience short-term benefit from the addition of mexiletine. Antiarrhythmic drugs should only be applied after an arrhythmia has occurred (see Table 1). This does not necessarily imply that ICD shocks need to have occurred. All prospective trials looking at shock reduction conducted to date included patients who had already experienced ICD shocks. Whether an a priori preventive therapy with antiarrhythmic agents might be beneficial remains to be studied. Such an approach could represent an additional option to sustain quality of life in ICD patients. In particular, documented AF in a patient with an ICD should be managed with specific programming and potentially antiarrhythmic drug therapy. ■

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10.

11.

12.

13.

14.

15.

16.

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;36:2793–867. DOI: 10.1093/ eurheartj/ehv316; PMID: 26320108 Schron EB, Exner DV, Yao Q, et al. Quality of life in the antiarrhythmics versus implantable defibrillators trial: impact of therapy and influence of adverse symptoms and defibrillator shocks. Circulation 2002;105:589–94. PMID: 11827924 Steinberg JS, Martins J, Sadanandan S, et al. Antiarrhythmic drug use in the implantable defibrillator arm of the Antiarrhythmics Versus Implantable Defibrillators (AVID) Study. Am Heart J 2001;142:520–9. DOI: 10.1067/ mhj.2001.117129; PMID: 11526368 Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008;359:1009–17. DOI: 10.1056/ NEJMoa071098; PMID: 18768944 Sood N, Ruwald AH, Solomon S, et al. Association between myocardial substrate, implantable cardioverter defibrillator shocks and mortality in MADIT-CRT. Eur Heart J 2014;35:106–15. DOI: 10.1093/eurheartj/eht451; PMID: 24179073 Kamphuis HC, de Leeuw JR, Derksen R, et al. Implantable cardioverter defibrillator recipients: quality of life in recipients with and without ICD shock delivery: a prospective study. Europace 2003;5:381–9. PMID: 14753636 Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J 2013;34:2281–329. DOI: 10.1093/eurheartj/eht150; PMID: 23801822 van Boven N, Bogaard K, Ruiter J, et al. Functional response to cardiac resynchronization therapy is associated with improved clinical outcome and absence of appropriate shocks. J Cardiovasc Electrophysiol 2013;24:316–22. DOI: 10.1111/ jce.12037; PMID: 23210664 Horton RP, Canby RC, Román CA, et al. Determinants of nonthoracotomy biphasic defibrillation. Pacing Clin Electrophysiol 1997;20:60–4. PMID: 9121972 Hohnloser SH, Verrier RL, Lown B, et al. Effect of hypokalemia on susceptibility to ventricular fibrillation in the normal and ischemic canine heart. Am Heart J 1986;112:32–5. PMID: 3728285 Goyal A, Spertus JA, Gosch K, et al. Serum potassium levels and mortality in acute myocardial infarction. JAMA 2012;307:157–64. DOI: 10.1001/jama.2011.1967; PMID: 22235086 Barold SS, Herweg B. The effect of hyperkalaemia on cardiac rhythm devices. Europace 2014;16:467–76. DOI: 10.1093/ europace/eut383; PMID: 24465006 Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709–17. DOI: 10.1056/ NEJM199909023411001; PMID: 10471456 Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004;351:543–51. DOI: 10.1056/ NEJMoa040135; PMID: 15295047 Ferreira-González I, Dos-Subirá L, Guyatt GH, et al. Adjunctive antiarrhythmic drug therapy in patients with implantable cardioverter defibrillators: a systematic review. Eur Heart J 2007;28:469–77. DOI: 10.1093/eurheartj/ehl478; PMID: 17227788 Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia: Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med 1995;333:77–82. DOI: 10.1056/NEJM199507133330201; PMID: 7539890

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17. Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial. JAMA 2006;295:165–71. DOI: 10.1001/jama.295.2.165; PMID: 16403928 18. Pacifico A, Hohnloser SH, Williams JH, et al. Prevention of implantable-defibrillator shocks by treatment with sotalol. d,l-Sotalol Implantable Cardioverter-Defibrillator Study Group. N Engl J Med 1999;340:1855–62. DOI: 10.1056/ NEJM199906173402402; PMID: 10369848 19. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369–429. DOI: 10.1093/ eurheartj/ehq278; PMID: 20802247 20. Freemantle N, Lafuente-Lafuente C, Mitchell S, et al. Mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide, and propafenone, for the management of atrial fibrillation. Europace 2011;13:329–45. DOI: 10.1093/europace/ euq450; PMID: 21227948 21. Lee CH, Nam G, Park H, et al. Effects of antiarrhythmic drugs on inappropriate shocks in patients with implantable cardioverter defibrillators. Circ J 2008;72:102–5. PMID: 18159108 22. Dorian P, Borggrefe M, Al-Khalidi HR, et al. Placebo-controlled, randomized clinical trial of azimilide for prevention of ventricular tachyarrhythmias in patients with an implantable cardioverter defibrillator. Circulation 2004;110:3646–54. DOI: 10.1161/01.CIR.0000149240.98971.A8; PMID: 15533855 23. Torp-Pedersen C, Møller M, Bloch-Thomsen PE, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med 1999;341:857–65. DOI: 10.1056/NEJM199909163411201; PMID: 10486417 24. Baquero GA, Banchs JE, Depalma S, et al. Dofetilide reduces the frequency of ventricular arrhythmias and implantable cardioverter defibrillator therapies. J Cardiovasc Electrophysiol 2012;23:296–301. DOI: 10.1111/j.15408167.2011.02183.x; PMID: 21955243 25. O’Toole M, O’Neill PG, Kluger J, et al. Efficacy and safety of oral dofetilide in patients with an implanted defibrillator: a multicenter study [Abstract]. Circulation 1999;100(Suppl 2):S794 26. Køber L, Torp-Pedersen C, McMurray JJV, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008;358:2678–87. DOI: 10.1056/NEJMoa0800456; PMID: 18565860 27. Fink A, Duray GZ, Hohnloser SH. A patient with recurrent atrial fibrillation and monomorphic ventricular tachycardia treated successfully with dronedarone. Europace 2011;13: 284–5. DOI: 10.1093/europace/euq365; PMID: 20965881 28. Gao D, van Herendael H, Alshengeiti L, et al. Mexiletine as an adjunctive therapy to amiodarone reduces the frequency of ventricular tachyarrhythmia events in patients with an implantable defibrillator. J Cardiovasc Pharmacol 2013;62: 199–204. DOI: 10.1097/FJC.0b013e31829651fe; PMID: 23609328 29. Dorian P, Newman D, Berman N, et al. Sotalol and type IA drugs in combination prevent recurrence of sustained ventricular tachycardia. J Am Coll Cardiol 1993;22:106–13. PMID: 8509529 30. Shimizu W, Aiba T, Antzelevitch C. Specific therapy based on the genotype and cellular mechanism in inherited cardiac arrhythmias. Long QT syndrome and Brugada syndrome. Curr Pharm Des 2005;11:1561–72. PMID: 15892662 31. Márquez MF, Bonny A, Hernández-Castillo E, et al. Long-term efficacy of low doses of quinidine on malignant arrhythmias in Brugada syndrome with an implantable cardioverterdefibrillator: a case series and literature review. Heart Rhythm 2012;9:1995–2000. DOI: 10.1016/j.hrthm.2012.08.027; PMID: 23059185 32. Morita N, Lee JH, Xie Y, et al. Suppression of re-entrant and multifocal ventricular fibrillation by the late sodium current blocker ranolazine. J Am Coll Cardiol 2011;57:366–75. DOI: 10.1016/j.jacc.2010.07.045; PMID: 21232675

33. Verrier RL, Kumar K, Nieminen T, et al. Mechanisms of ranolazine’s dual protection against atrial and ventricular fibrillation. Europace 2013;15:317–24. DOI: 10.1093/europace/ eus380; PMID: 23220484 34. Ferrari GM de, Dusi V, Spazzolini C, et al. Clinical management of catecholaminergic polymorphic ventricular tachycardia: the role of left cardiac sympathetic denervation. Circulation 2015;131:2185–93. DOI: 10.1161/ CIRCULATIONAHA.115.015731; PMID: 26019152 35. Bunch TJ, Mahapatra S, Murdock D, et al. Ranolazine reduces ventricular tachycardia burden and ICD shocks in patients with drug-refractory ICD shocks. Pacing Clin Electrophysiol 2011;34:1600–6. DOI: 10.1111/j.1540-8159.2011.03208.x; PMID: 21895727 36. Duray GZ, Schmitt J, Richter S, et al. Arrhythmic death in implantable cardioverter defibrillator patients: a long-term study over a 10 year implantation period. Europace 2009;11:1462–8. DOI: 10.1093/europace/eup246; PMID: 19797255 37. Kroll MW, Tchou PJ. Testing of implantable defibrillator functions at implantation. In: Ellenbogen KA, Kay GN, Wilkoff BL (eds). Clinical Cardiac Pacing and Defibrillation. Philadephia: WB Saunders, 2000;540–61 38. Antonelli D, Freedberg NA, Rosenfeld T, et al. Acute loss of capture due to flecainide acetate. Pacing Clin Electrophysiol 2001;24:1170. PMID: 11475838 39. Montefoschi N, Boccadamo R. Propafenone induced acute variation of chronic atrial pacing threshold: a case report. Pacing Clin Electrophysiol 1990;13:480–3. PMID: 1692131 40. Stevens SK, Haffajee CI, Naccarelli GV, et al. Effects of oral propafenone on defibrillation and pacing thresholds in patients receiving implantable cardioverter-defibrillators. Propafenone Defibrillation Threshold Investigators. J Am Coll Cardiol 1996;28:418–22. PMID: 8800119 41. Numata T, Abe H, Nagatomo T, et al. Effect of a single oral dose of pilsicainide on pacing thresholds in pacemaker patients with and without paroxysmal atrial fibrillation. Jpn Circ J 2000;64:750–4. PMID: 11059614 42. Grande JM, Grande A, Molina M, et al. Atrial selective effect of amiodarone to increase threshold of excitation. Pacing Clin Electrophysiol 2013;36:e93–6. DOI: 10.1111/j.15408159.2011.03272.x; PMID: 22132864 43. Reddy CP, Kuo CS, Jivrajka V, et al. Effect of amiodarone on electric induction, morphology, and rate of ventricular tachycardia and its relation to clinical efficacy. Pacing Clin Electrophysiol 1984;7:1055–62. PMID: 6209624 44. Dopp AL, Miller JM, Tisdale JE. Effect of drugs on defibrillation capacity. Drugs 2008;68:607–30. PMID: 18370441 45. Frame LH. The effect of chronic oral and acute intravenous amiodarone administration on ventricular defibrillation threshold using implanted electrodes in dogs. Pacing Clin Electrophysiol 1989;12:339–46. PMID: 2468144 46. Healey JS, Hohnloser SH, Glikson M, et al. Cardioverter defibrillator implantation without induction of ventricular fibrillation: a single-blind, non-inferiority, randomised controlled trial (SIMPLE). Lancet 2015;385:785–91. DOI: 10.1016/S0140-6736(14)61903-6; PMID: 25715991 47. Aktas MK, Huang DT, Daubert JP, et al. Effect of defibrillation threshold testing on heart failure hospitalization or death in the Multicenter Automatic Defibrillator Implantation TrialCardiac Resynchronization Therapy (MADIT-CRT). Heart Rhythm 2013;10:193–9. DOI: 10.1016/j.hrthm.2012.10.024; PMID: 23085128 48. Shukla HH, Flaker GC, Jayam V, Roberts D. High defibrillation thresholds in transvenous biphasic implantable defibrillators: clinical predictors and prognostic implications. Pacing Clin Electrophysiol 2003;26:44–8. PMID: 12685138 49. Hohnloser SH, Dorian P, Roberts R, et al. Effect of amiodarone and sotalol on ventricular defibrillation threshold: the optimal pharmacological therapy in cardioverter defibrillator patients (OPTIC) trial. Circulation 2006;114:104–9. DOI: 10.1161/ CIRCULATIONAHA.106.618421; PMID: 16818810 50. Chevalier P, Timour Q, Morel E, Bui-Xuan B. Chronic oral amiodarone but not dronedarone therapy increases ventricular defibrillation threshold during acute myocardial ischemia in a closed-chest animal model. J Cardiovasc Pharmacol 2012;59:523–8. DOI: 10.1097/FJC.0b013e31824d89fe; PMID: 22330675

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Management of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia and Vasovagal Syncope Satish Raj and Robert Sheldon Libin Cardiovascular Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada

Abstract Postural tachycardia syndrome (POTS), inappropriate sinus tachycardia (IST) and vasovagal syncope (VVS) are relatively common clinical syndromes that are seen by physicians in several disciplines. They are often not well recognised and are poorly understood by physicians, are associated with significant morbidity and cause significant frustration for both patients and their physicians. The 2015 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia and Vasovagal Syncope provides physicians with an introduction to these disorders and initial recommendations on their investigation and treatment. Here we summarise the consensus statement to help physicians in the management of patients with these frequently distressing problems.

Keywords Postural tachycardia syndrome, inappropriate sinus tachycardia, vasovagal syncope, syncope, autonomic, guidelines, dysautonomia, tachycardia Disclosure: Dr. Raj receives grants from National Institutes of Health, the Canadian Institutes of Health Research and Medtronic, and personal fees from Lundbeck Pharmaceuticals, GE Healthcare and Medicolegal Consulting, outside the submitted work. Dr. Sheldon receives grants from the Canadian Institutes of Health Research. Received: 18 January 2016 Accepted: 26 April 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(2):122–9 DOI: 10.15420/AER.2016.7.2 Access at: www.AERjournal.com Correspondence: Dr Robert Sheldon, University of Calgary, 3280 Hospital Drive NW, Calgary, Alberta T2N 4Z6, Canada. E: sheldon@ucalgary.ca

Syncope and palpitations are two common clinical presentations, and both pose difficulties in the approach to their management. They are both symptoms of a number of syndromes, and an efficient approach with targeted therapy is challenging. Cardiac arrhythmia specialists, who lack a compact and accessible guide to management, see many patients with these symptoms in consultation. Recognising this, in 2015 the Heart Rhythm Society (HRS) released an expert consensus document1 on three common syndromes: postural tachycardia syndrome (POTS), inappropriate sinus tachycardia (IST), and vasovagal syncope (VVS). This focused statement is complemented by several other contemporary reports (see Table 1): the 2011 Position Statement on Structured Investigation of Syncope by the Canadian Cardiovascular Society,2 the 2015 Position Statement for the Rationale and Requirement for the Syncope Unit3 by the European Heart Rhythm Association (EHRA), the 2016 Guideline for the Evaluation and Management of Syncope being prepared by the American College of Cardiology (ACC), the American Heart Association (AHA) and the HRS. The 2017 Guidelines for the Diagnosis and Management of Syncope are being prepared by the European Society of Cardiology (ESC). The consensus recommendations in this document use the class I, IIa, IIb and III classifications and the corresponding language used by the ACC at the time of the expert consensus document’s publication.1 Class I is a strong recommendation, denoting benefit greatly exceeding risk. Class IIa is a somewhat weaker recommendation, denoting benefit probably exceeding risk, and class IIb denotes benefit equivalent to, or possibly exceeding risk. Class III is a recommendation against a specific treatment because either there is a lack of benefit or there is harm. Level A denotes the highest level of evidence, usually from

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multiple clinical trials with or without registries. Level B evidence is of a moderate level, either from randomised trials (B-R) or well-executed non-randomised trials (B-NR). Level C evidence is from weaker studies with significant limitations and level E is simply a consensus expert opinion in the absence of credible published evidence. Here we will review contemporary, expert advice on the management of POTS, IST and VVS. We will highlight important issues and clarify and expand on several key points from the HRS expert consensus document.

Definitions The HRS writing group recognised the importance of providing simple, clear definitions that could be used at the bedside and uniform criteria for inclusion of subjects into studies (see Table 2).

Definition of Syncope Originally syncope was defined as a transient state of unconsciousness characterised by spontaneous recovery or recovery in the supine position.4 This definition was developed to describe tilt test outcomes and was not sufficiently descriptive for clinical use. Subsequently, the ESC defined syncope as a transient episode of loss of consciousness that is due to transient global cerebral hypoperfusion characterised by rapid onset, short duration and spontaneous complete recovery.5 This definition was more specific and included a pathophysiological basis for syncope. Unfortunately, the criterion of ‘global cerebral hypoperfusion’ proved challenging for clinicians dealing with transient loss of consciousness in clinical practice. In September 2013 a multi-specialty workshop of North American and European syncope experts met in Gargnano, Italy. At that consensus conference,6 the

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Management of Cardiovascular Autonomic Disorders

physiological criterion for syncope was removed, and a criterion that excluded other causes of loss of consciousness was substituted. This practical approach met with agreement by cardiologists, neurologists, internists, family doctors and emergency department physicians. The HRS document1 minimally modified the Gargnano definition of syncope (see Table 2).

Table 1: Contemporary Expert Statements on Various Facets of the Management of Syncope Disorders

Definition of Postural Tachycardia Syndrome

Rationale and

European

Requirement for

Heart Rhythm

The HRS definition of POTS (see Table 2) is based on the criteria outlined by the American Autonomic Society7. POTS is a syndrome that may actually be a collection of several disorders. POTS is also systemic and chronic and should persist for at least 3–6 months prior to diagnosis. Patients are not only troubled by postural tachycardia, but usually have other symptoms including tremulousness, generalised weakness, blurred vision, exercise intolerance, perceived inability to think clearly and fatigue. Significant orthostatic hypotension precludes the diagnosis of POTS. Postural tachycardia must develop within 10 minutes since prolonged head-up tilt causes excessive tachycardia in many healthy subjects.

Definition of Inappropriate Sinus Tachycardia IST is a clinical syndrome and not just a physiological manifestation, so the definition of IST is based on both symptoms and heart rate criteria (see Table 2).1 IST, as a clinical syndrome, requires the element of distress. Not everyone with sinus tachycardia is distressed by their tachycardia and therefore do not have IST. The specific heart rate criteria are based on the distributions of normal heart rates and are only modestly specific and sensitive. A good deal of clinical judgment is required in establishing the diagnosis.

Definition of Vasovagal Syncope The HRS document defines VVS as a syncope syndrome that usually 1) occurs with upright posture greater than 30 seconds, or with exposure to emotional stress, pain or medical settings; 2) features diaphoresis, warmth, nausea and pallor; 3) where known, is associated with hypotension and relative bradycardia, and 4) is followed by fatigue1 (see Table 2). The definition of VVS is based on published reports of symptoms of patients with positive tilt tests compared with those known or believed to have other disorders.8–12 The >30 second time requirement is intended to exclude patients with initial orthostatic hypotension.

Postural Tachycardia Syndrome

Statement Structured Investigation

Society Canadian

Year 2011

Niche Syncope investigation

of Syncope2 Cardiovascular Society

the Syncope Unit3

Association

Postural Tachycardia

Heart Rhythm

Syndrome (POTS),

Society

2015

Syncope unit rationale and mechanics

2015

Management of three cardiovascular

Inappropriate Sinus

autonomic disorders

Tachycardia (IST), and Vasovagal Syncope (VVS)1 Guideline for the

American

Evaluation and

College of

2016

approach to

Management

Cardiology,

management

of Syncope

American Heart

of syncope

Association, Heart

Rhythm Society

Guidelines for the

European

Diagnosis and

Society of

approach to

Management of

Cardiology

management of

2017

Syncope

Comprehensive

syncope

Table 2: Definitions of Syncope, Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia and Vasovagal Syncope Syncope A transient loss of consciousness, associated with inability to maintain postural tone, rapid and spontaneous recovery and the absence of clinical features specific for another form of transient loss of consciousness such as epileptic seizures. Postural

A clinical syndrome that is usually characterised by:

Tachycardia

1) frequent symptoms that occur with standing such as

Syndrome

lightheadedness, palpitations, tremulousness, generalised

weakness, blurred vision, exercise intolerance and fatigue;

2) an increase in heart rate of ≥30 beats within 10 minutes

of going from lying down to standing (or ≥40 beats in

those 12 to 19 years of age) and 3) the absence of

orthostatic hypotension (>20 mmHg drop in systolic BP).

Inappropriate

A daytime sinus heart rate >100 bpm at rest, with a mean

Sinus Tachycardia 24-hour heart rate >90 bpm not due to primary causes,

Presentation

and associated with distressing symptoms of palpitations.

POTS occurs in about 0.2 %7,13,14 and usually presents in young women between the ages of 15 and 45 years.13–18 It is a systemic illness whose main symptoms are orthostatic: lightheadedness, palpitations and tremulousness; gastrointestinal: bloating, nausea, diarrhoea, abdominal pain; and systemic: exercise intolerance, fatigue, sleep disturbance and migraine headaches.15 The symptoms of POTS are commonly exacerbated by dehydration, heat, alcohol and exercise. Many patients with POTS faint occasionally, although presyncopal episodes are much more common.

Diagnosis

There are few data about the long-term outcome. POTS is chronic, without known mortality, and many patients seem to improve over time. POTS has documented abnormalities in several pathophysiological processes 19 including autonomic denervation, hypovolaemia, hyperadrenergic stimulation, deconditioning and hypervigilance. Multiple mechanisms may co-exist in some patients.

Patient suspected of having POTS should receive a complete history and physical examination with orthostatic vital signs and a 12-lead ECG (see Table 3). The history should define the chronicity of the condition, potential causes of orthostatic tachycardia, modifying factors, impact on daily activities and family history (see Table 3). A dietary history of salt and water intake is valuable and an autonomic system review should assess for symptoms of an autonomic neuropathy. The increase

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Vasovagal

A syncope syndrome that usually 1) occurs with upright

Syncope posture greater than 30 seconds, or with exposure to emotional stress, pain, or medical settings; 2) features diaphoresis, warmth, nausea, and pallor; 3) where known, is associated with hypotension and relative bradycardia and 4) is followed by fatigue. BP = blood pressure. Based on the 2015 Heart Rhythm Society Expert Statement.1

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Clinical Arrhythmias Table 3: Investigation of Postural Tachycardia Syndrome According to the Heart Rhythm Society

clinic are nondiagnostic and the clinical suspicion for POTS is high, a tilt table test can be helpful.

Recommendation A complete history and physical exam with

A 24-hour Holter monitor can document that the tachycardia is indeed sinus tachycardia. A thyroid function test (for hyperthyroidism) and haematocrit (for anaemia) and transthoracic echocardiogram (to exclude a cardiomyopathy) can be useful in selected cases but should not be performed routinely. If the patient’s symptoms do not markedly improve then formal autonomic function testing should be considered.

