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Arrhythmia & Electrophysiology Review Volume 2 • Issue 2 • Winter 2013

www.AERjournal.com

Volume 2 • Issue 2 • Winter 2013

What About Tachycardia-induced Cardiomyopathy? Ethan R Ellis and Mark E Josephson

A Critical Reappraisal of the Current Clinical Indications to Cardiac Resynchronisation Therapy Antonio Sorgente and Riccardo Cappato

Catheter Ablation of Polymorphic Ventricular Tachycardia and Ventricular Fibrillation Josef Kautzner and Petr Peichl

The EHRA Practical Guide on the Use of New Oral Anticoagulants in Patients with Non-Valvular Atrial Fibrillation – A Brief Summary Katrina Mountfort In partnership

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

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Volume 2 • Issue 2 • Winter 2013

Editor-in-Chief Demosthenes Katritsis Athens Euroclinic, Greece

Deputy Editor – Arrhythmia Mechanisms / Basic Science Andrew Grace University of Cambridge, UK

Editorial Board Etienne Aliot

Andreas Götte

Carlo Pappone

University Hospital of Nancy, France

St Vincenz-Hospital Paderborn and University Hospital Magdeburg, Germany

Maria Cecilia Hospital, Italy

Fondazione Cardiocentro Ticino, Lugano, Switzerland

Hein Heidbuchel

University of Dresden, Germany

Carina Blomström-Lundqvist

Gerhard Hindricks

University Hospital Uppsal, Sweden

University of Leipzig, Germany

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

Johannes Brachmann

Carsten W Israel

Frédéric Sacher

Angelo Auricchio

University Hospital Leuven, Belgium

Klinikum Coburg, II Med Klinik, Germany

Pedro Brugada University of Brussels, UZ-Brussel-VUB, Belgium

JW Goethe University, Germany

Mark Josephson Beth Israel Deaconess Medical Center, Boston, US

Josef Kautzner

Hugh Calkins Johns Hopkins Medical Institutions, Baltimore, US

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

Riccardo Cappato IRCCS Policlinico San Donato, Milan, Italy

Alessandro Capucci Università Politecnica delle Marche, Ancona, Italy

Ken Ellenbogen Virginia Commonwealth University School of Medicine, US

Sabine Ernst Royal Brompton and Harefield NHS Foundation Trust, UK

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Samuel Lévy

Christopher Piorkowski Antonio Raviele

Bordeaux University Hospital / LIRYC / INSERM 1045

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

Jesper Hastrup Svendsen Rigshospitalet, Copenhagen University Hospital, Denmark

Aix-Marseille Université, France

Juan Luis Tamargo

Gregory YH Lip

University Complutense, Madrid, Spain

University of Birmingham Centre for Cardiovascular Sciences, UK

Sotirios Tsimikas

Antonis Manolis

Panos Vardas

Athens University School of Medicine, Greece

Marc A Vos

Jose Merino Hospital Universitario La Paz, Spain

Sanjiv M Narayan

University of California San Diego, US Heraklion University Hospital, Greece University Medical Center Utrecht, The Netherlands

Katja Zeppenfeld

University of California San Diego, US

Leiden University Medical Center, The Netherlands

Mark O’Neill

Douglas P Zipes

King’s College, London, UK

Krannert Institute of Cardiology, Indianapolis, US

Radcliffe Cardiology

In partnership with

Lifelong Learning for Cardiovascular Professionals

Managing Editor Jonathan McKenna • Designer Tatiana Losinska Publisher David Ramsey • Publication Manager Liam O’Neill

Radcliffe Cardiology •

Editorial Contact Jonathan McKenna | jonathan.mckenna@radcliffepublishing.com Circulation Contact David Ramsey | david.ramsey@radcliffepublishing.com Commercial Contact Liam O’Neill | liam.oneill@radcliffepublishing.com Cover image © | shutterstock.com Published by Radcliffe. Radcliffe is the trading name of Electric Word Plc. All information obtained by Radcliffe and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe 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. 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 Publishing, St Mark’s House, Shepherdess Walk, London N1 7LH, United Kingdom © 2013 All rights reserved

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Established: October 2012

Aims and Scope •  Arrhythmia & Electrophysiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in the arrhythmia and electrophysiology sphere. •  Arrhythmia & Electrophysiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. •  Arrhythmia & Electrophysiology Review provides comprehensive update 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 bi-annual journal comprising review articles, editorials, and case reports. • 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 Deputy Editor 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: Bi-annual

Current Issue: Winter 2013

• Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is returned to the reviewers to ensure the revised version meets their quality expectations. Once approved, the manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Submissions and Instructions to Authors • Contributors are identified by the Editor-in-Chief with the support of the Deputy Editor and Editorial Manager, and guidance from the Editorial Board. •  Following acceptance of an invitation, the author(s) and Editorial Manager, in conjunction with the Editor-in-Chief, formalise the working title and scope of the article. • Subsequently, the Editorial Manager provides an ‘Instructions to Authors’ document and additional submission details. •  The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the Editorial Manager for further details. The ‘Instructions to Authors’ information is available for download at www.AERjournal.com

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

Editorial Expertise

Distribution and Readership

Arrhythmia & Electrophysiology Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by a Deputy Editor and Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors who are recognised authorities from their respective fields. • Peer review – conducted by members of the journal’s Peer Review Board, that comprises experts appointed for their experience and knowledge of a specific topic. • An experienced team of Editors and Technical Editors.

Currently bi-annual, from 2014 Arrhythmia & Electrophysiology Review will be distributed tri-annually through controlled circulation to general and specialist senior cardiovascular professionals in Europe. All manuscripts published in the journal are free-to-access online at www.AERjournal.com and www.radcliffecardiology.com

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

Copyright and Permission Peer Review • On submission, all articles are assessed by the Editor-in-Chief or Deputy Editor to determine their suitability for inclusion. •  The Editorial Manager, following consultation with the Editor-in-Chief, Deputy Editor, and/or a member of the Editorial Board, sends the manuscript to members of the Peer Review Board, who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind. • Following review, manuscripts are either accepted without modification, accepted pending modification, in which case the manuscripts are returned to the author(s) to incorporate required changes, or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments.

Radcliffe 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 Editorial Manager.

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 manuscripts from other journals within Radcliffe cardiovascular portfolio – namely, Interventional Cardiology Review and European Cardiology Review. n

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

Radcliffe Cardiology 74

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Contents

Foreword 80

Arrhythmia & Electrophysiology Review – Moving Forward Demosthenes Katritsis, Editor-in-Chief Director, Department of Cardiology, Athens Euroclinic, Greece and Honorary Consultant Cardiologist, St Thomas’ Hospital, London, UK

Clinical Arrhythmias 82

What About Tachycardia-induced Cardiomyopathy? Ethan R Ellis 1 and Mark E Josephson 2 1. Clinical Fellow, Harvard Medical School, Beth Israel Deaconess Medical Center; 2. Herman C. Dana Professor of Medicine, Harvard Medical School, Chief of the Cardiovascular Division, Beth Israel Deaconess Medical Center and Director, Harvard-Thorndike Electrophysiology Institute and Arrhythmia Service, Beth Israel Deaconess Medical Center, Boston, US

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A Critical Reappraisal of the Current Clinical Indications to Cardiac Resynchronisation Therapy Antonio Sorgente and Riccardo Cappato Arrhythmia and Electrophysiology Department, Policlinico San Donato, Milan, Italy

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Cardiac Pacing – Is Telemonitoring Now Essential? Haran Burri Cardiology Service, University Hospital of Geneva, Geneva, Switzerland

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The Electrocardiogram in Athletes Revisited George D Katritsis 1 and Demosthenes G Katritsis 2 1. Faculty of Medicine, University of Bristol, Bristol, UK; 2. Department of Cardiology, Athens Euroclinic, Athens, Greece

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Stroke in Atrial Fibrillation – Long-term Follow-up of Cardiovascular Events Tze-Fan Chao, 1,2 Chern-En Chiang 1,2,3,4 and Shih-Ann Chen 1,2 1. Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital; 2. Institute of Clinical Medicine and Cardiovascular Research Center, National Yang-Ming University; 3. General Clinical Research Center, Taipei Veterans General Hospital; 4. Department of Medical Research and Education,Taipei Veterans General Hospital, Taipei, Taiwan

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Natriuretic Peptides as Predictors of Atrial Fibrillation Recurrences Following Electrical Cardioversion Theodoros A Zografos and Demosthenes G Katritsis Athens Euroclinic, Department of Cardiology, Athens, Greece

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The European Heart Rhythm Association Practical Guide on the Use of New Oral Anticoagulants in Patients with Non-valvular Atrial Fibrillation – A Brief Summary Katrina Mountfort, Medical Writer, Radcliffe Cardiology Reviewed by Paulus Kirchhof University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK

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© RADCLIFFE 2013

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Contents

Diagnostic Electrophysiology & Ablation 120

The Role of Three-dimensional Rotational Angiography in Atrial Fibrillation Ablation Georg Nölker, Dieter Horstkotte and Klaus-Jürgen Gutleben Department of Cardiology, Heart and Diabetes Center North Rhine-Westphalia, Ruhr University Bochum, Bochum, Germany

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Role of Magnetic Resonance Imaging of Atrial Fibrosis in Atrial Fibrillation Ablation David D Spragg, Irfan Khurram and Saman Nazarian Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, US

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Imaging-guided Ventricular Tachycardia Ablation Sebastiaan RD Piers and Katja Zeppenfeld Department of Cardiology, Leiden University Medical Centre, Leiden, The Netherlands

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Catheter Ablation of Polymorphic Ventricular Tachycardia and Ventricular Fibrillation Josef Kautzner 1 and Petr Peichl 2 1. Head; 2. Consultant Electrophysiologist, Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Supported Contributions 141

Observations and Considerations on Patient X-ray Exposure in the Electrophysiology Lab Xianxian Jiang¹ and Lukas RC Dekker² 1. Scientist, Philips Healthcare, Best, The Netherlands; 2. Cardiologist, Department of Cardiology, Catharina Hospital Eindhoven, Eindhoven, The Netherlands

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The Convergent Procedure – A Standardised and Anatomic Approach Addresses the Clinical and Economic Unmet Needs of the Persistent Atrial Fibrillation Population James McKinnie East Jefferson General Hospital, Metairie, Louisiana, US

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Foreword

Arrhythmia & Electrophysiology Review – Moving Forward

I

t is an honour and a pleasure for me to welcome our new members of the Editorial Board of Arrhythmia & Electrophysiology Review. These accomplished colleagues, together with the already existing members,

will undoubtedly contribute decisively towards the fulfilment of our goal; to summarise and disseminate current knowledge on arrhythmias. It is also a great pleasure to welcome Andrew Grace and congratulate him on his appointment as Deputy Editor, with a special interest in arrhythmia mechanisms and basic science. Apart from being a scientist who needs no introduction, Andrew has been a personal friend and colleague since our years at St George’s in London. I shall never forget the Don Giovanni background from his desk in the office we shared! The willingness of the international electrophysiology community to contribute to the journal by submitting learned and instructive reviews has also been a pleasant surprise to all of us in Arrhythmia & Electrophysiology Review. It has been a very exciting and I must admit educating endeavour to solicit, review and process all this high quality material. I do hope our readers share my views. We shall keep moving forward. The commitment and support of our colleagues has been most reassuring in the short but promising life of this journal. n

Demosthenes Katritsis, Editor-in-Chief Director, Department of Cardiology, Athens Euroclinic, Greece and Honorary Consultant Cardiologist, St Thomas’ Hospital, London, UK

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Clinical Arrhythmias

What About Tachycardia-induced Cardiomyopathy? Et ha n R E l l i s 1 a n d M a r k E J o s e p h s o n 2 1. Clinical Fellow, Harvard Medical School, Beth Israel Deaconess Medical Center; 2. Herman C. Dana Professor of Medicine, Harvard Medical School, Chief of the Cardiovascular Division, Beth Israel Deaconess Medical Center and Director, Harvard-Thorndike Electrophysiology Institute and Arrhythmia Service, Beth Israel Deaconess Medical Center, Boston, US

Abstract Long-standing tachycardia is a well-recognised cause of heart failure and left ventricular dysfunction, and has led to the nomenclature, tachycardia-induced cardiomyopathy (TIC). TIC is generally a reversible cardiomyopathy if the causative tachycardia can be treated effectively, either with medications, surgery or catheter ablation. The diagnosis is usually made after demonstrating recovery of left ventricular function with normalisation of heart rate in the absence of other identifiable aetiologies. One hundred years after the first reported case of TIC, our understanding of the pathophysiology of TIC in humans remains limited despite extensive work in animal models of TIC. In this review we will discuss the proposed mechanisms of TIC, the causative tachyarrhythmias and their treatment, outcomes for patients diagnosed with TIC, and future directions for research and clinical care.

Keywords Tachycardia-induced cardiomyopathy, tachycardia-mediated cardiomyopathy, supraventricular tachycardia, atrial fibrillation, cardiomyopathy, premature ventricular contractions, ventricular tachycardia Disclosure: The authors have no conflicts of interest to declare. Received: 28 April 2013 Accepted: 29 September 2013 Citation: Arrhythmia & Electrophysiology Review 2013;2(2):82–90 Access at: www.AERjournal.com Correspondence: Mark E Josephson, Herman C. Dana Professor of Medicine, Harvard Medical School, Chief of the Cardiovascular Division, Beth Israel Deaconess Medical Center, Director, Harvard-Thorndike Electrophysiology Institute and Arrhythmia Service, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, US. E: mjoseph2@bidmc.harvard.edu

Cardiomyopathies are heterogeneous heart muscle disorders with a wide range of aetiologies and clinical manifestations. They are often defined by their causes (i.e. hypertension, prior myocardial infarction, valvular heart disease), although current major society definitions describe cardiomyopathy as the presence of abnormal myocardial structure and/or function in the absence of underlying structural heart disease. Long-standing tachycardia is a well-recognised cause of heart failure and left ventricular dysfunction, and has led to the nomenclature, tachycardia-induced cardiomyopathy (TIC). TIC is generally a reversible cardiomyopathy if the tachycardia can be treated effectively, either with medications, surgery or catheter ablation. TIC can also manifest in patients with baseline left ventricular dysfunction from underlying structural heart disease that develop a worsening of their myocardial dysfunction in the setting of prolonged tachycardia, which can be reversed with control of the tachycardia. The diagnosis is usually made after demonstrating recovery of left ventricular function with normalisation of heart rate in the absence of other identifiable aetiologies. TIC was first described in 1913 in a young patient who presented with congestive heart failure (CHF) and atrial fibrillation (AF) with rapid ventricular response.1 In the subsequent decades, further reports were written documenting cases of complete resolution of CHF after cardioversion of AF to sinus rhythm.2–4 A century after the first reported case, we are still working to expand our understanding of the mechanisms underlying this disorder. A variety of chronic or incessant tachyarrhythmias have been implicated in the pathogenesis of TIC,

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the most classic being AF,5–7 atrial flutter,8 incessant supraventricular tachycardia,9–12 ventricular tachycardia13–16 and premature ventricular depolarizations17 (see Table 1). The most common presentation is a dilated cardiomyopathy with or without the causative tachycardia. Given that this diagnosis represents a potentially reversible cause of heart failure, its recognition is critically important. In this review, we will discuss the proposed mechanisms of TIC, the causative tachycardias and their treatment, outcomes for patients diagnosed with TIC, and future directions for research and clinical care.

Experimental Models Background The first experimental model of TIC was described by Whipple et al. in 1962 where he demonstrated that rapid, prolonged atrial pacing resulted in low output heart failure.18 This model has since become widely used as a model to study CHF. Animal studies, primarily in dogs and pigs, have shown that sustained rapid atrial or ventricular pacing results in systolic heart failure that is neurohormonally and haemodynamically similar to left ventricular systolic dysfunction in humans.19–23 The majority of what is known about the pathophysiologic mechanisms underlying TIC is supported by pacing-induced heart failure in animal models (see Table 2). It is important to recognise that although rapid pacing likely provides a close approximation to the effects of native tachyarrhythmias, this supposition cannot be definitively confirmed. Asynchronous ventricular pacing as well as atrioventricular (AV) sequential pacing at physiologic heart rates have been shown to be associated with increased rates of heart failure.24

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What About Tachycardia-induced Cardiomyopathy?

The mechanism of heart failure development in chronic right ventricular pacing is not entirely known but may in part be due to an abnormal activation pattern of the ventricle. This hypothesis is supported by the fact that various forms of abnormal ventricular activation have been shown to adversely affect left ventricular systolic function including chronic right ventricular pacing,25–27 left bundle branch block28,29 and ventricular pre-excitation.30,31 Given this, chronic atrial pacing is likely a more pure model of TIC, as it should result in fewer electromechanical changes in the ventricles beyond increased rate.

Haemodynamic Changes Sustained rapid atrial or ventricular pacing can produce severe biventricular systolic and diastolic dysfunction in animal models. The degree of ventricular dysfunction as well as its onset appear to be related to the rate and duration of pacing. By pacing at a slower rate or for a shorter duration, a lesser degree of left ventricular dysfunction can be produced.32–35 Although both chronic atrial and ventricular pacing result in left ventricular dysfunction, deterioration of left ventricular ejection fraction (LVEF) and left ventricular cavity dilation are more marked with chronic ventricular pacing than chronic atrial pacing.36 Intermittent ventricular pacing appears to produce a less advanced syndrome of heart failure compared with continuous ventricular pacing.37 As noted above, the differential effects between chronic atrial and ventricular pacing may be due to the effects of chronic dyssynchronous left ventricular contraction with ventricular pacing. The haemodynamic consequences of prolonged pacing in animal models include markedly elevated left ventricular filling pressures,38–40 impaired ventricular contractile function,23,40–43 reduced cardiac output, elevated systemic vascular resistance,20,21,38,42 and increased left ventricular wall stress.34,42,44,45 Loss of myocardial contractility has also been demonstrated as shown by a diminished or absent response to inotropic agents, volume loading and postextrasystolic potentiation.46 Disturbed elastic properties of the left ventricle (LV) have also been reported, which result in a stiffer ventricle and worsening LV diastolic function. In a normal heart, LV torsion reduces transmural fiber strain during systole, and recoil in early diastole is thought to enhance left ventricular filling. Animal models of TIC have shown that LV torsion decreases in the setting of pacing-induced heart failure, and with it the degree of diastolic recoil.47 These changes have been attributed to changes in the geometric orientation of the ventricle with changes in cardiac structural proteins as well as alterations in basement membrane and extracellular matrix function.48,49 As a response to these changes, similar to other forms of CHF, pacing-induced CHF in animal models results in upregulation of the neurohormonal axis leading to elevated levels of serum atrial natriuretic peptide (ANP), renin, aldosterone, angiotensin-II, epinephrine and norepinephrine.50,51 Interestingly, the vasodilator, natriuretic and renin-lowering effects of ANP are blunted in the canine model of TIC due to reduced cyclic guanosine monophosphate (GMP) expression in response to ANP.52 Atrial tissue levels of ANP are reduced while serum levels of ANP are elevated. Brain natriuretic peptide (BNP) levels are also elevated, though to a lesser extent than ANP.53

Structural Changes The most pronounced structural change in TIC is left ventricular cavity dilatation.33,38–40,44 LV dilation is more marked for end-systolic than end-diastolic volumes,41,42 and produces a spherical chamber geometry.38,39,54 Commonly, left ventricular cavity dilation is accompanied by little or no change in LV wall mass with a normal or reduced LV wall

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Table 1: Causes of Tachycardia-induced Cardiomyopathy Supraventricular Atrial fibrillation Atrial flutter Incessant atrial tachycardia Permanent junctional reciprocating tachycardia AV nodal reentrant tachycardia (rare) AV reentrant tachycardia (rare) 1:2 Non-reentrant dual AV nodal tachycardia Persistent rapid atrial pacing Ventricular Ventricular tachycardia Premature ventricular contractions Other Abnormal Activation Persistent right ventricular pacing Left bundle branch block Ventricular pre-excitation AV = Atrioventricular.

Table 2: Myocardial Changes in Animal Models of Tachycardia-induced Cardiomyopathy Haemodynamic Changes Depressed left ventricular function Elevated left ventricular filling pressures Impaired ventricular contractile function Reduced cardiac output Elevated systemic vascular resistance Increased left ventricular wall stress Left ventricular diastolic dysfunction Mitral regurgitation Structural Changes Left ventricular cavity dilation Subendocardial fibrosis Normal or reduced left ventricular wall thickness Reduced myocardial blood flow Cellular Changes Myocyte elongation Increased oxidative stress Myocyte hypertrophy Extracellular matrix/basement membrane disruption Myofibril alignment disruption Reduced myocardial energy stores Mitochondrial dysfunction Down regulation of beta adrenergic receptors Abnormal calcium handling Increased myocyte apoptosis Neurohormonal Changes Increased renin, aldosterone, angiotensin-II, epinephrine, norepinephrine, ANP, BNP, ET-1 ANP = atrial natriuretic peptide; BNP = brain natriuretic peptide; ET-1 = endothelin-1.

thickness.22,39 Cellular changes accompanying the change in chamber size include cellular elongation, decreased myocyte cross-sectional area and disruption of normal myofibril alignment.23,46 Other studies have reported increased numbers of cells in both the longitudinal and transverse sections of intact myocardium from animals with pacing-induced heart failure.55 Chamber dilation and wall thinning has been shown to correlate with loss of myocytes and an increase in volume of the remaining myocytes,56 although other studies have shown remodeling without myocyte hypertrophy.57 Some of these changes may be due to changes in the extracellular matrix with reduction in myocyte attachment to the basement membrane. Mitral regurgitation

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Clinical Arrhythmias has also been seen, likely as a result of an increase in left ventricular dimensions.38 This may then contribute to further left ventricular dilation and dysfunction. Myocardial ischaemia has also been proposed as a mechanism for TIC. Changes in the structure, distribution and function of the coronary vasculature in TIC have been demonstrated, including abnormal subendocardial and subepicardial blood flow ratios, and impaired coronary flow reserve.58,59 These changes may impair myocardial blood flow and limit oxygen delivery, accelerating myocardial injury and worsening ventricular dysfunction. However, it is not clear whether these changes truly contribute to myocardial dysfunction or are a result of increased myocardial demand with rapid pacing and decreased myocardial supply due to elevated ventricular filling pressures and decreased cardiac output. Increased areas of fibrosis have been seen along the subendocardial region of animal hearts with pacing-induced heart failure.23 It may be that increased levels of angiotensin II and aldosterone in this setting trigger increased myocardial fibrosis, as is the case in heart failure of various aetiologies. A significant increase in the number of ventricular myocytes undergoing apoptosis has been shown to be present in TIC.60

Cellular Changes Reduced myocardial energy stores have been implicated in the pathogenesis of TIC including decreased levels of creatine, phosphocreatine, adenosine triphosphate and glycogen, as well as enhanced activity of Krebs cycle oxidative enzymes and decreased activity of the sodium-potassium adenosine triphosphatase (Na-KATPase) pump. These changes are likely related to alterations in cellular metabolism in the setting of mitochondrial injury and decreased mitochondrial activity with increased activity of the Krebs cycle and oxidative stress.19,23,43,61 Increased levels of oxidative stress have been shown to accompany higher degrees of myocyte apoptosis in animal models of TIC. Chronic myocardial stimulation at high rates is believed to cause mitochondrial DNA oxidative damage preferentially given its higher sensitivity compared with nuclear DNA.62 Treatment with selegiline, an inhibitor of monoamine oxidase, has been shown to decrease oxidative stress, myocyte injury and apoptosis.63 Similar results have been shown with the administration of antioxidant vitamins to animals with TIC leading to reduced levels of oxidative stress and attenuated cardiac dysfunction. These effects were not observed in sham-operated animals.64 Elevated endothelin-1 (ET-1) levels have also been reported in animal models of pacing-induced heart failure, and seem to hasten the progression of TIC. ET-1 may play a role in mitochondrial dysfunction as it has been shown to produce mitochondrial changes in the electron transport chain.65 Downregulation of beta-adrenergic receptors and a resultant decreased sympathetic responsiveness has also been described in animals with TIC.66,67 This reduction in beta receptor density and responsiveness to beta-adrenergic stimulation has been shown to be independent of haemodynamic and neurohormonal factors.68 It has also been shown to normalise in the setting of rate control.69 However, it is not clear whether these changes contribute to myocardial dysfunction or whether they are a consequence of prolonged rapid pacing and chronically enhanced sympathetic activity.70 Abnormal calcium handling also seems to play a role in the pathogenesis of TIC. Extensive abnormalities in calcium channel activity and calcium transport in the sarcoplasmic reticulum have

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been seen as early as 24-hours after the initiation of rapid pacing. It appears that the severity of calcium cycling abnormalities correlates with the degree of ventricular dysfunction.43,71 Downregulation of calcium cycling has been correlated with lower activity of sarcoplasmic reticulum calcium transport adenosinetriphosphatase (ATPase) and myofibrillar calcium ATPase.72 Decreased availability of calcium to myocytes may lead to the reduction in contractility seen as a result of TIC.70 Isolated ventricular myocyte preparations have demonstrated decreased density of T-tubules and L-type calcium channels resulting in abnormal excitation–contraction coupling.73 It is important to recognise that many of the changes reported above are not unique to TIC, but are seen in multiple forms of chronic heart failure and may be related, at least in part, to the downstream effects of elevated filling pressures and decreased cardiac output rather than the tachycardia itself. Changes seen early after initiation of rapid pacing are more likely to be related to elevated heart rates themselves, whereas later changes are more likely to be due to a combination of elevated rates as well as the downstream effects of the heart failure syndrome.

Arrhythmogenesis The heart failure state leads to an arrhythmogenic substrate due to the electrical heterogeneity in the myopathic ventricle. Abnormalities in repolarization have been implicated in the genesis of ventricular arrhythmias in all forms of heart failure, with prolonged repolarization being the most frequently reported. Repolarization abnormalities have been demonstrated in a porcine model of TIC evidenced by prolonged QTc intervals, reduced transmural gradients and decreased spatial dispersion of repolarization. Despite these changes, in this study, no deaths due to polymorphic ventricular tachycardia (VT) were observed and the authors concluded that repolarization was uniformly prolonged in their TIC model, attenuating the animals’ predisposition to bradycardia-dependent arrhythmias.74 However, conflicting findings were found in a canine model of TIC where heterogeneous repolarization abnormalities were seen with subsequent development of polymorphic VT. As is the case with all forms of heart failure, in this study, the incidence of VT was increased as heart failure progressed.75 The question remains as to whether TIC has a different risk of ventricular arrhythmias and sudden death compared with other forms of heart failure. Rates of malignant arrhythmias and sudden death are likely to be related to the severity of myocardial dysfunction and heart failure, and therefore may substantially decrease with resolution of TIC.

Time Course and Recovery As noted above, the haemodynamic consequences seen in animal models of TIC can be seen as early as 24 hours after the initiation of rapid pacing. Some haemodynamic changes, such as increased intracardiac filling pressures, increased pulmonary artery pressures and decreased systemic arterial pressures generally plateau at one week, whereas cardiac output, ejection fraction and cardiac volumes may continue to worsen for up to 3–5 weeks.33,38,40,50 Changes in intracardiac filling pressures, cardiac output and systemic vascular resistance are generally reversible with cessation of rapid pacing, although in some cases ejection fraction may not return to baseline and abnormalities in contractile function may persist.33,76 Within 48 hours of cessation of pacing, intracardiac filling pressures, systemic arterial pressures, systemic vascular resistance and cardiac index have been shown to return to levels similar to control animals.34

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Significant improvements in LVEF have been shown by 24–48 hours with normalisation after 1–2 weeks.34,41 However, residual contractile dysfunction has been seen to persist in isolated myocytes for up to four weeks.77 Within four weeks, all haemodynamic variables return to control levels while end-systolic and end-diastolic volumes remain elevated twelve weeks after termination of pacing.33,41,42,54 Left ventricular hypertrophy has been shown to develop after the cessation of rapid pacing. The mechanism of this hypertrophy seen during recovery is not known but may be due to an inability to respond to hypertrophy signals during pacing or potentially a compensatory remodeling response.32,54,77 Proliferation of large collagen fiber bundles after termination of pacing has been seen and may contribute to the left ventricular hypertrophy noted during recovery.78

Premature Ventricular Contractions and Tachycardia-induced Cardiomyopathy Less is known about the effects of premature ventricular contractions (PVCs) on LV function given the smaller number of animal models in this setting. A recent study published the results of a canine model of PVC-induced cardiomyopathy through the use of right ventricular (RV) apical pacing in a bigeminal pattern. All animals with PVCs developed reduced LVEF and enlarged LV systolic dimension. In all dogs with PVCs, the cardiomyopathy was reversible four weeks after cessation of PVCs. Despite the development of LV dysfunction based on echocardiography, the dogs with PVC-induced cardiomyopathy did not show increased inflammation, fibrosis or apoptosis compared with control animals. Inflammatory infiltrates were absent and there was no evidence of abnormal mitochondrial phosphorylation. They did find that ventricular refractory periods prolonged in the PVC-induced cardiomyopathy model suggesting some amount of electrical remodeling, potentially related to alterations in intracellular ion channels. The authors concluded that the abnormalities in PVC-induced cardiomyopathy are functional rather than structural based on these findings.79 However, further research to replicate and expand on these findings is necessary.

Human Studies Multiple arrhythmias have been associated with TIC including AF, incessant supraventricular tachycardia of various forms and VT. Additionally, premature ventricular beats of sufficient frequency have also been associated with the development of TIC in humans. Restoration of sinus rhythm, control of the ventricular response or decrease in the frequency of premature contractions all result in an improvement in left ventricular function and clinical heart failure. Despite reports of reversible cardiomyopathy in the setting of chronic tachycardia for the last hundred years, prospective studies of TIC did not begin until the last few decades, and many reports are descriptive in nature with interpretation and application limited by small study size. TIC can occur at any age and has been reported as early as in utero80 but is also seen in infants, children81–83 and adults. The incidence of TIC is unknown, given that most reports in the literature are small retrospective series or case studies involving individual patients. Estimations of incidence are also limited by the fact that TIC is a diagnosis of exclusion and no single test can be performed to confirm or refute its presence. TIC is likely an under diagnosed phenomenon with the true incidence being higher than what has been reported thus far in the literature.

Atrial Fibrillation The most rigorously studied aetiology of TIC in human subjects is chronic AF. AF is known to increase risk of heart failure irrespective of

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the heart failure aetiology.84 However, in a certain subset of patients with heart failure and AF, restoration of sinus rhythm or control of ventricular rates will markedly improve or normalise left ventricular function suggesting the tachycardia itself as the underlying cause of the myopathy. Early studies of cardioversion for AF demonstrated an improvement in cardiac output, cardiopulmonary exercise testing and LVEF with return to sinus rhythm.85–88 A proportion of patients with ‘idiopathic’ dilated cardiomyopathy and chronic AF will have a significant increase in LVEF after pharmacologic or electrical conversion to sinus rhythm. A study assessing the time course of improvement in left ventricular function following cardioversion of AF to sinus rhythm demonstrated that atrial systolic function improved one week after return to sinus rhythm, whereas LVEF and peak oxygen consumption lagged behind and did not show improvement until one month following cardioversion. These results suggested the presence of an underlying ventricular myopathy causing heart failure rather than only the loss of atrial contractile function and atrioventricular synchrony.89 Further support of this concept has been shown in studies of chronic AF and heart failure treated with AV junction ablation and permanent ventricular pacing where a similar improvement in left ventricular function is seen with normalisation of ventricular rates irrespective of the atrial rhythm and function.6,90–93 However, it seems that rate alone is not the only causative factor in TIC. In a small series of patients with AF and a controlled ventricular response, AV junction ablation and pacemaker implantation resulted in a significant improvement in LVEF, fractional shortening and functional capacity suggesting that regularity and not rate alone has an effect on left ventricular function in chronic AF.94 A more recent study of catheter ablation for AF reported an improvement in LV function following catheter ablation. This study also found that only a minority of the patients with depressed LV function had elevated ventricular rates on routine monitoring prior to ablation.95 Another important insight derived from this study is that improvement in LV function following return to sinus rhythm was not an artifactual change related to difficulty in interpreting LV systolic function by echocardiogram when in AF, as this study measured LV function in sinus rhythm one day following the ablation as well as six months later. Although in this instance, one could also question whether the ejection fraction post-procedure was an adequate representation of pre-procedure LV function.96

Atrial Tachycardia Incessant atrial tachycardia (AT), although a relatively uncommon supraventricular tachycardia, is a well-known cause of TIC. The term incessant refers to an AT that is present at least 90 % of the time.97 The arrhythmogenic mechanism is generally increased automaticity of an ectopic atrial pacemaker.98 Rates tend to be related to levels of alertness and activity, and may increase during pregnancy as the ectopic focus tends to be sensitive to autonomic modulation. Myocardial dysfunction in the setting of incessant AT has been reported in approximately 10 % of patients and has been shown to be more prevalent in younger patients.99 Surgical treatment of incessant AT has been reported to result in improvement in dilated cardiomyopathy.11,100,101 Advancements in catheter ablation have allowed for definitive therapy of incessant AT without requiring surgery, which has also been shown to result in normalisation in LV function in a majority of patients.9,10 The most recent series of incessant AT patients reported normalisation of LV function in 97  % of patients after successful ablation.99

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Clinical Arrhythmias Figure 1: Atrioventricular Reciprocating Tachycardia and Tachycardia-induced Cardiomyopathy

Figure 2: Physiology of 1:2 Non-reentrant Dual Atrioventricular Nodal Tachycardia

Physiology of 1:2 Non-reentrant Dual Atrioventricular Nodal Tachycardia. The top panel depicts selected surface electrodes from a 12-lead electrocardiogram of a patient with 1:2 non-reentrant dual atrioventricular nodal tachycardia. This demonstrates two QRS complexes following each P wave. The bottom panel is a ladder diagram depicting the propagation of two wavefronts through the AV node both originating from a single atrial activation leading to two ventricular depolarizations for every atrial depolarization. A = atrium; AV = atrioventricular node; HB = His bundle; HP = His-Purkinje system; V = ventricle.

form of non-reentrant AV nodal tachycardia. In this scenario, a single sinus

A 62-year-old man without significant past medical history presented with new onset heart failure symptoms. His electrocardiogram on presentation revealed a wide complex tachycardia and an echocardiogram demonstrated a left ventricular ejection fraction (LVEF) of 10–15 % with normal left ventricular (LV) wall thickness and a moderately dilated LV cavity. An electrophysiology study was performed, which made the diagnosis of atrioventricular reciprocating tachycardia (AVRT) with a concealed left lateral accessory pathway, which was successfully abated. A follow-up echocardiogram one month later demonstrated an improved LVEF to 35–40 % and an echocardiogram performed one year later demonstrated normal LV wall thickness, cavity size and systolic function.

Reentrant Supraventricular Tachycardias Reentrant supraventricular tachycardias, including atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reciprocating tachycardia (AVRT) are most commonly paroxysmal but rarely can be incessant in nature. The latter category would include persistent junctional reciprocating tachycardia (PJRT), a form of incessant AVRT. When cardiomyopathy develops in this setting, the arrhythmias are generally incessant. Given that incessant reentrant supraventricular tachycardias are less common, they are also less well studied, with smaller series of patients reported, but TIC has been reported in the setting of AVNRT, AVRT and PJRT.102–106 As is the case with TIC and incessant AT, definitive treatment of the causative arrhythmia with pharmacologic suppression,105 surgery102,103 or catheter ablation,103,104,106 results in reversal of left ventricular dysfunction (see Figure 1). In general, once these arrhythmias become incessant, pharmacologic suppression is difficult and definitive treatment with catheter ablation is recommended.

1:2 Non-reentrant Dual Atrioventricular Nodal Tachycardia Dual AV nodal physiology provides the substrate for the most common paroxysmal supraventricular tachycardia, AVNRT. As noted above, it is rare for AVNRT to become incessant and lead to TIC. However, dual AV nodal physiology can also facilitate the development of TIC through an incessant

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beat may result in two ventricular depolarizations with double antegrade conduction via fast and slow pathways.107 1:2 tachycardia occurs when this phenomenon repeats with such frequency that tachycardia ensues (see Figure 2). The exact prevalence of 1:2 non-reentrant dual AV nodal tachycardia is difficult to determine as published studies of this tachycardia are limited, making the frequency of TIC in this setting difficult to determine. In a recent review of the literature, 44 cases of 1:2 nonreentrant dual AV nodal tachycardia were described between 1970 and 2010. Of these 44 cases, eight patients had a reduced LVEF <45  %. All eight of these patients underwent catheter ablation of the slow AV nodal pathway with subsequent normalisation of left ventricular function in all cases (see Figure 3). A ninth patient was reported to have normalisation of left ventricular dysfunction after rate control alone.108

Ventricular Tachycardia Reports of TIC in the setting of sustained monomorphic VT are much less common than with supraventricular tachycardias, since sustained VT is most often associated with some form of underlying structural heart disease. When VT leads to TIC, it is generally idiopathic and most commonly originates from the right ventricular outflow tract, left ventricular outflow tract or coronary cusps. Rarely, these arrhythmias may become persistent or repetitive enough to result in reversible left ventricular dysfunction.13,15,16 A recent single-centre series of 249 patients without overt structural disease and frequent monomorphic PVCs or repetitive sustained VT reported sustained monomorphic VT with or without PVCs in 11 % of patients. Only 7 % of patients had TIC. However, the presence of repetitive monomorphic VT was a significant predictor of TIC, particularly when it was the predominant arrhythmia on 24-hour Holter monitoring.109 As is the case with supraventricular arrhythmias, left ventricular dysfunction generally normalises following ablation of the arrhythmia.15,16,110

Premature Ventricular Contractions PVCs have been associated with the development of TIC in the absence of sustained ventricular arrhythmias, and the severity of TIC is generally related to the burden of ventricular ectopy.109,111–113 Although

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the number of ventricular activations may increase with frequent PVCs, true tachycardia may not be present despite development of cardiomyopathy suggesting that, as is the case with AF, other factors must play a role in the development of LV dysfunction beyond rate. It has been postulated that electrical activation originating within the ventricular myocardium due to PVCs causes an inefficient mechanical ventricular contraction lacking synchronous myocardial activation. When persisting on a repetitive long-term basis, dyssynchronous ventricular contraction presumably leads to deterioration in LV function through remodeling effects. This is supported by the fact that similar adverse effects of abnormal ventricular activation on left ventricular systolic function have been observed in patients with chronic right ventricular pacing,25–27 left bundle branch block28,29 and ventricular pre-excitation30,31 as noted previously. As with idiopathic VT, idiopathic PVCs have a predilection for the outflow tracts and coronary cusps, although the development of TIC is thought to be irrespective of the PVC origin.114,115 Several studies have shown that PVC frequency correlates with extent of LV dysfunction. Patients with decreased LVEF at the time of presentation have been found to have a higher mean PVC burden as compared with those with normal LV function.111,113,116 However, a clearly defined cut-off at which time TIC is likely to develop has not been determined nor has the approach to this definition. Some studies have focused on PVC burden as a percentage of total ventricular activations while others have examined the absolute number of PVCs in a 24-hour period. An early study reported that patients with a PVC burden of 20 % were more likely to have impaired LV function compared with those patients with a PVC burden of <20 %.76 A later study found that a PVC burden of 16 % by a receiver operating characteristic (ROC) curve analysis best separated patients with and without TIC.109 Most recently, a PVC burden of 24 % was reported to be strongly associated with the presence of cardiomyopathy, although this cut-off value failed to identify every individual at risk of cardiomyopathy and the critical burden for some patients was noted to be lower.111 From the perspective of absolute PVC number, >20,000 PVCs in 24 hours was reported to correlate with a reduction in LVEF.117,118 Interestingly, LV dilation was associated with an increased burden of PVCs but not an absolute PVC frequency.118 Another study reported that dividing patients into groups based on total PVC burden from <1,000 PVCs/day, 1,000–10,000 PVCs/day and >10,000 PVCs/day yielded a prevalence of LV dysfunction of 4 %, 12 % and 34 %, respectively.119 It is clear that the likelihood of TIC development increases with increasing PVC burden. However, what is also clear is that PVC burden is not the only contributing factor to impaired LV function. PVC QRS duration has been shown to be associated with the likelihood of TIC development. In one study, a PVC QRS duration of ≥140 milliseconds (msec) was an independent predictor of impaired LVEF.118 This finding was replicated at a second centre, which reported that PVC QRS duration was significantly greater in patients who developed PVC-induced cardiomyopathy as compared with those patients with PVCs but no LV dysfunction. In this study, a PVC QRS duration of >150 msec best differentiated patients with and without PVC-induced cardiomyopathy. An epicardial PVC origin was also independently associated with PVCinduced cardiomyopathy in these patients.120 Along similar lines, PVC QRS duration has been reported to independently predict reversibility of LV dysfunction, with a greater PVC duration predicting a lower likelihood of recovery. In this single-centre study, patients with a PVC QRS duration ≥170 msec were unlikely to normalise their LV function. There was also

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Figure 3: 1:2 Non-reentrant Dual Atrioventricular Nodal Tachycardia and Tachycardia-induced Cardiomyopathy

A 59-year-old woman with hypertension but no other past medical history presented with new onset heart failure symptoms. An echocardiogram revealed a left ventricular ejection fraction (LVEF) of 20 % with normal left ventricular (LV) wall thickness and a dilated LV cavity. Electrocardiogram revealed 1:2 non-reentrant dual atrioventricular nodal tachycardia, which was successfully ablated. Repeat echocardiogram performed two months later revealed normalisation of her LV cavity size and systolic function.

a gradient of PVC duration noted from those with normal, reversible, partially reversible and irreversible LV dysfunction.115 PVC coupling intervals have also been evaluated as a predictor of the development of TIC, although results have been inconsistent. One study reported that patients with PVC coupling intervals ≤600 msec had a lower mean LVEF than those patients with coupling intervals >600 msec.121 A more recent study reported that PVC interpolation predicted the development of PVC-induced cardiomyopathy independent of total PVC burden, albeit with an odds ratio only slightly above one.122 As with all forms of TIC, PVC-induced cardiomyopathy reverses with catheter ablation of PVCs in the majority of cases. In one series, LV function improved or normalised in more than 80 % of patients after a mean of three months following catheter ablation. Only a minority of these patients had echocardiograms performed within one week of ablation. However, in those patients where early echocardiography was performed, over 80 % demonstrated acute improvement in LV function.111 A more recent study reported that over half of all patients had a >25 % increase in LVEF at one-week following ablation and those patients with early improvement had a higher LVEF at 12 months of follow-up compared with patients without early improvement.123 It appears that complete elimination of PVCs is not necessary for improvement in LV function. One study reported an 80 % reduction of PVCs resulted in similar improvement in LV function compared with complete PVC elimination, although the magnitude of LVEF

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Clinical Arrhythmias improvement did correlate with the decline in residual PVC burden.114 A more recent study confirmed these findings reporting that the majority of patients with idiopathic PVCs and LV dysfunction whose PVC burden was reduced by more than 80 % normalised their LVEF within four months.124 This finding is important given that total elimination of some idiopathic PVCs can be challenging due to origins difficult to ablate from a transvenous approach.

Imaging Studies in Tachycardia-induced Cardiomyopathy Multiple animal models have suggested that the structural changes seen in TIC are unique from other forms of heart failure. Recent studies have looked at echocardiography and cardiac magnetic resonance (CMR) in humans with TIC in an attempt to better understand the underlying pathophysiology of TIC. It has been reported that patients with TIC and no other underlying structural disease have a smaller left ventricular end-diastolic diameter, LV volume when adjusted for body surface area (BSA) and LV mass index as compared with patients with idiopathic dilated cardiomyopathy at the time of initial presentation. In this study, LV end-diastolic dimension was the only independent predictor of TIC in multiple regression analysis and was felt to be the best echocardiographic predictor of TIC.125 Negative remodeling has been associated with TIC and has been shown to persist after resolution of the tachycardia. One study found that most echocardiographic abnormalities seen in TIC patients normalised following treatment of the causative tachycardia. However, when compared with gender, age and ejection fraction matched controls, patients with TIC had a significantly higher stroke volume, cardiac index, left ventricular end-systolic dimension, left ventricular end-systolic volume index and left ventricular end-diastolic index. The mean time interval between pre-treatment and post-treatment echocardiograms was 14 months in this group.126 These findings are consistent with previously discussed animal models of TIC, which found that after ejection fraction and other haemodynamic parameters normalised, LV volumes remained increased. However, in these animal models such persistent changes were only documented out to 12 weeks.33 Late gadolinium enhancement (LGE) on CMR has been shown to accurately identify areas of myocardial fibrosis and different patterns of LGE have been reported according to cardiomyopathy aetiology. One case series of patients with TIC related to ventricular arrhythmias found that LGE was present in only a single patient out of the 19 patients with TIC, imaged with CMR. Of note, five patients with primary cardiomyopathy were also scanned with CMR and four of the five patients had evidence of LGE.127 The investigators concluded that PVC-induced cardiomyopathy is less likely to have LGE on CMR as compared with other forms of cardiomyopathy. Consistent with this finding, a recent canine model of PVC-induced cardiomyopathy failed to demonstrate increased inflammation, fibrosis or changes in apoptosis or mitochondrial function.

Risk of Recurrence It has been reported that recurrent tachycardia in patients with a prior history of TIC can lead to recurrent cardiomyopathy at a faster and more severe rate as compared with initial presentations, suggesting that although LVEF normalises, some structural abnormalities related to remodeling persist. In a cohort of 24 patients with TIC, five patients were noted to have recurrent tachycardia. In all five patients, an abrupt drop in ejection fraction was noted and all patients developed clinical heart

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failure within six months. Heart failure was reversed over a similar six month period once adequate rate control was established.128 A separate case series also reported recurrence in two of twelve consecutive patients during an average follow-up period of 53 months. In both patients the time from tachycardia symptom onset to the development of recurrent heart failure was less than two weeks, and in one patient was in a single day. Both patients had a decline in LVEF to a level similar to their initial presentation. After control of the arrhythmias, both patients again normalised their ejection fractions.129 An early study of TIC reported a severe deterioration in left ventricular systolic function in two of twelve patients after reversion to AF following cardioversion.130 The more rapid decline in LV function in patients with TIC reported above would suggest persistent structural abnormalities in such patients, which would also be supported by the echocardiographic findings described above. These findings also give additional weight to the importance of maintaining a strong medical regimen for TIC patients even after normalisation of their ejection fraction.

Risk of Sudden Death There is little published data on the risk of sudden death in the setting of TIC. As noted above, animal models have reported conflicting results as to whether TIC leads to a proarrhythmic substrate increasing risk of ventricular arrhythmias. In the setting of clinical heart failure and depressed ejection fraction, one might suspect risks of malignant arrhythmias to be similar to other forms of heart failure. However, the more important question is whether an increased risk of sudden death in patients with a history of TIC persists even after normalisation of LV function. Case reports of patients with TIC who have died suddenly have been published in the literature. One centre reported three patients with a history of TIC who died suddenly. All three patients had TIC in the setting of AF and all patientsâ&#x20AC;&#x2122; LVEF normalised or near normalised with various rate control strategies including cardioversion, antiarrhythmic drugs (AADs) and an ablate and pace strategy. All patients died months to years after normalisation of their ejection fraction and per reports, had no heart failure symptoms nor symptoms of recurrent uncontrolled arrhythmia prior to their death. Of note, these three patients had significantly lower baseline LVEFs compared with the other patients with TIC.128 A separate site published a case report of a young man with incessant supraventricular tachycardia (SVT) who presented in congestive heart failure with evidence of a dilated cardiomyopathy on echocardiography. An endomyocardial biopsy revealed mild interstitial infiltration. His heart failure improved with medical therapy but his tachycardia persisted despite AADs. The patient died suddenly twenty days after discharge and it was postulated that his cardiomyopathy was tachycardia-induced. However, this report is limited by the fact that the patient did not have a clear diagnosis of TIC and could have had idiopathic dilated cardiomyopathy with concurrent SVT.131 A third study reported a patient with atrial flutter and cardiomyopathy, which recovered with heart rate control after eight months of therapy. The patients died suddenly four years after his initial presentation without preceding symptoms of tachycardia or CHF. At the time of this patientâ&#x20AC;&#x2122;s initial presentation with heart failure, he had the highest levels of BNP of all patients with TIC reported.129 Further prospective research is required to better determine whether there is a truly increased risk of ventricular arrhythmia and sudden death in patients with a history of resolved TIC.

