AER 6.3 by Radcliffe Cardiology

Arrhythmia & Electrophysiology Review Volume 6 • Issue 3 • Autumn 2017

Volume 6 • Issue 3 • Autumn 2017

www.AERjournal.com

Cardiac Effects of Lightning Strikes Theodoros Christophides, Sarosh Khan, Mahmood Ahmad, Hossam Fayed and Richard Bogle

End-of-life Management of Leadless Cardiac Pacemaker Therapy Niek EG Beurskens, Fleur VY Tjong and Reinoud E Knops

Key Lessons from the ELECTRa Registry in the Modern Era of Transvenous Lead Extraction Angelo Auricchio, François Regoli, Giulio Conte and Maria Luce Caputo

Prophylactic Catheter Ablation for Ventricular Tachycardia: Are We There Yet? Rahul K Mukherjee, Louisa O’Neill and Mark D O’Neill

Bipolar voltage on epicardial substrate showing scar mainly on right ventricle

Basket catheter with electrodes enabling higher-resolution mapping

Cardiovascular effects of lightening strikes

ISSN – 2050-3369

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AER 6.3 FC + 4mm Spine.indd All Pages

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*In a single center study, after the first ablation set **Compared to the focal ablation catheter 1. Luther. V. et al. A Prospective Study of Ripple Mapping in Atrial Tachycardias. CIRCEP. 2016 2. Body Surface Morphology Matching Pre-Clinical Evidence Report. Test report: REP9819. June 2017 3. Imanli, H. et al, A Novel CARTO® Segmentation Software for Contrast enhanced Computed Tomography guided radiofrequency ablation in patients with atrial fibrillation. HRS poster. 2016 These products can only be used by healthcare professionals in EMEA. Important information: Prior to use, refer to the instructions for use supplied with this device for indications, contra-indications, side effects, warnings and precautions. Always verify catheter tip location using fluoroscopy or IC signals and consult the CARTO® System User Guide regarding recommendations for fluoroscopy use. Sporton S, Earley M, Nathan A, and Schilling R, Electroanatomic versus fluoroscopic mapping for catheter ablation procedures: A prospective randomized study. Journal of Cardiovascular Electrophysiology 2004;15,3:310-315. THERMOCOOL® Navigation Catheters are indicated for the treatment of recurrent drug/device refractory sustained monomorphic ventricular tachycardia (VT) due to prior myocardial infarction (MI) in adults. These screenshots provide examples of parameters that are not intended as recommendations. All settings are user defined and must be based on clinical experience and medical judgment © Johnson & Johnson Medical NV/SA 2017

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Volume 6 • Issue 3 • Autumn 2017

Editor-in-Chief Demosthenes Katritsis Athens Euroclinic, Athens, Greece

Section Editor – Arrhythmia Mechanisms / Basic Science

Section Editor – Clinical Electrophysiology and Ablation

Section Editor – Implantable Devices

Andrew Grace

Karl-Heinz Kuck

Angelo Auricchio

University of Cambridge, UK

Asklepios Klinik St Georg, Hamburg, Germany

Fondazione Cardiocentro Ticino, Lugano, Switzerland

Charles Antzelevitch

Carsten W Israel

Carlo Pappone

JW Goethe University, Germany

IRCCS Policlinico San Donato, Milan, Italy

Warren Jackman

Sunny Po

Uppsala University, Uppsala, Sweden

University of Oklahoma Health Sciences Center, Oklahoma City, USA

Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, USA

Johannes Brachmann

Pierre Jaïs

Antonio Raviele

Lankenau Institute for Medical Research, Wynnewood, USA

Carina Blomström-Lundqvist

Klinikum Coburg, II Med Klinik, Germany

Pedro Brugada

University of Brussels, UZ-Brussel-VUB, Belgium

Alfred Buxton

Beth Israel Deaconess Medical Center, Boston, USA

Hugh Calkins

John Hopkins Medical Institution, Baltimore, USA

A John Camm

St George’s University of London, UK

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

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

Josef Kautzner

Frédéric Sacher

Pier Lambiase

Richard Schilling

Samuel Lévy

William Stevenson

Cecilia Linde

Richard Sutton

Institute for Clinical and Experimental Medicine, Prague, Czech Republic Institute of Cardiovascular Science, University College London, and Barts Heart Centre, London, UK Aix-Marseille University, France

Riccardo Cappato

IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

Ken Ellenbogen

Karolinska University, Stockholm, Sweden

Gregory YH Lip

University of Birmingham, UK

Virginia Commonwealth University School of Medicine, USA

Francis Marchlinski

Sabine Ernst

Royal Brompton and Harefield NHS Foundation Trust, London, UK

Juan Tamargo

University Complutense, Madrid, Spain

Marc A Vos

Hein Heidbuchel

Sanjiv M Narayan

Cardiovascular Center, University of Michigan, USA Stanford University Medical Center, USA

Mark O’Neill

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

University of Leipzig, Germany

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

Jose Merino

Fred Morady

Gerhard Hindricks

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

Panos Vardas

St Vincenz-Hospital Paderborn and University Hospital Magdeburg, Germany Antwerp University and University Hospital, Antwerp, Belgium

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

University of Pennsylvania Health System, Philadelphia, USA Hospital Universitario La Paz, Madrid, Spain

Andreas Götte

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

Heraklion University Hospital, Greece University Medical Center Utrecht, The Netherlands

Hein Wellens

University of Maastricht, The Netherlands

Katja Zeppenfeld

Leiden University Medical Center, The Netherlands

Douglas P Zipes

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

Managing Editor Rita Som • Production Jennifer Lucy • Design Tatiana Losinska Sales & Marketing Executive William Cadden • New Business & Partnership Director Rob Barclay Publishing Director Liam O’Neill • Managing Director David Ramsey • Commercial Director David Bradbury •

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Editorial Contact Rita Som rita.som@radcliffecardiology.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffecardiology.com •

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology. Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS © 2017 All rights reserved ISSN: 2050-3369 • eISSN: 2050–3377 © RADCLIFFE CARDIOLOGY 2017

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Established: October 2012

Aims and Scope • Arrhythmia & Electrophysiology Review aims to assist time-pressured physicians to keep abreast of key advances and opinion in the arrhythmia and electrophysiology sphere. • Arrhythmia & Electrophysiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • Arrhythmia & Electrophysiology Review provides comprehensive updates on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day 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 quarterly journal comprising review articles and editorials. • The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Section Editors and Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of Arrhythmia & Electrophysiology Review is replicated in full online at www.AERjournal.com

Frequency: Quarterly

Current Issue: Autumn 2017

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

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

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

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

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

Abstracting and Indexing Arrhythmia & Electrophysiology Review is abstracted, indexed and listed in PubMed, Embase, Scopus, Google Scholar and Summon by Serial Solutions. All articles are published in full on PubMed Central one month after publication.

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

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

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

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barcelona spain

THE ANNUAL CONGRESS OF THE EUROPEAN HEART RHYTHM ASSOCIATION

18 / 20 MARCH

2018

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Contents

Foreword

103

Time for Practical Clinical Tools Demosthenes Katritsis, Editor-in-Chief Athens, Greece

Guest Editorials

105

Effective Patient Care in a Data-Driven World Andrew Grace, Section Editor University of Cambridge, Cambridge, United Kingdom

107

Letter from the New President of the European Heart Rhythm Association John Camm University of London, London, United Kingdom

107

A Future Perspective on the Europace Journal: its Star is Rising Gerhard Hindricks University of Liepzig, Germany

Expert Opinions

109

Is There a Future for Remote Cardiac Implantable Electronic Device Management? Haran Burri Cardiology Department, University Hospital of Geneva, Geneva, Switzerland

111

Key Lessons from the ELECTRa Registry in the Modern Era of Transvenous Lead Extraction Angelo Auricchio, François Regoli, Giulio Conte and Maria Luce Caputo Division of Cardiology, Fondazione Cardiocentro Ticino, Lugano, Switzerland

Clinical Arrhythmias

114

Cardiac Effects of Lightning Strikes Theodoros Christophides,1 Sarosh Khan,2 Mahmood Ahmad,3 Hossam Fayed3 and Richard Bogle2 1. Barts Heart Centre, St Bartholomew’s Hospital, Barts Health NHS Trust, London; 2. Epsom & St Helier University Hospitals NHS Trust, Carshalton, Surrey; 3. Royal Free Hospital, Royal Free London NHS Foundation Trust, London, United Kingdom

118

Limitations and Challenges in Mapping Ventricular Tachycardia: New Technologies and Future Directions Adam J Graham,1 Michele Orini2 and Pier D Lambiase1 1. Barts Health NHS Trust, London; 2. Institute of Cardiovascular Science, UCL, London, United Kingdom

Catheter Ablation

125

Prophylactic Catheter Ablation for Ventricular Tachycardia: Are We There Yet? Rahul K Mukherjee,1 Louisa O’Neill1 and Mark D O’Neill1,2 1. Division of Imaging Sciences and Biomedical Engineering, King’s College London; 2. Department of Cardiology, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom

Devices

129

End-of-life Management of Leadless Cardiac Pacemaker Therapy Niek EG Beurskens, Fleur VY Tjong and Reinoud E Knops AMC Heart Center, Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

Mechanisms of Arrhythmia

134

Ventricular Arrhythmia after Acute Myocardial Infarction: ‘the Perfect Storm’ Justine Bhar-Amato, William Davies and Sharad Agarwal Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge, United Kingdom

100

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All ESC Congress resources in one online library

www.escardio.org/365

This product is supported by AstraZeneca, Bayer, Boehringer Ingelheim, the Bristol-Myers Squibb and Pfizer Alliance, Daiichi Sankyo Europe GmbH and Novartis Pharma AG in the form of an unrestricted educational grant.

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Foreword

Time for Practical Clinical Tools

he entire field of cardiovascular medicine is witnessing an era of rapid scientific progress that occurs against a backdrop of increasing emphasis on the importance of evidence-based practice. In this context, there has been a rapid development of

guidelines, scientific statements and position papers by major professional societies, such as the American College of Cardiology/American Heart Association, the European Society

of Cardiology and their numerous specialty divisions and working groups. A quick survey of 2016–2017 in the field of arrhythmias and related clinical entities, for example, reveals 10 such documents aimed at guiding clinicians in decision making.1–10 Explosive scientific developments and evolving, exciting, new clinical information necessitate fresh guidance. However, with such prolific production, it is a tall order to expect busy clinicians to notice, let alone read and embrace, all this continually emerging information, even in our interconnected digitised world. It is time that learned societies, as well as editors of cardiology journals, undertake the task of guiding, standardising and coordinating these activities. This effort should prevent overproduction of overlapping documents and contribute towards the generation of user-friendly practical clinical tools that summarise evidence-based practice under the auspices of established organisations. n Demosthenes Katritsis Editor-in-Chief, Arrhythmia & Electrophysiology Review Athens, Greece 1.

atritsis DG, Boriani G, Cosio FG, et al. European Heart K Rhythm Association (EHRA) consensus document on the management of supraventricular arrhythmias, endorsed by Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulación Cardiaca y Electrofisiologia (SOLAECE). Europace 2017;19(3):465–511. DOI: 10.1093/europace/ euw301; PMID: 27856540. Philip Saul J, Kanter RJ, Writing Committee, et al. PACES/HRS expert consensus statement on the use of catheter ablation in children and patients with congenital heart disease: developed in partnership with the Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS). Heart Rhythm 2016;13(6):e251–89. DOI: 10.1016/j.hrthm.2016.02.009; PMID: 26899545. Patton KK, Ellinor PT, Ezekowitz M, et al. Electrocardiographic early repolarization: a scientific statement from the American Heart Association. Circulation 2016;133(15):1520–9. DOI: 10.1161/ CIR.0000000000000388; PMID: 27067089. Antzelevitch C, Yan GX, Ackerman MJ, et al. J-Wave syndromes expert consensus conference report:

emerging concepts and gaps in knowledge. Europace 2017;19(4):665–94. DOI: 10.1093/europace/euw235; PMID: 28431071. Halvorsen S, Storey RF, Rocca B, et al. ESC Working Group on Thrombosis. Management of antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation: expert consensus paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J 2017;38(19):1455–62. DOI: 10.1093/eurheartj/ehw454; PMID: 27789570. Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/ HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. J Am Coll Cardiol 2017; DOI:10.1016/j. jacc.2017.03.003; PMID: 28286221; epub ahead of press. Niessner A, Tamargo J, Morais J, et al. Reversal strategies for non-vitamin K antagonist oral anticoagulants: a critical appraisal of available evidence and recommendations for clinical management-a joint position paper of the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy

and European Society of Cardiology Working Group on Thrombosis. Eur Heart J 2017;38(22):1710–6. DOI: 10.1093/ eurheartj/ehv676; PMID: 26705385. 8. Doherty JU, Gluckman TJ, Hucker WJ, et al. 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation: a report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol 2017;69(7):871–98. DOI: 10.1016/j.jacc.2016.11.024; PMID: 28081965. 9. Raval AN, Cigarroa JE, Chung MK, et al. Management of patients on non-vitamin k antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association. Circulation 2017;135(10):e604–33. DOI: 10.1161/ CIR.0000000000000477; PMID: 28167634. 10. Peberdy MA, Gluck JA, Ornato JP, et al. Cardiopulmonary resuscitation in adults and children with mechanical circulatory support: a scientific statement from the American Heart Association. Circulation 2017;135(24):e1115–34. DOI: 10.1161/ CIR.0000000000000504; PMID: 28533303.

DOI: 10.15420/AER.2017.6.3.FO1 ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

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German Rhythm Days 2017 Annual Meeting of the German Cardiac Societyâ€˜s EP working group

Berlin, Germany 12-14 October, 2017

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Guest Editorial

Effective Patient Care in a Data-Driven World Andrew Grace, Section Editor University of Cambridge, Cambridge, United Kingdom

Citation: Arrhythmia & Electrophysiology Review 2017;6(3):105–6. DOI: 10.15420/aer.2017.3.2:GE1 Correspondence: Andrew Grace, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, United Kingdom, E: aag1000@cam.ac.uk

ur society acquires and stores data at unprecedented rates. Making sense of it has become a subject of academic interest,1,2 it is widely discussed and has provided a focus of interest to professional advisors,3 in each case with the objective of

considering practical applications. Sophisticated interpretation of these data can provide powerful insights. Just recently, in the field of public economics, a massive scale examination that combined data from cross sections of the US Census and Current Population Survey and de-identified tax records categorically identified declining absolute income mobility, a finding with substantial policy implications. 4 Using such large-scale (‘big’) data though is not by any means straightforward and requires special skills far removed from simple maths.2 Uninformed analysis can have catastrophic consequences; it was significantly implicated in the financial crisis of 10 years ago.5 Essentially, no matter how much data is out there, it needs diligent collection, informed analysis and effective implementation to provide positive impact.1,2 The application of data analytics to healthcare has gained traction from the sheer scale of the recent unanticipated demands on clinical services,6, 7 not least in electrophysiology. In both biology and medicine data is being generated across a broader range of parameters derived from ever-increasing numbers of model systems and patients.6–8 One driving hope is that data science will allow sense to prevail with an increased efficiency along the biomedical continuum, enhancing discovery, development and implementation and assessment of treatment responses.7, 9–11 Electrophysiology remains a nascent sub-speciality, based always in quantitation (not least through data available from wearable and implanted devices), populated by a workforce with curious minds, some especially well grounded in mathematics and physical sciences so we have a starting advantage. And there are many tractable questions that are unanswered, particularly in predicting risk, much of it determined by a complex genetic architecture.12,13 One informal observation is that we tend as group members towards independence and are not always immediately willing to follow the guidance of others. This practical complexity has the potential to constrain community-wide efforts to achieve key goals of improving

AER_Grace_FINAL.indd 105

care while containing costs. We therefore have to put some aspects of our natural tendency to one side and engage closely in gathering data, informing each stage of analysis and facilitating integration so ensuring this is a physician-led enterprise. The substantial underestimates in the lead times to implementation of the findings from recent biomedical innovations, such as gene therapy, genomics and stem cells,14 has influenced recent commentators to offer appropriately reserved opinions regarding the speed of integration into practice of data science.8,15,7 In aggregate they also provide some principles to help physicians work through how they as individuals might best contribute: we need to articulate a clear sense of purpose regarding data gathering and analytics;6 we need to inform our teams this is going to take time and that approaches will evolve; we need to help refine electronic health records, that many of us now use daily, to reinforce the structural underpinnings of data collection (and no, we will not be going back to paper records);16 we should continue to refine our clinical skills as accurate taxonomy is our start point and disease misclassification reduces statistical power and impedes research; we also need to continue to be enthusiastic contributors to clinical trial recruitment, even though the work needed to maintain confidentiality and security with enhanced data de-identification has increased. It is likely that to be effective all of us will need specialist instruction in aspects of data science17 and the integration of training modules into fellowship programs, as has also been argued for in genomics.6,18 More generally, our professional societies have been playing an important part including working internationally. ‘BigData@heart’, the most recent public–private and European Society of Cardiology-backed consortium program, will, over 5 years, have among key objectives further standardising disease definitions and outcomes, providing reliable sub-phenotyping and documenting the burden of disease across time and geographies.19 The editors of the New England Journal of Medicine during its 200th anniversary celebrations articulated a future vision of medicine that employed clinical support algorithms derived entirely from data.11 A major concern among electrophysiologists (and of course, physicians

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Guest Editorial in general) is that such machine learning/structured algorithms will come to dominate and erode individual decision-making and maybe through default undermine relationships with patients.20 The key, as the authors explicitly stated,11 is that the data supports critical clinical choices.13 Physicians will still have to make decisions in close discussion with patients based on limited certainties regarding outcomes.