CoR LoE I E

orthostatic vital signs and 12-lead ECG should be performed in patients being investigated for POTS. Complete blood count and thyroid function

IIa

IIb

studies can be useful in selected patients being assessed for POTS. A 24-hour Holter monitor might be considered in selected patients being assessed for POTS, although clinical efficiency is uncertain. Detailed autonomic testing, transthoracic

IIb

echocardiogram, tilt table testing, or exercise stress testing might be considered in selected patients being assessed for POTS. CoR = class of recommendation; LoE = level of evidence; POTS = postural orthostatic tachycardia syndrome.1

Table 4: Treatment of Postural Tachycardia Syndrome According to the Heart Rhythm Society Recommendation Patients with POTS might be managed best

CoR LoE IIb E

with a multidisciplinary approach. The consumption of up to 2–3 litres of water

IIb

IIa

B-R

IIa

IIb

B-R

IIb

III

B-R

III

B-NR

and 10–12 g of NaCl daily by POTS patients might be considered. A regular, structured and progressive exercise program in patients with POTS can be effective. It is reasonable to treat patients with POTS who have short-term clinical decompensations

Treatment There are no therapies that are uniformly successful, and combinations of approaches are often needed (see Table 4). Few treatments have been tested with the usual rigour of randomised clinical trials and there is a lack of a consensus as to whether specific treatments should be targeted to subsets of POTS, or whether a uniform approach to all should be used. Treatment might be provided more comprehensively with collaborative approaches by multiple disciplines including physicians, psychologists, nurses, physical therapists, occupational therapists and recreational therapists (see Table 4).22 Conservative treatments should be tried first in all patients. These include withdrawing medications that might worsen POTS, use of compression garments and limiting gravitational deconditioning. Patients should engage in a regular, structured, graduated, supervised exercise program featuring aerobic reconditioning with some resistance training of the thighs,23,24 starting with non-upright exercises. Exercise programs can be effective even outside of formal exercise training centres.22 Patients with suspected hypovolaemia should drink at least 2–3 litres of water per day and dietary salt intake should be about 10–12 g/day if tolerated, including salt tablets if necessary.25

with an acute intravenous infusion of up to 2 litres of saline. It might be reasonable to attempt treating patients with POTS with fludrocortisone or pyridostigmine. Treatment of patients with POTS with midodrine or low-dose propranolol might be considered. It might be reasonable to treat patients with POTS who have prominent hyperadrenergic features with clonidine or a-methyldopa. Drugs that block the norepinephrine reuptake

Fludrocortisone might be useful in the treatment of POTS through enhanced sodium retention and plasma volume expansion, although its effectiveness for POTS has not been tested in randomised clinical trials.26 Its biological effects can take about one week to reach a steady state. Midodrine is a prodrug whose metabolite is a peripheral alpha-1 adrenergic receptor agonist that constricts both veins and arteries. It significantly reduces orthostatic tachycardia.27 Midodrine has a rapid onset and short half-life, requiring dosing up to 3 times daily during daytime hours. It should not be taken within 4–5 hours of bedtime, as it may cause or worsen supine hypertension.

transporter can worsen symptoms in patients with POTS and should not be administered. Regular intravenous infusions of saline in patients with POTS are not recommended in the absence of evidence, and chronic or repeated intravenous cannulation is potentially harmful. Radiofrequency sinus node modification, surgical correction of a Chiari malformation Type I and balloon dilation or stenting of the

Low-dose oral propranolol (10–20 mg) is effective at lowering standing heart rate and may improve symptoms in POTS patients acutely, while higher doses are less effective.28 Long-acting propranolol does not improve quality of life (QoL) in POTS patients.29 Other b-blockers have not been studied. Ivabradine slows sinus rates without impacting blood pressure. About 60 % of POTS patients treated with ivabradine in an open-label study improved.30 However ivabradine is not widely available.

CoR = class of recommendation; LoE = level of evidence; POTS = postural orthostatic tachycardia syndrome.1

Pyridostigmine is a peripheral acetylcholinesterase inhibitor that increases synaptic acetylcholine in the autonomic ganglia and at peripheral muscarinic receptors. It blunts orthostatic tachycardia31 and may improve chronic symptoms in most patients,32 but has side-effects including diarrhoea and abdominal pain that can limit its tolerability.

in heart rate with standing decreases slowly with advancing age20 and the standing heart rate may be ≥120 bpm in severe forms.7,16 Slightly higher values occur in the morning.21 If orthostatic vital signs in the

Central sympatholytic agents can be useful in patients with very hyperadrenergic features such as orthostatic hypertension with excessive tachycardia (hyperadrenergic POTS), but may not be as well

jugular vein are not recommended for routine use in patients with POTS and are potentially harmful.

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tolerated in neuropathic POTS where a peripheral neuropathy might compromise venous return from the lower extremities. Clonidine can blunt tachycardia and hypertension in patients with hyperadrenergic POTS,33 although methyldopa with its longer half-life is sometimes better tolerated.34 Both drugs can cause drowsiness, fatigue and worsen mental clouding. Modafinil might help the fatigue and cognitive dysfunction seen in some patients35 with only a minimal increase in tachycardia.36 Radiofrequency sinus node modification for the sinus tachycardia of POTS is not recommended as this often worsens symptoms and occasionally makes the patient pacemaker dependent.37 Some centres decompress the cerebellar tonsils38 or perform jugular venoplasty39 in an effort to ‘cure’ POTS. These are potentially dangerous and costly procedures without credible evidence of effectiveness in the treatment of POTS. They should not be offered to patients until prospective controlled data demonstrate its efficacy.

Syndrome Of Inappropriate Sinus Tachycardia Presentation The prevalence of the heart rate criteria for IST was estimated in a middle-aged population of men and women to be 1.2 %.40 This includes both symptomatic and asymptomatic subjects. There is a general sense that IST is chronic with no known mortality, but whether and how quickly patients improve is unknown. The pathophysiology is incompletely understood. It is likely that there are several different underlying pathologies that can result in this syndrome, including increased sinus node automaticity,41 increased sympathetic activity42 and sensitivity, decreased parasympathetic activity41 and impaired neurohumoral modulation.

Diagnosis A thorough history and physical exam should be performed focusing on possible causes of sinus tachycardia such as volume depletion, thyroid disease, drug use, psychological triggers, panic attacks and POTS (see Table 5). A 12-lead ECG is useful in documenting tachycardia and in demonstrating sinus rhythm. A 24-hour Holter monitor can be useful in confirming the diagnosis, since one of the criteria is based on average 24-hour heart rate. Treadmill exercise testing might be useful to document an exaggerated tachycardia response to exertion.42 Cardiovascular autonomic testing is rarely useful.

Treatment There are no positive long-term prospective clinical trials of any therapeutic intervention and symptoms may continue despite heart rate control. IST patients nearly always present distressed about the complexity of their problems. Lifestyle changes should be discussed early with all patients. β-adrenergic blockers may cause side-effects and should be used judiciously (see Table 6). Ivabradine holds considerable promise for the treatment of IST. It blocks the If current, is generally well tolerated and has a remarkable effect on heart rate. At doses of 5–7.5 mg twice daily it slows heart rate by 25–40 bpm.43,44 Ivabradine is not available in all countries but is likely to become increasingly so in the next 2–3 years. Several groups have reported on the modification or ablation of the sinus node in IST. Primary success rates are usually good, but the complication rates are significant. These include requirement for permanent pacing, transient or permanent phrenic nerve paralysis and transient superior vena cava syndrome. There is no evidence for

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Table 5: Investigation of Inappropriate Sinus Tachycardia Syndrome according to the Heart Rhythm Society Recommendation A complete history and physical exam and

CoR LoE I E

12-lead ECG are recommended. It might be useful to obtain complete blood

IIa

A 24-hour Holter monitoring might be performed.

IIb

It might be useful to obtain urine/serum

IIb

It might be useful to consider autonomic testing.

IIb

It might be useful to consider treadmill exercise

IIb

count and thyroid function studies.

drug screen.

testing. CoR = class of recommendation; LoE = level of evidence.1

Table 6: Treatment of Inappropriate Sinus Tachycardia Syndrome According to the Heart Rhythm Society Recommendation Reversible causes of sinus tachycardia should

CoR LoE I E

be sought and treated. Ivabradine can be useful in treating patients

IIa

B-R

III

with IST. Sinus node modification, surgical ablation and sympathetic denervation are not recommended as a part of routine care of patients with IST. CoR = class of recommendation; IST = inappropriate sinus tachycardia; LoE = level of evidence.1

long-term symptomatic improvement with radiofrequency ablation for IST. Patients and physicians alike need to be aware that while patients may be highly motivated, the consequences of aggressive therapeutic attempts can seriously outweigh any potential benefit.

Vasovagal Syncope Presentation VVS is very common. By age 60, 42 % of women and 32 % of men will have had at least one vasovagal faint,45,46 and most patients faint recurrently. VVS is manifested in about 1–3 % of toddlers as syncope with reflex anoxia or breath holding, and the incidence begins to increase markedly around age 11 years. The median age of first faint is about 14 years and most people with VVS have had their first faint before age 40 years.47 In specialist syncope clinics, late first presentations do occur with some regularity. The outcome of VVS patients is generally benign in that there is no increased mortality, but there is a high rate of recurrence. The overall 1-year recurrence rate in many reports is about 25–35 %.48 Those patients with recurrent VVS often have a significant loss of QoL.49 Fortunately most patients improve in the absence of specific therapy after assessment.50

Diagnosis The most important step in the diagnosis of VVS is an excellent and evidence-informed history. The key diagnostic features are in four categories: predisposing situations, prodromal symptoms, physical signs and recovery time and symptoms. VVS usually occurs after prolonged standing or in a sitting position, but can be triggered even in the supine position by exposure to medical or dental situations, pain, or scenes of injury. Prolonged can mean as little as 2–3 minutes and this is a key feature distinguishing VVS from initial orthostatic hypotension, in which syncope occurs within the first few seconds

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Clinical Arrhythmias Table 7: Investigation of Vasovagal Syncope According to the Heart Rhythm Society Recommendation Tilt table testing can be useful for the investigation

CoR LoE IIa B-NR

of patients with suspected vasovagal syncope who lack a confident diagnosis after initial assessment. Tilt table testing is reasonable for distinguishing

IIa

B-NR

convulsive syncope from epilepsy; to establish a diagnosis of pseudosyncope; and in patients with suspected vasovagal syncope but without clear diagnostic features. Tilt table testing is not recommended for predicting

III

B-R

IIa

B-R

the response to specific medical treatments for vasovagal syncope. Implantable loop recorders can be useful in the investigation of older patients with infrequently recurrent and troublesome syncope who lack a clear diagnosis and are at low risk of a fatal outcome. CoR = class of recommendation; LoE = level of evidence.1

of standing up. Prodromal features include progressive presyncope, diaphoresis, a sense of warmth or flushing, nausea or abdominal discomfort and visual blurring or frank loss of vision. While unconscious the patient is usually still, but both fine and coarse myoclonic movements are witnessed about 10 % of the time and can lead to diagnostic confusion with epilepsy.51 Unconsciousness usually lasts less than 1–2

substrate for VVS. In cardiology clinics, this is often accompanied by triggering agents such as isoproterenol, nitrates or clomipramine. However, with increasingly aggressive protocols comes increased sensitivity, but also the likelihood of decreased specificity. The tilt test may prove useful in elderly patients due to the difficulties in obtaining an informative history in some older patients and due to its usefulness in identifying the cause of unexplained falls.58 There are specific circumstances in which tilt table testing can be helpful (see Table 7). It can help distinguish convulsive syncope from true seizure activity; help in situations where, despite careful questioning, the cause of syncope remains unclear and establish a diagnosis of pseudosyncope. The latter is a poorly understood syndrome of apparent syncopal episodes in the absence of haemodynamic changes that might cause cerebral hypoperfusion. There are several current knowledge gaps regarding the use of tilt table testing. First, the tilt test has not been validated prospectively against populations with rigorously defined VVS. Second, there is no ‘ideal’ protocol, in that there is an inexorable trade-off between sensitivity and specificity. Also, the supplemental role of tilt testing when added to histories taken by experts, with or without quantitative diagnostic scores, has not been assessed. The indications for tilt testing are a matter of expert consensus.59

Prolonged Electrocardiographic Monitoring

minutes, but full recovery can be sluggish. Patients are usually very tired for minutes to hours following a syncopal spell. Further investigation usually is not needed.52 Diagnostic scores have been developed based on subjects with rigorously defined diagnoses.12,53,54 Generally, attempts at validation have not been done with subjects as rigorously defined.55,56 Although the scores report overall high degrees of accuracy, they may need revision and validation in larger populations. Nonetheless, they serve as useful reminders of important diagnostic points, and form reproducible criteria for entry into observational, genetic and randomised controlled interventional trials.

The current gold standard for diagnosing syncope due to cardiac arrhythmias is recording an ECG during an episode of clinical syncope (see Table 7). The diagnostic yield increases with the duration of monitoring and is significantly higher with implanted monitors. External monitors have a loop memory that continuously records and overwrites the ECG until activation records an ECG strip. Diagnostic sensitivity is at best 10–25 % after one month of monitoring. Implanted loop recorders are subcutaneous devices that last up to three years, storing the ECG retrospectively when activated by the patient after a syncopal episode, and also after automatic detection based on rate or rhythm criteria.

Tilt Table Testing

Implantable loop recorders (ILR) deliver a diagnosis in about 35 % of patients. Importantly, there have been randomised controlled trials of their clinical effectiveness, and the results consistently show that in older patients with unexplained syncope these devices should be used early rather than later in investigation.59–62 However, they have only been shown to improve care in the subset of patients who are older, have asystole documented on the ILR and a negative tilt test. These patients may benefit from permanent pacing.63,64

The usefulness of investigation strategies depends on the patient mix and the purpose of the investigation (see Table 7). In most cardiology settings it is most important to determine whether patients have arrhythmic causes of syncope. Generally there are two approaches to discern arrhythmic syncope: determining whether the patient has the substrate for particular kinds of syncope and determining directly whether patients have syncope associated with specific heart rhythm abnormalities or characteristics.

Conservative and Medical Treatment for Vasovagal Syncope Another important differential diagnosis for VVS is neurogenic orthostatic hypotension, which is often caused by autonomic nervous system failure. Blood pressure usually falls reproducibly and rapidly within three minutes of upright posture. Unlike VVS which has an intermittent reflex with a relative drop in heart rate and hypotension, autonomic failure is often associated with a fixed heart rate a persistent failure of vasoconstriction.57 Formal autonomic testing including a Valsalva manoeuvre can demonstrate this failure of vasoconstriction. Orthostatic hypotension was not explicitly discussed in the HRS expert consensus document. Head-up tilt table tests (see Table 7) feature prolonged passive postural stress to determine whether patients have the autonomic

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VVS is generally benign and seems to feature clusters of syncope interspersed with long quiescent periods. Older and younger individuals differ markedly, with complicating comorbidities and medical therapies more common in older patients. Despite its usually apparently benign profile, some patients with frequent episodes of VVS require active treatment. It is important to balance natural history, the potential for harm and the marked reduction in syncope seen in all control arms of randomised trials with symptom severity and the overall likelihood of treatment effectiveness. Education, reassurance and encouraging salt and fluid intake are indicated in patients with VVS where not contraindicated. Reducing medications that cause hypotension might be helpful, provided that it

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is feasible (see Table 8). Increasing salt and fluid intake may be helpful where it is safe. In general, long-term placebo-controlled prospective trials have not been encouraging.

Physical Counter Pressure Manoeuvres Isometric exercise of large muscles causes a blood pressure increase during the phase of impending reflex syncope on tilt tests, preventing or delaying loss of consciousness. Physical counter pressure manoeuvre reduced the likelihood of fainting by 39 % in one randomised prospective clinical trial.65 However, syncope recurred in a substantial minority of patients, and the study was open label. Nonetheless, physical counter pressure manoeuvres are largely free of risk and should constitute a core of management of patients with VVS of all severities.

Table 8: Lifestyle and Medical Treatment of Vasovagal Syncope According to the Heart Rhythm Society Recommendation Education, reassurance and encouraging salt

CoR LoE I E

and fluid intake are indicated in patients with vasovagal syncope where not contraindicated. Reducing or withdrawing medications that

IIa

may cause hypotension can be beneficial in patients with vasovagal syncope. Physical counterpressure manoeuvres can be useful IIa

B-R

in patients with vasovagal syncope who have a sufficiently long prodromal period. Fludrocortisone might be reasonable in patients

IIb

B-R

IIb

B-R

with frequent vasovagal syncope who lack contraindications to its use.

b-blockers These drugs have not been found to be effective in adequately designed and controlled randomised studies. The largest prospective, placebocontrolled, randomised critical trial of b-blocker therapy was the Prevention of Syncope Trial (POST) in which metoprolol was compared with placebo in patients with tilt-positive presumed VVS.66 While the overall result was negative, there was evidence of benefit in patients >40 years in a meta-analysis of a prespecified and prestratified substudy of POST and a large earlier observational study.67 In the absence of compelling evidence, it is not unreasonable to attempt therapy with metoprolol in older patients and to avoid using it in younger patients.

b-blockers might be considered in patients with frequent vasovagal syncope over age 40. Midodrine might be reasonable in patients with frequent vasovagal syncope and no hypertension or urinary retention. CoR = class of recommendation; LOE = level of evidence.1

Table 9: Pacemakers for Syncope According to the Heart Rhythm Society Recommendation Dual-chamber pacing can be effective in patients

CoR LoE IIa B-R

≥40 years with recurrent and unpredictable

Fludrocortisone

syncope who have a documented pause

The POST2 randomised clinical trial comparing fludrocortisone with placebo for VVS was recently completed.68 There was a strong trend to a significant benefit from fludrocortisone (p=0.07). In the absence of more compelling evidence, the HRS authors felt it might be reasonable to attempt therapy with fludrocortisone in patients whose symptom severity merits it.

≥3 seconds during clinical syncope or

Midodrine Five randomised trials of midodrine showed a consistent risk reduction of about 70 %.69 However, due to selection or design issues, none provide high-level evidence for adults. The major limitations of midodrine are frequent dosing, effects on supine hypertension, and lack of knowledge of its teratogenic effects. Older males may develop urinary retention. In the absence of compelling evidence, it might be reasonable to attempt therapy with midodrine in patients whose symptom severity merits it.

an asymptomatic pause ≥6 seconds. Tilt table testing might be considered to identify

IIb

B-NR

IIB

IIb

patients with a hypotensive response who would be less likely to respond to permanent cardiac pacing. Pacing might be considered in paediatric patients with recurrent syncope having documented symptomatic asystole and who are refractory to medical therapy. Dual-chamber pacing might be considered in adenosine-susceptible older patients who have unexplained syncope without a prodrome, a normal ECG and no structural heart disease. CoR = class of recommendation; LOE = level of evidence.1

midodrine or b-blockers (if older than 40 years) prior to pacing, recognising that there is no high-level evidence for their use.

Selective Serotonin Reuptake Inhibitors Based on a solid biological rationale, there have been several observational studies and three small randomised trials of serotonin transport inhibitors for the prevention of VVS.70–72 Results have been mixed and there remains considerable uncertainty about the effectiveness these drugs in preventing syncope.

Treatment Strategy For patients with only an occasional faint, the physician should reassure, advocate increased fluid and salt intake and teach counterpressure manoeuvres. Patients who have not fainted in the previous year should not receive attempts at medical therapy. For patients with recurrent episodes, begin conservatively and attempt to reduce drugs that might cause hypotension. For patients with recent recurrent episodes of VVS, it is reasonable to consider fludrocortisone,

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Pacemaker Treatment Cardiac pacing has a very limited role in patients with typical VVS (see Table 9). There are no positive, placebo-controlled studies of pacemakers in patients with VVS under age 40 years, and in these patients cardiac pacing should be the last choice. Pacing should be considered only in highly selected patients, i.e. those well over 40 years of age, affected by frequent recurrences associated with frequent injury, limited prodrome and documented asystole. Prolonged ECG monitoring, usually by an implantable loop recorder, is often necessary.63,64 There is emerging evidence that tilt table testing identifies patients with predominant reflex hypotension.63,64 Accordingly, tilt table testing may be performed to assess hypotensive susceptibility and identify patients who may not respond to permanent cardiac pacing. Although the documentation of a prolonged asystolic

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Clinical Arrhythmias reflex during tilt table testing predicts a similar response during spontaneous syncope, the benefit of pacing in positive cardioinhibitory tilt patients remains uncertain.63,64

Conclusions VVS, POTS and IST are all clinical syndromes that are poorly understood by physicians, associated with significant morbidity (but not mortality) for the patients, and significant frustrations for both patients and

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their physicians. The 2015 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope provides physicians with an introduction to these disorders and initial recommendations on their investigation and treatment. This statement should not be read as an all-inclusive ‘Bible’, but rather as a practical working document. Optimal care for our patients is likely to require going beyond this statement to personalise care to the individual. ■

Pediatr Adolesc Health Care 2014;44:108–33. DOI: 10.1016/ j.cppeds.2013.12.014; PMID: 24819031 Winker R, Barth A, Bidmon D, et al. Endurance exercise training in orthostatic intolerance: a randomized, controlled trial. Hypertension 2005;45:391–8. PMID: 15699447 Fu Q, Vangundy TB, Galbreath MM, et al. Cardiac origins of the postural orthostatic tachycardia syndrome. J Am Coll Cardiol 2010;55:2858–68. DOI: 10.1016/j.jacc.2010.02.043; PMID: 20579544; PMCID: PMC2914315 Raj SR, Biaggioni I, Yamhure PC, et al. Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome. Circulation 2005;111:1574–82. PMID: 15781744 Rowe PC, Calkins H, DeBusk K, et al. Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome: a randomized controlled trial. JAMA 2001;285: 52–9. PMID: 11150109 Jacob G, Shannon JR, Black B, et al. Effects of volume loading and pressor agents in idiopathic orthostatic tachycardia. Circulation 1997;96:575–80. PMID: 9244228 Raj SR, Black BK, Biaggioni I, et al. Propranolol decreases tachycardia and improves symptoms in the postural tachycardia syndrome: less is more. Circulation 2009;120:725–34. DOI: 10.1161/CIRCULATIONAHA.108.846501; PMID: 19687359; PMCID: PMC2758650 Fu Q, Vangundy TB, Shibata S, et al. Exercise training versus propranolol in the treatment of the postural orthostatic tachycardia syndrome. Hypertension 2011;58:167–75. DOI: 10.1161/HYPERTENSIONAHA.111.172262; PMID: 21690484; PMCID: PMC3142863 McDonald C, Frith J, Newton JL. Single centre experience of ivabradine in postural orthostatic tachycardia syndrome. Europace 2011;13:427–30. DOI: 10.1093/europace/euq390; PMID: 21062792; PMCID: PMC3043639 Raj SR, Black BK, Biaggioni I, et al. Acetylcholinesterase inhibition improves tachycardia in postural tachycardia syndrome. Circulation 2005;111:2734–40. PMID: 15911704 Kanjwal K, Karabin B, Sheikh M, et al. Pyridostigmine in the treatment of postural orthostatic tachycardia: a single-center experience. Pacing Clin Electrophysiol 2011;34:750–5. DOI: 10.1111/j.1540-8159.2011.03047.x.; PMID: 21410722 Gaffney FA, Lane LB, Pettinger W, Blomqvist CG. Effects of long-term clonidine administration on the hemodynamic and neuroendocrine postural responses of patients with dysautonomia. Chest 1983;83:436–8. PMID: 6295714 Shibao C, Arzubiaga C, Roberts LJn, et al. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension 2005;45:385–90. PMID: 15710782 Taneja I, Bruehl S, Robertson D. Effect of modafinil on acute pain: a randomized double-blind crossover study. J Clin Pharmacol 2004;44:1425–7. PMID: 15545315 Kpaeyeh JJ, Mar PL, Raj V, et al. Hemodynamic profiles and tolerability of modafinil in the treatment of postural tachycardia syndrome: a randomized, placebo-controlled trial. J Clin Psychopharmacol 2014;34:738–41. DOI: 10.1097/ JCP.0000000000000221; PMID: 25222185; PMCID: PMC4239166 Shen WK, Low PA, Jahangir A, et al. Is sinus node modification appropriate for inappropriate sinus tachycardia with features of postural orthostatic tachycardia syndrome? Pacing Clin Electrophysiol 2001;24:217–30. PMID: 11270703 Prilipko O, Dehdashti AR, Zaim S, Seeck M. Orthostatic intolerance and syncope associated with Chiari type I malformation. J Neurol Neurosurg Psychiatry 2005;76: 1034–6. PMID: 15965223; PMCID: PMC1739720 Tsivgoulis G, Faissner S, Voumvourakis K, et al. “Liberation treatment” for chronic cerebrospinal venous insufficiency in multiple sclerosis: the truth will set you free. Brain Behav 2015;5:3-12. DOI: 10.1002/brb3.297; PMID: 25722945; PMCID: PMC4321389 Still AM, Raatikainen P, Ylitalo A, et al. Prevalence, characteristics and natural course of inappropriate sinus tachycardia. Europace 2005;7:104–12. PMID: 15763524 Nwazue C, Paranjape SY, Black BK, et al. Postural tachycardia syndrome and inappropriate sinus tachycardiad: role of autonomic modulation and sinus node automaticity. J Am Heart Assoc 2014;3:e000700. DOI: 10.1161/JAHA.113.000700; PMID: 24721800; PMCID: PMC4187519 Morillo CA, Klein GJ, Thakur RK, et al. Mechanism of ‘inappropriate’ sinus tachycardia. Role of sympathovagal balance. Circulation 1994;90:873–7. PMID: 7913886 Cappato R, Castelvecchio S, Ricci C, et al. Clinical efficacy of ivabradine in patients with inappropriate sinus tachycardia: a prospective, randomized, placebo-controlled, double-blind,