Future Perspectives Our current understanding of the mechanisms of LV dysfunction in the setting of TIC is limited. Animal models have helped us better evaluate

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the cellular and haemodynamic mechanisms underlying a pacinginduced model of TIC, but the applicability of these animal models to human disease has yet to be proven. The diagnosis of TIC remains challenging and a high index of suspicion is required given the potential for LV recovery with appropriate treatment. An aggressive approach to arrhythmia treatment, whether it be catheter ablation, AADs or rate control is important in patients with otherwise idiopathic cardiomyopathy when TIC is suspected. Further study of the risk factors for development of TIC will be an important area of future research to help better identify patients who are likely to develop cardiomyopathy in the setting of tachycardia. This may also help identify patients

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who are likely to have improvement in their cardiomyopathy with appropriate treatment of their tachycardia. A genetic approach to TIC risk is also an important area of future research given the wide spectrum of disease in patients with TIC. Recently, a paper reported an angiotensin-converting enzyme polymorphism that increased serum ace levels, which was more common in patients with TIC as compared with patients with tachycardia but no LV dysfunction.132 Imaging techniques may also be helpful at providing insight into the underlying mechanisms of TIC and may also help better characterise patients with cardiomyopathy of unknown aetiology and tachycardia at the time of presentation. n

24. Thackray SD, Witte KK, Nikitin NP, et al. The prevalence of heart failure and asymptomatic left ventricular systolic dysfunction in a typical regional pacemaker population. Eur Heart J 2003;24:1143–52. 25. Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 2002;288:3115–23. 26. Gardiwal A, Yu H, Oswald H, et al. Right ventricular pacing is an independent predictor for ventricular tachycardia/ ventricular fibrillation occurrence and heart failure events in patients with an implantable cardioverter-defibrillator. Europace 2008;10:358–63. 27. Delgado V, Tops LF, Trines SA, et al. Acute effects of right ventricular apical pacing on left ventricular synchrony and mechanics. Circ Arrhythm Electrophysiol 2009;2:135–45. 28. Lee SJ, McCulloch C, Mangat I, et al. Isolated bundle branch block and left ventricular dysfunction. J Card Fail 2003;9:87–92. 29. Blanc JJ, Fatemi M, Bertault V, et al. Evaluation of left bundle branch block as a reversible cause of non-ischaemic dilated cardiomyopathy with severe heart failure. A new concept of left ventricular dyssynchrony-induced cardiomyopathy. Europace 2005;7:604–10. 30. Udink ten Cate FE, Kruessell MA, Wagner K, et al. Dilated cardiomyopathy in children with ventricular preexcitation: the location of the accessory pathway is predictive of this association. J Electrocardiol 2010;43:146–54. 31. Cadrin-Tourigny J, Fournier A, Andelfinger G, Khairy P. Severe left ventricular dysfunction in infants with ventricular preexcitation. Heart rhythm 2008;5:1320–2. 32. Shinbane JS, Wood MA, Jensen DN, et al. Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies. J Am Coll Cardiol 1997;29:709–15. 33. Damiano RJ Jr, Tripp HF Jr, Asano T, et al. Left ventricular dysfunction and dilatation resulting from chronic supraventricular tachycardia. J Thorac Cardiovasc Surg 1987;94:135–43. 34. Moe GW, Stopps TP, Howard RJ, Armstrong PW. Early recovery from heart failure: insights into the pathogenesis of experimental chronic pacing-induced heart failure. J Lab Clin Med 1988;112:426–32. 35. Redfield MM, Aarhus LL, Wright RS, Burnett JC Jr. Cardiorenal and neurohumoral function in a canine model of early left ventricular dysfunction. Circulation 1993;87:2016–22. 36. Zupan I, Rakovec P, Budihna N, et al. Tachycardia induced cardiomyopathy in dogs; relation between chronic supraventricular and chronic ventricular tachycardia. Int J Cardiol 1996;56:75–81. 37. Moe GW, Howard RJ, Grima EA, Armstrong PW. How does intermittent pacing modify the response to rapid ventricular pacing in experimental heart failure? J Card Fail 1995; 1:223–8. 38. Howard RJ, Moe GW, Armstrong PW. Sequential echocardiographic-Doppler assessment of left ventricular remodelling and mitral regurgitation during evolving experimental heart failure. Cardiovasc Res 1991;25:468–74. 39. Shannon RP, Komamura K, Stambler BS, et al. Alterations in myocardial contractility in conscious dogs with dilated cardiomyopathy. Am J Physiol 1991;260:H1903–11. 40. Ohno M, Cheng CP, Little WC. Mechanism of altered patterns of left ventricular filling during the development of congestive heart failure. Circulation 1994;89:2241–50. 41. Howard RJ, Stopps TP, Moe GW, et al. Recovery from heart failure: structural and functional analysis in a canine model. Can J Physiol Pharmacol 1988;66:1505–12. 42. Morgan DE, Tomlinson CW, Qayumi AK, et al. Evaluation of ventricular contractility indexes in the dog with left ventricular dysfunction induced by rapid atrial pacing. J Am Coll Cardiol 1989;14:489–95; discussion 496–8. 43. O’Brien PJ, Ianuzzo CD, Moe GW, et al. Rapid ventricular pacing of dogs to heart failure: biochemical and physiological studies. Can J Physiol Pharmacol 1990;68:34–9. 44. Tanaka R, Spinale FG, Crawford FA, Zile MR. Effect of chronic supraventricular tachycardia on left ventricular function and structure in newborn pigs. J Am Coll Cardiol 1992; 20:1650–60. 45. Moe GW, Angus C, Howard RJ, et al. Evaluation of indices of left ventricular contractility and relaxation in evolving canine experimental heart failure. Cardiovasc Res 1992;26:362–6.

46. Komamura K, Shannon RP, Ihara T, et al. Exhaustion of FrankStarling mechanism in conscious dogs with heart failure. Am J Physiol 1993;265:H1119–31. 47. Tibayan FA, Lai DT, Timek TA, et al. Alterations in left ventricular torsion in tachycardia-induced dilated cardiomyopathy. J Thorac Cardiovasc Surg 2002;124:43–9. 48. Zellner JL, Spinale FG, Eble DM, et al. Alterations in myocyte shape and basement membrane attachment with tachycardia-induced heart failure. Circ Res 1991;69:590–600. 49. Nakamura R, Egashira K, Machida Y, et al. Probucol attenuates left ventricular dysfunction and remodeling in tachycardia-induced heart failure: roles of oxidative stress and inflammation. Circulation 2002;106:362–7. 50. Riegger AJ, Liebau G. The renin-angiotensin-aldosterone system, antidiuretic hormone and sympathetic nerve activity in an experimental model of congestive heart failure in the dog. Clin Sci (Lond) 1982;62:465–9. 51. Moe GW, Stopps TP, Angus C, et al. Alterations in serum sodium in relation to atrial natriuretic factor and other neuroendocrine variables in experimental pacing-induced heart failure. J Am Coll Cardiol 1989;13:173–9. 52. Moe GW, Canepa-Anson R, Armstrong PW. Atrial natriuretic factor: pharmacokinetics and cyclic GMP response in relation to biologic effects in severe heart failure. J Cardiovasc Pharmacol 1992;19:691–700. 53. Moe GW, Grima EA, Wong NL, et al. Dual natriuretic peptide system in experimental heart failure. J Am Coll Cardiol 1993;22:891–8. 54. Tomita M, Spinale FG, Crawford FA, Zile MR. Changes in left ventricular volume, mass, and function during the development and regression of supraventricular tachycardia-induced cardiomyopathy. Disparity between recovery of systolic versus diastolic function. Circulation 1991;83:635–44. 55. Jovanovic S, Grantham AJ, Tarara JE, et al. Increased number of cardiomyocytes in cross-sections from tachycardiainduced cardiomyopathic hearts. Int J Mol Med 1999;3:153–5. 56. Kajstura J, Zhang X, Liu Y, et al. The cellular basis of pacing-induced dilated cardiomyopathy. Myocyte cell loss and myocyte cellular reactive hypertrophy. Circulation 1995;92:2306–17. 57. Spinale FG, Zellner JL, Tomita M, et al. Relation between ventricular and myocyte remodeling with the development and regression of supraventricular tachycardia-induced cardiomyopathy. Circ Res 1991;69:1058–67. 58. Spinale FG, Grine RC, Tempel GE, et al. Alterations in the myocardial capillary vasculature accompany tachycardia-induced cardiomyopathy. Basic Res Cardiol 1992;87:65–79. 59. Shannon RP, Komamura K, Shen YT, et al. Impaired regional subendocardial coronary flow reserve in conscious dogs with pacing-induced heart failure. Am J Physiol 1993; 265:H801–9. 60. Heinke MY, Yao M, Chang D, et al. Apoptosis of ventricular and atrial myocytes from pacing-induced canine heart failure. Cardiovasc Res 2001;49:127–34. 61. Spinale FG, Clayton C, Tanaka R, et al. Myocardial Na+,K(+)ATPase in tachycardia induced cardiomyopathy. J Mol Cell Cardiol 1992;24:277–94. 62. Khasnis A, Jongnarangsin K, Abela G, et al. Tachycardiainduced cardiomyopathy: a review of literature. Pacing Clin Electrophysiol 2005;28:710–21. 63. Qin F, Shite J, Mao W, Liang CS. Selegiline attenuates cardiac oxidative stress and apoptosis in heart failure: association with improvement of cardiac function. Eur J Pharmacol 2003;461:149–58. 64. Shite J, Qin F, Mao W, et al. Antioxidant vitamins attenuate oxidative stress and cardiac dysfunction in tachycardiainduced cardiomyopathy. J Am Coll Cardiol 2001;38:1734–40. 65. Marin-Garcia J, Goldenthal MJ, Moe GW. Selective endothelin receptor blockade reverses mitochondrial dysfunction in canine heart failure. J Card Fail 2002;8:326–32. 66. Calderone A, Bouvier M, Li K, et al. Dysfunction of the betaand alpha-adrenergic systems in a model of congestive heart failure. The pacing-overdrive dog. Circ Res 1991;69:332–43. 67. Marzo KP, Frey MJ, Wilson JR, et al. Beta-adrenergic receptor-G protein-adenylate cyclase complex in experimental canine congestive heart failure produced by rapid ventricular pacing. Circ Res 1991;69:1546–56.

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Clinical Arrhythmias 68. Yonemochi H, Yasunaga S, Teshima Y, et al. Rapid electrical stimulation of contraction reduces the density of betaadrenergic receptors and responsiveness of cultured neonatal rat cardiomyocytes. Possible involvement of microtubule disassembly secondary to mechanical stress. Circulation 2000;101:2625–30. 69. Omichi C, Tanaka T, Kakizawa Y, et al. Improvement of cardiac function and neurological remodeling in a patient with tachycardia-induced cardiomyopathy after catheter ablation. J Cardiol 2009;54:134–8. 70. Umana E, Solares CA, Alpert MA. Tachycardia-induced cardiomyopathy. Am J Med 2003;114:51–5. 71. Perreault CL, Shannon RP, Komamura K, et al. Abnormalities in intracellular calcium regulation and contractile function in myocardium from dogs with pacing-induced heart failure. J Clin Invest 1992;89:932–8. 72. Wolff MR, Whitesell LF, Moss RL. Calcium sensitivity of isometric tension is increased in canine experimental heart failure. Circ Res 1995;76:781–9. 73. Balijepalli RC, Lokuta AJ, Maertz NA, et al. Depletion of T-tubules and specific subcellular changes in sarcolemmal proteins in tachycardia-induced heart failure. Cardiovasc Res 2003;59:67–77. 74. Lacroix D, Gluais P, Marquié C, et al. Repolarization abnormalities and their arrhythmogenic consequences in porcine tachycardia-induced cardiomyopathy. Cardiovasc Res 2002;54:42–50. 75. Pak PH, Nuss HB, Tunin RS, et al. Repolarization abnormalities, arrhythmia and sudden death in canine tachycardia-induced cardiomyopathy. J Am Coll Cardiol 1997;30:576–84. 76. Yamamoto K, Burnett JC Jr, Meyer LM, et al. Ventricular remodeling during development and recovery from modified tachycardia-induced cardiomyopathy model. Am J Physiol 1996;271:R1529–34. 77. Spinale FG, Holzgrefe HH, Mukherjee R, et al. LV and myocyte structure and function after early recovery from tachycardia-induced cardiomyopathy. Am J Physiol 1995;268:H836–47. 78. Spinale FG, Tomita M, Zellner JL, et al. Collagen remodeling and changes in LV function during development and recovery from supraventricular tachycardia. Am J Physiol 1991; 261:H308–18. 79. Huizar JF, Kaszala K, Potfay J, et al. Left ventricular systolic dysfunction induced by ventricular ectopy: a novel model for premature ventricular contraction-induced cardiomyopathy. Circ Arrhythm Electrophysiol 2011;4:543–9. 80. Krapp M, Gembruch U, Baumann P. Venous blood flow pattern suggesting tachycardia-induced ‘cardiomyopathy’ in the fetus. Ultrasound Obstet Gynecol 1997;10:32–40. 81. Dhala A, Thomas JP. Images in cardiovascular medicine. Reversible tachycardia-induced cardiomyopathy. Circulation 1997;95:2327–8. 82. Sanchez C, Benito F, Moreno F. Reversibility of tachycardiainduced cardiomyopathy after radiofrequency ablation of incessant supraventricular tachycardia in infants. Br Heart J 1995;74:332–3. 83. De Giovanni JV, Dindar A, Griffith MJ, et al. Recovery pattern of left ventricular dysfunction following radiofrequency ablation of incessant supraventricular tachycardia in infants and children. Heart 1998;79:588–92. 84. Stewart S, Hart CL, Hole DJ, McMurray JJ. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am J Med 2002;113:359–64. 85. Shapiro W, Klein G. Alterations in cardiac function immediately following electrical conversion of atrial fibrillation to normal sinus rhythm. Circulation 1968;38:1074–84. 86. Lipkin DP, Frenneaux M, Stewart R, et al. Delayed improvement in exercise capacity after cardioversion of atrial fibrillation to sinus rhythm. Br Heart J 1988;59:572–7. 87. Atwood JE, Myers J, Sullivan M, et al. The effect of cardioversion on maximal exercise capacity in patients with chronic atrial fibrillation. Am Heart J 1989;118:913–8. 88. Sacrez A, Kieny JR, Bouhour JB, et al. [Effect of cardioversion of atrial fibrillation on left ventricular function in dilated cardiomyopathy. A multicenter study]. Arch Mal Coeur Vaiss 1990;83:15–21. 89. Van Gelder IC, Crijns HJ, Blanksma PK, et al. Time course of hemodynamic changes and improvement of exercise tolerance after cardioversion of chronic atrial fibrillation

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unassociated with cardiac valve disease. Am J Cardiol 1993;72:560–6. 90. Twidale N, Sutton K, Bartlett L, et al. Effects on cardiac performance of atrioventricular node catheter ablation using radiofrequency current for drug-refractory atrial arrhythmias. Pacing Clin Electrophysiol 1993;16:1275–84. 91. Heinz G, Siostrzonek P, Kreiner G, Gossinger H. Improvement in left ventricular systolic function after successful radiofrequency His bundle ablation for drug refractory, chronic atrial fibrillation and recurrent atrial flutter. Am J Cardiol 1992;69:489–92. 92. Redfield MM, Kay GN, Jenkins LS, et al. Tachycardia-related cardiomyopathy: a common cause of ventricular dysfunction in patients with atrial fibrillation referred for atrioventricular ablation. Mayo Clin Proc 2000;75:790–5. 93. Brignole M, Gianfranchi L, Menozzi C, et al. Influence of atrioventricular junction radiofrequency ablation in patients with chronic atrial fibrillation and flutter on quality of life and cardiac performance. Am J Cardiol 1994;74:242–6. 94. Natale A, Zimerman L, Tomassoni G, et al. Impact on ventricular function and quality of life of transcatheter ablation of the atrioventricular junction in chronic atrial fibrillation with a normal ventricular response. Am J Cardiol 1996;78:1431–3. 95. Gentlesk PJ, Sauer WH, Gerstenfeld EP, et al. Reversal of left ventricular dysfunction following ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2007;18:9–14. 96. Asirvatham SJ. Tachycardia-induced cardiomyopathy, without the tachycardia: yet another reason to ablate atrial fibrillation! J Cardiovasc Electrophysiol 2007;18:15–7. 97. Sung RJ. Incessant supraventricular tachycardia. Pacing Clin Electrophysiol 1983;6:1306–26. 98. Scheinman MM, Basu D, Hollenberg M. Electrophysiologic studies in patients with persistent atrial tachycardia. Circulation 1974;50:266–73. 99. Medi C, Kalman JM, Haqqani H, et al. Tachycardia-mediated cardiomyopathy secondary to focal atrial tachycardia: long-term outcome after catheter ablation. J Am Coll Cardiol 2009;53:1791–7. 100. Bertil Olsson S, Blomström P, Sabel KG, William-Olsson G. Incessant ectopic atrial tachycardia: successful surgical treatment with regression of dilated cardiomyopathy picture. Am J Cardiol 1984;53:1465–6. 101. Gillette PC, Wampler DG, Garson A Jr, et al. Treatment of atrial automatic tachycardia by ablation procedures. J Am Coll Cardiol 1985;6:405–9. 102. Packer DL, Bardy GH, Worley SJ, et al. Tachycardia-induced cardiomyopathy: a reversible form of left ventricular dysfunction. Am J Cardiol 1986;57:563–70. 103. Fishberger SB, Colan SD, Saul JP, et al. Myocardial mechanics before and after ablation of chronic tachycardia. Pacing Clin Electrophysiol 1996;19:42–9. 104. Aguinaga L, Primo J, Anguera I, et al. Long-term follow-up in patients with the permanent form of junctional reciprocating tachycardia treated with radiofrequency ablation. Pacing Clin Electrophysiol 1998;21:2073–8. 105. Leman RB, Gillette PC, Zinner AJ. Resolution of congestive cardiomyopathy caused by supraventricular tachycardia using amiodarone. Am Heart J 1986;112:622–4. 106. Corey WA, Markel ML, Hoit BD, Walsh RA. Regression of a dilated cardiomyopathy after radiofrequency ablation of incessant supraventricular tachycardia. Am Heart J 1993;126:1469–73. 107. Wu D, Denes P, Dhingra R, et al. New manifestations of dual A-V nodal pathways. Eur J Cardiol 1975;2:459–66. 108. Wang NC. Dual atrioventricular nodal nonreentrant tachycardia: a systematic review. Pacing Clin Electrophysiol 2011;34:1671–81. 109. Hasdemir C, Ulucan C, Yavuzgil O, et al. Tachycardia-induced cardiomyopathy in patients with idiopathic ventricular arrhythmias: the incidence, clinical and electrophysiologic characteristics, and the predictors. J Cardiovasc Electrophysiol 2011;22:663–8. 110. Grimm W, Menz V, Hoffmann J, Maisch B. Reversal of tachycardia induced cardiomyopathy following ablation of repetitive monomorphic right ventricular outflow tract tachycardia. Pacing Clin Electrophysiol 2001;24:166–71. 111. Baman TS, Lange DC, Ilg KJ, et al. Relationship between burden of premature ventricular complexes and left ventricular function. Heart Rhythm 2010;7:865–9. 112. Satish OS, Yeh KH, Wen MS, Wang CC. Premature ventricular

contraction-induced concealed mechanical bradycardia and dilated cardiomyopathy. J Cardiovasc Electrophysiol 2005;16:88–91. 113. Bogun F, Crawford T, Reich S, et al. Radiofrequency ablation of frequent, idiopathic premature ventricular complexes: comparison with a control group without intervention. Heart rhythm 2007;4:863–7. 114. Mountantonakis SE, Frankel DS, Gerstenfeld EP, et al. Reversal of outflow tract ventricular premature depolarization-induced cardiomyopathy with ablation: effect of residual arrhythmia burden and preexisting cardiomyopathy on outcome. Heart rhythm 2011;8:1608–14. 115. Deyell MW, Park KM, Han Y, et al. Predictors of recovery of left ventricular dysfunction after ablation of frequent ventricular premature depolarizations. Heart rhythm 2012;9:1465–72. 116. Hasdemir C, Musayev O, Kehribar DY, et al. Chronic Cough and Tachycardia-Induced Cardiomyopathy in a Patient with Idiopathic Frequent, Monomorphic Premature Ventricular Contractions. Pacing Clin Electrophysiol 2013;36(5):e156–8. 117. Niwano S, Wakisaka Y, Niwano H, et al. Prognostic significance of frequent premature ventricular contractions originating from the ventricular outflow tract in patients with normal left ventricular function. Heart 2009;95:1230–7. 118. Del Carpio Munoz F, Syed FF, Noheria A, et al. Characteristics of premature ventricular complexes as correlates of reduced left ventricular systolic function: study of the burden, duration, coupling interval, morphology and site of origin of PVCs. J Cardiovasc Electrophysiol 2011;22:791–8. 119. Kanei Y, Friedman M, Ogawa N, et al. Frequent premature ventricular complexes originating from the right ventricular outflow tract are associated with left ventricular dysfunction. Ann Noninvasive Electrocardiol 2008;13:81–5. 120. Yokokawa M, Kim HM, Good E, et al. Impact of QRS duration of frequent premature ventricular complexes on the development of cardiomyopathy. Heart rhythm 2012;9:1460–4. 121. Sun Y, Blom NA, Yu Y, et al. The influence of premature ventricular contractions on left ventricular function in asymptomatic children without structural heart disease: an echocardiographic evaluation. Int J Cardiovasc Imaging 2003;19:295–9. 122. Olgun H, Yokokawa M, Baman T, et al. The role of interpolation in PVC-induced cardiomyopathy. Heart rhythm 2011;8:1046–9. 123. Hasdemir C, Kartal Y, Simsek E, et al. Time Course of Recovery of Left Ventricular Systolic Dysfunction in Patients with Premature Ventricular Contraction-Induced Cardiomyopathy. Pacing Clin Electrophysiol 2013;36(5):612–7. 124. Yokokawa M, Good E, Crawford T, et al. Recovery from left ventricular dysfunction after ablation of frequent premature ventricular complexes. Heart rhythm 2013;10:172–5. 125. Jeong YH, Choi KJ, Song JM, et al. Diagnostic approach and treatment strategy in tachycardia-induced cardiomyopathy. Clin Cardiol 2008;31:172–8. 126. Dandamudi G, Rampurwala AY, Mahenthiran J, et al. Persistent left ventricular dilatation in tachycardia-induced cardiomyopathy patients after appropriate treatment and normalization of ejection fraction. Heart rhythm 2008;5:1111–4. 127. Hasdemir C, Yuksel A, Camli D, et al. Late gadolinium enhancement CMR in patients with tachycardia-induced cardiomyopathy caused by idiopathic ventricular arrhythmias. Pacing Clin Electrophysiol 2012;35:465–70. 128. Nerheim P, Birger-Botkin S, Piracha L, Olshansky B. Heart failure and sudden death in patients with tachycardiainduced cardiomyopathy and recurrent tachycardia. Circulation 2004;110:247–52. 129. Watanabe H, Okamura K, Chinushi M, et al. Clinical characteristics, treatment, and outcome of tachycardia induced cardiomyopathy. Int Heart J 2008;49:39–47. 130. Kieny JR, Sacrez A, Facello A, et al. Increase in radionuclide left ventricular ejection fraction after cardioversion of chronic atrial fibrillation in idiopathic dilated cardiomyopathy. Eur Heart J 1992;13:1290–5. 131. Afonso MR, França HH. [Sudden death and tachycardiomyopathy in a young man with incessant tachycardia]. Arq Bras Cardiol 1992;58:303–6. 132. Deshmukh PM, Krishnamani R, Romanyshyn M, et al. Association of angiotensin converting enzyme gene polymorphism with tachycardia cardiomyopathy. Int J Mol Med 2004;13:455–8.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

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Clinical Arrhythmias

A Critical Reappraisal of the Current Clinical Indications to Cardiac Resynchronisation Therapy Anton i o S o r g e n t e a n d Ri c c a r d o Ca p p a t o Arrhythmia and Electrophysiology Department, Policlinico San Donato, Milan, Italy

Abstract Cardiac resynchronisation therapy (CRT) is a well-established non-pharmacological treatment option for patients with refractory symptomatic heart failure (HF) already under optimal medical therapy. CRT is founded on the principle that interventricular conduction disturbances and more in particular left bundle branch block (LBBB) are deleterious to cardiac performance, and may contribute to the systolic and diastolic incompetency typical of patients with HF. Although CRT is associated with a not negligible percentage of non-response, all the international guidelines on chronic HF have extended their indications to CRT, also to patients with less symptomatic HF who are already showing signs of systolic dysfunction and interventricular dyssynchrony, without giving any substantial advice to reduce the number of failures of this therapy. This review seeks to point out the potential issues linked to CRT, with the aim of making a reappraisal of the clinical evidences supporting the current indications to CRT, and to figure out which type of research should be warranted in the field for the future to reduce the percentage of non-responders to this therapy.

Keywords Cardiac resynchronisation therapy, heart failure, left bundle branch block, NYHA class II Disclosure: The authors have no conflicts of interest to declare. Received: 1 October 2013 Accepted: 23 October 2013 Citation: Arrhythmia & Electrophysiology Review 2013;2(2):91–4 Access at: www.AERjournal.com Correspondence: Antonio Sorgente, Arrhythmia and Electrophysiology Unit, Policlinico San Donato, Via Morandi 30, 20097 San Donato Milanese, Milan, Italy. E: sorgente.antonio@gmail.com

Cardiac resynchronisation therapy (CRT) is a well-established non-pharmacological treatment option for patients with refractory symptomatic heart failure (HF) already under optimal medical therapy.1 CRT is founded on the principle that interventricular conduction disturbances and especially left bundle branch block (LBBB) are deleterious to cardiac performance and may contribute to the systolic and diastolic incompetency typical of patients with HF.2 Restoring the original synchrony of contraction with biventricular pacing has demonstrated to improve cardiac function and to reduce morbidity and mortality in this population.3 Recently, all the international guidelines on chronic HF have extended their indications to CRT, also to patients with less symptomatic HF who are already showing signs of systolic dysfunction and interventricular dyssynchrony.4 This change in the indications to CRT will surely increase the number of devices that will be implanted in the near future, potentially increasing the number of those patients known as ‘non-responders’. At present, the general understanding is that 20–30 % of patients do not benefit from CRT.3 Lack of response to CRT is a complicated enigma, which raises a lot of attempts at a solution. Indeed, response to CRT, in particular when identified with left ventricular reverse remodeling, has demonstrated to be predictive for long-term outcome in CRT patients. 5 This means that the scientific community should address its future efforts in understanding the reasons, which hide behind lack of response, because increase of response to CRT will eventually result in a better and longer survival of this group of patients.

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Bearing this in mind, our main concern is whether this extension of current indications to CRT affects the incidence of non-responders. Will this number be estimated to increase or decrease? As often happens, to give an answer to the future, it is advisable to look at the past. Indeed, this review seeks to point out the potential issues linked to CRT, with the aim of making a reappraisal of the clinical evidences supporting the current indications to CRT, and to figure out which type of research should be warranted in the field for the future to reduce the percentage of non-responders to this therapy.

What is the Definition of Response to Cardiac Resynchronisation Therapy? There is no universal agreement on what should be considered a positive response to CRT. It is well-known that the definition of response varies greatly among the studies, and that there is a myriad of criteria used to define it. Briefly, there are echocardiographic criteria, clinical criteria and composite criteria – obtained with a combination of the first two. The lack of a universal definition of response to CRT is contributing to the general uncertainty on its real effects, and is a clear obstacle to any significant advancement in the field. Searching PubMed for the words ‘response’ and ‘CRT’ evokes in the majority of cases studies aiming to understand the predictors of response to CRT; whereas articles trying to deepen the understanding of what has to be considered the response to CRT can be counted on the fingers of one hand. Bearing this in mind, it is worthwhile to report the findings of the study by Fornwalt et al.6 that sought to investigate agreement between the various published response criteria to CRT. From a wide literary search performed on Web of Science®

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Clinical Arrhythmias ‘Science Citation Index Expanded™’ database using the topics ‘cardiac resynchronization’ and ‘response’, the authors extrapolated 17 different response criteria from the 26 most relevant publications on the topic. Agreement between response criteria was assessed with information from the baseline and six-month follow-up visits for the 426 patients in the Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) study. Response criteria were classified as echocardiographic if they include echocardiographic measurements, such as left ventricular ejection fraction or left ventricular volumes; and clinical if they include clinical parameters such as New York Heart Association (NYHA) class, six-minute walking test or maximal oxygen consumption (VO2 max). They also found a study in which the criteria used to define the response to CRT were combined (echocardiographic and clinical). Not surprisingly, the agreement calculated with the Cohen kappa (κ) coefficient between all the identified response criteria was poor in 75 % of comparisons and strong only in 4 %. Even more significantly, the authors found a very poor concordance between echocardiographic and clinical response criteria and stated that “the agreement between echocardiographic and clinical criteria for defining a positive response to CRT is only slightly better than that expected by chance alone”. The findings of Fornwalt et al. are not surprising since both echocardiographic and clinical parameters are not completely reliable or interchangeable.

Echocardiographic Parameters Even if monodimensional mode (M-mode) and two-dimensional echocardiography have been routinely used for the inclusion of the patients in the major clinical trials on CRT, and provide excellent diagnostic and prognostic information, it is well-known that these techniques are operator-dependent and that they are based on the geometrical assumption that three-dimensional left ventricular structures can be derived from mono- or two-dimensional slices. The recent advances in computer processing and transducer technology that have made three-dimensional echocardiography (3DE) a reality will perhaps help in overcoming this limitation.7 Indeed, the incremental value of 3DE in assessing left ventricular volume and function is already a reality, and has recently been accredited in the American Society of Echocardiography position paper.8 The use of 3DE should be encouraged during the process of identification of responders to CRT in clinical trials to reduce operator-dependent bias. On the other hand, not all the new echocardiographic technologies have brought real innovation. The results of the PROSPECT trial9 are well-known and unfortunately have demonstrated the unusefulness of echocardiographic measures of mechanical synchrony in this field.

Clinical Parameters The most used clinical parameter in the assessment of the functional status of a patient with HF is NYHA class. Developed in 1928 for use as a clinical tool for a comprehensive cardiac diagnosis,10 NYHA classification has been promoted progressively to an entry criterion or an efficacy outcome measure in several clinical trials, not having the features of objectivity and reliability usually required to this type of measures. Even if uniformity in the definition of a NYHA class is of primary importance to achieve consistency in research settings, poor reproducibility of symptom assessment by physician is unfortunately well-known. A survey of 100 cardiologists11 revealed significant variability in the questions and criteria used to determine NYHA class, and even when same criteria were used to distinguish between different NYHA classes, different physicians often did not agree on

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their assessments. For example, 67 % of the interviewed cardiologists classified a patient who is able to climb a flight of stairs, stopping only one time as NYHA class II and 33 % as NYHA class III. Interestingly, in some studies,12,13 it has shown the difference in patients’ self-assessed functional classification compared with clinician reported NYHA classification. Furthermore, a poor correlation has also been found between NYHA class and some objective measures of cardiac function such as peak oxygen consumption and six-minute walk distances.14 The definition of response to CRT is affected by other not negligible inconsistencies. One inconsistency is related to the definition of the minimum amount of follow-up required to assess the response to CRT – some studies focused on a very short-term timeframe (1–2 days from the implantation), others reported on three or six months. Nevertheless, it has to be stated that, in the clinical setting, evaluation of response to CRT can be done up until one year after the implant, but in most cases occurs in the first six months. A standardisation of the minimum follow-up is warranted for the future. Furthermore, no clear information is available on the inclusion of death in the definition of response to CRT. To reduce these contradictions it will be useful in future to link the response to CRT to the most objectivable parameters, such as left ventricular end-systolic volume reduction, which has showed to predict long-term survival better than improvement in the clinical status.15

What is the Minimum Value of QRS Duration Amenable for Cardiac Resynchronisation Therapy? All international guidelines recommend the implantation of a biventricular pacing device alone or in combination with a defibrillator back-up in patients with symptomatic HF and a duration of the QRS ≥120 milliseconds (ms). The cut-off of 120 ms has been obtained from the most important clinical trials, such as Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) and CArdiac REsynchronisation in Heart Failure (CARE-HF) for patients in NYHA class III and IV, and REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) for patients in NYHA class II (in Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT] trial the cut-off was ≥130 ms). However, how strict should the adherence to this QRS cut-off be? As brilliantly noted by Kramer et al.16 there is a huge discrepancy between the entry and exit criteria in these trials. The 120 ms cut-off used in CARE-HF, COMPANION and REVERSE is significantly different from the mean QRS of the patients really enrolled in these trials, which was between 150 and 160 ms. Furthermore, all subgroup analysis on patients with narrower QRS have failed to demonstrate a clear benefit from CRT. Against this backdrop, all the international guidelines on the topic have given the strongest recommendation to CRT to patients with a QRS duration ≥120 ms, leaving very little space for further investigation in subgroups with narrower QRS intervals. Indeed, any institutional review board or investigator would consider it unethical to exclude in future studies a subgroup of patients who have already received a strong recommendation to receive a CRT device and who potentially can benefit from CRT. A short mention should be made on the importance of QRS morphology. The electrocardiographic criteria of LBBB, which include a QRS duration ≥130 ms, QS or rS in lead V1, broad R waves in leads I, aVL, V5 or V6 and absent q waves in leads V5 and V617 should always be taken into consideration in the process of selection of a candidate for CRT. Indeed in the MADIT-CRT trial18 and in the National Cardiovascular Data

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Registry’s Implantable Cardioverter Defibrillator (ICD) registry,19 patients with a non-LBBB QRS pattern have no benefit from CRT as compared with patients showing a typical LBBB QRS pattern.

What Has to be Included in the Primary Endpoints of Cardiac Resynchronisation Therapy Trials? Are There Specific Admission Criteria to be Fulfilled to Define the Appropriateness of Hospitalisation? No uniform criteria for hospitalisations in the major CRT trials were adopted, nor was there uniformity in the definition of the primary endpoints in the different trials. For example, in the COMPANION trial20 “hospitalization events were defined as an admission to a hospital for any reason that was associated with a date change or the outpatient use of intravenous inotrope and/or vasoactive drugs for HF and for a duration >4 hours”. In the CARE-HF trial,21 “All hospitalizations were adjudicated in a blinded fashion by the end-points committee… Hospitalization with worsening heart failure was defined by the occurrence of increasing symptoms and the need for treatment with intravenous diuretics or a substantial increase in oral diuretics (an increase of at least 40 mg of furosemide per day, 1 mg of bumetanide per day, or 10 mg of torsemide per day) or the initiation of a combination of a thiazide and a loop diuretic”. In the MADIT-CRT trial,22 “the primary end point was death from any cause or nonfatal heart-failure events, whichever came first. The diagnosis of heart failure, which was made by physicians who were aware of study-group assignments, required signs and symptoms consistent with congestive heart failure that was responsive to intravenous decongestive therapy on an outpatient basis or an augmented decongestive regimen with oral or parenteral medications during an in-hospital stay”. In the REVERSE trial,23 “The primary end point of the study was the HF clinical composite response… Using this end point, we classified patients into into 1 of 3 response groups at 12 months after randomization: worsened, unchanged, or improved”. It is difficult for the average clinician to make a reasonable resumptive statement on the results of these high-profile trials, and to understand which patients could benefit mostly from CRT without being affected by a fastidious headache. Lack of agreement in the definition of primary endpoints is not an exclusive of CRT trials. HF trials have been struggling continuously in the past years in looking for objective measures of clinical status, with the conclusion that endpoints critical for one HF study have demonstrated to poorly predict the outcome in another trial, or to be confined to the list of adverse events or exclusion criteria in other publications. For example, rehospitalisations for HF, which are mainly used in the prediction of the outcome in CRT trials, have been relegated to subgroup analysis in ventricular assist device trials. It is time that the HF community standardises the outcomes, which have to be assessed in the randomised clinical trials, considering the huge difference between a patient enrolled in an outpatient source and a patient enrolled during an active hospitalisation.

What is the Definition of ‘Optimal wMedical Therapy’? All the current indications on CRT advise implantation of biventricular devices in patients with HF with electrocardiogram (ECG) evidence

1.

E  uropean Heart Rhythm Association (EHRA); European Society of Cardiology (ESC); Heart Rhythm Society; Heart Failure Society of America (HFSA); American Society of Echocardiography (ASE); American Heart Association (AHA); European Association of Echocardiography (EAE) of ESC; Heart Failure Association of ESC (HFA), Daubert JC, Saxon L, Adamson PB, et al. 2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and

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2.

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of interventricular dyssynchrony and treatment with optimal medical therapy. Just looking at the newest clinical trials on CRT that have induced the extension of the actual indications in patients with less symptomatic HF (REVERSE and Resynchronization–Defibrillation for Ambulatory Heart Failure Trial [RAFT]),24 we encountered a lack in uniformity concerning the definition of optimal medical therapy and how it should be pursued. The REVERSE and RAFT studies suggested target doses of optimal therapy prior to enrolment per discretion of the physician, in accordance with the American College of Cardiology/ European Society of Cardiology/Canadian Cardiovascular Society (ACC/ESC/CCS) guidelines definition of optimal pharmacological therapy including optimal dosing. Unfortunately, while the RAFT trial encouraged up-titration of medications throughout the study, the REVERSE protocol did not require subjects to be on the target dose prior to enrolment, and discouraged up-titration. The consequence is a difficulty in making a real comparison of the two studies and in judging the real benefit given by CRT. It is not surprising then that in the REVERSE trial there was not a true optimisation of drug therapy and doses of HF drug therapy prior to enrolment were significantly below what reasonably could be considered optimal. Indeed, only a reduced percentage of the patients enrolled were under beta-blocker or angiotensin-converting enzyme inhibitors (ACEI)/ angiotensin receptor blockers (ARB) (23.0 % on target beta-blocker dose and only 10.6 % on target ACEI/ARB at baseline). Furthermore, the patients in the CRT-ON arm consistently had a higher mean dose of ACEI/ARB and more subjects were on target doses of ACEI/ARB. There was also a differential dosing at baseline and up to 12 months with the CRT-ON having higher doses of ACEI/ARB. Even though in the RAFT trial up-titration was encouraged throughout the study, only 15.7 % were on target beta-blocker dose and 9.6 % were on target ACEI or ARB at baseline. Furthermore, although medication doses remained fairly stable during the study, in the CRT-defibrillator (D) arm there was a percentage of subjects on target dose superior to that on target dose in the implantable cardioverter defibrillator (ICD) arm. This difference was probably related to the up-titration of dosages during the study and could partially be responsible for the perceived benefit of CRT in this trial. In conclusion, absence of uniformity in the definition of response to CRT, in the minimum QRS required for CRT, in the definition of endpoints and in what should be considered for optimal medical therapy impedes a clear understanding of the results of the major clinical trials and hinders progress in the field. Therefore, we endorse any attempt the scientific community would do in the future to standardise all these complicated matters. For example, future research should concentrate its efforts on the identification of the so-called super-responder patients who might optimise the cost-effectiveness relationship related to CRT. Perhaps a significant help in this context will be given by linking the aetiology and the extent of left ventricular fibrosis to response, as recently demonstrated in different studies using cardiac magnetic resonance as a guide to selection of CRT candidates, and to the deployment of left ventricular leads.25–27 n

management. Europace 2012;14(9):1236–86.  trik M, Regoli F, Auricchio A, Prinzen F. Electrical and S mechanical ventricular activation during left bundle branch block and resynchronization. J Cardiovasc Transl Res 2012;5:117–26. McAlister FA, Ezekowitz J, Hooton N, et al. Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: a systematic review. JAMA 2007;297:2502–14.

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 cMurray JJ, Adamopoulos S, Anker SD, et al. ESC M Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787–847. Ypenburg C, van Bommel RJ, Borleffs CJ, et al. Long-term prognosis after cardiac resynchronization therapy is related

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to the extent of left ventricular reverse remodeling at midterm follow-up. J Am Coll Cardiol 2009;53(6):483–90. F  ornwalt BK, Sprague WW, BeDell P, et al. Agreement is poor among current criteria used to define response to cardiac resynchronization therapy. Circulation 2010; 121:1985–91. Yamani H, Cai Q, Ahmad M. Three-dimensional echocardiography in evaluation of left ventricular indices. Echocardiography 2012;29(1):66–75. Hung J, Lang R, Flachskampf F, et al. 3D echocardiography: a review of the current status and future directions. J Am Soc Echocardiogr 2007;20(3):213–33. C  hung ES, Leon AR, Tavazzi L, et al. Results of the Predictors of Response to CRT (PROSPECT) trial. Circulation 2008;117:2608–16. Bennett JA, Riegel B, Bittner V, Nichols J. Validity and reliability of the NYHA classes for measuring research outcomes in patients with cardiac disease. Heart Lung 2002;31(4):262–70. R  aphael C, Briscoe C, Davies J, et al. Limitations of the New York Heart Association functional classification system and self-reported walking distances in chronic heart failure. Heart 2007;93:476–82. Ekman I, Cleland JCF, Swedberg K, et al. Symptoms in patients with heart failure are prognostic predictors. Insights from COMET. J Card Fail 2005;11(4):288–92. E  isenberg L. Disease and illness: Distinctions between professional and popular ideas of sickness. Cult Med Psychiatry 1977;1:9–23. S  mith RF, Johnson G, Ziesche S, et al. Functional capacity in heart failure. Comparison of methods for assessment and

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their relation to other indexes of heart failure. Circulation 1993;87(6 Suppl):VI88–93. 15. Bertini M, Höke U, van Bommel RJ, et al. Impact of clinical and echocardiographic response to cardiac resynchronization therapy on long-term survival. Eur Heart J Cardiovasc Imaging 2013;14(8):774–81. 16. Kramer DB, Josephson ME. Three questions for evidencebased cardiac electrophysiology. Circ Cardiovasc Qual Outcomes 2010;3(6):704–9. 17. Willems JL, Robles de Medina EO, Bernard R, et al. Criteria for intraventricular conduction disturbances and preexcitation. World Health Organizational/International Society and Federation for Cardiology Task Force Ad Hoc. J Am Coll Cardiol 1985;5:1261–75. 18. Zareba W, Klein H, Cygankiewicz I, et al. Effectiveness of Cardiac Resynchronization Therapy by QRS Morphology in the Multicenter Automatic Defibrillator Implantation TrialCardiac Resynchronization Therapy (MADIT-CRT). Circulation 2011;123(10):1061–72. 19. Peterson PN, Greiner MA, Qualls LG, et al. QRS duration, bundle-branch block morphology, and outcomes among older patients with heart failure receiving cardiac resynchronization therapy. JAMA 2013;310(6):617–26. 20. Anand IS, Carson P, Galle E, et al. Cardiac resynchronization therapy reduces the risk of hospitalizations in patients with advanced heart failure: results from the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial. Circulation 2009;119:969–77. 21. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–49.

22. K  utyifa 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. 23. G  old MR, Thébault C, Linde C, et al. Effect of QRS duration and morphology on cardiac resynchronization therapy outcomes in mild heart failure: results from the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) study. Circulation 2012;126(7):822–9. 24. Food and Drug Administration. Executive Summary. Circulatory System Devices Panel Meeting, 2011. Available at: www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials/ MedicalDevices/MedicalDevicesAdvisoryCommittee/ CirculatorySystemDevicesPanel/UCM282274.pdf (accessed 24 October 2013). 25. Leyva F, Foley PW, Chalil S, et al. Cardiac resynchronization therapy guided by late gadolinium-enhancement cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2011;13:29. 26. C  halil S, Stegemann B, Muhyaldeen SA, et al. Effect of posterolateral left ventricular scar on mortality and morbidity following cardiac resynchronization therapy. Pacing Clin Electrophysiol 2007;30(10):1201–9. 27. Chalil S, Foley PW, Muyhaldeen SA, et al. Late gadolinium enhancement-cardiovascular magnetic resonance as a predictor of response to cardiac resynchronization therapy in patients with ischaemic cardiomyopathy. Europace 2007;9(11):1031–7.

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Cardiac Pacing – Is Telemonitoring Now Essential? H a ra n B u r r i Cardiology Service, University Hospital of Geneva, Geneva, Switzerland

Abstract Modern pacemakers and implantable defibrillators are able to automatically perform tests executed manually during in-office visits; such as measurement of sensing and pacing thresholds. In addition, the devices also record a wealth of diagnostic data that are of clinical relevance. The advent of wireless technology in these devices allows automatic transmission of these data that can be consulted remotely by the physician. There is now solid evidence indicating that remote device follow-up can safely reduce the number of in-office visits, thereby improving convenience for patients and caregivers alike. Remote monitoring with automatic alerts for arrhythmias, heart failure and technical issues, has been shown to dramatically reduce delay to diagnosis of these events compared with standard follow-up; potentially improving patient safety and outcome. For these reasons, remote device management is becoming the standard of care.

Keywords Remote monitoring, telemedicine, implantable cardioverter defibrillator, pacemaker Disclosure: Haran Burri receives fellowship and research grants from Biotronik, Boston Scientific, Medtronic, Sorin and St. Jude Medical. He also serves as a member of the Latitude Advisory Board. Acknowledgement: Haran Burri was funded in part by a grant from the La Tour Foundation for cardiovascular research. Received: 10 March 2013 Accepted: 21 October 2013 Citation: Arrhythmia & Electrophysiology Review 2013;2(2):95–8 Access at: www.AERjournal.com Correspondence: Haran Burri, Cardiology Service, University Hospital of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland. E: haran.burri@hcuge.ch

Patients implanted with a pacemaker (PM) or implantable cardioverter defibrillator (ICD) require regular follow-ups to control the proper function of the implanted device. These technical checks have traditionally been performed manually in-office using a dedicated device programmer. In 1971, transtelephonic monitoring was introduced to remotely follow-up basic parameters (such as battery status and thresholds) of PMs. Many modern PMs and ICDs are able to automatically perform technical checks such as battery status, lead impedance, and sensing and pacing thresholds. With the evolution of communication technology, remote device management has become available that allows PMs or ICDs to automatically transmit this information to the physician. Current guidelines stipulate that the patient should be seen in person at least once a year until battery depletion, with remote management being possible after initial post-operative follow-up.1 When alluding to remote device management, a distinction should be made between remote follow-up (which involves scheduled automatic device interrogations), remote monitoring (which involves automatic unscheduled transmission of alert events such as onset of atrial fibrillation) and patient initiated interrogations (which are full device interrogations initiated manually by the patient, e.g. in response to symptoms).2 Remote device management is widely implemented in the US, where it is reimbursed since 2006, and is being increasingly adopted in Europe.3 This article aims to briefly overview the current status of remote device management.

Existing Systems Remote device management for PMs and ICDs was pioneered by Biotronik, and all other major device companies (Boston Scientific, Medtronic, Inc, Sorin and St. Jude Medical) now also offer their own systems. These function in a similar manner, although they do have

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technical differences. Older implantable devices require a telemetry wand for manual interrogation by the patient, which is an obvious setback. Recent implantable devices have an incorporated antenna that allows wireless automatic data transmission with a unit installed in the patient’s home, and that does not require any action by the patient (other than correctly setting up the system). The data are sent via landline phone or the Global System for Mobile communications (GSM™) network to a secure database server. A message is then sent to the physician by email, short message service (SMS) or by fax (depending on the system and its configuration), who may then consult the data via a secure internet access (see Figure 1). None of the existing systems currently allow remote programming of the implanted device, mainly for security reasons (although this would be technically feasible).

Is Remote Follow-up Safe? It has been shown that <10 % of all scheduled in-office visits are ‘actionable’ (i.e. that they result in changes in medication or device programming). A study reported that 94 % of scheduled in-office ICD clinic visits may just as well have been performed remotely.4 Remote device follow-up allows to safely reduce the numbers of in-office visits, which is attractive both from the patient’s perspective (less travel and waiting time) as well as the healthcare provider’s perspective (quicker and more flexible followup). In the Lumos-T Safely RedUceS RouTine Office Device Follow-Up (TRUST) trial,5 1,339 patients with a single- or dual-chamber ICD were randomised to three-monthly in-office versus remote follow-ups (with an in-office follow-up performed after implantation and at 12-months in all patients). There was a 45 % decrease in numbers of in-office visits in the home monitoring group (2.1/year versus 3.8/year, P<0.001), without any

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Clinical Arrhythmias Figure 1: Typical Function of a Remote Device Management System

The randomized trial of long-term remote monitoring of pacemaker recipients (COMPAS) trial in patients with dual-chamber PMs found that home monitoring allowed delaying scheduled in-office visits for as much as 18 months after device implantation, without any significant difference in major adverse events compared with patients with routine follow-up.7 Current guidelines stipulate that all patients should be seen in-office at least once a year.1 However, over a third of ICD or cardiac resynchronisation therapy defibrillator (CRT-D) patients would prefer to be seen in-office at intervals of 18-months or longer.8 It may be that one day, selected low-risk PM patients may be followedup remotely (especially when using devices with remote monitoring, see below) for the entire device lifetime.