1. 2. 3.

5. 6.

T he Alan Turing Institute. 2017. Available at: www.turing.ac.uk (accesses 16 August 2017) Spiegelhalter DJ. Statistics. The future lies in uncertainty. Science 2014;345:264–265. doi: 10.1126/science.1251122; PMID: 25035471. Mayhew H, Saleh T, Williams S. Making data analytics work for you. McKinsey Quaterly 2016. Available at: www.mckinsey.com/ business-functions/digital-mckinsey/our-insights/makingdata-analytics-work-for-you-instead-of-the-other-way-around (accessed 16 August 2016). Chetty R, Grusky D, Hell M, Hendren N, Manduca R, Narang J. The fading american dream: Trends in absolute income mobility since 1940. Science 2017;356:398–406. doi: 10.1126/science. aal4617; PMID: 28438988. Broughton PD. Big data hasn’t changed everything. Wall Street Journal 2 July 2013. Kim J. Big data, health informatics, and the future of cardiovascular medicine. J Am Coll Cardiol 2017;69:899–901. doi: 10.1016/j.jacc.2017.01.006; PMID: 28209228. Krumholz HM. The promise of big data: Opportunities and challenges. Circ Cardiovasc Qual Outcomes 2016;9:616–617.

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9. 10. 11.

12.

13.

14.

We are in an era of momentous change in medicine but have no doubt that big data-based evidence will be central to much that we will do, whether that be a translational interpretation of biology or determining financial resource allocation. Arrhythmia and Electrophysiology Review will endeavour to keep our readers at the vanguard of developments. n

doi: 0.1161/CIRCOUTCOMES.116.003366; PMID: 28263935. Groeneveld PW, Rumsfeld JS. Can big data fulfill its promise? Circ Cardiovasc Qual Outcomes 2016;9:679–682. doi: 10.1161/CIRCOUTCOMES.116.003366; PMID: 28263942 Savage N. The measure of a man. Cell. 2017;169:1159–1161. doi: 10.1016/j.cell.2017.05.037; PMID: 28622499. Topol E. The smart-medicine solution to the health-care crisis. Wall Street Journal 7 July 2017. Kohane IS, Drazen JM, Campion EW. A glimpse of the next 100 years in medicine. N Engl J Med 2012;367:2538–2539. doi: 10.1056/NEJMe1213371; PMID: 23268669. Grace AA, Roden DM. Systems biology and cardiac arrhythmias. Lancet 2012;380:1498–1508. doi: 10.1016/S01406736(12)61462-7; PMID: 23101717 Yeh RW, Kramer DB. Decision tools to improve personalized care in cardiovascular disease: Moving the art of medicine toward science. Circulation 2017;135:1097–1100. doi: 10.1161/ CIRCULATIONAHA.116.024247. Joyner MJ, Paneth N, Ioannidis JP. What happens when

15.

16.

17. 18.

19. 20.

underperforming big ideas in research become entrenched? JAMA 2016;316:1355–1356. doi: 10.1001/jama.2016.11076; PMID: 27467098. Groeneveld PW. Moving beyond big data to causal inference and clinical implementation. J Am Coll Cardiol 2017;69:901–902. Rudin RS, Bates DW, MacRae C. Accelerating innovation in health IT. N Engl J Med 2016;375:815–817. doi: 10.1056/ NEJMp1606884; PMID: 27579633. Munevar S. Unlocking big data for better health. Nature Biotechnology 2017;35:684–686. doi:10.1038/nbt.3918. Aday AW, MacRae CA. Genomic medicine in cardiovascular fellowship training. Circulation 2017;136:345–346. DOI: 10.1161/ CIRCULATIONAHA.117.027568 IMI BigData@Heart. 2017. Available at: www.Bigdata-heart.Eu (accessed 16 August 2017). Sniderman AD, D’Agostino RB, Sr., Pencina MJ. The role of physicians in the era of predictive analytics. JAMA 2015;314:25–26. doi: 10.1001/jama.2015.6177; PMID: 26151261.

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Guest Editorial

Letter from the New President of the European Heart Rhythm Association John Camm

Citation: Arrhythmia & Electrophysiology Review 201;6(3):107. DOI: 10.15420/aer.2017.31.GE2 Correspondence: John Camm, Professor of Clinical Cardiology, St George’s, University of London. E: jcamm@sgul.ac.uk

am delighted to greet you as the new President of the European Heart Rhythm Association (EHRA), the premier professional society for cardiac electrophysiologists, cardiac arrhythmia physicians and surgeons, and allied electrophysiology and pacing professionals. I have been elected as the EHRA president this year, succeeding Gerhard Hindricks. The president-elect is Hein Heidbuchel, Cecilia Linde is treasurer and Robert Hatala is the secretary. I have served EHRA as editor-in-chief of Europace and in various other roles for the last decade, and before that I was chairman of what was then the European Society of Cardiology (ESC) Working Group on Cardiac Arrhythmias.

other European networks and organisations. We will all be challenged by the unfortunate Eucomed regulations that will severely limit sponsorship to attend the meetings and congresses organised by professional societies. This will have a detrimental effect on specialty education. These impartial activities cannot be replaced by the training and marketing meetings that might be offered by industry as ‘educational’ substitutes. We must all guard against this threat to our professional development, and support our European Heart Rhythm Association and national specialty groups. United we stand, divided we fall! n

This will be a crucial year for the Association as we seek to work more closely with national specialty groups, ESC working groups and

John Camm, President, European Heart Rhythm Association (EHRA)

A Future Perspective on the Europace Journal: its Star is Rising Gerhard Hindricks

Citation: Arrhythmia & Electrophysiology Review 2017;6(3):107–8. DOI: 10.15420/aer.2017.6.3.GE3 Correspondence: Gerhard Hindricks, Heart Centre, University of Liepzig, Department of Electrophysiology, Strümpellstr. 39, 04289 Leipzig, Germany. E: gerhard.hindricks@leipzig-ep.de

ffective from 1 July 2017, I have the privilege and honour of taking the position of Editor-in-Chief of the Europace journal. Over the past decade, the journal has tremendously developed under the leadership of John Camm as the Editor-in-Chief. The impact factor of the journal has reached an all-time high of 4.5, and the journal has been

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established as a top journal in the field. Indeed, John Camm and his editorial board have taken the right strategic decisions for the journal: a focus on clinical science and education with a direct impact on the practice of arrhythmia diagnosis and treatment. The number of new manuscripts submitted will also reach an all-time high in 2017, with more

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Guest Editorial than 1300 manuscripts expected. In principle, I intend to follow the same successful path. Together with the editorial board, we will concentrate on manuscripts from clinical trials with guideline relevance, continue to publish EHRA and ESC consensus documents and position papers, and the highest-quality, state-of-the-art review articles written by key opinion leaders in the field. In addition, the important fields of e-health and m-health will gain more visibility in the journal. The most important element to be attractive for authors with â€˜hot messagesâ€™ is certainly a solid and fair review process, the speed of manuscript handling and decision-making, and finally, of course, rapid publication. We can and will improve the speed of manuscript handling, and we will supplement this with the option of Europace Fast Track Publication for highly-relevant and important messages. For this segment, we are aiming for a time window of 6 weeks from submission

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to publication. Moreover, we will intensify the online visibility of the journal and provide supplement material, slides, commentaries and podcasts from the major articles published. Our alliance with Arrhythmia Electrophysiology Review is a fruitful and successful one. Arrhythmia Electrophysiology Review supplements the spectrum of publications with high-quality review articles, mainly with important clinical messages, that also reach out to cardiologists and general practitioners with particular interest in arrhythmias. All this has one focus: you! To meet your interests, scientific and educational expectations better, we encourage you to enrich our strategies with your ideas and suggestions that we highly appreciate. n Gerhard Hindricks, Editor-in-Chief, Europace

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Expert opinion

Is There a Future for Remote Cardiac Implantable Electronic Device Management? Haran Burri Cardiology Department, University Hospital of Geneva, Geneva, Switzerland

Abstract In the era of communication technology, remote monitoring has been a paradigm shift in the way patients with cardiac implantable electronic devices are managed. It has been endorsed by scientific societies and is being increasingly adopted in the clinical setting. Despite the various advantages associated with this strategy, data on improved clinical outcome are still sparse. The recently published study on the remote management of heart failure using implanted devices and formalised follow-up procedures, which turned out to be negative, has cast doubt on whether remote monitoring should still be used. This article provides a critical appraisal of the study, and discusses the issue of remote data management.

Keywords Remote monitoring, cardiac implantable electronic devices, implantable cardioverter defibrillator, cardiac resynchronisation therapy Disclosure: Haran Burri has received research grants, speaker fees or institutional fellowship support from Abbott, Biotronik, Boston Scientific, LivaNova, Medtronic and St-Jude Medical. He is one of the co-principal investigators of the MORE-CARE study funded by Medtronic. Received: 4 July 2017 Accepted: 10 August 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(3):109–10. DOI: 1015420/aer.2017:10:1 Correspondence: Haran Burri, MD, Cardiology Department, University Hospital of Geneva, Rue Gabrielle Perret Gentil 4, 1211 Geneva 14, Switzerland. E: haran.burri@hcuge.ch

Remote follow-up and monitoring of patients implanted with cardiac implantable electronic devices (CIEDs) has been introduced over a decade ago, and is now indicated according to European (class IIa indication1) and American (class I indication2) guidelines. There have been high expectations that this technology will improve patient outcome, as it significantly shortens response to actionable events (e.g. AF) compared with standard in-office follow-up.3,4 However, several randomised trials have failed to meet this promise.5,6 The remote management of heart failure using implanted devices and formalised follow-up procedures (REM-HF) study has been published recently.7 This trial, conducted at nine centres in England, randomised 1650 patients implanted with an ICD, cardiac resynchronisation therapy defibrillator or cardiac resynchronisation therapy pacemaker to either remote management with weekly transmissions or to usual care. After a median follow-up of 2.8 years, there were no differences in the primary outcome of mortality or cardiovascular admissions, nor in any of the secondary endpoints (although there was a trend in reduced mortality). This study is remarkable in that it is – as yet – the largest study in this field, with the longest follow-up, few exclusion criteria (e.g. AF was admissible and there was no age limit), and included devices from three major manufacturers. The results were disappointing: there were no differences in the primary endpoint of total mortality or cardiovascular hospitalisation, nor in any of the secondary endpoints. However, there are a number of points that need to be discussed. First, the study was performed in tertiary expert centres where specialised heart failure clinics already manage these complex patients to a high level of quality of care. Therefore, incremental benefit of any intervention is likely to be more difficult to achieve, and results may not be extrapolated to other less specialised settings.

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Second, this was not a study randomising remote device management with standard in-office care, as patients in the control group could be remotely monitored (except to manage heart failure). Third, the active group required weekly transmissions to be actively performed by the patients, with almost 40 % of patients transmitting <75 % of the time at 2 years. This is in contrast to automatic pre-defined alerts, which are the usual form of remote management, and that achieve successful transmissions in >90 % of the time.4,8 Remote monitoring by automatic alerts, using devices not included in REM-HF (Biotronik), has been shown in the TRUECOIN patient-level meta-analysis to reduce mortality compared with standard care.9 Last, but not least, the patients in the remote management group generated 79,325 transmissions. This means that each centre received on average 10–15 transmissions/day to process (this number was certainly higher towards the end of patient enrolment). Only 226 (0.3 %) transmissions resulted in medication change by the monitor and only 910 (1.1 %) resulted in the patient being advised to seek medical attention. Therefore, very few actions resulted from transmissions in the remote management group. In any process aiming to improve patient outcome, three fundamental factors are implicated: 1) availability of good data, 2) proper interpretation of these data and 3) generation of meaningful action. In the case of REM-HF, there was most probably data overload, with parameters that are sometimes difficult to interpret individually (e.g. transthoracic impedance, heart rate variability etc.). This is probably one of the reasons why so little action was taken. For the reasons detailed above, it is not surprising that the study was negative. The key to improving outcome with remote CIED management lies most probably in data management. Triage of alerts into

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Expert Opinion risk categories enables healthcare personnel to focus attention on those patients who are most likely to require medical intervention, thereby avoiding clinical deterioration. Cowie (who is also the last author of REM-HF) and collaborators devised the Medtronic “Heart Failure Risk Status” score based on an automatic algorithm that combines data extracted from remote monitoring transmissions (on intrathoracic impedance, nocturnal heart rate, heart rate variability, daily activity and arrhythmic events), to stratify patients into high, medium and low risk.10 Patients with a high risk score had a significant six-fold increased likelihood of being admitted for heart failure in the following month compared with those with a low risk score. These findings were later confirmed in independent cohorts from the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT)11 and Monitoring Resynchronization Devices And Cardiac Patients (MORE-CARE) trials.12 Of note, the proportion of high-risk alerts was 10 % in all three reports, underlining the potential not only for improving data interpretation using integrated diagnostics, but also for facilitating data triage. Other devices companies are also working on risk stratification tools. In the Multisensor Chronic Evaluation In Ambulatory Heart Failure Patients (MultiSENSE) study, an algorithm by Boston Scientific combining different parameters (heart sounds, respiration, thoracic impedance, heart rate, and activity) showed promising results for predicting heart failure

rignole M, Auricchio A, Baron-Esquivias G, et al. B 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace 2013;15:1070–118. DOI: 10.1093/europace/eut206; PMID: 23801827. Slotwiner D, Varma N, Akar JG, et al. HRS Expert Consensus Statement on remote interrogation and monitoring for cardiovascular implantable electronic devices. Heart Rhythm 2015;12:e69–100. DOI: 10.1016/j.hrthm.2015.05.008; PMID: 25981148. 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 Mar 8;57(10):1181-9. doi: 10.1016/j.jacc.2010.12.012 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. DOI: 10.2196/jmir.2608; PMID: 23965236. Parthiban N, Esterman A, Mahajan R, Twomey DJ, Pathak RK, Lau DH, et al. Remote monitoring of implantable cardioverterdefibrillators: A systematic review and meta-analysis of clinical outcomes. J Am Coll Cardiol 2015;65:2591–600. DOI: 10.1016/j.jacc.2015.04.029; PMID: 25983009. Boriani G, Da Costa A, Quesada A, et al. Effects of remote monitoring on clinical outcomes and use of healthcare resources in heart failure patients with biventricular defibrillators: results of the MORE-CARE multicentre randomized controlled trial. Eur J Heart Fail 2017;19:416–25. DOI: 10.1002/ejhf.626; PMID: 27568392. Morgan JM, Kitt S, Gill J, et al. Remote management of heart failure using implantable electronic devices. Eur Heart J 2017; DOI: 10.1093/eurheartj/ehx227; PMID: 28575235; epub ahead of press.

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10.

11.

12.

13.