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Study on Syncope of Uncertain Etiology (ISSUE-3). Circ Arrhythm Electrophysiol 2014;7:10–6. DOI: 10.1161/ CIRCEP.113.001103; PMID: 24336948 64. Brignole M, Menozzi C, Moya A, et al. Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial. Circulation 2012;125:2566–71. DOI: 10.1161/ CIRCULATIONAHA.111.082313; PMID: 22565936 65. van Dijk N, Quartieri F, Blanc JJ, et al. Effectiveness of physical counterpressure maneuvers in preventing vasovagal syncope: the Physical Counterpressure Manoeuvres Trial (PC-Trial). J Am Coll Cardiol 2006;48:1652–7. PMID: 17045903 66. Sheldon R, Connolly S, Rose S, et al. Prevention of Syncope

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Trial (POST): a randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope. Circulation 2006;113:1164–70. PMID: 16505178 67. Sheldon RS, Morillo CA, Klingenheben T, et al. Agedependent effect of beta-blockers in preventing vasovagal syncope. Circ Arrhythm Electrophysiol 2012;5:920–6. DOI: 10.1161/CIRCEP.112.974386; PMID: 22972872 68. Sheldon R, Raj SR, Rose MS, et al; POST 2 Investigators. Fludrocortisone for the prevention of vasovagal syncope: A randomized, placebo-controlled trial. J Am Coll Cardiol 2016;68:1–9. DOI: 10.1016/j.jacc.2016.04.030; PMID: 27364043 69. Izcovich A, Gonzalez Malla C, Manzotti M, et al. Midodrine for orthostatic hypotension and recurrent reflex syncope: A systematic review. Neurology 2014;83:1170–7. DOI: 10.1212/

WNL.0000000000000815; PMID: 25150287 70. Theodorakis GN, Leftheriotis D, Livanis EG, et al. Fluoxetine vs. propranolol in the treatment of vasovagal syncope: a prospective, randomized, placebo-controlled study. Europace 2006;8:193–8. PMID: 16627439 71. Takata TS, Wasmund SL, Smith ML, et al. Serotonin reuptake inhibitor (Paxil) does not prevent the vasovagal reaction associated with carotid sinus massage and/or lower body negative pressure in healthy volunteers. Circulation 2002;106:1500–4. PMID: 12234955 72. Di Girolamo E, Di Iorio C, Sabatini P, et al. Effects of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on refractory vasovagal syncope: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 1999;33:1227–30. PMID: 10193720

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Classification, Electrophysiological Features and Therapy of Atrioventricular Nodal Reentrant Tachycardia Demosthenes G Katritsis and Mark E Josephson Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

Abstract Atrioventricular nodal reentrant tachycardia (AVNRT) should be classified as typical or atypical. The term ‘fast-slow AVNRT’ is rather misleading. Retrograde atrial activation during tachycardia should not be relied upon as a diagnostic criterion. Both typical and atypical atrioventricular nodal reentrant tachycardia are compatible with varying retrograde atrial activation patterns. Attempts at establishing the presence of a ‘lower common pathway’ are probably of no practical significance. When the diagnosis of AVNRT is established, ablation should be only directed towards the anatomic position of the slow pathway. If right septal attempts are unsuccessful, the left septal side should be tried. Ablation targeting earliest atrial activation sites during typical atrioventricular nodal reentrant tachycardia or the fast pathway in general for any kind of typical or atypical atrioventricular nodal reentrant tachycardia, are not justified. In this review we discuss current concepts about the tachycardia circuit, electrophysiologic diagnosis, and ablation of this arrhythmia.

Keywords Atrioventricular, nodal, reentrant, tachycardia Disclosure: The authors have no conflicts of interest to declare. Received: 7 February 2016 Accepted: 22 May 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(2):130–5 DOI: 10.15420/AER.2016.18.2 Access at: www.AERjournal.com Correspondence: Dr D Katritsis, Division of Cardiology, Beth Israel Deaconess Medical Center, 185 Pilgrim Rd, Baker 4, Boston, MA, USA 02215. E: dkatrits@bidmc.harvard.edu

Atrioventricular nodal reentrant tachycardia (AVNRT) denotes re-entry in the area of the AV node, and represents the most common regular arrhythmia in the human.1 Although several models have been proposed to explain the mechanism of the arrhythmia in the context of the complex anatomy and the anisotropic properties of the atrioventricular (AV) node and its atrial extensions (see Figure 1),2 the actual circuit of AVNRT still remains elusive. Recent studies suggest a three-dimensional AV node with greater variability in the space constant of tissue and poor gap junction connectivity due to differential expression of connexin isoforms, that provide an explanation of dual conduction and nodal reentrant arrhythmogenesis.3,4 AV junctional arrhythmias are presented in Table 1. Classification schemes for AVNRT have been mainly based on the conventional concept of longitudinally dissociated dual AV nodal pathways that conduct around a central obstacle (see Table 2). In typical slow-fast AVNRT the onset of atrial activation appears prior to, at the onset, or just after the QRS complex, thus maintaining an atrial–His/His–atrial ratio, AH/HA >1. The HA interval is usually <70 ms, measured from earliest deflection of the His bundle activation to the earliest rapid deflection of the atrial activation in the His bundle electrogram, and the VA interval, measured from the onset of ventricular activation on surface ECG to the earliest rapid deflection of the atrial activation on the His bundle electrogram, is <60 ms.1,5,6 In atypical, fast-slow form of atypical AVNRT, the retrograde atrial electrogram begins after ventricular activation with an AH/HA ratio <1. The HA interval is prolonged, ≥70 msec, and the VA interval is ≥60

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msec.5,6 The atypical, slow-slow form, represents, by definition, an arrhythmia utilising two slow pathways. The AH/HA ratio is ≥1 but the HA interval is ≥70 msec, and the AH interval exceeds 200 ms.7–9 There are several inherent limitations of this classification. The distinction between fast-slow and slow-slow atypical AVNRT is often arbitrary in view of the lack of a unanimously accepted definition. In order to establish the diagnosis of a truly fast-slow form, it has been proposed that the AH interval should be less than 185 ms10 or 200 ms.6 This criterion, however, has not been adopted by other investigators.11–13 Thus, tachycardias with a relatively prolonged AH interval but an AH/ HA ratio <1 cannot be reliably classified as either fast-slow or slow-slow (see Figure 2). Furthermore, the term ‘fast-slow’ implies that the fast component of slow-fast AVNRT is the same as the fast in the fast-slow type. There is now evidence that this is not the case in patients who present with both types of tachycardia.14,15 Typical slow-fast and atypical fast-slow AVNRT appear to utilise different anatomical pathways for fast conduction. In addition, electrophysiological behaviour compatible with multiple pathways may also be seen, and in some patients, several forms of AVNRT may be inducible at electrophysiology study. We have previously published a simplified classification scheme (see Table 2) that takes into account the shortcomings of conventional classification, and reflects evolving concepts regarding the nature of the AVNRT circuit in various forms of the arrhythmia (see Figure 1).5 AVNRT should be classified either as typical or atypical. In addition, not only the AH/HA and absolute HA intervals should be necessarily used as criteria for diagnosis of typical AVNRT. The ventriculo-atrial (VA) interval is also a

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Atrioventricular Nodal Reentrant Tachycardia

Figure 1: Proposed Circuit of Atrioventricular Nodal Reentrant Tachycardia

Figure 2: Atypical Atrioventricular Nodal Reentrant Tachycardia I II

Typical AVNRT S/AAT

III V1

RI CS

Atypical AVNRT

HRA

His 1–2

VA=300 ms AH=260 ms

CS 9–10 CS 7–8

HA=360 ms

CS 5–6 During typical AVNRT (slow-fast), right- or left-sided circuits may occur with antegrade conduction through the inferior inputs and retrograde conduction through the superior inputs (S) or the anisotropic atrionodal transitional area (AAT). In atypical AVNRT conduction occurs anterogradely through one of the inferior inputs, left (LI) or right (RI) and retrogradely through the inferior inputs and retrogradely through the other one. Depending on the orientation of the circuit we may record the so-called ‘fast-slow’ or slow-slow’ types. AVNRT = atrioventricular nodal re-entrant tachycardia; CS = coronary sinus; FO = foramen ovale; TV = tricuspid valve.5

Table 1: Atrioventricular Junctional Arrhythmias Atrioventricular nodal reentrant tachycardia Non-reentrant junctional tachycardia Non-paroxysmal junctional tachycardia Focal junctional tachycardia Other non-reentrant variants

Table 2: Conventional Classification of Atrioventricular Nodal Reentrant Tachycardia Types

CS 3–4 CS 1–2 RV

The form is fast-slow according to the AH<HA definition, but slow-slow according to the AH >200 ms criterion. AH = atrial–His; CS = coronary sinus; HA = His-atrial; HRA = high right atrium; RV = right ventricle; VA = ventricolu-atrial interval.5

Table 3: Novel Proposed Classification of Atrioventricular Nodal Reentrant Tachycardia Types

VA (His)

AH/HA

Typical AVNRT

≤70 ms

≤60 msec

Atypical AVNRT

>70 ms

>60 msec

Variable

The distinction is for categorisation only, and not relevant for mechanism or therapy. Atypical AVNRT has been traditionally classified as fast-slow (HA >70 ms, VA >60, AH/HA <1, and AH <200 ms) or slow-slow (HA >70 ms, VA >60 ms, AH/HA >1, and AH >200 ms). Not all of these criteria are always met and atypical AVNRT may not be sub-classified accordingly. AH = atrial–His interval; HA = His–atrium interval. Interval measured from the onset of ventricular activation (VA) on surface ECG to the earliest deflection of the atrial activation on the His bundle electrogram.5

AH/HA

VA (His)

Usual ERAA

<60 msec

RHis, CS os, LHis

Figure 3: Typical Slow-Fast Atrioventricular Nodal Reentrant Tachycardia

Fast-Slow

>60 msec

CS os, LRAS, dCS

Slow-Slow

>60 msec

CS os, dCS

Typical AVNRT Slow-Fast Atypical AVNRT

Variable earliest retrograde atrial activation has been described for all types. AH = atrial–His interval; CS os = ostium of the coronary sinus; dCS = distal coronary sinus; ERAA = earliest retrograde atrial activation; HA = His–atrium interval; LHis = His bundle electrogram recorded from the left septum; LRAS = low right atrial septum; RHis = His bundle electrogram recorded from the right septum. Interval measured from the onset of ventricular activation (VA) on surface ECG to the earliest deflection of the atrial activation in the His bundle electrogram.1

III V1 V6 HRA His 1–2

practical and easily obtainable criterion, when the His bundle potential cannot be reproducibly and reliably recorded during tachycardia (see Table 3). As discussed later, retrograde atrial activation sequence or demonstration of a lower common pathway, should not be necessarily considered as reliable criteria for classification of AVNRT types.

His 3–4 CS 11–12 CS 9–10 CS 7–8 CS 5–6 CS 3–4

Electrophysiological Features Earliest Atrial Retrograde Activation Heterogeneity of both fast and slow conduction patterns has been well described, and all forms of AVNRT may display anterior, posterior and middle retrograde activation patterns. In typical, slow-fast AVNRT, posterior or even left atrial Fast pathways may occur in ≤8 % of patients.12,13,16,17 There has also been evidence that were left septal His recordings routinely performed in patients with AVNRT, the proportion

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CS 1–2 Earliest retrograde atrial activation is simultaneously recorded at distal CS (CS 1–2) and proximal His (His 3–4). I to V6: 12-lead ECG leads. CS = coronary sinus; His = His bundle electrogram; HRA = high right atrium.5

of left-sided retrograde Fast pathways might be considerably higher than previously reported.18 Figure 3 and Figure 4 present typical AVNRT (slow-fast) with variable earliest retrograde atrial activation.

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Clinical Arrhythmias Figure 4: Typical Slow-Fast Atrioventricular Nodal Reentrant Tachycardia

Figure 5: Atypical Atrioventricular Nodal Reentrant Tachycardia I

I II aVL R His 3–4 R His 1–2 L His 1–2 L His 3–4 CS 3–4 CS 1–2 Abl 1–2 Abl 3–4

Simultaneous mapping of the right septum (R His), left septum (L His) and the anatomic area of the Slow pathway is undertaken. Earliest retrograde atrial activation is recorded on the left septum. I to V6: 12-lead ECG leads. Abl = ablation electrode at the anatomical area of the Slow pathway; CS = coronary sinus; His = His bundle electrogram; HRA = high right atrium.5

In atypical AVNRT, the earliest retrograde atrial activation is traditionally reported at the base of the triangle of Koch, near the coronary sinus ostium. Detailed mapping of retrograde atrial activation in large series of patients, however, has produced variable results. Earliest atrial activation can be well recorded at the coronary sinus ostium, the low right atrial septum, or the His bundle area.11–13,17 In certain cases of atypical AVNRT, retrograde atrial activation is even suggestive of a left lateral accessory pathway.8,9

II V1 HRA His 1–2 HRA 3–4 HRA 1–2 LV 3–4 LV 1–2 CS 5–6 Cs 3–4 Cs 1–2 RV The form is conventionally fast-slow (AH<HA, HA>70 ms, AH<200 ms), and earliest retrograde atrial activation recorded at the His bundle electrode. I to V6: 12-lead ECG leads; CS = coronary sinus; His = His bundle electrogram; HRA = high right atrium; LV = left ventricle; RV = right ventricle.5

Figure 6: Atypical Atrioventricular Nodal Reentrant Tachycardia

II V1 V6

Relative AH/HA Intervals The AH time and the relative AH/HA intervals have been proposed as a criterion for distinction between fast-slow and slow-slow AVNRT. However, both absolute and relative values may be meaningless in certain occasions. They depend on autonomic status, age, use of isoprenaline and sedatives and conduction properties of pathways involved, and may change during a single electrophysiology study. We have often noticed different AH/HA times in the same patient at similar or different tachycardia cycle lengths. Furthermore, when a His bundle electrogram cannot be recorded during tachycardia, a diagnosis based exclusively on them is impossible.19

Upper and Lower Common Pathways Early studies have considered the possibility of additional AV nodal tissue extrinsic to the tachycardia circuit in order to explain various electrophysiologic phenomena observed during AVNRT,20 and the concepts of upper and lower common pathways have been longstanding controversies of AVNRT. The existence of an upper common pathway can now be rather easily refuted by subsequent evidence indicating that multiple atrial breakthroughs are extremely common,

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VA=150 ms

HRA AH=230 ms His 1–2

CS 9–10

It is obvious, therefore, that classification based on earliest atrial retrograde activation is inappropriate. Figure 5 and Figure 6 depicts fast-slow and slow-slow AVNRT, respectively, with earliest retrograde atrial activation at the His bundle electrode.

VA=180 ms AH=100 ms HA=240 ms

HA=160 ms

CS 7–8 CS 5–6 CS 3–4 CS 1–2 RV

The form is conventionally slow-slow (AH>HA, HA>60 ms, AH>200 ms), and earliest retrograde atrial activation is recorded at the His bundle.5

and retrograde activation often changes in timing and/or activation without significant alteration in tachycardia cycle, thus negating the notion of a simplistic focal atrial exit site.21–23 The perinodal transitional tissue is the route to the atrium, and in this context it may be considered as a common pathway of tissue but not a discrete site. The breakthrough is whatever leads to atrial activation via transitional tissue; thus there are many possibilities (see Figures 3–6). The lower common pathway, as initially considered by Mendez and Moe,24 has a more sound physiological basis. The notion of a lower

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Table 4: Electrophysiology Techniques for the Differential Diagnosis of Narrow QRS Tachycardias

V Pacing in SR

V Pacing During Tachycardia

VA ratios during

His-synchronous extrastimuli41

V pacing and

A Pacing in SR

A Pacing During Tachycardia

Easily Applicable

tachycardia33,34

Ventriculoatrial

Comparison of AH during pacing and tachycardia57

Entrainment

index35

- AAV/AAHV response42

- With and without stable fusion43

- SA-VA and cPPI-TCL intervals44–47

- Differential entrainment or cessation48

Cumbersome

Delta HA during V

Pre-excitation index49

pacing and tachycardia36

Differential entrainment58

Entrainment

VHA pattern37

Para-Hisian pacing38

- Anterograde His capture50 - Progressive fusion during or after

the transition zone51,52

Delta HA during entrainment

Induction of retrograde

RBBB39

and tachycardia53

SAinit-VA and cPPIinit-

- Para-Hisian entrainment54–56

TCL intervals during

induction of tachycardia40

A = atrial; AH = atrio-His interval; cPPI = corrected post-pacing interval; HA = His-atrial interval; RBBB = right bundle branch block; SA = stimulus to atrium interval; SR = sinus rhythm; TCL = tachycardia cycle length; V = ventricular; VA = ventriculo-atrial interval.19

common pathway has been utilised in order to explain phenomena of AV block without recording of a His electrogram as well as retrograde Wenckebach periodicity during AVNRT.25–28 The lower common pathway is defined as the conduction path between the distal turnaround point of the AVNRT circuit and the His bundle. The conduction time over the lower common pathway has been usually estimated by subtracting the His to atrium interval during tachycardia (measured from the onset of the His electrogram to the onset of the atrial electrogram) from that during ventricular pacing (measured from the end of the His electrogram to the onset of the atrial electrogram) at the same cycle length and considered a measurable interval in the majority of typical AVNRT cases. Initially, a lower common pathway was demonstrated in up to 75 % of 28 patients with AVNRT who were studied,20 whereas in subsequent studies with the use of para-Hisian pacing, the presence of a lower common pathway was identified in 78 % of 23 patients studied.27 No evidence of a lower common pathway has been detected in typical slow-fast AVNRT.29 However, AV block during AVNRT without recording activation of the His bundle can also be explained by proximal intra-Hisian block.30 In up to one-third of patients with AVNRT the lower turnaround point of the circuit is within the His bundle, thus arguing against an intranodal circuit as a universal feature of AVNRT.31 Differences in the location of the lower turnaround sites of AV nodal reentry relatively to the His bundle have also been shown in experimental studies.32 Thus, block during AVNRT does not necessarily define a ‘lower common pathway’; it just defines longer refractory period below the circuit. This is often seen at the onset of very fast AVNRT, which may expose the HisPurkinje tissue to long-short periods and can lead to functional phase 3 block, having nothing to do with the reentrant circuit. The electrophysiological proof of the existence of a lower common pathway depends on several assumptions that may not be valid, in a way that even if a lower common pathway exists, applied methodologies

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are unable to accurately detect and measure it.23 Furthermore, there are certain cases in the electrophysiology laboratory where an antegrade, let alone a retrograde, His bundle electrogram may not be reproducibly and reliably recorded.19 Thus, upper and lower common pathways seem to represent concepts the mechanism, relevance and practical applicability of which remain speculative.

Differential Diagnosis Differential diagnosis of a narrow QRS tachycardia, such as AVNRT, may be difficult.17 Although several ECG clues may assist differential diagnosis, this is usually accomplished at electrophysiology study and, most often, is between atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia due to a concealed accessory pathway, and atrial tachycardia. Atrial and, mainly, ventricular pacing manoeuvres during sinus rhythm or tachycardia have been used with variable success rate. In clinical practice, these techniques cannot be applied to all cases, and multiple criteria have to be used for the differential diagnosis of narrow complex tachycardias with atypical characteristics. In Table 4 we summarise our experience with various techniques and manoeuvres for the differential diagnosis of narrow-QRS tachycardias in the electrophysiology laboratory.33–59

Ablation Chronic administration of antiarrhythmic drugs (such as β-blockers, non-dihydropyridine calcium channel blockers, flecainide or propafenone) may be ineffective in up to 50 % of cases.1 Thus, catheter ablation is the current treatment of choice. Slow pathway ablation or modification is effective in both typical and atypical AVNRT. Usually, a combined anatomical and mapping approach is employed with ablation lesions delivered at the inferior or mid part of the triangle of Koch.60,61 Multicomponent atrial electrograms or low amplitude potentials, although not specific for identification of slow pathway

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Clinical Arrhythmias conduction, are successfully used to guide ablation at these areas. Ablation should be only directed towards the anatomic position of the slow pathway. If right septal attempts are unsuccessful, the left septal side should be tried.62,63 This approach offers a success rate of 95 %, is associated with a risk of 0.5–1 % AV block and has approximately 4 % recurrence rate. There

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is no mortality associated with this procedure.64,65 Advanced age is not a contraindication for slow pathway ablation.66 The preexistence of first-degree heart block may carry a higher risk for late AV block and slow pathway modification, as opposed to complete elimination, is probably preferable in this setting.67 Cryoablation may carry a lower risk of AV block, but it is negligible and this mode of therapy is associated with a significantly higher recurrence rate.67 ■

Atrioventricular nodal reentrant tachycardia: Studies on upper and lower “common pathways”. Circulation 1987;75:930–40. PMID: 3568310 McGuire MA, Lau KC, Johnson DC, et al. Patients with two types of atrioventricular junctional (AV nodal) reentrant tachycardia. Evidence that a common pathway of nodal tissue is not present above the reentrant circuit. Circulation 1991;83:1232–46. PMID: 2013144 Anselme F, Hook B, Monahan K, et al. Heterogeneity of retrograde fast-pathway conduction pattern in patients with atrioventricular nodal reentry tachycardia: observations by simultaneous multisite catheter mapping of Koch’s triangle. Circulation 1996;93:960–8. PMID:8598087 Katritsis DG. Upper and lower common pathways in atrioventricular nodal reentrant tachycardia: refutation of a legend? Pacing Clin Electrophysiol 2007;30:1305–8. DOI: 10.1111/j.1540-8159.2007.00861.x; PMID: 17976089 Mendez C, Moe GK. Demonstration of a dual A-V nodal conduction system in the isolated rabbit heart. Circ Res 1966;19:378–93. PMID: 5914850 Otomo K, Okamura H, Noda T, et al. Unique electrophysiologic characteristics of atrioventricular nodal reentrant tachycardia with different ventriculoatrial block patterns: effects of slow pathway ablation and insights into the location of the reentrant circuit. Heart Rhythm 2006;3:544–54. DOI: 10.1016/ j.hrthm.2006.01.020; PMID: 16648059 Otomo K, Nagata Y, Uno K, et al. Atypical atrioventricular nodal reentrant tachycardia with eccentric coronary sinus activation: Electrophysiological characteristics and essential effects of left-sided ablation inside the coronary sinus. Heart Rhythm 2007;4:421–32. DOI: 10.1016/j.hrthm.2006.12.035; PMID: 17399627 Anselme F, Poty H, Cribier A, et al. Entrainment of typical AV nodal reentrant tachycardia using para-Hisian pacing: evidence for a lower common pathway within the AV node. J Cardiovasc Electrophysiol 1999;10:655–61. PMID: 10355921 Kazemi B, Haghjoo M, Arya A, Sadr-Ameli MA. Spontaneous high degree atrioventricular block during AV nodal reentrant tachycardia. Europace 2006;8:421–2. DOI: 10.1093/europace/ eul046; PMID: 16687425 Heidbuchel H, Ector H, Van de Werf F. Prospective evaluation of the length of the lower common pathway in the differential diagnosis of various forms of AV nodal reentrant tachycardia. Pacing Clin Electrophysiol 1998;21:209–16. PMID: 9474674 Man KC, Brinkman K, Bogun F, et al. 2:1 atrioventricular block during atrioventricular node reentrant tachycardia. J Am Coll Cardiol 1996;28:1770–4. DOI: 10.1016/S0735-1097(96)00415-9; PMID: 8962565 Li YG, Bender B, Bogun F, et al. Location of the lower turnaround point in typical AV nodal reentrant tachycardia: a quantitative model. J Cardiovasc Electrophysiol 2000;11:34–40. PMID: 10695459 Patterson E, Scherlag BJ. Slow:fast and slow:slow AV nodal reentry in the rabbit resulting from longitudinal dissociation within the posterior AV nodal input. J Interv Card Electrophysiol 2003;8:93–102. PMID: 12766500 Crozier I, Wafa S, Ward D, Camm J. Diagnostic value of comparison of ventriculoatrial interval during junctional tachycardia and right ventricular apical pacing. Pacing Clin Electrophysiol 1989;12:942–53. PMID: 2472622 Tai CT, Chen SA, Chiang CE, Chang MS. Characteristics and radiofrequency catheter ablation of septal accessory atrioventricular pathways. Pacing Clin Electrophysiol1999;22:500–11. PMID: 10192859 Martinez-Alday JD, Almendral J, Arenal A, et al. Identification of concealed posteroseptal Kent pathways by comparison of ventriculoatrial intervals from apical and posterobasal right ventricular sites. Circulation 1994;89:1060–7. PMID: 8124791 Miller JM, Rosenthal ME, Gottlieb CD, et al. Usefulness of the ΔHA interval to accurately distinguish atrioventricular nodal reentry from orthodromic septal bypass tract tachycardias. Am J Cardiol 1991;68:1037–44. PMID: 1927917 Owada S, Iwasa A, Sasaki S, et al. “V-H-A Pattern” as a criterion for the differential diagnosis of atypical AV nodal reentrant tachycardia from AV reciprocating tachycardia. Pacing Clin Electrophysiol 2005;28:667–74. DOI: 10.1111/j.15408159.2005.00151.x; PMID: 16008802 Hirao K, Otomo K, Wang X, et al. Para-Hisian pacing. A new method for differentiating retrograde conduction over an accessory AV pathway from conduction over the AV node. Circulation 1996;94:1027–35. PMID: 8790042 Kapa S, Henz BD, Dib C, et al. Utilization of retrograde right bundle branch block to differentiate atrioventricular nodal from accessory pathway conduction. J Cardiovasc Electrophysiol