Does Remote Monitoring Improve Patient Outcome? The implanted device communicates wirelessly and automatically with a transmitter installed at the patient’s home. Data are then sent via landline phone connection or by the GSM network to a secure database. The physician is alerted by an SMS, email or fax message, and can then consult the data on a secure webpage. The patient may then be contacted by the physician if necessary.

Figure 2: (Top) Print Screen of the Home Monitoring Webpage Indicating Red Alerts for a Patient who Received Multiple Shocks Due to Lead Fracture While on Holiday in the South of Italy; (Bottom) Electrogram Recording Showing Artefacts on the Rate–Sense Ventricular Channel Indicating Lead Fracture

Remote monitoring has been shown to dramatically reduce the time to detection of events such as arrhythmias and technical issues.5–7,9 Remote monitoring of cardiac arrhythmias, heart failure status (by parameters such as heart rate, daily activity, lung fluid, etc.) as well as device integrity (see Figure 2), has the potential to improve patient outcome. Data analysed as secondary endpoints from several trials are encouraging. In the Clinical Evaluation of Remote Notification to Reduce Time to Clinical Decision (CONNECT) trial9 randomising 1,997 patients implanted with a dual-chamber or biventricular ICDs to remote monitoring versus in-office visits, there was an 18 % reduction (P=0.002) in the length of stay for cardiovascular hospitalisation in the remote monitoring arm. This led to an estimated cost-saving of US$1,793 (95 % confidence interval: US$1,644–1,940) per hospitalisation. In the COMPAS trial7 patients on remote monitoring had a significantly reduced risk of hospitalisation for atrial arrhythmias or for stroke (P<0.05). Incidence of inappropriate shock was also reduced by remote monitoring from 10.4 to 5.0 % (P=0.03) in a sub-analysis of the Effectiveness and Cost of ICD Follow-Up Schedule with Telecardiology (ECOST) trial.10 In the ALTITUDE registry, among 10,272 matched subjects implanted with an ICD or a CRT-D device, patients who were on remote monitoring had an approximately 50 % relative reduction of total mortality compared with those on standard care.11 In the Evolution of Management Strategies of Heart Failure Patients With Implantable Defibrillators (EVOLVO) study,12 patients randomised to remote monitoring had a 35 % (P=0.005) reduction in emergency visits for arrhythmias, heart failure and device-related events compared with a control group with audible alerts (which probably increased the number of emergency visits in this study). These data are encouraging, but need to be confirmed by adequately powered randomised trials, several of which are currently underway.13,14

Which Patient Should Receive Remote Device Management?

The patient was contacted by phone on the same day and instructed to place a magnet on her device and have it inactivated immediately at the nearest hospital to avoid subsequent shocks.

increase in adverse events. In this trial using wireless transmitters with a simple and automatic setup process, 91 % of the daily transmissions were successfully transmitted to the device clinic, ensuring that at any stage recently refreshed data were automatically available for review. A similar rate of 93 % of successful automatic transmission of alerts was reported in the first phase of the MOnitoring Resynchronization dEvices and CARdiac patiEnts (MORE-CARE) trial.6

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There are currently no guidelines on which patient should be followed by remote device management. Some centres include all patients implanted with a device equipped with wireless technology, but current practice is to choose patients on a case-by-case basis. Travel distance and patient mobility should be considered for remote follow-up. Elderly, debilitated patients benefit from remote device management, with participation of the patient’s family or caregivers if manual transmissions are necessary.15 Patients who are professionally active or who spend considerable time abroad are also good candidates for remote follow-up. As it concerns remote monitoring, the sickest patients (e.g. those most likely to present arrhythmias, heart failure, or who are pacemaker-dependent) are those who may benefit the most. Likewise, devices that are most prone to technical issues (e.g. cardiac resynchronisation therapy, leads

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under recall, batteries nearing elective replacement, etc.) are most likely to generate alerts that are of clinical relevance.

Implications for Workflow Whereas remote follow-up is a convenience for both patients8,16 and caregivers,17 remote monitoring adds work burden to the device clinic. Phone contact with the patients in response to the alerts can be time-consuming and may increase patient anxiety. Technical troubleshooting, reviewing of alert messages and patient contact in response to these alerts may require considerable time and effort. Most centres have a device nurse who periodically logs on to the secure servers to perform remote follow-up and to deal with the alert messages. The nurse may perform triage of the alerts (local protocols on how to deal with the different alerts are useful in this respect), and thus filter the data that require attention by the physician. In a study with 117 device patients on a remote monitoring system, a nurse spent 59 minutes/week screening the messages, with 12 minutes/week by the cardiologist to deal with issues that required specific attention.17 Automated algorithms based upon integrated diagnostics (e.g. combining data for lung fluid overload with other parameters18) may also help triage alerts, but these need to be validated in clinical trials. Patients often express a desire to know about the results of their device check, whether in-person or remote. Results of an automatic remote follow-up may be communicated by sending a letter, but some systems allow automatic feedback to the patient (e.g. a text or voice message, St. Jude Medical Merlin.net®) or via a message on the home monitor screen (Boston Scientific LATITUDE®). As current and future generations of patients are likely to increase their use of SMS and email, these may be increasingly employed in the future to provide a rapid, efficient and cheap means to communicate results. It is accepted that remote monitoring is usually only provided during office hours, and patients should be made aware that it does not replace emergency healthcare.2 Many centres require that the patient signs an informed consent form that explains these points.

Economic Aspects A review on the economic implications of remote device management for patients, manufacturers, caregivers and payers has recently been published.19 A Markov model using data from published trials reports that remote device management generates negligible costs after seven years of use (and is increasingly cost-saving after 10 years) despite the initial cost of the home transmitter of £1,334.20 This is mainly due to prolongation of battery life (resulting from a reduction in shocks). In the EVOLVO study, patients on remote monitoring had a reduction of emergency room visits compared with those with audible alerts), leading to cost-savings of 888 euros/patient.21

1. Wilkoff BL, Auricchio A, Brugada J, et al. HRS/EHRA Expert Consensus on the Monitoring of Cardiovascular Implantable Electronic Devices (CIEDs): description of techniques, indications, personnel, frequency and ethical considerations: developed in partnership with the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA); and in collaboration with the American College of Cardiology (ACC), the American Heart Association (AHA), the European Society of Cardiology (ESC), the Heart Failure Association of ESC (HFA), and the Heart Failure Society of America (HFSA). Endorsed by the Heart Rhythm Society, the European Heart Rhythm Association (a registered branch of the ESC), the American College of Cardiology, the American Heart Association. Europace 2008;10:707–25. 2. Dubner S, Auricchio A, Steinberg JS, et al. ISHNE/EHRA expert consensus on remote monitoring of cardiovascular implantable electronic devices (CIEDs). Europace 2012;14:278–93.

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Trials are currently underway in Europe that will be useful to make more accurate evaluations of the financial impact of this technology. Remote follow-up of PMs and ICDs has been reimbursed in the US since 2006, in Germany since 2008 and also in a few other countries, but still needs to be addressed across most of Europe.2,22

Future Perspectives There is room for improvement for some systems to avoid recurrent technical issues (mainly related to data transmission) and ease of utilisation (e.g. avoid requiring in-office visits to reset alerts, full online configuration of alert settings, more possibilities of communicating with the patient via the transmitter, etc.). Energy consumption by the system should be minimised to avoid premature battery drain. Daily transmissions by the Home Monitoring® system of Biotronik for instance consume the equivalent of only a single maximal energy shock over the lifetime of the device according to the manufacturer. The Medtronic system consumes approximately 1–2 days of device longevity for each transmission,23 which are therefore usually performed at intervals of several weeks or months. Prolonging time-to-box replacement by monitoring battery voltage and reducing numbers of shocks with remote monitoring should, however, offset the excess consumption. Data transmission by the GSM network is usually preferred to landline transmission, and most systems have implemented this, at least as an option. Another important technical aspect is that the implanted device should be able to perform all routine measurements (e.g. pacing thresholds of all leads, especially of the left ventricular lead) to be able to replace in-office visits (not all devices are currently able to do so). Direct importation of interrogated data into electronic medical records (EMR) would be a great asset to staff performing device follow-up. Even though most systems are Health Level Seven (HL-7) compatible, few allow direct importation into EMR. A common platform that allows importation of data from most major device companies and exportation to the hospital EMR is commercially available (MediConnect® from Fleischhacker, Germany). Another aspect is the wealth of data available on remote monitoring databases for conducting clinical research.11 The databases are also useful for tracking and reporting product performance.

Conclusions Remote management of PMs and ICDs is preferred to in-office follow-up by many patients and physicians. It will be increasingly adopted to deal with the growing number of device patients, and is also likely to improve outcome. However, the issue of reimbursement needs to be properly addressed by healthcare authorities of most European countries, with economic models tailored to local requirements that will allow this technology to be viable in the long term. n

3. Halimi F, Cantù F; European Heart Rhythm Association (EHRA) Scientific Initiatives Committee (SIC). Remote monitoring for active cardiovascular implantable electronic devices: a European survey. Europace 2010;12:1778–80. 4. Heidbüchel H, Lioen P, Foulon S, et al. Potential role of remote monitoring for scheduled and unscheduled evaluations of patients with an implantable defibrillator. Europace 2008; 10:351–7. 5. 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. 6. Boriani G, Da Costa A, Ricci RP, et al. The MOnitoring Resynchronization dEvices and CARdiac patiEnts (MORE-CARE) randomized controlled trial: phase 1 results on dynamics of early intervention with remote monitoring.

J Med Internet Res 2013;15:e167. 7. Mabo P, Victor F, Bazin P, et al. A randomized trial of long-term remote monitoring of pacemaker recipients (The COMPAS trial). Eur Heart J 2012;33:1105–11. 8. Petersen HH, Larsen MC, Nielsen OW, et al. Patient satisfaction and suggestions for improvement of remote ICD monitoring. J Interv Card Electrophysiol 2012;34:317–24. 9. Crossley GH, Boyle A, Vitense H, et al. The CONNECT (Clinical Evaluation of Remote Notification to Reduce Time to Clinical Decision) trial: the value of wireless remote monitoring with automatic clinician alerts. J Am Coll Cardiol 2011;57:1181–9. 10. 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. 11. Saxon LA, Hayes DL, Gilliam FR, et al. Long-Term outcome after ICD and CRT implantation and influence of remote

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Clinical Arrhythmias device follow-up: the ALTITUDE survival study. Circulation 2010;122:2359–67. 12. Landolina M, Perego GB, Lunati M, et al. Remote monitoring reduces healthcare use and improves quality of care in heart failure patients with implantable defibrillators: the evolution of management strategies of heart failure patients with implantable defibrillators (EVOLVO) study. Circulation 2012;125:2985–92. 13. Burri H, Quesada A, Ricci RP, et al. The MOnitoring Resynchronization dEvices and CARdiac patiEnts (MORE-CARE) study: rationale and design. Am Heart J 2010;160:42–8. 14. Ip J, Waldo AL, Lip GY, et al. Multicenter randomized study of anticoagulation guided by remote rhythm monitoring in patients with implantable cardioverter-defibrillator and CRT-D devices: Rationale, design, and clinical characteristics of the initially enrolled cohort The IMPACT study. Am Heart J 2009;158:364–70.e1.

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15. Folino AF, Breda R, Calzavara P, et al. Remote follow-up of pacemakers in a selected population of debilitated elderly patients. Europace 2013;15:382–7. 16. Ricci RP, Morichelli L, Quarta L, et al. Long-term patient acceptance of and satisfaction with implanted device remote monitoring. Europace 2010;12:674–9. 17. Ricci RP, Morichelli L, Santini M. Home monitoring remote control of pacemaker and implantable cardioverter defibrillator patients in clinical practice: impact on medical management and health-care resource utilization. Europace 2008;10:164–70. 18. Whellan DJ, Ousdigian KT, Al-Khatib SM, et al. Combined heart failure device diagnostics identify patients at higher risk of subsequent heart failure hospitalizations: results from PARTNERS HF (Program to Access and Review Trending Information and Evaluate Correlation to Symptoms in Patients With Heart Failure) study. J Am Coll Cardiol 2010;55:1803–10.

19. Burri H, Heidbüchel H, Jung W, et al. Remote monitoring: a cost or an investment? Europace 2011;13:ii44–8. 20. Burri H, Sticherling C, Wright D, et al. Cost-consequence analysis of daily continuous remote monitoring of implantable cardiac defibrillator and resynchronization devices in the UK. Europace 2013;15(11):1601–8. 21. Zanaboni P, Landolina M, Marzegalli M, et al. Cost-utility analysis of the EVOLVO study on remote monitoring for heart failure patients with implantable defibrillators: randomized controlled trial. J Med Internet Res 2013;15:e106. 22. Boriani G, Burri H, Mantovani LG, et al. Device therapy and hospital reimbursement practices across European countries: a heterogeneous scenario. Europace 2011; 13:ii59–65. 23. Medtronic. Clinician Manual Supplement Protecta™ XT/ Protecta™, 489 Projected Service Life Information Related to Remote Monitoring, Manual no. M945739A001A, Minneapolis 490 (MN): Medtronic Inc., 2010.

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Clinical Arrhythmias

The Electrocardiogram in Athletes Revisited Georg e D K a trit s i s 1 a n d D e m o s t h e n e s G K a t r i t s i s 2 1. Faculty of Medicine, University of Bristol, Bristol, UK; 2. Department of Cardiology, Athens Euroclinic, Athens, Greece

Abstract Cardiovascular-related sudden death is the leading cause of mortality in athletes during sport. Thus, it is of clinical importance to identify ECG changes that represent normal adaptation in athletes, and differentiate them from truly pathological findings. However, a distinction between adaptive and pathological ECG changes in athletes is not always easy. This article discusses exercise-induced ECG changes and the differential diagnosis of conditions that present with similar ECG patterns.

Keywords Athlete’s heart, early repolarization, cardiomyopathy, Brugada Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: Andrew Grace, Deputy Editor of Arrhythmia & Electrophysiology Review, acted as editor for this article. Received: 23 September 2013 Accepted: 28 October 2013 Citation: Arrhythmia & Electrophysiology Review 2013;2(2):99–104 Access at: www.AERjournal.com Correspondence: Demosthenes G Katritsis, Athens Euroclinic, 9 Athanassiadou Street, Athens 11521, Greece. E: dkatritsis@euroclinic.gr

Sudden Cardiac Death in Athletes Cardiovascular-related sudden death is the leading cause of mortality in athletes during sport.1,2 The incidence of sports-related sudden death of any cause in the general population is 0.5–1.7 per 100,000 persons per year.3 This is higher in professional athletes, with a reported incidence of sudden cardiac death (SCD) as 1/43,770 participants per year in the National Collegiate Athletic Association (NCAA),1 and 1/3,100 per year among NCAA Division I male basketball players.1 In other studies, the reported incidence of SCD ranges from 0.26 to 3.60/100,000 per year with the higher rates seen in African/Afro-Caribbean (black) athletes.2,4–8 For comparison, the incidence of SCD in the general population, not necessarily related to sport, is estimated at 100–200/100,000 annually and increases as a function of advancing age, being 100-fold less in adolescents and adults younger than 30 years (1/100,000) than it is in adults older than 35 years.9–11 Vigorous exertion may trigger cardiac arrest or SCD, especially in untrained persons, but habitual vigorous exercise diminishes the risk of sudden death during vigorous exertion.12 Most studies have found inverse associations between regular physical activity and SCD.13 Concerning sports-related sudden death in the general population, a clear diagnosis is made in <25 % of the cases, but is most frequently an acute coronary syndrome (75 %).3 In trained athletes, a diagnosis is usually made in up to 65 % of the cases and usually is cardiovascular disease such as hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), congenital coronary anomalies, genetic channelopathies and myocarditis, with blunt trauma, commotio cordis and heat stroke being less frequent (see Table 1).2–4 Recently, findings from the Race Associated Cardiac Arrest Event Registry (RACER) initiative indicate that marathons and half-marathons are associated with a low overall risk of cardiac arrest (1/184,000) or sudden death (1/259,000). However, event rates, most commonly attributable to hypertrophic cardiomyopathy or atherosclerotic coronary disease, have risen over the past decade among male marathon runners.14

© RADCLIFFE 2013

A mandatory national pre-participation screening strategy with routine electrocardiograms (ECGs) is recommended by the European Society of Cardiology (ESC)15 and the International Olympic Committee,16 mainly based on the beneficial results of screening observed in the Veneto region of Italy.5 The American Heart Association has expressed reservations about the cost-efficiency of this approach, and does not endorse ESC screening.17 Although debatable,2,7 the recent report on data from the US NCAA argues for closer scrutiny.1 Regardless, it is of clinical importance to identify ECG changes that represent normal adaptation in athletes, and differentiate them from truly pathological findings.

Exercise-induced Electrocardiogram Remodeling A differentiation between adaptive and pathological ECG changes in athletes is not always easy.18 Recommendations have been published by the ESC,16 a group of US experts,19 and recently, by an international group of experts in sports cardiology and sports medicine (Seattle criteria, see Tables 2–4).20

Differentiation from Pathologic Conditions Conduction Abnormalities Sinus bradycardia is normal. Only heart rates <30 beats per minute (bpm) and pauses 3 seconds (sec) during wake suggest sick sinus syndrome. First and second degree Type 1 (Wenckebach) blocks are benign and usually resolve with hyperventilation or exercise. Axis between -30 and +115 degrees is also normal.

Left Ventricular Hypertrophy Left ventricular (LV) hypertrophy and dilation occurs with isotonic exercise, whereas isometric exercise will promote LV hypertrophy alone.21 The single most common cardiovascular cause of these unexpected catastrophes appears to be HCM, accounting for about one-third of cases (see Figure 1).22,23 Wall thickness resembling HCM may occur in sporting disciplines that combine isometric and isotonic activity, such as cycling and rowing. Since the phenotypic expression of HCM is variable, and not uncommonly

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Clinical Arrhythmias Table 1: Common Cardiovascular Conditions Associated With Sudden Death in Athletes*

Figure 1: Twelve-lead Electrocardiogram of an Asymptomatic Athlete with Hypertrophic Cardiomyopathy

HOCM Congenital coronary anomalies Genetic channelopathies (Brugada, early repolarization syndrome, LQTS, SQTS, CPVT) Coronary artery disease ARVC Myocarditis Bicuspid aortic valve with stenosis or dilated aortic root WPW Blunt trauma Commotio cordis *: In sports-related sudden cardiac death in the general population, coronary artery disease is the commonest cause. Source: Katritsis, et al. 201318

Table 2: Normal ECG Findings in Athletes These common training-related ECG alterations are physiological adaptations to regular exercise, considered normal variants in athletes and do not require further evaluation in asymptomatic athletes. 1. Sinus bradycardia (≥ 30 bpm) 2. Sinus arrhythmia 3. Ectopic atrial rhythm

The disease was suspected at pre-participation evaluation thanks to electrocardiogram abnormalities consisting of increased QRS voltages and inverted T-waves in lateral leads. Hypertrophic cardiomyopathy was diagnosed by echocardiography afterwards. Source: Corrado, et al. 2010.15

Figure 2: Patterns of Early Repolarization

4. Junctional escape rhythm 5. 1° AV block (PR interval > 200 ms) 6. Mobitz Type I (Wenckebach) 2° AV block 7. Incomplete RBBB 8. Isolated QRS voltage criteria for LVH Except: QRS voltage criteria for LVH occurring with any non-voltage criteria for LVH such as left atrial enlargement, left axis deviation, ST segment depression, T-wave inversion or pathological Q waves 9. Early repolarisation (ST elevation, J-point elevation, J-waves or terminal QRS slurring) 10. Convex (‘domed’) ST segment elevation combined with T-wave inversion in leads V1–V4 in black/African athletes AV = atrioventricular; bpm = beats per minute; LVH = left ventricular hypertrophy; ms = milliseconds; RBBB = right bundle branch block. Source: Drezner JA, 2013.20

includes patients with mild and localised LV hypertrophy, the differential diagnosis with athlete’s heart may be difficult. Usually, however, by contrast to most patients with HCM, athletes have increased left and right ventricular cavity dimensions, and normal diastolic function.22–24 Physiological LV hypertrophy can also be differentiated from hypertrophic cardiomyopathy by tissue Doppler imaging velocity measurements.25 In some cases, protracted deconditioning may be the only way to establish a diagnosis. LV hypertrophy certainly needs further evaluation in the presence of family history of SCD or non-voltage ECG criteria suggesting pathological ECG hypertrophy.

Q Waves Q waves >3 millimetres (mm) in depth and/or >40 milliseconds (ms) duration in any lead except aVR, III and V1, suggest HCM. Standard criteria for myocardial infarction26 in athletes should also be considered in those >40 years of age.

Early Repolarization and ST-T Abnormalities Early repolarization is defined electrocardiographically by either a sharp well defined positive deflection or notch immediately following a positive QRS complex at the onset of the ST-segment, or slurring at the terminal part of the QRS complex (J-waves or J-point elevation, see Figure 2).27 The early repolarization pattern has long been considered

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In the upper panel there is ‘classic definition’ that describes a pattern that is common in the inferior leads of male, black athletes. Source: Perez, et al. 2012.38

to be a benign ECG manifestation (6–13 % in the general population) that is seen more commonly in young healthy men and athletes (22–44 %), and its clinical signi ficance has been questioned.28 Inferolateral early repolarization may be seen in young athletes and is a dynamic phenomenon caused by exercise.29 However, there are data indicating that the early repolarization pattern may be associated with a risk for ventricular fibrillation (VF) and SCD, depending on the location of early repolarization, magnitude of the J-wave and degree of any ST elevation present.27,30–35 A horizontal/descending type (defined as ≤0.1 millivolt (mV) elevation of the ST-segment within 100 ms after the J-point) in the inferior leads, as opposed to a rapidly ascending ST-segment type, may help to identify those individuals who are clearly at risk (see Figures 3 and 4).33,34 However, several obscure points remain with this syndrome. In the Atherosclerosis Risk in Communities (ARIC)

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The Electrocardiogram in Athletes Revisited

Figure 3: Horizontal/Descending ST-segment Patterns from Two Subjects in the General Population

A

B

Figure 5: Different Patterns of Precordial Early Repolarization in Two Healthy Athletes – (A) ST-segment Elevation with Upward Concavity (Arrows), Followed by a Positive T-wave (Arrowheads) and (B) ST-segment Elevation with Upward Convexity (Arrows), Followed by a Negative T-wave (Arrowheads)

A

B

Source: Corrado, et al. 2010.15

Figure 6: Electrocardiogram of a Well-trained, Asymptomatic 24-year-old Soccer Player Source: Tikkanen, et al. 2011.34

Figure 4: Rapidly Ascending (A) and Horizontal (B) ST-segment in the Leads Deploying J-waves (J-waves Marked with Arrowhead)

A

B

ST-segment elevation is observed in V2–V6, but with characteristics totally different from those seen in Brugada syndrome. A coved-type ST-segment elevation is not observed. A rounded or upsloping ST elevation in seen in V2 and V3, whereas V4–V5 show a pattern resembling that commonly encountered in early repolarization syndrome. Source: Antzelevitch, et al. 2005.39 ‘Concave/rapidly ascending’: when there is 0.1 mV elevation of the ST-segment within 100 ms after the J-point and the ST-segment merged gradually with the T-wave. ‘Horizontal/ descending’: when the ST-segment elevation is 0.1 mV within 100 ms after the J-point and continues as a flat ST-segment until the onset of the T-wave. Source: Rosso, et al. 2012.33

study, J-point elevation was associated with an increased risk of SCD in whites and in females, but not in blacks or males.32 An early repolarization pattern in the inferolateral leads occurs in 5 % of apparently healthy individuals,31,36 it may not be consistently seen, and even the horizontal/ descending ST type was seen in 3 % of controls.33,34 A pattern of J-wave and/or QRS slurring (but not of ST elevation) has been associated with cardiac arrest/sudden death in athletes,37 but many healthy athletes have early repolarization with a rapidly ascending pattern. Thus, interpretation of this ECG pattern is not always straightforward. Another confounding factor is the type of ST-segment elevation encountered in well-trained athletes.38 Two types predominate; an elevated ST-segment with upward concavity and positive T-wave is seen in Caucasians, and

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an elevated ST-segment with upward convexity and negative T-wave in African-Caribbean athletes (see Figures 5 and 6). ST-segment elevation is distinguished from Brugada syndrome by an upslope rather than a downslope pattern, and by remaining largely unaffected when challenged with a sodium channel blocker (see Figures 7–9).39,40 African athletes display a large proportion of ECG abnormalities, including an increase in R/S-wave voltage, ST-segment elevation and inverted or diffusely flat T-waves.41 T-wave inversion in the lateral leads is not a training-related phenomenon and may represent the initial expression of underlying cardiomyopathy. However, T-wave inversions in leads V1–V4, appear to represent an ethnic variant of athletes heart.42 Among other conditions, this pattern may also be seen in ARVC (see Figure 10).

Right Ventricular Abnormalities Right ventricular (RV) dilatation and increased free wall thickness have been seen in athletes who perform isotonic or isometric exercise. In

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Clinical Arrhythmias Figure 7: Electrocardiogram Abnormality Diagnostic or Suspected of Brugada Syndrome

Figure 9: Borderline Brugada Electrocardiogram Pattern Mimicking Incomplete Right Bundle Branch Block

A

Type 1 ECG (coved-type ST-segment elevation) is the only diagnostic ECG in Brugada syndrome and is defined as a J-wave amplitude or an ST-segment elevation of ≥2 mm or 0.2 mV at its peak (followed by a negative T-wave with little or no isoelectric separation). Type 2 ECG (saddleback type ST-segment elevation), defined as a J-wave amplitude of ≥2 mm, gives rise to a gradually descending ST-segment elevation (remaining ≥1 mm above the baseline) followed by a positive or biphasic T-wave that results in a saddle-back configuration. Type 3 ECG is a right precordial ST-segment elevation (saddle-back type, coved type, or both) without meeting the aforementioned criteria. Source: Mizusawa and Wilde, 2012.40

Figure 8: Differential Diagnosis Between Representative Right Precordial Electrocardiogram Patterns from (A) a Brugada Patient and (B) Two Trained Athletes

B A

B

Unlike the ‘R-wave’ of RBBB, the ‘J-wave’ (arrows) of Brugada electrocardiogram (ECG) is confined to right precordial leads (V1 and V2) without reciprocal ‘S-wave’ (of comparable voltage and duration) in the leads L1 and V6 (arrowhead). (B) In this case, definitive diagnosis of Brugada ECG was achieved by a drug challenge with sodium channel blockers, which unmasked diagnostic ‘coved-type’ (arrows) pattern (V1 and V2). Source: Corrado, et al. 2010.15

Table 3: Abnormal ECG Findings in Athletes These ECG findings are unrelated to regular training or expected physiological adaptation to exercise, may suggest the presence of pathological cardiovascular disease, and require further diagnostic evaluation. Abnormal ECG Finding Definition T-wave inversion >1 mm in depth in two or more leads V2–V6, II and

aVF, or I and aVL (excludes III, aVR and V1)

ST segment depression ≥0.5 mm in depth in two or more leads Pathologic Q waves

>3 mm in depth or >40 ms in duration in two or

more leads (except for III and aVR)

Complete left bundle

QRS ≥120 ms, predominantly negative QRS complex

branch block

in lead V1 (QS or rS), and upright monophasic R

wave in leads I and V6

Intraventricular

Any QRS duration ≥140 ms

conduction delay

Vertical lines mark the J-point (STJ) and the point 80 ms after the J-point (ST80) where the amplitudes of ST-segment elevation are calculated.‘Coved’ type ST-segment elevation in the patient with Brugada syndrome is characterised by a ‘downsloping’ elevated ST-segment with a STJ/ST80 ratio of 1.9. Right precordial early repolarization patterns in both athletes show an ‘upsloping’ ST-segment elevation with STJ/ST80 ratio <1; 0.70 for the ‘concave’ toward the top (B, top) and 0.68 for the ‘convex’ toward the top (B, bottom) ST-segment elevation. Source: Corrado, et al. 2010.15

black athletes without concomitant symptoms or family history, T-wave inversion and RV enlargement may be a benign finding.43 Recently, intensive, endurance exercise of increased duration (i.e. marathon runners) was reported to result in transient RV dysfunction that is usually reversible, although septal fibrosis was seen in athletes who undergo intensive training for prolonged periods.41 The clinical significance of this observation is uncertain. ARVC is a rare condition, with an estimated prevalence in the general population ranging from 0.10 to 0.02 %,42 but it represents one of the most arrhythmogenic forms of human heart disease and a major cause of sudden death in the young45 (see Figures 10 and 11). Arrhythmias originating from the right ventricular outflow tract (RVOT) either in the form of frequent ventricular ectopics or sustained or not-sustained ventricular tachycardia (VT), may represent idiopathic VT (a rather benign condition) or ARVC. An electrocardiographic scoring system for distinguishing RVOT arrhythmias in patients with ARVC

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Left axis deviation

−30° to −90°

Left atrial enlargement

Prolonged P wave duration of >120 ms in leads I

or II with negative portion of the P wave ≥1 mm in

depth and ≥40 ms in duration in lead V1

Right ventricular

R−V1+S−V5>10.5 mm AND right axis deviation

hypertrophy pattern

>120°

Ventricular pre-excitation PR interval <120 ms with a delta wave (slurred

upstroke in the QRS complex) and wide QRS(>120 ms)

Long QT interval*

QTc≥470 ms (male)

QTc≥480 ms (female)

QTc≥500 ms (marked QT prolongation)

Short QT interval*

QTc≤320 ms

Brugada-like ECG pattern High take-off and downsloping ST segment elevation

followed by a negative T wave in ≥2 leads in V1–V3

Profound sinus

<30 BPM or sinus pauses ≥ 3 s

bradycardia Atrial tachyarrhythmias Supraventricular tachycardia, atrial-fibrillation, atrial-flutter Premature ventricular

≥2 PVCs per 10 s tracing

contractions Ventricular arrhythmias Couplets, triplets and non-sustained ventricular tachycardia *The QT interval corrected for heart rate is ideally measured with heart rates of 60–90 bpm. Consider repeating the ECG after mild aerobic activity for borderline or abnormal QTc values with a heart rate <50 bpm. Drezner JA, et al. Electrocardiographic interpretation in athletes: the ‘Seattle Criteria’. Source: Drezner, et al. 201320

from idiopathic VT has been developed and may be applied to VT or ventricular ectopics46 (see Figure 12 and Table 5).

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The Electrocardiogram in Athletes Revisited

Figure 10: (A) Early Repolarization Pattern in a Healthy Black Athlete Characterised by Right Precordial T-wave Inversion (Arrowhead) Preceded by ST-segment Elevation (Arrow) and (B) Right Precordial T-wave Inversion in a Patient with Arrhythmogenic Right Ventricular Cardiomyopathy

Figure 11: Twelve-lead Electrocardiogram in an Asymptomatic Athlete with Arrhythmogenic Right Ventricular Cardiomyopathy

A

The athlete was referred for further echocardiographic examination and cardiac magnetic resonance because of electrocardiogram abnormalities found at pre-participation evaluation, which consisted of inverted T-waves in the inferior and anteroseptal leads and low QRS voltages in the peripheral leads. Source: Corrado, et al. 2010.15

Table 5: Electrocardiographic Scoring System for Distinguishing RVOT Arrhythmias in Patients with ARVC from Idiopathic VT

B

ECG Characteristic Anterior T wave inversions (V1-V3) in sinus rhythm

Points 3

VT/PVC:

Note that unlike early repolarization, in the ARVC the right precordial leads do not demonstrate any elevation of the ST-segment. Source: Corrado, et al. 2010.15

Table 4: Classification of Abnormalities of the Athlete’s Electrocardiogram Group 1: Common and Group 2: Uncommon and Training-related ECG Training-unrelated ECG Changes Changes Sinus bradycardia

T wave inversion

First-degree AV block

ST segment depression

Incomplete RBBB

Pathological Q waves

Early repolarization

Left atrial enlargement

Isolated QRS voltage criteria for left

Left axis deviation/left anterior

ventricular hypertrophy

hemiblock

Right axis deviation/left posterior

hemiblock

Right ventricular hypertrophy

Ventricular pre-excitation

Complete LBBB or RBBB

Long or short QT interval

Brugada-like early repolarization

European Association of Cardiovascular Prevention and Rehabilitation. Recommendations for interpretation of 12-lead electrocardiogram in the athlete. Source: Corrado, et al. 201015

Bundle Branch Block Incomplete right bundle branch block (RBBB) (QRS <120 ms) is common. However, it should be differentiated from ARVC and Brugada syndrome.

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Lead I QRS Duration ≥ 120 msec

2

QRS Notching (multiple leads)

2

V5 Transition or later

1

Anterior T-wave inversions is defined as T-wave negativity in at least leads V1, V2, and V3. Lead I QRS duration ≥ 120 msec is defined as the duration from the initial deflection of the QRS complex to the end of the QRS complex in lead I. QRS notching in multiple leads is defined as a QRS complex deflection on the up-stroke or down-stroke of >0.5 mV that did not cross baseline occurring in at least two leads. (Figure 12). The precordial transition point is designated as the earliest precordial lead where the R-wave amplitude exceeded the S-wave amplitude. Source: Hoffmayer, et al. 201346.

Figure 12: Example of QRS Notching

Arrows show QRS notching in lead II, III, aVF and aVL. Source: Hoffmayer, et al. 201346

Complete left bundle branch block (LBBB) or RBBB with hemiblock necessitates cardiological work-up including myocardial imaging. ECG of the siblings should also be obtained to exclude genetically determined atrioventricular (AV) conduction disease. Brugada syndrome can also be masked by complete RBBB. For diagnosis in cases of clinical suspicion, relief of RBBB, demonstration of typical ST-segment elevation on repeated ECG recordings, pharmacological tests, or pacing from the right ventricle can be useful.47

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Clinical Arrhythmias Figure 13: Summary of Recommendations for Preparticipation Examination Electrocardiogram Screening ECG Abnormality

Criteria for Further Evaluation Example

Q waves

>3 mm in depth or >40 ms duration in any lead except III, aVR, aVL and V1

LBBB RBBB IVCD

Any QRS > 120 ms

ST depression

>0.5 mm below PR isoelectric line between J-junction and beginning of T waves in V4, V5, V6, I, and aVL >1 mm in any lead

QRP axis deviation

More leftward than -30° More rightward than 115°

T wave inversion

>1 mm in leads other than III, aVR and V1 (except V2 and V3 in woman <25 ears)

QTc interval

>470 ms in males >480 ms in females <340 ms in any athlete

Atrial abnormalities

Right: P wave amplitude >2.5 mm Left: i) Negative portion of P wave in V1, V2 of >40 ms duration and 1 mm in depth; or ii) total P wave duration >120 ms

Brugada pattern

Presence of Type 1 pattern: coved ST segment in V1 and V2 gradually descending into inverted T wave

Pre-Excitation

Delta wave and PR interval <120 ms

Right ventricular hypertrophy

>30 years: i) R wave > 7 mm in V1; or ii) R/S ratio >1 in V1; or III) sum of R wave in V1 and S wave in V5 or V6 > 10.5 mm <30 years: above plus right atrial enlargement, T wave inversion in V2, V3, or right axis deviation > 115°

Ventricular extrasystoles, heart block, and supraventricular arrhythmia

Atrial fibrillation/flutter, supraventricular tachycardia, complete heart block or ≥2 PVCs in one 12 lead ECG

RAA = right atrial abnormality; LAA = left atrial abnormality; RVH = right ventricular hypertrophy; RAD = right axis deviation; RBBB = right bundle branch block; TWI = T-wave inversion; QTc = heart-rate correction of the QT interval. Source: Uberoi, et al. 2011.19

QT Interval Suspicion of long QT (>470 ms in men and >480 ms in women) or short QT (<340 ms) should lead to evaluation by a specialist. A QTC 380 ms may also be a marker of abuse of anabolic-androgenic steroids.

1. Harmon KG, Asif IM, Klossner D, Drezner JA. Incidence of sudden cardiac death in national collegiate athletic association athletes. Circulation 2011;123:1594–600. 2. Maron BJ, Doerer JJ, Haas TS, et al. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980-2006. Circulation 2009;119(8):1085–92. 3. Marijon E, Tafflet M, Celermajer DS, et al. Sports-Related Sudden Death in the General Population. Circulation 2011;124:672–81. 4. Chandra N, Bastiaenen R, Papadakis M, Sharma S. Sudden cardiac death in young athletes: practical challenges and diagnostic dilemmas. J Am Coll Cardiol 2013;61:1027–40. 5. 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(13):1593–601. 6. Holst AG, Winkel BG, Theilade J, et al. Incidence and etiology of sports-related sudden cardiac death in Denmark--implications for preparticipation screening. Heart rhythm 2010;7(10):1365–71. 7. Roberts WO, Stovitz SD. Incidence of sudden cardiac death in Minnesota high school athletes 1993-2012 screened with a standardized pre-participation evaluation. J am coll cardiol 2013;62(14):1298–301. 8. Steinvil A, Chundadze T, Zeltser D, et al. Mandatory electrocardiographic screening of athletes to reduce their risk for sudden death proven fact or wishful thinking? J am coll cardiol 2011;57(11):1291–6. 9. Kong MH, Fonarow GC, Peterson ED, et al. Systematic review of the incidence of sudden cardiac death in the United States. J Am Coll Cardiol 2011;57:794–801. 10. Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation 2010;121:e46–215. 11. de Vreede-Swagemakers JJ, Gorgels AP, Dubois-Arbouw WI, et al. Out-of-hospital cardiac arrest in the 1990’s: a population-based study in the Maastricht area on incidence, characteristics and survival. J Am Coll Cardiol 1997;30:1500–5. 12. Albert CM, Mittleman MA, Chae CU, et al. Triggering of sudden death from cardiac causes by vigorous exertion. N Engl J Med 2000;343:1355–61. 13. Deo R, Albert CM. Epidemiology and genetics of sudden cardiac death. Circulation 2012;125:620–37. 14. Kim JH, Malhotra R, Chiampas G, et al. Cardiac arrest during long-distance running races. N Engl J Med 2012;366:130–40. 15. Corrado D, Pelliccia A, Heidbuchel H, et al. Recommendations for interpretation of 12-lead electrocardiogram in the athlete. Eur Heart J 2010;31:243–59. 16. Bille K, Figueiras D, Schamasch P, et al. Sudden cardiac death in athletes: The Lausanne Recommendations. Eur J Cardiovasc Prev Rehabil 2006;13(6):859–75.

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Recommendations for pre-participation ECG screening are presented in Figure 13. n

17. Maron BJ, Thompson PD, Ackerman MJ, et al. Recommendations and considerations related to preparticipation screening for cardiovascular abnormalities in competitive athletes: 2007 update: a scientific statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology Foundation. Circulation 2007;115:1643–55. 18. Katritsis DG, Gersh BJ, Camm AJ. Athlete’s Heart. In: Clinical Cardiology, Current Practice Guidelines. Oxford University Press, Oxford, UK. 2013;683–8. 19. Uberoi A, Stein R, Perez MV, et al. Interpretation of the electrocardiogram of young athletes. Circulation 2011;124:746–57. 20. Drezner JA, Ackerman MJ, Anderson J, et al. Electrocardiographic interpretation in athletes: the ‘Seattle criteria’. Br J Sports Med 2013;47:122–4. 21. Baggish AL, Wood MJ. Athlete’s heart and cardiovascular care of the athlete: Scientific and clinical update. Circulation. 2011;123:2723-2735 22. Maron BJ. Distinguishing hypertrophiccardiomyopathy from athlete’s heart physiological remodelling: clinical significance, diagnostic strategies and implications for preparticipation screening. Br J Sports Med 2009;43:649–56. 23. Maron BJ. Contemporary insights and strategies for risk stratification and prevention of sudden death in hypertrophic cardiomyopathy. Circulation 2010;121:445–56. 24. Pelliccia A, Maron BJ, Spataro A, et al. The upper limit of physiologic cardiac hypertrophy in highly trained elite athletes. N Engl J Med 1991;324:295–301. 25. Nagueh SF, McFalls J, Meyer D, et al. Tissue Doppler imaging predicts the development of hypertrophic cardiomyopathy in subjects with subclinical disease. Circulation 2003;108:395–8. 26. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Eur Heart J 2012;33:2551–67. 27. Obeyesekere MN, Klein GJ, Nattel S, et al. A clinical approach to early repolarization. Circulation 2013;127:1620–9. 28. Surawicz B, Macfarlane PW. Inappropriate and confusing electrocardiographic terms: J-wave syndromes and early repolarization. J Am Coll Cardiol 2011;57:1584–6. 29. Noseworthy PA, Weiner R, Kim J, et al. Early repolarization pattern in competitive athletes: clinical correlates and the effects of exercise training. Circ Arrhythm Electrophysiol 2011;4:432–40. 30. Derval N, Simpson CS, Birnie DH, et al. Prevalence and characteristics of early repolarization in the CASPER registry: cardiac arrest survivors with preserved ejection fraction registry. J Am Coll Cardiol 2011;58:722–8. 31. Haïssaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008; 358:2016–23. 32. Olson KA, Viera AJ, Soliman EZ, et al. Long-term prognosis

associated with J-point elevation in a large middle-aged biracial cohort: the ARIC study. Eur Heart J 2011;32:3098–106. 33. Rosso R, Glikson E, Belhassen B, et al. Distinguishing “benign” from “malignant early repolarization”: the value of the ST-segment morphology. Heart Rhythm 2012;9:225–9. 34. Tikkanen JT, Junttila MJ, Anttonen O, et al. Early repolarization: electrocardiographic phenotypes associated with favorable long-term outcome. Circulation 2011;123:2666–73. 35. Wu SH, Lin XX, Cheng YJ, et al. Early repolarization pattern and risk for arrhythmia death: a meta-analysis. J Am Coll Cardiol 2013;61(6):645–50. 36. Tikkanen JT, Anttonen O, Junttila MJ, et al. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009;361:2529–37. 37. Cappato R, Furlanello F, Giovinazzo V, et al. J wave, QRS slurring, and ST elevation in athletes with cardiac arrest in the absence of heart disease: marker of risk or innocent bystander? Circ Arrhythm Electrophysiol 2010;3:305–11. 38. Perez MV FK, Froelicher V. Semantic confusion: The case of early repolarization and the j point. Am J Med . 2012;125:843-844. 39. Antzelevitch C BP, Borggrefe M, et al. Brugada syndrome: Report of the second consensus conference: Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005;111 :659–670. 40. Mizusawa Y, Wilde AA. Brugada syndrome. Circ Arrhythm Electrophysiol 2012;5 :606–16. 41. Di Paolo FM, Schmied C, Zerguini YA, et al. The athlete’s heart in adolescent Africans: an electrocardiographic and echocardiographic study. J Am Coll Cardiol 2012;59:1029–36. 42. Papadakis M, Carre F, Kervio G, et al. The prevalence, distribution, and clinical outcomes of electrocardiographic repolarization patterns in male athletes of African/AfroCaribbean origin. Eur Heart J 2011;32:2304–13. 43. Zaidi A, Ghani S, Sharma R, et al. Physiological right ventricular adaptation in elite athletes of African and Afro-Caribbean origin. Circulation 2013;127:1783–92. 44. La Gerche A, Burns AT, Mooney DJ, et al. Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes. Eur Heart J 2012;33:998–1006. 45. Saffitz JE. Arrhythmogenic cardiomyopathy: advances in diagnosis and disease pathogenesis. Circulation 2011;124:e390–2. 46. Hoffmayer KS, Bhave PD, Marcus GM, et al. An electrocardiographic scoring system for distinguishing right ventricular outflow tract arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy from idiopathic ventricular tachycardia. Heart Rhythm 2013;10 :477–482. 47. Aizawa Y, Takatsuki S, Sano M, et al. Brugada syndrome behind complete right bundle-branch block. Circulation 2013;128(10):1048–54.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW


Clinical Arrhythmias

Stroke in Atrial Fibrillation – Long-term Follow-up of Cardiovascular Events T ze- Fa n C ha o, 1 ,2 Ch e r n - E n Ch i a n g 1, 2, 3, 4 a n d S h i h - A n n Ch e n 1, 2 1. Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital; 2. Institute of Clinical Medicine and Cardiovascular Research Center, National Yang-Ming University; 3. General Clinical Research Center, Taipei Veterans General Hospital; 4. Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan

Abstract The incidence of atrial fibrillation (AF) was around 1.5 per 1000 person-years in Taiwan. Systemic thromboembolism is the most severe complication of AF. Risk stratification and adequate thromboembolism prophylaxis is the cornerstone of treatment in AF patients. The CHA2DS2-VASc score is powerful in selecting “truly low-risk” patients who are not necessary to receive anticoagulation therapies. It is also useful in predicting thromboembolic events and mortality for patients undergoing AF ablation. Recently, more and more biomarkers and imaging parameters were reported to be associated with adverse events in AF patients. How could these biomarkers and imaging tools change the current strategy of stroke prevention in AF deserves further investigations.

Keywords Atrial fibrillation, incidence, stroke, CHA2DS2-VASc score, catheter ablation Disclosure: The authors have no conflicts of interest to declare. Received: 16 April 2013 Accepted: 28 August 2013 Citation: Arrhythmia & Electrophysiology Review 2013;2(2):105–8 Access at: www.AERjournal.com Correspondence: Shih-Ann Chen, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan. E: epsachen@ms41.hinet.net

Burden of Atrial Fibrillation Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice, accounting for approximately one-third of hospitalisations for cardiac rhythm disturbances.1 Between 1980 and 2000, the age-adjusted incidence of AF significantly increased from 3.04 to 3.68 per 1,000 person-years in the US.2 The prevalence of AF was lower among African Americans than among Caucasians,3 and it also seemed to be lower in the Asian population.4,5 In a nationwide cohort of 702,502 participants in Taiwan, the AF incidence was around 1.5 per 1,000 person-years.6 Since a considerable number of AF patients was paroxysmal in nature, the incidence and prevalence of AF could be significantly underestimated. Systemic thromboembolism is the most severe complication of AF. It accounts for about 15–20 % of ischaemic strokes.7 AF-related strokes were associated with a poor prognosis as more than 50  % of the survivors remain with a severe deficit, and recurrence may be as high as 12  % per year.8 The risk of AF-related stroke was higher in Caucasian populations than in Asians populations (see Figure 1).4,9–15 AF could in fact drive a prothrombotic or hypercoagulable state, by virtue of its fulfilment of Virchow’s triad for thrombogenesis (blood stasis, endocardial dysfunction/damage, and abnormal haemostasis).16 Therefore, stroke prevention with oral anticoagulants (OACs) is central to the management of AF.