14.

events.13 Algorithms from other companies using fewer parameters such as transthoracic impedance only14 or minute ventilation combined with daily activity15 were less predictive, and response to data that are non-specific may even result in inappropriate treatment that is harmful.16 It nevertheless remains to be proven by randomised trials that the use of risk-stratification algorithms leads to improved patient outcome. Beyond improvement in patient outcome, remote CIED management is a matter of convenience, both for patients as well as for caregivers.17 It allows improved adherence to follow-up,18 reduces healthcare utilisation8,19 and is invaluable for monitoring device function. 20 Furthermore, it allows generation of large amounts of data for scientific research21 and quality control (e.g. lead survival and device longevity for manufacturer product performance reports). In conclusion, the results of REM-HF merely show that remote CIED management should not be performed by weekly manual transmissions, which are cumbersome for the patient and lead to data overflow for device clinics, without any improvement in patient outcome. Modern-day technology allows more streamlined solutions, which continue to evolve. Without any doubt, remote CIED patient management is not only here to stay, but will continue to grow. n

arma N, Epstein AE, Irimpen A, et al; TRUST Investigators. V Efficacy and safety of automatic remote monitoring for implantable cardioverter-defibrillator follow-up: the Lumos-T Safely Reduces Routine Office Device Follow-up (TRUST) trial. Circulation 2010;122:325–32. DOI: 10.1161/ CIRCULATIONAHA.110.937409; PMID: 20625110. Hindricks G, Varma N, Kacet S, et al. Daily remote monitoring of implantable cardioverter-defibrillators: insights from the pooled patient-level data from three randomized controlled trials (IN-TIME, ECOST, TRUST). Eur Heart J 2017;38:1749–55. DOI: 10.1093/eurheartj/ehx015. Cowie MR, Sarkar S, Koehler J, et al. Development and validation of an integrated diagnostic algorithm derived from parameters monitored in implantable devices for identifying patients at risk for heart failure hospitalization in an ambulatory setting. Eur Heart J 2013;34:2472–80. DOI: 10.1093/eurheartj/eht083; PMID: 23513212. Gula LJ, Wells GA, Yee R, et al. A novel algorithm to assess risk of heart failure exacerbation using ICD diagnostics: validation from RAFT. Heart Rhythm 2014;11:1626–31. DOI: 10.1016/j.hrthm.2014.05.015; PMID: 24846373. Burri H, Da Costa A, Quesada A, et al. Risk stratification of heart failure and cardiovascular hospitalizations using integrated device diagnostics in patients with a cardiac resynchronization therapy defibrillator. Europace 2017; DOI: 10.1093/europace/eux206; PMID: 28679168; epub ahead of press. Boehmer JP, Hariharan R, Devecchi FG, et al. A multisensor algorithm predicts heart failure events in patients with implanted devices: Results from the MultiSENSE study. JACC Heart Fail 2017;5:216–25. DOI: 10.1016/j.jchf.2016.12.011; PMID: 28254128. Heist EK, Herre JM, Binkley PF, et al. Analysis of different devicebased intrathoracic impedance vectors for detection of heart failure events (from the Detect Fluid Early from Intrathoracic Impedance Monitoring study). Am J Cardiol 2014;114:1249–56. DOI: 10.1016/j.amjcard.2014.07.048; PMID: 25150135.

15. A uricchio A, Gold MR, Brugada J, et al. Long-term effectiveness of the combined minute ventilation and patient activity sensors as predictor of heart failure events in patients treated with cardiac resynchronization therapy: Results of the Clinical Evaluation of the Physiological Diagnosis Function in the PARADYM CRT device Trial (CLEPSYDRA) study. Eur J Heart Fail 2014;16:663–70. DOI: 10.1002/ejhf.79; PMID: 24639140. 16. Hindricks G, Varma N. Remote monitoring and heart failure: monitoring parameters, technology, and workflow. Eur Heart J 2016;37:3164–6. DOI: 10.1093/eurheartj/ehw201; PMID: 27381588. 17. Burri H, Heidbüchel H, Jung W, Brugada P. Remote monitoring: a cost or an investment? Europace 2011;13:Suppl 2:ii44-ii48. DOI: 10.1093/europace/eur082; PMID: 21518749. 18. Varma N, Michalski J, Stambler B, Pavri BB; TRUST Investigators. Superiority of automatic remote monitoring compared with in-person evaluation for scheduled ICD follow-up in the TRUST trial - testing execution of the recommendations. Eur Heart J 2014;35:1345–52. DOI: 10.1093/ eurheartj/ehu066; PMID: 24595864. 19. Heidbuchel H, Hindricks G, Broadhurst P, et al. EuroEco (European Health Economic Trial on Home Monitoring in ICD Patients): a provider perspective in five European countries on costs and net financial impact of follow-up with or without remote monitoring. Eur Heart J 2014;36:158–69. DOI: 10.1093/ eurheartj/ehu339; PMID: 25179766. 20. Varma N, Michalski J, Epstein AE, Schweikert R. Automatic remote monitoring of implantable cardioverter-defibrillator lead and generator performance: the Lumos-T Safely RedUceS RouTine Office Device Follow-Up (TRUST) trial. Circ Arrhythm Electrophysiol 2010;3:428–36. DOI: 10.1161/ CIRCEP.110.951962; PMID: 20716717. 21. Cheng A, Landman SR, Stadler RW. Reasons for loss of cardiac resynchronization therapy pacing: insights from 32 844 patients. Circ Arrhythm Electrophysiol 2012;5:884–8. DOI: 10.1161/ CIRCEP.112.973776; PMID: 22923341.

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Expert Opinion

Abstract The implantation rate of cardiac electronic devices has grown over the past decades. The number of treated patients has increased in parallel with the complexity of the patient population treated, being older, frailer, having more complex devices (in particular, cardiac resynchronisation therapy) and presenting with a greater comorbidity burden. As a consequence, there is a rising number of related implanted system complications, including malfunction and infection. Thus, the demand for transvenous lead extraction (TLE) has also substantially increased. To identify the indication to TLE by various operators and centres, techniques used to perform TLE, and the safety and efficacy of the current clinical practice of TLE, a large prospective registry has been started in Europe – the European Lead Extraction Controlled (ELECTRa) Registry. The key findings of the ELECTRa Registry are discussed in the present review and placed in the context of previous knowledge. The ELECTRa Registry confirms that the TLE procedure is a safe and effective treatment, with an acceptable risk–benefit ratio that is comparable with other well-known cardiological invasive procedures. Of course, TLE is accompanied by potential life-threatening complications; the vast majority of these can be managed by an experienced multidisciplinary team. Multiple factors predict complications, including patient/lead profile, centre experience and procedure volumes, which may suggest caution when accepting a patient for TLE.

Keywords Transvenous lead extraction, cardiac implantable electronic devices, infection, implantable cardioverter-defibrillator, cardiac pacemaker, cardiac resynchronisation therapy Disclosure: The authors have no conflicts of interest to declare. Received: 13 July 2017 Accepted: 22 July 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(3):111–3. DOI: 10.15420/aer.2017.25.1 Correspondence: Angelo Auricchio, MD PhD, Cardiac Electrophysiology Unit, Division of Cardiology, Fondazione Cardiocentro Ticino, Via Tesserete 48, 6900 Lugano, Switzerland. E: angelo.auricchio@cardiocentro.org

The number of cardiovascular implantable electronic devices (CIEDs) has increased progressively during the past decades, with a parallel increase in the demand for transvenous lead extraction (TLE). Indication and class of recommendation for TLE have been extensively discussed in a recent expert consensus document.1 With the exception of a few prospectively conducted registries,2,3 the vast majority of evidence about the procedural success and complications of TLE has been derived by retrospective analyses of databases, mostly conducted in the USA (Table 1). Few centres in Europe have reported on lead extraction, and objective data are lacking. Furthermore, the majority of past TLE registries have included relatively young patients with few comorbidities. This runs in contrast to the clinical characteristics of patients currently referred for TLE. Improved pharmacological therapy for heart failure and more extensive use of cardiac resynchronisation therapy have resulted in a significant prolongation of patient survival. However, patients with CIEDs are now significantly more frail, present with a greater comorbidity burden and are treated with more complex devices than those implanted two decades ago. The present review discusses the key findings of the European Lead Extraction ConTRolled (ELECTRa) Registry and places them in the context of previous knowledge.

As a consequence, in November 2012, a large multicentre prospective registry of consecutive TLE procedures was initiated by EHRA. This ELECTRa Registry aimed to identify the indication to TLE by various operators and centres, techniques used to perform TLE, and the safety and efficacy of the current clinical practice of TLE in Europe. The results of the registry have been recently published in the European Heart Journal,5 and further discussed at the most recent annual EHRA scientific meeting in Vienna in June 2017. This registry represents a milestone in the knowledge development of modern TLE. Furthermore, the management of the registry by scientific organisations (EHRA and the EURObservational Research Programme by the European Society of Cardiology) is an outstanding model for conducting industryindependent registries and studies.

Following publication of the results of a European survey conducted by the European Heart Rhythm Association (EHRA) in 2012,4 the significant underdevelopment of TLE across European countries became clear.

The first important observation of the ELECTRa Registry was that infections were slightly more frequent than non-infective indications for TLE, the former accounting for approximately 53 % of cases. As

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The ELECTRa Registry included 73 centres from 19 European countries who enrolled 3555 consecutive patients, of whom 3510 underwent TLE. The primary objective was to evaluate the acute and long-term safety of TLE. Secondary objectives were to describe the characteristics of patients, leads, indications, techniques and outcomes. The complication rates in low- and high-volume (30 or more TLE per year) centres were compared.

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Expert Opinion Table 1: Overview of Large Prospective and Retrospective Registries for Transvenous Lead Extraction Conducted Over the Last Two Decades

Year of

No. of

Study

Complete Rx

Partial Rx

Failure

Publication

patients

centres

design

success rate (%)

rate (%)

Major complication

rate (%)

US Database

1994

1,299

Retrospective

86.8

7.5

5.7

2.5

US Database

1996

2,338

Prospective

93.0

5.0

2.3

1.4

Laser US total experience

1999

1,684

Retrospective

90.0

3.0

7.0

1.9

LExICon study

2010

1,449

Retrospective

96.5

2.3

1.1

1.4

LEADER 2012

2012

2,021

Prospective

93.3

4.2

2.5

1.4

ELECTRa Registry 2017 3,335 73 Prospective Overall 95.7 2.8 1.5

1.6

High volume

96.2

2.6

1.3

1.5

Low volume

93.4

4.0

2.6

2.3

Definition of complete, partial and failure rate may differ slightly among studies. In the ELECTRa Registry, radiological failure (considered for each lead) was defined when more than 4 cm length of a lead was abandoned after a removal attempt, partial success when less than 4 cm of a lead remained in the patient’s body, and complete success when the lead was completely removed. ELECTRa = European Lead Extraction Controlled.

recently discussed by Tarakji and colleagues in a review article on patients at risk of infection,6 CIED infection imposes a substantial financial burden resulting from prolonged hospitalisation, long duration of antibiotic therapy, device explanation and eventually re-implantation. Moreover, in the ELECTRa Registry, patients with systemic infection had a near five-fold increase in all-cause mortality compared with the other patient categories. Preliminary analysis of the ELECTRa Registry showed that the 1-year mortality rate was 15.1 % in patients with systemic infection, 6.9 % in patients with a more local infection and 3.0 % in patients without infection. These data confirm the extremely poor prognosis of infected CIED patients, and call for action. Although the ELECTRa Registry has not reported data regarding time delays between diagnosis of infection and TLE, it could be hypothesised that the higher mortality rate observed among patients with CIED infection may result at least in part from a significant delay to definitive treatment. Mortality rates in these situations may be modifiable, with early recognition and prompt treatment. The first presentation of patients with CIED infection is frequently detected by non-electrophysiologists, who usually start treatment with local or oral antibiotics. Thus, the education of emergency department physicians, primary care providers, infection disease specialists and general cardiologists regarding the diagnosis of CIED infection and the need for urgent complete removal of all hardware may reduce the associated mortality risk. The findings of the ELECTRa Registry demonstrate that despite successful TLE, mortality remains high for CIED infection. Although this may include both local and systemic infection, it is certainly higher for systemic infection. Moreover, patients with infected CIED frequently have more severe long-standing comorbidities than other patients undergoing TLE. This highlights the need to reduce the incidence of CIED-related infections, especially in certain patient populations, e.g. renal dialysis patients. Thus, one of the key lessons of the ELECTRa Registry may be that patients with device and lead infections require immediate attention and referral to a centre dealing with TLE. The complete clinical and radiological success rates of TLE were extremely high, approximating 97 and 96 %, respectively (Table 1). This may be a reassuring observation for general practitioners and cardiologists. It is well known that not all indicated patients with CIED-related infection are being referred for lead extraction. A major hurdle explaining this issue is founded on the assumption that TLE is a dangerous

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procedure, which is contradicted by the findings of the ELECTRa Registry. Indeed, the procedure-related major complication rate (including death) was 1.7 %, with procedure-related death as low as 0.5 %. TLE compares favourably with similar invasive electrophysiological and non-electrophysiological procedures such as catheter ablation, percutaneous coronary intervention and transcatheter aortic valve implantation from a complication risk perspective. The radiological and clinical success of TLE was higher in high-volume centres than in low-volume centres (Table 1). Moreover, low-volume centres more frequently removed leads with traction alone than did high-volume centres. This point substantiates the need for more adequate training in TLE with sheaths (mechanical, powered or laser) for those operators acting in low-volume centres, which may ultimately lead to an increased removal success rate. As indicated above, the rate of in-hospital procedure-related major complications (the primary endpoint) was 1.7 %, including a mortality rate of 0.5 %, with no significant difference between high- and low-volume centres. However, overall in-hospital major complications were lower in the high-volume centres than in the low-volume centres (2.4 versus 4.1 %). The low-volume centres also showed a double risk of clinical failure of the procedure and of death from all causes during hospital stay. This observation is probably one of the most important key lessons of the ELECTRa Registry. Although the scope of the registry and the data collection did not allow determination of the minimum number of TLE procedures needed to reduce the complication rate or to increase the survival rate, it may be inferred from the ELECTRa Registry data that the performance of 40–50 TLE procedures per year is sufficient to significantly reduce the likelihood of major events occurring. The ELECTRa Registry data not only help to identify those factors associated with clinical failure but also, more importantly, with procedure-related major complications. Female gender (OR 2.11), lead dwelling time of more than 10 years (OR 3.54), the use of powered sheaths alone and the femoral approach were all factors associated with higher complication and death rates. A possible explanation for the gender-associated difference in outcome may reside in the fact that women have smaller and more fragile vessels that are more vulnerable to damage. Furthermore, when leads are in situ for a long time, the

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ELECTRa Registry risk of fibrosis increases, the adhesions become tenacious, the lead is exposed to longer physical and mechanical deterioration that may lead to iatrogenic fracture, and the operator needs to use technologies that require skill and experience to detach adhesions from the vessel wall, thus increasing the risk of laceration and perforation. Therefore, when a low-volume centre encounters a patient presenting with these clinical characteristics, it may be important to consider referring the patient to a high-volume centre. Another important lesson from the ELECTRa Registry is that in the event of major cardiac complications occurring during or immediately after TLE, patients are often saved if complications are quickly recognised and treated. Although bridge balloons are available and are successfully used clinically, the ELECTRa experience emphasises the need to also have expert surgical back-up available in case of complications. Furthermore, it shows that the outcome of TLE is not solely dependent

ilkoff BL, Love CJ, Byrd CL, et al. Transvenous lead W extraction: Heart Rhythm Society expert consensus on facilities, training, indications, and patient management: this document was endorsed by the American Heart Association (AHA). Heart Rhythm 2009;6:1085–104. DOI: 10.1016/j.hrthm.2009.05.020; PMID: 19560098 Wazni O, Epstein LM, Carrillo RG, et al. Lead extraction in the contemporary setting: the LExICon study. J Am Coll Cardiol 2010;55(6):579–86. DOI: 10.1016/j.jacc.2009.08.070; PMID: 20152562