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2009;20:751–8. DOI: 10.1111/j.1540-8167.2009.01447.x; PMID: 19298561 Obeyesekere M, Gula LJ, Modi S, et al. Tachycardia induction with ventricular extrastimuli differentiates atypical atrioventricular nodal reentrant tachycardia from orthodromic reciprocating tachycardia. Heart Rhythm 2012;9:335–41. DOI: 10.1016/j.hrthm.2011.10.015; PMID: 22001824 Katritsis DG, Becker AE, Ellenbogen KA, et al. Effect of slow pathway ablation in atrioventricular nodal reentrant tachycardia on the electrophysiologic characteristics of the inferior atrial inputs to the human atrioventricular node. Am J Cardiol 2006;97:860–5. DOI: 10.1016/j.amjcard.2005.09.135; PMID: 16516590 Knight BP, Zivin A, Souza J, et al. A technique for the rapid diagnosis of atrial tachycardia in the electrophysiology laboratory. J Am Coll Cardiol 1999;33:775–81. PMID: 10080480 Ormaetxe JM, Almendral J, Arenal A, et al. Ventricular fusion during resetting and entrainment of orthodromic supraventricular tachycardia involving septal accessory pathways. Implications for the differential diagnosis with atrioventricular nodal reentry. Circulation 1993;88:2623–31. PMID: 8252673 Michaud GF, Tada H, Chough S, et al. Differentiation of atypical atrioventricular node reentrant tachycardia from orthodromic reciprocating tachycardia using a septal accessory pathway by the response to ventricular pacing. J Am Coll Cardiol 2001;38:1163–7. PMID: 11583898 González-Torrecilla E, Arenal A, Atienza F, et al. First postpacing interval after tachycardia entrainment with correction for atrioventricular node delay: a simple maneuver for differential diagnosis of atrioventricular nodal reentrant tachycardias versus orthodromic reciprocating tachycardias. Heart Rhythm 2006;3:674–9. DOI: 10.1016/j.hrthm.2006.02.019; PMID: 16731468 Bennett MT, Leong-Sit P, Gula LJ, et al. Entrainment for distinguishing atypical atrioventricular node reentrant tachycardia from atrioventricular reentrant tachycardia over septal accessory pathways with long-RP tachycardia. Circ Arrhythm Electrophysiol 2011;4:506–9. DOI: 10.1161/ CIRCEP.111.961987; PMID: 21636810 Veenhuyzen GD, Coverett K, Quinn FR, et al. Single diagnostic pacing maneuver for supraventricular tachycardia. Heart Rhythm 2008;5:1152–8. DOI: 10.1016/j.hrthm.2008.04.010; PMID: 18554986 Segal OR, Gula LJ, Skanes AC, et al. Differential ventricular entrainment: a maneuver to differentiate AV node reentrant tachycardia from orthodromic reciprocating tachycardia. Heart Rhythm 2009;6:493–500. DOI: 10.1016/j.hrthm.2008.12.033; PMID: 19324309 Miles WM, Yee R, Klein GJ, et al. The preexcitation index: An aid in determining the mechanism of supraventricular tachycardia and localizing accessory pathways. Circulation 1986;74:493–500. PMID: 3742751 Nagashima K, Kumar S, Stevenson WG, et al. Antegrade conduction to the His bundle during right ventricular overdrive pacing distinguishes septal pathway AV reentry from atypical AV nodal reentry tachycardias. Heart Rhythm 2015;12:735–43. DOI: 10.1016/j.hrthm.2015.01.003; PMID: 25576777 AlMahameed ST, Buxton AE, Michaud GF. New criteria during right ventricular pacing to determine the mechanism of supraventricular tachycardia. Circ Arrhythm Electrophysiol 2010;3:578–84. DOI: 10.1161/CIRCEP.109.931311; PMID: 20971759 Dandamudi G, Mokabberi R, Assal C, et al. A novel approach to differentiating orthodromic reciprocating tachycardia from atrioventricular nodal reentrant tachycardia. Heart Rhythm 2010;7:1326–9. DOI: 10.1016/j.hrthm.2010.05.033; PMID: 20638932 Ho RT, Mark GE, Rhim ES, et al. Differentiating atrioventricular nodal reentrant tachycardia from atrioventricular reentrant tachycardia by DeltaHA values during entrainment from the ventricle. Heart Rhythm 2008;5:83–8. ; DOI: 10.1016/ j.hrthm.2007.09.017; PMID: 1818002 Reddy VY, Jongnarangsin K, Albert CM, et al. Para-Hisian entrainment: a novel pacing maneuver to differentiate orthodromic atrioventricular reentrant tachycardia from atrioventricular nodal reentrant tachycardia. J Cardiovasc Electrophysiol. 2003;14:1321–8. PMID: 14678108 Pérez-Rodon J, Bazan V, Bruguera-Cortada J, et al. Entrainment from the para-Hisian region for differentiating atrioventricular node reentrant tachycardia from orthodromic atrioventricular reentrant tachycardia. Europace 2008;10: 1205–11. DOI: 10.1093/europace/eun249; PMID: 18776198

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Atrioventricular Nodal Reentrant Tachycardia

56. Singh DK, Viswanathan MN, Tanel RE, et al. His overdrive pacing during supraventricular tachycardia: a novel maneuver for distinguishing atrioventricular nodal reentrant tachycardia from atrioventricular reciprocating tachycardia. Heart Rhythm 2014;11:1327–35. DOI: 10.1016/j.hrthm.2014.04.038; PMID: 24793458 57. Man KC, Niebauer M, Daoud E, et al. Comparison of atrial-His intervals during tachycardia and atrial pacing in patients with long RP tachycardia. J Cardiovasc Electrophysiol 1995;6:700–10. PMID: 8556190 58. Sarkozy A, Richter S, Chierchia GB, et al. A novel pacing manoeuvre to diagnose atrial tachycardia. Europace 2008;10:459–66. DOI: 10.1093/europace/eun032; PMID: 18299309 59. Kalbfleisch SJ, Strickberger SA, Williamson B, et al. Randomized comparison of anatomic and electrogram mapping approaches to ablation of the slow pathway of atrioventricular node reentrant tachycardia. J Am Coll Cardiol 1994;23:716–23. PMID: 8113557

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60. Giazitzoglou E, Korovesis S, Kokladi M, et al. Slow-pathway ablation for atrioventricular nodal reentrant tachycardia with no risk of atrioventricular block. Hellenic J Cardiol 2010;51: 407–12. PMID: 20876053 61. Katritsis DG, Giazitzoglou E, Zografos T, et al. An approach to left septal slow pathway ablation. J Interv Card Electrophysiol 2011;30:73–79. DOI: 10.1007/s10840-010-9527-z; PMID: 21153692 62. Katritsis DG, Papagiannis J. Anatomically left-sided septal slow pathway ablation in dextrocardia and situs inversus totalis. Europace 2008;10:1004–5. DOI: 10.1093/europace/eun163; PMID: 18556684 63. Spector P, Reynolds MR, Calkins H, et al. Meta-analysis of ablation of atrial flutter and supraventricular tachycardia. Am J Cardiol 2009;104:671–7. DOI: 10.1016/j.amjcard.2009.04.040; PMID: 19699343 64. Bohnen M, Stevenson WG, Tedrow UB, et al. Incidence and predictors of major complications from contemporary catheter ablation to treat cardiac arrhythmias. Heart Rhythm 2011;8:

1661–6. DOI: 10.1016/j.hrthm.2011.05.017; PMID: 21699857 65. Rostock T, Risius T, Ventura R, et al. Efficacy and safety of radiofrequency catheter ablation of atrioventricular nodal reentrant tachycardia in the elderly. J Cardiovasc Electrophysiol 2005;16:608–10. PMID: 15946358; DOI: 10.1111/j.15408167.2005.40717.x 66. Li YG, Gronefeld G, Bender B, et al. Risk of development of delayed atrioventricular block after slow pathway modification in patients with atrioventricular nodal reentrant tachycardia and a pre-existing prolonged pr interval. Eur Heart J 2001;22:89–95. DOI: 10.1053/euhj.2000.2182; PMID: 11133214 67. Deisenhofer I ZB, Yin YH, Pitschner HF, et al. Cryoablation versus radiofrequency energy for the ablation of atrioventricular nodal reentrant tachycardia (the cyrano study): Results from a large multicenter prospective randomized trial. Circulation 2010;122:2239–45. DOI: 10.1161/CIRCULATIONAHA.110.970350; PMID: 21098435

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Diagnostic Electrophysiology & Ablation

Holter Monitoring and Loop Recorders: From Research to Clinical Practice Alessio Galli, Francesco Ambrosini and Federico Lombardi Cardiovascular Diseases Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Department of Clinical and Community Sciences, University of Milan, Milan, Italy

Abstract Holter monitors are tools of proven efficacy in diagnosing and monitoring cardiac arrhythmias. Despite the fact their use is widely prescribed by general practitioners, little is known about their evolving role in the management of patients with cryptogenic stroke, paroxysmal atrial fibrillation, unexplained recurrent syncope and risk stratification in implantable cardioverter defibrillator or pacemaker candidates. New Holter monitoring technologies and loop recorders allow prolonged monitoring of heart rhythm for periods from a few days to several months, making it possible to detect infrequent arrhythmias in patients of all ages. This review discusses the advances in this area of arrhythmology and how Holter monitors have improved the clinical management of patients with suspected cardiac rhythm diseases.

Keywords Holter monitoring, loop recorder, syncope, atrial fibrillation, sudden death, cardiomyopathy Disclosure: The authors have no conflicts of interest to declare. Acknowledgment: This study was partially supported by an unconditional Fondazione Polizzotto grant. We would like to thank engineer Silvia Bisetti and Medtronic Inc for data reported in Table 2. Received: 8 February 2016 Accepted: 27 April 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(2):136–43 DOI: 10.15420/AER.2016.17.2 Access at: www.AERjournal.com; Correspondence: Alessio Galli, Cardiovascular Diseases Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via Francesco Sforza, 35 - 20122 Milan, Italy. E: aleg170389@gmail.com

Since the 1960s, Holter monitoring has been a cornerstone for diagnosing suspected arrhythmias in patients of all ages.1 The most common monitoring systems allow the continuous registration of three or more leads for 24–48 hours; newer Holter monitors allow continuous electrocardiogram (ECG) registration for 2 weeks.1 Extending the time of ECG registration will increase the diagnostic yield of Holter monitoring, especially for those rhythm disturbances that are infrequent but recurrent.1,2 This need for a prolonged ECG monitoring has been addressed by event recorders, which can monitor patients for up to 3 years, storing the ECG obtained a few minutes before and after the onset of an arrhythmia in its memory and transmitting data to the cardiac unit.1,2 When interpreting the results of the ECG, the cardiologist has to determine whether symptoms reported by the patient could be linked to significant disturbances in heart rhythm.2 In other circumstances the detection of atrial or ventricular arrhythmias may alert the cardiologist, even if they occur asymptomatically, thus prompting a specific therapeutic decision such as starting antiarrhythmic or anticoagulant drugs or implanting a pacemaker or a cardioverter defibrillator.2

Cardiac Monitoring Systems Cardiac rhythm monitoring has an established diagnostic and prognostic role in different circumstances: syncope, palpitations and monitoring of patients with known or suspected episodes of atrial fibrillation (AF), e.g. those with stroke of uncertain aetiology (cryptogenic stroke).1–3 ECG monitoring may also play a role in identifying ventricular tachycardia (VT) in patients with recognised risk of sudden cardiac death.4 As many devices with different characteristics are available, the choice of the

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most suitable monitoring system largely depends on the likelihood of detecting a significant correlation between symptoms and ECG findings.1

Holter Monitors Traditional ambulatory Holter monitors are simple devices that usually have three leads and continuously register the ECG. They can be short- (24–48 hours) or long-duration (1–2 weeks) devices.1 Two-week Holter monitoring is preferred when diagnosing or excluding AF in cryptogenic stroke, but loop recorders and outpatient telemetry have even higher detection rates.1 There are two main advantages of a continuous Holter monitoring system: the possibility of quantifying the real burden of an arrhythmia, and the detection of rhythm disturbances outside the limits set by an algorithm or memory. The quantification of arrhythmic events may aid the clinician in making a therapeutic decision, especially for those arrhythmias that occur frequently and those that have disabling symptoms. Despite their advantages, ambulatory Holter monitors also have many limits: a relatively brief duration of monitoring, the impossibility of transmitting real-time data to the attending cardiac unit and the need for close collaboration between the patient and health professionals.

Loop Recorders and Post-event Recorders Newer generation monitors are the so-called event recorders. According to their specific functions they can be divided into two categories: loop recorders, which include external loop recorders (ELRs) and implantable loop recorders (ILRs); and post-event recorders (non-looping recorders).1

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Holter Monitoring and Loop Recorders

Loop recorders are event recorders with a ‘loop memory’: they continually analyse the ECG and retain information pertaining to relevant arrhythmias that are automatically detected thanks to predefined algorithms and the registration of the ECG a few minutes before the onset of the arrhythmia.1,2 As event recorders can be activated by the patient when he or she experiences symptoms, they can reliably document a correlation between symptoms and an arrhythmia, as well as excluding a causative role of heart rhythm disturbances in determining syncope or palpitations when such symptoms occur without any arrhythmia (class I, level B evidence).2 ELRs can monitor the ECG for a maximum of 30 days.1,2 An ELR can be connected to a belt around the chest, without the need for traditional electrodes.5 ILRs are small devices that are designed for subcutaneous implantation in the chest wall via a minimally-invasive surgical procedure.3 The preferred site for implantation is the left parasternal area of the chest, even if the ILR can be placed in other locations, e.g. the left axilla, the inframammary region and the space between the supraclavicular notch and the left breast area.3 They can be fixed to the chest wall in order to reduce the number of artefacts on the ECG signal that are attributable to the mechanical instability of the device.3 Despite higher costs, ILRs are safe, have a low rate of infection (2–4 %)6 and can continue monitoring for up to 3 years.2 They may also be useful for noncompliant patients, as there are no external parts to be worn.3 Like other event recorders, ILRs are designed to transmit data to a distant diagnostic station.1,2 This remote monitoring function can be automatic, via the internet, or on demand, with the patient being required to activate telephonic transmission of the ECG data. Data transmission is simple, and patients can be trained to do this.1,2 Remote monitoring may prompt intervention and therapy if a clinically relevant arrhythmia is detected. ILRs allow the registration of only one lead, rendering the interpretation of the ECG difficult in some cases.1–3 Moreover, they have limited storage capability (generally less than 1 hour) and thus some arrhythmias may be missed if they are very frequent.1,2 Most currently used ILRs are compatible with MRI, however the device’s technical manual should be carefully consulted to determine whether such imaging is safe. If directed towards the device, sources of radiation for both diagnostic, e.g. CT, and therapeutic purposes may impair its function.

trial of 266 patients with presyncope, syncope or severe palpitations, MCOT allowed a diagnosis in 41 % of patients, while the ELR arm had a diagnosis in only 15 % of cases (P<0.001).12

Loop Recorders in Syncope and Palpitations The European Society of Cardiology gives a class I indication for ILRs in early phase evaluation in patients with recurrent syncope of uncertain origin and ELRs in patients with recurrent palpitations when conventional ECG monitoring has not established a diagnosis.2 When palpitations are severe and infrequent, with an inter-symptom interval >4 weeks, or ELR findings are inconclusive, the use of an ILR may be indicated (class IIA).2 The rationale for these recommendations is that syncope usually occurs less frequently than palpitations, making an ILR more suitable for an early diagnosis when one or more 24-hour Holter monitoring sessions have been negative despite the recurrence of symptoms.2 Devices with a maximal monitoring duration of 1 month, such as ELRs, can diagnose most rhythm disturbances causing palpitations when symptoms occur at least monthly.2 Locati and colleagues reported a similar diagnostic yield over 1 month between ELRs and ILRs in presyncope, syncope and palpitations.4 The authors concluded that an ELR may be indicated for the initial screening of patients with recurrent unexplained syncope or presyncope in place of a more expensive ILR, which remains an option if, after 1 month, monitoring with an ELR has proven negative.4

Mobile Cardiac Outpatient Telemetry

Data from the Place of Reveal in the Care Pathway and Treatment of Patients with Unexplained Recurrent Syncope (PICTURE) registry on 570 patients with unexplained recurrent syncope show that in 1 year, 36 % of patients with syncope of unknown origin are expected to have symptoms and ILRs can guide the diagnosis in up to 78 % of events, even when traditional diagnostic tests (including ambulatory ECG monitoring) have failed.13 The International Study on Syncope of Uncertain Etiology (ISSUE-1) study showed that the majority of syncopal events documented with an ILR is likely to be neurally mediated, with asystolic pauses and reflex bradycardia being the most frequently associated rhythm disturbances.14 Loop recorders effectively guide therapeutic decisions: data gathered from the prospective multicentre observational study ISSUE-2 show that therapy including pacemaker or implantable cardioverter defibrillator (ICD), anti-arrhythmic drug therapy and catheter ablation guided by ILR findings leads to a significant reduction in the number of symptoms per year (92 % relative risk reduction), making ILRs suitable for the early management of patients with recurrent unexplained syncope of suspected neurally mediated origin.15 The multicentre randomised controlled ISSUE-3 trial on pacing therapy for asystolic neurally mediated syncope confirms that ILRs effectively guide treatment decisions, with a 57 % reduction in syncope recurrence when dual-chamber permanent pacing is adopted as compared with no pacing.16 Reports from Farwell and colleagues extend the high diagnostic value of ILRs to all patients with unexplained recurrent syncope, not only those with neurally mediated syncope.17

To overcome many limits of the event recorders, mobile or real-time cardiac outpatient telemetry (MCOT) systems have been developed.1 They are external ambulatory monitors that can monitor patients for up to 30 days.1 Their continuous analysis of the ECG and realtime transmission of every single event to the attending cardiac unit gives them an advantage over ELRs.1 It is estimated that traditional 24–48-hour Holter monitors have a diagnostic yield of 15–28 %,8–10 while ELRs have a yield of up to 63 %.11 In a randomised controlled

In our experience on a heterogeneous cohort of patients with syncope or presyncope and negative extensive evaluation including 24-hour Holter monitoring or in-hospital telemetry, an ILR-guided diagnosis was obtained in about half of cases. The most frequent pathogenic mechanisms were bradycardia, asystole and advanced atrioventricular block, with tachycardia accounting for a minority of cases (see Figures 1 and 2). ILR findings prompted the implantation

Post-event recorders can be used for 14–30 days.1 The monitoring function starts when the patient puts the device on his or her chest as symptoms commence. For this reason, the diagnostic yield of post-event recorders is limited by the potential loss of events causing disabling symptoms that prevent patients from activating the device.1,3 There is also the risk that patients may forget to activate the device. Some post-event recorders have an extended backward memory, e.g. 15 minutes, which allows time to handle the patient before pressing the button to save a recording.7

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Diagnostic Electrophysiology & Ablation Figure 1: In a Patient with Recurrent Syncope of Undetermined Cause, the Implantable Loop Recorder Diagnosed Episodes of Non-sustained and Sustained Ventricular Tachycardia. Symptoms Resolved After Ablation

Figure 2: In a Patient with Recurrent Syncope of Undetermined Cause, the Implantable Loop Recorder Showed Episodes of High-degree Atrioventricular Block. Symptoms Resolved After Pacemaker Implantation

with unknown AF, both persistent and paroxysmal, are ischaemic stroke and other thromboembolic events, which could be prevented by a prompt diagnosis of AF and consequent anticoagulant therapy.20,21 As there is poor correlation between the occurrence of AF and symptoms, an ECG monitoring strategy is needed when paroxysmal AF is suspected.20,21 This is the case for patients with cryptogenic stroke (stroke with unknown aetiology after thorough evaluation), in whom AF episodes most often occur asymptomatically.22 In 20–40 % of patients, the cause of ischaemic stroke cannot be determined after a complete diagnostic evaluation including ambulatory Holter monitoring for 24 hours or longer.23–27 Two multicentre randomised controlled trials tested the hypothesis that loop recorders increase the number of patients correctly diagnosed as having AF, potentially sparing a significant number of recurrent strokes. Investigators from the 30-Day Cardiac Event Monitor Belt for Recording Atrial Fibrillation after a Cerebral Ischemic Event (EMBRACE) trial showed that an ELR strategy improves the detection rate of AF over a traditional approach of 24 hours of continuous Holter monitoring in cryptogenic stroke and transient ischaemic attacks of undetermined cause.5 AF lasting 30 seconds or longer was detected after 30 days in 45 out of 280 patients (16.1 %) with the use of an ELR (ER910AF Cardiac Event Monitor, Braemar Inc), against a detection rate of nine out of 277 (3.2 %) in the control group (P<0.001). The authors estimated that for every eight patients assigned to the ELR, one would be diagnosed as having AF despite negative 24-hour ECG monitoring. Additional data in favour of the early use of loop recorders in the diagnosis of AF as cause of cryptogenic stroke come from the Cryptogenic Stroke and Underlying (CRYSTAL) AF trial.22 Four-hundred-

of a pacemaker or an electrophysiological study and specific therapy (transcatheter ablation or implantation of a cardioverter defibrillator) in patients with documented arrhythmic syncope.18 Apart from well-established indications in the diagnosis of cardiac causes of syncope, presyncope and palpitations, there is growing evidence that loop recorders may play a role in the management of suspected AF and in the risk stratification of patients with structural heart disease.2,3 It is likely that future guidelines on the use of loop recorders will encompass these clinical situations, in light of recent evidence.