The Usefulness of the CHA 2 DS 2 -VASc Score in Identifying ‘Truly Low-risk’ Patients The most important point in determining the strategy of stroke prevention for AF is how to estimate the thromboembolic (TE) risk accurately. The CHADS2 score is the most commonly used scheme

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in stroke risk stratifications for AF patients,17 despite the fact that it classifies a large proportion of patients as being at ‘intermediate risk’, and several important TE risk factors were omitted in the scoring system.18 Recently, a newly developed scoring system, CHA2DS2-VASc score, which extends the CHADS2 scheme by considering additional stroke risk factors (vascular diseases and female gender) was recommended to be used to guide the antithrombotic therapies for AF patients.19,20 The CHA2DS2-VASc score is most useful in identifying truly low-risk patients, and no antithrombotic therapy is necessary for patients with a CHA2DS2-VASc score of 0.21–23 In the study performed by Taillandier et al., which enrolled a total of 616 AF patients with a CHA2DS2-VASc score of 0, an OAC was prescribed on an individual basis in 273 patients (44  %), antiplatelet therapy alone in 145 patients (24  %), and no antithrombotic therapy in 198 patients (32 %).22 During a follow-up of 876 ± 1,135 days, 38 patients experienced adverse events (10 stroke/thromboembolism, 19 major bleeding, 17 deaths). Prescription of OACs and/or antiplatelet therapy was not associated with an improved prognosis for stroke/thromboembolism (relative risk: 0.99, 95  % confidence interval: 0.25–3.99, p-value: 0.99), nor improved survival or net clinical benefit (combination of stroke/ thromboembolism, bleeding and death). More recently, a nationwide cohort study in Taiwan further demonstrated that AF males with a CHA2DS2-VASc score of 0 have a truly low-risk for stroke, which was similar to that of non-AF patients (1.6 versus 1.6 %, p-value: 0.92) during a follow-up of 57.4 ± 35.7 months.24 In the same study, the annual stroke rate was around 0.92 % for AF females with a CHA2DS2-VASc score of 1 (only due to gender),24 which was lower than that of life-threatening bleeding of dabigatran use in the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) study (1.22 % per year for dabigatran 110 milligrams [mg];

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Clinical Arrhythmias Table 1: Summary of the Studies Investigating the Adverse Events After Catheter Ablation of Atrial Fibrillation Author (Year)

Patient Number and Use of Anticoagulants after Adverse Event Rate Characteristics Catheter Ablation

Main Findings and Predictors of Adverse Events

Oral et al. (2006)29

Paroxysmal AF: 490

Warfarin was used for 3 months

Rate of TEs: 0.9 % within

Discontinuation of anticoagulant therapy

Chronic AF: 265

after catheter ablation. Among 522

30 days of ablation

appears to be safe after successful

55 ± 11 years

patients who remained in sinus

procedure; 0.3 % beyond

catheter ablation of AF, both in

56 % had ≥1 risk

rhythm, warfarin was discontinued in 30 days after the procedure

patients without risk factors for stroke

factor for stroke

79 % of patients without risk factors

and in patients with risk factors other

and in 68 % of patients with ≥1

than age >65 years and history of

risk factor of stroke after 3 months

stroke

Bunch et al. (2009)30 630 AF patients who

123 patients (CHADS2 score 0–1) The 1-year survival free of AF were treated with aspirin (325 mg/day), for the total study population

Low-risk patients with a low CHADS2 score (0–1) can safely be discharged

underwent 934

ablation procedures

and 507 patients (CHADS2 score 0–1: was 71.6 %. There were no

following their procedure on

45.2 %, ≥2: 54.8 %) were treated with strokes/TIA in the aspirin group

aspirin alone

warfarin (goal INR=2–3) after ablation

and 4 events (4 strokes, 0 TIAs)

in the warfarin group. Two

patients in the warfarin group

died of fatal haemorrhage (1

intracranial, 1 gastrointestinal)

Tao et al. (2011)31

520 AF patients

Warfarin was administered for all

Eight (1.5 %) patients suffered

Male: 70.6 %

patients for 3 months after catheter

from late TE (1 month after

only predictor of late TE (OR 5.542, 95 %

56.6 ± 11.8 years

ablation. If no recurrence was

ablation) during the follow-up of

CI 1.416–45.013, p=0.019)

documented for 3 months, warfarin

28 ± 8 months. When TE occurred,

was discontinued for patients with

most (6/8 , 75 %) patients were

documented with reoccurred AF

a CHADS2 score of 0–1. There was a total of 181 patients who withdrew

warfarin

the patients kept anticoagulation

or atrial flutter episodes, and all of

therapy of warfarin with the

actual range of INR of 1.6–2.2

Yagishita et al.

524 AF patients who

(2011)32

received follow-up for at least 3 months to keep the INR

Recurrence of AF/atrial flutter was the

Warfarin was used in every patient for Mean follow-up was 44 ± 13 months. None of the patients

Maintenance of sinus rhythm after catheter ablation of AF

at least 2 years after

between 2 and 3.

without AF recurrence

was associated with a lower

catheter ablation.

Continuation of warfarin beyond

suffered TE events, whereas 3

incidence of TE events

CHADS2 score ≥2: 16 %

3 months was determined at

Recurrences occurred the discretion of the physician.

recurrence did (p-value <0.001).

in 95 patients (18.1 %)

of 95 patients (3 %) with AF

Warfarin was discontinued in 400

One of the 3 was a late AF

(93 %) of 429 patients without

recurrence occurring >12 months

AF recurrence

after catheter ablation

Chao et al. (2011)33

440 paroxysmal and

19 patients (3.4 %) received long-term Systemic TEs occurred in 18

Both the CHADS2 and CHA2DS2-

125 non-paroxysmal

warfarin after catheter ablation

VASc scores were useful predictors of

AF patients

patients (3.2 %) during the

follow-up of 39.2 ± 22.6 months, systemic TEs after catheter ablation with an annual rate around 0.97 % of AF

AF = atrial fibrillation; CI = confidence interval; INR = international normalised ratio; OR = odds ratio; TE = thromboembolism; TIA = transient ischaemic attack.

1.45  % per year for dabigatran 150 mg).25 It should be emphasised that the bleeding risk in RE-LY is under ideal, clinical trial circumstances, and the bleeding rate could probably be even higher in real life. Therefore, OACs may not be necessary for AF females who are younger than 65 years of age and have no significant co-morbidities when weighing the risk and benefit of oral anticoagulant therapies. These evidences further support the recommendation of the 2012 focused updated of the European Society of Cardiology (ESC) guideline suggesting that anticoagulation is not necessary for male patients with a CHA2DS2-VASc score of 0 and female patients with gender alone as a single risk factor (still a CHA2DS2-VASc score of 1) if they fulfil the criteria of ‘age <65 and lone AF’.26 How to estimate the risk of bleeding is also an important issue when determining the strategy for stroke prevention in AF patients. The Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly, Drugs/Alcohol (HAS-BLED) score was derived from the AF population

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enrolled in the Euro Heart Survey,27 and was recommended to be used to evaluate the bleeding risk of OAC therapy in the ESC guideline.26

Long-term Thromboembolic Events After Catheter Ablation of Atrial Fibrillation Since the popularity of catheter ablation of AF continues to escalate,28 understanding the incidence and predictors of TE events after AF ablation is important in determining the strategy of stroke prevention after ablation procedures. Several studies have reported the rate of TE events after AF ablation, which are summarised in Table 1.29–33 Although these studies differed in patients’ CHADS2 scores, strategy of the use of anti-thrombotic agents and ablation procedures, the annual rate of systemic thromboembolisms was lower than 1  % in these investigations. Recurrence of atrial arrhythmias after catheter ablation was an important predictor of TE events, and maintenance of sinus rhythm was beneficial. It may emphasise the advantage of catheter ablation, which can achieve sinus rhythm more effectively

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Stroke in Atrial Fibrillation – Long-term Follow-up of Cardiovascular Events

Could Catheter Ablation of Atrial Fibrillation Reduce Long-term Cardiovascular Events? Catheter ablation is clearly superior to antiarrhythmic drugs regarding sinus rhythm maintenance,34 and may improve quality of life of patients. In the study performed by Fichtner et al., which enrolled a total of 133 AF patients, they demonstrated that the quality of life improved significantly three months after ablation in all patients (regardless of ablation success or AF type) and stayed significantly improved after several years.35 However, the effects of catheter ablation on long-term cardiovascular events and mortality were less understood. Bunch et al. compared the risk of adverse events among 4,212 consecutive patients who underwent AF ablation, 16,848 age/gender matched controls with AF and 16,848 age/gender matched controls without AF.36 The results showed that AF ablation patients have a significantly lower risk of death, stroke and dementia in comparison with AF patients without ablation, which suggested AF ablation may eliminate the increased risk of death and stroke associated with AF. In another study performed by Lin et al., which investigated the effects of catheter ablation on long-term major adverse cardiovascular events (such as stroke/transient ischaemic attack, acute coronary events, peripheral embolism and death),37 a total of 174 patients undergoing AF ablation (minimal CHA2DS2-VASc score of 1) were matched with 174 patients receiving medical treatment using the propensity scores. They demonstrated that in AF patients with a CHA2DS2-VASc score of ≥1, catheter ablation of AF reduced the risk of the total/cardiovascular mortality and total vascular events. However, the above studies were retrospective in nature with insoluble limitations, and further prospective trials, such as Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) and Early treatment of Atrial fibrillation for Stroke prevention Trial (EAST), are necessary to confirm these findings.

Other Predictors of Cardiovascular Events, Which Are Not Included in the CHA 2 DS 2 -VASc Scoring System In addition to the clinical parameters included in the CHA2DS2-VASc scoring system, several predictors of adverse events were identified and may potentially refine clinical risk stratification in AF (see Table 2).38–52 Renal dysfunction was demonstrated to be an important risk factor of strokes in AF patients, although it was not included in the CHA2DS2-VASc scheme.38,39 Since patients with renal dysfunction have a high risk of major bleeding despite good anticoagulation control,53 renal function may not be helpful in identifying patients who should receive anticoagulation therapy. On the contrary, normal renal function may be useful in selecting patients with truly low-risk of TE events, and anticoagulation therapy may not be necessary for these patients. In a recent study, Chao et al. investigated the association between renal dysfunction, defined as an estimated glomerular filtration rate <60 millilitres per minute (ml/min) per 1.73 square metres (m2), and the risk of systemic thromboembolisms in 547 patients receiving AF ablation.40 They found that among patients with a CHA2DS2-VASc score of 0 or 1 and with no renal dysfunction, the TE event rate was only 0.3  %. The result suggested that it may be safe

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Table 2: Factors Associated With Cardiovascular Events in Atrial Fibrillation, Which Are Not Included in the CHA 2 DS 2 VASc Scoring System Predictors Systemic Disease Renal dysfunction38–40 Biomarkers Plasma von Willebrand factor (vWF) levels41–42 Soluble vascular cell adhesion molecule-1 (sVCAM-1) and matrix metalloproteinase 2 (MMP-2)43 Troponin I and NT-proBNP44 High-sensitivity cardiac troponin T and interleukin-645 Adiponectin46 D-dimer47 Imaging Tools Peak velocity of the LA appendage on TEE48 LA fibrosis detected by DE-MRI49 Atrial electromechanical interval on TTE50 Chicken wing LA appendage morphology (protective effect)51 LA appendage dimension52 DE-MRI = delayed enhanced magnetic resonance imaging; LA = left atrium; NT-proBNP = N-terminal prohormone of brain natriuretic peptide; TEE = transoesophageal echocardiogram; TTE = transthoracic echocardiography.

Figure 1: Risk of Atrial Fibrillation-related Stroke in Different Countries 8

Western countries

7 Relative risk of stroke

for AF patients compared with antiarrhythmic drugs. In the study performed by Chao et al., which enrolled a total of 565 patients receiving catheter ablation,33 CHA2DS2-VASc score was proved to be a useful scheme in predicting adverse events independently from AF type, ablation outcome, left atrial size and left ventricular ejection fraction, and was helpful in identifying patients at risk of adverse events among those with a CHADS2 score of 0 or 1. The result of this study further validated the usefulness of the CHA2DS2-VASc score in predicting TE events in AF patients after catheter ablation.

7.1

Asia

6.9

6 5

5.6

5.6

4

3.87

3

3.6 2.78

2 1 0

US

Iceland

UK

Taiwan

China

Japan Singapore

The risk of AF-related stroke was higher in Caucasian populations than in Asians populations.9–15

to discontinue OACs for these patients after catheter ablation of AF. Therefore, whether the combination of renal function and CHA2DS2-VASc scheme could improve the ability of the CHA2DS2-VASc score alone in selecting truly low-risk patients deserves further investigation. Several biomarkers and parameters derived from different imaging tools were reported to be associated with adverse events in AF patients. In the RE-LY sub-study, elevations of troponin I and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are common in patients with AF and independently related to increased risks of stroke and mortality.44 Similarly, a recent study from Spain showed that high-sensitivity cardiac troponin T and interleukin-6 could provide prognostic information that was complementary to clinical risk scores for prediction of long-term cardiovascular events and death.45 However, how these biomarkers could change the current strategy of stroke prevention in AF remains unknown. Several recent studies focused on the potential role of parameters derived from imaging tools, such as echocardiography and delayed

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Clinical Arrhythmias enhanced magnetic resonance imaging, in predicting TE events in AF. Nevertheless, most of these studies were single-centre observations and further validations are necessary.

Conclusion In summary, risk stratification and adequate thromboembolism prophylaxis is the cornerstone of treatment in patients with AF. The CHA2DS2-VASc 1. Fuster V, Rydén LE, Cannom DS. ACC/AHA/ESC 2006 Guidelines 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 European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e257–354. 2. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;114:119–25. 3. 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. 4. Chiang CE, Zhang S, Tse HF, et al. Atrial fibrillation management in Asia: From the Asian expert forum on atrial fibrillation. Int J Cardiol 2013;164:21–32. 5. Tse HF, Wang YJ, Ai-Abdullah MA, et al. Stroke Prevention in Atrial fibrillation - An Asian Stroke Perspective. Heart Rhythm 2013;10:1082–8. 6. Chao TF, Liu CJ, Chen SJ, et al. CHADS(2) score and risk of new-onset atrial fibrillation: A nationwide cohort study in Taiwan. Int J Cardiol 2013;168(2):1360–3. 7. Lip GY, Lim HS. Atrial fibrillation and stroke prevention. Lancet Neurol 2007;6:981–93. 8. Mattle HP. Long-term outcome after stroke due to atrial fibrillation. Cerebrovasc Dis 2003;16 Suppl 1:3–8. 9. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983–8. 10. Nakayama T, Date C, Yokoyama T, et al. A 15.5-year followup study of stroke in a Japanese provincial city. The Shibata Study. Stroke 1997;28:45–52. 11. Onundarson PT, Thorgeirsson G, Jonmundsson E, et al. Chronic atrial fibrillation--epidemiologic features and 14 year follow-up: a case control study. Eur Heart J 1987;8:521–7. 12. Yap KB, Ng TP, Ong HY. Low prevalence of atrial fibrillation in community-dwelling Chinese aged 55 years or older in Singapore: a population-based study. J Electrocardiol 2008;41:94– 8. 13. Zhou Z, Hu D. An epidemiological study on the prevalence of atrial fibrillation in the Chinese population of mainland China. J Epidemiol 2008;18:209–16. 14. Chien KL, Su TC, Hsu HC, et al. Atrial fibrillation prevalence, incidence and risk of stroke and all-cause death among Chinese. Int J Cardiol 2010;139:173–80. 15. Wittkowsky AK. Effective anticoagulation therapy: defining the gap between clinical studies and clinical practice. Am J Manag Care 2004;10:S297–306; discussion S312–7. 16. Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited. Lancet 2009;373:155–66. 17. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi fication schemes for predicting stroke: results from the National Registry of Atrial fibrillation. JAMA 2001;285:2864–70. 18. Lip GY, Halperin JL. Improving stroke risk strati fication in atrial fibrillation. Am J Med 2010;123:484–8. 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. 20. European Heart Rhythm A, European Association for CardioThoracic S, Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: The Task Force for the

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score is powerful in selecting truly low-risk patients who do not necessarily need to receive anticoagulation therapies. It is also useful in predicting TE events and mortality for patients undergoing AF ablation. Recently, more and more biomarkers and imaging parameters were reported to be associated with adverse events in AF patients. How could these biomarkers and imaging tools change the current strategy of stroke prevention in AF remains unknown and deserves further investigations. n

Management of Atrial fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369–429. 21. Olesen JB, Lip GY, Hansen ML, et al. Validation of risk strati fication schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011;342:d124. 22. Taillandier S, Olesen JB, Clementy N, et al. Prognosis in patients with atrial fibrillation and CHA2DS2-VASc Score = 0 in a community-based cohort study. J Cardiovasc Electrophysiol 2012;23:708–13. 23. Potpara TS, Polovina MM, Licina MM, et al. Reliable identification of “truly low” thromboembolic risk in patients initially diagnosed with “lone” atrial fibrillation: the Belgrade atrial fibrillation study. Circ Arrhythm Electrophysiol 2012;5:319– 26. 24. Chao TF, Liu CJ, Chen SJ, et al. Atrial fibrillation and the risk of ischemic stroke: does it still matter in patients with a CHA2DS2-VASc score of 0 or 1? Stroke 2012;43:2551–5. 25. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. 26. 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. 27. 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. 28. Cappato R, Calkins H, Chen SA, et al. Updated worldwide survey on the methods, ef ficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:32–8. 29. Oral H, Chugh A, Ozaydin M, et al. Risk of thromboembolic events after percutaneous left atrial radiofrequency ablation of atrial fibrillation. Circulation 2006;114:759–65. 30. Bunch TJ, Crandall BG, Weiss JP, et al. Warfarin is not needed in low-risk patients following atrial fibrillation ablation procedures. J Cardiovasc Electrophysiol 2009;20:988–93. 31. Tao H, Ma C, Dong J, et al. Late thromboembolic events after circumferential pulmonary vein ablation of atrial fibrillation. J Interv Card Electrophysiol 2010;27:33–9. 32. Yagishita A, Takahashi Y, Takahashi A, et al. Incidence of late thromboembolic events after catheter ablation of atrial fibrillation. Circ J 2011;75:2343–9. 33. Chao TF, Lin YJ, Tsao HM, et al. CHADS(2) and CHA(2)DS(2)VASc scores in the prediction of clinical outcomes in patients with atrial fibrillation after catheter ablation. J Am Coll Cardiol 2011;58:2380–5. 34. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, de finitions, endpoints, and research trial design. Europace 2012;14:528–606. 35. Fichtner S, Deisenhofer I, Kindsmuller S, et al. Prospective assessment of short- and long-term quality of life after ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2012;23:121–7. 36. Bunch TJ, Crandall BG, Weiss JP, et al. Patients treated with catheter ablation for atrial fibrillation have long-term rates of death, stroke, and dementia similar to patients without atrial fibrillation. J Cardiovasc Electrophysiol 2011;22:839–45. 37. Lin YJ, Chao TF, Tsao HM, et al. Successful catheter ablation reduces the risk of cardiovascular events in atrial fibrillation patients with CHA2DS2-VASc risk score of 1 and higher. Europace 2013;15(5):676–84.

38. Go AS, Fang MC, Udaltsova N, et al. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation 2009;119:1363–9. 39. Piccini JP, Stevens SR, Chang Y, et al. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts. Circulation 2013;127:224–32. 40. Chao TF, Tsao HM, Ambrose K, et al. Renal dysfunction and the risk of thromboembolic events in patients with atrial fibrillation after catheter ablation--the potential role beyond the CHA(2)DS(2)-VASc score. Heart Rhythm 2012;9:1755–60. 41. Conway DS, Pearce LA, Chin BS, et al. Prognostic value of plasma von Willebrand factor and soluble P-selectin as indices of endothelial damage and platelet activation in 994 patients with nonvalvular atrial fibrillation. Circulation 2003;107:3141–5. 42. Roldan V, Marin F, Muina B, et al. Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients. J Am Coll Cardiol 2011;57:2496–504. 43. Ehrlich JR, Kaluzny M, Baumann S, et al. Biomarkers of structural remodelling and endothelial dysfunction for prediction of cardiovascular events or death in patients with atrial fibrillation. Clin Res Cardiol 2011;100:1029–36. 44. Hijazi Z, Oldgren J, Andersson U, et al. Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy. Circulation 2012;125:1605–16. 45. Roldan V, Marin F, Diaz J, et al. High sensitivity cardiac troponin T and interleukin-6 predict adverse cardiovascular events and mortality in anticoagulated patients with atrial fibrillation. J Thromb Haemost 2012;10:1500–7. 46. Hernandez-Romero D, Jover E, Marin F, et al. The prognostic role of the adiponectin levels in atrial fibrillation. Eur J Clin Invest 2013;43:168–73. 47. Mahé I, Bergmann JF, Chassany O, et al. A multicentric prospective study in usual care: D-dimer and cardiovascular events in patients with atrial fibrillation. Thromb Res 2012;129:693–9. 48. Cianfrocca C, Loricchio ML, Pelliccia F, et al. C-reactive protein and left atrial appendage velocity are independent determinants of the risk of thrombogenesis in patients with atrial fibrillation. Int J Cardiol 2010;142:22–8. 49. Daccarett M, Badger TJ, Akoum N, et al. Association of left atrial fibrosis detected by delayed-enhancement magnetic resonance imaging and the risk of stroke in patients with atrial fibrillation. J Am Coll Cardiol 2011;57:831–8. 50. Chao TF, Lin YJ, Tsao HM, et al. Prolonged Atrium Electromechanical Interval Is Associated with Stroke in Patients with Atrial fibrillation After Catheter Ablation. J Cardiovasc Electrophysiol 2013;24:375–80. 51. Di Biase L, Santangeli P, Anselmino M, et al. Does the left atrial appendage morphology correlate with the risk of stroke in patients with atrial fibrillation? Results from a multicenter study. J Am Coll Cardiol 2012;60:531–8. 52. Beinart R, Heist EK, Newell JB, et al. Left atrial appendage dimensions predict the risk of stroke/TIA in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2011;22:10–5. 53. Wieloch M, Jönsson KM, Själander A, et al. Estimated glomerular filtration rate is associated with major bleeding complications but not thromboembolic events, in anticoagulated patients taking warfarin. Thromb Res 2013;131:481–6.

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Clinical Arrhythmias

Natriuretic Peptides as Predictors of Atrial Fibrillation Recurrences Following Electrical Cardioversion T heodoros A Z o g r a f o s a n d D e m o s t h e n e s G K a t r i t s i s Athens Euroclinic, Department of Cardiology, Athens, Greece

Abstract Electrical cardioversion (ECV) can be effective in restoring sinus rhythm (SR) in the majority of patients with atrial fibrillation (AF). Several factors that predispose to AF recurrences, such as age, AF duration and left atrial size have been used to guide a decision for cardioversion, but increasing evidence suggests that they may be rather poor markers of left atrial structural remodeling that determines the long-term success of a rhythm control strategy. In this context, the use of easily obtainable biomarkers, such as the levels of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), to predict AF recurrences may be preferable. Since ANP production is associated with the extent of functional atrial myocardium, and both ANP and BNP reflect atrial pressure and mechanical stretching, these peptides are good candidate biomarkers to assess predisposition to AF recurrences. In this review we focus on the pathophysiological mechanisms and the available clinical evidence regarding the prediction of AF recurrences following successful ECV from pre-procedural ANP and BNP levels.

Keywords Atrial fibrillation, electrical cardioversion, atrial natriuretic peptide, B-type natriuretic peptide Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: Andrew Grace, Deputy Editor of Arrhythmia & Electrophysiology Review, acted as editor for this article. Received: 6 October 2013 Accepted: 4 November 2013 Citation: Arrhythmia & Electrophysiology Review 2013;2(2):109–14 Access at: www.AERjournal.com Correspondence: Demosthenes G Katritsis, Athens Euroclinic, 9 Athanasiadou Street, Athens 11521, Greece. E: dkatritsis@euroclinic.gr

Atrial fibrillation (AF) affects 1–2 % of the population, and its prevalence is expected to increase in the next 50 years.1,2 The treatment of these patients includes either restoration and maintenance of sinus rhythm (SR) or control of the ventricular rate.3 Electrical cardioversion (ECV) can be effective in restoring SR in the majority of patients; however, it is associated with several risks and complications, including thromboembolic events, post-cardioversion arrhythmias and the risks of anaesthesia.3 Furthermore, ECV is effective in less than half of the patients, since AF recurrences are common, with a 40 % rate of AF recurrences within the month.4 Factors that predispose to AF recurrence are age, AF duration before cardioversion, number of previous recurrences, increased left atrial (LA) size or reduced LA function, and the presence of coronary heart disease or, pulmonary or mitral valve disease.5 Nevertheless, increasing evidence suggests that the above-mentioned factors may be poor markers of LA structural remodeling, which determines the propensity to AF recurrences. In fact, the extent of atrial fibrosis appears to be highly variable between patients with the same risk factors for AF.6 The extent of fibrosis can be determined using delayed enhancement magnetic resonance imaging; however, it could be adequately assessed by the secretory function of the remaining atrial myocardium. A method to choose patients for whom ECV would be more successful based on easily obtainable biomarkers, such as natriuretic peptides (NPs), may improve clinical outcomes and cost-efficiency. In this review, we focus on the pathophysiological mechanisms and the available clinical evidence regarding the prediction of AF recurrences following successful ECV from pre-procedural NP levels.

© RADCLIFFE 2013

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Natriuretic Peptide System The NP system consists of three different NPs sharing a common 17-amino acid ring, namely – atrial NP (ANP), B-type or brain NP (BNP) and C-type NP (CNP) (see Figure 1). Their biological actions are mediated through membrane-bound NP receptors (NPRs) – NPR-A, NPR-B and NPR-C.

Atrial Natriuretic Peptide Mammalian atrial myocytes have been found to contain specific granules, with characteristics compatible with a secretory function.7 The importance of these granules was demonstrated by de Bold et al., who reported the occurrence of a natriuretic response following cross-animal injection of atrial myocardium extract.8 This natriuretic effect was later ascribed to a 28-amino acid peptide, which was simultaneously isolated and sequenced by several research groups, and was found to be strictly localised within the specific granules.9–11 In cardiac myocytes, ANP is synthesised and stored as a 126-amino acid precursor, pro-ANP, which is cleaved to biologically active ANP and the N-terminal portion of pro-ANP (NT-proANP) by a transmembrane cardiac serine protease, corin, during the secretion process.12 ANP secretion is primarily regulated by mechanical stretching of the atria, secondary to increased loading, but an increase in the rate of contraction also causes an increase in ANP. Equally potent stimuli for ANP release are hypoxia and myocardial ischaemia.13 Several other factors have been associated with ANP regulation, such as angiotensin II, vasopressin and adrenergic agonists, which seem to induce ANP secretion; nevertheless, there is some controversy as to whether this

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Clinical Arrhythmias Figure 1: Natriuretic Peptides and their Respective Receptors

Binding of NPR-A with its ligand (ANP or BNP) increases production of cyclic guanosine monophosphate. NPR-C binds with high affinity to all three NPs and facilitates their clearance from the circulation through receptor-mediated internalisation and degradation. ANP = atrial natriuretic peptide; BNP = B-type natriuretic peptide; cGMP = cyclic guanosine monophosphate; CNP = C-type natriuretic peptide; NPR-A = natriuretic peptide receptor-A; NPR-B = natriuretic peptide receptor-B; NPR-C = natriuretic peptide receptor-C; GTP = guanosine triphosphate.

is due to a direct effect or due to affecting venous return or cardiac afterload.13 Paracrine factors derived from endothelial cells modulate ANP secretion as well. Endothelin, a potent vasoconstrictor, stimulates ANP secretion and enhances stretch-induced ANP secretion, whereas nitric oxide (NO), an important vasodilator, inhibits ANP secretion.13 ANP in plasma is characterised by a short half-life, which ranges between 2 and 4 minutes and rapid metabolic clearance.14,15 In contrast to BNP and NT-proBNP, ANP has much higher renal extraction, with a renal fractional extraction of approximately 50 %.16 In accordance with BNP, ANP is inactivated by two pathways; enzymatic degradation by neutral endopeptidase and lysosomal degradation after binding to NPR-C. ANP binds with greater affinity to NPR-C compared with BNP, which contributes significantly to its shorter plasma half-life.17

Brain Natriuretic Peptide Even though BNP was initially isolated from porcine brain, and was therefore named ‘brain natriuretic peptide’,18 it was later found that in humans BNP is highly synthesised and secreted in the ventricles, in contrast to ANP, which is preferentially secreted from the atria.19 Nevertheless, both peptides can be synthesised in either chamber under pathological conditions.20 The BNP messenger RNA (mRNA) expression is more than twofold higher in atria than in ventricles, but the BNP production in the ventricles is considered more important for the contribution to BNP plasma concentrations due to the larger mass of the ventricles.21 In patients with AF, Inoue et al. have suggested that BNP is predominantly produced in the atrium.22 In contrast to ANP, which seems to be well conserved in mammals, BNP and NT-proBNP differ among mammalian species. Another significant difference is that, unlike ANP, BNP has minimal storage in granules and most of BNP regulation is done during gene expression, with most BNP synthesised in bursts of activation from physiological and pathophysiological stimuli when peptide secretion occurs.23

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Zografos_edited.indd 110

In response to left ventricular stretch and wall tension, natriuretic peptide precursor (NPPB) gene is translated into a 134-amino acid precursor, which undergoes rapid removal of a 26-amino acid signal peptide, resulting in the formation of proBNP1-108. Upon cleavage from prohormone convertases, furin and corin, an active BNP hormone comprising 32-amino acid residues (BNP1-32), along with a physiologically inactive N-terminal fragment (NT-proBNP1-76) are formed from proBNP.24 Even though BNP and NT-proBNP are produced in equimolar proportions, circulating NT-proBNP levels are approximately sixfold higher compared with BNP levels, due to a difference in half-life times.25 BNP has a half-life of approximately 20 minutes, whereas NT-proBNP has a longer half-life of approximately 120 minutes.26 Due to its longer half-life, NT-proBNP levels are more stable and less sensitive to acute stress. These differences in plasma half-lives can be ascribed to different clearance mechanisms. Even though evidence suggests that renal extraction of BNP is comparable to that of NT-proBNP and consistent with the renal extraction of other bio-active peptides,27 glomerular filtration plays only a minor role in the elimination of BNP, which is primarily eliminated by binding to NPR-C and through enzymatic degradation by neutral endopeptidases. In contrast, NT-proBNP is thought to be largely cleared by renal excretion.26 BNP exerts more potent natriuretic and blood pressure-lowering effects compared with ANP, whereas both NPs suppress the renin-angiotensin-aldosterone system to the same extent.28 Furthermore, there is evidence that BNP has a direct anti-fibrotic effect on cardiac fibroblasts, by opposing transforming growth factor-beta (TGF-beta) regulated genes related to fibrosis (such as collagen 1, fibronectin, connective tissue growth factor [CTGF], plasminogen activator inhibitor-1 [PAI-1] and tissue inhibitor of metalloproteinase-3 [TIMP3]), myofibroblast conversion and proliferation (alpha-smooth muscle actin 2 and non-muscle myosin heavy chain, platelet-derived growth factor [PDGFA], insulin-like growth factor 1 [IGF-1], fibroblast growth factor-18 [FGF18] and IGF binding protein-10 [IGFBP10]) and inflammation (cyclooxygenase-2 [COX2], Interleukin 6 [IL6], tumor necrosis factor [TNF] alpha-induced protein 6 and TNF superfamily, member 4).29

Natriuretic Peptide Receptors The biological actions of NPs are mediated by the membrane-bound NPRs. The basic topology of NPR-A, which preferentially binds ANP and BNP, consists of an extracellular ligand-binding domain (a short hydrophobic membrane-spanning region) and an intracellular domain, which contains a guanylyl cyclase catalytic domain in its C-terminus.30 Association of NPR-A with its cognate ligand (ANP or BNP) causes a conformational change that relaxes tonic inhibition of guanylyl cyclase activity and increases production of cyclic guanosine monophosphate (cGMP).31 NPR-B, which preferentially binds CNP, shares a similar structure with NPR-A. As mentioned, NP clearance from the blood is mediated by NPR-C, which has an extracellular domain that is structurally homologous to that of the other NPRs. NPR-C binds with high affinity to all three NPs and facilitates their clearance from the circulation through receptor-mediated internalisation and degradation.31

Brain Natriuretic Peptide as a Predictor of Atrial Fibrillation Recurrences Post-electrical Cardioversion Elevated levels of BNP and NT-proBNP in patients with AF compared with patients in SR have long been described.32–34 Upon restoration of SR, levels of BNP rapidly normalise.35,36 Furthermore, BNP and NT-proBNP levels have been shown to predict the risk of AF occurrence in various

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Natriuretic Peptides as Predictors of Atrial Fibrillation Recurrences Following Electrical Cardioversion

Follow-up Period

ECG

AF Detection

163 ± 122 pg/mL

210.89 ± 35.80 pg/mL 38

BNP in SR Group

9

120 ± 92 pg/mL

340.60 ± 42.74 pg/mL 20

BNP in AF Group

54

188.00 ± 30.75 pg/mL 26

293 ± 106 pg/mL

30

Table 1: Observational Studies of the Association of Preprocedural BNP or NT-proBNP Levels and AF Recurrences Following Successful ECV

6 months ECG

67

358 ± 339 pg/mL

AF Group n

34.5 % 2 weeks

88

ECG

1647 ± 1,272 pg/mL

717 ± 449 pg/mL

24h Holter, monthly ECG 848 ± 522 ng/mL

71.3 ± 26.1 pg/mL

31

741 (514–1,401) pg/mL 44

14

38

21

47

1,362 ± 862 pg/mL

2996 ± 3.965 pg/mL

664 ± 349 pg/mL

953 ± 456 ng/mL

99.6 ± 35.5 pg/mL

9

973 (474–1,533) pg/mL 42

11

19

32

30

12 months

Physical, ECG

398 ± 268 pg/mL

SR Group n

23.2 ± 6.5 36 %

91 ± 24 pg/mL

36

3 weeks

ECG

58

Preserved LVEF months

140 ± 98 pg/mL

Study Study Characteristics AF Duration n AF Recurrence Rate BNP

6 (4–9) months 14

24h ambulatory ECG

177 ± 140 pg/mL

Ari et al. (55.50 ± 2.98)

ECG

62 %

4 weeks

Weekly visits, ECG

5

NYHA class I or II, 6 months

ECG

24 months

preserved LVEF 28 % 1 year

Beck da Silva et al.

38 %

93 45 %

NYHA I or II 142

Falcone et al. 66

3.7 months

29

Preserved LVEF (61.1 ± 9.6) 37 ± 26 days

182.2 ± 25.9 pg/mL

NYHA I or II, preserved

36

Kawamura et al.

121.6 ± 15.7 pg/mL

Lelouche et al.

Physical, ECG

4.5 ± 1.7

553 days

LVEF (53 ± 12) 45 %

NYHA II or III,

65

64

Mabuchi et al.

119 ± 113 pg/mL

months

20

37 (1–350) days 84

137 ± 123 pg/mL

LVEF: 40.7 ± 2.2

24h Holter,

NYHA I–III,

140 ± 144 days

ECGs at follow-up

76 %

Watanabe et al. LVEF: 0.59 ± 0.10

33 %

340 ± 81 days

18

Kallergis et al.

Freynhofer et al.

Buob et al.

Barassi et al.

Govindan et al.

Lone AF, LVEF:

Persistent AF

LVEF 0.57 ± 0.11

No clinical CHF,

LVEF: 0.58 (0.44–0.71)

NYHA Ι or ΙΙ,

(56.7 ± 10.4)

Preserved LVEF

53

ECG, Holter

44 %

1 month

735 ± 370 pg/mL

57.1 ± 8.5

ECG monitoring

49 %

35

6 months

29 %

638 ± 329 pg/mL

NYHA I, LVEF: 58.7 ± 5.8 3 months

days

25

3 months (0–15) 57

<18 months

86

Weekly phone

41 %*

NYHA I, LVEF: 58.1 ± 6.4 101.3 ± 92.6

90 ± 75 days

40

3 weeks

77

Wozakowska et al.

NA

34 %

NT-proBNP

>3 months

53

Lombardi et al.

1570.5 (397.1–2,202.1) 10

pg/mL

1,124 (925–1,542)

19

interviews, ECG

pg/mL

(1 month–1 year)

759 (618–1,139) pg/mL 30

761.4 (467.8–1,170.9) 89

973.6 (541.5–1,191.3) 24

days

181.5 ± 32.7

pg/mL

pg/mL

6 months

Ambulatory ECG

Lone AF,

10.9 ± 8.3

746.2 (500.8–1,262.6) 40

69 %

4 weeks

LVEF: 0.57 ± 0.06

weeks

pg/mL

129

39 %

Mollmann et al. Persistent AF,

Median

49

normal LVEF

10.5 weeks

ECG at follow-up

ECG

Shin et al.

Persistent AF, NYHA I,

11 days

FS: 29.9 ± 7.3

29.4 %

Tveit et al.

34

*Four patients failed the initial cardioversion. AF = atrial fibrillation; BNP = B-type natriuretic peptide; CHF = congestive heart failure; ECG = electrocardiogram; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal portion of proBNP; NYHA = New York Heart Association; SR = sinus rhythm.

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33 7.3 ± 1.9 nmol/L LV systolic function

AF = atrial fibrillation; ANP = atrial natriuretic peptide; CHF = congestive heart failure; LV = left ventricular; NT-proBNP = N-terminal portion of proBNP; SR = sinus rhythm.

19 4.4 ± 2.0 nmol/L

21 5.9 ± 2.4 nmol/L

24 5.1 ± 3.5 nmol/L

12 month 33/54 54 <18 months Non-valvular AF, preserved Govindan et al. 2012

>1 month

43 12.3 ± 15.3 weeks Preserved LV systolic function Bartkowiak et al. 2010

19/43

1 month

48 4.92 ± 4.36 nmol/L 26 underlying disease

74 Broad spectrum of

months

13.2 ± 11.0

Similar findings are reported in several studies assessing the recurrence of AF following catheter ablation. Patients with higher baseline levels of BNP and NT-proBNP have higher rates of AF recurrence.41,42 Whereas, both BNP and NT-proBNP have been recognised as independent predictors of AF recurrence in the majority of studies, there are reports that failed to identify such an association.43,44

48/74

clinical settings. Elevated pre-operative levels of BNP or NT-proBNP have been associated with increased risk of new-onset AF following coronary artery bypass grafting surgery.37,38 The association of preoperative BNP levels with the post-operative development of AF has also been documented in patients undergoing general thoracic surgery and major non-cardiac surgery.39,40

Kim et al. 2009

23 NYHA I or II Thomas et al. 2005

>1 month and <1 year disease, NYHA I, II or III

6.68 ± 4.09 nmol/L

9 250 ± 62 pg/mL 14 150 ± 34 pg/mL 9/23

1 month

6 60.2 ± 11.2 pg/mL

NT-proANP

29 65.8 ± 12.3 pg/mL

29 58.1 ± 13.0 pg/mL

36 67.4 ± 10.0 pg/mL

6/35 7.1 ± 7.1 months Broad spectrum of underlying Wozakowska et al. 2004

65 20.4 months CHF, NYHA II or III Mabuchi et al. 2000

(2–13 months)

35

29/65

1 month

11

2 months

9

112 ± 58 fmol/mL 129 ± 58 fmol/mL

70 ± 48 pmol/L 63 ± 50 pmol/L

11/19 6 ± 5 months Non-valvular AF, NYHA I or II Theodorakis et al. 1996

19

20 months median CHF, NYHA II or III van den Berg et al. 1995

18

9/18

3 months

8

Zografos_edited.indd 112

6 weeks

9

112

ANP

AF Group n ANP in AF Group SR Group n ANP in SR Group Study Study Characteristics AF Duration n AF Follow-up Recurrence Period Rate

Table 2: Observational Studies of the Association of Preprocedural ANP or NT-proANP Levels and AF Recurrences Following Successful ECV

Clinical Arrhythmias

In the context of the above mentioned data, several observational studies have assessed the value of BNP and NT-proBNP levels in predicting AF recurrences following ECV (see Table 1). Evidence from the majority of these studies supports an association between BNP or NT-proBNP levels before ECV and the risk of AF recurrence.45–54 Nevertheless, other studies have failed to observe a relationship.55–58 In fact, in the three most recent studies, a statistically significant association between baseline BNP or NT-proBNP levels and SR maintenance was not observed.59–61 A meta-analysis that included ten of the above-mentioned studies concluded that higher BNP levels before ECV were associated with an increased risk of AF recurrence following successful ECV, suggesting that the measurement of BNP levels could improve the initial selection of suitable patients for ECV.62 In the patients included in the above-mentioned studies, which mainly have preserved ejection fraction, high BNP/NT-proBNP levels may be the consequence of several pathogenic mechanisms. BNP levels may reflect a higher degree of systematic inflammation, which is consistently associated with AF.63 In vitro studies suggest that BNP may be selectively up-regulated at the transcriptional and translational level by pro-inflammatory cytokines, and that plasma BNP levels may increase as a response to systemic inflammation in the absence of haemodynamic changes.64,65 The frequent occurrence of AF in patients with inflammatory conditions, such as myocarditis and pericarditis, and the finding of marked inflammatory infiltrates, myocyte necrosis and fibrosis in atrial biopsies from patients with lone AF, support an association between AF and inflammation.66 Further evidence of a pro-inflammatory state in patients with AF comes from an observed increase in inflammatory markers, such as C-reactive protein (CRP) and interleukin-6 in patients with persistent and permanent AF compared with controls.67,68 Consequently, patients with a higher degree of inflammation observed by higher BNP levels may have greater and more active atrial structural remodeling, thereby hindering SR maintenance.69 Furthermore, high BNP or NT-proBNP levels may predict a greater predisposition to AF recurrences by reflecting increased LA pressure. Atrial arrhythmias frequently occur under conditions associated with atrial dilation.70 The effect of atrial pressure in atrial refractoriness was evaluated in several animal models as well as in humans. Increased atrial pressure results in increased susceptibility to AF that is associated with shortening of the atrial effective refractory period (AERP),71,72 possibly by opening of stretch-activated ion channels.73 Furthermore, atrial conduction delay in patients with paroxysmal AF or patients with diabetes and hypertension was associated with increased LA pressure and impaired left ventricular (LV) relaxation.74 An association between BNP and myocardial stretch, as well as intra-atrial pressures has been well established. In patients

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Natriuretic Peptides as Predictors of Atrial Fibrillation Recurrences Following Electrical Cardioversion

with preserved ejection fraction (EF) a significant correlation between NT-proBNP and LA appendage emptying velocity was observed reflecting atrial strain.56 Moreover, in patients with diastolic dysfunction, increased BNP levels have been associated with higher left ventricular end-diastolic pressure (LVEDP) and have been proposed as a diagnostic marker for diastolic dysfunction.75 Elevated LVEDP results in excessive tension in ventricular and also atrial walls, which may stimulate ventricular and atrial BNP production. Therefore, elevated BNP levels in patients with AF may reflect diastolic dysfunction, which is an independent predictor of AF, especially in the elderly.76 The presence and severity of diastolic dysfunction has been repeatedly demonstrated to predict AF development in patients with risk factors for cardiac disease, such as diabetes, and in patients after myocardial infarction.77–79

Atrial Natriuretic Peptide as a Predictor of Atrial Fibrillation Recurrences Post-electrical Cardioversion The link between ANP or NT-proANP and AF has been equally well established. Patients with AF have higher ANP levels compared with patients in SR,80,81 which usually decrease following ECV and SR restoration.82,83 Elevated ANP levels can predict the development of paroxysmal AF in patients with congestive heart failure84 or following cardiac surgery.85 In accordance with these studies, there is accumulating evidence regarding the role of an assay detecting mid-regional proANP (MR-proANP). Given that NT-proANP has a much longer half-life than mature ANP and is more stable under laboratory conditions,86,87 NT-proANP seems as a more reliable analyte to measure. Available assays for the detection of NT-proANP used an antibody against the N-terminal region combined with a second antibody against either the mid-region or the C-terminal region.88–90 Since under certain conditions, the N-terminal region may be minimally accessible for antibody binding, an immunoassay for the mid-region of proANP was developed in 2004.91 Improvement in analytical performance by MR-proANP assays could improve their ability in identifying patients at increased risk for AF. In the Mälmo Diet and Cancer Study, higher MR-proANP levels predicted incident AF, whereas in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico - Atrial Fibrillation (GISSI-AF) study, higher MR-proANP levels independently predicted a higher risk for AF recurrence.92,93 Finally, MR-proANP concentration has recently been shown to reliably identify the time from onset of AF to presentation.94 Several studies have examined the association of SR maintenance post-ECV with ANP and NT-proANP levels before the procedure (see

1. Davis RC, Hobbs FD, Kenkre JE, et al. Prevalence of atrial fibrillation in the general population and in high-risk groups: the ECHOES study. Europace 2012;14:1553–9. 2. Naccarelli GV, Varker H, Lin J, Schulman KL. Increasing prevalence of atrial fibrillation and flutter in the United States. Am J Cardiol 2009;104:1534–9. 3. 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. Europace 2012;14:1385–413. 4. Gall NP, Murgatroyd FD. Electrical cardioversion for AF-the state of the art. Pacing Clin Electrophysiol 2007;30:554–67. 5. 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). Europace 2010;12:1360–420. 6. Kottkamp H. Human atrial fibrillation substrate: towards a specific fibrotic atrial cardiomyopathy. Eur Heart J 2013;34:2731–8. 7. Kisch B. Electron microscopy of the atrium of the heart. I. Guinea pig. Exp Med Surg 1956;14:99–112. 8. de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. A rapid and potent natriuretic response to intravenous

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Table 2). 51,60,95–100 In half of the existing studies, ANP levels were higher in patients who succeeded in maintaining SR,51,96,99,100 whereas in the other half, ANP levels were lower.60,95,97,98 According to the available evidence, an association between AF recurrences after successful ECV and ANP levels before the procedure cannot be established. The discrepancies observed in the available studies can be explained considering the mechanism of ANP production in patients with AF. As mentioned, ANP secretion is mainly regulated by mechanical stretching of the atria. This can be reflected in the positive correlation between ANP levels and LA volume, which has been established in several studies using echocardiography and cardiac magnetic resonance.101–104 In accordance with BNP levels, higher ANP levels have been associated with LV diastolic dysfunction and increased filling pressures,105–107 hence patients with higher ANP levels during the acute phase of an episode of persistent AF may be predisposed to an increased risk of AF recurrences. Apart from between-patient differences, increased ANP levels during an AF episode are probably an acute physiological response to increased atrial pressure.108 Following restoration of SR, plasma ANP concentration is rapidly decreased in conjunction with filling pressures.83 Thereafter, a gradual normalisation of ANP levels is observed concomitantly with atrial mechanical function improvement.109 When SR is not restored and AF becomes long-standing, several morphological changes, termed structural remodeling, ensue in the atrial myocardium. The main changes include interstitial fibrosis and cellular dedifferentiation and apoptosis,110–112 resulting in functional cell loss and reduced ANP production. This inverse association between atrial structural damage and ANP production has been observed in a histopathological study of patients with mitral valve disease,113 and is considered the basis of the inverse association between AF duration and ANP levels.114,115 Hence, in patients with long-standing AF, lower ANP levels reflect pronounced atrial remodeling and would predict a difficulty in maintaining SR following cardioversion. In conclusion, according to the evidence provided, the use of BNP or NT-proBNP for prediction of long-term response to ECV appears to be useful. Therefore, further research should be done to investigate a cut-off value indicating that SR maintenance is feasible following ECV. Conversely, since ANP concentration can be influenced in an opposing manner by both filling pressure and the extent of structural remodeling, its use as a predictor of AF recurrences is not reasonable, which is also reflected in the relevant studies. n

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17. Suresh M, Farrington K. Natriuretic peptides and the dialysis patient. Semin Dial 2005;18:409–19. 18. Sudoh T, Minamino N, Kangawa K, Matsuo H. Brain natriuretic peptide-32: N-terminal six amino acid extended form of brain natriuretic peptide identified in porcine brain. Biochem Biophys Res Commun 1988;155:726–32. 19. Daniels LB, Maisel AS. Natriuretic peptides. J Am Coll Cardiol 2007;50:2357–68. 20. Yasue H, Yoshimura M, Sumida H, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 1994;90:195–203. 21. Mukoyama M, Nakao K, Hosoda K, et al. Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest 1991;87:1402–12. 22. Inoue S, Murakami Y, Sano K, et al. Atrium as a source of brain natriuretic polypeptide in patients with atrial fibrillation. J Card Fail 2000;6:92–6. 23. Mair J. Biochemistry of B-type natriuretic peptide--where are we now? Clin Chem Lab Med 2008;46:1507–14. 24. Semenov AG, Tamm NN, Seferian KR, et al. Processing of pro-B-type natriuretic peptide: furin and corin as candidate