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on the procedure per se. It is also dependent on multiple patient factors and comorbidities that require advanced and highly skilled multidisciplinary team management, including an electrophysiologist, cardiac imaging specialist, microbiologist and surgeon. Such expertise, which allows for coordinated patient management, may be facilitated in high-volume centers. In conclusion, the ELECTRa Registry findings confirm the previously described observations that the TLE procedure is a safe and effective treatment. It has an acceptable risk–benefit ratio and is comparable with other well-known cardiological invasive procedures. Of course, TLE is accompanied by potential life-threatening complications, the majority of which are manageable by an experienced multidisciplinary team. Multiple factors predict complications, including patient/lead profile, centre experience and procedure volumes, which may suggest caution when accepting a patient for TLE. n

aytin M, Wilkoff BL, Brunner M, et al. Multicenter experience M with extraction of the Riata/Riata ST ICD lead. Heart Rhythm 2014;11:1613–8. DOI: 10.1016/j.hrthm.2014.05.014; PMID: 24854215 Bongiorni MG, Blomström-Lundqvist C, Kennergren C, et al. Scientific Initiative Committee, European Heart Rhythm Association. Current practice in transvenous lead extraction: a European Heart Rhythm Association EP Network survey. Europace 2012;14:783–6. DOI: 10.1093/europace/eus166; PMID: 22622992

ongiorni MG, Kennergren C, Butter C, et al. The European B Lead Extraction ConTRolled (ELECTRa) study: a European Heart Rhythm Association (EHRA) registry of transvenous lead extraction outcomes. Eur Heart J 2017. DOI: 10.1093/ eurheartj/ehx080; PMID: 28369414; epub ahead of press. Tarakji KG, Ellis CR, Defaye P, Kennergren C. Cardiac implantable electronic device infection in patients at risk. Arrhythm Electrophysiol Rev 2016;5:65–71. DOI: 10.15420/ aer.2015.27.2; PMID: 27403296

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Clinical Arrhythmias

Cardiac Effects of Lightning Strikes Theodoros Christophides, 1 Sarosh Khan, 2 Mahmood Ahmad, 3 Hossam Fayed 3 and Richard Bogle 2 1. Barts Heart Centre, St Bartholomew’s Hospital, Barts Health NHS Trust, London; 2. Epsom & St Helier University Hospitals NHS Trust, Carshalton, Surrey; 3. Royal Free Hospital, Royal Free London NHS Foundation Trust, London, United Kingdom

Abstract Lightning strikes are a common and leading cause of morbidity and mortality. Multiple organ systems can be involved, though the effects of the electrical current on the cardiovascular system are one of the main modes leading to cardiorespiratory arrest in these patients. Cardiac effects of lightning strikes can be transient or persistent, and include benign or life-threatening arrhythmias, inappropriate therapies from cardiac implantable electronic devices, cardiac ischaemia, myocardial contusion, pericardial disease, aortic injury, as well as cardiomyopathy with associated ventricular failure. Prolonged resuscitation can lead to favourable outcomes especially in young and previously healthy victims.

Keywords Lightning strike, myocardial injury, arrhythmia, cardiac implantable electronic devices, cardiopulmonary arrest Disclosure: The authors have no conflicts of interest to declare. Received: 10 March 2017 Accepted: 16 June 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(3):114–7. DOI: 10.15420/aer.2017:7:3 Correspondence: Dr Theodoros Christophides, Barts Heart Centre, St Bartholomew’s Hospital, Barts Health NHS Trust, West Smithfield, London, EC1A 7BE, UK; E: tchristophides@doctors.org.uk

Lightning strikes between clouds and ground objects occur when the difference in electrical potential between the two is greater than 30,000 Volts, as thus they are able to exceed the atmospheric electrical resistance, generating currents that vary from 30,000 to 100,000 Amperes, and lasting between 0.1–0.001 seconds. As per data from the Lightning Imaging Sensor (LIS)-equipped satellite developed by the National Aerospace Agency (NASA), globally it is estimated that 44 flashes occur per second, with 1.4 billion flashes occurring in a year.1,2 Thunderstorms with associated lightning occur in all parts of the UK throughout the year, with the highest incidence in the southeastern part of England between May and August.3,4 According to the Tornado and Storm Research Organisation (TORRO), in a typical year between 200,000 and 300,000 lightning counts take place, and of these approximately one in four will provide a cloud-to-ground electrical discharge. Twenty-four thousand people are thought to die from lightning-related injuries every year around the world.5 The yearly worldwide death rates from lightning range from 0.2 to 1.7 per million population.6 In the UK between 1988 and 2012, the TORRO database has recorded 445 incidents involving 722 people, with an annual average of two fatalities and 30 injured victims per year, and hospital coding records show that 63 patients were treated in an in-patient or out-patient setting due to lighting-related pathologies.7 In one third of the recorded incidents, more than one person was involved. Half of the recorded incidents occurred indoors and these were non-fatal, though the majority of people suffered a strike when they were involved in outdoor activities.7 The electrical current may reach the body in several ways, both directly and indirectly and this has been well reviewed by Elsom and Webb.7 In a direct strike which commonly involves the upper extremities,

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the current passes over the surface of the body, without most of it penetrating the victim (‘external flashover’). Depending on the amount and duration of current penetration, injuries may vary from simple erythema to serious multi-organ injury and cardio-pulmonary arrest. Indirect mechanisms of injury involve the victim making contact with an electrified object or the ground, which act as conductors for a nearby lightning strike, and these mechanisms are mainly responsible for indoor injuries. Apart from the direct effects of electricity, victims may also suffer injuries from blunt trauma due to explosive air expansion and pressure waves, get caught in nearby fires, or wounded by falling objects or projectiles.7 Almost every organ system can be involved in lightning strikes, and prognosis depends on systemic effects. There are similarities with domestic and industrial electric shock accidents and reported pathology includes skin changes (including the characteristic fern-like or Lichtenberg figure erythema), localised and deep burns, severe muscle contractions with paralysis and necrosis, central and peripheral nervous system injuries, secondary multi-organ failure as well as cardiovascular effects. The latter are the focus of this review (Figure 1) as they are very common and one of the main modes leading to death in these victims.8–10 The physical injuries may resolve completely or may be associated with long-term effects, including psychological sequelae for the survivors.11

Cardiac Effects of Lightning Injury Arrhythmias The huge rise in voltage accompanying lightning strikes can result in a massive direct current shock, which in turn is capable of depolarising the entire myocardium.9,12 Furthermore, increased autonomic stimulation as a result of the shock received, with an associated catecholaminergic surge have additive effects on the heart rate and rhythm.13,14

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Cardiac Effects of Lightning Strikes It has been thought initially that electrically-induced asystole was the commonest presenting rhythm; hence by proceeding and resuscitating these victims, there was a good chance of a successful outcome.15–17 However, subsequent research has shown that ventricular arrhythmias, including ventricular tachycardia (VT) and fibrillation (VF), are much more common than initially thought.16,18 In a large case series by Wetli and colleagues, ventricular arrhythmias have been reported by paramedics arriving on site, as the first recorded rhythm in at least 50 % of the victims whose electrocardiographic (ECG) data were available.18 Specifically, out of 20 victims VF was recorded in 10 patients, idioventricular rhythm in one, pulseless electrical activity (PEA) in one and asystole in eight patients.18 It is also important to note that asystole may be perpetuated, or be secondary to medullary dysfunction.19 Less sinister arrhythmias such as atrial fibrillation have also been reported, which can readily cardiovert to sinus rhythm in the ensuing days, especially with beta-blocker therapy.20–22 Other important ECG changes which have not been linked with any arrhythmias include QT prolongation, likely due to repolarisation abnormalities. Several mechanisms can be attributed to this, including alterations in intracellular calcium metabolism.23 McIntyre and colleagues reported QTc prolongation to 500 ms in a lighting victim which developed 2 days after the index event, whereas in a patient reported by Palmer et al., the QTc prolonged to 680 ms, and normalised after 1 month, hence the potential need for initial and long-term ECG follow-up of these patients.23,24 Finally, with regards to management of these patients in the immediate setting, even though asystole or PEA are traditionally associated with worse prognosis, as the majority of the victims of lightning strikes tend to be young with no underlying comorbidities, prolonged resuscitation can lead to successful outcomes. 25,26

Cardiac Implantable Electronic Devices Though the passage of electric current typically does not damage or reprogram the cardiac implantable electronic devices (CIEDs), device therapy can be inadvertently affected if the degree of electromagnetic interference (EMI) is significant enough to overcome the electric insulation. Metallic objects of different sizes carried by victims, such as bra fasteners and safety pins have been reported to acquire magnetic properties in lightning victims.18 Furthermore, transient intense magnetic fields have also been documented to develop in the surrounding environment of a lightning strike.27 The above raise the theoretical risk of proxy sources for EMI if found close to the device pocket. There have been several case reports for electrocution victims in whom their CIED delivered an appropriate therapy. Ginwalla et al. described the case of an electrocuted patient saved by their Implantable Cardioverter Defibrillator (ICD), which was able to pace asynchronous when needed with initiation of their noise reversion mode, and defibrillate successfully a ventricular arrhythmia following resolution of the surrounding EMI.28 Similarly, electrocution victims have also been successfully defibrillated by their ICD, as reported by Perret and Lappegård. 29,30 Nonetheless, EMI from electrical equipment, commonly due to current leakage, while usually not enough to result in electrocution, is well known to result in inappropriate device therapies.31–33

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Figure 1: Summary of the Cardiac Effects of Lightning Strikes

Cardiac Effects

Aortic injury and dissection

Cardiac contusion and pericardial disease

Myocardial ischaemia and infarction

Vasospasm / Vascular injury

Atrial / Ventricular Arrhythmias and Asystole (including inappropriate CIED therapies)

Ventricular failure and myocardial stunning (including Takotsubo Syndrome)

Catecholamine Surge

CIED = cardiac implantable electronic device.

However, the literature is scarce with regards to the effects of lightning strike and CIEDs. Only a couple of case reports exist with both appropriate and inappropriate shocks documented. Anderson and colleagues reported an inappropriate ICD shock in a patient who was in a shower house that was hit by a lightning. Subsequent device interrogation has shown multiple episodes of interference after the lightning strike, which briefly rose significantly in amplitude for the device to erroneously detect this as VF and deliver an inappropriate shock.34 Interestingly, the original shock received by the patient during the strike was also detected by the device. In contrast, Kondur and colleagues reported on the case of a 75-year-old patient who was successfully defibrillated by his ICD, following electrocution by a lightning strike.35 There is no sufficient data that look at the long term impact of lightning on the hardware such as the leads and their connection points. Though metallic objects carried by patients such as coins and zip fasteners have been found to be fused and morphologically altered, there are no reports of any internal destruction of CIED components.18

Myocardial Infarction ECG changes suggestive of myocardial ischaemia have been widely reported in the literature for some time.16,36,37 These include ST segment elevation and depression, as well as widespread T wave inversions. Furthermore, there is scarce evidence that there may be a correlation of localising ischaemic ECG changes with myocardial injury on autopsy specimens.13,38 Tachyarrhythmias described above may also have a secondary adverse effect by starving the myocardium of oxygen. Nonetheless some controversy still exists as to whether these can correlate fully with underlying pathological evidence of myocardial necrosis due to coronary-mediated ischaemia. Cardiac enzymes have been reported either as being elevated or within normal limits in patients who had ECG changes suggestive of cardiac ischaemia.24,39 This is not surprising as several mechanisms may have an impact on the levels of biochemical markers apart from coronary ischaemia, including cardiac contusion (which is reviewed below), tachyarrhythmias, acute kidney injury, leakage from skeletal muscle as well as the resuscitation process itself.

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Clinical Arrhythmias On a macroscopic level, coronary vasospasm as well as thrombotic occlusions have been proposed as the underlying mechanisms leading to a reduction in coronary blood flow.24 Transient coronary vasospasm may explain to an important extent why in patients with ST segment changes, their immediate coronary angiography results show patent vessels with no signs of stenosis – a finding also seen in electrocution victims.40–44 Looking closely at these cases, in several patients the ST segment changes followed defibrillation for malignant arrhythmias, which raises the prospect that these may also represent persistent repolarisation changes due to cellular injury, which may spontaneously resolve if left enough time. Furthermore, these changes are seen in previously healthy children struck by lightning, making the prospect of coronary lesions unlikely.41 Microscopically, in several cases myocardial infarction has been established in histological cardiac examinations of the victims, with features of possible thrombotic infarction such as endothelial damage and coagulation necrosis.13,38,40

aetiologies including arrhythmias, cardiac ischaemia and myocardial necrosis. These mechanisms, and specifically catecholamine-mediated cardiotoxicity or ischaemia due to coronary vasospasm associated with lighting strikes, may also explain the finding of Takotsubo Syndrome with apical ballooning, included in several case reports of both young and older victims.45 In 2005, Hayashi and colleagues reported the first case of a 62-year-old mountaineer, who was struck by lightning and her echocardiography was suggestive of a takotsubo-like pattern of left ventricular hypokinesis. This resolved after 48 hours.46 Though transient, this condition should not be underestimated as Dundon et al. described the case of a younger female who developed more significant complications with cardiogenic shock following lightning-induced takotsubo cardiomyopathy.47 In the latter case, the patient’s cardiac function returned to normal after 6 weeks. Interestingly, in both of these cases the victims were female, which correlates with the overall gender bias of this condition, as nine out of 10 patients tend to be female.45

Further studies are required to better correlate myocardial ischaemia as a direct effect of persistent coronary occlusion in these victims and thus identify those who would benefit from immediate coronary interventions after resuscitation.

Though not commenting on the pattern of left ventricular dysfunction, Rivera and colleagues described a similar case of rapid deterioration of a 42-year-old, female lightning victim, who developed cardiogenic shock requiring inotropic support, attributed to myocardial stunning. Similar to the cases above, her condition improved, and 9 days after the index event, she made a complete recovery with full restoration of her cardiac function.48 Levosimendan, a calcium sensitiser, was used as the inotropic agent, and given the patient’s response, the authors pondered whether disturbances in calcium metabolism as well as reduced calcium sensitivity of myofilaments may play a key role in this situation.48 No inotropic support was required in the patients reported

Myocardial Contusion, Pericardial Disease and Aortic Injury Cardiac contusion is an important mode of mortality and morbidity in children and adult victims. Even though this can lead to instant death, victims have also been reported to succumb to this type of injury days after the index event.18 In autopsy studies, haemorrhagic spots have been identified in areas not associated with large coronary vessels, as well as tracking along large unobstructed tributaries to the coronary tree. These areas can span the whole of the myocardium wall, from subendocardial to epicardial regions and there is often an associated myocardial tearing and haemopericadium with tamponade.18 The mechanisms of injury can either be related to the direct effect of current passage or secondary effects due to explosive environmental effects and blunt trauma. Depending on the extent of myocardial damage and degree of cardiac stunning, patients may develop cardiogenic shock which can be reversed with supportive measures.24 Elevations in cardiac enzymes including troponin and creatine kinase have been reported; however, the prognostic significance has yet to be determined.40 Cardiac contusion should thus be suspected in all victims who present with cardiovascular compromise and have features of impaired contractility and relaxation on their cardiac imaging. Close cardiovascular monitoring can also detect early on pericardial collections which apart from contusion, may also accompany pericarditis which may be the result of myocardial inflammation and necrosis. Pericardial effusions have been reported to develop and persist in the first 2 weeks, and in rare cases pericarditis can reoccur for several months after the event.40 Finally, reference should be made to aortic trauma, as separation of the medial and intimal layers or medial defects, ultimately leading to fatal dissections, has also been well described.18 The mechanisms of these are likely to be similar to the ones causing cardiac contusion and the two pathologies can potentially co-exist.

Ventricular Failure and Myocardial Stunning As described in the previous section, patients may develop cardiovascular compromise and ventricular failure due to a host of

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by Dundon and Hayashi above.46,47

Protective Measures for Exposed Individuals During Lightning Storms Lightning strikes can have devastating effects, with significant cardiac and non-cardiac complications. Over the last three decades, there has been a reduction in the case fatality rate.7,49,50 This can be attributed to several reasons including better public education and safety regulations for outdoor and indoor activities, lightning protection measures in buildings and other structures, as well as medical pathways and protocols to promptly tend to and manage victims effectively.7 Nonetheless, despite ease of access to more accurate weather forecasting and thunderstorm warning systems, people may still get caught in adverse weather. Key precautionary measures to limit the risk of potential injury during a lightning strike are summarised below.