Possible Contraindications There are some patients in whom the use of an event or loop recorder as initial diagnostic tool may be contraindicated in light of an estimated high risk of a life-threatening arrhythmia. Patients at high risk are those with an indication for a pacemaker or ICD independent of the diagnosis of the cause of syncope, those with structural (e.g. heart failure) or coronary heart disease, those with clinical and ECG findings that drive suspicion for an arrhythmic syncope, and patients with important comorbidities.2 When one or more of these characteristics are present, the recommended strategy is hospitalisation for treatment or extensive evaluation including in-hospital prolonged telemetric monitoring or electrophysiological study.2 An ILR becomes an option after an extensive diagnostic work-up has proven negative.2 The same recommendations apply to high-risk patients with palpitations.2

and-forty-one patients aged 40 years or more with a diagnosis of cryptogenic stroke or transient ischemic attacks of undetermined cause were randomly assigned to an ILR (Reveal XT, Medtronic Inc) or a conventional ECG monitoring strategy. The follow-up was completed at 12 months, with the primary endpoint being the time to first detection of AF lasting 30 seconds or longer at 6 months. AF was diagnosed at 6 months in 19 (8.9 %) of the 221 patients randomised to the ILR compared with three patients (1.4 %) in the control group (P<0.001). The majority of AF episodes occurred in the first 6 months after randomisation, but the diagnostic yield of the ILR accrued until the end of the follow-up period. By 12 months, AF had been correctly diagnosed in 29 patients (12.4 %) in the ILR group and only four patients (2 %) in the control group (P<0.001). An observational study on 60 patients with cryptogenic stroke showed that ILRs might have a higher diagnostic yield than ambulatory Holter monitoring lasting 7 days.28 This finding is consistent with results from the CRYSTAL AF trial, in which the mean time between randomisation and the first episode of AF was longer than a week (38 ± 28 days).22 The AF detection rate in the CRYSTAL AF trial was lower than in the EMBRACE trial, even though the follow-up was considerably longer (12 months compared with 1 month). However, the population studied in the CRYSTAL AF trial was younger and had a lower prevalence of hypertension: two baseline characteristics associated with a reduced risk of AF.19,29

Loop Recorders in Cryptogenic Stroke AF has a prevalence of 1–2 % in the general population and up to 9–10 % in people aged over 65 years.19 The major risks associated

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Loop recorders such as ER910AF and Reveal XT are programmed to automatically detect episodes of AF using algorithms based on the

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Holter Monitoring and Loop Recorders

irregularity of the R-R interval.5,22 They are also capable of remote transmission of data. For example, the transmission of data registered by the Reveal XT can be accomplished through a CareLink Network.22 In consideration of the high diagnostic yield of AF-detecting ELRs as shown by the EMBRACE investigators, we believe that an ELR could be used as first-line monitoring strategy in cryptogenic stroke after an initial extensive evaluation including 24–48-hour ambulatory Holter monitoring has been negative. In our opinion, the more expensive ILRs remain a valuable option for long-term monitoring in a stepwise approach to patients with cryptogenic stroke with high suspicion of AF despite negative 30-day follow-up with an ELR.

Holter Monitors and Loop Recorders in Patient Follow-Up Ambulatory Holter monitoring for 24 hours or more is useful in the follow-up of patients with persistent or permanent AF in whom a rate-control strategy has been adopted, allowing for optimisation of therapy with normal heart rate as the target.1 New-generation ILRs with algorithms for the detection of AF are being used in research and in clinical practice to monitor patients after transcatheter ablation of AF.30 About 40 % of 129 patients that had pulmonary vein isolation with radiofrequency for rhythm control had recurrence of AF within 1 year from the procedure, as documented by the ILR Reveal XT.31 Results of the cryoballoon isolation of pulmonary veins are comparable.32 These data are consistent with a meta-analysis of 63 studies that shows a recurrence rate of 43 % after a single procedure and of 29 % after repeated procedure.33 Detection of recurrent AF requires a second ablation or a change in therapeutic strategy (e.g. rate control), making ILRs very important in treatment decisions for AF patients.20,21,30 Current guidelines recommend at least a 2-year follow-up after catheter ablation, with repeated ECGs and ECG monitoring.30 ECG monitoring strategies include short- and long-term ambulatory Holter monitoring, ELRs, MCOT systems and ILRs.30 ILRs may identify AF recurrences when they are very infrequent and ILRs are suitable for long-term follow-up of patients whose therapy is driven by silent AF detection, e.g. the decision to give anticoagulation to patients with thromboembolic risk factors.30 There is some evidence that the amount of arrhythmia in AF patients correlates with thromboembolic risk, but a large study is required to validate this finding.34 The arrhythmic burden can be quantified with a continuous monitoring system, even though ILR data have shown a good correlation with continuous Holter monitoring.35,36 Finally, the registration of the beginning of an AF episode with event recorders may help to establish the pathogenic mechanism of the arrhythmia. For example, AF episodes that are preceded by frequent atrial ectopic activity most likely have a focal origin.37 In this case, pulmonary vein isolation with transcatheter ablation should be expected to halt the arrhythmia.37

Smartphone ECG Monitoring A novel technology that has shown promising results in the monitoring of patients with AF is smartphone-enabled ECG, like AliveCor (AliveCor Inc).38 The AliveCor is a small device containing two electrodes that can turn a smartphone into a single-lead ECG. This system has been validated with 12-lead ECG, is not costly and allows for remote transmission of data.39 Pilot studies report a good correlation with standard ECGs in diagnosing AF and supraventricular tachycardia, but results are preliminary.40,41 Of interest, there was high acceptance of this diagnostic tool by patients,40 so it may have a future role in the screening

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of arrhythmias in symptomatic patients.39 Cardiac monitoring with the AliveCor system is intermittent and can be performed several times per day with continuous recording for up to 5 minutes. For this reason it could be especially useful in diagnosing symptomatic arrhythmias.

Algorithms and Diagnostic Accuracy of ILRs The main diagnostic issue with ILRs is that they have ECG storage limits and artefacts can potentially overwrite real arrhythmias. However, the detection algorithms of ILRs have been extensively validated using continuous Holter monitoring as the gold standard.35,36 In the Reveal XT Performance Trial (XPECT), the detection algorithm of the Reveal XT, which is based on R-R interval variation analysis every 2 minutes, identified AF patients with a sensitivity of 96 % and specificity of 85 %.35 Sensitivity is lower (85 %) when considering the detection of all episodes of AF.35,36 Diagnostic accuracy for AF is even higher with the new-generation Reveal LINQ (Medtronic Inc), which also has a P-wave detection algorithm (sensitivity of 97 % and specificity of 97 % for AF patient detection and sensitivity of 97 % for detection of all episodes of AF ≥2 minutes in duration).36 Both the Reveal XT and the Reveal LINQ data on AF burden are highly correlated with Holter recordings (Pearson coefficient >0.9).35,36 In a CareLink Network remote monitoring cohort study of ILR performance in detecting all types of tachyarrhythmias using a R-R interval-based algorithm, 64 % of episodes detected were true tachycardia.42 Common artefacts included signal noise, T-wave and P-wave oversensing. VT and fibrillation that can be induced with programmed electrical stimulation are detected by an ILR with a sensitivity of 99 %.42

Risk Stratification in Patients at Risk of Sudden Cardiac Death An active field of research is the use of loop recorders for the prognostic stratification of patients at increased risk of sudden cardiac death. The Cardiac Arrhythmias and Risk Stratification After Myocardial Infarction (CARISMA) study recruited 312 patients who had a left ventricular ejection fraction ≤40 % in the acute phase (up to 21 days) of a myocardial infarction to receive an ILR (Reveal Plus 9526, Medtronic Inc).4,43 Over a period of 2 years, the ILR detected arrhythmias in 46 % of patients, with the majority of episodes being asymptomatic and occurring in the first 3 months after myocardial infarction.44 Table 1 reports the incidences of different types of arrhythmias in this study. Despite optimal therapy, 27 patients (9 %) died of cardiac causes (lethal arrhythmias, myocardial infarction, heart failure) during the follow-up; 13 of these were arrhythmic deaths (Table 1). Twenty-five patients (8 %) experienced at least one fatal or near-fatal arrhythmia (symptomatic sustained VT or ventricular fibrillation) that was potentially treatable by an ICD and in 17 cases (five deaths) diagnosis was made with the ILR recordings.45 Considering that none of the patients with an ICD had a sudden death during the 2-year follow-up,45 an ILR may prompt the early implantation of an ICD when potentially life-threatening ventricular arrhythmias are present, even when the patient is asymptomatic (a sustained VT occurred asymptomatically in about 50 % of cases).4 A Cox regression analysis performed by the CARISMA study group showed that sustained VT neither predicted cardiac death nor all-cause mortality.4 However, after an episode of sustained VT or ventricular fibrillation was documented on the ILR, an ICD was implanted for secondary prevention.4 For this reason the value of sustained VT as a predictor of cardiac death (in particular sudden death) could have been underestimated. The rhythm disturbances

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Diagnostic Electrophysiology & Ablation Table 1: Cardiac Arrhythmia Incidence in the CARISMA Study, as Detected by Implantable Loop Recorders Arrhythmia

Number of patients (2-year incidence, %)

Sinus bradycardia (≤30 bpm, ≥8 beats)

20 (6.7)

High-degree AV block (second-to-third degree; ≤30 bpm, ≥8 beats)

29 (9.8)

Sinus arrest (≥5 s)

16 (5.4)

New-onset atrial fibrillation

82 (27.6)

Non-sustained ventricular tachycardia

39 (13.1)

Number of related cardiac deaths (both sudden and non-sudden) 5*

Sustained ventricular tachycardia

9 (3.0)

Ventricular fibrillation

8 (2.7)

*Number of deaths related to all types of bradyarrhythmia. Higher incidences are in bold. Sudden cardiac death was defined as unexpected death within 1 hour of onset of symptoms or unexpected and unwitnessed death within 24 hours after the deceased was last seen alive. Death was presumed cardiac if there was no specific evidence of non-cardiac death. Death was considered related to an arrhythmia if a life-threatening arrhythmia occurred within 1 hour of the presumed time of death. Modified from Bloch Thomsen4 and Gang et al.44

that predicted cardiac death were sinus bradycardia (HR 4.15; 95 % CI 1.37–12.62; P<0.05) and high-degree atrioventricular block (HR 6.75; 95 % CI 2.57–17.84; P<0.001).4 Mortality was evenly distributed among patients with high-degree atrioventricular block whether or not they received a pacemaker or an ICD, probably indicating that severe bradyarrhythmias (≤30 bpm, ≥8 beats) are associated with more advanced structural heart disease and a worse prognosis despite appropriate pacing.4,43 Apart from these important conclusions, it should be noted that the ILR used in the CARISMA study had some programmability limitations. For example, tachyarrhythmias were detected only if they were ≥16 beats in duration and ≥125 bpm in heart rate; some arrhythmias, such as AF with ventricular rates <125 bpm and slow VT, could have been underdetected. New-generation devices with increased sensitivity may show a higher incidence of arrhythmias in post-myocardial infarction patients.

Ongoing Studies on the Prognostic Value of Loop Recorders ILRs have been used in the evaluation of unexplained recurrent syncope in patients with structural heart disease, showing a higher prevalence of arrhythmic causes in this group.46,47 The benefit of ILR-guided therapy in patients at high risk of sudden cardiac death, e.g. those with a reduced left ventricular ejection fraction, should be evaluated in a large clinical trial randomising patients to receive an ILR or no ILR. Data from the US Ventricular Tachyarrhythmia Detection by Implantable Loop Recording in Patients with Heart Failure and Preserved Ejection Fraction (VIP-HF) prospective observational study (NCT01989299) will extend our knowledge on the burden of arrhythmias amenable to ICD treatment in patients with structural heart disease and normal or near-normal ejection fraction. Another on-going study, the Identifying High Risk Patients Post Myocardial Infarction with Reduced Left Ventricular Function Using External Loop Recorders (INSPIRE-ELR) trial (NCT01995552) has been designed to describe the incidence of any post-myocardial infarction arrhythmia, whether it requires a specific therapy or not. The main difference with CARISMA is that INSPIRE-ELR uses an ELR (NUVANT MCT system, Corventis Inc) instead of an ILR. ILRs could be used in diagnosing or excluding arrhythmias in patients with inherited or acquired cardiomyopathies (Brugada syndrome, long or short QT syndrome, hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, amyloid cardiomyopathy, etc.) and recurrent syncope or palpitations that remain unexplained despite extensive in-hospital evaluation.2 Data on ILR use in these rare diseases are limited and mainly retrospective48–50 and the safety of an ILR approach

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for distinguishing benign causes of syncope and palpitations from lifethreatening arrhythmias requiring an ICD or a pacemaker should be evaluated in clinical trials. In the Cardiac Arrhythmias in Epilepsy (CARELINK) study (NCT01946776), an ILR will be implanted in patients with difficult-to-treat epilepsy who are at increased risk of sudden unexpected death in epilepsy. The aim of the study is the description of the 2-year incidence and prevalence of clinically relevant arrhythmias, especially those that are seizure-related. Collected data will possibly clarify the pathogenic mechanisms of sudden unexpected death in epilepsy and suggest new prevention strategies.

Holter-derived Parameters as Predictors of Sudden Cardiac Death Continuous ECG recordings may be used to analyse the autonomic control of the heart, which may be expressed by heart rate variability and heart rate turbulence.51,52 Heart rate variability is determined from the periodic variations in R-R intervals, which are driven by the sympathetic and parasympathetic modulatory activities, while heart rate turbulence is determined by analysing the variations in R-R intervals that follow premature ventricular contractions.51,52 Imbalanced autonomic control of the heart may trigger a sudden cardiac death.52 Other measures like QRS duration, QT dispersion and the changes in beat-to-beat T-wave amplitude and duration (T-wave alternans) indicate anomalies in intra-myocardial impulse propagation or in ventricular repolarisation; both alterations may act as substrates for lethal arrhythmias.52 In the CARISMA study, Holter monitoring was performed 1 and 6 weeks after an acute myocardial infarction to test several parameters as predictors of the primary endpoint of fatal or near-fatal arrhythmia that is potentially treatable by an ICD.45 Among left ventricular ejection fraction, heart rate variability and turbulence, signal-averaged ECG, QRS duration and QT dispersion, maximum work load and heart rate on exercise, number of ventricular premature beats and nonsustained VT, T-wave alternans and programmed electrical stimulation, only heart rate variability (in particular a reduced very-low-frequency component <5.7 ms2) and induction of sustained monomorphic VT with programmed electrical stimulation effectively predicted the primary endpoint. The measure of heart rate variability could be a non-invasive marker of cardiac autonomic dysfunction, but its clinical use is limited by poor standardisation of methods.52

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Table 2: Technical Characteristics of the Reveal XT and Newer-generation Reveal LINQ Implantable Loop Recorders. The Reveal LINQ is Smaller and More Suitable for Paediatric Patients Characteristics

Reveal LINQ

Reveal XT

Dimensions (mm)

44.8 × 7.2 × 4.0

62.0 × 19.0 × 8.0

Weight (g)

2.5

Volume (mL)

1.2

Duration (years)

Implantation method

Injection (minimally invasive skin incision

Subcutaneous pocket

and insertion) MRI compatibility

1.5 and 3 T

Scan time limits (minutes)

No limits

Wireless

Yes

Algorithm for R-wave sensing

Dynamic sensing threshold

AF algorithm based also on P wave

Yes

Conditions detected

Asystole, bradycardia, VT, VF, AT, AF

Automatic activation

Yes

Patient-activated

Yes

Total ECG storage (minutes)

59 (27 automatic + 2 AF + 30 manual activation)

49.5

Total ECG storage upon patient activation

22.5

14 pre- + 1 post-activation

GSM monitor

Yes (at home)

Remote transmission of data

Complete

Possibility of programming alarms

Yes

(minutes) Maximal length of registration per symptomatic episode (minutes)

AF: atrial fibrillation; AT: atrial tachycardia; MRI: magnetic resonance imaging; VF: ventricular fibrillation; VT: ventricular tachycardia.

Loop Recorders in Children The utility of ILRs has been demonstrated in several series of paediatric patients, with the majority of cases of recurrent unexplained syncope and palpitations receiving a diagnosis (between 50 and 70 %).53–59 Most frequently complaints are associated with normal sinus rhythm or neurally mediated sinus bradycardia, especially when there is no history of congenital or acquired heart disease.58–59 These findings provide reassurance of the benign nature of some symptoms. The patient, his/her family or bystanders should activate the device every time symptoms occur, because sinus rhythm is not automatically recorded. In cases where a clinically significant or lifethreatening arrhythmia is diagnosed with the ILR, a specific therapy is generally required, such as the implantation of an ICD, a pacemaker, transcatheter ablation or drug therapy.58,59 ILRs have been effectively implanted in children under 1 year of age53,54 and may have a higher diagnostic yield than ELRs, especially in younger children, as they do not have any external wearable part and do not require a strict patient collaboration. The development of new miniaturised ILRs, such as the Reveal LINQ, may increase the use of ILRs in paediatric patients. Table 2 summarises the characteristics of the Reveal LINQ as compared with those of the previous model, the Reveal XT. Patient-activated event recorders (non-looping) are an alternative to ILRs in children who can receive a training to perform self-

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monitoring when they have symptoms. Park and colleagues reported a high diagnostic yield with the Omron HeartScan 801 (Omron Corporation, Kyoto, Japan) event recorder, an external device that registers a single-channel ECG after it is manually activated and put on the chest.60 Of 30 patients with paroxysmal palpitations (aged 4–16 years) a clinically-significant arrhythmia could be excluded in 26 patients, who had sinus tachycardia during symptoms. Four patients received a diagnosis of supraventricular tachycardia and they were successfully ablated.

Discussion Many devices are available that allow for monitoring of heart rhythm and rate in patients with suspected or known arrhythmias (Table 3). Loop recorders and MCOT are designed for long-term monitoring of cardiac rhythm and they can provide a diagnosis in silent AF patients even when traditional Holter monitoring has failed, thus guiding therapy in patients with cryptogenic stroke. 5,22,61 The prognostic utility of ILRs in patients at risk of arrhythmic death should be evaluated in large studies such as CARISMA, in the hope that in future ILR findings will help the clinician in deciding when an ICD or a pacemaker is appropriate. Remote transmission of ECG with loop recorders, MCOT, pacemakers and ICDs may facilitate the follow-up of patients, possibly reducing the economic burden on the healthcare system.1 Devices with even more sensitive algorithms for automatic detection of arrhythmias are under

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Diagnostic Electrophysiology & Ablation Table 3: Main Characteristics of Different Cardiac Monitoring Devices Holter monitoring

Post-event recorders

External loop recorders (ELRs)/

Implantable loop recorders

mobile cardiac output telemetry Advantages

- Low cost; continuous

- Duration of monitoring up to

monitoring

1 month - The device does not need to be worn 24 hours - Remote monitoring possible

- The same as ELRs

- Automatic detection of

- Duration of monitoring up to

asymptomatic arrhythmias, ECG recording before and after

3 years - No need for patient collaboration

arrhythmia onset - Possibility of real-time continuous

- Remote monitoring possible

monitoring with MCOT - Duration of monitoring up to 1 month - Remote monitoring possible Limits

- Intermediate cost

- High cost

(generally 24–48 hours; no

- Non-continuous monitoring

- ECG storage limits for ELRs

-M inimally invasive surgery for

more than 2 weeks)

- Does not register

- Compliant patients

- Short duration of monitoring

- Compliant patients

implantation

asymptomatic arrhythmias

- Non-continuous monitoring

and heart rhythm during

- ECG storage limits

disabling symptoms that prevent patients activating the device - ECG storage limits - Compliant patients Indications

- Initial evaluation of patients

- Infrequent palpitations (≤1

- Palpitations or syncope with ≤1

with syncope, palpitations

month) not accompanied

month inter-symptom intervals

and frequently recurring

by disabling symptoms

- Patients with cryptogenic stroke

in patients with suspected arrhythmias and >1 month intersymptom intervals

to underline AF

symptoms (≤1 week)

- Infrequent syncope or palpitations

- Patients with cryptogenic stroke

- 2-week Holter monitoring in cryptogenic stroke to

and high suspicion of AF despite

underline AF

negative evaluation with 2-week Holter monitoring or ELR/mobile

- 24–48-hour Holter for

cardiac output telemetry

monitoring the efficacy of

- Monitoring of patients who have

rate control therapy in AF

undergone transcatheter ablation

patients

for AF AF: atrial fibrillation. Modified from Giada et al.,

20123

development. 2 In future, loop recorders may provide real-time indications on haemodynamic parameters, such as blood pressure and intra-thoracic fluid status. 2 Another possible direction of research is the development of ILRs sensing ST segment changes, in order to monitor therapy in patients with chronic ischaemic heart disease. 2 This review focuses on loop recorders. Despite recommended use, only a minority of patients receive an ILR as diagnostic tool.62 We hope that better knowledge of the advantages, limits and indications of cardiac monitors will prompt better adherence to current guidelines. ■

Zimetbaum P, Goldman A. Ambulatory arrhythmia monitoring: choosing the right device. Circulation 2010;122:1629–36. DOI: 10.1161/CIRCULATIONAHA.109.925610; PMID: 20956237 Brignole M, Vardas P, Hoffmann E, et al. Indications for the use of diagnostic implantable and external ECG loop recorders. Europace 2009;11:671–87. DOI: 10.1093/ europace/eup097; PMID: 19401342 Giada F, Bertaglia E, Reimers B, et al. Current and emerging indications for implantable cardiac monitors. Pacing Clin Electrophysiol 2012;35:1169–78. DOI: 10.1111/j.15408159.2012.03411.x; PMID: 22530875 Bloch Thomsen PE, Jons C, Raatikainen MJ, et al. Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction Study Group. Long-term recording of cardiac arrhythmias with an implantable cardiac monitor in patients with reduced ejection fraction after acute

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Clinical Perspective • This review summarises the indications, advantages and limits of different cardiac monitoring systems: Holter monitors, loop recorders, post-event recorders and mobile cardiac outpatient telemetry (MCOT). • Loop recorders are useful diagnostic tools to underline paroxysmal atrial fibrillation in cryptogenic stroke. In future, these devices may also play a role in establishing a prognosis and guiding therapy in patients at high risk of sudden death (e.g. in patients with cardiomyopathies or heart failure). • Loop recorders and event recorders are useful diagnostic tools in confirming or excluding arrhythmias even in children.

myocardial infarction: The Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) Study. Circulation 2010;121:1258–64. DOI: 10.1161/ CIRCULATIONAHA.109.902148; PMID: 20837897 Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med 2014;370:2467–77. DOI: 10.1056/NEJMoa1311376; PMID: 24963566 Pachulski R, Cockrell J, Solomon H, et al. Implant evaluation of an insertable cardiac monitor outside the electrophysiology lab setting. PLoS ONE 2013;8:e71544. DOI: 10.1371/journal.pone.0071544; PMID: 23977071 Locati ET, Vecchi AM, Vargiu AS, et al. Role of extended external loop recorders for the diagnosis of unexplained syncope, pre-syncope, and sustained palpitations. Europace 2014;16:914–22. DOI: 10.1093/europace/eut337; PMID: 24158255

Bass EB, Curtiss EI, Arena VC, et al. The duration of Holter monitoring in patients with syncope. Is 24 hours enough? Arch Int Med 1990;150:1073–78. PMID: 2331188 9. Gibson TC, Heitzman MR. Diagnostic efficacy of 24-hour electrocardiographic monitoring for syncope. Am J Cardiol 1984;53:1013–17. PMID: 6702676 10. Krahn AD, Renner SM, Klein GJ, et al. The utility of Holter monitoring compared to loop recorders in the evaluation of syncope and presyncope. Ann Noninvasive Electrocardiol 2000;5:284–9. DOI: 10.1111/j.1542-474X.2000.tb00400.x 11. Rockx MA, Hoch JS, Klein GL, et al. Is ambulatory monitoring for “community-acquired” syncope economically attractive? A cost-effectiveness analysis of a randomized trial of external loop recorders versus Holter monitoring. Am Heart J 2005;150:e1.1065–75. PMID: 16290999 12. Rothman SA, Laughlin JC, Seltzer J, et al. The diagnosis of cardiac arrhythmias: a prospective multi-center randomized