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Clinical Arrhythmias convertases. Clin Chem 2010;56:1166–76. 25. Hojs R, Bevc S, Ekart R. Biomarkers in hemodialysis patients. Adv Clin Chem 2012;57:29–56. 26. Wang AY. Clinical utility of natriuretic peptides in dialysis patients. Semin Dial 2012;25:326–33. 27. Goetze JP, Jensen G, Møller S, et al. BNP and N-terminal proBNP are both extracted in the normal kidney. Eur J Clin Invest 2006;36:8–15. 28. Pidgeon GB, Richards AM, Nicholls MG, et al. Differing metabolism and bioactivity of atrial and brain natriuretic peptides in essential hypertension. Hypertension 1996;27:906– 13. 29. Kapoun AM, Liang F, O’Young G, et al. B-type natriuretic peptide exerts broad functional opposition to transforming growth factor-beta in primary human cardiac fibroblasts: fibrosis, myofibroblast conversion, proliferation, and inflammation. Circ Res 2004;94:453–61. 30. Potter LR, Hunter T. Guanylyl cyclase-linked natriuretic peptide receptors: structure and regulation. J Biol Chem 2001;276:6057– 60. 31. 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Beck-da-Silva L, de Bold A, Fraser M, et al. Brain natriuretic peptide predicts successful cardioversion in patients with atrial fibrillation and maintenance of sinus rhythm. Can J Cardiol 2004;20:1245–8. 47. Falcone C, Buzzi MP, D’Angelo A, et al. Apelin plasma levels predict arrhythmia recurrence in patients with persistent atrial fibrillation. Int J Immunopathol Pharmacol 2010;23:917–25. 48. Freynhofer MK, Jarai R, Höchtl T, et al. Predictive value of plasma Nt-proBNP and body mass index for recurrence of atrial fibrillation after cardioversion. Int J Cardiol 2011;149:257– 9. 49. Kallergis EM, Manios EG, Kanoupakis EM, et al. Effect of sinus rhythm restoration after electrical cardioversion on apelin and brain natriuretic Peptide prohormone levels in patients with persistent atrial fibrillation. Am J Cardiol 2010;105:90–4. 50. Lellouche N, Berthier R, Mekontso-Dessap A, et al. Usefulness of plasma B-type natriuretic peptide in predicting recurrence of atrial fibrillation one year after external cardioversion. Am J Cardiol 2005;95:1380–2. 51. Mabuchi N, Tsutamoto T, Maeda K, Kinoshita M. Plasma cardiac natriuretic peptides as biochemical markers of recurrence of atrial fibrillation in patients with mild congestive heart failure. Jpn Circ J 2000;64:765–71. 52. Möllmann H, Weber M, Elsässer A, et al. NT-ProBNP predicts rhythm stability after cardioversion of lone atrial fibrillation. Circ J 2008;72:921–5. 53. Shin DI, Jaekel K, Schley P, et al. Plasma levels of NT-proBNP in patients with atrial fibrillation before and after electrical cardioversion. Z Kardiol 2005;94:795–800. 54. Wozakowska-Kaplon B, Opolski G. Exercise-induced natriuretic peptide secretion predicts cardioversion outcome in patients with persistent atrial fibrillation: discordant ANP and B-type natriuretic peptide response to exercise testing. Pacing Clin Electrophysiol 2010;33:1203–9. 55. 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cardioversion of persistent atrial fibrillation. Pacing Clin Electrophysiol 2006;29:559–63. 56. Lombardi F, Tundo F, Belletti S, et al. C-reactive protein but not atrial dysfunction predicts recurrences of atrial fibrillation after cardioversion in patients with preserved left ventricular function. J Cardiovasc Med (Hagerstown) 2008;9:581– 8. 57. Tveit A, Seljeflot I, Grundvold I, et al. Candesartan, NT-proBNP and recurrence of atrial fibrillation after electrical cardioversion. Int J Cardiol 2009;131:234–9. 58. Watanabe E, Arakawa T, Uchiyama T, et al. High-sensitivity C-reactive protein is predictive of successful cardioversion for atrial fibrillation and maintenance of sinus rhythm after conversion. Int J Cardiol 2006;108:346–53. 59. Kawamura M, Munetsugu Y, Kawasaki S, et al. Type III procollagen-N-peptide as a predictor of persistent atrial fibrillation recurrence after cardioversion. Europace 2012;14:1719–25. 60. Govindan M, Borgulya G, Kiotsekoglou A, et al. Prognostic value of left atrial expansion index and exercise-induced change in atrial natriuretic peptide as long-term predictors of atrial fibrillation recurrence. Europace 2012;14:1302–10. 61. Barassi A, Pezzilli R, Morselli-Labate AM, et al. Serum amyloid a and C-reactive protein independently predict the recurrences of atrial fibrillation after cardioversion in patients with preserved left ventricular function. Can J Cardiol 2012;28:537–41. 62. Tang Y, Yang H, Qiu J. Relationship between brain natriuretic peptide and recurrence of atrial fibrillation after successful electrical cardioversion: a meta-analysis. J Int Med Res 2011;39:1618–24. 63. Guo Y, Lip GY, Apostolakis S. Inflammation in atrial fibrillation. J Am Coll Cardiol 2012;60:2263–70. 64. Ma KK, Ogawa T, de Bold AJ. 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Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation 2002;105:595–601. 76. Tsang TS, Gersh BJ, Appleton CP, et al. Left ventricular diastolic dysfunction as a predictor of the first diagnosed nonvalvular atrial fibrillation in 840 elderly men and women. J Am Coll Cardiol 2002;40:1636–44. 77. From AM, Scott CG, Chen HH. The development of heart failure in patients with diabetes mellitus and pre-clinical diastolic dysfunction a population-based study. J Am Coll Cardiol 2010;55:300–5. 78. Jons C, Joergensen RM, Hassager C, et al. Diastolic dysfunction predicts new-onset atrial fibrillation and cardiovascular events in patients with acute myocardial infarction and depressed left ventricular systolic function: a CARISMA substudy. Eur J Echocardiogr 2010;11:602–7. 79. Tsang TS, Barnes ME, Gersh BJ, et al. Risks for atrial fibrillation and congestive heart failure in patients >/=65 years of age with abnormal left ventricular diastolic relaxation. Am J Cardiol 2004;93:54–8. 80. Wallen T, Landahl S, Hedner T, et al. Atrial peptides, ANP(198) and ANP(99-126) in health and disease in an elderly population. Eur Heart J 1993;14:1508–13. 81. Rossi A, Enriquez-Sarano M, Burnett JC Jr, et al. Natriuretic peptide levels in atrial fibrillation: a prospective hormonal and Doppler-echocardiographic study. J Am Coll Cardiol 2000;35:1256–62. 82. Lechleitner P, Genser N, Hauptlorenz S, et al. [Values of atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) in cardioversion]. Z Kardiol 1991;80:574–9. 83. Arakawa M, Miwa H, Noda T, et al. Alternations in atrial natriuretic peptide release after DC cardioversion of nonvalvular chronic atrial fibrillation. Eur Heart J 1995;16:977–85. 84. Yamada T, Fukunami M, Shimonagata T, et al. 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postoperative atrial fibrillation after surgery for symptomatic aortic stenosis. Cardiology 2006;105:207–12. 86. Davidson NC, Coutie WJ, Struthers AD. N-terminal proatrial natriuretic peptide and brain natriuretic peptide are stable for up to 6 hours in whole blood in vitro. Circulation 1995;91:1276–7. 87. Hall C, Aaberge L, Stokke O. In vitro stability of N-terminal proatrial natriuretic factor in unfrozen samples: an important prerequisite for its use as a biochemical parameter of atrial pressure in clinical routine. Circulation 1995;91:911. 88. Missbichler A, Hawa G, Schmal N, Woloszczuk W. Sandwich ELISA for proANP 1-98 facilitates investigation of left ventricular dysfunction. Eur J Med Res 2001;6:105–11. 89. Stridsberg M, Pettersson T, Pettersson K. A two-site delfia immunoassay for measurements of the N-terminal peptide of pro-atrial natriuretic peptide (nANP). Ups J Med Sci 1997;102:99– 108. 90. Numata Y, Dohi K, Furukawa A, et al. 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Clinical Arrhythmias

The European Heart Rhythm Association Practical Guide on the Use of New Oral Anticoagulants in Patients with Non-valvular Atrial Fibrillation – A Brief Summary K a trina Moun t f o r t , M e d i c a l Wr i t e r, R a d c l i f f e Ca r d i o l o g y R e v i e w e d b y Pa u l u s Ki r c h h o f University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK

Abstract New oral anticoagulants (NOACs) are an alternative to vitamin K antagonists (VKAs) in the prevention of stroke in patients with non-valvular atrial fibrillation (AF). The European Heart Rhythm Association (EHRA) has produced a practical guide to detail the use of NOACs in clinical practice. The guide includes a practical start-up and follow-up scheme, emphasising the importance of strict adherence to the regimen – the anticoagulant effect drops rapidly after 12–24 hours. There is also guidance on how to measure the anticoagulant effect of NOACs, switching between anticoagulant regimes and dealing with dosing errors. Physicians will have to consider the pharmacokinetic effect of drugs and co-morbidities when prescribing NOACs – plasma levels of NOACs may be affected by P-glycoprotein (P-gp) substrates, as well as cytochrome P450 (CYP3A4) inducers or inhibitors. In patients with chronic kidney disease, reduced doses of NOACs may be indicated. Guidance is also given on the management of bleeding complications, and the cessation and reinitiation of NOACs in patients undergoing surgical interventions. Finally, the use of NOACs in specific clinical situations is considered; these include patients with AF and coronary artery disease (CAD), patients presenting with acute stroke while taking NOACs and patients with cancer.

Keywords Atrial fibrillation, new oral anticoagulants, dabigatran, apixaban, rivaroxaban, edoxaban Acknowledgement: Paulus Kirchhof was a co-author of the European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Received: 17 October 2013 Accepted: 25 October 2013 Citation: Arrhythmia & Electrophysiology Review 2013;2(2):115–9 Access at: www.AERjournal.com

New oral anticoagulants (NOACs), including dabigatran1 (a direct thrombin inhibitor), apixaban,2 rivaroxaban3 and edoxaban4 (activated factor Xa inhibitors, not yet approved) have become alternatives to vitamin K antagonists (VKAs) for thromboembolic prevention in patients with non-valvular atrial fibrillation (AF), as a result of their numerous clinical advantages. However, there is a need for a practical guide detailing their use in specific clinical situations, which cannot be provided by practice guidelines due to lack of evidence and supporting data.5 For similar reasons, the summary of product characteristics (SmPC) supplied by the manufacturer cannot provide such information. Furthermore, SmPCs are written for each individual agent, while the NOACs can often be treated as a group in practical terms. The European Heart Rhythm Association (EHRA) has therefore produced a practical guide to help with the use of the NOACs in clinical practice until more ‘real life’ data are available.6 This article aims to provide a brief summary of this guide.

Practical Start-up and Follow-up Scheme for Patients on New Oral Anticoagulants Before prescribing NOACs to patients with AF, a risk–benefit analysis should be carried out. When choosing a NOAC, the possibility of drug– drug interactions (DDIs) with co-medications should be considered. At the time of prescribing NOACS, patient education is crucial. The concomitant use of proton pump inhibitors (PPIs) is also recommended to reduce the risk of gastrointestinal bleeding. Patients should carry details about their therapy; a generic information card could serve for all NOACs. Most

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importantly, at start-up, it is vital to educate the patient on the importance of strict adherence to regimen, stressing the dangers of discontinuation or missing a dose. A structured follow-up procedure for patients taking NOACs is essential, preferably every three months. Follow-ups can be undertaken by general practitioners (GPs), appropriate secondary care physicians, or nurse co-ordinated AF clinics.7 During each visit, the following should be checked: • • • •

compliance, including inspecting remaining medication; signals of thromboembolism; adverse effects (AEs), particularly bleeding; and use of co-medications.

Monitoring haemoglobin, renal and hepatic function should be performed yearly; more frequently in patients receiving dabigatran, in elderly and/or frail patients and those with compromised renal function.5

How to Measure the Anticoagulant Effect of New Oral Anticoagulants Routine monitoring of coagulation is not required, although quantitative assessment of drug exposure may be useful in some emergency situations. In the absence of good data, a history of drug intake is probably the best available information on the anticoagulant effect.

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Clinical Arrhythmias Table 1: Absorption and Metabolism of New Oral Anticoagulants Bioavailability

Dabigatran 3–7 %

Apixaban Edoxaban* Rivaroxaban 50 % 62 % 66 % (without food)

~100 % with food

Prodrug

no

yes

no no

Clearance: non-renal/renal of adsorbed dose

20 %/80 %

73 %/27 %

50 %/50 %

65 %/35 %

no

yes (elimination;

minimal (<4 %

yes (elimination)

if normal renal function Liver metabolism: CYP3A4

minor CYP3A4)

of elimination)

Absorption with food

no effect

no effect

6–22 % more

+39 %

Intake with food?

no

no

no official recommendation yet

mandatory

Absorption with H2B/PPI

plasma level -12 to -30 %

no effect

no effect

no effect

Asian ethnicity

plasma level +25 %

no effect

no effect

no effect

GI tolerability

dyspepsia 5–10 %

no problem

no problem

no problem

Elimination half-life

12–17 hours

12 hours

9–11 hours

5–9 hours (young)/

11–13 hours (elderly)

GI = gastrointestinal; PPI = proton pump inhibitors. * = Not yet approved.

Table 2: Potential Drug–Drug Interactions – Effects on New Oral Anticoagulant Plasma Levels Atorvastatin P-gp/CYP3A4

Dabigatran Apixaban +18 % no data yet

Edoxaban* no effect

Rivaroxaban no effect

Digoxin

P-gp

no effect

no data yet

no effect

no effect

Verapamil

P-gp/week CYP3A4

+12–180 %

no data yet

+53 % (slow release) minor effect

Diltiazem

P-gp/week CYP3A4

no effect

+40 %

no data

minor effect

Quinidine

P-gp

+50 %

no data yet

+80 %

+50 %

Amiodarone

P-gp

+12–60 %

no data yet

no effect

minor effect

Dronedarone

P-gp/CYP3A4

+70–100 %

no data yet

+85 %

no data yet

Ketoconazole; itraconazole;

P-gp and BCRP/CYP3A4

+140–150 %

+100 %

no data yet

up to +160 %

voriconazole; posaconazole

Interaction

Dabigatran Apixaban

Edoxaban

Rivaroxaban

Fluconazole

CYP3A4

no data

no data

no data

+42 %

Cyclosporin; tacrolimus

P-gp

no data

no data

no data

+50 %

Clarithromycin; erythromycin

P-gp/CYP3A4

+15–20 %

no data

no data

+30–54 %

HIV protease inhibitors

P-gp and BCRP/CYP3A4

no data

strong increase

no data

up to +153 %

Rifampicin; St John’s wort;

P-gp and BCRP/

-66 %

-54 %

-35 %

up to -50 %

carbamezepine; phenytoin; phenobarbital

CYP3A4/CYP2J2

Antacids

GI absorption

-12–30 %

no data

no effect

no effect

BCRP = breast cancer resistance protein; P-gp = P-glycoprotein. * = Not yet approved.

When interpreting anticoagulation assays, it is important to know exactly when the NOAC was administered relative to the time of blood sampling. The maximum effect on clotting tests is gained around three hours after administration. For dabigatran, thrombin time (TT), ecarin clotting time (ECT),8,9 activated thromboplastin time (aPTT)8,9 and prothrombin test (PT)9,10 may be used. Anti-factor Xa chromogenic assays are also commercially available; though their use has not been comprehensively validated.

Dose reduction of NOACs is essential in patients treated with concomitant medications that increase the NOAC plasma level.14,15 Therefore a system of levels of alert has been devised whereby red indicates a contraindication for use, orange indicates adaptation of the NOAC dose and yellow indicates dose maintenance, unless there are two concomitant yellow interactions, in which case dose reduction is recommended. A detailed table of potential DDIs is presented in Table 2.

Switching Between Anticoagulant Regimens Drug–Drug Interactions and Pharmacokinetics of New Oral Anticoagulants The uptake, metabolism and elimination of NOACs are summarised in Table 1. Mechanisms underlying potential DDIs include the P-glycoprotein (P-gp) transporter involved in absorption and renal clearance.11 Plasma levels of NOACs may be affected by P-gp substrates, which include many drugs used in AF patients (e.g. verapamil, dronedarone, quinidine). Cytochrome P450 (CYP3A4) is involved in the hepatic clearance of rivaroxaban,12 but dabigatran is unaffected.13 Plasma levels of rivaroxaban may therefore be affected by CYP3A4 inducers or inhibitors.

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When switching between anticoagulant regimes, anticoagulant efficacy must be maintained while minimising bleeding risk. Switching from VKAs to NOAC can be immediate if the international normalized ratio (INR) is less than 2.0. Due to the slow onset of action of VKAs, when switching from NOACs to VKAs, the two drugs should be administered concomitantly until the INR reaches an appropriate level.

Ensuring Compliance with New Oral Anticoagulant Intake Ensuring compliance with NOAC intake is vital because the anticoagulant effect drops rapidly after 12–24 hours. Daily dosing

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The EHRA Practical Guide on the Use of NOACs in Patients with Non-valvular Atrial Fibrillation

Figure 1: Management of Bleeding in Patients Taking New Oral Anticoagulants

NOAC = New Oral Anticoagulant; PCC = Prothrombin complex concentrate; aPCC = activated prothrombin complex concentrate; RBC = red blood cell; rFVlla = Recombinant Factor Vlla.

(QD) has been associated with better compliance than twice daily dosing (BID) in other drugs,16 but there is insufficient data to instruct an optimum regime. Patient education may involve leaflets and instruction at initiation, patient safety cards and group sessions. Technological aids such as medication boxes may help. If low compliance persists, a therapy switch to VKAs may be appropriate.

Management of Bleeding Complications

How to Deal with Dosing Errors

Recommendations on bleeding management are summarised in Figure 1.

Dosing errors must be dealt with promptly. In case of a missed dose on a BID regime, the missed dose can be taken up to six hours after the scheduled intake. If this is not possible, the dose should be skipped and the next scheduled dose taken. For QD, the missed dose can be taken up to 12 hours after scheduled intake. After a double dose, on BID, skip the next planned dose and restart BID after 24 hours. On QD, continue the normal regimen. Hospitalisation is advised in case of overdose.

Patients with Chronic Kidney Disease Chronic kidney disease (CKD) confers the risk of thromboembolic events and bleeding in AF patients,17,18 as well as being a risk factor for stroke and systemic embolism.19 NOACs may be used in AF patients with mild or moderate CKD. Careful consideration should be given before administering dabigatran, which is primarily cleared renally, to patients with CKD. Individual risk–benefit analyses should be undertaken. Reduced doses of FXa inhibitors may be indicated in patients with reduced renal function (creatinine clearance [CrCl] 30–50 ml/min).10 Dose reductions are indicated in patients with CrCl <50 ml/min for apixaban2 and rivaroxaban.20 NOACs should be avoided in AF patients with haemodialysis; VKAs may be preferable. Renal function should be monitored at yearly intervals if CrCl exceeds 60 ml/min and the NOAC dose adapted in response to any change. If renal function is impaired (30–60 ml/min), six-monthly monitoring is recommended. In advanced CKD (CrCl ≤30 ml/min), monitoring should be carried out every three months. These are expert suggestions that are not supported by good data.

What To Do If There is a Suspected Overdose Without Bleeding, or a Clotting Test is Indicating a Risk of Bleeding Doses of NOACs above those recommended are associated with increased bleeding risk. In cases of acute recent ingestion of

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overdose, activated charcoal should be given to reduce absorption. Coagulation tests can assess possible bleeding risks. However, given the short plasma half-life of NOACs, in the absence of bleeding, a ‘wait-and-see’ approach is recommended.

Not Life-threatening Bleeding In view of the short plasma half-life of NOACs, time is the most important antidote.21 Restoration of haemostasis should occur within 12–24 hours after the last dose. It is therefore important to establish the exact time of last intake and factors influencing plasma concentration, such as co-medications and CKD. Dialysis is an option for removal of dabigatran,22 but the risks of bleeding at the puncture site must be balanced against the risk of waiting.

Life-threatening Bleeding In addition to the measures for not life-threatening bleeding, prothrombin complex concentrate (PCC) may be used.23

Patients Undergoing a Planned Surgical Intervention or Ablation Surgical interventions that carry a bleeding risk24 require temporary cessation of NOACs. When the intervention involves no significant bleeding risk (e.g. dental interventions, cataract, glaucoma intervention), the procedure can be carried out at the trough concentration of the NOAC (i.e. 12 or 24 hours after the last intake). If possible, the intervention should be scheduled 18–24 hours after the last intake, then NOACs restarted six hours later. For procedures with a minor bleeding risk, NOACs should be discontinued 24 hours before the procedure. For high-risk interventions such as pulmonary vein isolation (PVI) or thoracic surgery, the last NOAC should be taken 48 hours previously. In cases of impaired kidney function, earlier interruption of therapy may be indicated. For procedures with immediate and complete haemostasis, NOACs can be resumed 6–8 hours after the intervention. However, for many surgical interventions, the risks of resuming NOACs within 48–72 hours after the procedure may outweigh the risk of cardioembolism.

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Clinical Arrhythmias Low molecular weight heparins (LMWH) may be used 6–8 hours after surgery if haemostasis has been achieved, restarting NOACs 48–72 hours after the procedure. Maximal anticoagulation effect will be achieved within two hours of ingestion. For AF patients undergoing PVI, a strategy of bridging with VKAs is preferred.25

compliance, a prior transoesophageal echocardiogram (TOE) should be considered.

Patients Presenting with Acute Stroke While on New Oral Anticoagulants Acute Phase

Patients Undergoing an Urgent Surgical Intervention In cases of emergency intervention, the NOAC should be discontinued, surgery deferred, if possible, for at least 12 hours and ideally 24 hours after the last dose.

Patient with Atrial Fibrillation and Coronary Artery Disease The combination of AF and coronary artery disease (CAD) is relatively common, and is associated with significantly higher mortality rates.26 Recommendations are based on three clinical scenarios.

Patients with Acute Haemorrhagic Stroke NOAC therapy should be discontinued. The use of procoagulants, as described above, may be considered.

Patients with Acute Ischaemic Stroke Thrombolytic therapy cannot be given within 48 hours after the last dose of NOACs. In case of uncertainty regarding the last dose, a prolonged aPTT (dabigatran) or PT (FXa inhibitors) contraindicates the use of thrombolytics. If NOACs have been given within 48 hours and coagulation tests are not available or abnormal, recanalisation of the occluded vessels may be considered.

Scenario 1 – Acute Coronary Syndrome Management in Atrial Fibrillation Patients on New Oral Anticoagulants

Post-acute Phase

Risk scores for ischaemic and bleeding events may guide therapeutic decisions.27 NOACs should be discontinued upon presentation with acute coronary syndrome (ACS). Unless contraindicated, low-dose aspirin should be given, as well as a P2Y12 inhibitor. In cases of ST-elevation myocardial infarction (STEMI), additional parenteral anticoagulation should be used. In cases of non-ST elevation MI (NSTEMI), after discontinuing the NOAC and waning of its effect, fondaparinux (preferred), unfractionated heparin (UFH) or enoxaparin may be initiated. For percutaneous coronary intervention (PCI) in NSTEMI, the NOAC should be discontinued and the NOAC effect should have disappeared before the intervention. Periprocedural anticoagulation is recommended.

If the cardioembolic risk is high and risk of new haemorrhage low, NOACs may be restarted after 10–14 days. For patients with low cardioembolic risk and high bleeding risk, reinitiation of NOACs is contraindicated unless bleeding has been reversed.

Haemorrhagic Stroke

Ischaemic Stroke If the infarct size is not expected to increase the risk of secondary intracerebral bleeding, NOACs may be reinitiated in patients with transient ischaemic attack (TIA) after one day, in small, non-disabling infarcts after three days, moderate stroke after six days and large infarcts not before two weeks.

Transient Ischaemic Attack of Cardioembolic Origin In the chronic setting (<1 year after ACS), anticoagulant therapy should be personalised, based on atherothrombotic, cardioembolic and bleeding risks. For therapy beyond the first year, treatment as in scenario 3 may be used.

Scenario 2 – Management of the Patient with a Recent Acute Coronary Syndrome (<1 Year) Who Develops New Onset Atrial Fibrillation According to ACS guidelines, dual antiplatelet therapy should be given for up to one year. If AF develops, anticoagulants may be considered. In patients with low atherothrombotic risk, VKAs monotherapy may be considered after 1–3 months, especially if they have elevated bleeding risk.

Scenario 3 – A Stable Coronary Artery Disease Patient (Acute Coronary Syndrome >1 Year Ago) Develops Atrial Fibrillation Stable CAD patients developing AF should receive anticoagulation. Any of the NOACs may be used in preference to VKAs, without increased risk of myocardial ischaemic events.28

Cardioversion in a New Oral Anticoagulant Treated Patient In patients with AF >48 hours duration undergoing cardioversion, oral anticoagulants should be given for at least three weeks previously, and for four weeks afterwards. Clinical data show no significant additional risk in patients treated with NOACs and VKAs.29 If NOAC compliance is assured, cardioversion should be safe. If in doubt about

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NOACs should be restarted as soon as possible; bridging with LMWH is not required.

Ischaemic Stroke of Cardioembolic Origin Initiation of NAOCs depends on the infarct size and risk of new embolic stroke; bridging with LMWH is not required.

Patients with Atrial Fibrillation and Significant Carotid Stenosis Carotid endarterectomy and not stenting is recommended to avoid triple therapy, which is associated with increased bleeding.

New Oral Anticoagulants Versus Vitamin K Antagonists in Atrial Fibrillation Patients with a Malignancy Patients with malignancies are at increased risk for thromboembolic events – tumours may secrete prothrombotic factors or induce inflammatory responses. Cancer therapy also inflicts bleeding risks through surgery, tissue damage or myelosuppression. Many malignancies are associated with increased risk of mucosal bleeding. Furthermore, chemotherapy may interact with coagulation mechanisms. Multidisciplinary care by cardiologists and oncologists is required. If anticoagulant therapy is needed, the greater clinical experience of, and reversal options with VKAs indicate that they should be chosen over NOACs. Established NOAC therapy should be continued where possible. Patients undergoing radiation therapy or chemotherapy without a marked myelosuppressive effect should continue NOACs,

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adapting the dose if indicated. In patients undergoing myelosuppressive chemotherapy or radiation therapy, temporary dose reduction or

1.

 onnolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus C warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. 2. C  onnolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806–17. 3. P  atel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. 4. R  uff CT, Giugliano RP, Antman EM, et al. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J 2010;160:635–41. 5. 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. 6. H  eidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625–51. 7. Hendriks JM, de Wit R, Crijns HJ, et al. Nurse-led care vs. usual care for patients with atrial fibrillation: results of a randomized trial of integrated chronic care vs. routine clinical care in ambulatory patients with atrial fibrillation, Eur Heart J 2012;33:2692–9. 8. van Ryn J, Baruch L, Clemens A. Interpretation of point-of-care INR results in patients treated with dabigatran, Am J Med 2012;125:417–20. 9. Huisman MV, Lip GY, Diener HC, et al. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: resolving uncertainties in routine practice. Thromb Haemost 2012;107 :838–47. 10. M  ueck W, Lensing AW, Agnelli G, et al. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deepvein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention, Clin Pharmacokinet 2011;50:675–86.

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cessation of NOACs should be considered, with monitoring of blood counts, bleeding signs, and liver and renal function. n

11. G  noth MJ, Buetehorn U, Muenster U, et al. In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban, J Pharmacol Exp Ther 2011;338:372–80. 12. Mueck W, Kubitza D, Becka M, Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol 2013;76:455–66. 13. Wang L, Zhang D, Raghavan N, et al. In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies. Drug Metab Dispos 2010;38:448–58. 14. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, 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), Europace 2010;12:1360–420. 15. LaHaye SA, Gibbens SL, Ball DG, et al. A clinical decision aid for the selection of antithrombotic therapy for the prevention of stroke due to atrial fibrillation. Eur Heart J 2012;33:2163–71. 16. Laliberté F, Nelson WW, Lefebvre P, et al. Impact of daily dosing frequency on adherence to chronic medications among nonvalvular atrial fibrillation patients. Adv Ther 2012;29:675–90. 17. 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. 18. 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. 19. Piccini JP, Stevens SR, Chang Y, et al. Response to letter regarding article, “renal dysfunction as a predictor of stroke and systemic embolism in patients With nonvalvular atrial fibrillation: validation of the R2CHADS2 index in the ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study Cohorts”. Circulation 2013;128:e172–3. 20. 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. 21. Levi M, Eerenberg E, Kamphuisen PW. Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents. J Thromb Haemost 2011;9:1705–12. 22. Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, singlecentre study. Clin Pharmacokinet 2010;49:259–68. 23. van Ryn J, Ruehl D, Priepke H, et al. Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor dabigatran, by recombinant factor VIIa or activated prothrombin complex concentrate. Haematologica 2008;93 (Suppl 1):148. 24. Torn M, Rosendaal FR. Oral anticoagulation in surgical procedures: risks and recommendations. Br J Haematol 2003;123:676–82. 25. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of dabigatran versus warfarin for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry, J Am Coll Cardiol 2012;59:1168–74. 26. Lopes RD, Pieper KS, Horton JR, et al. Short- and long-term outcomes following atrial fibrillation in patients with acute coronary syndromes with or without ST-segment elevation. Heart 2008;94:867–73. 27. Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2999–3054. 28. Hohnloser SH, Oldgren J, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial. Circulation 2012;125:669–76. 29. Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation 2011;123:131–6.

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Diagnostic Electrophysiology & Ablation

The Role of Three-dimensional Rotational Angiography in Atrial Fibrillation Ablation Georg Nölk er, D i e t e r H o r s t k o t t e a n d Kl a u s - J ü r g e n G u t l e b e n Department of Cardiology, Heart and Diabetes Center North Rhine-Westphalia, Ruhr University Bochum, Bochum, Germany

Abstract Three-dimensional (3D) imaging became the cornerstone of catheter guidance in atrial fibrillation (AF) ablation procedures during the last few years. Multislice computed tomography (MSCT) and magnetic resonance imaging (MRI) have been the technologies of choice for pre-procedural imaging of the left atrium (LA) and the pulmonary veins to make lesions more precisely set in a highly variable and difficult to understand 3D environment. These technologies have been used not only for pre-procedural orientation but have also been overlayed to fluoroscopic views in many fluoroscopy-guided ablation procedures. As image integration into non-fluoroscopic 3D imaging systems became available, 3D reconstructions of MSCT and MRI became the standard approach in many centres. However, 3D imaging is not a cornerstone during ablation as it is not indispensable and ablation can be performed without. Although rare, some very important and key centres do not routinely use 3D imaging during ablation. Being remote to the ablation procedure, these imaging technologies may have the disadvantage of not reflecting the current status of a variable LA volume and scheduling of an additional diagnostic procedure may complicate the workflow of AF ablation procedures. Intra-procedural imaging techniques are likely to overcome both issues. Beside others, rotational angiography has been introduced for proving highly actual imaging by intra-procedural acquisition of 3D shells suitable for overlay to fluoroscopy without need for registration and image integration into 3D mapping systems registered by point-by-point electroanatomical mapping or 3D echocardiographic imaging.

Keywords Atrial fibrillation, pulmonary vein isolation, catheter ablation, intracardiac echocardiography, image integration, rotational angiography Disclosure: Georg Nölker received honoraria for lectures from Siemens AG and Biosense Webster, Inc. Klaus-Jürgen Gutleben received honoraria for proctorship from Biosense Webster, Inc. Dieter Horstkotte has no conflicts of interest to declare. Received: 21 June 2013 Accepted: 10 October 2013 Citation: Arrhythmia & Electrophysiology Review 2013;2(2):120–3 Access at: www.AERjournal.com Correspondence: Georg Nölker, Department of Cardiology, Heart and Diabetes Center North Rhine-Westphalia, Ruhr University Bochum, Georgstrasse 11, 32545 Bad Oeynhausen, Germany. E: gnoelker@hdz-nrw.de

Catheter ablation is an established treatment option for patients with symptomatic atrial fibrillation (AF).1–3 Pulmonary vein (PV) angiography has been the initial imaging tool in AF ablation and is still used by up to 50 % of leading electrophysiologists.3 PV angiography still plays a major role in balloon-based ablation techniques routinely performed without electroanatomical mapping (EAM). Some very experienced centres do not feel any need for three-dimensional (3D) imaging due to their ability to orientate in two-dimensional (2D) fluoroscopic views. 3D imaging is likely to better reflect relations between anatomic structures and ensures that all PVs are clearly identified. Therefore, it is not surprising that the majority of studies done on image integration of 3D shells into EAM show positive effects on radiation exposure, procedural and long-term success.4–6 In particular, results of large multicentre registries clearly show the benefit of image integration regarding freedom from AF7 in comparison with fluoroscopy-guided ablation. Integration of 3D reconstructions of pre-procedurally acquired data sets derived from multislice computed tomography (MSCT) or magnetic resonance imaging (MRI) into EAM systems has been introduced to guide left atrial (LA) ablation procedures.8–13 However, these remote imaging technologies may not perfectly reflect the status found during ablation due to changes in cardiac rhythm and preload, and their impact on the LA volume for example. Therefore, the search for an intra-procedural technology close to realtime imaging continued and led to the development of rotational angiography.

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Principles of Rotational Angiography Different protocols of this technique have been introduced over time14–19 having in common the principle of a C-arm run around the patients` region of interest (in case of AF ablation the LA) with acquisition of X-ray images with a certain rate of frames per second using a flat panel detector (see Figure 1). To enhance cardiac structures, contrast media is administered into the right atrium or the pulmonary artery and C-arm run is started after a delay reflecting the pulmonary transition time. Individual pulmonary transition time can be estimated by a bolus injection of contrast media into the pulmonary artery. This compensates for delayed enhancements due to low cardiac output. Alternatively, direct injection into the LA is performed and the C-arm run is started with a short delay. A more intense contrast of the LA may be seen after direct injection. However, contrast injection into the LA may lead to an artificial enlargement of its image. For enhancement of the oesophagus the patient is asked to swallow contrast paste. All these approaches provide data sets that allow for measurements in virtually unlimited planes and 3D reconstruction of the LA, PV, aorta and the oesophagus applying software on different specialised computer systems (e.g. Syngo X-Workplace, Siemens, Forchheim, Germany and EP Navigator, Philips, Best, The Netherlands).

Accuracy in Comparison with Multislice Computed Tomography Accuracy is a critical point of imaging during AF ablation as ablating too far ostially bears the risk of inducing PV stenosis and of missing

© RADCLIFFE 2013

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Rotational Angiography in Atrial Fibrillation Ablation

antral foci, and overseeing small PVs may lead to ineffectiveness of the procedure. Furthermore, suboptimal orientation may lead to perforation and other avoidable complications. The gold standard of 3D imaging in AF ablation is MSCT. Two studies have compared accuracy of MSCT with rotational angiography. In our study,16 planes from pre-procedural MSCT and DynaCT Cardiac (Siemens AG, Forchheim, Germany) were automatically parallelised and cross-sectional diameters of PVs, LA appendage and LA and aorta were correlated. In our series we found an overall correlation of diameter of 0.99 and no significant difference in diameters derived from rotational angiography and MSCT. However, although not being significantly different between the two modalities, correlation between pre- and intra-procedural volumes of the LA was less good (0.86). This may be due to the remoteness of MSCT as discussed above. In addition, the position of the oesophagus may also vary significantly between a pre-procedural and thereby remote imaging and an intra-procedural rotational angiography supporting the assumption that higher actuality of imaging is relevant. However, intra-procedural changes of structures and positions remain a domain of realtime imaging technologies. Kriatselis and co-workers20 showed later that acceptable imaging in comparison with MSCT can also be achieved with a smaller detector. In their data set a correlation of 0.82–0.92 for the PVs and 0.80–0.87 for the LA volume was found.

Figure 1: Image Aquisition in Rotational Angiography

A

B

C

D

E

F

G

H

I

J

K

L

The upper row of images (A–F) shows the continuous movement of the C-arm along a 198° arc from 99° right anterior oblique (A) to 99° left anterior oblique (F) within five seconds. Notably, the patient is positioned with his arms above his head and is asked for breathhold for optimal imaging quality. The lower row of images (G–L) shows the corresponding X-ray images at each angiographic position of the C-arm. 248 projection image data are collected at 60 frames per second by a 30 x 40 cm flat panel detector with 4 x 4 pixel spacing achieving a pixel size of 600 x 600 micrometre (μm).

Figure 2: Section of a 3D Reconstruction Derived from a Rotational Angiography is Depicted in Red as an Overlay to a Fluoroscopic View. The Circumferential Multipolar Mapping Catheter (‘Lasso’) has been Inserted into the Right Superior Pulmonary Vein

Three-dimensional Reconstructions of Rotational Angiography as an Overlay to Fluoroscopic Views Having a 3D reconstruction of the LA and the PV available for pre-procedural orientation was found to be helpful but was only a stepping stone towards image integration. The first step of image integration was to superimpose 3D reconstructions to fluoroscopic views during the ablation (see Figure 2). Technologies are available to make the superimposed 3D shell automatically follow moves of the C-arm to provide a continuous 3D guidance to the operator (e.g. Syngo iPilot dynamic, Siemens, Forchheim, Germany). As image acquisition by rotational angiography is performed with the patient at the same place where ablation is done, no registration or adjustment of the reconstruction is needed as long as the patient does not move. 16 In case of need for registration due to movements, protocols have been introduced to facilitate this based on the position of the LA related to the spinal column and the trachea and mainstem bronchi. 21 A limitation of the overlay technology still is the missing compensation for respiration. However, the overlay technique can be used as a single navigation tool in AF ablation17 with an acceptable short-term outcome and low complication rates. Meanwhile, superimposition of ablation points to fluoroscopy and rotational angiography has been integrated into software of different manufacturers. This may reduce the need for EAM systems furthermore, as long as advanced functionality like activation mapping is not required. Ablation then is fully fluoroscopy-based and by this radiation exposure due to long fluoroscopy times may be high.17,22

Image Integration of Rotational Angiography into Three-dimensional Mapping Systems Image integration of 3D shells into EAM-systems has lots of theoretical advantages over overlay techniques. In particular, activation mapping in case of transformation of AF into atrial tachycardias is possible; navigation in a 3D environment can be performed without or with a minimal amount of additional radiation and parameters like contactforce can be related to ablation points in the EAM. Moreover, it has

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“Lasso” - Catheter

ICE - Probe ICE = intracardiac echocardiography.

been shown that integration of 3D reconstructions into EAM may improve the outcome.13 Pre-procedural MRI and MSCT scans can be accurately registered to EAM-systems and integration of these has been the gold standard of image integration for a long time. Integration of the rotational angiography-based reconstructions is likely to have the same advantages of MRI/MSCT integration and may be even superior because of its high degree of actuality and its seamless integration into the workflow in the electrophysiology laboratory. 3D reconstructions of the rotational (see Figure 3) angiography can be transferred to both the EnSite (St Jude Medical) and the Carto® (Biosense Webster, Inc) system either directly online via hospital networks or via hard copies in terms of a compact disc (CD). Image integration of rotational angiography then follows the same steps well-known for MSCT/MRI, and accuracy of imaging compared with MSCT has been demonstrated to be acceptable with a deviation between EAM and rotational angiography of 2.2 ± 0.4 millimetres (mm).23 3D reconstructions of intracardiac echo may serve as an alternative to EAM for integration of rotational angiography. This can be done before LA access and thereby LA dwelling time is reduced and inaccuracy of EAM due to pushing a mapping catheter against the LA wall may be reduced.24 This technique is also very accurate in

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Diagnostic Electrophysiology & Ablation Figure 3: 3D Reconstruction of a Rotational Angiography (DynaCT Cardiac, Siemens, Forchheim, Germany) of the Left Atrium and Pulmonary Veins (Depicted in Grey) Integrated and Registered in a 3D Mapping System (EnSite Velocity, St Jude Medical, Sylmar, CA, US) in a Posterior View

spent 14.4 ± 3.2 minutes and Kriatselis et al.17 reported on 6.0 ± 3.0 minutes for preparation and performance, 4.0 ± 2.0 minutes for 3D reconstruction and 5.0 ± 3.0 minutes and of a total time for acquisition and reconstruction of 13.0 ± 5.0 minutes in another series20 being close to the times reported by Li et al. Our acquisition and reconstruction time seems to be shorter (7.0 ± 5.0 minutes) with a larger detector (30 x 40 centimetres [cm]; Siemens, Forchheim, Germany) at a frame rate of 60 per second, which is likely to improve imaging quality and thereby may reduce reconstruction time at the price of higher radiation exposure.16

Ways to Improve Imaging Quality in Rotational Angiography Although X-ray systems with capability of rotational angiography have been installed in many electrophysiology laboratories in the last few years, use of these systems is still limited. This may be at least partly due to a learning curve in application of this novel technology, which may be shortened when a few key points are kept in mind.

Colours on the shell symbolise local activation times of a macro-reentrant tachycardia from earliest to latest colour-coded in white over red and green to purple. Red dots represent ablation points in an early-meets-late zone where the tachycardia terminated during ablation. The tip of the ablation catheter can be seen in green close to the ablation points. The coronary sinus catheter (CS) is depicted in yellow.

registration of an intra-procedural shell by another one and additional EAM points do not improve registration accuracy.

Radiation Exposure by Rotational Angiography Rotational angiography as an X-ray-based imaging system is potentially harmful for the operator and the patients. Radiation exposure has been reported to be 2.2 ± 0.2 to 6.6 ± 1.8 millisievert (mSv) based on estimations from the dose-area product.18,20,25 The huge variety of values may be traced back to different ways of estimation applied and to the different protocols used for image acquisition. However, comparisons to MSCT by some groups18,20 showed a significantly lower effective radiation dose in rotational angiography compared with MSCT. This is confirmed by our own unpublished data, finding 15.5 ± 10.1 mSv in patients with MSCT image integration compared with 9.0 ± 4.2 mSv in patients with rotational angiography (p<0.0003) in terms of total procedural and pre-procedural effective doses. For sure, radiation exposure of MRI would have been zero and more recent MSCT protocols have demonstrated to save a lot of radiation. However, low-dose protocols for rotational angiography are under way. Radiation exposition to the operator can be minimised by initialising the C-arm run from the control room, this reduces the time of exposure to the time needed for placing the pigtail catheter and isocentering of the patient.

Time and Costs In times of limited financial resources for healthcare even in the Western European and North American countries, besides its benefits, costs are a relevant matter of discussion. One group has calculated the costs of rotational angiography in terms of technical fee without personal costs and resulted in €91–95 per examination compared with €100–125 caused by a MSCT.20 These are rough estimations and differences in workload will have an impact as well as variations in costs of different systems. However, rotational angiography does not seem to be costly in comparison with MSCT. The time required for acquisition and segmentation of rotational angiography varies a little between different groups: Li et al.18

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Isocentering is of critical importance especially when a small detector is used. With a 20 x 20 cm detector, two landmarks may help the operator to isocenter: • The tracheal bifurcation is always found some millimetres superior to the roof of the LA and closer to the right than to the left superior pulmonary vein in a posterior-anterior projection. • The vertebral column is always at the back of the posterior wall of the LA in a lateral view and when half of it is depicted in the 20 x 20 cm detector in a lateral projection the LA is centred well. Contrast can be improved by direct injection of contrast medium into the LA. This may have the disadvantage of longer LA dwelling time and will require either rapid ventricular pacing or adenosine to avoid an immediate washout of the dye. Both of these have their own disadvantages like induction of arrhythmias, need for general anaesthesia and others. In addition, administration of 50–60 millilitres (mL) of contrast medium into the LA while rapid ventricular pacing and/ or adenosine is applied may lead to an artificial enlargement resulting in an overestimation of the LA volume by rotational angiography. Higher enhancing contrast medium may be another option to increase contrast (e.g. Imeron 400 MCT, Bracco Imaging, Konstanz, Germany with 400 milligram [mg] Iodine per mL). Any cables and skin electrodes have disturbing effects on X-ray imaging, removal of all these before image acquisition or use of X-ray transparent material improves imaging quality. A pigtail catheter filled with contrast medium after injection leads to imaging artifacts. This can be avoided by withdrawing the catheter after contrast medium administration or flushing the catheter with a few millilitres of saline. In case of working in a magnetic laboratory, the pigtail catheter can also be removed remotely by the Cardiodrive Catheter Advancement System (Stereotaxis Inc, St Louis, MO, US).

Limitations In case of right-sided contrast injection, estimation of pulmonary transition time is of critical importance and may induce a learning period until this can be done properly. Rotational angiography will always add a certain amount of radiation exposure to the procedure bearing a risk of inducing malignant diseases. Contrast enhancement is necessarily associated with administration of contrast media. This may be an issue in patients

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with impaired renal function as well as in those suffering from severe congestive heart failure or thyroid dysfunctions. Finally, there is an undeniable but certainly very limited risk of anaphylactic reaction.

Conclusion and Perspective Rotational angiography introduced as an imaging technology in AF ablation is highly accurate in displaying crucial structures

1. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation (full text): a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 guidelines for the management of patients with atrial fibrillation) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Europace 2006;8:651–745. 2. 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. 3. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart Rhythm 2012;9:632–96. 4. Kistler PM, Rajappan K, Jahngir M, et al. The impact of CT image integration into an electroanatomical mapping system on clinical outcomes of catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2006;17:1093–101. 5. Kistler PM, Earley MJ, Harris S, et al. Validation of threedimensional cardiac image integration: use of integrated CT image into electroanatomic mapping system to perform catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2006;17:341–8. 6. Martinek M, Nesser HJ, Aichinger J, et al. Impact of integration of multislice computed tomography imaging into three-

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for PV isolation comparable with MSCT. Furthermore, being an intra-procedural imaging technique, it provides a high level of actuality and may improve workflows when scheduling of an additional imaging procedure can be avoided. Image-integration of 3D reconstructions based on rotational angiography into EAM is feasible, accurate and fast. Therefore, rotational angiography may replace other imaging technologies for AF ablation. n

dimensional electroanatomic mapping on clinical outcomes, safety, and efficacy using radiofrequency ablation for atrial fibrillation. Pacing Clin Electrophysiol 2007;30:1215–23. 7. Bertaglia E, Bella PD, Tondo C, et al. Image integration increases efficacy of paroxysmal atrial fibrillation catheter ablation: results from the CartoMerge Italian Registry. Europace 2009;11:1004–10. 8. Tops LF, Bax JJ, Zeppenfeld K, et al. Fusion of multislice computed tomography imaging with three-dimensional electroanatomic mapping to guide radiofrequency catheter ablation procedures. Heart Rhythm 2005;2:1076–81. 9. Dong J, Calkins H, Solomon SB, et al. Integrated electroanatomic mapping with three-dimensional computed tomographic images for real-time guided ablations. Circulation 2006;113:186–94. 10. Dong J, Dickfeld T, Dalal D, et al. Initial experience in the use of integrated electroanatomic mapping with threedimensional MR/CT images to guide catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2006;17:459–66. 11. Malchano ZJ, Neuzil P, Cury RC, et al. Integration of cardiac CT/MR imaging with three-dimensional electroanatomical mapping to guide catheter manipulation in the left atrium: implications for catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2006;17:1221–9. 12. Tang K, Ma J, Ma FS, et al. Initial experience with circumferential pulmonary vein ablation guided by fusion of magnetic resonance imaging with three-dimensional electroanatomic mapping. Chin Med J (Engl) 2006;119:1047–52. 13. Bertaglia E, Brandolino G, Zoppo F, et al. Integration of three-dimensional left atrial magnetic resonance images into a real-time electroanatomic mapping system: validation of a registration method. Pacing Clin Electrophysiol 2008; 31:273–82. 14. Orlov MV, Hoffmeister P, Chaudhry GM, et al. Threedimensional rotational angiography of the left atrium and esophagus -- A virtual computed tomography scan in the electrophysiology lab? Heart Rhythm 2007;4:37–43. 15. Thiagalingam A, Manzke R, D‘Avila A, et al. Intraprocedural volume imaging of the left atrium and pulmonary veins with rotational X-ray angiography: Implications for catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2008;19;293–300. 16. Nölker G, Gutleben KJ, Marschang H, et al. Three-dimensional left atrial and esophagus reconstruction using cardiac

C-arm computed tomography with image integration into fluoroscopic views for ablation of atrial fibrillation: accuracy of a novel modality in atrial fibrillation ablation in comparison with multislice computed tomography. Heart Rhythm 2008;5:1651–7. 17. Kriatselis C, Tang M, Nedios S, et al. Intraprocedural reconstruction of the left atrium and pulmonary veins as a single navigation tool for ablation of atrial fibrillation: a feasibility, efficacy, and safety study. Heart Rhythm 2009;6:733–41. 18. Li JH, Haim M, Movassaghi B, et al. Segmentation and registration of three-dimensional rotational angiogram on live fluoroscopy to guide atrial fibrillation ablation: a new online imaging tool. Heart Rhythm 2009;6:231–7. 19. Ector J, De Buck S, Nuyens D, et al. Adenosine-induced ventricular asystole or rapid ventricular pacing to enhance three-dimensional rotational imaging during cardiac ablation procedures. Europace 2009;11:751–62. 20. Kriatselis C, Nedios S, Akrivakis S, et al. Intraprocedural imaging of left atrium and pulmonary veins: a comparison study between rotational angiography and cardiac computed tomography. Pacing Clin Electrophysiol 2011;34:315–22. 21. Orlov MV. How to perform and interpret rotational angiography in the electrophysiology laboratory. Heart Rhythm 2009;6:1830–6. 22. Knecht S, Wright M, Akrivakis S, et al. Prospective randomized comparison between the conventional electroanatomical system and three-dimensional rotational angiography during catheter ablation for atrial fibrillation. Heart Rhythm 2010;7:459–65. 23. Nölker G, Asbach S, Gutleben KJ, et al. Image-integration of intraprocedural rotational angiography-based 3D reconstructions of left atrium and pulmonary veins into electroanatomical mapping: accuracy of a novel modality in atrial fibrillation ablation. J Cardiovasc Electrophysiol 2010;21:278–83. 24. Nölker G, Gutleben KJ, Asbach S, et al. Intracardiac echocardiography for registration of rotational angiographybased left atrial reconstructions: a novel approach integrating two intraprocedural three-dimensional imaging techniques in atrial fibrillation ablation. Europace 2011;13:492–8. 25. Wielandts JY, De Buck S, Ector J, et al. Three-dimensional cardiac rotational angiography: effective radiation dose and image quality implications. Europace 2010;12:194–201.