Outdoor Exposure Any person who is caught in a thunderstorm while engaging in outdoor activity in an exposed terrain such as a hill or the seaside, should promptly seek an appropriate shelter. Promptly exit and avoid any body of water where the body will act as a peak or ‘beacon’ for a potential strike. Seek a well-grounded, enclosed building, or if this is not available an enclosed metal-topped vehicle (which will dissipate the electric current around the victim and directly to the ground).7 Hiding under trees can be a lethal decision as electric current from a potential tree strike can conduct to the victim from the trunk, or significantly injure the person from explosive decompression of vaporized sap.51 Furthermore, following a strike, it is important to avoid touching objects or building structures which are insulated from the ground, as they may retain electrical charge for some time.7 However, this does not apply to the body of a victim, and if cardiopulmonary resuscitation is required, including defibrillation, this should be initiated promptly.

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Cardiac Effects of Lightning Strikes Carrying or wearing small metallic objects such as keys or necklaces will not make a person more prone to be struck, but these can cause substantial localized burns or conduct an electrical current to deeper body structures, such as in the case of earphones or mobile phones and inner skull injuries.7

has been a substantial decrease over the last 30 years in the number of indoor fatalities compared to previous decades, which can be attributed to a combination of better lightning protection systems and effective grounding, as well as enclosing exposed wiring and plumbing in walls. 7,49,50

Indoor Exposure

Conclusions

Apart from the rare risk of lightning entering the building through an opening such as a door or window, most indoor victims receive an electrical charge through indirect means involving electrical wiring or plumbing which conduct electricity from a nearby strike. Common culprits to be avoided are corded phones, computers which are plugged to the electrical mains and radiators.50,51

Cardiac effects of lightning strikes are an important mode of morbidity and mortality; these include benign and life-threatening arrhythmias, inappropriate therapies from cardiac implantable electronic devices, cardiac ischaemia, myocardial and aortic injury as well as cardiomyopathy with associated ventricular failure. Further research is required to identify prognostic markers, either with regards to the patient’s biochemistry or cardiac imaging results, in the acute setting in the ‘stable’ patient, thus establishing which ones may likely develop more sinister complications later on, as well as those who will benefit from close rhythm monitoring on discharge. Finally, as the association between electrocardiographic ischaemic changes and underlying coronary obstruction is not fully established, further studies are required in this area to identify which patients require to be rushed to the cath lab at an early stage, thus avoiding unnecessary invasive procedures. n

Lightning protection systems incorporating lighting conductors or rods, the concept of which was originally described by Benjamin Franklin, protect structures and their occupants during electrical storms.52 These are made from highly conducting materials such as copper or aluminum, and when they are struck by lightning, they provide a low-resistance path and hence preferential route for the electrical current to travel from the top of the building to the ground, and away from the structure they protect. In the UK, there

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36. S inha AK. Lightning-induced myocardial injury: a case report with management. Angiology 1985;36:327–31. DOI: 10.1177/000331978503600510; PMID: 4025941 37. Epperly TD, Steward JR. The physical effects of lightning injury. J Fam Pract 1989;29:267–72. PMID: 2671249 38. Hansen GC, McIlwraith GG. Lightning injury: two case histories and a review of management. Br Med J 1973;4(5887):271–4. PMID: 4753241 39. Andrews CJ, Cooper MA. Clinical presentation of the lightning victim. In: Andrews CJ, Cooper MA, Darveniza M, Mackerras D (eds). Lightning Injuries: Electrical, Medical and Legal Aspects. Boca Raton, FL, CRC, 1992; 47–70. 40. Lichtenberg R, Dries D, Ward K, et al. Cardiovascular effects of lightning strikes. J Am Coll Cardiol 1993;21:531–6; PMID: 8426021 41. Saglam H, Yavuz Y, Yurumez Y, Ozkececi G, Kilit C. A case of acute myocardial infarction due to indirect lightning strike. J Electrocardiol 2007;40:527–30. DOI: 10.1016/j. jelectrocard.2007.03.015; PMID: 17543327 42. Rash W. Cardiac injury and death by lightning strike. J Emerg Nurs 2008;34:470–1. DOI: 10.1016/j.jen.2008.07.001; PMID: 18804728 43. Karadas S, Vuruskan E, Dursun R, et al. Myocardial infarction due to lightning strike. J Pak Med Assoc 2013;63:1186–8. PMID: 24601203 44. Xenopoulos N, Movahed A, Hudson P, Reeves WC. Myocardial injury in electrocution. Am Heart J 1991;122:1481–4. PMID: 1951020 45. Gianni M, Dentali F, Grandi AM, et al. Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review Eur Heart J 2006;27:1523–9. DOI: 10.1093/eurheartj/ehl032; PMID: 16720686 46. Hayashi M, Yamada H, Agatsuma T, et al. A case of Takotsuboshaped hypokinesis of the left ventricle caused by a lightning strike. Int Heart J 2005;46:933–8. PMID: 16272786 47. Dundon BK, Puri R, Leong DP, et al. Takotsubo cardiomyopathy following lightning strike. Emerg Med J 2008;25:460–1. DOI: 10.1136/emj.2007.048876; PMID: 18573973 48. Rivera J, Romero KA, González-Chon O, et al. Severe stunned myocardium after lightning strike. Crit Care Med 2007;35: 280–5. DOI: 0.1097/01.CCM.0000251129.70498.C1; PMID: 17133184 49. Elsom DM. Deaths caused by lightning in England and Wales, 1852–1990. Weather 1993;48:83–90. DOI: 10.1002/j.14778696.1993.tb05846.x 50. Elsom DM. Deaths and injuries caused by lightning in the United Kingdom: analyses of two databases. Atmos Res 2001;56:325–334. DOI: 10.1016/S0169-8095(00)00083-1 51. Elsom DM. Surviving being struck by lightning: a preliminary assessment of the risk of lightning injuries and death in the British Isles. Int J Meteorol 1996;21:197–206. 52. Jernegan MW. Benjamin Franklin’s “Electrical Kite” and Lightning Rod. The New England Quarterly 1928;1:180–196. DOI: 10.2307/359764

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Clinical Arrhythmias

Limitations and Challenges in Mapping Ventricular Tachycardia: New Technologies and Future Directions Adam J Graham, 1 Michele Orini 1,2 and Pier D Lambiase 1,2 1. Barts Heart Centre, London; 2. Institute of Cardiovascular Science, UCL, London, United Kingdom

Abstract Recurrent episodes of ventricular tachycardia in patients with structural heart disease are associated with increased mortality and morbidity, despite the life-saving benefits of implantable cardiac defibrillators. Reducing implantable cardiac defibrillator therapies is important, as recurrent shocks can cause increased myocardial damage and stunning, despite the conversion of ventricular tachycardia/ ventricular fibrillation. Catheter ablation has emerged as a potential therapeutic option either for primary or secondary prevention of these arrhythmias, particularly in post-myocardial infarction cases where the substrate is well defined. However, the outcomes of catheter ablation of ventricular tachycardia in structural heart disease remain unsatisfactory in comparison with other electrophysiological procedures. The disappointing efficacy of ventricular tachycardia ablation in structural heart disease is multifactorial. In this review, we discuss the issues surrounding this and examine the limitations of current mapping approaches, as well as newer technologies that might help address them.

Keywords Ventricular tachycardia, substrate mapping, arrhythmia, cardiomyopathy, catheters, ripple mapping Disclosure: Pier D Lambiase receives speaker fees, educational grants and research grants from Medtronic and Boston Scientific. Received: 21 July 2017 Accepted: 15 August 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(3):118–24. DOI: 10.15420/aer.2017.20.1 Correspondence: Adam Graham, Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, West Smithfield, London, EC1A 7BE, UK. E: Adam.graham@bartshealth.nhs.uk

Recurrent episodes of ventricular tachycardia (VT) in patients with structural heart disease are associated with increased mortality and morbidity, despite the life-saving benefits of implantable cardiac defibrillators (ICDs).1,2 Because ICD therapies are abortive and do not alter the underlying arrhythmogenic substrate, their reduction becomes important, especially as recurrent shocks can cause increased myocardial damage and stunning, despite the conversion of VT/VF.3,4 Antiarrhythmic drugs can reduce the number of ICD therapies, but their long-term use is hindered by side-effects, especially with the most effective agent, amiodarone.5 In the absence of revolutionary drugs or antifibrotic regenerative therapies, catheter ablation has emerged as a potential therapeutic option either for primary or secondary prevention of these arrhythmias. This is particularly relevant to post-MI cases where the substrate is well defined. However, the outcomes of catheter ablation of VT in structural heart disease remain unsatisfactory in comparison with other electrophysiological procedures; initial first time success rates are only 50–70 % in most large series versus 80–90 % in normal heart VT.6 The disappointing efficacy of VT ablation in structural heart disease is multifactorial, relating to both our inability to fully delineate the substrate’s fixed and functional electrophysiology determining VT initiation and maintenance, as well as the delivery of adequate lesion sets to the critical arrhythmogenic sites.

Mapping during VT There have been rapid advances in the field of ventricular arrhythmia therapy over the past two decades following the seminal studies characterising post-infarction VT substrates during cardiac surgery.7–10 Activation mapping is now utilised to locate the point of the earliest

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activation of tachycardia, with entrainment subsequently performed to not only confirm re-entry as the arrhythmia mechanism but to allow for accurate delineation of the critical components of a circuit.11 The main target for ablation being the central isthmus, represented by mid-diastolic potentials during VT and specific entrainment criteria. 12 The entrainment of VT in the right ventricle of a patient with arrhythmogenic right ventricular cardiomyopathy is illustrated in Figure 1. Electro-anatomical mapping and advances in catheter technology have made VT ablation procedures routine in tertiary centres, particularly in post-infarction VT where arrhythmias are more amenable to these activation and entrainment mapping strategies. Indeed, elegant mechanistic studies have identified the role of border zone ultrastructure, scar geometry and anisotropy in determining wavefront curvature and functional block critical to initiate re-entry.13 Ciaccio et al. showed that infarct scar geometric features can be utilised to localise VT isthmuses, and sites of slow stable conduction lie in close proximity to sites of functional block.14 These principles have been applied clinically in post-infarction VT and recently utilised to define pro-arrhythmic areas based on electrogram morphology and stability; for example, Shannon entropy.15,16 However, in non-ischaemic cardiomyopathy, specific features of the substrate (e.g., myocyte disarray promoting anisotropy in hypertrophic cardiomyopathy or disruption of myocyte electro-mechanical coupling by desmosomal mutations in arrhythmogenic cardiomyopathy) create functional changes in the tissue to promote conduction block and re-entry. Furthermore, the scar is often very diffuse, making simple delineation of border zones seen in post-infarction VT challenging to define for substrate modification in these disorders.

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Limitations in Mapping Ventricular Tachycardia Therefore, functional changes independent of fibrosis might play an important role in ventricular arrhythmogenesis. This means that ablation relying on identifying fibrotic regions as potential VT isthmuses is probably inadequate, especially since it is assumed that the mechanism of VT involves a critical isthmus, but it is also possible that micro re-entry in an adjacent site is the primary driver with a bystander isthmus.17 Such sites will elude conventional ablation catheter bipolar mapping due to lack of resolution, but could be defined in tachycardia with higher-density mapping catheters (e.g., PentaRay or Orion basket); the functional and structural features of these sites can be dissected. This would explain the lower success rates of ablation in dilated cardiomyopathy versus post-MI VT, as the mechanism has not been defined or the circuit eludes conventional ablation catheter mapping.18–20 Therefore, despite our ability to identify post-MI VT isthmuses with a view to ablation in stable circuits, there remain significant knowledge gaps in predicting the probability of VT and their anatomical location in individual cases, especially non-ischaemic cardiomyopathies, and the planning of the substrate modification required. As a result, extensive endo-epicardial ablation and ‘scar homogenis ation’ are frequently performed to modify potentiallyarrhythmogenic sites with limited functional analysis.21 This risks unnecessary myocardial damage and pro-arrhythmia.22 Furthermore, in cardiomyopathy patients, diffuse areas of epicardial fibrosis act as potential re-entry sites, but the arrhythmias are often unmappable because they are haemodynamically unstable or not sustained.23 A

Figure 1: Example of Concealed Entrainment from the Middle of the VT Isthmus in a Patient with IHD

There is acceleration of the tachycardia to the paced cycle length 20 ms faster than the TCL. Morphology of the paced QRS complexes is identical to the VT surface QRS morphology; this represents entrainment with concealed fusion. Post-pacing interval is 4 ms shorter than the TCL, and there is a mid-diastolic potential evident on the ablation catheter signal. Stim–QRS interval is identical to the mid-diastolic potential–QRS time (244 ms), indicating that pacing is occurring mid-cycle, consistent with pacing in the centre of the VT circuit isthmus. IHD = ischaemic heart disease; TCL = tachycardia cycle length; VT = ventricular tachycardia.

Figure 2: Bipolar Voltage of Epicardial Substrate in Patient with ARVC in LAO Projection

deeper understanding of mechanisms of VT in these cases (i.e., micro re-entry, functional block leading to isthmus formation, repetitive Purkinje activity, the interplay between structural inhomogeneities and dynamic conduction–repolarisation interactions) is required to optimise therapeutic targeting and risk stratification in VT. A major limitation of mapping during VT is haemodynamic intolerance of the arrhythmia, with as few as 10 % of arrhythmias induced being stable.24 Advances in interventional cardiology have led to smaller infarct sizes and VTs with shorter cycle lengths accounting for the decreasing use of mapping during tachycardia due to their haemodynamic instability or transient nature.25 The obstacle posed by unstable VTs could be addressed using haemodynamic support devices. Percutaneous left ventricular assist devices allow more detailed and prolonged mapping of unstable VTs, with more VTs terminated by ablation, although no impact on the inducibility of VT at the end of procedures is evident.26 Whether these disappointing results are due to selection bias needs to be analysed in further trails.27 Extracorporeal membrane oxygenation has also been studied in this context. Its use allows for mapping, ablation and subsequent non-inducibility of VTs that were previously inducible at the end of substrate-based approaches. In this study, the acute procedural success, in terms of non-inducibility, was associated with better longterm outcomes. The approach had low complication rates and could be increasingly utilised in the future.28 However, prospective studies are lacking and will be necessary for rigorous evaluation of the technique. On a practical level, although entrainment mapping is seen by many as the gold standard for the interrogation of a re-entrant circuit, it also suffers limitations that stretch beyond the afore-mentioned haemodynamic issues. Problems include inability to capture or having to increase pacing outputs, which increase the volume of captured tissue leading to inaccuracies in defining the exact site of the isthmus,

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Threshold for low voltage scar set at 0.30 mV (red), with normal voltage tissue set at 1.0 mV (purple). Scar is seen predominantly distributed across the right ventricle. Multiple ablation lesions are displayed as grey and red spherical tags. ARVC = arrhythmogenic right ventricular cardiomyopathy; LAO = left anterior oblique.

as the captured area can be over 2 cm away. Even if consistent capture is achieved, oscillations in the tachycardia cycle length can introduce errors, resulting in misleading post-pacing intervals or local tissue properties causing latency and long return cycle lengths, appearing as bystander sites. These confounding issues might only become apparent after ablation has not terminated the tachycardia. Finally, due to the muscular bundles that form the isthmus being only a few hundred microns in diameter, the diastolic component can be very low in amplitude and difficult to detect, especially if the noise levels in the catheter laboratory are high and mapping system filters saturated at specific frequencies.29

Substrate Mapping Due to these limitations, and the fact that patients can have multiple haemodynamically unstable or non-sustained VT, substrate mapping and ablation have gained popularity. During sinus rhythm mapping, low-amplitude, fractionated electrograms and late potentials associated with surviving bundles of myocardial tissue surrounded by fibrous