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13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

study comparing mobile cardiac outpatient telemetry versus standard loop event monitoring. J Cardiovasc Electrophysiol 2007;18:241–7. PMID: 17318994 Edvardsson N, Frykman V, van Mechelen R, et al. Use of an implantable loop recorder to increase the diagnostic yield in unexplained syncope: results from the PICTURE registry. Europace 2011;13:262–9. DOI: 10.1093/europace/euq418; PMID: 21097478 Moya A, Brignole M, Menozzi C, et al; International Study on Syncope of Uncertain Etiology (ISSUE) Investigators. Mechanism of syncope in patients with isolated syncope and in patients with tilt-positive syncope. Circulation 2001;104:1261–7. PMID: 11551877 Brignole M, Sutton R, Menozzi C, et al. International Study on Syncope of Uncertain Etiology 2 (ISSUE 2) Group. Early application of an implantable loop recorder allows effective specific therapy in patients with recurrent suspected neurally mediated syncope. Eur Heart J 2006;27:1085–92. PMID: 16569653 Brignole M, Menozzi C, Moya A, et al. International Study on Syncope of Uncertain Etiology 3 (ISSUE 3) Group. Pacemaker therapy in patients with neurally-mediated syncope and documented asystole. Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a Randomized trial. Circulation 2012;125:2566–71. DOI: 10.1161/ CIRCULATIONAHA.111.082313; PMID: 22565936 Farwell DJ, Freemantle N, Sulke N. The clinical impact of implantable loop recorders in patients with syncope. Eur Heart J 2006;27:351–6. PMID: 16314338 Lombardi F, Calosso E, Mascioli G, et al. Utility of implantable loop recorder (Reveal Plus) in the diagnosis of unexplained syncope. Europace 2005;7:19–24. PMID: 15670962 Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol 2014;6:213–20. DOI: 10.2147/CLEP.S47385; PMID: 24966695 Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369–429. DOI: 10.1093/eurheartj/ehq278; PMID: 20802247 January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/ HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation 2014;130:2071–104. DOI: 10.1161/ CIR.0000000000000040; PMID: 24682348 Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370:2478–86. DOI: 10.1056/NEJMoa1313600; PMID: 24963567 Grau AJ, Weimar C, Buggle F, et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke 2001;32:2559–66. PMID: 11692017 Kolominsky-Rabas PL, Weber M, Gefeller O, et al. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke 2001;32:2735–40. PMID: 11739965 Schulz UG, Rothwell PM. Differences in vascular risk factors between etiological subtypes of ischemic stroke: importance of population-based studies. Stroke 2003;34:2050–9. PMID: 12829866 Amarenco P, Bogousslavsky J, Caplan LR, et al. New approach to stroke subtyping: the A-S-C-O (phenotypic) classification of stroke. Cerebrovasc Dis 2009;27:502–8. DOI: 10.1159/000210433; PMID: 19342826 Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. Stroke 1993;24:35–41. PMID: 7678184 Ritter MA, Kochhauser S, Duning T, et al. Occult atrial fibrillation in cryptogenic stroke: detection by 7-day electrocardiogram versus implantable cardiac monitors. Stroke 2013;44:1449–52. DOI: 10.1161/ STROKEAHA.111.676189; PMID: 23449264 Healey JS, Connolly SJ. Atrial fibrillation: hypertension as a

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Myocardial Infarction study group. Prediction of fatal or nearfatal cardiac arrhythmia events in patients with depressed left ventricular function after an acute myocardial infarction. Eur Heart J 2009;30:689–98. DOI: 10.1093/eurheartj/ehn537; PMID: 19155249 Solano A, Menozzi C, Maggi R, et al. Incidence, diagnostic yield and safety of the implantable loop-recorder to detect the mechanism of syncope in patients with and without structural heart disease. Eur Heart J 2004;25:1116–9. PMID: 15231369 Mason PK, Wood MA, Reese DB, et al. Usefulness of implantable loop recorders in office-based practice for evaluation of syncope in patients with and without structural heart disease. Am J Cardiol 2003;92:1127–9. PMID: 14583373 Stöllberger C, Keller H, Steger C, Finsterer J. Implantable loop-recorders in myopathic and non-myopathic patients with left ventricular hypertrabeculation/noncompaction. Int J Cardiol 2013;163:146–8. DOI: 10.1016/j.ijcard.2011.05.082; PMID: 21652098 Sayed RH, Rogers D, Khan F, et al. A study of implanted cardiac rhythm recorders in advanced cardiac AL amyloidosis. Eur Heart J 2015;36:1098–105. DOI: 10.1093/ eurheartj/ehu506; PMID: 25549725 Kubala M, Aïssou L, Traullé S, et al. Use of implantable loop recorders in patients with Brugada syndrome and suspected risk of ventricular arrhythmia. Europace 2011;14:898–902. DOI: 10.1093/europace/eur319; PMID: 21979995 Stein PK, Bosner MS, Kleiger RE, Conger BM. Heart rate variability: A measure of cardiac autonomic tone. Am Heart J 1994;127:1376–81. PMID: 8172068 Gimeno-Blanes FJ, Blanco-Velasco M, BarqueroPérez O, et al. Sudden cardiac risk stratification with electrocardiographic indices – a review on computational processing, technology transfer, and scientific evidence. Front Physiol 2016;7:82. DOI: 10.3389/fphys.2016.00082; PMID: 27014083 Bloemers BL, Sreeram N. Implantable loop recorders in pediatric practice. J Electrocardiol 2002;35:131–5. PMID: 12539110 Rossano J, Bloemers B, Sreeram N, et al. Efficacy of implantable loop recorders in establishing symptom-rhythm correlation in young patients with syncope and palpitations. Pediatrics 2003;112:e228–33. PMID: 12949317 Kothari DS, Riddell F, Smith W, et al. Digital implantable loop recorders in the investigation of syncope in children: Benefits and limitations. Heart Rhythm 2006;3:1306–12. PMID: 17074636 Gass M, Apitz C, Salehi-Gilani S, et al. Use of the implantable loop recorder in children and adolescents. Cardiol Young 2006;16:572–8. PMID: 17116271 Sanatani S, Peirone A, Chiu C, et al. Use of an implantable loop recorder in the evaluation of children with congenital heart disease. Am Heart J 2002;143:366–72. PMID: 11835044 Frangini PA, Cecchin F, Jordao L, et al. How revealing are insertable loop recorders in pediatrics? Pacing Clin Electrophysiol 2008;31:338–43. DOI: 10.1111/j.15408159.2008.00995.x; PMID: 18307630 Al Dhahri KN, Potts JE, Chiu CC, et al. Are implantable loop recorders useful in detecting arrhythmias in children with unexplained syncope? Pacing Clin Electrophysiol 2009;32:1422–7. DOI: 10.1111/j.1540-8159.2009.02486.x; PMID: 19694968 Park MH, de Asmundis C, Chierchia GB, et al. First experience of monitoring with cardiac event recorder electrocardiography Omron system in childhood population for sporadic, potentially arrhythmia-related symptoms. Europace 2011;13:1335–9. DOI: 10.1093/europace/eur159; PMID: 21616943 Tayal AH, Tian M, Kelly KM, et al. Atrial fibrillation detected by mobile cardiac outpatient telemetry in cryptogenic TIA or stroke. Neurology 2008;71:1696–701. DOI: 10.1212/01.wnl. 0000325059.86313.31; PMID: 18815386 Sciaraffia E, Chen J, Hocini M, et al. Use of event recorders and loop recorders in clinical practice: results of the European Heart Rhythm Association Survey. Europace 2014;16:1384–6. DOI: 10.1093/europace/euu222; PMID: 25172620

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Reduction of Fluoroscopy Time and Radiation Dosage During Catheter Ablation for Atrial Fibrillation Kenichiro Yamagata, Bashar Aldhoon, Josef Kautzner Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic

Abstract Radiofrequency catheter ablation has become the treatment of choice for atrial fibrillation (AF) that does not respond to antiarrhythmic drug therapy. During the procedure, fluoroscopy imaging is still considered essential to visualise catheters in real-time. However, radiation is often ignored by physicians since it is invisible and the long-term risks are underestimated. In this respect, it must be emphasised that radiation exposure has various potentially harmful effects, such as acute skin injury, malignancies and genetic disease, both to patients and physicians. For this reason, every electrophysiologist should be aware of the problem and should learn how to decrease radiation exposure by both changing the setting of the system and using complementary imaging technologies. In this review, we aim to discuss the basics of X-ray exposure and suggest practical instructions for how to reduce radiation dosage during AF ablation procedures.

Keywords Atrial fibrillation, fluoroscopy, imaging technology, radiation exposure, radiofrequency ablation Disclosure: Kenichiro Yamagata is supported by the Biotronik International Fellows Program 2015 (JHRS-EHRA); Josef Kautzner is a scientific advisor and speaker for Biosense Webster, Boston Scientific/EP Technologies, Medtronic, Sorin Group and St. Jude Medical, and a speaker for Biotronik GmbH. Bashar Aldhoon has no conflicts of interest to declare. Received: 3 February 2016 Accepted: 19 May 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(2):144–9 DOI: 10.15420/AER.2016.16.2 Access at: www.AERjournal.com Correspondence: Kenichiro Yamagata, Department of Cardiology, Institute for Clinical and Experimental Medicine (IKEM), Vídenˇská 1958/9, Prague 4, 140 21, Czech Republic. E: look.cardiology@gmail.com

The number of catheter ablations for atrial fibrillation (AF) treatment has gradually increased over the last 15 years since the first report on the importance of pulmonary vein (PV) foci for triggering AF.1 Catheter ablation for AF is a complex procedure with multiple steps, such as transseptal puncture, mapping of the left atrium and PVs and extensive linear ablation around PV ostia. Not surprisingly, this procedure has been associated with higher radiation doses than conventional ablation procedures.2–4 Over the last two decades, catheter ablation has evolved from an almost experimental and uncertain procedure to a routine and well-established practice worldwide. However, literature data reveal significant differences among individual centres regarding the use of fluoroscopy time (FT) and radiation dosage per procedure. From the patient’s point of view, the average 1 hour of FT during AF ablation is estimated to increase the risk of a fatal cancer by up to 0.1 %.4 In addition, patients with AF may require repeat procedures that contribute to a high amount of total lifetime radiation exposure.5,6 From the physician’s point of view, the radiation exposure dose may represent only 1–2 % of the patient’s dose. Nevertheless, a high volume of ablations per operator is associated with a higher probability of receiving a substantial radiation dose.7 Radiation exposure has been associated with malignancies, cataracts, thyroid dysfunction and other diseases.8–19 Hence, every electrophysiologist should know how to lower radiation exposure. Here we review the basics of X-ray and discuss the health hazards induced by radiation exposure. We also focus on the current strategies

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being used to decrease X-ray dosage, emphasising the role of nonfluoroscopic catheter-guiding technologies.

X-ray Physics and the Principle of Imaging The physics of X-ray imaging is based on the interaction of X-rays with matter. X-rays are composed of both electromagnetic waves and particles (photons) that are powerful enough to penetrate deeply into and through matter. In the human body, this interaction results in a shadow image, where X-rays are emitted from a point source and absorbed differently in various tissues. This absorption effect is called the radiation dose, which is inherent to X-ray imaging. The radiation dose is defined as the energy released in reference matter. For the entrance dose before the skin, the reference material is air and, therefore, measurement of radiation energy absorbed in air volume is called air kerma (kinetic energy released per unit of mass), measured in J/kg or Gray (Gy). Although energy released in matter is small, it has biological effects. Sievert (Sv) is the unit used to evaluate the impact of biological ionising radiation on biological tissues. In the case of X-rays and biological tissue, 1 Gy is equal to 1 Sv.20 X-rays interact with human tissues in different ways. Some X-rays deviate with or without changes in energy, a process known as scatter. Other X-rays penetrate the tissue or are completely absorbed. Scatter has two unfavourable consequences. First, it blurs the shadow image originating from one point source. Second, it exits the body of the patient in different directions and delivers a radiation dose to other individuals in the near vicinity.21

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Equipment that produces X-ray images consists of an X-ray tube, an image detector with an anti-scatter device on the other side and a table between them supporting the patient. An X-ray tube emits X-ray photons with a continuum of different energies. In principle, the highest energy (in keV) corresponds to the highest voltage applied to the X-ray tube (kVp).

Radiation Exposure Induces Health Hazards Biological effects of radiation exposure can be viewed as a function of time. Part of the X-ray beam energy is absorbed in the tissue within milliseconds. This induces the release of energy inside tissues, causing biological effects within seconds. These effects comprise two mechanisms. One is direct cellular damage, represented by DNA breakage, especially in dividing or immature cells. The other is indirect, due to hydrolysis and the formation of free radicals, ultimately leading to cell apoptosis. The DNA repair system can correct some of these effects, although high or repeated exposure leads to irreparable changes such as DNA double-strand breaks. Two types of biological effect can be differentiated with variable clinical outcomes. Deterministic effects occur once the radiation dose exceeds a specific threshold, and their severity becomes linear to the dose.22 Significantly, although there is a threshold, the actual value may change according to previous exposure or the patient’s health condition (including use of prescribed drugs) and this should be taken into consideration.23–26 The skin and eyes are the best known organs that are vulnerable to X-ray with deterministic effects (erythema, skin burn, hair loss, necrosis and cataract), with a suggested threshold of 2 Gy and 500 μGy, respectively.22,27–32 The International Commission on Radiological Protection has outlined the correlation between radiation dosage and its effect on each organ (see Table 1).32,33 Regarding the onset of clinical manifestations, effects can be prompt (<2 weeks after the procedure), early (2–8 weeks), mid-term (6–52 weeks) and long-term (>52 weeks). Obviously, there is significant individual variability in manifestations and their timing. In one study, the lifetime risk for fatal malignancies after 1 hour of fluoroscopy for an ablation procedure was estimated at 0.07 % and 0.1 % for male and female patients, respectively.4 Organs at highest risk were the lungs, stomach, active bone marrow and, in female patients, breast tissue. As this risk calculation was performed at a setting of 7.5 frames per second, no collimation use and the left anterior oblique (LAO) and right anterior oblique (RAO) in their preference, using the techniques mentioned later may reduce the risk to an extremely low level. Stochastic effects are not associated with a particular threshold and cannot be predicted. Therefore, these effects are probabilistic in nature and their occurrence is not threshold dependent. Their onset increases proportionally according to the intensity of exposure, but not in terms of severity. Malignancies and genetic diseases are prone to occur, but the severity of the diseases cannot be determined by dosage.22 A recent report showed a higher incidence of glioblastoma multiforme at the left hemisphere among interventionists.34 As this study was only a voluntary reported case series, the true incidence of the tumour among physicians is unknown. Nevertheless, it is of interest that glioblastoma is related to radiation exposure and that the incidence was higher in the hemisphere facing the X-ray tube. Another survey reported that breast cancer that is also sensitive to radiation exposure was more frequent in the left side among female cardiologists.28

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Table 1: Clinical Effects of Radiation Exposure to the Skin and Eye Lens Organ Skin

Effects Early transient

Threshold dose (Gy) 2

Time of onset 2–24 hours

~1.5 weeks

~3 weeks

erythema

Main erythema

reaction

Temporary

epilation

Permanent

epilation Dermal >12

>52 weeks

necrosis Eye

Lens opacity

>1-2

>5 years

(detectable) Lens/cataract >5

>5 years

(debilitating) Source: modified from International Commission on Radiological Protection.32

Dose Metrics and Measurements Several parameters are used to express and monitor patient dosage, of which the most important are FT, dose area product (DAP) and cumulative air kerma at the reference point. FT is displayed on all interventional fluoroscopy systems. FT accounts for all of the time spent using fluoroscopy and thus can be viewed as a quality assurance measure for the physician and a definite procedure. However, it is well known that FT poorly correlates with other dose indicators.35,36 In addition, it can be calculated differently depending on the manufacturer (either total time with pedal pressed or just a sum of the X-ray pulses). DAP, or the kerma area product, is defined as the product of the air kerma (the energy extracted from an X-ray beam per unit mass of air) and the area of the cross-section of the X-ray beam. It is a surrogate measurement for the entire amount of energy delivered to the patient by the beam, measured in μGy·m2.37 Table 2 shows conversion rates for commonly used units.

How to Decrease Radiation Exposure There is a difference in the origin of radiation exposure between patients and physicians. For patients, the primary beam is the source of radiation exposure. On the contrary, as the X-ray passes forward straight from the X-ray tube to the detector, the main source of physicians’ exposure is the X-ray emitted from the patient via photoelectric effect and Compton scattering. The latter Compton scattering gives the largest radiation dose to the physician and is a phenomenon of X-rays interacting with atoms, thus scattering radiation in various angles.

Reduction of X-ray Dose and Time Optimising the Fluoroscopy System for Electrophysiology Procedures Many physicians may believe that there is no need to modify system settings. As fluoroscopy systems are manufactured for various percutaneous procedures, they can be adjusted, particularly for electrophysiology (EP) procedures. One big difference between the settings used by electrophysiologists and other interventionists is that electrophysiologists do not need precise images during the procedure. They can navigate within the heart to a great extent using

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Diagnostic Electrophysiology & Ablation Table 2: Unit Conversion for Dose Area Product Unit μGy·cm2

How to convert to μGy∙m Divide by 10

cGy·cm2

Equal to μGy·m2

dGy·cm2

Multiply by 10

Gy·cm2

Multiply by 100

electrograms and/or non-fluoroscopy mapping or imaging systems. One major difference is the frame rate for fluoroscopy, which is usually set to 15 frames per second in the angioplasty laboratory compared with 2 frames per second in our laboratory. Soft X-rays are usually absorbed or scattered by photoelectric effect and have the least impact on image quality. By adding a copper or aluminium filter, we can omit these X-rays resulting in a 30–50 % reduction of the radiation dose.38,39 Many systems automatically add or remove the filter according to image brightness by automatic dose reduction control (ADRC). New systems are obligatorily equipped with these filters. However, in the case of an old fluoroscopy system it is worth asking the provider for filter settings. A secondary radiation grid placed in front of the detector is essential for sharpening the image by omitting the scattered X-ray. The direct effect of solely removing this grid in the EP field was studied in a phantom model and resulted in a reduction of roughly 50 % of the radiation dose, irrespective of the fluoroscopy angle.40 This study also analysed the effect in clinical cases, where image quality seemed to be acceptable as only 5 out of 417 cases required the grid to be replaced during the procedure. Especially in obese patients in whom X-ray is more scattered, DAP with and without the grid increases the radiation dose twofold.41 There are a few more changeable settings from the software side. Tube voltage, pulse duration and radiation limitation by ADRC can be changed in some systems. Although changing these settings invariably results in lower image quality, electrophysiologists do not need such high quality, and lower resolution images are usually acceptable once they get used to the image.42,43 The number of factors that can be modified in the individual system varies and should be clarified with the vendor.

Compliance With General Principles of Radiation Protection Collimation reduces image area and decreases the DAP linearly according to the narrowed field. An effort to maximise collimation can decrease the radiation dose by up to 12 %.44 However, many electrophysiologists do not use collimation at all during procedures. Asymmetric collimation can achieve another 60–80 % reduction compared with normal collimation, although it has not yet been commercialised.45 In contrast, magnification seems to show the same area as collimation, but increases the radiation dose by ADRC and increases DAP. Magnification should generally be avoided in EP procedures. Projection angle is another important parameter as angling to low LAO (50–60°) compared with shallow RAO (30°) positions results in a twofold increase in X-ray dose received by the patient.4,46–48 This difference is due to the fact that in LAO, the X-ray passes through the liver, vertebral column and mediastinum, which require a higher dose of X-rays to permeate, whereas in RAO the X-ray mainly passes through the lung containing air allowing the X-ray to permeate easily. To the physician, LAO causes more scattered radiation as the X-ray tube approximates

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the physician increasing the exposure dose up to sixfold compared with RAO.46 Based on our experience, we believe that the use of lowoblique projections during catheter ablation of AF is rarely required. Both raising the patient’s table by 10 cm and positioning the detector 10 cm nearer to the patient result in approximately 15 % reduction of the radiation dose.11,49 The frame rate may also be changed. As radiation exposure increases per frame in a linear way, it should be set as low as acceptable. The most ‘aggressive’ setting uses an ECG-triggered pulse, which can potentially decrease the frame rate below 1 per second, depending on the heart rate. In our experience, 2 frames per second is a reasonable compromise for use during EP procedures.

Reduction of X-ray Usage Time Even if attempts are made to decrease the X-ray dose/time, it can be counterbalanced by longer fluoroscopy usage. To avoid this, the use of unnecessary fluoroscopy should be avoided. There are other technologies that can reduce fluoroscopy time and the radiation dose during complex catheter ablations, such as ablation for AF. Some employ a 3D electroanatomic mapping system (e.g. the CARTO® system [Biosense Webster] using magnetic fields or the EnSite™ NavX™ system [St. Jude Medical] using transthoracic currents).50,51 These systems can project the catheter tip in real-time on a virtual 3D image, limiting the need for fluoroscopy.52–55 In the CARTO system, when real-time catheter positioning is achieved by updating CARTO-XP® to the CARTO® 3 version, it results in a significant reduction of FT, which may contribute to a reduction of the radiation dose.56,57 One limitation of 3D mapping systems is that they only provide virtual images of the heart, which may differ from real-time anatomy.58,59 To compensate for this and to visualise catheter shaft or sheath positions, fluoroscopy still needs to be used intermittently. Another useful strategy for reducing radiation during complex catheter ablation procedures is intracardiac echocardiography (ICE). 60–62 ICE provides a real-time image of the heart, which is different from 3D mapping systems.63 CARTO 3 and ICE-derived CARTOSOUND® (Biosense Webster) can be combined to compensate for the limitation of the solo 3D mapping system by rapidly updating the anatomical map during the procedure.64 There are preliminary studies that have combined 3D mapping systems and ICE, leading to the use of zero fluoroscopy ablation procedures.65,66 The largest limitation of ICE is the high cost of the probe, which must be discussed in terms of the balance between the above merits in each facility. Contact force-sensing catheters also have the advantage of reducing radiation time. When they are integrated with the 3D mapping system, electrophysiologists can control catheter-tissue contact without confirming by movement of the catheter tip on fluoroscopy.67,68 Recent advances in technology, such as CARTOUNIVU™ (Biosense Webster) and MediGuide™ (St. Jude Medical), have increased the potential for decreasing radiation exposure.69–71

Changing Settings in Real-world Practice One recent report used a detector entrance dose setting of 8 nGy for fluoroscopy and compared it with 23 nGy when ablating complex left atrial arrhythmias.72 They achieved a great reduction in DAP from

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878 μGy·m2 to 200 μGy·m2 in their study, which is lower than previous reports ranging from 789 to11,199 μGy·m2.69–73

Figure 1: Image of an ICE and CARTO ® 3D Map During Ablation

In our institution, we use 23 nGy for the detector entrance dose. We comply with collimation and avoid oblique views as much as possible in combination with 3D mapping systems and ICE (see Figure 1). Due to these efforts, our average DAP for catheter ablation of AF was 252 μGy·m2 among 113 patients.74

One can argue that these adjustments may reduce radiation exposure, but can also inversely increase complications due to image deterioration. However, this has not been our experience while using ICE imaging. In a large series of cases of catheter ablation for AF from our centre, the rate of potentially life-threatening complications was <1 %.75 However, we recommend making step-by-step changes and getting accustomed to each setting before changing all of the settings at once.