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Role of Magnetic Resonance Imaging of Atrial Fibrosis in Atrial Fibrillation Ablation Da v id D Spra g g , I r f a n Kh u r ra m a n d S a m a n N a z a r i a n Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, US

Abstract Atrial fibrillation (AF) likely involves a complex interplay between triggering activity, usually from pulmonary vein foci, and maintenance of the arrhythmia by an arrhythmogenic substrate. Both components of AF, triggers and substrate have been linked to atrial fibrosis and attendant changes in atrial electrophysiology. Recently, there has been a growing use of imaging modalities, particularly cardiac magnetic resonance (CMR), to quantify the burden of atrial fibrosis and scar in patients either undergoing AF ablation, or who have recently had the procedure. How to use the CMR derived data is still an open area of investigation. The aim of this article is to summarise what is known as atrial fibrosis, as assessed by traditional catheter-based techniques and newer imaging approaches, and to report on novel efforts from our group to advance the use of CMR in AF ablation patients.

Keywords Atrial fibrillation, fibrosis, catheter ablation Disclosure: Saman Nazarian is on the MRI advisory panel for Medtronic, and is a scientific advisor to and principal investigator for research funding to Johns Hopkins University from Biosense Webster, Inc., National Heart, Lung and Blood Institute of the National Institutes of Health grants K23HL089333 and R01HL116280 fund Dr Nazarian’s research. The remaining authors have no conflicts of interest to declare. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Received: 5 September 2013 Accepted: 14 October 2013 Citation: Arrhythmia & Electrophysiology Review 2013;2(2):124–7 Access at: www.AERjournal.com Correspondence: David D Spragg, Johns Hopkins Hospital, Carnegie 568, 600 N Wolfe Street, Baltimore, MD 21287-0409, US. E: dspragg1@jhmi.edu

Atrial fibrillation (AF) is a remarkably common arrhythmia, affecting roughly 6 % of patients over 65 years of age, with an estimated US prevalence of over two million patients.1 That prevalence is likely to increase as patients live longer, and will contribute to rising morbidity and mortality over time.2–4 Efforts to treat AF remain imperfect. Rhythm control approaches typically consist either of antiarrhythmic drug use or, increasingly, catheter ablation of atrial targets. Over the last decade there has been general consensus among treating electrophysiologists that for most patients, isolation of triggering foci in the pulmonary vein (PV) ostia is the mainstay of ablative therapy.5 Recently, this paradigm has been challenged, in part because of better understanding of atrial fibrosis and ensuing abnormal patterns of atrial conduction that may serve to sustain AF once induced.6 Novel approaches targeting stable electrical rotors may represent a new approach to catheter ablation of AF. The purpose of this review is to summarise the state of knowledge about fibrosis as a contributor to AF, and how cardiac magnetic resonance (CMR) is increasingly utilised to assess for atrial fibrosis and inform clinical decision-making.

Basic Mechanisms Decades ago Gordon Moe reported that AF was due to the functional reentry of several wandering wavelets coursing through atrial tissue.7–9 The hypothesis was based largely on modeling work. Allessie and colleagues performing cardiac mapping studies further investigated this hypothesis years later. Pacing-induced AF was shown by Allessie to shorten atrial refractory periods, thus increasing the potential for reentry and the perpetuation of AF.10–12 Subsequent investigators have

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found that in addition to the fundamental changes in refractoriness of atrial tissue, conduction velocity is significantly reduced in diseased atria that are prone to fibrillation.13 Changes in atrial conduction are likely the result of altered myocyte connectivity, due both to changes in gap junction-mediated electrical coupling and to the formation of interstitial fibrosis and scarring.14–17 This combination of deranged conduction (with likely areas of frank conduction block), reduced refractoriness and triggering foci conspire to create a perfect substrate for initiation and maintenance of reentry. Triggered beats arrive at areas of unidirectional block, and are conducted slowly through fibrotic tissue. Shortened refractory periods allow for rapid electrical recovery of diseased tissue and the perpetuation of the arrhythmia. The role of fibrosis in this process has been investigated in experimental models and in patients. Forced generation of fibrosis in a variety of investigational constructs, by gene overexpression in mice,18 by tachycardia-induced myopathies,19,20 in ageing models,21,22 and in models of valvular heart disease,23 all are linked with the development of sustained AF. In humans, AF is typically seen in conditions known to cause increased burdens of atrial scar, including congestive heart failure (CHF), valvular disease and coronary disease.24–27 While there appears to be a clear association between conditions linked with increased atrial fibrosis and AF, how fibrosis may contribute to AF is more speculative. As discussed above, one plausible mechanism is through alterations in atrial conduction properties. A second mechanism may be that fibrotic regions, like the PV ostia, give rise to triggering beats that initiate AF from non-PV foci.

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Scar Mapping Catheter ablation strategies have evolved significantly over the last 15 years. Early ablation approaches emulated the long lesions created by the surgical maze procedure of Dr James Cox, and were designed to compartmentalise atrial tissue into discreet regions incapable of sustaining AF.28–31 With Haïssaguerre’s observation that PV foci serve as triggering sites that frequently initiate AF,32 ablation strategies quickly evolved towards those designed to isolate or eliminate PV triggers. Focal and segmental ablation has largely given way to wide area circumferential ablation approaches, with adjunctive therapy (linear lesions, ablation of ganglia, mapping and ablation of rotors) performed occasionally for persistent AF.5 Catheter ablation has allowed for direct, voltage-based assessment of left atrial (LA) fibrosis in humans with AF. Natale and colleagues have reported on perhaps the largest series of patients (700) undergoing initial pulmonary vein isolation (PVI).33 They describe that areas of frank scar, as determined by catheter-based assessment of electrogram amplitude, were present in 6 % of patients, and that scar appeared to correlate with large LA size, low ejection fraction (EF) and elevated C-reactive protein (CRP) levels. Patients with scar had an AF recurrence rate of 57 %, compared with 19 % recurrence in those free of scar. The investigators concluded that scarred regions likely contribute to AF both by providing regions of slow conduction and block, and also potentially by giving rise to ectopic, triggered beats. Other investigators have also documented not only scar, but significant regional heterogeneity of scar distribution in patients with AF versus non-AF controls. AF patients appear to have an increased total burden of scar, with a concentration of fibrotic tissue particularly in the posterior LA wall.34 More recently, investigators have turned to noninvasive scar assessment using CMR, and correlating those image-based measurements with catheter-based ones. A discussion of magnetic resonance (MR)-based scar quantification is provided below.

Cardiac Magnetic Resonance for Assessment of Left Atrial Scar The use of late gadolinium enhanced (LGE) CMR to assess the overall burden and distribution of LA scar was first proposed by Dr Dana Peters. After the initial report by Peters, Marrouche and colleagues made significant strides in applying this technique to the management of patients with atrial arrhythmia. However, the technique requires significant expertise for proper implementation in scanners and for proper image analysis. Therefore, it has been slow to be adopted in routine practice. Our group has focused on methodologies to improve objective quantification of scar and generalizability of results to clinical practice.

How Does Late Gadolinium Enhanced Identify Scar Tissue? The technique of LGE takes advantage of differential uptake and washout kinetics of gadolinium contrast in blood, healthy myocardium and myocardial scar. Contrast levels peak in the blood ahead of normal myocardium and scar. Therefore, imaging immediately after contrast injection results in enhancement of the blood pool and cardiac chambers thus providing optimal images for segmentation of the LA. Contrast perfuses into normal myocardium and scar later than the cardiac chambers. However, due to poor perfusion of scar tissue, contrast washout from scar is delayed compared with normal myocardium. At the time of late imaging, contrast has washed out of normal myocardium, and has high concentrations in scar

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myocardium. Therefore, LGE imaging highlights scar myocardium. The technique has been used for two principal aims in AF patients: • t o characterise the pre-existing LA scar burden prior to AF ablation for prognostic purposes; and • t o characterise the post-ablation scar burden and distribution, both for prognosis and for potential planning of redo ablation procedures.

Pre-ablation Assessment of Left Atrial Scar The first report that applied LGE imaging to LA scar was performed in patients who had undergone AF catheter ablation. Peters and colleagues obtained high-spatial-resolution free-breathing LGE images in 23 patients with AF. They examined the LA in 15 patients before ablation and in 18 patients at least 30 days after ablation. The presence of LGE on images and circumferential completeness of scar around the pulmonary veins was assessed. Contrary to later results, the investigators found no pre-ablation LGE in any participants. However, post-ablation LGE was seen in all patients. Only 62  % of patients images revealed greater than 90 % circumferential LGE of the pulmonary veins.35 Following this work, Marrouche and colleagues reported on a series of 46 patients that underwent LGE CMR prior to and after AF ablation. Pre-procedure CMR detected LA fibrosis in 8.7 % of patients.36 Two years following this initial study, Marrouche and colleagues refined their image analysis methodology for assessment of LGE burden, and introduced the Utah scoring system. In this study, which focused on patients with lone AF,37 the Utah system categorised patients by the extent of enhanced LA area, dividing patients into four groups: 1 (<5 %), 2 (5–20 %), 3 (20–35 %) and 4 (>35 %). In this cohort of patients, procedural outcomes were predicted by baseline LA scar burden. After a mean follow-up of 324 days all patients in the group 1 were free of AF, in contrast with only 4 % of patients in group 4, which remained free of AF. The authors concluded that CMR is a powerful tool for pre-procedural patient selection for catheter ablation of AF. Subsequently, Marrouche and colleagues have proposed that the strategy used during AF ablation, such as stand-alone PVI versus coupling of PVI with linear ablations or debulking, be informed by scar burden as assessed by LGE CMR.38,39 The outcomes of patient-specific ablation strategies tailored based upon the pre-procedural scar burden remain unknown.

T1 Mapping of Left Atrial Myocardium The technique of CMR T1 mapping is an emerging tool for objective quantification of myocardial fibrosis, previously applied to noninvasively quantitate the degree of ventricular global diffuse (rather than cohesive) fibrosis. We recently performed a study to examine the feasibility of LA myocardial T1 mapping in 51 patients before AF ablation and in 16 healthy volunteers. The T1 relaxation time is shorter in tissues that contain diffuse fibrosis. We found that the median LA T1 relaxation time was shorter in patients with AF compared with healthy volunteers, and was shorter in patients with AF with prior ablation compared with patients without prior ablation. In a generalised estimating equations model, adjusting for data clusters per participant, age, prior ablation, AF type, hypertension and diabetes, each 100 milliseconds (ms) increase in T1 relaxation time was associated with 0.1 millivolt (mV) increase in intracardiac bipolar LA voltage (P=0.025). This novel methodology, which provides an objective and easy to measure estimate of diffuse fibrosis, may improve the quantification of fibrotic changes in thin-walled myocardial tissues.40

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Diagnostic Electrophysiology & Ablation The Assessment of Left Atrial Scar After Ablation A number of studies have focused on assessing the utility of LGE imaging of LA scar after ablation. The burden of scar visualised by LGE after ablation includes not only endogenous atrial fibrosis, but also the ablation lesion set. Scar burden prior to ablation is negatively associated with post-ablation outcome. However, after AF ablation the implications of high scar burden on LGE images are different. It has been reported that increased density of LA scar after AF ablation associates with improved procedural outcomes. Marrouche and colleagues reported that in 144 patients that had undergone AF ablation, the LA total LGE burden and the degree of circumferential isolation of pulmonary vein ostia were directly proportional with freedom from AF after the procedure.41 Completely circumferential scar surrounding all four pulmonary veins was seen in only 7 % of patients. It has been proposed that post-procedure CMR can be used to assess the adequacy ablation,42 that ablated regions on CMR correlate well with ablation sets recorded on electroanatomical mapping systems,43 and that repeat ablation can be guided by LGE CMR images obtained after the initial procedure.41 The resolution of CMR, as performed at Johns Hopkins Hospital, remains suboptimal for identification of conduction gaps in lesion sets. In a recent study, we enrolled 10 patients undergoing repeat ablation for AF recurrence to undergo pre-procedural LGE-CMR of the LA in conjunction with high-density voltage mapping of the LA during the ablation procedure. LA wall regions with hyperenhancement were segmented from LGE-CMR images and retrospectively co-registered with the electroanatomic LA map. Of 37 pulmonary veins, 30 had regained electrical continuity with the LA. At the end of the repeat procedure, all patients underwent successful re-isolation of all pulmonary veins using standard ablation techniques. In this cohort of patients we noted a significant association between scar identified by LGE and low-voltage regions of the LA. However, there was no association between scar gaps and PV reconnection sites.44

Other Potential Uses for Left Atrial Scar Images Non-invasive assessment of LA scar burden using LGE CMR may also prove helpful for stroke risk stratification in the setting of

1. Feinberg WM, Blackshear JL, Laupacis A, et al. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995;155:469–73. 2. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 1991;84:527–39. 3. Singer DE. Overview of the randomized trials to prevent stroke in atrial fibrillation. Ann Epidemiol 1993;3:563–7. 4. Singer DE. Anticoagulation for atrial fibrillation: Epidemiology informing a difficult clinical decision. Proc Assoc Am Physicians 1996;108:29–36. 5. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart Rhythm 2012;9:632–96. 6. Narayan SM, Krummen DE, Shivkumar K, et al. Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol 2012;60:628–36.

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AF,45 for assessment of LA pump function post-ablation,46 and for evaluation of collateral damage to structures abutting the LA during AF ablation.47 It is likely that with improving techniques for higher spatial and contrast resolution, the utility of CMR imaging for pre-, peri- and post-procedural guidance of AF ablation will continue to increase.

Potential Limitations of the Technique The CMR technique of LGE for imaging LA scar requires significant expertise for image acquisition and image analysis. Therefore, the generalizability of results is not optimal. Additionally, image artifacts due to arrhythmia, patient movement and breathing, and poor myocardium or fat signal suppression, result in inadequate image quality in a significant proportion of cases even at the most experienced centres. However, new techniques for image acquisition and analysis may soon improve the quality and reproducibility of images, as well as the generalizability of results to routine clinical practice. Further improvements in image resolution and contrastto-noise ratio by using higher field strength scanners, equilibrium contrast imaging by continuous infusion of contrast, endogenous contrast mechanisms, and/or reducing the sensitivity of images to motion artifacts with prolonged scan-time using free breathing acquisitions combined with temporal filtering or parallel reconstruction are likely. Adoption of image analysis techniques that standardise measurements of scar across all patients will also improve the inter-patient and longitudinal intra-patient comparability of LA fibrosis.

Conclusions The presence of LA scar likely contributes to AF initiation and maintenance, the response to ablation, LA function post-ablation, and the risk of stroke over time. The CMR techniques of LGE and T1 mapping will likely improve our understanding of the atrial arrhythmia substrate. Patient-specific strategies for AF ablation based upon such pre-procedural images have the potential to revolutionise our current strategies, especially for treatment of persistent AF. However, significant challenges remain due to the thin profile of the LA wall, which is near the limit of CMR image resolution. Improved techniques for optimal image resolution and reproducible image analysis are necessary. n

7. Moe GK. A conceptual model of atrial fibrillation. J Electrocardiol 1968;1:145–6. 8. Moe GK, Abildskov JA. Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge. Am Heart J 1959;58:59–70. 9. Moe GK, Rheinboldt WC, Abildskov JA. A COMPUTER MODEL OF ATRIAL FIBRILLATION. Am Heart J 1964;67:200–20. 10. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 1995;92:1954–68. 11. Allessie MA, Kirchhof CJ, Konings KT. Unravelling the electrical mysteries of atrial fibrillation. Eur Heart J 1996;17 Suppl C:2–9. 12. Allessie MA, Konings K, Kirchhof CJ, Wijffels M. Electrophysiologic mechanisms of perpetuation of atrial fibrillation. Am J Cardiol 1996;77:10A–23A. 13. Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs: Atrial remodeling of a different sort. Circulation 1999;100:87–95. 14. Elvan A, Huang XD, Pressler ML, Zipes DP. Radiofrequency catheter ablation of the atria eliminates pacing-induced sustained atrial fibrillation and reduces connexin 43 in dogs. Circulation 1997;96:1675–85. 15. Mary-Rabine L, Albert A, Pham TD, et al. The relationship of human atrial cellular electrophysiology to clinical function and ultrastructure. Circ Res 1983;52:188–99. 16. Patel P, Jones DG, Hadjinikolaou L, et al. Changes in human atrial connexin expression in atrial fibrillation and ischemic heart disease. Circulation 1997;96:92–2. 17. van der Velden HM, van Kempen MJ, Wijffels MC, et al. Altered pattern of connexin40 distribution in persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol 1998;9:596– 607. 18. Verheule S, Sato T, Everett T 4th, et al. Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial

fibrosis caused by overexpression of TGF-beta1. Circ Res 2004;94:1458–65. 19. Lin CS, Lai LP, Lin JL, et al. Increased expression of extracellular matrix proteins in rapid atrial pacing-induced atrial fibrillation. Heart Rhythm 2007;4:938–49. 20. Pan CH, Lin JL, Lai LP, et al. Downregulation of angiotensin converting enzyme ii is associated with pacing-induced sustained atrial fibrillation. FEBS Lett 2007;581:526–34. 21. Anyukhovsky EP, Sosunov EA, Chandra P, et al. Ageassociated changes in electrophysiologic remodeling: A potential contributor to initiation of atrial fibrillation. Cardiovasc Res 2005;66:353–63. 22. Anyukhovsky EP, Sosunov EA, Plotnikov A, et al. Cellular electrophysiologic properties of old canine atria provide a substrate for arrhythmogenesis. Cardiovasc Res 2002;54:462–9. 23. Everett TH 4th, Wilson EE, Verheule S, et al. Structural atrial remodeling alters the substrate and spatiotemporal organization of atrial fibrillation: A comparison in canine models of structural and electrical atrial remodeling. Am J Physiol Heart Circ Physiol 2006;291:H2911–23. 24. Bailey GWH, Braniff BA, Hancock EW, Cohn KE. Relation of left atrial pathology to atrial fibrillation in mitral valvular disease. Ann Intern Med 1968;69:13–20. 25. Boldt A, Wetzel U, Lauschke J, et al. Fibrosis in left atrial tissue of patients with atrial fibrillation with and without underlying mitral valve disease. Heart 2004;90:400–5. 26. Ohtani K, Yutani C, Nagata S, et al. High prevalence of atrial fibrosis in patients with dilated cardiomyopathy. J Am Coll Cardiol 1995;25:1162–9. 27. Sugiura T, Iwasaka T, Ogawa A, et al. Atrial fibrillation in acute myocardial-infarction. Am J Cardiol 1985;56:27–9. 28. Haïssaguerre M, Jaïs P, Shah DC, et al. Right and left atrial radiofrequency catheter therapy of paroxysmal atrial

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fibrillation. J Cardiovasc Electrophysiol 1996;7:1132–44. 29. Jaïs P, Shah DC, Haïssaguerre M, et al. Efficacy and safety of septal and left-atrial linear ablation for atrial fibrillation. Am J Cardiol 1999;84:139R–46R. 30. Jaïs P, Shah DC, Takahashi A, et al. Long-term follow-up after right atrial radiofrequency catheter treatment of paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 1998;21:2533–8. 31. Natale A, Leonelli F, Beheiry S, et al. Catheter ablation approach on the right side only for paroxysmal atrial fibrillation therapy: Long-term results. Pacing Clin Electrophysiol 2000;23:224–33. 32. Haïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659–66. 33. Verma A, Wazni OM, Marrouche NF, et al. Pre-existent left atrial scarring in patients undergoing pulmonary vein antrum isolation - an independent predictor of procedural failure. J Am Coll Cardiol 2005;45:285–92. 34. Marcus GM, Yang YF, Varosy PD, et al. Regional left atrial voltage in patients with atrial fibrillation. Heart Rhythm 2007;4:138–44. 35. Peters DC, Wylie JV, Hauser TH, et al. Detection of pulmonary vein and left atrial scar after catheter ablation with threedimensional navigator-gated delayed enhancement MR

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imaging: Initial experience. Radiology 2007;243:690–5. 36. McGann CJ, Kholmovski EG, Oakes RS, et al. New magnetic resonance imaging-based method for defining the extent of left atrial wall injury after the ablation of atrial fibrillation. J Am Coll Cardiol 2008;52:1263–71. 37. Mahnkopf C, Badger TJ, Burgon NS, et al. Evaluation of the left atrial substrate in patients with lone atrial fibrillation using delayed-enhanced MRI: implications for disease progression and response to catheter ablation. Heart Rhythm 2010;7:1475–81. 38. Akoum N, Daccarett M, McGann C, et al. Atrial fibrosis helps select the appropriate patient and strategy in catheter ablation of atrial fibrillation: a DE-MRI guided approach. J Cardiovasc Electrophysiol 2011;22:16–22. 39. Segerson NM, Daccarett M, Badger TJ, et al. Magnetic resonance imaging-confirmed ablative debulking of the left atrial posterior wall and septum for treatment of persistent atrial fibrillation: Rationale and initial experience. J Cardiovasc Electrophysiol 2010;21:126–32. 40. Beinart R, Khurram IM, Liu S, et al. Cardiac magnetic resonance t1 mapping of left atrial myocardium. Heart Rhythm 2013; 10:1325–31. 41. Badger TJ, Daccarett M, Akoum NW, et al. Evaluation of left atrial lesions after initial and repeat atrial fibrillation ablation lessons learned from delayed-enhancement MRI in repeat

ablation procedures. Circ Arrhythm Electrophysiol 2010;3:249–59. 42. Reddy VY, Schmidt EJ, Holmvang G, Fung M. Arrhythmia recurrence after atrial fibrillation ablation: Can magnetic resonance imaging identify gaps in atrial ablation lines? J Cardiovasc Electrophysiol 2008;19:434–7. 43. Taclas JE, Nezafat R, Wylie JV, et al. Relationship between intended sites of RF ablation and post-procedural scar in af patients, using late gadolinium enhancement cardiovascular magnetic resonance. Heart Rhythm 2010;7:489–96. 44. Spragg DD, Khurram I, Zimmerman SL, et al. Initial experience with magnetic resonance imaging of atrial scar and co-registration with electroanatomic voltage mapping during atrial fibrillation: success and limitations. Heart Rhythm 2012;9:2003–9. 45. Daccarett M, Badger TJ, Akoum N, et al. Association of Left Atrial Fibrosis Detected by Delayed-Enhancement Magnetic Resonance Imaging and the Risk of Stroke in Patients With Atrial Fibrillation. J Am Coll Cardiol 2011;57:831–8. 46. Wylie JV, Peters DC, Essebag V, et al. Left atrial function and scar after catheter ablation of atrial fibrillation. Heart Rhythm 2008;5:656–62. 47. Meng J, Peters DC, Hsing JM, et al. Late gadolinium enhancement of the esophagus is common on cardiac mr several months after pulmonary vein isolation: preliminary observations. Pacing Clin Electrophysiol 2010;33:661–6.

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Diagnostic Electrophysiology & Ablation

Imaging-guided Ventricular Tachycardia Ablation Seba st i a a n RD Pi e r s a n d K a t j a Z e p p e n f e l d Department of Cardiology, Leiden University Medical Centre, Leiden, The Netherlands

Abstract Over the past decades important advances have been made in the field of ventricular tachycardia (VT) ablation, and as a result, VT ablation is now more widely being performed. The identification of ablation target sites still relies on electroanatomical substrate mapping, which is time-consuming, hampered by the intramural location of some scars and limited by epicardial fat. The potential of various imaging modalities to overcome these limitations have stimulated clinical electrophysiologists to perform studies on image integration during VT ablation. Imaging guidance has been used to identify, delineate and characterise the substrate for VT; to provide detailed anatomical information; to avoid ablation on coronary arteries; to delineate epicardial fat tissue; and to assess ablation lesions. In this review, reported applications and the potential advantages and limitations of different imaging modalities are discussed.

Keywords Image integration, ventricular tachycardia, catheter ablation, magnetic resonance imaging, computed tomography, intracardiac echocardiography, positron emission tomography, single-photon emission computed tomography Disclosure: The Department of Cardiology receives unrestricted research grants from Boston Scientific, Medtronic and Biotronik. Katja Zeppenfeld receives consulting fees from St Jude Medical. Received: 18 July 2013 Accepted: 18 October 2013 Citation: Arrhythmia & Electrophysiology Review 2013;2(2):128–34 Access at: www.AERjournal.com Correspondence: Katja Zeppenfeld, Department of Cardiology (C-05-P), Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands. E: k.zeppenfeld@lumc.nl

Over the last 20 years ventricular tachycardia (VT) ablation has evolved from a treatment modality for selected patients with recurrent haemodynamically tolerated VT (which can be mapped during ongoing arrhythmia), to a therapeutic option for patients with tolerated and untolerated VT using substrate-based ablation strategies.1 The substrate for VT after myocardial infarction (MI) consists of areas of myocardial fibrosis interspersed with viable myocytes creating slow conduction through the scar.2 The latter is an important precondition for reentry; the most common underlying mechanism of scar-related VT. Inhomogeneous scars also occur in other diseases such as non-ischaemic cardiomyopathy (NICM), sarcoidosis and repaired congenital heart disease.3–5 Substrate-based VT ablation procedures currently depend on extensive electroanatomical mapping (EAM) to delineate bipolar1,6 and unipolar7,8 low voltage areas, and to identify abnormal electrograms such as fragmented electrograms and late potentials.4,9–11 The limitations of EAM (time-consuming, inaccurate delineation of intramural scars, attenuation of electrograms by epicardial fat) on the one hand, and the availability of different imaging modalities (providing detailed anatomical information,12–15 characterising myocardial scars,12,16–22 delineating epicardial fat15,23) as well as the progress in imaging acquisition and processing on the other hand, have stimulated clinical electrophysiologists to study image integration during VT ablation procedures. Various imaging modalities such as multidetector computed tomography (MDCT), contrast-enhanced magnetic resonance imaging (CE-MRI), intracardiac echocardiography (ICE) and nuclear imaging modalities have been applied; however, most available data are derived from MDCT and CE-MRI studies conducted in the post-MI patients – MDCT because of the higher spatial resolution if compared with CE-MRI and nuclear imaging modalities, and CE-MRI as current gold standard to

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visualise fibrosis. Image integration has been used to identify and delineate the substrate for VT during the procedure,12,16–22 to avoid ablation in the vicinity of coronary arteries,15,23 to delineate epicardial fat tissue15,21 and to assess ablation lesions.24,25 In this review, reported applications and the potential advantages and limitations of the different imaging modalities are discussed.

Image Registration An important prerequisite for the use of image integration to guide mapping and ablation is the accurate registration of EAM and imaging data. Of note, image registration has mainly been performed during stable sinus or paced rhythm, and may be less reliable during VT activation mapping due to potential differences in cardiac morphology. An overview of studies on integration of imaging data with ventricular EAM and the reported registration accuracy is provided in Table 1. It is important to realise that a small registration error (the distance from an imaging surface to the EAM surface) does not necessarily imply good registration accuracy. Automated surface registration tools, which are provided by commercially available three-dimensional (3D) mapping systems,13,15,22,25–30 typically minimise this distance by translation movements and circumferential and axial rotation. These registration algorithms may result in significant rotation errors, especially if only the symmetrically shaped left ventricle (LV) is mapped and low resolution imaging modalities are used.31 Indeed the registration accuracy of MRI images with LV EAM has been evaluated using different registration models, and it could be demonstrated that the best correlation between bipolar voltage and scar transmurality could be achieved by avoiding any circumferential or axial rotation during the registration process.32 Mapping of well defined anatomical

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Table 1: Registration Methods and Accuracy Imaging Modality Author MRI Codreanu et al.18

Publication Year 2008

Registration Registration Landmarks (If Applicable) Error (mm) Method N/R LM Aorta, LV apex, MA

Registration Mode offline offline

Desjardins et al.33

2009

4.3

LM + SURF

Aorta, LV apex, MA

Bogun et al.17

2009

4.8

LM + SURF

Aorta, LV apex, MA

online

Ilg et al.29

2010

3.5

LM + SURF

N/R

online

Andreu et al.16

2011

3.4

LM + SURF

Aorta, LV apex, MA, RV

online

Wijnmaalen et al.22 2011

3.8

LM + SURF

Left main

online

Dickfeld et al.19 2011

3.9

VA

NA

online

Perez-David et al.20 2011

N/R

LM

LV apex and MA

offline

Tao et al.32 2012 4.3 SURF

NA

offline

Gupta et al.28

2012

3.8

LM + SURF

Aorta, LV apex, MA

online online

Piers et al.21

2012

3.2

LM + VA

Left main

Spears et al.34

2012

3.6

LM + SURF

Aorta, LV apex, MA or His

offline

Cochet et al.*12

2013

N/R

LM + SURF

Aorta, CS, left atrium, MA

online

Sasaki et al.30

2012

2.8

LM + SURF

Aorta, LV apex, MA, RV septal insertions

offline

MDCT

Desjardins et al.51

2010

3.0

LM + SURF

Epicardial apex, most lateral tricuspid and MA

offline

Tian et al.14

2010

3.3

VA + SURF

NA

online

v Huls v Taxis et al.15 2013

2.8

LM + SURF

Left main

online

Piers et al.21

2012

2.0

LM + SURF

Left main

online

Komatsu et al.13

2013

N/R

LM + SURF

CS, aortic root, LV apex and MA

online

PET/CT

Fahmy et al.27

2008

5.1

LM + SURF

Coronary ostia, cusps, apex

online**

Dickfeld et al.60 2008

3.7

VA

NA

online

Tian et al.61

2009

4.3

VA + SURF

NA

online

SPECT

Tian et al.64

2012

4.4

LM + SURF

MA

offline

* Combined MDCT and MRI, ** 16/19 patients. CS = coronary sinus; CT = computed tomography; His = bundle of His; LM = landmark; LV = left ventricular; MA = mitral annulus; MDCT = multidetector computed tomography; MRI = magnetic resonance imaging; NA = not applicable; N/R = not reported; PET = positron emission tomography; RV = right ventricle; SPECT = singlephoton emission computed tomography; SURF = surface registration; VA = visual alignment.

structures such as the ostium of the left main artery or additional chambers can improve the registration accuracy. In a phantom model, incorporation of EAM of the aorta in the registration process resulted in substantial improvement, as assessed visually and by the EAM-to-MRI surface distance of both LV and aorta.31 Several clinical studies have used the aorta and the ostia of the coronary arteries, which can confirm correct position by contrast injection if an open irrigated-tip catheter is used (see Figure 1, panel A),15,21,22 or a coronary sinus catheter12,13 to improve registration accuracy or to monitor the registration stability throughout the procedure.

Figure 1: Integration of Magnetic Resonance Imaging-derived Scar and Multidetector Computed Tomography-derived Coronary Artery Anatomy and Epicardial Fat with Electroanatomical Maps in a Patient with a Scar in the Epicardial Right Ventricle Outflow Tract

Lessons Learned from Integration of Preacquired Magnetic Resonance Imaging Images

The coronary artery anatomy is derived from the MDCT scan using special software (Medis medical imaging systems BV, Leiden, the Netherlands), allowing visualisation of small branches (panel A). During the procedure the position of the left main coronary artery (confirmed by contrast injection, circle in panel A) was tagged on the map to integrate the MDCT-derived coronary artery anatomy and MRI-derived scar (displayed in black) with the endocardial EAM (panel B). Subsequent epicardial EAM revealed low voltage areas around the atrioventricular groove, interventricular groove and acute margin, which are consistent with MDCT-derived epicardial fat (panels C and D), but also a low voltage area at the epicardial right ventricular outflow tract corresponding with the location of the MRI-derived scar. Fragmented electrograms were observed in this area, supporting the presence of scar. EAM = electroanatomical mapping; LAD = left anterior descending; MDCT = multidetector computed tomography; MRI = magnetic resonance imaging; RA = right atrium; RCA = right coronary artery.

The feasibility of MRI integration during EAM of the LV was first demonstrated by Reddy et al. in phantom and animal models in 2004.31 To evaluate the registration accuracy, iron oxide injections were performed in five pigs before MRI acquisition. Their position was marked on the integrated MRI image and subsequently targeted for radiofrequency (RF) catheter ablation. At gross pathology the ablation lesions were localised close (mean distance 1.8 ± 0.5 millimetres [mm]) to the iron oxide targets, suggesting that MRI integration may allow imaging-guided ablation of MRI-derived target sites. In humans, offline comparison of EAM data and CE-MRI-derived scar data could demonstrate a good overall correlation between the MRI-reconstructed post-MI scar surface and low bipolar voltage areas. However, CE-MRI allowed even improved identification of scar areas not sufficiently delineated by EAM, thereby paving the way for true MRI guidance during the VT ablation procedure.18,33 The first study on realtime integration of MRI-derived scar distribution during VT ablation could demonstrate that the integrated scar information facilitated substrate mapping and could be used as a guide to VT isthmus sites in 15

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A. Coronary arteries RCA

B. Endo bipolar C. Epi bipolar voltage voltage RA

D. Epicardial fat 0–3 mm 3–5 mm 5–7 mm >7 mm

LAD

post-MI patients.22 These findings were confirmed in a second series of 13 patients with frequent premature ventricular complexes (PVCs) and 10 patients with VT after MI.28 It should be noted that although scars due to MI are predominantly localised subendocardially, non-transmural parts of the scar, in particular, remain undetected by bipolar voltage mapping (see Figure 2).22 These parts of the scar may, however, contain critical parts of the VT reentry circuits, and can be visualised during realtime integration of the CE-MRI-derived scar information; supporting the important complementary information provided by MRI.22 The limitation of electroanatomical voltage mapping to fully delineate the 3D geometry of scar has also been reported in patients

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Diagnostic Electrophysiology & Ablation Figure 2: Magnetic Resonance Imaging-derived 3D Scar Reconstruction Integrated with Electroanatomic Mapping

The endocardial bipolar voltage map (panel A) shows only a limited low voltage area, smaller than the MRI-based non-transmural scar (panels C and D). The unipolar voltage map (panel B) reveals a larger low voltage area, which is more consistent with the true size of the scar area. The MRI-derived scar is integrated with the electroanatomical maps based on the left main (LM) landmark (panel E). MRI = magnetic resonance imaging.

Figure 3: Magnetic Resonance Imaging-based Border Zone Channel Identification I

VT

PM

with NICM, in whom scars are typically localised intramurally or subepicardially.17,21,34 Intra-procedural registration of MRI-derived scars in patients with NICM has demonstrated that critical components of ventricular arrhythmias are confined to scar tissue;17 and it has been reported that MRI integration in patients presenting with VT can reveal scars not identified by EAM, which may have important diagnostic and therapeutic consequences.25 In a small series of NICM patients, the distribution of contrast enhancement, which was classified as endocardial, intramural or epicardial, corresponded with the location (endocardium or epicardium) containing critical components of the VT circuit. This finding suggests an important role for MRI in choosing the appropriate procedural strategy, which can be either endocardial, epicardial or both.17 Notably, half of the patients had predominantly endocardial scar in this study,17 which is reported to be less common in

Zeppenfeld_edited.indd 130

Not only the presence of enhanced regions, but also MRI-derived scar characteristics have been correlated with VT-related sites and local electrophysiological findings in patients with prior MI and NICM. Isolated potentials and critical sites of reentrant VT (based on pace and entrainment mapping) were associated with high infarct scar transmurality.30 In another study, also conducted in post-MI patients, 71  % of VT isthmus sites were localised within the infarct core (defined as signal intensity [SI] >3 standard deviations above remote myocardium), while the remaining isthmus sites were localised in transmural border zone with SI slightly lower than this cut-off.33 Electrogram characteristics consistent with slow conduction such as prolonged duration, late potentials and fractionated electrograms were also related to higher scar transmurality in patients with NICM.21 The association between MRI-derived scar characteristics and EAM-based electrophysiological parameters has recently been used to create non-invasive 3D substrate maps in post-MI patients. These MRI-derived substrate maps showed a remarkably high resemblance to the endocardial electroanatomical substrate maps.30

10 %

Subendocardial (10 %) pixel signal intensity map and endocardial bipolar voltage map, with an extensive area of scar in the anterior wall. A border zone channel is shown in the 10 % shell, consistent with the conduction channel identified on the voltage map (white arrows). The 12-lead electrocardiogram on the left shows the induced monomorphic ventricular tachycardia (VT). Electrocardiogram on the right shows pace map from the middle of the conduction channel (yellow asterisk in both maps). Pacing from the channel reproduces the induced VT morphology with a long stimulus-to-QRS delay, as expected by the location of the stimulus delivery on the channel. Additionally, there is a late potential channel in the EAM (blue dots) not visible on the cardiac magnetic resonance. EAM = electroanatomic map; PM = pace mapping; VT = ventricular tachycardia. Derived with permission from FernándezArmenta, et al., 2013.37

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patients with NICM.35 Further studies are required before MRI-derived scar distribution can be used to guide preprocedural planning.

Similar to the method that adapts bipolar voltage thresholds of EAM to display channels of relatively higher voltages within low voltage regions,36 some investigators have attempted to identify relatively low SI channels within higher SI post-MI scars on MRI.16,20,37 Using variable SI and voltage thresholds, a good correlation regarding the location (segments) and orientation (perpendicular or parallel to the mitral annulus) of relatively low SI channels and relatively high voltage channels has been reported.20 In a recent paper, a favourable association between lower SI channels within high SI regions based on ‘pixel SI scanning’ (i.e. modifying the thresholds to 60 ± 5 % and 40 ± 5 %37) and channels of slow conduction identified by high density endocardial activation mapping during sinus rhythm has been reported (see Figure 3). Of importance, 17 of these 45 identified SI channels were related to VT based on pace mapping and entrainment mapping, and on localisation within the same American Heart Association (AHA) segment with the same orientation (parallel or perpendicular to the mitral annulus or intermediate).37 The validation of 3D lower SI channels within high density scars is limited by the lack of a gold standard, which would be histological 3D scar reconstruction. Application of different scar identification methods and cut-off values impede the comparison of reported data. Considering the known limited field of view of bipolar mapping,38 simply correlating the 3D CE-MRI-derived SI channels with two-dimensional (2D) bipolar voltage channels or with progressively delayed low voltage electrogram channels cannot overcome these limitations.7 In addition, advanced imaging techniques providing relatively high spatial resolution CE-MRI (1.4 x 1.4 x 1.4 mm in a recent paper37) are still unlikely to delineate channels at a microscopic level,2 which produce very low amplitude late potentials during sinus rhythm4 and diastolic potentials during VT.39 Despite all current limitations, the integration of high resolution CE-MRI-derived 3D scar characteristics with EAM is exciting. Additional studies are, however, required to determine the intra-observer and inter-observer variability of the channel identification process, both on MRI images and on EAM (including different applied scar detection methods and cut-off values for SI). Ideally, the identified channels should be compared to histology, and the clinical relevance of the channels needs to be determined by assessing the impact of ablation of CE-MRI-derived channels on procedural outcome.

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Compared with other imaging modalities, the advantages of MRI integration include a higher resolution for detection and localisation of non-transmural scar areas, and the possibility of tissue characterisation (T1-weighted sequences after gadolinium administration to assess for extracellular matrix, T2-weighted sequences to assess for myocardial oedema). However, currently, MRI integration requires extensive and time-consuming (± 1 hour) image pre-processing by specialists experienced in CE-MRI, which restrict its wide applicability. The most important limitation of MRI is its use in device recipients, as the majority of patients undergoing VT ablation have an implantable cardioverter defibrillator (ICD). Although ICDs may not necessarily preclude MRI if appropriate safety measures are taken, detailed evaluation of important parts of the LV (in particular the anterior segments) is hampered by artefacts due to the pulse generator.19,30 However, also based on the results of two recently published randomised controlled trials conducted in post-MI patients,40,41 early VT ablation may be considered in an increasing number of patients before ICD implantation, suggesting that CE-MRI integration may play an increasing role in the future.

Contrast-enhanced Magnetic Resonance Imaging as a Gold Standard Although considered a gold standard, the technique of CE-MRI to delineate 3D scar geometry still has limitations. Firstly, contrast enhancement is not specific for fibrosis; T2-weighted sequences should therefore also be performed to assess for myocardial oedema.42 Secondly, the delineation of scars and in particular border zones is hampered by the partial volume effect (i.e. the averaging that occurs between high and low SI regions), which may cause overestimation of the scar size.43 Thirdly, current scar identification methods vary between studies (e.g. full-width half-maximum method, standard deviation of remote region-based methods) and although scar characteristics predict ventricular tachyarrhythmias in patients after MI independent of the scar identification method used, the size of the border zone varies by a factor of five depending on the method.44 Finally, the present scar identification methods are based on the SI of scar and/or remote myocardium in a look-locker sequence, which depend on the amount of diffuse fibrosis in remote myocardium, and on the maximum density of fibrosis in the scar area, the heart rate, contrast dose, glomerular filtration rate, haematocrit and other variables;45 scars are therefore not directly comparable between patients. Novel techniques are required to allow more accurate and objective characterisation of scars. A general disadvantage of integrating pre-acquired imaging data during VT ablation is the potential change that may occur between scan and procedure (e.g. volume, orientation of the heart) – a logical next step would therefore be on-site MRI.

On-site Magnetic Resonance Imaging Guidance On-site MRI may provide an all-in-one solution during VT ablation, allowing catheter tracking without fluoroscopy; anatomical guidance; substrate delineation (including intramural and subepicardial scars); MRI-based identification of ablation target sites; and evaluation of ablation lesions. In 2008 the feasibility of realtime MRI-based catheter tracking to perform an electrophysiology study was first demonstrated in 10 mongrel dogs and two humans.46 In another study in pigs, a realtime MRI-tracked mapping catheter could be visualised on pre-acquired magnetic resonance angiography (MRA) and CE-MRI images. Realtime MRI-based tracking could be used to construct an EAM of the LV, which matched well with the pathological specimen.47 Although in both studies RF filters were applied to remove MRI-induced artefacts,

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Figure 4: Integration of Multidetector Computed Tomography-derived Images to Assess the Proximity of Coronary Arteries at Ablation Target Sites A

RAO View

LAO View Aorta

Position Catheter LCA

Aorta

-76 ms

RV

RV LV

-127 ms

B

LV

LM Aorta

Aorta

RCA

LV

Position Catheter LCA

LM

RCA LV

12.20 mV

Position Catheter

Position Catheter

0.09 mV The distance between the catheter tip and coronary arteries on integrated MDCT images and coronary angiography is shown in a right anterior oblique (RAO) view (left) and left anterior oblique (LAO) view (right) in two patients. In one, limited activation mapping identified a target site located on the left coronary artery (LCA) on both MDCT and angiography (upper panels). In another, the target site (based on pace mapping) was located <7 mm from the right coronary artery (RCA) confirmed by angiography (lower panels). LM = left main; LV = left ventricle; PA = pulmonary artery; RV = right ventricle. Reproduced with permission from van Huls van Taxis, et al., 2013.15

significant artefacts remained interfering with both the surface electrocardiogram (ECG) and the intracardiac electrograms, which is an important current limitation. Although the use of CE-MRI has been reported to allow evaluation of ablation lesions hours-to-months after RF energy application;24,29 no study has yet analysed the value of MRI to characterise and assess acute lesion formation during VT ablation. The required continuous gadolinium contrast infusion is only one of the problems that need to be solved. However, despite these hurdles, direct evaluation of lesion formation would be desirable to assess completeness of linear lesion but also to monitor substrate-based ablation targeting intramural scar or scar covered by epicardial fat.

Integration of Pre-acquired Multidetector Computed Tomography Images The high resolution of current MDCT images allows the detailed anatomic reconstruction of the heart, including the cardiac chambers, aortic sinus cusps, coronary vessels, epicardial fat thickness and the atrial appendages.15 The feasibility of MDCT-guided catheter manipulation was first reported in a porcine model in 2003,48 and the accuracy of MDCT-guided RF applications was demonstrated in nine mongrel dogs with a 2.1 ± 1.1 mm position accuracy of RF lesions with respect to the targeted MDCT markers.26 In humans, integration of the anatomic reconstruction of the coronary artery anatomy has been used to avoid RF energy applications at, or in close proximity to, coronary arteries, thereby potentially preventing complications of epicardial ablation (see Figure 4). The registration accuracy was confirmed by coronary angiograms in various angulations in a case report23 and in a study in 28 patients.15 The high accuracy, which can be evaluated by a single coronary injection is important as coronary angiography in some (in particular caudal) angulations can be precluded by the location pad of the EAM system, hampering accurate estimation of the distance to coronary arteries by angiography. The integration of MDCT images can also facilitate catheter ablation in patients with complex anatomy due to congenital heart disease.49

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Diagnostic Electrophysiology & Ablation Figure 5: Prediction of an Epicardial Target Site and the Proximity of Coronary Arteries and Epicardial Fat A

B

Endocardial electroanatomical activation maps of the LV, right ventricle outflow tract (RVOT), aorta (Ao) and great cardiac vein (GCV) (panel A). Similar activation time of the LV, RVOT and GCV was observed. The white triangle demonstrates the predicted epicardial target area in the vicinity of the LAD, covered by >4 mm of fat. The final fusion image was registered with the endocardial maps, using the left main coronary artery (LM) landmark. Limited epicardial activation mapping confirmed the earliest activation within the predicted area not suitable for ablation (panel B). Cx = circumflex artery; LAD = left anterior descending; LV = left ventricle; RCA = right coronary artery. Reproduced with permission from van Huls van Taxis, et al., 2013.15

Figure 6: Multidetector Computed Tomography-derived Wall Thinning Areas and the Electroanatomical Substrate in a Patient with Non-ischaemic Dilated Cardiomyopathy

In patients with epicardial idiopathic ventricular arrhythmias the approximate site of origin can often be estimated based on electroanatomical activation mapping of the endocardial RV, LV, aortic cusps and coronary sinus, if appropriate. The integration of MDCT images with EAM data may predict epicardial ablation failure in selected patients, which can be due to the close proximity of coronary arteries and/or a thick epicardial fat layer at the predicted epicardial site of origin (see Figure 5); thereby potentially preventing unnecessary pericardial puncture and its associated risks.15 Detailed contrast-enhanced MDCT scans can provide important anatomic (wall thickness, see Figure 6), dynamic (wall thickening) and perfusion (hypoenhancement) information, which may guide to MI areas during VT ablation.14 However, in a small series of 13 post-MI patients, 87 % of abnormal electrograms, but only 46 % of termination sites were localised within 5 mm of MDCT-derived wall thinning areas; perhaps suggesting a limited value of MDCT-derived wall thinning for identification of the VT substrate.13 Data on the use of MDCT for detection of the arrhythmogenic substrate in patients with NICM are remarkably sparse, with only three patients being included in one study.12 Compared with other imaging modalities, the main advantage of MDCT integration during VT ablation is its superior spatial resolution. Furthermore, MDCT can be performed without precautions in patients with implantable devices, and with only minor lead artefacts. Pre-processing of MDCT images is relatively easy when segmentation is performed on the CARTO® system (± 15–30 minutes), but may be time-consuming if advanced coronary artery and epicardial fat images are required (± 2 hours). As a main limitation, contrast-enhanced MDCT is associated with significant radiation exposure (currently ± 2–12 millisieverts [mSv] depending on acquisitions).14,53

Intracardiac Echocardiography Correlation between voltage and wall thinning at MDCT in a patient with non-ischaemic dilated cardiomyopathy. Myocardial wall thinning is seen in the lateral wall of the left ventricle on four chambers (panel A), three chambers (panel B) and short axis (panel C) reconstructions of the contrast-enhanced MDCT volume. No delayed enhancement was seen at MRI. Areas of wall thickness <5 mm are mapped on the epicardial surface and integrated in the NavX system (panel D). The epicardial voltage map is registered to the imaging model, demonstrating a match between wall thinning and low voltage (panel E). Brown dots indicate sites of local abnormal ventricular activities targeted by ablation. A high-frequency fragmented signal occurring during the far field ventricular electrogram is seen (yellow frame), indicating the presence of persisting local electrical activity within scar. Please note that these high-frequency signals are fractionated but not late as they are recorded within the QRS. Reproduced with permission from Cochet, et al., 2013.12

Apart from the coronary arteries, an important limitation for epicardial mapping and ablation is the presence of epicardial fat.15,50,51 Epicardial fat can be delineated by MDCT with high spatial resolution, and has been shown to cover significant parts of the ventricles, with on average 25 % of surface being covered with >4 mm fat in patients undergoing epicardial PVC or VT ablation.15 In particular, the acute margin, anterior right ventricular (RV) free wall, interventricular groove and atrioventricular groove may be covered by significant fat layers (see Figure 1).15,52 Importantly, not only scar but also epicardial fat attenuates bipolar electrogram amplitudes, thereby limiting the accuracy of epicardial substrate mapping.15,21,51 In addition, epicardial RF energy applications may be ineffective in the presence of >7 mm fat.15,51 The integration of MDCT-derived fat thickness can therefore be very helpful to classify low voltage areas (due to fat or true scar in the absence of fat, see Figure 1) and to predict and explain ineffective RF energy applications during epicardial VT ablation.