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Clinical Arrhythmias tissue are identified.30,31 Early work employing subendocardial surgical resection of these areas eliminated approximately 50 % of the abnormal signals and reduced VT recurrence.32 Homogenisation of scars, involving ablation of these abnormal potentials within scars, reduces VT recurrence in patients with ischaemic cardiomyopathy.21 Translation of these results to non-ischaemic cardiomyopathy is difficult, with outcome measures less impressive than with ischaemic cohorts.22 The extensive ablation of late potentials in a patient with arrhythmogenic right ventricular cardiomyopathy is illustrated in Figure 2. Extensive ablation of local abnormal ventricular activities has also been demonstrated to significantly reduce VT recurrences in secondary prevention cases, but extensive ablation is required with long procedure times of up to 186 +/–78 minutes. This highlights the question of how much ablation is truly required to prevent recurrences.33 As such, there is no universal agreement on optimal ablation strategy for scar substrate. Randomised trials examining substrate-based ablation exist in the form of the ablation of clinical ventricular tachycardia versus addition of substrate ablation on the long term success rate of VT ablation (VISTA) and the substrate mapping and ablation in sinus rhythm to halt ventricular tachycardia (SMASH-VT) trials. The VISTA trial demonstrated that an extensive substrate-based approach was superior to a more focused activation mapping strategy. For obvious reasons, only tolerated VT was included in the activation mapping arm, and whether these results can be extrapolated to the wider VT cohort of patients is unclear.34 The randomised, primary-prevention trial, SMASH VT, showed a reduction in VT events using a substrate-based approach.35 The positive results of this trial, which achieved a 70 % reduction in arrhythmic events at 2 years, has not been replicated. There are many reasons that could explain why the results have been disappointing. Voltage mapping using standard parameters of >1.5 mV as normal tissue and <0.5 mV as scar tissue might lead to underestimation of the heterogeneity of the tissue mapped.36 The use of bipolar voltage to locate islands of surviving myocardium that could form conducting channels supporting VT is limited by the current technologies employed, primarily 3.5-mm bipolar ablation catheters. Using smaller electrode sizes with closer bipolar spacing to minimise far-field potentials can increase resolution, and has been to shown delineate areas of surviving myocardium that were labelled as inert scars on maps produced with larger electrodes (e.g., using multipolar PentaRay and duodecapolar catheters).37–39 Electrode spacing is not the only potential source of error when attempting to delineate scars. The angle at which the catheter is placed on the muscle can lead to falsely low bipolar voltage if it too steep, as the electrodes are activated simultaneously and signal cancellation occurs.40 Wavefront direction is another source of error, with late potentials present during apical pacing disappearing during ectopic beats.36 This phenomenon is also seen when comparing maps created during sinus rhythm and during right ventricle pacing. Sinus rhythm maps show larger scar areas with fewer late potentials.41 Similarly, differential pacing sites during mapping impact voltage maps created. With the characterisation of scars being different, especially in septal locations and areas of low density, the sensitivity of voltage maps could be improved by using separate pacing locations during mapping.42 Furthermore, isthmuses present during VT might be absent when mapping in sinus rhythm. The concept of block being functional rather than anatomical has been shown in computer models of VT and in clinical studies.43,44 In essence, dynamic changes in conduction-

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repolarisation lead to transient lines of block, which are cycle-length dependent, creating the opportunity of re-entry to develop at a site. Mechanistically, tissue susceptibility to re-entry depends on the spatial interaction between refractoriness and conduction dynamics, as re-entry requires that a wavefront of excitation finds electricallyexcitable tissue always ahead of it. Favourable conditions for re-entry might be met when conduction velocity is slowed by a premature beat and where short repolarisation allows the tissue to regain excitability, therefore potentially enabling the establishment of a re-entrant circuit.45 A metric to quantify tissue susceptibility to re-entry and predict critical sites for VT initiation based on this principle has recently been proposed.46 Localising a VT exit site is often attempted during ablation using the 12-lead electrocardiogram (ECG). These sites can be paced during sinus rhythm and compared morphologically to 12-lead ECGs, with most modern mapping systems containing software to produce a degree of match between the two. Due to the prevalence of ICDs in the patient cohort, a 12-lead ECG of the clinical VT is rarely captured, and the cycle length of the tachycardia stored on an ICD is often used to identify whether an induced VT is likely to be clinical. Despite the lack of a preprocedural ECG, VT induced during the case can be used to guide the operator to potential areas of interest. In idiopathic VT, the 12-lead ECG can localise anatomical regions where a VT exit site is most likely to be present. While similar algorithms have been used with some success in patients with structurally-abnormal hearts,47 the applicability of facets of these algorithms is questionable. In an invasive non-contact mapping study, the use of concordance in the precordial leads was not found to be useful in infarct-related VT.48 Furthermore, algorithms to assess for epicardial exit sites, which would be useful in preprocedural planning, have proved inaccurate.49 Pacing in sinus rhythm from sites of concealed entrainment produces unmatched pace maps in just under one-third of cases.50 Proposed mechanisms underlying the limitations of pace mapping include differential areas of block present during sinus rhythm and VT resulting in different QRS morphologies, and different pacing outputs resulting in divergent myocardial capture.51 Despite these issues, the utilisation of pace mapping to locate, and subsequently ablate, scar areas with multiple exit sites has been shown to improve VT-free survival in a single-centre study;52 the implication being the potential to deliver more targeted ablation lesions in regions more likely to support VT.

Epicardial Access Studies investigating non-ischaemic cardiomyopathy have demonstrated a greater proportion of potentially-arrhythmogenic substrate in the epicardium compared to the endocardium.53,54 These studies utilised percutaneous epicardial access for mapping, with this technique first described in patients with Chagas disease.55 Cano et al. found that epicardial low-voltage areas were more prevalent and larger in the epicardium compared to the endocardium in nonischaemic cardiomyopathy.54 In ischaemic cardiomyopathy, its utility is less convincing, with an endocardial predilection for scars in these cohorts. However, when initial endocardial ablation has failed, a combined approach in redo procedures might produce positive results.56 Damage to subdiaphragmatic organs during puncture can occur, and haemorrhage from diaphragmatic vessels has been reported. Pericardial effusion is common; it occurs due to damage caused to the myocardium by ablation and puncture of the right ventricle or coronary arteries. The latter of these also needs to be considered during ablation, with imaging utilised to ensure

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Limitations in Mapping Ventricular Tachycardia Figure 3: Wideband Cardiac MRI Showing Inferolateral Scar (left). Image on the Right is Prior to Application of Wideband Technology to Remove the Artefact Caused by the ICD Generator

Figure 4: Orion Basket Catheter Used with the RHYTHMIA System, Containing 64×0.4 mm2 Electrodes with 2.5 mm Centre-to-centre Spacing to Enable Higher-resolution Mapping

Courtesy of Dr Charlotte Manistay, Barts Heart Centre. ICD = implantable cardiac defibrillator.

Figure 5: High-resolution Mapping of Sustained Monomorphic VT (right) and Electrograms from the Roving Catheter (left)

ablation is remote from the arteries.57 Despite these potential risks, it has proved to be a safe procedure with low complication rates.58 In summary, although current practice varies in different centres, an epicardial approach is usually performed when there has been a failed endocardial approach or the underlying substrate is likely to be epicardial. The latter is delineated based on aetiology and potentially preoperative scar imaging.59

Complications Major complications occur in approximately 8–10 % of VT ablation procedures,60 with lower mortality. The three main complications are vascular injury, stroke and cardiac tamponade. In a large, single-centre study of both idiopathic VT and structurally-abnormal heart VT, accesssite vascular injury was the most frequent complication at 3.6 %, with stroke and tamponade both <1 %.61 No procedural deaths occurred in this study. The incidence of vascular complication might be higher in ischaemic heart disease cohorts, and although the incidence of stroke is low, the use of irrigated catheters is also purported to reduce the risk of stroke further by preventing coagulum formation on catheter tips.62 Complications can perhaps be further minimised with the use of a lower-power output of 30–40 watts during ablation.61 Anticoagulation during ablation is achieved with intravenous heparin, and post-ablation anticoagulation is recommended for 6–12 weeks with either aspirin or warfarin.63

Endpoints for VT Ablation Traditional focus is on the labelling of clinical and non-clinical VTs occurring during ablation. Clinical VT being denoted as such if it is similar to the 12-lead ECG, the cycle length recorded from an ICD or occurs spontaneously during mapping. However, arrhythmias labelled as non-clinical might in fact occur spontaneously in the out-of-hospital setting.12 Studies have differed in their approaches to these distinct re-entrant circuits. Using programmed electrical stimulation at the end of a procedure, some focus only on the clinical VT and others have included non-clinical VTs for their non-inducibility endpoints. Guideline consensus states that non-inducibility of clinical VT in response to programmed electrical stimulation should be considered the minimum endpoint after ablation.63 Della Bella et al. found that non-inducibility of all VTs was associated with significantly lower cardiac mortality.64 Others have shown inducibility of nonclinical VT to be associated with recurrence.65,66 In contrast, a recent pooled analysis of studies showed that non-inducibility of VT was not associated with lower recurrence.67 With no available studies

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Area of earliest activation can be seen in red in the inferior basal region, with the wavefront path highlighted by the curved arrow. Entire cycle length is localised to a single pivot point, suggestive of discrete local re-entry with an adjacent site of early activation; this would need to be fully confirmed with additional point collection and entrainment at the pivot site. Used with permission from Boston Scientific. VT = ventricular tachycardia.

specifically designed to address the question of optimal endpoints, it is difficult to produce standardised outcome measures. The recent increased use of substrate homogenisation necessitates a standardised method for assessing whether all targeted late potentials have been successfully ablated.59 Scar remapping is one suggested method of assessment, and with more expedient mapping, technologies might become more commonplace.68 Lack of capture with high-output pacing has been used in addition to late potential abolition as an endpoint. This has been employed particularly when late potentials are still recorded, despite extensive delivery of radiofrequency energy.21

Future Directions Cardiac MRI Delineation of Scar and Pro-Arrhythmic Circuits Cardiac MR imaging of scars shows promise as an adjunct to traditional electrophysiologically-based mapping. Gadolinium late enhancement demarcates extracellular space and is a well-validated surrogate marker of dense fibrosis. It can delineate heterogeneous tissue within scars that could form the isthmus of a re-entrant circuit.69 Despite the potential utility of cardiac MRI to identify potential ablation targets, its use remains limited. The main problem being the artefact caused by ICD generators and leads in many VT patients. A novel wideband technique enables optimised scar evaluation in patients with ICDs without any adverse sequelae (Figure 3). The acquired pixel

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Clinical Arrhythmias Figure 6: Posterior–anterior View of Epicardial Bipolar Voltage Map (left) Showing Extensive Epicardial Scar. Posterior–anterior View of ECG–I Map (CardioInsight system, Medtronic) Showing Site of Earliest Activation (Earliest White) of Ventricular Tachycardia in the Same Patient

Electrogram (arrow) shows a Q wave indicative of the epicardial site of earliest activation corresponding to scar border zone site marked ‘X’. Endocardial bipolar voltage maps from this patient showed no scar. ECG-I = electrocardiographic imaging.

spatial resolution of cardiac MRI using wide-band late enhancement at our centre is fixed by the sequence parameters at 1.4×1.4×4 mm (contiguous segmented 4-mm slices throughout the ventricles). This represents a sample of 8 µg of myocardium using non-interpolated data. It compares favourably to previously-published data for scar imaging by MRI, and is similar to resolution of voltage maps in vivo (3–5 mm). Crucially, MRI-derived scar analysis can also determine scar transmurality with distance from endo/epicardial borders. A transmural scar of >75 % corresponds to areas of slow conduction, known to be a necessary component for a re-entrant circuit, and scars >25 % of left ventricle wall thickness is necessary for critical sites involved in the maintenance of VT.70 Recent work has highlighted the capacity of navigator-gated inversion recovery 3D sequencing to correctly identify conducting channels when compared to electro-anatomical maps. The technique correlates well with electro-anatomical maps, and no significant deviation is seen in lead parameters.71 The availability of the integration of MRI scar and channel maps into available electroanatomical mapping software could provide valuable information to electrophysiologists during catheter ablation. More studies need to be conducted to evaluate both the validity and efficacy of this approach. This is especially relevant when one considers the resolution of cardiac MRI relative to that of contact mapping catheters and the size of the channels in question, which might be only be <1 mm in diameter. Cardiac MRI using 1.5 tesla magnets has a resolution of 4 mm, whereas 2-mm (1-mm spacing), high-density EP catheters, which take into account stability and electrode density, can resolve up to 2 mm of tissue and recognise very low amplitude signals in diffuse scars beyond the resolution of gadolinium.72 This is because gadolinium uptake is measured relative to ‘normal’ segments, and thus could miss diffuse fibrosis akin to balanced ischaemia being reported as ‘normal perfusion’ on nuclear imaging.

Entrainment mapping was also employed in this study, and areas where criteria for entrainment were met were associated sites distinct from the re-entrant circuit. The length of isthmuses was also overestimated by entrainment.73 Although allowing for faster mapping, this system does not solve the problem posed by haemodynamically-unstable rhythms, as sequential mapping in tachycardia is still required. It could however improve outcomes in tolerated VT. With regards to substrate mapping, the RHYTHMIA system, in conjunction with a basket, shows better correlation with MRI scar maps than standard catheter mapping.74 Reported human studies are thus far limited, with most studies examining the atrial substrate. In one series, the system was able to successfully map 24 of 28 atrial tachycardias that were incompletely mapped during the prior procedures employing standard techniques, and 22 were successfully terminated.75 The safety and efficacy of the procedure in ventricular arrhythmia have been reported in one study. Findings were positive, showing no complications, consistent recording of abnormal electrograms and good medium-term outcomes for freedom from VT.76 Other technologies, such as ripple mapping, might also help solve problems posed by current mapping techniques. The system displays electrogram components as a dynamic bar that protrudes from standard geometry. It has been shown to correctly identify conducting channels in scarred myocardium, and has been used in VT ablation with successful preliminary results.77,78 These newer mapping systems could be further integrated in future with technologies, such as intracardiac echocardiography, to allow improved visualisation of ventricular anatomy.79 Additionally, this technology has been shown to accurately identify wall motion abnormalities and corresponding scars,80 thus potentially aiding in the localisation of the arrhythmogenic substrate, and can aid ablation in regions of the heart that are troublesome to target.81

Electrocardiographic Imaging The global changes in electrophysiological parameters over both ventricles are not easily accessible using conventional sequential mapping techniques, and thus information is lost. This is especially critical to modelling approaches attempting to predict arrhythmia, which then have to rely on structural surrogates, such as gadolinium uptake and diffusion on MRI, to estimate conductivity parameters as opposed to global electrophysiological data. The ECG Imaging (ECG-I) system, developed by Yoram Rudy, utilises inverse solution mathematics to generate a unipolar electrogram map derived from high-density surface ECG jacket recording, which is projected onto the patient’s CT-derived cardiac geometry. It has been validated in canine models, patients undergoing cardiac surgery and ablation of focal ventricular ectopy.82–89

Multielectrode High-Resolution Mapping The limitations of current mapping systems have demanded the development of new technologies that achieve higher temporal and spatial resolution. This is made possible by using smaller electrodes with closer spacing, automated software allowing rapid data collection and accurate time annotation of electrograms with multiple components. The RHYTHMIA high-density mapping system, utilising a 64-electrode, high-density mapping Orion basket catheter, has led to important insights into the mechanisms of VT (Figures 4 & 5). A porcine study confirmed that in mapped sustained VT, portions of block in a re-entrant circuit was functional rather than anatomical.73 This finding confirms previous work stated above72, and has been confirmed in a further study.