Remote Navigation System for Preventing Radiation Exposure to Physicians Remote navigation systems can be used to reduce radiation exposure, mainly for the physician. Two types of remote navigation systems used to manipulate catheters with a magnetic field or a steerable sheath are currently available. Clinical outcomes are comparable to manual manipulation, even though the procedure time is longer using remote navigation systems.76 There are still limited data in this field, but FT and DAP are consistently lower using remote systems.77–85 Intuitive navigation implemented in remote navigation suites appears to be one possible explanation. Remote navigation seems to be easier than manual manipulation as there is less of a need for fluoroscopy. This results in the reduction of DAP for the patient. As the physician remains remote from the X-ray tube during ablation, radiation exposure is avoided.86

Magnetic Resonance Imaging-guided-based Electrophysiology Intervention Real-time magnetic resonance (MR)-based EP is another option for reducing radiation exposure, although the technique is still in the investigation phase.87,88 The speed of acquiring the image still requires more time compared with X-ray imaging. The most important concern for electrophysiologists may be the quality of intracardiac electrogram during MR usage. Besides these technical disadvantages that have to be improved, the largest advantage of this technique is not only the X-ray-free procedure, but also acquiring the intra-procedure ablation lesion formation. This technique may facilitate reaching a clear ablation endpoint as the ablation lesion can be directly visualised.

Personal Protective Equipment and Devices Effective and proper use of personal protection is obligatory for all members of the EP laboratory to minimise radiation exposure. General

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B Ablation Catheter

Lasso Catheter A: Image of the ICE of the left atrium. The ablation catheter and the lasso catheter are placed at the roof of the left superior PV and inside the left superior PV, respectively. B: Image of a CARTO 3D map of the left atrium. Posterior–anterior view of the left atrium. Catheters are placed as in Figure 1A. CARTO tags definition: red = ablated points as the PV ostium, blue = mitral annulus. ICE = intracardiac echocardiography; PV = pulmonary vein.

protection, such as lead aprons, neck collars and shielding screens, are considered obligatory.89 To avoid orthopaedic complications associated with heavy aprons, the use of separated lead aprons or lightweight aprons are recommended with an equivalent effect. A thyroid collar is especially recommended when aged <40 years as the risk of thyroid cancer is high. Other small protectors, such as leaded glasses and leaded gloves, are less effective and efforts to lower radiation exposure need to be balanced against the discomfort of wearing them.90–92 Some centres use radiation-protection units, such as radioprotection cabins (Cathpax®, Lemer Pax), which protect from almost all scattered radiation without the need to wear lead aprons during the procedure.93 Another protector is a suspended lead apron mounted on the ceiling or on a floor unit (Zero Gravity™, Biotronik)94. As these protectors are designed to avoid Compton scattering, there is almost no effect on the patient as the body is the origin of the radiation.

Conclusion Although the use of X-ray is still common during the majority of AF ablation procedures in clinical practice, it is important to realise that radiation can be harmful for both patients and physicians. By complying with the general principles of radiation protection and using new technologies, significant reduction of radiation exposure can be achieved. The principle of ‘As Low (radiation) As Reasonably Achievable (ALARA)’ should become the gold standard in any EP unit. ■

Clinical Perspective • The number of atrial fibrillation ablations is increasing. • The use of X-ray poses a relevant health risk, both to patients and physicians. • By increasing the awareness of the physician and changing the system settings, radiation dosage can be decreased.

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Anatomical Substrates and Ablation of Reentrant Atrial and Ventricular Tachycardias in Repaired Congenital Heart Disease Charlotte Brouwer, 1 Mark G Hazekamp 2 and Katja Zeppenfeld 1 1. Department of Cardiology, Leiden University Medical Centre, The Netherlands; 2. Department of Cardiothoracic Surgery, Leiden University Medical Centre, The Netherlands

Abstract Advances in surgical repair techniques for various types of congenital heart disease have improved survival into adulthood over the past decades, thus exposing these patients to a high risk of atrial and ventricular arrhythmias later in life. These arrhythmias arise from complex arrhythmogenic substrates. Substrate formation may depend on both pathological myocardial remodelling and variable anatomical boundaries, determined by the type and timing of prior corrective surgery. Accordingly, arrhythmogenic substrates after repair have changed as a result of evolving surgical techniques. Radiofrequency catheter ablation offers an important therapeutic option but remains challenging due to the variable anatomy, surgically created obstacles and the complex arrhythmogenic substrates. Recent technical developments including electroanatomical mapping and image integration for delineating the anatomy facilitate complex catheter ablation procedures. The purpose of this review is to provide an update on the changing anatomical arrhythmogenic substrates and their potential impact on catheter ablation in patients with repaired congenital heart disease and tachyarrhythmias.

Keywords Ablation, arrhythmogenic substrate, atrial tachycardia, congenital heart disease, electroanatomical mapping, tachyarrhythmias, ventricular tachycardia Disclosure: The authors have no conflicts of interest to declare. Acknowledgements: The authors thank Ron Slagter for his help in designing and preparing Figure 1. Received: 16 February 2016 Accepted: 19 May 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(2):150–60 DOI: 10.15420/AER.2016.19.2 Access at: www.AERjournal.com Correspondence: Katja Zeppenfeld, MD, PhD, Leiden University Medical Centre, Department of Cardiology, C5-P, PO Box 9600, 2300 RC Leiden, The Netherlands. E: K.Zeppenfeld@lumc.nl

The reported incidence of congenital heart disease (CHD) depends on the number of trivial lesions included, such as atrial and ventricular septal defects (ASDs and VSDs). Moderate-to-severe CHD numbers remain stable with 6 per 1,000 live births.1 Survival into adulthood has improved dramatically over the last 25 years and has been driven mainly by a decreased mortality in moderate and severe forms of CHD in childhood, including tetralogy of Fallot, truncus arteriosus, atrioventricular septal defect (AVSD), transposition of the great arteries (TGA) and univentricular hearts. For individuals born between 1990 and 1992 survival to the age of 18 was 78 % for tetralogy of Fallot, 77 % for AVSD, 71 % for TGA and 49 % for the heterogeneous group of patients with univentricular hearts.2 Improved surgical outcome during infancy increases the risk of late complications such as atrial and ventricular arrhythmias, thus contributing to morbidity and mortality later in life.3,4 Arrhythmias may be part of the underlying disease but may also be the consequence of the type of corrective surgery and the age at which it was performed (see Table 1). Areas of dense fibrosis owing to surgical incisions as well as patch material, valve annuli and veins can form regions of conduction block that create anatomical isthmuses of myocardial bundles.5,6 Interstitial fibrosis due to longstanding cyanosis, pressure and/or

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volume overload, ageing and pathological hypertrophy may provide the substrate for slow conduction within these anatomically defined isthmuses.7,8 In particular, the duration of right atrial volume overload and right ventricular pressure overload have been associated with structural remodelling.7,9 The coincidence of both of these specific features – anatomical boundaries and pathological remodelling over time – in adult patients with CHD may explain the high incidence of atrial and ventricular reentrant arrhythmias. Radiofrequency catheter ablation (RFCA) is an important therapeutic option for targeting these arrhythmias as drug refractoriness and unsuccessful antitachycardia pacing are often encountered.10,11 However, RFCA remains challenging due to the variable anatomy with occasionally difficult or limited access (occluded femoral vessels, interrupted inferior vena cava (IVC), surgically created obstacles, prostheses and baffles), the sometimes hypertrophied myocardium and a complex and highly variable arrhythmogenic substrate that is dependent on the original malformation and the type of repair that has been performed.8,12,13 The purpose of this review is to provide an update on the changing anatomical substrate found in contemporary patients with repaired CHD and its impact on catheter ablation.

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Type and Timing of Surgery and its Impact on Atrial and Ventricular Arrhythmias

Table 1: Approximate Risk for Arrhythmias in Various Congenital Heart Defects

Surgical approaches and the timing of intervention in various types of CHD have changed over the past decades and are likely to affect the incidence and the potential substrate for arrhythmias (see Figure 1).

Type of CHD

IART

ASD

VSD

The first clinical surgical closure of an ASD was performed in 1948.14 Between 1948 and 1953 many methods of surgical repair were explored until Gibbons introduced the cardiopulmonary bypass in the mid-1950s. After its introduction, surgical ASD closure with direct sutures or with the use of a pericardial patch became widely accepted as the gold standard for ASD closure.14 Nowadays, minimally invasive surgical approaches using a limited oblique incision in the right atrium are increasingly used. Over recent decades, percutaneous device closure, which was originally described by King and Mills in 1974, has become an established alternative to surgery in selected patients with suitable anatomy.15 The arrhythmia burden after repair of ASD is substantial regardless of the type of closure performed, particularly when repair is performed during adulthood.16–19 In a large retrospective cohort of 213 patients after surgical ASD closure 2.3 % of patients developed new onset atrial arrhythmias and 60 % of patients with preoperative atrial flutter or fibrillation continued to have arrhythmias post-surgery after a follow-up period of 3.8 years.16 A retrospective study of 184 patients after percutaneous device closure demonstrated new-onset arrhythmias in 3.3 % of patients 4 months after repair.19 Silversides et al. reported an annual risk of new-onset atrial arrhythmias of 1 % in 101 patients after percutaneous ASD closure.18 The first intracardiac repair of tetralogy of Fallot was performed in 1954 by Lillehei on a 10-month-old boy. Subsequent series of early interventions reported a high perioperative mortality that led to the introduction of a 'two-stage repair' with a palliative shunt followed by total repair later in childhood. Total repair included (patch) closure of the perimembranous or less frequently observed muscular VSD and relief of the infundibular or valvular right ventricular outflow tract (RVOT) obstruction. This repair was initially performed through a vertical or transverse right ventriculotomy often combined with the use of an RVOT or a large transannular patch to augment the restrictive RVOT. Right ventriculotomy and the use of a transannular patch with resulting pulmonary regurgitation and chronic volume overload often lead to right ventricle (RV) dilatation and dysfunction. Consequently, a combined transatrial–transpulmonary approach has been introduced, which is now usually performed early in life. The arrhythmia burden in repaired tetralogy of Fallot is considerable and increases markedly after the age of 45. The prevalence of AT was 20.1 % in a recent multicentre study, the majority classified as intra-atrial reentry tachycardia (IART).20 A significant number of patients had atrial fibrillation (AF), which is more likely in older patients with left ventricular dysfunction and left atrial dilatation. The vast majority of ventricular arrhythmias documented in repaired tetralogy of Fallot patients are monomorphic and fast ventricular tachyarrhythmias (VT) with a reported prevalence of 14.2 %.20 The modern approach of earlier repair using a transatrial– transpulmonary intervention is likely to have an important impact on the potential substrate and the incidence of ventricular arrhythmias. The classic Fontan procedure, which is a direct atriopulmonary connection designed in 1971 for patients with tricuspid atresia has

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MSVT

VA/SCD

+ +

CoA + residual

AVSD

Ebstein’s anomaly

TOF

+++

TGA (atrial switch)

+++

ccTGA

LVOTO ++ Fontan classic

+++

Fontan lateral tunnel

+ +

*complex D-TGA. + = low risk; ++ = medium risk; +++ = high risk; AP = accessory pathway; AF = atrial fibrillation; ASD = atrial septal defect; AVSD = atrioventricular septal defect; (cc) TGA = (congenitally corrected) transposition of the great arteries; CHD = congenital heart disease; CoA = coarctation of the aorta; IART = intra-atrial reentrant tachycardia; LVOTO = left ventricular outflow tract obstruction; MSVT = monomorphic ventricular tachycardia; SCD = sudden cardiac death; TOF = tetralogy of Fallot; VA = ventricular arrhythmia; VSD = ventricular septal defect.

led to progressive systemic venous atrium (SVA) dilatation. With the aim of improving pulmonary blood flow it has been replaced by modifications to the procedure, which have also been applied to other forms of single ventricle circulation, such as hypoplastic right and left heart syndromes as well as other univentricular hearts. One of the modifications is the lateral tunnel technique, introduced in 1988. It uses an intra-atrial patch to create a baffle to link the IVC to the superior vena cava (SVC), which is then connected to the pulmonary artery.21 The remaining morphological right and left atria serve as the pulmonary venous atrium (PVA). The extracardiac conduit-type Fontan described in 1990 consists of a direct extracardiac connection between the IVC and the right pulmonary artery using a Gore-Tex® conduit.22 The lateral tunnel has resulted in a significant decrease in late atrial tachyarrhythmias (AT) with a 15-year AT-free survival of 87 % compared with 61 % after the classic Fontan. If adjusted for the duration of follow-up the event-free survival was similar for the lateral tunnel and the extracardiac conduit Fontan in a recent paediatric cohort.23 However, considering the young population and the time dependency of an evolving arrhythmogenic substrate, a longer follow-up is required. The Fontan operation and its modifications do not require ventricular incisions or patch material. Accordingly, monomorphic VT are unlikely and ventricular arrhythmias may be mainly attributed to impaired function and pathological remodelling of the systemic ventricle. In dextro-transposition of the great arteries (D-TGA), there is a concordant atrioventricular (AV) connection in combination with ventriculoarterial discordance, with the aorta connecting to the morphological RV, and the pulmonary trunk to the morphological left ventricle (LV). It can occur in an isolated form (simple TGA) or in association with other congenital malformations (complex TGA: VSD in approximately 40 %, or less frequently in combination with pulmonary outflow tract obstruction). Senning performed the first atrial switch operation in 1959 using the atrial septum to create a baffle to redirect the blood flow from the caval veins to the LV. The RV remains the systemic ventricle. The Mustard procedure, introduced

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Diagnostic Electrophysiology & Ablation Figure 1: Schematic Overview of Prior and Modern Surgical Approaches in Various Types of Congenital Heart Disease and Resulting Anatomical Isthmuses for Tachyarrhythmias (Blue Lines) Prior Surgical Approach A

Modern Surgical Approach D

The dominant underlying mechanism is intraatrial (macro) reentrant: • •

•

1. Surgical techniques for repair of Tetralogy of Fallot. Left panel: A. transventricular approach with large transannular patch; B. Right Ventricular incision and ventricular septal defect (VSD) closure with patch; C. Four potential anatomical isthmuses for VT are indicated. Right panel: D. transatrial-transpulmonary approach with a small transannular patch and VSD closure with patch preventing isthmus 1 and 2. Two potential isthmuses for atrial tachycardia are indicated. The remaining anatomical isthmus 3 for ventricular tachyarrhythmias depends on the size of the VSD (E,F). Isthmus 4 not shown. 2. Fontan surgical techniques: A. atriopulmonary connection; B. lateral tunnel, C. extracardiac tunnel. The cavotricuspid isthmus (CTI) is indicated. 3. Surgical techniques for transposition of the great arteries. Left panel: Mustard procedure (above) showing the variable spatial relationship between the ostium of the coronary sinus and the baffle. Consecutive surgical steps of the Senning procedure (below). Ablation of the CTI (indicated) after Mustard and Senning procedures often acquires access to the both atria. Right panel: modern arterial switch operation.

in 1964, uses a baffle from pericardium or synthetic material. Both procedures predispose patients to sinus node dysfunction and late AT with an incidence of 60 % and 24 %, respectively, at 20 years postsurgery.24 Simple TGA does not require incisions of the ventricles or patch material, which have been associated with monomorphic VT. However, in complex TGA, VSD patch closure, ventricular incisions and resection of outflow tract obstruction may result in anatomical boundaries facilitating macroreentrant VT as in patients with repaired tetralogy of Fallot. Since 1975, anatomical correction with the arterial switch operation, first described by Jatene et al., has become the treatment of choice. During this procedure, the aorta and pulmonary trunk are disconnected from their arterial roots and 'switched' to connect to the correct ventricle.25 The prevalence of AT after the arterial switch remains low: in a reasonably large series o≠nly 3/65 (4.6 %) patients had a history of atrial flutter in adulthood.26 To determine whether the arterial switch operation also influences the potential substrate for monomorphic VT in complex TGA a longer follow-up is required.

Atrial Tachyarrhythmias ATs are the most common arrhythmias observed in unselected patients with CHD, with a reported prevalence of 15 %.27 The frequency is highest after Fontan palliation and after atrial switch operation, followed by ASD closure and repaired tetralogy of Fallot (see Figure 2).28 Ageing plays an important role with a lifetime risk of 50 % once a CHD patient has entered the adult population.27

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Cavotricuspid isthmus dependent flutter (CTIDF), which accounts for 40–60 % of all AT; Incisional IART using a suture line/prosthetic material as central obstacle, often involving the right lateral atriotomy (20–40 %), or, more rarely; Macro-reentrant or localised reentrant AT independent from these structures.29,30

Of importance, CTIDF and IART often coexist and are not distinguishable on surface electrocardiograms (ECGs).31 Considering the high incidence of CTIDF in patients with corrected CHD empirical cavotricuspid isthmus (CTI) ablation has been considered in noninducible patients.32 Although less frequent, non-automatic focal atrial tachycardias (FATs) do occur, accounting for 5–10 % of all AT.29,33,34 These non-automatic FATs are indistinguishable from macroreentrant by routinely applied noninvasive means. Foci are predominantly found in the SVA and may be due to microreentry or triggered activity.35 Body surface mapping is an interesting new technology, but whether it allows reliable differentiation between AT mechanisms in the presence of atrial scarring requires further investigation.

Mapping and Ablation 3D-electroanatomical mapping (EAM) to facilitate RFCA procedures has been successfully used for AT in patients with CHD.5,12,13,29,36,37 In patients with incessant or reproducibly inducible and haemodynamically tolerated AT, activation mapping can be performed to identify a focal source with a centrifugal spread of activation35 or to record the continuous sequence of activation covering the cycle length of a (macro-) reentrant AT.5 Zones of slow conduction can be identified and entrainment mapping can be used to confirm participation within the reentry circuit.5,31 Considering the complex and variable anatomy with multiple potential reentry circuits, a substrate-based approach facilitated by 3D mapping may be useful in selected patients. This method can also be applied in those who have an otherwise unmappable AT due to an inability to induce the clinically documented AT, multiple and changing circuits or haemodynamically poorly tolerated AT. The latter is more often encountered in patients with Fontan circulation or poor function of the systemic ventricle after the atrial switch operation. In particular the longer cycle length of IART may lead to 1:1 conduction and haemodynamic compromise (see Figure 3).5,38 3D voltage and activation mapping can be performed during stable sinus rhythm to identify boundaries of potential reentry circuit isthmuses. Sites with no atrial potential distinguishable from noise (generally ≤0.03 mV) and/or sites at which high output pacing (10 mA/2 ms) can be considered as dense scar or unexcitable tissue.5,39 Contact force measurement or catheter visualisation by intracardiac echocardiography (ICE) may be helpful to exclude poor contact and to identify true unexcitable scar. Delineation of unexcitable tissue may be important as far field electrograms up to 0.3 mV may mimic viable myocardium at sites with transmural fibrosis.40 Unexcitable sites can be displayed together with the caval veins, valve annuli and lines of double potentials. Double potentials may be located between the caval veins and the posterolateral SVA consistent with the crista terminalis but may also indicate atriotomy and suture lines.29,33 After

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Considering the percutaneous access difficulties, particularly of the CTI in patients after complex surgical repair such as Fontan or atrial switch procedures, intra-operative transection of the CTI during initial repair could be a reasonable and desirable consideration in the future in selected patients.

Technical Developments The use of an irrigated tip catheter has increased acute procedural success in patients with CHD.36,41 Long, steerable sheaths and real-time contact force measurement may be particularly helpful for differentiating between scar and non-contact sites in severely diseased and dilated atria after the classic Fontan. Whether this technique translates into more confluent and durable lesions and better outcome requires further studies. Image integration (multi-slice computed tomography, cardiac MR) can facilitate ablation by visualising the complex anatomy and its relation to the catheter position. Late gadolinium enhancement cardiac MR may also be performed pre-procedurally to identify a potential arrhythmic substrate by visualising regions of myocardial fibrosis.42,43 However, whether anatomical isthmuses related to VT can be visualised by current magnetic resonance imaging (MRI) technology requires further evaluation.

Figure 2: Prevalence of Supraventricular and Ventricular Tachyarrhythmias in Congenital Heart Disease, Classified According to Main Diagnosis 60 50

Prevalence (%)

delineation of all boundaries that create intervening isthmuses potentially related to AT, these isthmuses can be targeted by a linear RFCA lesion connecting the unexcitable boundaries during SR.

Supraventricular Ventricular

40 30 20 10 0

Tetralogy of fallot

TGA

Aortic Pulmonary stenosis stenosis

ASD

AVSD

Aortic Fontan coarctation

ASD = atrial septal defect; AVSD = atrioventricular septal defect; TGA = transposition of the great arteries. Data from the Dutch national CONCOR registry.22

Figure 3: Procedural Workflow for Atrial Tachycardia Ablation in a Classic Fontan Patient with a Haemodynamically Poorly Tolerated Atrial Tachycardia

ICE and its real-time integration with EAM may have additional advantages as it can facilitate real-time acquisition of the anatomy and landmark visualisation.38 ICE can also facilitate transseptal and baffle puncture and help to monitor tissue contact.13 Non-contact mapping allowing simultaneous recordings of >3000 virtual electrograms has been successfully applied to elucidate the mechanism of right AT in a small group of patients, the majority after ASD closure.44 In patients with Fontan circulation who may benefit most from rapid mapping of multiple and often poorly tolerated AT, noncontact mapping was hampered by the size of the SVA with inaccurate scar delineation and appeared an inferior method to EAM.45 A promising new technology is high-density multi-electrode contact mapping with small and narrow-spaced electrodes. This is likely to facilitate substrate mapping by fast and accurate delineation of areas of slow conduction and small re-entry circuits in briefly tolerated AT. Remote-controlled magnetic navigation (RMN) systems can potentially overcome navigation difficulties in CHD by providing improved catheter stability and manoeuvrability, reproducible catheter movement and precise delineation of cardiac anatomy.10,46 Irrigated tip RMN catheters and a fully integrated 3D electroanatomical system for superimposing EAM maps on the fluoroscopic reference images are now available.47,48 Use of RMN systems in combination with 3D electroanatomical systems has been reported to be safe and effective for ablation in patients with variable CHD complexities.10,46,48–50 Several studies suggest a significant reduction in fluoroscopy time using RMN, especially in patients with complex CHD.10,48,50 Whether RMN is superior to conventional mapping requires randomised trials that are unlikely to be available in the near future.

Endpoint of Ablation Different definitions of procedural success and ablation endpoints have been applied and follow-up data acquisition varies between groups.

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A. Induced clinical atrial tachycardia (AT) with 1:1 conduction. B. Schematic overview of classic Fontan anatomy and right lateral view of the anatomic shell of the systemic venous atrium (SVA), derived from electroanatomical mapping integrated with MSCT (left ventricle, hypoplastic right ventricle (not segmented), aortic root and coronary arteries). Unexcitable boundaries are indicated by black lines. C. Right lateral view of bipolar voltage and activation map during sinus rhythm. Voltage and activation time is colour-coded according to colour bar; grey tags indicate unexcitable tissue and blue tags indicate double potentials. Continuous conduction is shown (white arrows) through a low bipolar voltage area between two unexcitable boundaries. With the catheter placed at the site indicated by the white circle, the AT could be briefly reinduced. Entrainment at this site (not shown) confirmed participation in the re-entry circuit. D. Electroanatomical map of the SVA showing connection of the unexcitable boundaries by RF applications (red line). Red tags indicate ablation sites. E. Activation map after ablation during pacing from the SVA close to the line. White arrows indicate the changed activation sequence after the linear RF ablation lesions connecting unexcitable boundaries consistent with unidirectional conduction block.