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Intracardiac echocardiography (ICE) provides realtime anatomical information and allows monitoring of catheter-tissue contact, lesion formation and potential complications without radiation exposure.54–58 The anatomical information provided by ICE has been shown to be useful to guide catheter ablation of the papillary muscles, 54,55 or to avoid RF delivery near the coronary artery ostia and on the aortic leaflets, as has been demonstrated in one series of five patients.58 An experimental study in seven pigs after left anterior descending infarction demonstrated a close correlation between ICE-derived infarct size and low voltage (≤2 millivolts [mV]) areas.59 In one study, Akinetic and thinned areas on ICE corresponded with the electroanatomic scar during VT ablation in 18 humans (15/18 post-MI).54 In a series of 18 patients with NICM and abnormal echogenicity on ICE imaging it could be demonstrated that the areas of increased echogenicity in the lateral wall corresponded with the endocardial and/or epicardial electroanatomical substrate.56 In these studies ICE images were visually interpreted and data on inter-observer and intra-observer variability are not available. Whether ICE-derived reconstruction of scar areas in post-MI patients and patients with NICM provides complementary substrate information to EAM data requires further investigation. Important limitations of ICE include the two-dimensional nature of ICE images, the considerable costs and the time required to acquire and interpret ICE images.

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Imaging-guided Ventricular Tachycardia Ablation

Nuclear Image Guidance Nuclear imaging has the advantage of not being limited by the presence of implantable devices. Three studies have analysed the value of hybrid positron emission tomography (PET)/computed tomography (CT) imaging, combining low-resolution metabolic activity information from PET scans with high-resolution anatomic information from MDCT scans.27,60,61 Although areas with low metabolic activity corresponded well with low voltage areas, the net benefit of PET integration during VT ablation may be limited due to the inferior resolution of PET (currently 4–7 mm62), significant radiation exposure, high costs and the time required to create mapping system-compatible images from the PET data.63 Notably, the value of PET for identification of intramural and subepicardial scars, which are common in NICM, remains unclear as only two of the 41 patients in these studies had NICM.27,60,61 PET scanning is limited by the high costs of cyclotrons, which are required to produce radionuclides. Single-photon emission computed tomography (SPECT) images are more widely available but have an even lower resolution (±12 mm).64 SPECT-derived scar images were integrated with EAM in a small series of 10 patients, demonstrating that all successful ablation sites were located within 1 centimetre (cm) of the SPECT-derived scar area.64 Similar to PET, the added value of SPECT integration to EAM during VT ablation may be limited due to its poor resolution.

Bimodality or Multimodality Image Integration Different imaging modalities can provide complementary information, which may be important during complex ablation procedures as has been illustrated in several case reports.49,65 In a study conducted in 10 patients with NICM, MDCT-derived fat images and MRI-derived scar images were integrated with the epicardial EAM during VT ablation and provided important insights in the complex interplay between scar, viable myocardium and epicardial fat. It could be demonstrated that in the presence of >2.8 mm fat neither bipolar nor unipolar voltage mapping can distinguish scar from fat. Specific electrogram morphologies were not affected by fat, but identified only 25 % of all scar sites.21 In a second series, MDCT and MRI-derived images were fused and integrated during VT ablation procedures in

1. 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. 2. de Bakker JM, van Capelle FJ, Janse MJ, et al. Slow conduction in the infarcted human heart. ‘Zigzag’ course of activation. Circulation 1993;88:915–26. 3. Koplan BA, Soejima K, Baughman K, et al. Refractory ventricular tachycardia secondary to cardiac sarcoid: electrophysiologic characteristics, mapping, and ablation. Heart Rhythm 2006;3:924–29. 4. Nakahara S, Tung R, Ramirez RJ, et al. Characterization of the arrhythmogenic substrate in ischemic and nonischemic cardiomyopathy implications for catheter ablation of hemodynamically unstable ventricular tachycardia. J Am Coll Cardiol 2010;55:2355–65. 5. Zeppenfeld K, Schalij MJ, Bartelings MM, et al. Catheter ablation of ventricular tachycardia after repair of congenital heart disease: electroanatomic identification of the critical right ventricular isthmus. Circulation 2007;116:2241–52. 6. Hsia HH, Callans DJ, Marchlinski FE. Characterization of endocardial electrophysiological substrate in patients with nonischemic cardiomyopathy and monomorphic ventricular tachycardia. Circulation 2003;108:704–10. 7. Hutchinson MD, Gerstenfeld EP, Desjardins B, et al. Endocardial unipolar voltage mapping to detect epicardial ventricular tachycardia substrate in patients with nonischemic left ventricular cardiomyopathy. Circ Arrhythm Electrophysiol 2011;4:49–55. 8. Polin GM, Haqqani H, Tzou W, et al. Endocardial unipolar voltage mapping to identify epicardial substrate in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm 2011;8:76–83. 9. Arenal A, Glez-Torrecilla E, Ortiz M, et al. Ablation of electrograms with an isolated, delayed component as treatment of unmappable monomorphic ventricular

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nine patients with various underlying diseases to provide detailed anatomical information (e.g. coronary artery anatomy during epicardial VT ablation) and to guide to the arrhythmogenic substrate (using MRIderived scar areas and MDCT-derived wall thinning areas).12 These data illustrate the potential clinical applications of advanced bimodality image integration.12,21

Future Perspectives Currently, integration of MDCT, MRI and nuclear images requires pre-processing of imaging data, which is time-consuming (typically 1–2 hours based on one study12 and our own experience15,21,22) and requires experienced observers and special software. Development of advanced software to allow more efficient or even automated analysis of imaging data would therefore be of interest, and would also make advanced image integration techniques available to electrophysiologists who do not have supporting imaging specialists. Integration of MRI-derived images has been shown to accurately delineate ventricular scar without time-consuming EAM. Realtime image integration would be even more valuable if more specific scar features that are related to VT could be identified and displayed. In the future, MRI-based identification of critical reentry circuit sites may then allow MRI-guided delivery of RF energy applications and thereby true imagingguided VT ablation, which has already been demonstrated feasible and accurate in an animal model.31 Although image integration has provided important insights into the substrate for VT, to date it has not been demonstrated that the integration of MDCT, MRI or nuclear imaging data is cost-effective, improves preprocedural planning, total radiation exposure (including both imaging-related radiation and intraprocedural fluoroscopy), EAM time and, most importantly, the outcome of VT ablation. Prospective randomised studies comparing imaging-guided VT ablation to standard VT ablation in the setting of different diseases are required to determine whether the promising technology translates into improved acute and long-term outcome. n

tachycardias in patients with structural heart disease. J Am Coll Cardiol 2003;41:81–92. 10. Bogun F, Good E, Reich S, et al. Isolated potentials during sinus rhythm and pace-mapping within scars as guides for ablation of post-infarction ventricular tachycardia. J Am Coll Cardiol 2006;47:2013–9. 11. Brunckhorst CB, Stevenson WG, Jackman WM, et al. Ventricular mapping during atrial and ventricular pacing. Relationship of multipotential electrograms to ventricular tachycardia reentry circuits after myocardial infarction. Eur Heart J 2002;23:1131–8. 12. Cochet H, Komatsu Y, Sacher F, et al. Integration of merged delayed-enhanced magnetic resonance imaging and multidetector computed tomography for the guidance of ventricular tachycardia ablation: a pilot study. J Cardiovasc Electrophysiol 2013;24:419–26. 13. Komatsu Y, Cochet H, Jadidi A, et al. Regional myocardial wall thinning at multidetector computed tomography correlates to arrhythmogenic substrate in postinfarction ventricular tachycardia: assessment of structural and electrical substrate. Circ Arrhythm Electrophysiol 2013;6:342–50. 14. Tian J, Jeudy J, Smith MF, et al. Three-dimensional contrastenhanced multidetector CT for anatomic, dynamic, and perfusion characterization of abnormal myocardium to guide ventricular tachycardia ablations. Circ Arrhythm Electrophysiol 2010;3:496–504. 15. van Huls van Taxis CF, Wijnmaalen AP, Piers SR, et al. RealTime Integration of MDCT-Derived Coronary Anatomy and Epicardial Fat: Impact on Epicardial Electroanatomic Mapping and Ablation for Ventricular Arrhythmias. JACC Cardiovasc Imaging. 2013;6:42–52. 16. Andreu D, Berruezo A, Ortiz-Pérez JT, et al. Integration of 3D electroanatomic maps and magnetic resonance scar characterization into the navigation system to guide ventricular tachycardia ablation. Circ Arrhythm Electrophysiol 2011;4:674–83. 17. Bogun FM, Desjardins B, Good E, et al. Delayed-enhanced

magnetic resonance imaging in nonischemic cardiomyopathy: utility for identifying the ventricular arrhythmia substrate. J Am Coll Cardiol 2009;53:1138–45. 18. Codreanu A, Odille F, Aliot E, et al. Electroanatomic characterization of post-infarct scars comparison with 3-dimensional myocardial scar reconstruction based on magnetic resonance imaging. J Am Coll Cardiol 2008;52:839–42. 19. Dickfeld T, Tian J, Ahmad G, et al. MRI-Guided ventricular tachycardia ablation: integration of late gadoliniumenhanced 3D scar in patients with implantable cardioverterdefibrillators. Circ Arrhythm Electrophysiol 2011;4:172–84. 20. Perez-David E, Arenal A, Rubio-Guivernau JL, et al. Noninvasive identification of ventricular tachycardia-related conducting channels using contrast-enhanced magnetic resonance imaging in patients with chronic myocardial infarction: comparison of signal intensity scar mapping and endocardial voltage mapping. J Am Coll Cardiol 2011;57:184–94. 21. Piers SR, van Huls van Taxis CF, Tao Q, et al. Epicardial substrate mapping for ventricular tachycardia ablation in patients with non-ischaemic cardiomyopathy: a new algorithm to differentiate between scar and viable myocardium developed by simultaneous integration of computed tomography and contrast-enhanced magnetic resonance imaging. Eur Heart J 2012;34:586–96. 22. Wijnmaalen AP, van der Geest RJ, van Huls van Taxis CF, et al. Head-to-head comparison of contrast-enhanced magnetic resonance imaging and electroanatomical voltage mapping to assess post-infarct scar characteristics in patients with ventricular tachycardias: real-time image integration and reversed registration. Eur Heart J 2011;32:104–14. 23. Zeppenfeld K, Tops LF, Bax JJ, Schalij MJ. Images in cardiovascular medicine. Epicardial radiofrequency catheter ablation of ventricular tachycardia in the vicinity of coronary arteries is facilitated by fusion of 3-dimensional electroanatomical mapping with multislice computed tomography. Circulation 2006;114:e51–2.

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Diagnostic Electrophysiology & Ablation 24. Dickfeld T, Kato R, Zviman M, et al. Characterization of radiofrequency ablation lesions with gadolinium-enhanced cardiovascular magnetic resonance imaging. J Am Coll Cardiol 2006;47:370–8. 25. Tian J, Ahmad G, Mesubi O, et al. Three-dimensional delayedenhanced cardiac MRI reconstructions to guide ventricular tachycardia ablations and assess ablation lesions. Circ Arrhythm Electrophysiol 2012;5:e31–5. 26. Dong J, Calkins H, Solomon SB, et al. Integrated electroanatomic mapping with three-dimensional computed tomographic images for real-time guided ablations. Circulation 2006;113:186–94. 27. Fahmy TS, Wazni OM, Jaber WA, et al. Integration of positron emission tomography/computed tomography with electroanatomical mapping: a novel approach for ablation of scar-related ventricular tachycardia. Heart Rhythm 2008;5:1538–45. 28. Gupta S, Desjardins B, Baman T, et al. Delayed-enhanced MR scar imaging and intraprocedural registration into an electroanatomical mapping system in post-infarction patients. JACC Cardiovasc Imaging 2012;5:207–10. 29. Ilg K, Baman TS, Gupta SK, et al. Assessment of radiofrequency ablation lesions by CMR imaging after ablation of idiopathic ventricular arrhythmias. JACC Cardiovasc Imaging 2010;3:278–85. 30. Sasaki T, Miller CF, Hansford R, et al. Myocardial structural associations with local electrograms: a study of postinfarct ventricular tachycardia pathophysiology and magnetic resonance-based noninvasive mapping. Circ Arrhythm Electrophysiol 2012;5:1081–90. 31. Reddy VY, Malchano ZJ, Holmvang G, et al. Integration of cardiac magnetic resonance imaging with three-dimensional electroanatomic mapping to guide left ventricular catheter manipulation: feasibility in a porcine model of healed myocardial infarction. J Am Coll Cardiol 2004;44:2202–13. 32. Tao Q, Milles J, VAN Huls VAN, et al. Toward magnetic resonance-guided electroanatomical voltage mapping for catheter ablation of scar-related ventricular tachycardia: a comparison of registration methods. J Cardiovasc Electrophysiol 2012;23:74–80. 33. Desjardins B, Crawford T, Good E, et al. Infarct architecture and characteristics on delayed enhanced magnetic resonance imaging and electroanatomic mapping in patients with postinfarction ventricular arrhythmia. Heart Rhythm 2009;6:644–51. 34. Spears DA, Suszko AM, Dalvi R, et al. Relationship of bipolar and unipolar electrogram voltage to scar transmurality and composition derived by magnetic resonance imaging in patients with nonischemic cardiomyopathy undergoing VT ablation. Heart Rhythm 2012;9:1837–46. 35. McCrohon JA, Moon JC, Prasad SK, et al. Differentiation of heart failure related to dilated cardiomyopathy and coronary artery disease using gadolinium-enhanced cardiovascular magnetic resonance. Circulation 2003;108:54–9. 36. Arenal A, del CS, Gonzalez-Torrecilla E, et al. Tachycardiarelated channel in the scar tissue in patients with sustained monomorphic ventricular tachycardias: influence of the voltage scar definition. Circulation 2004;110:2568–74.

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37. Fernandez-Armenta J, Berruezo A, Andreu D, et al. Threedimensional Architecture of Scar and Conducting Channels Based on High Resolution ce-CMR: Insights for Ventricular Tachycardia Ablation. Circ Arrhythm Electrophysiol 2013;6(3):528–37. 38. Piers SR, Tao Q, van Huls van Taxis CF, et al. ContrastEnhanced MRI-Derived Scar Patterns and Associated Ventricular Tachycardias in Nonischemic Cardiomyopathy: Implications for the Ablation Strategy. Circ Arrhythm Electrophysiol 2013 [Epub ahead of print]. 39. Stevenson WG, Khan H, Sager P, et al. Identification of reentry circuit sites during catheter mapping and radiofrequency ablation of ventricular tachycardia late after myocardial infarction. Circulation 1993;88:1647–70. 40. Kuck KH, 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. 41. 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. 42. Friedrich MG, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic resonance in myocarditis: A JACC White Paper. J Am Coll Cardiol 2009;53:1475–87. 43. Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation 1999;100:1992–2002. 44. de Haan S, Meijers TA, Knaapen P, et al. Scar size and characteristics assessed by CMR predict ventricular arrhythmias in ischaemic cardiomyopathy: comparison of previously validated models. Heart 2011;97:1951–6. 45. Gai N, Turkbey EB, Nazarian S, et al. T1 mapping of the gadolinium-enhanced myocardium: adjustment for factors affecting interpatient comparison. Magn Reson Med 2011;65:1407–15. 46. Nazarian S, Kolandaivelu A, Zviman MM, et al. Feasibility of real-time magnetic resonance imaging for catheter guidance in electrophysiology studies. Circulation 2008;118:223–9. 47. Dukkipati SR, Mallozzi R, Schmidt EJ, et al. Electroanatomic mapping of the left ventricle in a porcine model of chronic myocardial infarction with magnetic resonance-based catheter tracking. Circulation 2008;118:853–62. 48. Solomon SB, Dickfeld T, Calkins H. Real-time cardiac catheter navigation on three-dimensional CT images. J Interv Card Electrophysiol 2003;8:27–36. 49. Piers SR, Dyrda K, Tao Q, Zeppenfeld K. Bipolar ablation of ventricular tachycardia in a patient after atrial switch operation for dextro-transposition of the great arteries. Circ Arrhythm Electrophysiol 2012;5:e38–40. 50. d’Avila A, Houghtaling C, Gutierrez P, et al. Catheter ablation of ventricular epicardial tissue: a comparison of standard and cooled-tip radiofrequency energy. Circulation 2004;109:2363–9. 51. Desjardins B, Morady F, Bogun F. Effect of epicardial fat on electroanatomical mapping and epicardial catheter ablation. J Am Coll Cardiol 2010;56:1320–7.

52. Abbara S, Desai JC, Cury RC, et al. Mapping epicardial fat with multi-detector computed tomography to facilitate percutaneous transepicardial arrhythmia ablation. Eur J Radiol 2006;57:417–22. 53. van der Bijl N, Joemai RM, Geleijns J, et al. Assessment of Agatston coronary artery calcium score using contrastenhanced CT coronary angiography. AJR Am J Roentgenol 2010;195:1299–305. 54. Bunch TJ, Weiss JP, Crandall BG, et al. Image integration using intracardiac ultrasound and 3D reconstruction for scar mapping and ablation of ventricular tachycardia. J Cardiovasc Electrophysiol 2010;21:678–84. 55. Seiler J, Lee JC, Roberts-Thomson KC, Stevenson WG. Intracardiac echocardiography guided catheter ablation of incessant ventricular tachycardia from the posterior papillary muscle causing tachycardia--mediated cardiomyopathy. Heart Rhythm 2009;6:389–92. 56. Bala R, Ren JF, Hutchinson MD, et al. Assessing epicardial substrate using intracardiac echocardiography during VT ablation. Circ Arrhythm Electrophysiol 2011;4:667–73. 57. Jongbloed MR, Bax JJ, van der Burg AE, et al. Radiofrequency catheter ablation of ventricular tachycardia guided by intracardiac echocardiography. Eur J Echocardiogr 2004;5:34–40. 58. Lamberti F, Calo’ L, Pandozi C, et al. Radiofrequency catheter ablation of idiopathic left ventricular outflow tract tachycardia: utility of intracardiac echocardiography. J Cardiovasc Electrophysiol 2001;12:529–35. 59. Callans DJ, Ren JF, Michele J, et al. Electroanatomic left ventricular mapping in the porcine model of healed anterior myocardial infarction. Correlation with intracardiac echocardiography and pathological analysis. Circulation 1999;100:1744–50. 60. Dickfeld T, Lei P, Dilsizian V, et al. Integration of threedimensional scar maps for ventricular tachycardia ablation with positron emission tomography-computed tomography. JACC Cardiovasc Imaging 2008;1:73–82. 61. Tian J, Smith MF, Chinnadurai P, et al. Clinical Application of PET/CT Fusion Imaging for Three-Dimensional Myocardial Scar and Left Ventricular Anatomy during Ventricular Tachycardia Ablation. J Cardiovasc Electrophysiol 2008 [Epub ahead of print]. 62. Pichler BJ, Wehrl HF, Judenhofer MS. Latest advances in molecular imaging instrumentation. J Nucl Med 2008;49 Suppl 2:5S–23S. 63. Bengel FM, Higuchi T, Javadi MS, Lautamäki R. Cardiac positron emission tomography. J Am Coll Cardiol 2009;54:1–15. 64. Tian J, Smith MF, Ahmad G, et al. Integration of 3-dimensional scar models from SPECT to guide ventricular tachycardia ablation. J Nucl Med 2012;53:894–901. 65. Tian J, Smith MF, Jeudy J, Dickfeld T. Multimodality fusion imaging using delayed-enhanced cardiac magnetic resonance imaging, computed tomography, positron emission tomography, and real-time intracardiac echocardiography to guide ventricular tachycardia ablation in implantable cardioverter-defibrillator patients. Heart Rhythm 2009;6:825–8.

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Diagnostic Electrophysiology & Ablation

Catheter Ablation of Polymorphic Ventricular Tachycardia and Ventricular Fibrillation Jo s e f Ka u t z n e r 1 a n d P e t r P e i c h l 2 1. Head; 2. Consultant Electrophysiologist, Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Abstract Recently, catheter ablation (CA) has become a therapeutic option to target focal triggers of polymorphic ventricular tachycardia and ventricular fibrillation (VF) in the setting of electrical storm (ES). This strategy was first described in subjects without organic heart disease (i.e. idiopathic VF) and subsequently in other conditions, especially in patients with ischaemic heart disease. In the majority of cases, the triggering focus originates in the ventricular Purkinje system. In patients with Brugada syndrome, besides ablation of focal trigger in the right ventricular outflow tract, modification of a substrate in this region has been described to prevent recurrences of VF. In conclusion, CA appears to be a reasonable strategy for intractable cases of ES due to focally triggered polymorphic ventricular tachycardia and VF. Therefore, early transport of the patient into the experience centre for CA should be considered since the procedure could be in some cases life-saving. Therefore, the awareness of this entity and link to the nearest expert centre are important.

Keywords Ventricular fibrillation, polymorphic ventricular tachycardia, catheter ablation, ventricular premature beats, Brugada syndrome, long QT syndrome, ischaemic heart disease Disclosure: Josef Kautzner is a member of the scientific advisory board for Biosense Webster, Boston Scientific and St Jude Medical. He received speaker honoraria from Biotronik, Biosense Webster, Hansen Medical, Medtronic and St Jude Medical. Petr Peichl received speaker honoraria from St Jude Medical. Acknowledgement: Supported by Ministry of Health, Czech Republic – conceptual development of research organization („Institute for Clinical and Experimental Medicine – IKEM, IN 00023001“) Received: 21 August 2013 Accepted: 16 September 2013 Citation: Arrhythmia & Electrophysiology Review 2013;2(2):135–40 Access at: www.AERjournal.com Correspondence: Josef Kautzner, Department of Cardiology, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21 Prague 4, Czech Republic. E: joka@medicon.cz

Ventricular fibrillation (VF) is a complex arrhythmia that leads invariably to cardiac arrest. Its mechanisms remain largely unclear. Similar to atrial fibrillation, the mother rotor hypothesis is one plausible alternative.1,2 In larger animals, some authors reported that the dominant frequency of VF could be recorded at a junction of the left ventricular posterior wall and the septum.3–6 Others have shown that the posterior papillary muscle could be the major anchoring structure of VF reentrant wavelets, and the site harboring prominent Purkinje potentials and the dominant domain.7 Some studies suggest that the dominant domain in this region reflects both focal firing from the Purkinje network and reentry around the posterior papillary muscle.8,9 In the clinical arena, a bulk of experience has accumulated on catheter ablation (CA) of focal sources of VF. It confirms the important role of focal triggers in driving VF in different clinical settings.10–12 In addition, recent reports have suggested that CA may modify a substrate for polymorphic ventricular tachycardia (VT) or VF, at least in conditions such as Brugada syndrome.13,14 Therefore, it appears that different mechanisms are not mutually exclusive in the large animal or human heart.15 The role of this paper is to review available data on CA of polymorphic VT and VF in a human.

young patient with history of resuscitated cardiac arrest due to idiopathic VF who presented with electrical storm (ES) following replacement of his implantable cardioverter defibrillator (ICD).16 It was apparent that every episode of polymorphic VT and VF was triggered by a short-coupled, monotopic ventricular premature beat. Its electrocardiogram (ECG) morphology (right bundle branch block with left axis deviation and QRS duration around 130 milliseconds [ms]) suggested possible origin in the conduction system of the left posterior fascicle. The coupling interval of ectopic beat was 240 ms. After a series of shocks due to ES, the decision was made to perform CA of the trigger. Mapping of this focus at the left ventricular septum revealed the origin in the distal Purkinje network of the posterior fascicle with P potential preceding local ventricular activation during ectopy by 60–80 ms. CA completely suppressed ectopic activity and terminated ES without subsequent recurrences (see Figure 1). Similar anecdotal cases have initiated an interest and led finally to a cooperative study under a leadership of Michel Haïssaguerre.10,11

Focally Triggered Ventricular Fibrillation Without Organic Heart Disease Idiopathic Ventricular Fibrillation

Pioneering Period The first cases of CA of focal triggers in polymorphic VT or VF were performed in several centres in the late 1990s. In 1998, we observed a

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An initial pilot report and later analysis of a series of 27 patients published by Haïssaguerre et al.10,11 showed that predominant site of triggering foci for idiopathic VF is in the His-Purkinje network of the left

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Diagnostic Electrophysiology & Ablation Figure 1: Twelve-lead Electrocardiogram with Intracardiac Electrograms from Ablation Catheter (Abl-d and Abl-p) and Arterial Pressure (Press) During Our First Catheter Ablation of Focally Triggered Idiopathic Ventricular Fibrillation

subjects with inherited long QT syndrome (LQTS), ICD appears to be the best means to prevent sudden cardiac death.18 However, patients are at risk of ES that necessitates complex management. In some cases, arrhythmias could be triggered by a focal source and thus amenable to CA. To date, there have been few reports on CA in LQTS patients – all have involved cases of congenital LQTS.19–21 The largest series described VF ablation in four patients with LQTS.19 The triggering ectopy was monomorphic in two patients and polymorphic in the other two. Interestingly, the site of ablation was again the distal Purkinje network in three patients and the right ventricular outflow tract in one patient. The patients were followed up for a mean period of 24 months with no recurrences of VF (an ICD was inserted in two of the patients).

Brugada Syndrome

The first ectopic beat (arrow) is preceded by a sharp deflection from the Purkinje system. Note that the second sinus rhythm beat is followed by the same sharp signal, which is not conducted to the surrounding myocardium. Application at that site abolished ectopy and prevented recurrence of ventricular arrhythmias.

or right ventricle. The first initiating beat of VF had typically an identical ECG morphology and coupling interval of 297 ± 41 ms. Location of these triggers was determined by mapping the earliest electrical activity. Importantly, the foci occurred in the Purkinje conducting system in 23 patients – from the left ventricular septum in 10, from the anterior right ventricle in nine and from both in four. Only in the remaining four patients, the premature beats originated from the right ventricular outflow tract musculature, without any relation to the conduction system. After radiofrequency CA, 24 patients (89 %) had no recurrence of VF without drug during a follow-up of 24 ± 28 months. Long-term follow-up of patients after CA of idiopathic VF has recently been published by Knecht et al.17 It comprises 38 patients (21 men) age 42 ± 13 years, refractory to a median of two antiarrhythmic drugs. In this larger cohort, triggering ventricular premature beats originated from the right (n=16), the left (n=14) or both (n=3) Purkinje network systems. During a median post-procedural follow-up of 63 months, seven (18  %) of 38 patients experienced some recurrence of VF at a median of four months. Five of these seven patients underwent repeated ablation with subsequent survival without VF recurrences. Survival free of VF was predicted only by transient bundle branch block in the originating ventricle during the electrophysiological study (p<0.0001). The number of significant events (confirmed VF or aborted sudden death) was reduced from four (interquartile range 3–9) before to 0 (interquartile range 0–4) after ablation (p<0.01). Our experience over the last 15 years covers a series of four subjects with focally triggered idiopathic VF. Two presented with a focus in the left ventricle and two had right ventricular location. One of them presented with two foci in the right ventricle. Long-term prognosis is very good without recurrences of VF.

Brugada syndrome may present with recurrent VF that may or may not be initiated by premature ventricular beats. Compared with most cases of idiopathic VF, ectopic activity in patients with Brugada syndrome appears to originate invariably from the right ventricular outflow tract. The first report on CA of a triggering focus of polymorphic VT or VF was presented again by Haïssaguerre et al.19 Subsequently, other anecdotal cases were published on successful ablation of triggering ectopy within the right ventricular outflow tract sites in patients with this condition.22,23 More interestingly, other authors explored the possibility of modifying a substrate for VF in patients with Brugada syndrome. The first prospective study of VF ablation in Brugada syndrome patients was reported by Nademanee et al.13 This group evaluated nine patients (all male; median age 38 years) with recurrent VF that required multiple ICD shocks. Endocardial and epicardial electroanatomic mapping of both ventricles together with computed tomography (CT) image integration were performed. Interestingly, abnormal low-voltage areas with prolonged duration and fractionated late potentials around the anterior aspect of the right ventricular outflow tract epicardium were found of all subjects. CA targeted at the abnormal arrhythmogenic substrate in this location successfully abolished further arrhythmic episodes in all but one patient during a follow-up period of 20 ± 6 months. The most interesting observation was that CA resulted in normalisation of the Brugada ECG pattern (all had type 1 pattern pre-ablation). A similar finding was described by the Bordeaux group in a case report24 and confirms previous pilot experimental evidence.25 More recently, a group from Thailand14 reported on observations in 10 patients with Brugada syndrome (all men; median age 36.5 years). Four subjects presented with ES while the remaining group had no arrhythmias. All patients underwent electrophysiological study using noncontact mapping with the multielectrode array placed in the right ventricular outflow tract. The isopotential map was analysed during sinus rhythm and the region with electrical activity occurring during J point to +60 (J+60) milliseconds interval of the V1 or V2 of surface ECG was considered as the late activation zone. Interestingly, such a late activation zone was always found in the right ventricular outflow tract with variable distribution in both groups. Endocardial CA of the late activated areas modified Brugada ECG pattern in three of four patients (75 %) and suppressed ES in all four patients during long-term follow-up (12–30 months). One patient had complete right bundle branch block from the ablation procedure.

Long QT Syndrome Both patients with inherited and acquired long QT interval syndrome are at risk of developing polymorphic VTs and/or VF. In high-risk

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All the above studies provide important evidence that the increasingly recognised subtle structural abnormalities observed in the right

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ventricular outflow tract region of patients with Brugada syndrome26 may be a potential target to treat recurrent VF in this condition. They also open up the possibility of ‘substrate modification’ to treat recurrent VF, even if pathological premature ectopic beats are not present at the time of the study.

Figure 2: Electroanatomical Maps of the Left Ventricle in a Patient After Previous Myocardial Infarction, Depicting Location of the Triggering Foci From Different Regions of the Purkinje System (Right Anterior Oblique Views)

Focally Triggered Ventricular Fibrillation in Organic Heart Disease Ischaemic Heart Disease Bansch et al.12 reported for the first time their experience of CA in four patients with incessant VT and VF triggered by monomorphic premature ectopic beats after acute myocardial infarction. Again, similar to idiopathic polymorphic VT or VF, the triggering foci were located within the Purkinje system, specifically in the left posterior fascicle. CA of the triggering premature ectopic beats successfully controlled ES and none of the patients experienced further episodes of VF within the followup period ranging between 5 and 33 months. The authors estimated that the scenario occurs relatively rarely in patients following acute myocardial infarction. In their experience, CA was only required in four reported patients out of a total of 2,340 post-infarction patients (i.e. 0.17 % of cases). Similarly, Enjoji et al.27 reported their experience with CA of triggering premature ventricular contractions in four patients with acute coronary syndrome and low ejection fraction who suffered from multiple VF or VT episodes, despite successful revascularisation. The premature ectopic beats originated again in the Purkinje fiber network, and were located in the left ventricular posteroinferior region of the left ventricle. Szumowski et al.28 performed CA of triggering ectopy in a small series of patients both early and late after myocardial infarction. Using the three-dimensional (3D) electroanatomical mapping system, they documented the site of origin of the triggering foci in Purkinje arborisation, close to the border zone of the necrosis or scar. They also observed repetitive activation of the Purkinje system during polymorphic VT, and persistent Purkinje activity despite the absence of propagation to the ventricular myocardium. These findings implicate the role of Purkinje arborisation in the scar border zone after previous myocardial infarction not only in the initiation, but also in the maintenance of initial beats of polymorphic VT and VF. Marrouche et al.29 investigated the mode of initiation of ES in patients with ischaemic cardiomyopathy who had suffered their myocardial infarction more than six months earlier. Eight patients required CA to suppress ES. Using electroanatomical mapping, the authors demonstrated that in five cases the culprit ectopic activity originated from the scar border zone, often preceded by Purkinje potentials. In three subjects without frequent ventricular ectopy, the ablation strategy consisted of linear lesion along the length of the border zone in order to eliminate all detected Purkinje potentials. This appeared to be successful and over a 10 ± 6 month follow-up period, VF only recurred in one patient. Recently, we published our experience with CA of triggering foci of VF in ischaemic heart disease, reporting on nine subjects (mean age 62 ± 7 years, two females, all after myocardial infarction between three days to 171 months, mean left ventricular ejection fraction (LVEF) 25 ± 7 %).30 In six of them (67  %), the ablation procedure was performed on mechanical ventilation. CA was successful in eight patients. During a follow-up of 13 ± 7 months, two patients died of progressive heart failure without any recurrence of ventricular arrhythmias. Another patient had recurrence of focally triggered VF from the other fascicle. The other had recurrence of ES due to monomorphic VT that was successfully re-ablated by substrate modification. Our more recent unpublished experience comprises 19 subjects with focally triggered VF

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Red colour depicts region of myocardial necrosis with bipolar voltage below 0.45 mV, green color represents transitional zone. Yellow tags annotate conduction system and dark red tags correspond to site of ablation. Corresponding 12-lead electrocardiograms are on right panels. Initially, the patient had monotopic ectopy (I) that was successfully abolished by focal ablation at the high septum (upper panel). However, the patient had next day recurrence of ES due to occurrence of new triggering ectopy (II) originating from the posterior fascicle. The re-ablation was performed more extensively across the whole middle part of septum (lower panel), which successfully prevented VF recurrences.

after myocardial infarction and/or after cardiac surgery. Thirteen of them were admitted early after infarction, four remotely and two following coronary artery bypass surgery. CA was successful in suppressing the ES in 17 out of 19 patients. Mean procedural time reached 171 ± 53 minutes (min) with fluoroscopic time of 12 ± 9 min. Interestingly, we observed six early recurrences of ectopy from a different region than originally ablated. Three of them were transient and disappeared spontaneously. Three patients underwent successful re-ablation of the newly manifested focus (see Figure 2). Four patients deceased early after the procedure, two due to heart failure, one due to multiorgan failure (after multiple direct current [DC] shocks before transfer for CA) and the other due to electromechanical dissociation and pericardial effusion after emergency introduction of temporary pacing catheter. Importantly, 80 % (12/15) of acute survivors had no recurrence of ES during 26 ± 21 months of follow-up. The above mentioned two clinical scenarios (i.e. ES early and late after myocardial infarction) appear to have different mechanisms. In early post-infarction period, the trigger appears to originate in Purkinje fibers surviving in the region of myocardial necrosis and/or scar. This view is supported by some experimental data showing survival of Purkinje fibers in the region of myocardial infarction.31 These cells are more resistant and therefore can survive even severe ischaemia. They can also be nourished by retrograde perfusion through various ventricular sinusoidal channels,32 through the left atrial venous system33 or simply by diffusion of oxygen from ventricular cavity blood through the endocardium.34 These surviving Purkinje fibers crossing the border-zone of the myocardial infarction demonstrate heightened automaticity, triggered activity and supernormal excitability.35–37 On the other hand, the reason for sudden appearance of ectopic activity from Purkinje fibers in the late post-infarction period is not clear. Subclinical infarction may be the

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Diagnostic Electrophysiology & Ablation Figure 3: Twelve-lead Electrocardiogram at the Time of Electrical Storm After Acute Myocardial Infarction

The panel A shows frequent monotopic ectopy with relatively narrow QRS complex. The panel B depicts initiation of VF by ectopic beat of the same morphology as the preceding ectopy.

Figure 4: Electrocardiogram Recording During Delivery of Radiofrequency Current in the Region of Focal Trigger. It Depicts Thermally-induced Polymorphic Ventricular Tachycardia

Aortic Valve Disease Focally triggered VF was also described in an adolescent patient after aortic valve repair of a perforated non-coronary cusp with resulting severe aortic regurgitation.41 During electrophysiological study, frequent short runs of VF initiated by ventricular ectopic beats with a narrow QRS complex were observed. After extensive mapping of the right and left ventricles, two distinct sources of ectopy originating from anteroseptal and inferoseptal areas of the left ventricle could be successfully ablated. Ectopic beats were preceded by distinct Purkinje potentials with intervals from the Purkinje potential to QRS onset of ventricular premature beats (VPBs) of 68 and 30 ms at effective sites, respectively. Another patient with ES after aortic valve replacement was reported by a group from Leipzig.42 Using the electroanatomic mapping system, the authors were able to abolish the triggering focus at mid-inferior septum of the left ventricle. Again, Purkinje system was the site of origin of this ectopy.

Cardiac Amyloidosis underlying cause that promotes ectopic activity from the surviving Purkinje cells. Anecdotal cases suggest that patients with focally triggered VF may have some anatomical abnormalities that promote arrhythmogenesis. For instance, Nogami et al.38 described autopsy specimens from a patient with ischaemic cardiomyopathy who underwent radiofrequency CA for VF. They revealed fibromuscular bands connecting the posterior papillary muscle and ventricular septum at the successful ablation sites of the trigger ectopic activity. Microscopic examinations showed Purkinje cells in the centre of that fibromuscular band. It is also less known why ectopic activity starts to trigger VF late after myocardial infarction.

Non-ischaemic Cardiomyopathy Some authors reported successful CA of focal VF in patients with non-ischaemic dilated cardiomyopathy and refractory ES despite optimal heart failure medication and the use of antiarrhythmic drugs.39,40 In one case, non-contact mapping was employed to localise triggering focus outside of the conduction system. Subsequent ablation abolished ES.39 In a series of five patients, 3D electroanatomical mapping was used to tag the site of focus and Purkinje-like potentials.40 Limited endocardial scar was revealed near the mitral annulus with Purkinje-like potentials close to scar zone in four subjects who underwent CA. During one-year follow-up, only one patient had recurrence of ES.

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Anecdotal reports showed that CA might be curative in focally triggered VF in cardiac amyloidosis.43 Interestingly, electrophysiological testing revealed that the sites of earliest activation were localised endocardially within the left ventricle in the absence of significant scar tissue. In the first case, no Purkinje potentials were recorded at spot of trigger in inferolateral apical region. In the other case, the earliest activation during ectopy was recorded within the left posterior fascicle. After CA, ventricular ectopy subsided in both cases and there were no further VF recurrences.

Technique of Catheter Ablation From the above section, it can be appreciated that CA targets predominantly ectopic focus that triggers ES due to polymorphic VT and VF. In subjects with idiopathic form, ablation site is usually contained within a relatively small area.10,11 CA of triggering ectopy appears to have a favourable outcome, despite occasional presence of other foci without documented initiation of VF. As a result of the possibility of disappearance of ectopy during mapping (â&#x20AC;&#x2DC;bumpingâ&#x20AC;&#x2122; the ectopic focus with the catheter), it appears to be useful to employ the electroanatomical mapping system for tagging the sites of interest. This allows both 3D reconstruction of left ventricular endocardial surface with annotation of location of the conduction system and delineation of myocardial necrosis or scar as low voltage areas. Patients with ischaemic cardiomyopathy often present with more than

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one ectopic focus. In our experience the risk of early recurrences of ES after successful ablation of one trigger supports the strategy to ablate all ectopic foci. It emphasises the need for ECG recording of ectopy on 12-lead ECG. Such recordings serve as roadmaps for subsequent ablation (see Figure 3). More important than in idiopathic VF, the use of the electroanatomical mapping system is recommendable. Besides annotation of the earliest activation during the ectopy, it allows displaying the extent of myocardial necrosis and/or scar, and CA may address more Purkinje tissue along the margin of the affected tissue. In addition, this strategy could be used when no ectopy is present during the mapping or if catheter manipulation induces left bundle branch block, making analysis of conduction system difficult. Electroanatomical system can also support modification of substrate for monomorphic VTs, provided they occur at the same time. On the other hand, a subendocardial location of Purkinje tissue allows very rapid stabilisation of the clinical status when necessary. Few applications of radiofrequency current after rapid mapping usually terminate ES quickly and provide more time for detailed mapping and ablation. It is also important to emphasise that delivery of radiofrequency current at ectopic source sites often leads to acceleration of ectopy (see Figure 4) and may trigger runs of polymorphic VT or VF that have to be terminated by DC shock. Sometimes, even after stabilisation of ES, other extremes may be encountered – absence of ectopic activity. In such cases, some authors recommend the use of isoproterenol to induce ventricular ectopic beats for more focused mapping when absent during ablation procedure. Interestingly, a different strategy has been used for CA in the majority of cases with ES in Brugada syndrome. As mentioned above, mapping and ablation were performed in the right ventricular outflow tract, either epicardially or endocardially.13,14 The main target was zones of delayed activation and late potentials.

Unresolved Problems We believe that the situation is analogous to pathophysiology of atrial fibrillation. Although ECG pattern of atrial fibrillation may be similar in different patients, many factors influence individual manifestation

1. J alife J. Ventricular fibrillation: Mechanisms of initiation and maintenance. Annu Rev Physiol 2000;62:25–50. 2. Z aitsev AV, Berenfeld O, Mironov SF, et al. Distribution of excitation frequencies on the epicardial and endocardial surfaces of fibrillating ventricular wall of the sheep heart. Circ Res 2000;86:408–17. 3. Chen J, Mandapati R, Berenfeld O, et al. High-frequency periodic sources underlie ventricular fibrillation in the isolated rabbit heart. Circ Res 2000;86:86–93. 4. N  ewton JC, Smith WM, Ideker RE. Estimated global transmural distribution of activation rate and conduction block during porcine and canine ventricular fibrillation. Circ Res 2004;94:836–42. 5. Nanthakumar K, Huang J, Rogers JM, et al. Regional differences in ventricular fibrillation in the open-chest porcine left ventricle. Circ Res 2002;91:733–40. 6. H  uang J, Walcott GP, Killingsworth CR, et al. Quantification of activation patterns during ventricular fibrillation in open-chest porcine left ventricle and septum. Heart Rhythm 2005;2:720–8. 7. Pak HN, Kim YH, Lim HE, et al. Role of the posterior papillary muscle and purkinje potentials in the mechanism of ventricular fibrillation in open chest dogs and Swine: Effects of catheter ablation. J Cardiovasc Electrophysiol 2006;17:777–83. 8. Pak HN, Oh YS, Liu YB, et al. Catheter ablation of ventricular fibrillation in rabbit ventricles treated with beta-blockers. Circulation 2003;100:3149–56. 9. Pak HN, Kim GI, Lim HE, et al. Both Purkinje cells and left ventricular posteroseptal reentry contribute to the maintenance of ventricular fibrillation in open-chest dogs and swine: effects of catheter ablation and the ventricular cutand-sew operation. Circ J 2008;72:1185–19. 10. H  aïssaguerre M, Shah DC, Jaïs P, et al. Role of Purkinje conducting system in triggering of idiopathic ventricular fibrillation. Lancet 2002;359:677–8. 11. Haïssaguerre M, Shoda M, Jaïs P, et al. Mapping and ablation of idiopathic ventricular fibrillation. Circulation 2002;106:962–7.

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of the arrhythmia. Yet, we reached the agreement that pulmonary venous isolation is considered a technique of choice to keep triggering foci at bay and treat paroxysmal atrial fibrillation with a high degree of success. In analogy to this development, better understanding of mechanisms of VF and critical structures for its maintenance may help to use more effectively CA. At this stage we have more questions than answers. In any case, it is clear that CA cannot be considered as a curative procedure for focally triggered VF, both in idiopathic cases and in patients with structural heart disease. Despite the fact that some patients may be without recurrences for certain period, VF can still reappear.11,17,19 Therefore, an ICD will remain a necessity in these subjects, especially when LVEF is depressed. Given the number of potential underlying causes and mechanisms, the need for particular expertise and relative scarcity of referrals (which does not necessarily reflect scarcity of cases but more probably lack of awareness) it is unlikely that we will have large randomised trials. Instead, observational studies using modifications of strategies designed based on empirical experience and/or some novel discoveries in experimental models will serve as a source of scientific evidence.

Conclusions Within the last 15 years, CA has emerged as a potentially important treatment strategy to target clearly identifiable focal triggers of polymorphic VT and VF in the setting of ES. It has been used in a limited number of centres both in patients with idiopathic and structural heart disease-related VF with very favourable results. In view of the invasive nature of CA for VF, potential complications and expertise required, patients presenting with ES should still be managed along conventional lines in the first instance. These measures, which include deep sedation, antiarrhythmic medication and/or overdrive ventricular pacing, may be effective in the majority of cases. However, CA could be a reasonable therapeutic option for intractable cases and early transport of the patient into the experience centre for CA should always be considered. Therefore, the awareness of this entity and link to the expert centre are important. n

12. B  änsch D, Oyang F, Antz M, et al. Successful catheter ablation of electrical storm after myocardial infarction. Circulation 2003;108:3011–6. 13. 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. 14. Sunsaneewitayakul B, Yao Y, Thamaree S, Zhang S. Endocardial mapping and catheter ablation for ventricular fibrillation prevention in Brugada syndrome. J Cardiovasc Electrophysiol 2012;23 Suppl 1:S10–6. 15. N  ash MP, Mourad A, Clayton RH, et al. Evidence for multiple mechanisms in human ventricular fibrillation. Circulation 2006;111:536–42. 16. Kautzner J, Bytešník J. Catheterablationofarrhythmogenicfocus in “short-coupled“ variant ofTorsade de Pointes (abstract). Pacing Clin Electrophysiol 2000;23:717. 17. K  necht S, Sacher F, Wright M, et al. Long-term follow-up of idiopathic ventricular fibrillation ablation: a multicenter study. J Am Coll Cardiol 2009;54:522–8. 18. Olde Nordkamp LR, Wilde AA, Tijssen JG, et al. The ICD for primary prevention in patients with inherited cardiac diseases: indications, use, and outcome: a comparison with secondary prevention. Circ Arrhythm Electrophysiol 2013;6:91–100. 19. Haïssaguerre M, Extramiana F, Hocini M, et al. Mapping and ablation of ventricular fibrillation associated with long-QT and Brugada syndromes. Circulation 2003;108:925–8. 20. Srivathsan K, Gami AS, Ackerman MJ, Asirvatham SJ. Treatment of ventricular fibrillation in a patient with prior diagnosis of long QT syndrome: importance of precise electrophysiologic diagnosis to successfully ablate the trigger. Heart Rhythm 2007;4:1090–3. 21. Cheng Z, Gao P, Cheng K, et al. Elimination of fatal arrhythmias through ablation of triggering premature ventricular contraction in type 3 long QT syndrome. Ann Noninvasive Electrocardiol 2012;17:394–7.