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ECG-I has the potential to map arrhythmias using a single cardiac cycle, and thus could be relevant in the mapping of unstable VT (Figure 6). When assessing ECG-I data in patients with prior MI, a good correlation between scars on MRI and low-amplitude virtual electrograms was demonstrated. Fractionated potentials also had good correlation with sites of fibrosis on MRI, albeit less so than for low-amplitude electrograms. This feature could be attributable to the false identification of epicardial fat as scars on MRI. Late potentials can also be seen within scarred myocardium. During sinus rhythm mapping, these scarred areas alter the activation wavefront and form areas of conduction block. This information could be used to limit

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Limitations in Mapping Ventricular Tachycardia ablation to specific pre-identified regions when a substrate-mapping approach is employed.90 The system has also studied post-MI VT. Activation time was used to map the re-entrant circuits, which were correctly mapped to areas of scar. Predictions of site of onset were accurate for distinguishing between epicardial, intramural and endocardial locations utilising electrogram morphology; that is, pure Q waves representing true epicardial sites. This latter point highlights an important facet for clinical use. The prediction of the necessity of epicardial access could significantly shorten procedure times and enable a more focused ablation strategy.91 Additionally, given that many VTs cannot be sequentially mapped, knowledge of the exit site would be invaluable for the clinician during ablation. Current validation studies show an accuracy for mapping the site of origin of 4–6 mm.92 This degree of resolution might not be sufficient to guide ablation, but could enable expedited pace mapping of exit sites. Whether these potential

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oldenberg I, Gillespie J, Moss AJ, et al. Long-term benefit G of primary prevention with an implantable cardioverterdefibrillator: an extended 8-year follow-up study of the multicenter automatic defibrillator implantation trial. Circulation 2010;122(13):1265–71. DOI: 10.1161/ CIRCULATIONAHA.110.940148; PMID: 20837894. Connolly SJ, Gent M, Roberts RS, et al. Canadian Implantable defibrillator study (CIDS): a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation 2000;101(11):1297–1302. PMID: 10725290 Sweeney MO, Sherfesee L, DeGroot PJ, et al. Differences in effects of electrical therapy type for ventricular arrhythmias on mortality in implantable cardioverter-defibrillator patients. Heart Rhythm 2010;7(3):353–60. DOI: 10.1016/ j.hrthm.2009.11.027; PMID: 20185109. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008;359(10):1009–17. DOI: 10.1056/ NEJMoa071098; PMID: 18768944. Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial. JAMA 2006;295(2):165–171. DOI: 10.1001/jama.295.2.165; PMID: 16403928. Tung R, Vaseghi M, Frankel DS, et al. Freedom from recurrent ventricular tachycardia after catheter ablation is associated with improved survival in patients with structural heart disease: an International VT Ablation Center Collaborative Group study. Heart Rhythm 2015;12(9):1997–2007. DOI: 10.1016/j.hrthm.2015.05.036; PMID: 26031376. Josephson ME, Horowitz LN, Farshidi A, et al. Recurrent sustained ventricular tachycardia. 2. Endocardial mapping. Circulation 1978;57(3):440–7. PMID: 624153. Josephson ME, Horowitz LN, Spielman SR, et al. Comparison of endocardial catheter mapping with intraoperative mapping of ventricular tachycardia. Circulation 61(2);1980:395–404. PMID: 7351066. Josephson ME, Horowitz LN, Farshidi A, Kastor JA. Recurrent sustained ventricular tachycardia. 1. Mechanisms. Circulation 1978;57(3):431–40. PMID: 624152. Brugada P, Abdollah H, Wellens HJ. Continuous electrical activity during sustained monomorphic ventricular tachycardia. Observations on its dynamic behavior during the arrhythmia. Am J Cardiol 1985;55(4):402–11. PMID: 3969877. Stevenson WG, Delacretaz E, Friedman PL, Ellison KE. Identification and ablation of macroreentrant ventricular tachycardia with the CARTO electroanatomical mapping system. Pacing Clin Electrophysiol 1998;21(7):1448–56. PMID: 9670190. Stevenson WG, Soejima K. Catheter ablation for ventricular tachycardia. Circulation 2007;115(21):2750–60. DOI: https://doi. org/10.1161/CIRCULATIONAHA.106.655720. Ciaccio EJ, Coromilas J, Wit AL, et al. Formation of functional conduction block during the onset of reentrant ventricular tachycardia. Circ Arrhythm Electrophysiol 2016;9(12): pii: e004462. DOI: 10.1161/CIRCEP.116.004462; PMID: 27879278. Ciaccio EJ, Ashikaga H, Kaba RA, et al. Model of reentrant ventricular tachycardia based on infarct border zone geometry predicts reentrant circuit features as determined by activation mapping. Heart Rhythm 2007;4(8):1034–45. DOI: 10.1016/j.hrthm.2007.04.015; PMID: 17675078. Nayyar S, Kuklik P, Ganesan AN, et al. Development of time- and voltage-domain mapping (V-T-mapping) to localize ventricular tachycardia channels during sinus rhythm. Circ Arrhythm Electrophysiol 2016;9(12): pii: e004050. DOI: 10.1161/ CIRCEP.116.004050; PMID: 27913399. Peters NS, Ciaccio EJ. The barrel of the smoking gun: finding diastolic pathways during sinus rhythm. Circ

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applications would improve outcomes need to be tested in large trials, although procedure planning, workflow and catheter laboratory time might be reduced.

Conclusions Advances in high-density and non-invasive mapping technologies are enabling far more detailed interrogation of myocardial substrates than previously possible, coupled with major technological developments in imaging. This means that we can now study potential circuits and plan procedures in a more informed manner.93 The key challenges of mapping unstable VTs remain to be fully addressed, as well as optimising substrate-based approaches to enable more targeted, less extensive ablation, if this is possible. This will require deeper understanding of the dynamic behaviour of the tissue critical to facilitate re-entry, with the ultimate goal of undertaking more personalised and refined ablation strategies. n

Arrhythm Electrophysiol 2016;9(12):pii: e00475. DOI: 10.1161/ CIRCEP.116.004752; PMID: 27913401. 17. J osephson ME. Electrophysiology at a crossroads: a revisit. Heart Rhythm 2016;13(12):2317–22. DOI: 10.1016/ j.hrthm.2016.07.024; PMID: 27542727. 18. Tung R, Michowitz Y, Yu R, et al. Epicardial ablation of ventricular tachycardia: an institutional experience of safety and efficacy. Heart Rhythm 2013;10(4):490–8. DOI: 10.1016/ j.hrthm.2012.12.013; PMID: 23246598. 19. Dinov B, Fiedler L, Schönbauer R, et al. Outcomes in catheter ablation of ventricular tachycardia in dilated nonischemic cardiomyopathy compared with ischemic cardiomyopathy: results from the prospective heart centre of leipzig VT (HELP_VT). Circulation 2014;129(7):728–36. DOI: 10.1161/ CIRCULATIONAHA.113.003063; PMID: 24211823 20. Merino JL. Mechanisms underlying ventricular arrhythmias in idiopathic dilated cardiomyopathy: implications for management. Am J Cardiovasc Drugs 2001;1(2):105–18. PMID: 14728040. 21. Di Biase L, Santangeli P, Burkhardt DJ, et al. Endo-epicardial homogenization of the scar versus limited substrate ablation for the treatment of electrical storms in patients with ischemic cardiomyopathy. J Am Coll Cardiol 2012;60(2):132–41. DOI: 10.1016/j.jacc.2012.03.044; PMID: 22766340. 22. Gökog˘lan Y, Mohanty S, Gianni C, et al. Scar homogenization versus limited-substrate ablation in patients with nonischemic cardiomyopathy and ventricular tachycardia. J Am Coll Cardiol 2016;68(8):1990–8. DOI: 10.1016/j.jacc.2016.08.033; PMID: 27788854. 23. Yalin K, Golcuk E, Bilge AK, et al. Combined analysis of unipolar and bipolar voltage mapping identifies recurrences after unmappable scar-related ventricular tachycardia ablation. Europace 2015;17(10):1580–6. DOI: 10.1093/europace/ euv013; PMID: 25750215. 24. Schilling RJ, Davies DW, Peters NS. Clinical developments in cardiac activation mapping. Eur Heart J 2000;21(10):801–7. DOI: 10.1053/euhj.1999.1766; PMID: 10781351. 25. Wijnmaalen AP, Schalij MJ, Von Der Thüsen JH, et al. Early reperfusion during acute myocardial infarction affects ventricular tachycardia characteristics and the chronic electroanatomic and histological substrate. Circulation 2010;121(2):1887–95. DOI: 10.1161/CIRCEP.110.959213; PMID: 21285394. 26. Miller MA, Dukkipati SR, Mittnacht AJ, et al. Activation and entrainment mapping of hemodynamically unstable ventricular tachycardia using a percutaneous left ventricular assist device. J Am Coll Cardiol 2011;58(13):1363–71. DOI: 10.1016/j.jacc.2011.06.022; PMID: 21920266. 27. Miller MA, Reddy VY. Percutaneous hemodynamic support during scar-ventricular tachycardia ablation: is the juice worth the squeeze? Circ Arrhythm Electrophysiol 2014;7(2)192–4. DOI: 10.1161/CIRCEP.114.001590; PMID: 24736421. 28. Baratto F, Pappalardo F, Oloriz T, et al. Extracorporeal membrane oxygenation for hemodynamic support of ventricular tachycardia ablation. Circ Arrhythmia Electrophysiol 2016;9(12):pii: e004492. DOI: 10.1161/CIRCEP.116.004492; PMID: 27932426. 29. Tung R. Challenges and pitfalls of entrainment mapping of ventricular tachycardia. Circ Arrhythmia Electrophysiol 2017;10(4):1–11. DOI: 10.1161/CIRCEP.116.004560; PMID: 28408650. 30. Fenoglio JJ Jr, Pham TD, Harken AH, et al. Recurrent sustained ventricular tachycardia: structure and ultrastructure of subendocardial regions in which tachycardia originates. Circulation 1983;68(3):518–33. PMID: 6223722. 31. Cassidy DM, Vassallo JA, Miller JM, et al. Endocardial catheter mapping in patients in sinus rhythm: relationship to underlying heart disease and ventricular arrhythmias. Circulation 1986;73,(4):645–52. PMID: 3948367.

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ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

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Catheter Ablation

Prophylactic Catheter Ablation for Ventricular Tachycardia: Are We There Yet? Rahul K Mukherjee, 1 Louisa O’Neill 1 and Mark D O’Neill 1,2 1. Division of Imaging Sciences and Biomedical Engineering, King’s College London; 2. Department of Cardiology, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom

Abstract Ventricular tachycardia (VT), often degenerating into ventricular fibrillation, is the leading cause of sudden cardiac death. Catheter ablation of VT is associated with relatively low, long-term success rates, while the optimal timing of ablation in patients with ischaemic and nonischaemic cardiomyopathy remains unclear. Contemporary practice in most centres is to consider ablation late in the disease process following the failure of anti-arrhythmic medications and/or following recurrent implantable cardioverter-defibrillator shocks. Three major randomised, controlled trials have been published investigating the role of prophylactic catheter ablation for VT. In the present review, we assess the evidence from these and other related trials in VT ablation to understand if there is sufficient evidence to advocate prophylactic catheter ablation in patients with VT.

Keywords Ventricular tachycardia, catheter ablation, implantable cardioverter-defibrillator, substrate, non-inducibility Disclosure: The authors have no conflicts of interest to declare. Received: 14 July 2017 Accepted: 10 August 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(3):125–8. DOI: 10.15420/aer.2017:17:1 Correspondence: Dr Rahul K. Mukherjee. King’s College London, Fourth floor, North Wing, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH. E: rahul.r.mukherjee@kcl.ac.uk

Recurrent ventricular tachycardia (VT) in patients who have an implantable cardioverter-defibrillator (ICD) with subsequent shocks is associated with reduced quality of life and an adverse prognosis. Pharmacological treatments are associated with significant side-effects. Catheter ablation has been used to reduce the number of ICD therapies in patients with ischaemic and non-ischaemic cardiomyopathy, and improve VT-free survival. The optimal timing of ablation, however, remains unclear, with a limited number of randomised, multicentre trials suggesting potential benefits of ‘prophylactic’ ablation. Over the past decade, significant advances in ablation strategies, technology and imaging techniques have been made. A number of large, multicentre, clinical trials are seeking to address some of the unanswered questions in VT ablation using standardised ablation strategies and procedural endpoints. Until we have more data on the impact of VT ablation on mortality, functional status and quality of life, the uptake of ‘prophylactic’ ablation across centres is likely to be limited. ICDs improve survival in patients with VT. However, patients who receive both appropriate and inappropriate recurrent shocks from their ICDs have an increased risk of death over the medium term, partly due to the progression of heart failure.1 Recurrent ICD shocks can also lead to severe psychological impairment and reduce quality of life, while having little or no effect on the underlying arrhythmogenic substrate.2 The Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular Tachycardia (SMASH-VT) study, first published a decade ago, reported a significant decrease in the number of ICD therapies in patients receiving adjunctive catheter ablation in addition to ICD implantation compared to patients receiving ICD implantation alone.3 Subsequently,

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the Ventricular Tachycardia Ablation in Coronary Heart Disease (VTACH) study reported an improvement in VT-free survival in patients with ischaemic cardiomyopathy undergoing catheter ablation with ICD implantation versus ICD alone.4 Neither of these studies demonstrated a mortality benefit of catheter ablation. Although the number of catheter ablation procedures for VT has increased over time, there remain unanswered questions about the role of prophylactic catheter ablation at the time of ICD implantation, the optimal timing of ablation, the most effective ablation strategies and which groups of patients derive the greatest benefit.5 Performing randomised controlled trials in VT ablation has proved notoriously difficult (Table 1). The SMASH-VT trial, despite having a 4-year enrolment period across three high-volume centres, recruited 128 patients in total. In order to aid recruitment further, patients who had an ICD for primary prevention, and subsequently received an appropriate ICD therapy, were included following commencement of the trial as an additional qualifying criteria. The VTACH trial had a 3.5-year enrolment period across 16 centres, and recruited 110 patients in total. The VTACH study completed follow up in 2006 and was published in 2010. The pace of progress in interventional electrophysiology has been rapid, with frequent, iterative modifications to ablation techniques, strategies and technologies that are likely to have occurred over this period. Furthermore, optimal ICD programming (high-rate therapy with a 2.5-second delay before initiation of therapy at a heart rate ≥200 BPM, or delayed therapy with a 60-second delay at 170–199 BPM or 12-second delay at 200–249 BPM) can reduce the occurrence of inappropriate therapy, as well as all-cause mortality, compared to conventional programming, which challenges the robustness of an endpoint of either appropriate or inappropriate shocks according to a contemporary definition.6

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Catheter Ablation Table 1: Major Clinical Trials in VT Ablation Reference

Patient group

No. patients

Reddy et al., 2007 ICM (ablation and 128 (SMASH-VT)* ICD versus ICD alone)

Ablation strategy

Primary endpoint

Follow up

Substrate-based Survival free from ICD 22.5 ± 5.5 approach with therapy months (mean) mapping in sinus rhythm

Clinical outcome Reduced incidence of ICD therapy in ablation group versus ICD only

Kuck et al., 2010 ICM (ablation and 110 Pace mapping ± Time to first recurrence 22.5 months (VTACH)* ICD versus ICD entrainment mapping of VT/VF (SD: 9.0) alone) ± substrate modification

Longer time to recurrence of VT/VF in ablation group versus control group

Kuck et al., 2017 (SMS)*

No difference in time to first recurrence of VT/VF between ablation and control groups

ICM with LV EF 111 Pace mapping ± Time to first recurrence 2.3 ± 1.1 years <40 % (ablation entrainment mapping of VT/VF (mean) and ICD versus ± substrate modification ICD alone)

Di Biase et al., ICM (clinical ablation 118 2015 (VISTA) versus substrate- based ablation)

Activation and entrainment Recurrence of VT 12 months mapping; clinical VT, haemodynamically-stable/ mappable VT targeted (clinical group) Ablation empirically extended throughout scar based on substrate map + target abnormal potentials in SR (substrate group)

Extensive substratebased ablation superior to ablation targeting only clinical and stable VTs

Dinov et al., 2014 ICM and NICM 227 (HELP-VT) (ICM versus NICM patients undergoing VT ablation)

Activation and entrainment VT-free survival 1 year mapping to locate possible exit sites and critical isthmuses; complete elimination of all clinical and non-clinical stable monomorphic VT

Improved VT-free survival at 1 year in patients with ICM compared to patients with NICM

Sapp et al., 2016 ICM (patients with 259 Activation mapping. All Composite of death, 27.9 ± 17.1 (VANISH) ICM and ICDs who induced VTs targeted VT storm or appropriate months (mean) have VT randomised for ablation. If unstable ICD shock to ablation or VT or VF, induced substrate- escalated drug based approach used therapy) for ablation

Lower rate of the composite primary outcome of death, VT storm or appropriate ICD shock in patients undergoing catheter ablation versus escalated drug therapy

*Prophylactic catheter ablation randomised, controlled trials. HELP = Heart Centre of Leipzig; ICD = implantable cardioverter-defibrillator; ICM = ischaemic cardiomyopathy; LV EF = left ventricular ejection fraction; NICM = non-ischaemic cardiomyopathy; SD = standard deviation; SMASH = substrate mapping and ablation in sinus rhythm to halt ventricular tachycardia; SMS = substrate modification study; SR = sinus rhythmn; VANISH = ventricular tachycardia ablation versus escalated anti-arrhythmic drug therapy in ischaemic heart disease; VF = ventricular fibrillation; VISTA = ablation of clinical ventricular tachycardia versus addition of substrate ablation on the long term success rate of VT ablation; VT = ventricular tachycardia; VTACH = ventricular tachycardia ablation in coronary heart disease.