Accordingly, a wide range of acute procedural success rates (63–95 %) and outcome data have been reported. Outcomes are difficult to compare. They are dependent on patient population and the experience of the centres and operators. Table 2 provides an overview of the more recently published series.10,12,13,33,41,44,46,50–53 A bidirectional isthmus block is an established endpoint for CTIDF and has improved long-term outcome in patients after atrial switch operations.54 The procedural endpoint is less clear for IART for which termination during ablation is still often considered as 'procedural success' with or without non-inducibility at the end of the procedure.33,34,41,46,51,53 AT recurrence rates after RFCA are considerably high, ranging from 20–45 % at short-term follow-up. However, they can reach 85 % for complex CHD such as Fontan palliation, even if complete procedural success (defined as termination of all targeted IART and non-inducibility) has been achieved.53 The mechanism of AT recurrences may differ from the initial AT mechanism.12,13,33,37,46,51–53

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Location

Year of

CHD Type (n)

Method

Inclusion

Imaging (n)

Patients no

AT, mean cl

AT, (n)

AT type Success (%)

Acute Endpoint

Definition After Any

Recurrence FU Time

Mean

154

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170 NP

All (84) 81

London, UK

2007–12

AM,LL

CMR

116

228

Fontan, Mustard,

ASD, Ebstein, IART (87)

CTIDF (47)

TOF (59)

CTIDF (50)

EAT (100)

FAT (92)

IART (84)

CTIDF (94)

FAT (88)

FAT + DB in 34

IART/CTIDF/

NI in 32

TDA in all +

IART (81)

(not specified)

NI and/or DB

TDA + NI

TGA (4), TOF (10),

Valvular (9),

VSD (2)

Fontan (14),

–

AM, SM

Ebstein (1),

ASD (11), CoA (2),

Netherlands

2000–04

Leiden, the

De Groot, 2010

380 (FAT)

309 (IART)

288 (IDAF)

FAT (5)

IART (22)

CTIDF (27)

FAT (100)

IART (55)

IART/FAT: TDA

CTIDF: DB

CTIDF/IART/FAT

EAT (4)

303 (IART)

FAT (13)

127

–

FAT (13)

IART (19)

CTIDF (5)

IART (45)

AM, SM

1997–2010

Mah, 2011

Boston, US

TOF (3), VSD (3)

PD (1), PS (2),

TA (4), TGA (10),

Netherlands

–

RMN, AM

AVSD (2), Ebstein (6),

AoS (1), ASD (4)

the

2007–11

Rotterdam,

Akca, 2012

Other (51)

TOF, VSD FAT (43)

Ueda, 2013

Senning(13)

Mustard (16)

TGA

Other (70)

–

Modern (37)

NP FAT (22)

Fontan

FAT (100)

IART (81)

CTIDF (100)

Classic (52)

2006–10

IART (78)

Boston, US

Correa, 2013

CTIDF (14)

Other (21)

312 FAT (8)

Intracard. (48)

ICE IART (11)

Extracard. (4)

Fontan (52)

55 (NP)

34 (NP)

39 (NP)

19 redo

21 (NP)

30 (NP)

Ablation (%)

2006–12

50 (16)

Boston, US

Correa, 2015

(Continued)

(Successful) (Months)

Year

Author,

Table 2: Overview of Recent Literature Concerning Atrial Tachycardia Ablation in Patients with Repaired Congenital Heart Disease

Diagnostic Electrophysiology & Ablation

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Location

CHD Type (n)

Method

Inclusion

Year of

Imaging (n)

Patients no

AT,

AT, mean cl

(n)

AT type Success (%)

Acute Endpoint

Definition After Any

Recurrence FU Time

Mean

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2006–08

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London, UK

FAT (2) CTIDF (1)

–

312

IART (40)

TDA+ NI + DB

lesions)

DB (Linear

TDA, NI

DB (CTIDF)

DB (simple CHD)

NI (Fontan)

TDA (TGA)

TDA, NI

19 (NP)

33 (36)

28 (NP)

9 (NP)

57 (48)

Ablation (%)

AT = atrial tachycardia; AM = activation mapping; AoS = aortic stenosis; APV = anomalous pulmonary vein drainage; ASD = atrial septal defect; AVSD = atrioventricular septal defect; CHD = congenital heart disease; CMR = cardiac magnetic resonance imaging; CoA = coarctation of the aorta; (cc)TGA = (congenitally corrected) transposition of the great arteries; CTIDF = cavotricuspid isthmus dependent flutter; CTI = cavotricuspid isthmus; DB = demonstrated bidirectional conduction block along the ablation line; EAT = ectopic atrial tachycardia; EM = entrainment mapping; FAT = focal atrial tachycardia; FU = follow-up; IART = intra-atrial reentrant tachycardia; ICE = intra-cardiac echography; IMG = image integration; LL = linear lesions; NI = non-inducibility after ablation; NP = data not provided; PD = patent ductus; PS = pulmonary stenosis; RMN = remote magnetic navigation; SM = substrate mapping; TA = tricuspid atresia; TDA = termination during ablation; TOF = tetralogy of Fallot; VSD = ventricular septal defect.

biventricular (20)

Fontan (9)

other

2002–03

Boston, US

CTIDF (27)

Triedman, 2005

Other (1)

12 FAT (1)

–

AM, SM

100

APV (1), ASD (9),

IART (6)

CTIDF(4)

FAT (2)

IART (9)

2002–07

IART (14)

CTIDF (8)

IART

TGA (1), TOF (1)

Republic

Liew, 2008

320

(3) VSD (1)

Czech

ICE

(cc)TGA (4), Fontan

Prague,

Peichl, 2009

AM, SM

Senning (4)

2004–07

Mustard (2),

321

Fontan (9),

ASD (2), Ebstein (1),

Germany

–

118

VSD (5) RMN, AM

130

Munich,

TOF (18),

–

Wu, 2010

TGA (21),

AM, SM, LL

Other (14),

Fontan (21),

ASD (21), AVSD (9),

Canada

1993–2009

Toronto,

Yap, 2010

(Successful) (Months)

Year

Author,

Table 2 (Continued): Overview of Recent Literature Concerning Atrial Tachycardia Ablation in Patients with Repaired Congenital Heart Disease

Ablation of Atrial and Ventricular Tachycardias in Repaired Congenital Heart Disease

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Diagnostic Electrophysiology & Ablation Figure 4: Retrograde Approach for Access to the Pulmonary Venous Atrium in a Patient with Cavotricuspid Dependent Atrial Flutter After a Senning Procedure for d-Transposition of the Great Arteries

which can often be terminated by focal ablation.56 Although pericaval reentry, which is typically slower than periannular reentry, can also be ablated by transecting the CTI-isthmus between the IVC and the hypoplastic or atretic valve, the latter may be more challenging due to an ambiguous anatomy and the risk of AV node injury. In a series of 52 patients after total cavopulmonary connection, the majority of non-CTI-dependent reentrant circuits were located within the intracardiac baffle. It is important to note that focal AT can also be encountered and are often successfully ablated within the intracardiac tunnel.35,51,52

d-Transposition of the Great Arteries with Atrial Switch

Right posterior oblique view of the bipolar voltage map of the systemic venous atrium (SVA) integrated with 3D anatomic data of the pulmonary venous atrium (PVA) acquired with intracardiac echocardiography (ICE). Bipolar voltages are colour coded: low voltages (<0.5 mV) are displayed in red. Green dots indicate double potentials, red dots indicate radiofrequency (RF) lesions. The PVA was accessed using a retrograde approach. Linear RF lesions connecting the tricuspid valve annulus and the inferior caval vein resulted in cavotricuspid dependent atrial flutter (CTIDF) termination. Insets show catheter position during termination of the tachycardia on fluoroscopic right and left oblique views. IART = intra-atrial reentry tachycardia; ICV = indicates inferior caval vein; LAO = left anterior oblique view; PVs = pulmonary veins; RAO = right anterior oblique view; SCV = superior caval vein. Adapted with permission from den Uijl et al.38

In a small series of 16 patients with various CHD all identified isthmuses based on electroanatomical substrate mapping were targeted, regardless of whether an AT was related to it. Unidirectional conduction block was applied as lesion endpoint. This approach was successful for 28 in 29 identified isthmuses. During a median followup of 14 months, only one new macro-reentrant AT was documented in one patient.5 The appealing concept of substrate-based ablation needs to be evaluated prospectively in a larger population.

Right Lateral Atriotomy After right lateral atriotomy for ASD closure, repair of tetralogy of Fallot or as a part of many other corrective surgeries, the most common macro-reentrant circuit is a CTI-dependent flutter (52–71 %), followed by a macro-reentrant circuit with the lateral incision as central obstacle (21–31 %).29,33,34 Regardless of the initial ablation site >50 % of all recurrences occurred at either the CTI or the lateral SVA scar supporting an empirical linear ablation between the lateral SVA scar and the IVC.33

The most important mechanism for AT in D-TGA patients after Mustard or Senning is CTIDF, accounting for 64–77 % of all spontaneous and induced AT. This is followed by IART and localised reentry, which may be confined to the PVA or SVA.29,30 The tricuspid valve and variable portions of the CTI are located on the pulmonary venous side, dependent on the surgical variant.57 In 81 % access to the CTI cannot be achieved via a systemic route but requires either a retrograde transaortic access through the AV-valve or a trans-baffle puncture (see Figure 4).54

Trans-baffle Access An angiogram of the SVA can identify baffle leaks that may be crossed. In the absence of fenestrations or leaks, a trans-baffle puncture can be guided by fluoroscopy, transoesophageal echo or ICE with acute success rates of up to 96 %, if performed in experienced centres.58 In selected cases radiofrequency assisted transseptal perforation may be considered.59 In the extracardiac conduit Fontan transconduit access to the PVA can be challenging.

Ventricular Arrhythmias The incidence of sudden cardiac death (SCD) in repaired CHD is 0.9–2.6 per 1,000 patient years, which is 25–100-fold higher than for the general population.60,61 Corrected cardiac defects often associated with ventricular arrhythmias and SCD are TGA, repaired tetralogy of Fallot and left sided outflow lesions (see Table 1). Cohort studies reporting on mortality cannot provide the type of ventricular arrhythmia leading to a presumed arrhythmic death.62 Ventricular arrhythmias encompass polymorphic VT, ventricular fibrillation in the absence of surgical scar and monomorphic VT; with a higher prevalence in patients who have undergone ventricular incision and patch closure of VSD. VT in repaired tetralogy of Fallot patients can serve as a paradigm for these postoperative monomorphic arrhythmias that are approachable by RFCA.

After classic Fontan operation patients may encounter multiple IART circuits at various locations due to progressive SVA enlargement and time-dependent development of low-voltage areas that may serve as reentry circuit borders.5,55

Indeed, based on ICD interrogation in patients with repaired tetralogy of Fallot and TGA, implanted for primary and secondary prevention, >80 % of all ventricular arrhythmias that prompted ICD therapy in repaired tetralogy of Fallot and around 50 % in TGA patients are fast and monomorphic VT often with heart rates >200 bpm.63,64 When rapid and untreated, these monomorphic VT may be fatal even in the presence of preserved cardiac function.

CTI-dependent flutter (or cavomitral in L-looped ventricles) usually requires access to the PVA, either by a pre-existing fenestration, a trans-baffle puncture or, rarely, via a retrograde access.51 In patients with lateral tunnels, circuits may be localised to the low right atrium even in the absence of the tricuspid valve. Pericaval reentry is common with an area of slow conduction associated with the lower margin of the crista terminalis or low SVA surgical scars (e.g. cannulation site),

Moderate-to-severe systemic ventricular dysfunction is a dominant predictor for SCD in an unselected population of adults with CHD.54 Of interest, in a recent cohort two-thirds of early-to-middle-aged adult tetralogy of Fallot patients who died suddenly or experienced life-threatening VT had a preserved cardiac function before the first event.65 In addition, two-thirds of repaired tetralogy of Fallot patients referred for RFCA of fast and potential life-threatening, monomorphic

Fontan Circulation

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Table 3: Overview of Recent Literature Concerning Ventricular Tachycardia Ablation in Patients with Repaired Congenital Heart Disease Author, Year

Location

Year of

CHD Type

Method

Inclusion (n)

Patients

Sus-VT (n)

(n)

VTCL

Acute

Recurrence

Mean Success

Burton, 1993 Atlanta, US 1992 TOF PM 2 2

(ms) 270

2/2

0/2

Biblo, 1994

Cleveland, US

1991

TOF

430

1/1

0/1

Goldner, 1994

Manhasset, US

1994

TOF

240

1/1

0/1

Cinushi, 1995

NIigata,

1995

TOF

AM + LL

420

2/2

0/1

1996

TOF (7), VSD (1),

377

9/11

2/11

Japan Gonska, 1996†

Karlsruhe,

Germany

TGA + VSD (1),

PS (2)

Horton, 1997

Dallas, US

TOF

AM + LL

430

2/2

0/2

Baral, 2004

Southampton, UK 2004

ccTGA + Ebstein +

AM (NC) +

380

1/1

0/1

1997

TVR

ENT

Rostock, 2004

Hamburg,

2004

TOF

AM + LL

340

1/1

0/1

1990–2003

TOF (8), VSD (3),

–

10/20

4/10

346

4/7

6/7

Germany Morwood, 2004

Boston, US

Other (3)

Patients

Procedures

Furushima, 2005

Niigata, Japan

2005

TOF/DORV

AM + LL

Targeted 8

Kriebel, 2007

Göttingen,

269

8/10

2/8

Germany,

Charleston, US

Zeppenfeld, 2007

Leiden, the

276

11/11

1/11

Netherlands

350

1/1

0/1

340

1/1

0/1

295

25/34‡ 0/25†

2007

1998–2007

TOF

SSM + LVA (NC) + LL

TOF (9), AVSD (1),

SSM + EUS +

TGA + VSD (1)

LL + IMG

(1/11, CT)

Nair, 2011

Hamilton,

SSM + PM +

Canada

IMG (CT)

Piers, 2012

Leiden, the

SSM + AM +

Netherlands

2011 2012

TGA + VSD + sPS TGA + sPS

Kapel, 2015

Leiden, the

2001–12

IMG (CT, CMR)

TOF (28), TGA +

SSM + EUS +

Netherlands,

sPS (1), TGA +

LL + IMG

Boston, US

VSD (1)

(242–346)*

VSD + sPS (1),

PS (1) VSD +

bAV (1), AVSD (1)

* = median (IQR); ‡ = acute success defined as non-inducibility and transection of anatomical isthmus; † = one patient had ICD shock for VF. AVSD = atrioventricular septal defect; AM = activation mapping; (cc)TGA = (congenitally corrected) transposition of the great arteries; CHD = congenital heart disease; CMR = cardiac magnetic resonance imaging; CT = computed tomography; DORV = double outlet right ventricle; ENT = entrainment; EUS = electrically unexcitable scar; IMG = image integration; LL = linear lesions; LVA = low voltage areas; NC = non-contact; PM = pace mapping; (s)PS = (sub)pulmonary stenosis; SSM = substrate mapping; sus-VT = sustained ventricular tachycardia; TOF = Tetralogy of Fallot; TVR = tricuspid valve replacement; VSD = ventricular septal defect; VTCL = ventricular tachycardia cycle length.

VT also had a preserved biventricular function at the time of ablation.8 Whether more subtle parameters such as longitudinal LV function may help to identify patients at risk needs further study. Over the last decade progress has been made to determine the anatomical basis of monomorphic VT in repaired tetralogy of Fallot and complex TGA, which is crucial for both risk stratification and treatment.

Up to 97 % of all spontaneous and induced monomorphic VT in CHD patients referred for RFCA, or studied for risk stratification, are macroreentrant VT with a critical reentry circuit isthmus located within electroanatomically defined isthmuses.6,8,76 The majority of these VTs are fast and haemodynamically poorly tolerated requiring a substratebased ablation approach.6,8,76

Anatomical Substrate for Ventricular Tachyarrhythmia and Impact on Catheter Ablation

Mapping and Ablation

The feasibility of catheter ablation of VT in patients after repair of CHD has been reported and Table 3 summarises the available data.6,8,66–78 The majority of treated patients were repaired tetralogy of Fallot patients. Accordingly, data on the mechanism and substrate of ventricular arrhythmias in other CHD is sparse.

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A 3D reconstruction of all potential anatomical isthmuses can be obtained during sinus rhythm by identifying the boundaries, facilitated by the use of 3D mapping systems as described for AT. Bipolar electrograms >1.5 mV are considered normal ventricular voltage. At sites with amplitudes <0.5 mV, high-output pacing (10 mA, 2 ms) can be performed to identify unexcitable tissue, which is consistent with

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Diagnostic Electrophysiology & Ablation Figure 5: Procedural Workflow for Ablation of a Haemodynamically Nontolerated Ventricular Tachycardia in a Patient After Repair of Tetralogy of Fallot

Figure 6: Interoperative View During Pulmonary Valve Replacement Using a Pulmonary Homograft in a Patient with Repaired Tetralogy of Fallot

Caudal

Medial

Lateral

A. 12-Lead ECG recording of a spontaneous ventricular tachycardia (VT). B. The clinical VT could be induced during programmed stimulation C. Modified PA-view of electroanatomical bipolar voltage (top) and activation map (bottom) during sinus rhythm. Voltages and activation time are colour-coded according to colour bars, unexcitable tissue is displayed by gray tags. Anatomical isthmus 3 is shown between the ventricular septal defect-patch and the pulmonary valve (PV) in white-dashed brackets. Activation mapping shows continuous conduction through anatomical isthmus 3. D. Pace-mapping at isthmus 3 showed a good pace-match of VT suggesting that the VT isthmus site is located within anatomical isthmus 3. E. Bipolar voltage and activation map during SR after linear RF ablation, connecting the unexcitable boundaries. Red tags indicate ablation sites. White arrows indicate the changed activation sequence through isthmus 3 consistent with unidirectional conduction block. Reprinted with permission from Kapel et al.8 TA = tricuspid annulus.

patch material or surgical scars. Depending on the malformation and the type of repair different anatomical isthmuses may be present. Four anatomical isthmuses related to VT in repaired tetralogy of Fallot have been identified (see Figure 1): Isthmus 1 bordered by the tricuspid annulus and the scar or patch in the anterior RVOT; isthmus 2 between the pulmonary annulus and the RV free wall incision or RVOT patch sparing the pulmonary valve annulus; isthmus 3 between the pulmonary annulus and the VSD patch or septal scar; and isthmus 4 between the VSD patch or septal scar and the tricuspid annulus in patients with muscular VSDs.6 Additional anatomical isthmuses have been described in complex TGA or after surgery for VSD and pulmonary stenosis.8,77,79 The critical reentry circuit isthmus of an induced VT can be determined by activation and entrainment mapping for haemodynamically tolerated VT or by pace-mapping for unstable arrhythmias. 6,8 An alternative approach for mapping poorly tolerated VT is noncontact mapping. The system consists of a multielectrode balloon array and allows simultaneous acquisition of virtual unipolar electrograms. The activation sequence of fast VTs in 10 tetralogy of Fallot patients has been reported, the majority being macroreentrant circuits. The anatomical location of the critical isthmus could be identified in all patients. 76 If the critical isthmus is located within an anatomically defined isthmus the anatomical isthmus can be transsected by

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Cranial The dashed line indicates the anterior suture line of the homograft. The pulmonary homograft is held by the forceps and is already sutured posteriorly, indicated by the black line and located at the upper edge of the ventricular septal defect patch (asterisks). Accordingly, important parts of the infundibular septum are covered by the homograft. RV = right ventricle; VCS = vena cava superior. Adapted with permission from Kapel.81

connecting the adjoining anatomical boundaries by linear radio frequency (RF) lesions during sinus rhythm (SR).

Endpoint of Ablation Demonstration of conduction block after isthmus transection provides a defined procedural endpoint similar to that for achieving block in the CTI (see Figure 5). 8 A systematic substrate mapping and ablation approach has been applied in 34 adults with CHD (82 % tetralogy of Fallot). Complete procedural success was defined as noninducibility of any VT and transection of the critical anatomical isthmus, which was achieved in 25 patients. None of these patients had recurrence of a monomorphic VT during 46 Âą 29 months of follow-up. 8 These data suggest that macroreentrant VT based on an anatomical substrate can be treated effectively with catheter ablation. Isthmus ablation with confirmed conduction block should be attempted and, if successful, may be considered curative in patients with preserved cardiac function and no competing arrhythmia mechanism.

Arrhythmogenic Anatomical Isthmuses Anatomical isthmuses are present in almost all repaired tetralogy of Fallot patients but not all are related to VT. Specific features of the anatomical isthmuses after initial repair, such as isthmus width and

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Ablation of Atrial and Ventricular Tachycardias in Repaired Congenital Heart Disease

thickness of the myocardium, may be one decisive factor for further remodelling over time thereby forming the substrate for late VT. In post-mortem series of repaired tetralogy of Fallot, isthmus 3 and 1 were present in almost all specimens, whereas isthmus 2 and 4 were observed in only 25 % and 13 %, respectively.6,80 In specimens from patients aged ≥5 years at the time of death, isthmus 3 was significantly narrower and thinner with more interstitial and replacement fibrosis than isthmus 1.80 In particular, narrow isthmuses with interstitial fibrosis may provide the substrate for slow conduction crucial for re-entrant VT.

With the introduction of a combined transatrial-transpulmonary approach and only limited patch augmentation for pulmonary valve stenosis, anatomical isthmuses 1 and 2 may be prevented in the majority of patients. However, isthmus 3 will remain. Evaluation of its potential arrhythmogeneity by EAM is appealing and could allow personalised risk stratification and tailored treatment for contemporary patients with repaired tetralogy of Fallot. Whether preventive transection of isthmus 3 during initial repair in the very young is feasible, reasonable and safe needs careful, multidisciplinary consideration.

Conclusion To identify the characteristics of anatomical isthmuses that may serve as a substrate for VT, detailed electroanatomical voltage and activation mapping during SR has been performed in a cohort of 74 tetralogy of Fallot patients with at least one risk factor for ventricular arrhythmia, including 13 with prior documented VT. Narrow and slow conducting anatomical isthmuses (calculated conduction velocity <0.5 m/s) were the substrate for all 37 documented and induced ventricular tachycardia in 24 patients with preserved cardiac function (unpublished data). Considering the strong link between slow conducting anatomical isthmuses that can be identified and ablated during stable sinus rhythm and monomorphic VT in repaired tetralogy of Fallot, inducibility of the clinical arrhythmia and haemodynamic tolerance is no longer a prerequisite for successful ablation. Important reasons for ablation failure are hypertrophied myocardium and protection of portions of anatomical isthmuses by patch material.81 In particular, in patients who have undergone pulmonary valve replacement (PVR) the implanted pulmonary homograft may cover parts of the infundibular septum preventing transection of anatomical isthmus 3 (see Figure 6). If ablation from the RV fails to transect the anatomical isthmuses a left-sided approach may be helpful for those anatomical isthmuses which involve the septum.81 The strong association between anatomically defined isthmuses, macroreentrant VT and the inability to transect isthmus 3 after PVR may justify pre-operative mapping and preventive ablation in patients with slow conducting anatomical isthmuses who require reoperation for pulmonary valve regurgitation.

1. 2.

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10.

11.

12.

13.

14.

With improved longevity for patients after repair of CHD, management of atrial and ventricular arrhythmias will continue to be of great importance. Patients with repaired CHD represent a highly heterogeneous group, displaying considerable anatomical diversity and complex, variable arrhythmogenic substrates. Enhanced understanding of the underlying substrate as well as technical developments for mapping and RFCA have improved outcomes in patients after CHD repair. However, continued focus on the understanding of the arrhythmogenic substrate in conjuncture with technical developments for the accurate delineation of its 3D anatomy and improved ablation techniques to achieve continuous and durable lesions is essential in order to further improve outcomes in this diverse population. ■

Clinical Perspective • In patients with repaired congenital heart disease (CHD), improved longevity results in a high risk for late tachyarrhythmias leading to significant morbidity and mortality. • Arrhythmogenic substrates in patients after repair of CHD have changed as a result of evolving surgical techniques. • Radiofrequency catheter ablation remains challenging in patients with repaired CHD due to variable anatomy, surgically created obstacles and complex arrhythmogenic substrates. • A substrate-based approach facilitated by 3D-electroanatomical mapping and accurate delineation of the anatomy is desired in catheter ablation procedures in patients with repaired CHD.

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