22. Darmon JP, Bettouche S, Deswardt P, et al. Radiofrequency ablation of ventricular fibrillation and multiple right and left atrial tachycardia in a patient with Brugada syndrome. J Interv Card Electrophysiol 2004;11:205–9. 23. Nakagawa E, Takagi M, Tatsumi H, Yoshiyama M. Successful radiofrequency catheter ablation for electrical storm of ventricular fibrillation in a patient with Brugada syndrome. Circ J 2008;72:1025–9. 24. Shah AJ, Hocini M, Lamaison D, et al. Regional substrate ablation abolishes Brugada syndrome. J Cardiovasc Electrophysiol 2011;22:1290–1. 25. Morita H, Zipes DP, Morita ST, et al. Epicardial ablation eliminates ventricular arrhythmias in an experimental model of Brugada syndrome. Heart Rhythm 2009;6:665–71. 26. Papavassiliu T, Veltmann C, Doesch C, Spontaneous type 1 electrocardiographic pattern is associated with cardiovascular magnetic resonance imaging changes in Brugada syndrome. Heart Rhythm 2010;7:1790–6. 27. Enjoji Y, Mizobuchi M, Muranishi H, et al. Catheter ablation of fatal ventricular tachyarrhythmias storm in acute coronary syndrome–role of Purkinje fiber network. J Interv Card Electrophysiol 2009;26:207–15. 28. Szumowski L, Sanders P, Walczak F, et al. Mapping and ablation of polymorphic ventricular tachycardia after myocardial infarction. J Am Coll Cardiol 2004;44:1700–6. 29. Marrouche NF, Verma A, Wazni O, et al. Mode of initiation and ablation of ventricular fibrillation storms in patients with ischemic cardiomyopathy. J Am Coll Cardiol 2004;43:1715–20. 30. Peichl P, Cihák R, Kozeluhová M, et al. Catheter ablation of arrhythmic storm triggered by monomorphic ectopic beats in patients with coronary artery disease. J Interv Card Electrophysiol 2010;27:51–9. 31. Friedman PL, Stewart JR, Fenoglio JJ jr, Wit AL. Survival of Subendocardial Purkinje Fibers after Extensive Myocardial Infarction in Dogs: in vitro and in vivo correlations. Circ Res 1973;33:597–611.

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Diagnostic Electrophysiology & Ablation 32. M  yers WW, HonicCR. Amount and distribution of Rb transported into myocardium from ventricular lumen. Am J Physiol 1966;211:739–45. 33. Moir T W. Study of luminal coronary collateral circulation in the beating canine heart. Circ Res 1969;24:735–44. 34. Bagdonas AA, Stuckey JH, PieraJ, et al. Effects of ischemia and hypoxia on the specialized conduction system of the canine heart. Am Heart J 1961;61:206–18. 35. Arnar DO, Bullinga JR, Martins JB. Role of the Purkinje system in spontaneous ventricular tachycardia during acute ischemia in a canine model. Circulation 1997;96:2421–9. 36. Berenfeld O, Jalife J. Purkinje-muscle reentry as a mechanism of polymorphic ventricular arrhythmias in a three-dimensional

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model of the ventricles. Circ Res 1998;82:1063–77. 37. K  upersmith J, Li ZY, Maidonado C. Marked action potential prolongation as a source of injury current leading to border zone arrhythmogenesis. Am Heart J 1994;127:1543–53. 38. N  ogami A, Kubota S, Adachi M, Igawa O. Electrophysiologic and histopathologic findings of the ablation sites for ventricular fibrillation in a patient with ischemic cardiomyopathy. J Interv Card Electrophysiol 2009;24:133–7. 39. K  irubakaran S, Gill J, Rinaldi CA. Successful catheter ablation of focal ventricular fibrillation in a patient with nonischemic dilated cardiomyopathy. Pacing Clin Electrophysiol 2011;34:e38–42. 40. S  inha AM, Schmidt M, Marschang H, et al. Role of left

ventricular scar and Purkinje-like potentials during mapping and ablation of ventricular fibrillation in dilated cardiomyopathy. Pacing Clin Electrophysiol 2009;32:286–90. 41. Li YG, Gronefeld G, Israel C, Hohnloser SH. Catheter ablation of frequently recurring ventricular fibrillation in a patient after aortic valve repair. J Cardiovasc Electrophysiol 2004;15:90–3. 42. Bode K, Hindricks G, Piorkowski C, et al. Ablation of polymorphic ventricular tachycardias in patients with structural heart disease. Pacing Clin Electrophysiol 2008;31:1585–91. 43. Mlcochova H, Saliba WI, Burkhardt DJ, et al. Catheter ablation of ventricular fibrillation storm in patients with infiltrative amyloidosis of the heart. J Cardiovasc Electrophysiol 2006;17:426–30.

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Supported Contribution

Observations and Considerations on Patient X-ray Exposure in the Electrophysiology Lab X ia nx i a n J i a n g ¹ a n d L u k a s RC D e k k e r ² 1. Scientist, Philips Healthcare, Best, The Netherlands; 2. Cardiologist, Department of Cardiology, Catharina Hospital Eindhoven, Eindhoven, The Netherlands

Abstract To assess patient radiation during catheter ablation procedures and operator differences. From 84 patients (51 males, age 63 ± 10 years) undergoing complex catheter ablation by three experienced operators we collected: body mass index (BMI), procedure type and time, fluoroscopy time, dose area product (DAP), air kerma and X-ray system setting (cine, collimation and angiographic imaging angle). A new factor, fluoroscopy DAP–fluoroscopy time ratio, was introduced to compare operator differences. The results show the average procedure time was 179 (± 57) minutes (min), fluoroscopy time was 31 (± 21) min, DAP was 26.4 (± 19.6) Gy.cm² and air kerma was 0.26 (± 0.19) Gy. Procedure types were: pulmonary vein isolation (PVI) (52 %), redo PVI (11 %), pulmonary vein ablation catheter (PVAC) (14 %), ventricular tachycardia (VT) (8 %) and others (15 %). Inter-operator difference was observed in fluoroscopy and cine usage. Fluoroscopy DAP-time ratios showed a similar level of patient radiation dose rate by operator A and B (correlation: 0.89), and a significantly higher dose rate by operator C (correlation: 0.20, p<0.001; 0.26, p<0.01, to operator A and B). In conclusion, operators should be aware of patient radiation exposure levels and the influencing factors. Inter- and intra-operator differences can be measured and bench marked for improvement in X-ray efficiency and patient radiation reduction.

Keywords Catheter ablation, electrophysiology, patient radiation dose, operator difference, radiation reduction Disclosure: Xianxian Jiang is an employee of Philips Healthcare. Lukas RC Dekker has no conflicts of interest to declare. Received: 30 October 2013 Accepted: 6 November 2013 Citation: Arrhythmia & Electrophysiology Review 2013;2(2):141–4 Access at: www.AERjournal.com Correspondence: Lukas RC Dekker, Department of Cardiology, Catharina Hospital Eindhoven, Eindhoven, The Netherlands. E: lukas.dekker@catharina_ziekenhuis.nl

Support: The publication of this article was supported by Philips Healthcare.

Due to its high success rates and low complication risks, catheter ablation has evolved as a first-line treatment for various cardiac arrhythmias, including more complex arrhythmias such as ventricular tachycardia (VT) and atrial fibrillation (AF).1–4 Greater understanding of arrhythmia substrates and the development of advanced electroanatomical mapping systems have contributed to a rapid growth in the numbers of complex catheter ablations performed worldwide.1 Nevertheless, in spite of a growing use of non-fluoroscopic mapping systems to guide these procedures, fluoroscopy still constitutes to be an indispensable tool for image guidance in these procedures.4

Better understanding and awareness of these parameters may lead to a reduction of potentially harmful X-ray exposure for both patients and workers in the EP lab. Easy measures such as image collimation, avoidance of steep projection angles, minimising source image distance (SID) as well as using low dose fluoroscopy and avoidance of magnification significantly reduce patient and operator radiation dose exposure.5 The purpose of this paper is to explain the meaning and determinants of radiation dose parameters, and to share thoughts on how these parameters can be interpreted to reduce X-ray exposure in the EP lab without jeopardising procedural outcome and safety.

Exposure to ionising radiation is related to subacute skin injury5 as well as radiation-induced cancer and genetic abnormalities.6–10 These risks are of particular concern for young patients and patients undergoing long and complex or repeated procedures. Operators, including technicians and nurses, especially those performing large numbers of procedures, are also exposed to risks from radiation such as malignancy.11 Radiation exposure to patients in the electrophysiology (EP) lab, as published in many studies, may vary widely,5,12–14 sometimes even exceeding threshold dose required for the onset of radiation-induced skin injuries.5–11,15

Methods

Therefore, it is of pivotal importance to understand the radiation dose-related parameters as provided by the X-ray system (i.e. dose area product (DAP), air kerma (AK) and fluoroscopy time) and particularly these parameters in relation to operator’s preference in X-ray usage.

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Study Design We included 84 consecutive patients (51 males and 34 females) undergoing complex catheter ablation procedures by three experienced electrophysiologists in the Catharina Heart Center in Eindhoven, The Netherlands (end-August to mid-November 2011). At each procedure we collected the following data: patient body mass index (BMI), procedure type and time, fluoroscopy time, DAP, AK and the operating physician. In addition, technical parameters including cine usage, SID, X-ray projection angle and image collimation were retrieved from X-ray system logging to recognise the operators’ X-ray usage preferences and differences. The ablation procedures were categorised as: • Pulmonary vein isolation (PVI), during which an electromagnetic mapping system is used, such as CARTO® (Biosense Webster,

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Supported Contribution

• •

Diamond Bar, US) or Ensite™ (St Jude Medical, St Paul, US). Redo of PVI for paroxysmal AF, which in this centre is performed with a circular diagnostic catheter and a thermo-cool ablation catheter while using X-ray as the sole imaging modality. Pulmonary vein ablation catheter (PVAC, Medtronic, Minneapolis, US) procedure for paroxysmal AF, in which EP-navigator and a multi-electrode phased radio-frequency (RF) PVAC are used – in a subgroups of PVAC-procedures three-dimensional (3D) rotational atriography was used.16 VT ablation including procedures for both scar dependent VT and idiopathic VT, for which CARTO or Ensite mapping were always used. Supraventricular tachycardia (SVT) ablation, solely dependent on X-ray imaging. Atrial tachycardia ablation for which CARTO or Ensite mapping were always used.

All the procedures were done in one catheterisation lab using a monoplane flat panel angiographic system (Allura Xper FD10, Philips Healthcare, Best, The Netherlands). This registry was approved by the hospital’s ethics committee.

Understanding of Radiation Dose Parameters in Practice Angiographic systems report a set of radiation dose parameters. We hereby explain in simple terms what they mean for better understanding in practice.

Table 1: Patient and Procedure Characteristics Age, years

63 ± 10

Weight, kg

83 ± 15

Height, cm

175 ± 11

BMI, kg/m2

27 ± 4

BMI <25 kg/m2, n (%)

28 (34)

BMI 25 to <30 kg/m2, n (%)

37 (44)

BMI ≥30 kg/m2, n (%)

18 (22)

Procedure time, minutes

179 ± 57

Fluoroscopy time, minutes

31 ± 21

Number of cine runs

4±3

AK, Gy

0.26 ± 0.18

Dose area product (DAP), Gy.cm2

25.9 ± 18.0

Data are mean ± SD AK = air kerma; BMI = body mass index; SD = standard deviation.

procedure type, the clinical difficulty and the operator’s catheter skills. DAP is correlated to fluoroscopy time17 and hence influenced by these predetermined factors listed above. However, the correlation is weak due to other influencing factors e.g. patient obesity.14 Moreover, DAP is also determined by the operator’s conscious effort in minimising patient radiation by measures such as image collimation and avoidance of steep projection angles. As a result, in order to evaluate and compare operators’ active effort in minimising patient radiation, despite other clinical factors, we derived a novel parameter in which procedural DAP from fluoroscopy is normalised by fluoroscopy time.

Fluoroscopy DAP–Fluoroscopy Time Ratio Typically, radiation is measured and reported in both the concentration and the total amount. Radiation concentration describes the ‘strength’ or per-unit energy delivered to (or absorbed by) the patient under X-ray exposure. AK is a measure of this kind. It stands for kinetic energy released per unit mass of air. It is a measure of the amount of radiation energy, in the unit of joules (J) per unit mass (kg) of air, i.e. gray (Gy=J/ kg). Due to the cone shape of the X-ray beam, the further away from the X-ray source, the less concentrated the radiation is. By regulation, AK is always reported as the measure at the same reference point in the X-ray beam where it is considered as the radiation entry point to the patient’s body (i.e. 15 cm from the isocentre toward the X-ray source). AK is regulated by the angiographic system to ensure constant image quality. DAP on the other hand describes the total amount of radiation toward the patient. It is the product of dose concentration and exposed area at the plane of measurement, i.e. DAP (Gy.cm²) = AK x irradiated area. Given a fixed AK, DAP varies according to the change of X-ray beam size (e.g. by image collimation).

Patient body size is a major determinant of the radiation dose level and of this ratio. It should be taken into account when analysing this novel parameter.14

Patient Effective Dose Simulation Commercially available software PCXMC (Radiation and Nuclear Safety Authority, Helsinki, Finland) was used for patient effective dose simulation, using the mean values of the observation results.

Statistical Analysis

The clinical relevance of these two parameters is that:

Data are presented as mean ± standard deviations, unless stated differently. Inter-operator difference was tested by correlation calculations on the fluoroscopy DAP–fluoroscopy time ratios between the patient subgroups per operator. Operator characteristics in patient radiation dose during catheter ablation procedures were derived by regression tests on the fluoroscopy DAP–fluoroscopy time ratios per patient. For each operator, a polynomial trendline was calculated and plotted against patient body size.

Results

AK as a radiation concentration measure is an effective indicator of acute radiation injury (deterministic risk, e.g. skin burn and hair loss); and DAP as a measure of the amount of energy irradiated to the patient, could be used to relate to potential stochastic effect (e.g. cancer risk).

A Novel Parameter on the Operator – Fluoroscopy Dose Area Product to Fluoroscopy Time Ratio Fluoroscopy time indicates the amount of fluoroscopy imaging that is needed to accomplish a clinical procedure. It is dependent on the

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General Observations and Procedure Differences General observations are listed in Table 1. The patients had an average age of 63 (± 10) and an average BMI of 27 (± 4) kg/m². Forty-four percent of the patients were overweight (BMI 25–30 kg/m²) and 22 % were obese (BMI ≥30 kg/m²). With all the catheter ablation procedures included, we observed an average DAP of 25.9 (± 18.0, third quartile: 34.1) Gy.cm² and an average AK of 0.26 (± 0.18, third quartile: 0.38) Gy. Mean procedure time was 179 (± 57) minutes (min). Mean fluoroscopy time was 31 (± 21) minutes. On average, 4 (± 3) cine runs were acquired per procedure. Based on the above mean values, effective dose simulation estimated an equivalent dose of 9.3 millisievert (mSv) per procedure.

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Observations and Considerations on Patient X-ray Exposure in the Electrophysiology Lab

Table 2: Fluoroscopy Time and Dose Area Product for Each Catheter Ablation Category Fluoroscopy time, minutes

PVI (n=44) 35 ± 18

Re-PVI (n=8) 47 ± 38

PVAC (n=11) 20 ± 4

VT (n=7) 23 ± 18

SVT (n=6) 12 ± 6

Atrial tachycardia (n=8) 35 ± 26

All (n=84) 31 ± 21

DAP, Gy.cm2

30.2 ± 17.6

35.2 ± 21.0

21.5 ± 13.9

18.5 ± 19.5

5.7 ± 2.9

20.5 ± 14.9

25.9 ± 18.0

% in DAP by fluoroscopy

82 %

77 %

61 %

99 %

99 %

91 %

82 %

Data are mean ± SD, DAP = dose area product; PVAC = pulmonary vein ablation catheter; PVI = pulmonary vein isolation; SD = standard deviation; SVT = supraventricular tachycardia; VT = ventricular tachycardia.

Figure 1: Fluoroscopy Time and Dose Area Product According to Body Mass Index 45

Mean fluoroscopy time (minutes)

35

Mean DAP (Gy.cm2)

45 11.7

30 DAP (Gy.cm2)

35 30 25 20 15

25 20

2.1 25.7

3.1

23

BMI<25

BMI 25–30

BMI≥30

30 25 20

15 16.3

10

0

5

40 35

27

21.6

15 10

5

10 0

43

5 Operator A Fluoroscopy DAP

Operator B Cine DAP

Operator C

Fluoroscopy time (minutes)

40

Figure 2: Operator Differences in Fluoroscopy Usage and Efficiency

0

Fluoroscopy time (minutes)

BMI = body mass index; DAP = dose area product.

DAP = dose area product.

The catheter ablation procedures were categorised as PVI (52 %), redo PVI (10 %), PVAC (13 %), VT (8 %), SVT (7 %) and atrial tachycardia (10 %). As shown in Table 2, differences in fluoroscopy and DAP time were observed between procedure types. Redo of PVI required the most fluoroscopy (47, ± 38 min) and lead to the highest radiation dose (DAP: 35.2, ± 21.0 Gy.cm²), whereas SVT required the least fluoroscopy (12, ± 6 min) and the lowest radiation dose (5.7, ± 2.9 Gy.cm²). Large standard deviation in fluoroscopy time was observed for most of the procedure types except PVAC.

ratios were calculated per operator to exclude variations in procedure type and procedure difficulty; it therefore serves as an estimate of the operators X-ray awareness. When comparing the fluoroscopy DAP– fluoroscopy time ratios, operator A and B showed similar levels of fluoroscopy usage efficiency (correlation: 0.89), whereas operator C was less efficient and significantly different from the others (correlation: 0.20, p<0.001; 0.26, p<0.01, to operator A and B).

Mean fluoroscopy DAP per procedure was 20.4 (± 14.6, third quartile: 31.2) Gy.cm². It accounted for 82 % of the overall procedural DAP, with the remaining of DAP contributed by cine or rotational X-ray acquisition. Fluoroscopy and the resulted DAP were found predominant in VT, SVT and atrial tachycardia procedures (99–91 % of procedure DAP), and least so in PVAC ablations (61 % of procedure DAP).

Patient Size – Impact on Radiation Dose In three patient groups according to BMI (<25, 25–30, ≥30 kg/m², respectively), there was no significant difference in fluoroscopy time (p>0.48). However, DAP per group had significant differences (0.002>p>0.082). Proportional impact of patient BMI on DAP is shown in Figure 1. In catheter ablation procedures, due to direct exposure of X-ray, patient chest size is particularly relevant and a more precise description of the body size compared to BMI. Patient chest size was derived as the average thickness in the chest area per patient during the entire procedure. This was measured and recorded by the X-ray system. In Figure 3, patient chest size was plotted against the fluoroscopy DAP–fluoroscopy time ratio in the corresponding procedure. A generic trend of rising radiation dose level (per unit time) with increased chest size was observed, regardless of procedure type and the operator.

Operator Characteristics Inter-operator differences were observed in fluoroscopy time, fluoroscopy DAP and cine DAP (see Figure 2). Fluoroscopy DAP–fluoroscopy time

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Operator specific characteristics in the fluoroscopy DAP–fluoroscopy time ratio were analysed using regression tests in the corresponding patient subgroups. Operator influence on patient radiation dose level were modelled by polynomial trendlines based on patient chest size (confidence interval [CI] 95 %, see Figure 3). Operator A and B showed great similarity in radiation dose level (per unit time) at all patient chest sizes, whereas operator C had a consistently higher level. X-ray system usage per operator (see Table 3) showed common choice in SID and image projection angles. By X-ray collimation, operator A and B had an average of 28 % smaller exposed image size, hence less radiation to the patient. All three operators mainly used low dose modes in fluoroscopy. Operator C had a large percentage of cine demanding procedures and showed a preference of using a high cine image frame rate, resulting in higher average cine DAP than operator A and B.

Discussion Our results in DAP, AK, fluoroscopy time and equivalent patient effective dose in catheter ablation procedures are at lower to comparable levels to those reported in the literature.5,7,8,10,12 Interestingly, compared with a recent multicentre study by Kidouchi et al.,18 our results showed lower levels of radiation dose on patients with higher BMI values. This could be due to differences in the angiography systems and way of working. Results reported in the literature and in this study consistently show widespread procedure duration and patient radiation dose in catheter ablation procedures, resulting in large standard deviations in these

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Supported Contribution

Fluoroscopy DAP-time ratio (mGy.cm2/hr)

Figure 3: Characteristic Patient Radiation Dose Trendlines per Operator 24

Patient BMI

Operator A Operator B Operator C

20

Table 3: Operator Characteristics and Differences Operator A Operator B Operator C 28.2±4.4 26.6±4 27.1±3.9

Procedure types that requires minimal 40 %

32 %

12 %

101±6

100±5

101±5

194±69

198 ±65

274 ±68

0.8 ±1.5

0.5±1.9

0.0±1.4

X-ray image rotation: LAO-RAO, °

6±28.6

6.8±28.7

3.4±28.4

Percentage of DAP by fluoroscopy

92 %

84 %

65 %

Low dose setting usage in

90 %

97 %

84%

3.75

7.5

15

cine (VT, SVT, atrial tachycardia), % X-ray source to image distance

16

(SID), cm 12

Imaged area (incl. image collimation), cm²

8

X-ray image angulation: cranial-caudal, °

4 0

20 22 24 26 28 30 32 34 36 Average imaged chest thickness per patient in water equivalence (cm)

(CI=95 %, excl. outlier). DAP = dose area product

fluoroscopy, % Most frequently used cine image

parameters. The reason lies in varying procedural types and complexity, patient size differences, and not to neglect, operator differences in using X-ray and optimising radiation efficiency. Table 2 shows that, in this study, different procedure types require different amount of fluoroscopic and cine images. VT and SVT require short fluoroscopy time and almost no cine, whereas other types of ablations demand longer fluoroscopy and more cine runs. Figure 1 and Figure 3 clearly illustrate the strong correlation between patient size and radiation dose, as has been published previously.14 In general, the larger the patient, the more radiation is required during the ablation procedure. According to the regression test shown in Figure 3, patients with comparable chest size could receive different level of X-ray radiation exposure due to the operator differences. However, the generic trend of increasing radiation exposure with body size is deterministic. Instead of AK and DAP, fluoroscopy time is often used in clinical practice as an easy estimate for patient radiation level in catheter ablation procedures. With the complexity of procedural difference in X-ray imaging needs, patient chest size variations and operator differences, fluoroscopy time can hardly provide reliable comparison between cases or between operators. Figure 2 illustrates that between operators, DAP distribution in fluoroscopy and cine varies due to the operator’s specialized procedure types and the operator’s preference in using X-ray. Table 3 indicates that indeed operator C had more cine demanding procedure (Re-do PVI, PVAC) than operator A and B and preferred to use higher cine image frame rate. In this study we proposed a new parameter, the fluoroscopy DAP-fluoroscopy time ratio, to further compare the operators’ efforts in reducing radiation, independently of procedure time, type and difficulty, as well as catheter skills. Shown in Figure 3, patients treated by operator A and B could expect similar levels

1. Cappato R, Kuck KH. Catheter ablation in the year 2000. Curr Opin Cardiol 2000;15:29–40. 2. Calkins H, Yong P, Miller JM, et al. Catheter ablation of accessory pathways, atrioventricular nodal reentrant tachycardia, and the atrioventricular junction: final results of a prospective, multicenter clinical trial. The Atakr Multicenter Investigators Group. Circulation 1999;99:262–70. 3. Segal OR, Chow AW, Markides V, et al. Long-term results after ablation of infarct-related ventricular tachycardia. Heart Rhythm 2005;2:474–82. 4. Cappato R, Calkins H, Chen SA, et al. Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation 2005;111:1100–5. 5. Lickfett L, Mahesh M, Vasamreddy C, et al. Radiation exposure during catheter ablation of atrial fibrillation. Circulation 2004;110:3003–10. 6. Mahesh M. Fluoroscopy: patient radiation exposure issues. Radiographics 2001;21:1033–45. 7. Calkins H, Niklason L, Sousa J, et al. Radiation exposure during radiofrequency catheter ablation of accessory atrioventricular connections. Circulation 1991; 84:2376–82.

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rate¹, per sec ¹Exclusive of procedures that require 15 cine images per second by default. LAO = left anterior oblique; RAO = right anterior oblique.

of fluoroscopy dose rate per unit time, while patients treated by operator C would generally receive higher dose rate at all body sizes. Based on findings in Table 3, improvement in X-ray collimation and low dose fluoroscopy usage could potentially help operator C reduce fluoroscopy dose rate and therefore lower the fluoroscopy DAP. Despite operator differences, in our centre, we emphasize low radiation during interventions by utilising low fluoroscopy setting, low cine frame rate, small SID and avoidance of steep image projection angles. All these elements contribute to minimising X-ray exposure in catheter ablations in EP labs. As X-ray currently remains necessary for all routine EP procedures, it inevitably poses potential risks to the patient and the staff. Lowering X-ray exposure will lower patient and occupational radiation dose. Despite the fact that developments in X-ray techniques and image processing have reduced exposure, dose awareness and simple actions importantly further reduce X-ray exposure.19 Moreover, in the field of EP practice, comprehensive X-ray usage training on physicians, multicentre radiation dose studies and further optimisation of X-ray imaging techniques, could all contribute to reduce radiation exposure.

Conclusion Operators in the electrophysiology lab should be aware of patient radiation exposure levels and the influencing factors to patient radiation dose. Interand intra-operator differences can be measured and benchmarked for improvement in X-ray efficiency and patient radiation reduction. n

8. Lindsay BD, Eichling JO, Ambos HD, Cain ME. Radiation exposure to patients and medical personnel during radiofrequency catheter ablation for supraventricular tachycardia. Am J Cardiol 1992;70:218–23. 9. Kovoor P, Ricciardello M, Collins L, et al. Risk to patients from radiation associated with radiofrequency ablation for supraventricular tachycardia. Circulation 1998;98:1534–40. 10. Perisinakis K, Damilakis J, Theocharopoulos N, et al. Accurate assessment of patient effective radiation dose and associated detriment risk from radiofrequency catheter ablation procedures. Circulation 2001;104:58–62. 11. Theocharopoulos N, Damilakis J, Perisinakis K, et al. Occupational exposure in the electrophysiology laboratory: Quantifying and minimizing radiation burden. Br J Radiol 2006;79:644–51. 12. Macle L, Weerasooriya R, Jais P, et al. Radiation exposure during radiofrequency catheter ablation for atrial fibrillation. Pacing Clin Electrophysiol 2003;26:288–91. 13. Lakkireddy D, Nadzam G, Verma A, et al. Impact of a comprehensive safety program on radiation exposure during catheter ablation of atrial fibrillation: a prospective study. J Interv Card Electrophysiol 2009;24:105–12.

14. Ector J, Dragusin O, Adriaenssens B, et al. Obesity is a major determinant of radiation dose in patients undergoing pulmonary vein isolation for atrial fibrillation. J Am Coll Cardiol 2007;50:234–42. 15. Rosenthal LS, Beck TJ, Williams J, et al. Acute radiation dermatitis following radiofrequency catheter ablation of atrioventricular nodal reentrant tachycardia. Pacing Clin Electrophysiol 1997;20:1834–9 16. Von Bary C, Weber S, Dornia C, et al. Evaluation of pulmonary vein stenosis after pulmonary vein isolation using a novel circular mapping and ablation catheter (PVAC). Circ Arrhythm Electrophysiol 2011;4:630–6. 17. Butter C, Schau T, Meyhoefer J, Neumann K, Minden H, Engelhardt J. Radiation exposure of paitent and physician during implantation and upgrade of cardiac resynchronization devices. Pacing Clin Electrophysiol 2010 Aug;33(8):1003-12 18. Kidouchi T, Suzuki S, Furui S, et al. Entrance skin dose during radiofrequency catheter ablation for tachyarrhythmia: a multicenter study. Pacing Clin Electrophysiol 2011;34(5) :563–70. 19. Fetterly KA, Magnuson DJ, Tannahill GM, et al. Effective use of radiation shields to minimize operator dose during invasive cardiology procedures. JACC Cardiovasc Interv 2011;4:1133–9.

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The Convergent Procedure – A Standardised and Anatomic Approach Addresses the Clinical and Economic Unmet Needs of the Persistent Atrial Fibrillation Population James McKinnie East Jefferson General Hospital, Metairie, Louisiana, US

Abstract A standardised treatment management approach is needed to address the escalating worldwide prevalence of atrial fibrillation (AF). The persistent and longstanding persistent AF patient population particularly needs this standardised treatment option to manage their AF. These patients have underlying structural heart disease that result in increased hospitalizations, long-term medical management that increases the cost burden of the healthcare system. Approximately 100 patients have undergone the Convergent Procedure at our center since its introduction 2 years ago, as a treatment option for AF patients. The epicardial and endocardial ablation procedures performed sequentially in a single setting has shown a single procedure success rate of 80%, similar to published success rates at other centers. The epicardial posterior wall isolation silences a majority of known substrates and the endocardial procedure completes the pulmonary vein isolation, creates the cavotricuspid line and provides diagnostic confirmation. The Convergent Procedure should be considered as a first line treatment option for the persistent and longstanding persistent AF patient population who have very limited or no treatment options for the long-term successful management of their AF.

Keywords Atrial fibrillation, ablation, Convergent Procedure, persistent atrial fibrillation, longstanding persistent atrial fibrillation, epicardial-endocardial ablation Disclosure: James McKinnie has consulted for nContact, Inc. Received: 25 October 2013 Accepted: 7 November 2013 Citation: Arrhythmia & Electrophysiology Review 2013;2(2):145–8 Access at: www.AERjournal.com Correspondence: James McKinnie, Jefferson Electrophysiology, 4224 Houma Boulevard, Suite 400, Metairie, Louisiana 70006, US. E: epwizard@aol.com

Support: The publication of this article was supported by nContact, Inc.

Atrial fibrillation (AF) is escalating into an epidemic throughout the world with more than a million people in the US developing the disease every year. In fact, the prevalence in the US and Europe has totalled over 14 million patients and is growing at an alarming rate.1,2 Costs of managing AF are spiralling out of control with hospitalisations growing much faster than those for other cardiovascular diseases, including heart failure and myocardial infarctions.3 Without definitive treatments for AF, patients will continue to suffer and burden healthcare systems around the world. When you read these statistics it quickly becomes clear that there is an unmet need for a treatment management approach for AF that has successful outcomes, improves the individual’s quality of life and has a positive impact on health economics. A review of the AF patient profile indicates that while most AF patients are symptomatic, those with pre-existing conditions have much higher morbidity and mortality rates than those without additional risk factors (e.g. lone AF).4,5 With only 2–3 % of AF patients classified as idiopathic or lone AF, AF treatments aimed at increasing the longterm success and reducing the economic burden must address the vast majority of patients afflicted with underlying medical conditions.6,7 Despite the need to address the treatment options for this larger cohort of AF patients, the majority of minimally invasive treatment

© RADCLIFFE 2013

modalities have focused primarily on paroxysmal AF patients; especially those with normal atria and no risk factors that influence structural remodeling. This ignores the large unmet need of patients with persistent AF with enlarged atria and suffering from progressive atrial remodeling. Persistent and permanent AF patients have larger left atria and higher CHADS2 than paroxysmal AF.8 The associated atrial remodeling, correlated to atrial enlargement and additional risk factors, increases the complexity of effective treatment modalities and the subsequent economic burden to the healthcare system. AF represents multiple aetiologies depending on underlying conditions that affect tissue remodeling and atrial enlargement. These substrates include ganglionated plexi, stable or meandering rotors, ectopic foci or a combination of substrates.9 All substrates, except for ectopic foci located within the pulmonary veins (PVs), involve the posterior left atrium and/or require ablation along both epicardial and endocardial surfaces. The Convergent Procedure was evaluated and introduced at our hospital as a multidisciplinary treatment option for AF patients. Our centre has performed close to 100 Convergent Procedures over a two-year period. We are seeing impressive results (>80 % AF free) for this multidisciplinary convergent approach, performed as

145


Supported Contribution Figure 1: Illustration of Epicardial Silencing of Posterior Left Atrium

Figure 2: Illustration of Endocardial Ablation Along Pericardial Reflections

a single procedure, in the persistent and long-standing persistent patient populations. Similar results (>80 % AF free) have been reported by other centres performing the Convergent Procedure.23–26 In fact, these results exceed results reported for either less invasive surgical or catheter ablation approaches alone.27 Following the results seen at our centre and reported by other centres, we believe the Convergent Procedure is one of the most promising and interesting new approaches to treat AF today. The Convergent Procedure should be adopted as an initial treatment option within any arrhythmia centre wanting to offer ablation to patients with enlarged atria and/or non-paroxysmal AF. The Convergent Procedure, a unique multidisciplinary approach, provides the following advantages differentiating it from other approaches: 1. Closed-chest epicardial access via transdiaphragmatic pericardial window: • enhances patient recovery by avoiding damage to the intercostal nerves; • mitigates respiratory complications by avoiding the need to deflate the lungs, especially single lung ventilation; • reduces bleeding complications by leaving the attachments between the atrium and the pericardium intact; and • provides direct endoscopic visibility of the posterior left atrium. 2. Epicardial ablation of posterior left atrium: • silences the posterior left atrium to interrupt all known AF substrates’ anatomic locations; and

146

• a  blates the multitude of AF substrates to address the large unmet demand – namely AF patients with enlarged atria, higher CHADS2 and non-paroxysmal types who previously had limited treatment options. 3. Multidisciplinary treatment fits within electrophysiology (EP) practice requirements: • performed as a single-setting procedure in the EP laboratory; • allows patients to remain anticoagulated with therapeutic international normalized ratios (INRs); • leverages the ability to create an anatomic set of epicardial transmural lesions with endocardial fine-tuning that ensures PV isolation and ablates endocardial structures not accessible epicardially; • inserts a pericardial drain during epicardial portion to mitigate the risk of tamponade, which is the most common complication of catheter ablation; and • allows patients to be discharged 2–3 days post-procedure. With several hospitals performing the Convergent Procedure, standardising the procedure was crucial. Several physician-led ‘best practices’ meetings have evolved the Convergent Procedure to focus on providing more rigorous, standardised protocols for consistency among hospitals offering the Convergent Procedure as a treatment option for their patients. Simplification of epicardial ablation has resulted in detailed protocols that include the application of a series of parallel, adjoining lesions that overlap to silence the entire posterior left atrium outlined by the attachments between the left atrium and the pericardium (see Figure 1). The result has been an easier to perform epicardial ablation portion of the procedure, as well as reduced total procedure time. The epicardial lesions are also positioned along the left atrial tissue outside the orifice to the PVs to ensure isolation, not only of the PVs themselves but also the antrum, orifice and left atrial tissue that extends adjacent to the attachments between the left atrium and pericardium. Whereas many stand-alone catheter ablation techniques for isolating the PVs create lesions on the antrum, they do not address substrates located along the PV orifice or along the left atrium outside the PV antrum. Stand-alone catheter ablation is able to achieve PV isolation, although reconnections frequently require repeat ablation procedures. From a stand-alone endocardial mapping and ablation perspective, developing standardised protocols has been challenging as EPs have often utilised ‘customised’ patient approaches for catheter ablation. Stand-alone catheter ablation strategies differ widely, especially for non-paroxysmal AF patients. Some EPs adhere to a more simplistic ablation, focused on isolating the PVs where ‘less ablation is more’, while others believe in a debulking thought process where ‘more ablation is better’. The issue with debulking during catheter ablation is the inability to differentiate whether targeted ablation of irregular electrograms have been created by point ablation or are due to the underlying arrhythmia substrate(s). The Convergent Procedure encourages the adoption of the ‘less is more’ endocardial ablation ideology while still silencing the posterior left atrium and addressing all known substrates. The endocardial ablation portion of the Convergent Procedure completes isolation of the PVs by ablating left atrial tissue along the attachments between the left atrium and pericardium (see Figure 2). Limiting endocardial ablation to completing PV isolation mitigates gaps in endocardial lesions that may be proarrhythmic.

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The Convergent Procedure

130 120 110 100

80 70

15 17 16

140 130 120 110 100

15 16 17

90 80 70

The epicardial portion of the procedure has a short ablation time (less than one hour), but ablates a much larger volume of atria than catheter ablation because of the longer, wider and deeper lesions that can be created with ablation instrumentation directing energy delivery and the conduction of heat towards the natural heat sink of circulating blood. From a lesion pattern point of view, the Convergent Procedure emphasises the importance of silencing the posterior left atrium, isolating the PVs and completing a cavotricuspid isthmus line. Taking into account the lack of understanding of triggers that initiate AF and circuits that maintain AF, especially in nonparoxysmal patients, the anatomic approach of the Convergent Procedure does not utilise termination of AF or organisation into an atrial tachycardia or flutter as a metric for procedure completion. In addition, chasing complex fractionated atrial electrograms (CFAEs) is avoided because knowingly leaving gaps between lesions by ablating discrete points of irregular electrograms during AF leads to atypical flutter; those irregular potentials may simply constitute colliding wavefronts that have nothing to do with initiation or maintenance of AF. Leaving gaps between discrete ablation points alters the conduction property and produces tissue changes that are amenable to micro- or macro-reentrant circuits. Therefore, to ensure isolation of the PVs and truly evaluate the silencing of the posterior, patients are cardioverted into normal sinus rhythm where signals have higher amplitudes to better evaluate lesion completeness. In our single-centre experience, atypical flutter and atrial tachycardia have been avoided when sticking to this standardised protocol. Conversely, atypical flutters have only been observed in patients in whom CFAEs have been targeted outside the core lesion pattern. In terms of patient selection, the Convergent Procedure should be considered as a primary treatment option for symptomatic, drug refractory non-paroxysmal AF patients and those with enlarged atria. The clinical rationale and economic benefit to AF patients who are non-paroxysmal, have enlarged left atria, and/or have pre-existing conditions is clear. They can undergo multiple catheter ablation procedures in a stepwise, sequential approach where outcomes have been shown to decline over time as the disease progresses,10-13 or select the multidisciplinary Convergent Procedure that addresses multiple substrates known to cause AF, many of which are not safely accessible by endocardial ablation.

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160 150 140 130 120 110 100 90 80 70

18 15 14 16 17 19 20

60

Catheter - Free from AF

Catheter Ablation Failure - Recurrence of AF 160 150 140 130 120 110 100 90 80

16 14 18 15 17 20 19

70 60

Catheter - AF Recurrence

Convergent Procedure 89 % Sinus Rhythm in Enlarged Atria 21,22

Average Left Atrial Volume (ml)

140

150

Average Left Atrial Volume (ml)

150

90

Catheter Ablation Success - Prevention of AF

Persistent AF 160 Average Left Atrial Volume (ml)

Average Left Atrial Volume (ml)

Paroxysmal AF 160

Figure 4: Relationship Between Left Atrial Volume and Outcomes

Average Left Atrial Volume (ml)

Figure 3: Relationship Between Left Atrial Volume and Atrial Fibrillation Type

160

21

150 140 130 120

22

110 100 90 80 70 60

Convergent - All Patients

The distribution and complexity of AF substrates is correlated with left atrial size, because structural remodeling resulting in atrial enlargement is commonly associated with the development of fibrosis, which alters tissue conduction properties in a widely diffuse configuration. Patients with persistent AF have been shown to have much larger left atrial volumes than paroxysmal AF patients (see Figure 3).15â&#x20AC;&#x201C;17 The relationship between left atrial volume and disease complexity demonstrates why stand-alone catheter ablation has been most successful for paroxysmal AF, where assuring PV isolation alone has a higher probability of addressing clinical substrates without relying on additional lesions. Catheter ablation studies that differentiated success and failure based on left atrial volume reported the average left atrial volume for patients who were deemed free from atrial arrhythmias ranged between 68 and 110 ml, while the average volume for patients in which atrial arrhythmias recurred ranged from 96 to 123 ml (see Figure 4).14â&#x20AC;&#x201C;20 The fine line between success and failure of standalone catheter ablation highlights a threshold at which an alternative treatment modality should be selected. The Convergent Procedure fills that void by targeting patients with enlarged left atrial sizes/ volumes and demonstrating promising single procedure outcomes.21,22 The ability to offer both catheter ablation and the Convergent Procedure in an arrhythmia centre is important because they target different patient populations. As stated previously, catheter ablation is effective in lone AF patients with normal left atria. The Convergent Procedure is technically more difficult in these young patients with small atria and no risk factors that cause progressive structural remodeling. This population has a pericardium that tightly envelops the heart and reduces the pericardial space into which epicardial devices can traverse. In addition, the posterior left atrium, defined by the distance between the right and left PVs and bounded by the pericardial attachments, is incredibly small, reducing the need for posterior silencing. As such, simple PV isolation most likely addresses clinical substrates in lone, paroxysmal patients. Conversely, the Convergent Procedure has demonstrated excellent efficacy in patients with enlarged atria in which structural remodeling has stretched the pericardium and increased the separation between the PVs, establishing a well defined cavity along the posterior left atrium.23â&#x20AC;&#x201C;26 This is the population in which stand-alone catheter ablation has struggled. The Convergent Procedure provides a comprehensive, minimally invasive option for this previously untreatable population by silencing the posterior left atrium with a

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Supported Contribution closed-chest approach that augments PV isolation in a standardised, anatomically guided procedure. This persistent AF patient population is not typically seen by EPs. These patients are largely managed by their primary care physicians and less often by cardiologists, both of whom have become sceptical of ablation modalities for these more complex atrial arrhythmias. Thus, it is important to bring awareness of the Convergent Procedure to the cardiologists and other physicians, and educate them on the benefits of this new ‘heart team approach’. In essence, utilising an epicardial ablation device to leverage the EP mapping, recording and navigation technologies assures a viable, comprehensive and complete treatment option for this complex disease. This team approach makes good common sense because it silences the posterior left atrium, is performed in a single setting consistent with EP standard protocols, takes about the same time as a PV isolation catheter ablation procedure (four hours), utilises a system of multidisciplinary checks and balances, and leverages the best features of therapeutic and diagnostic technologies to provide predictable outcomes.

1. Colilla S, Crow A, Petkun W, et al. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. Adult population. Am J Cardiol 2013;112(8):1142–7. 2. Krijthe BP, Kunst A, Benjamin EJ, et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur Heart J 2013;34(35):2746–51. 3. Wong CX, Brooks AG, Leong DP, et al. The increasing burden of atrial fibrillation compared with heart failure and myocardial infarction: a 15-year study of all hospitalizations in Austrailia. Arch Intern Med 2012;172(9):739–41. 4. Nieuwlaat R, Prins MH, Le Heuzey JY, et al. Prognosis, disease progression, and treatment of atrial fibrillation patients during 1 year: follow-up of the Euro Heart Survey on atrial fibrillation. Eur Heart J 2008;29:1181–9. 5. Stöllberger C, Winkler-Dworak M, Finsterer J, et al. Factors influencing mortality in atrial fibrillation. Post hoc analysis of an observational study in outpatients. Int J Cardiol 2005;103:140–4. 6. Weijs B, Pisters R, Nieuwlaat R, et al. Idiopathic atrial fibrillation revisited in a large longitudinal clinical cohort. Europace 2012;14:184–90. 7. Jahangir A, Lee V, Friedman PA, et al. Long-term progression and outcomes with aging in patients with lone atrial fibrillation: a 30-year follow-up study. Circulation 2007;115:3050–6. 8. Meitz A, Zimmermann M, Urban P, Bloch A; Association of Cardiologists of the Canton of Geneva. Atrial fibrillation management by practice cardiologists: a prospective survey on the adherence to guidelines in the real world. Europace 2008;10:674–80. 9. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management, and follow-up, definitions, endpoints, and research trial design.

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Cardiologists have limited ability to manage these patients, leading to a sense of hopelessness within these patients as their quality of life progressively declines. These are knowledgeable patients who know existing treatment limitations. The key to accessing this unmet market need is physician and patient education and awareness. In summary, the Convergent Procedure should be a first-line treatment option for the persistent AF population. These patients represent a sizeable percentage of the AF population with high morbidity and mortality issues that add a significant economic burden to the healthcare system. Providing definitive, long-term treatment to this patient population may provide the greatest savings to the healthcare system. The Convergent Procedure is a promising approach that addresses the treatment needs of a difficult patient population and has the potential to reduce the burden this disease has on the healthcare economic system. Bringing in this type of programme requires full physician support and must be presented to the highest levels of the hospital where the management thinks strategically. The Convergent Procedure represents an opportunity that aligns all stakeholder interests including physicians, patients, hospitals and healthcare payers. n

Europace 2012;14(4):528–606. 10. Chao TF, Ambrose K, Tsao HM, et al. Relationship between the CHADS(2) score and risk of very late recurrences after catheter ablation of paroxysmal atrial fibrillation. Heart Rhythm 2012;9:1185–91. 11. Chao TF, Tsao HM, Lin YJ, et al. Clinical outcome of catheter ablation in patients with nonparoxysmal atrial fibrillation: results of 3-year follow-up. Circ Arrhythm Electrophysiol 2012;5:514–20. 12. Sorgente A, Tung P, Wylie J, Josephson ME. Six year followup after catheter ablation of atrial fibrillation: a palliation more than a true cure. Am J Cardiol 2012;109:1179–86. 13. Tilz RR, Rillig A, Thum AM, et al. Catheter ablation of longstanding persistent atrial fibrillation: 5-year outcomes of the Hamburg Sequential Ablation Strategy. J Am Coll Cardiol 2012:60(19):1921–9. 14. Helms AS, West JJ, Patel A, et al. Relation of left atrial volume from three-dimensional computed tomography to atrial fibrillation recurrence following ablation. Am J Cardiol 2009;103:989–93. 15. Hof IE, Velthuis BK, Chaldoupi SM, et al. Pulmonary vein antrum isolation leads to a significant decrease of left atrial size. Europace 2011;13:371–5. 16. Parikh SS, Jons C, McNitt S, et al. Predictive capability of left atrial size measured by CT, TEE, and TTE for recurrence of atrial fibrillation following radiofrequency catheter ablation. Pacing Clin Electrophysiol 2010;33:532–40. 17. Fredersdof S, Ucer E, Jungbauer C, et al. Lone atrial fibrillation as a positive predictor of left atrial volume reduction following ablation of atrial fibrillation. Europace 2013 [Epub ahead of print]. 18. Sohns C, Sohns JM, Vollmann D, et al. Left atrial volumetry from routing diagnositc work up prior to pulmonary vein ablation is a good predictor of freedom from atrial fibrillation. Eur Heart J Cardiovasc Imaging 2013;14:684–91. 19. von Bary C, Dornia C, Eissnert C, et al. Predictive value of

left atrial volume measured by non-invasive cardiac imaging in the treatment of paroxysmal atrial fibrillation. J Interv Card Electrophysiol 2012;34:181–8. 20. Chao TF, Sung SH, Wang KL, et al. Associations between the atrial electromechanical interval, atrial remodelling and outcome of catheter ablation in paroxysmal atrial fibrillation. Heart 2011;97:225–30. 21. Thosani AJ, Gerczuk P, Liu E, et al. Closed Chest Convergent Epicardial–Endocardial Ablation of Non-paroxysmal Atrial Fibrillation – A Case Series and Literature Review. Arrhythmia & Electrophysiology Review 2013;2(1):65–8. 22. Robinson MC, Chiravuri M, McPherson C, Winslow R. Maximizing ablation, limiting invasiveness, and being realistic about atrial fibrillation: the convergent hybrid. EP Lab Digest 2012;13(6):34–6. 23. Gersak B, Pernat A, Robic B, Sinkovec M. Low rate of atrial fibrillation recurrence verified by implantable loop recorder monitoring following a convergent epicardial and endocardial ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2012;23(10):1059–66. 24. Geršak B, Zembala MO, Müller D, et al. European experience of the convergent atrial fibrillation procedure: multicenter outcomes in consecutive patients. J Thorac Cardiovasc Surg 2013;pii: S0022–5223(13)00798–8. 25. Civello K, Smith CA, Boedefeld W. Combined endocardial and epicardial ablation for symptomatic atrial fibrillation: single center experience in 100+ consecutive patients. J Innov CRM 2013;000:1–7. 26. Gilligan DM, Joyner CA, Bundy GM. Multidisciplinary Collaboration for the Treatment of Atrial Fibrillation: Convergent Procedure Outcomes from a Single Center. J Innov CRM 2013;4:1396–403. 27. Boersma LVA, Castella M, van Boven W, et al. Atrial fibrillation catheter ablation versus surgical ablation treatment (FAST): a 2-center randomized clinical trial. Circulation 2012;125(1):23–30.

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