Although appropriate for the time, neither of the original trials assessing prophylactic VT ablation had what would now be considered optimal ICD programming incorporated into their study protocols. The SMASH-VT study excluded patients receiving class I or III antiarrhythmic medications, while in the VTACH study, 35 % of patients in each arm received amiodarone, and 75 % of patients received beta-blockers at randomisation. Amiodarone and b-blockers are known to reduce the risk of ICD shocks, 7 but interestingly in the Ventricular tachycardia Ablation versus Escalated Anti-arrhythmic Drug Therapy in Ischaemic Heart Disease (VANISH) trial, in patients with ischaemic cardiomyopathy who had VT, escalation in antiarrhythmic drug therapy was associated with a higher composite of death, VT storm or appropriate ICD shock compared to patients who received catheter ablation.8 The VTACH trial reported a cross-over of 22 % from the control group to the catheter ablation group, while seven patients randomised to VT ablation did not receive any ablation due to procedure-related events, lack of appropriate targets, access problems or technical

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issues.4 A high cross-over rate is difficult to avoid in studies of catheter intervention where blinding of the operator cannot be achieved, and where it would be considered unethical to offer a sham procedure for the management of a potentially life-threatening arrhythmia. There might also be physician bias present when making treatment decisions to enrol patients into a trial that randomises on the basis of having a procedure versus no procedure. Despite being 10 years on from the first prospective, randomised, controlled trial investigating prophylactic catheter ablation for VT, many centres perform VT ablation often as a last resort late in the disease process, after patients have failed multiple anti-arrhythmic medications, when the procedural risk might in fact be at its highest. A European Heart Rhythm Association Research Network survey of current practice among electrophysiologists in managing VT in patients with ICDs found that most operators performed ablation for recurrent shocks or electrical storm, with prophylactic ablation rarely performed.9 This reluctance to intervene earlier might be due to the continued uncertainty surrounding the impact of VT ablation on disease progression, functional status and mortality in otherwise

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Prophylactic Catheter Ablation for VT stable patients. Since these original trials, there have been several advances in imaging techniques, as well as ablation strategies, to guide VT ablation. Both cardiac CT (to assess wall thinning) and cardiac MRI (to assess late gadolinium enhancement/scar) can be used to define the structural substrate for VT. These imaging techniques have been integrated with electro-anatomic mapping to motivate either additional mapping in regions of interest or to determine the need for epicardial access in patients with ischaemic and non-ischaemic cardiomyopathy.10 Using 3D navigator-gated, high-resolution, late gadolinium enhancement MRI to assess myocardial scar, Andreu et al. have suggested that it might be possible to depict channels of slow conduction in border-zone regions of scars with good correlation to electro-anatomic mapping.11 There is ongoing work in this area, and it is conceivable that we might one day be using MRI routinely to define ablation targets and potentially improve procedural success. There are several techniques to perform VT ablation, including activation and entrainment mapping during VT when the tachycardia is stable or haemodynamically tolerated, pace-mapping when the clinical VT is not inducible or substrate-based strategies. Substrate-based ablation can consist of late potential abolition, elimination of local abnormal ventricular activities, conduction channel ablation and electric isolation of low voltage areas and scar homogenisation.12 Differences in mapping techniques and ablation strategies used make comparisons between studies difficult to interpret. The SMASH-VT study employed a combination of pace mapping and/or entrainment mapping to identify regions of arrhythmogenic tissue within an area of infarct and target for ablation, while the VTACH trial also allowed for substrate modification (defined as the absence of all channels within an area of interest) in patients with non-inducible VT.3,4 The SMASH-VT study performed ablation of late or fractionated potentials in a small group of patients with severe ventricular dysfunction. Advanced imaging techniques to define myocardial substrate in 3D were not available for either study. There has been recent interest in substrate-based ablation strategies to guide VT ablation over ablation limited to clinical and mappable VTs. The multicentre Ablation of Clinical Ventricular Tachycardia versus Addition of Substrate Ablation on the Long-term Success Rate of VT Ablation (VISTA) trial randomised patients with ischaemic cardiomyopathy to either substrate-based ablation where all ‘abnormal’ electrograms within scars were targeted, or limited ablation of clinical VT guided by pace mapping, activation mapping and entrainment mapping. There were 60 patients included in the ‘clinical ablation’ arm and 58 patients in the ‘substrateguided’ arm, and while there was no difference in mortality between the two groups, there was an improvement in the cumulative recurrence probability of VT using the substrate-based approach.13 In this context, the recently-published substrate modification study (SMS) adds an important perspective. A total of 111 patients with ischaemic cardiomyopathy and left ventricular ejection fraction (LV EF) <40 % were randomised to either catheter ablation prior to ICD implantation or ICD implantation alone. Over a follow up of 2.3±1.1 years, there was no difference in the primary endpoint–time to first recurrence of VT/VF. However, there was a >50 % reduction in the total number of ICD interventions during follow up in the catheter ablation arm.14 There were significant differences in the design of the SMS compared to the SMAST-VT and VTACH trials, which could account for some of the findings. In the SMS, 27 % of patients received amiodarone, while these patients were excluded from SMASH-VT. There were differences in ICD programming between studies, which

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might have accounted for differences in recurrence rates between trials. The procedural endpoint in SMS was non-inducibility of VT with or without additional substrate modification, while substrate modification was a predefined endpoint in VTACH when VT was non-inducible. Therefore, it is possible that some patients with noninducible VT might have had more extensive ablation in the VTACH trial compared to the SMS. Enrolment into the SMS took 7 years to complete, echoing the problems encountered with recruitment in previous VT ablation clinical trials. Previous work has shown significant differences in the procedural success of catheter ablation depending on the patient group studied. The Heart Centre Leipzig (HELP)-VT study demonstrated significantly worse VT-free survival in patients with non-ischaemic cardiomyopathy versus patients with ischaemic cardiomyopathy (40.5 % versus 57.0 % at 1-year follow up).15 The underlying substrate might be different in non-ischaemic cardiomyopathy, where epicardial ablation is more frequently required. Subgroup analysis from the VTACH trial suggested that patients with an LV EF <30 % derived no benefit from ablation in terms of VT-free survival, whereas those with EF >30 % derived a greater benefit.4 This observation might also account for the failure to reach the primary endpoint in the SMS, where all patients enrolled had a LV EF <40 %, leading to a possible underestimation of the potential benefit of VT ablation. These studies provide important insights into which patients should be offered catheter ablation. One of the limitations of clinical trials in VT is the lack of a standardised definition of acute procedural success with studies defining noninducibility of ‘clinical VTs’ as procedural success, while others define complete non-inducibility, including all late potential abolition, as procedural success. It remains unclear whether additional ablation to achieve complete scar homogenisation is required for long-term success. Without uniform procedural endpoints, it is difficult to compare the quality of ablation between different clinical trials. VT ablation can be a challenging procedure and is associated with a significant risk of complications, including cardiac tamponade, stroke, vascular injury, thromboembolism, perforation as well as procedurerelated death. While the risk of complications in idiopathic VT ablation might be comparable to other low-risk ablation procedures, the risks of VT ablation in structural heart disease is considerably higher. A recent retrospective analysis from a large, multicentre registry of >2,000 patients undergoing VT ablation in structural heart disease found an early mortality rate of 5 % within 30 days of the procedure, while the cumulative overall mortality at 1 year was 13 %.16 The procedure itself can also be time consuming, which could have potential implications on resource allocation if more VT ablations were to be performed on a prophylactic basis. These issues could limit the applicability of prophylactic VT ablation to high-volume tertiary centres with more expertise and resources to avoid and/or deal with complications. There is limited evidence to suggest that clinicians are considering catheter ablation for VT late in the disease process in the realworld setting. The Pilot Study of Catheter Ablation for Ventricular Tachycardia in Patients with an Implantable Cardioverter Defibrillator (CALYPSO) pilot trial suggested that most patients had already failed anti-arrhythmic medications prior to being considered for VT ablation, and that these patients subsequently had high rates of VT recurrence and death.17 ‘Prophylactic’ catheter ablation, either prior to or at the time of ICD implantation, might therefore allow modification of

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Catheter Ablation arrhythmia substrate early in the disease, and potentially allow the full benefits of ablation to be realised. The three main randomised clinical trials assessing prophylactic catheter ablation for VT described above have given some important insights into which patients might derive the greatest benefit from ablation, and how differences in ablation strategy could affect clinical outcome, but more evidence is required. Unanswered questions include: • Should patients with structural heart disease undergoing ICD implantation be considered for prophylactic substrate ablation in the absence of VT? • What is the appropriate ablation strategy and endpoint in an individual patient? • At what point in a patient’s history is a catheter intervention for VT appropriate? There are a number of ongoing clinical trials which could shed some light on some of these questions, as well as provide important data that could help us understand the role of VT ablation. The preventive ablation of ventricular tachycardia in patients With myocardial infarction (BERLIN) VT trial is a prospective, randomised, multicentre study that aims to assess the impact of prophylactic VT ablation prior to ICD implantation compared to ICD implantation and best medical care until a third appropriate shock and catheter ablation thereafter. The study will aim to recruit over 200 patients and assess the impact of prophylactic VT ablation on all-cause mortality and unplanned hospital admissions for congestive heart failure or VT/VF as the primary endpoint. The trial will aim to complete recruitment at the end of 2018 and should provide insights into the role of VT ablation in reducing mortality, hospital admissions as well as assessing its impact on functional status and quality of life (secondary endpoints).

oole JE, Johnson GW, Hellkamp AS, et al. Prognostic P importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008;359(10):1009–17. DOI: 10.1056/ NEJMoa071098; PMID: 18768944. Wissner E, Stevenson WG, Kuck KH. Catheter ablation of ventricular tachycardia in ischaemic and non-ischaemic cardiomyopathy: where are we today? A clinical review. Eur Heart J 2012;33(12):1440–50. DOI: 10.1093/eurheartj/ehs007; PMID: 22411192. Reddy VY, Reynolds MR, Neuzil P, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med 2007;357(26):2657–65. DOI: 10.1056/NEJMoa065457; PMID: 18160685. 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(9708):31–40. DOI: 10.1016/S0140-6736(09)61755-4; PMID: 20109864. Pokorney SD, Friedman DJ, Calkins H, et al. Catheter ablation of ventricular tachycardia: lessons learned from past clinical trials and implications for future clinical trials. Heart Rhythm 2016;13(8):1748–54. DOI: 10.1016/j.hrthm.2016.04.001; PMID: 27050910. Moss AJ, Schuger C, Beck CA, et al. Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med 2012; 367(24):2275–83. DOI: 10.1056/NEJMoa1211107; PMID: 23131066.

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The substrate targeted ablation using the flexAbility™ ablation catheter system for the reduction of ventricular tachycardia (STAR)VT trial, which has recently completed its enrolment phase, is a large, multicentre, randomised, controlled trial investigating the impact of scar-based VT ablation compared to routine drug therapy on freedom from ICD shocks and cardiovascular-related hospitalisations. The study will recruit patients with both ischaemic and non-ischaemic cardiomyopathy, while patients in both study arms will receive ICD/ cardiac resynchronisation therapy-defibrillators (CRT-Ds) and routine drug therapies. This study will help us address the question of whether VT ablation results in fewer appropriate ICD therapies and VT recurrences compared to anti-arrhythmic drugs using modern-day technologies and a standardised substrate-based ablation strategy. The PARTITA trial, investigating whether timing of VT ablation affects prognosis in patients with an implantable cardioverter-defibrillator, is an ongoing multicentre, randomised, controlled trial that aims to recruit 590 patients by late 2018. This study will randomise patients to receive catheter ablation either immediately after an appropriate ICD shock, or to delay ablation until an arrhythmic storm occurs. The findings of this trial will be crucial in helping to determine what the optimal timing of VT ablation should be. In conclusion, although there is some evidence that prophylactic VT ablation might be of benefit in some groups of patients, but this evidence cannot be described as compelling. More data are needed from trials utilising contemporary advances in ablation technologies and cardiac imaging with standardised ablation strategies, procedural endpoints and follow-up protocols. In this regard, the ongoing trials described here might provide important and exciting data to support the need for prophylactic VT ablation, but we are not there yet. n

onnolly SJ, Dorian P, Roberts RS, et al. Comparison of C beta-blockers, amiodarone plus beta-blockers or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC study: a randomised trial. JAMA 2006;295(2):165–71. DOI: 10.1001/jama.295.2.165; PMID: 16403928. 8. Sapp JL, Wells GA, Parkash R. et al. Ventricular tachycardia ablation versus escalation of anti-arrhythmic drugs. N Engl J Med 2016;375(2):111–21. DOI: 10.1056/NEJMoa1513614; PMID: 27149033. 9. Dagres N, Cantu F, Geelen P, et al. Current practice of ventricular tachycardia ablation in patients with implantable cardioverter-defibrillators. Europace 2012;14(1):135–7. DOI: 10.1093/europace/eur411; PMID: 22167388. 10. Yamashita S, Sacher F, Mahida S, et al. Image integration to guide catheter ablation in scar-related ventricular tachycardia. J Cardiovasc Electrophysiol 2016; 27(6):699–708. DOI: 10.1111/jce.12963; PMID: 26918883. 11. Andreu D, Ortiz-Perez JT, Fernandez-Armenta J, et al. 3D delayed-enhanced magnetic resonance sequences improve conducting channel delineation prior to ventricular tachycardia ablation. Europace 2015;17(6):938–45. DOI: 10.1093/europace/euu310; PMID: 25616406. 12. Tung R, Josephson ME, Bradfield JS, Shivkumar K. Directional influences of ventricular activation on myocardial scar characterisation. Circ Arrhythm Electrophysiol 2016;9(8):e004155. DOI: 10.1161/CIRCEP.116.004155; PMID: 27516464.

13. D i Biase L, Burkhardt JD, Lakkireddy D, et al. Ablation of stable VTs versus substrate ablation in ischaemic cardiomyopathy. J Am Coll Cardiol 2015;66(25):2872–82. DOI: 10.1016/j.jacc. 2015.10.026; PMID: 26718674. 14. Kuck KH, Tilz RR, Deneke T, et al. Impact of substrate modification by catheter ablation on implantable cardioverter-defibrillator interventions in patients with unstable ventricular arrhythmias and coronary artery disease. Circ Arrhythm Electrophysiol 2017;10(3):e004422. DOI: 10.1161/ CIRCEP.116.004422; PMID: 28292751. 15. Dinov B, Fiedler L, Schonbauer R, et al. Outcomes in catheter ablation of ventricular tachycardia in dilated nonischemic cardiomyopathy compared with ischemic cardiomyopathy: results from the Prospective Heart Centre of Leipzig VT (HELP-VT) Study. Circulation 2014;129(7): 728–36. DOI: 10.1161/CIRCULATIONAHA.113.003063; PMID: 24211823. 16. Santangeli P, Frankel DS, Tung R, et al. Early mortality after catheter ablation of ventricular tachycardia in patients with structural heart disease. J Am Coll Cardiol 2017;69(17):2105–15. DOI: 10.1016/j.jacc.2017.02.044; PMID: 28449770. 17. Al-Khatib SM, Daubert JP, Anstrom KJ, et al. Catheter ablation for ventricular tachycardia in patients with an implantable cardioverter defibrillator (CALYPSO) pilot trial. J Cardiovasc Electrophysiol 2015;26(2):151–7. DOI: 10.1111/jce.12567; PMID: 25332150.

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Devices

Abstract The clinically available leadless pacemakers for patients with a single-chamber pacing indication have shown to be safe and effective. However, the optimal end-of-life strategy of this novel technique is undefined. Suggested strategies comprise of (a) placing an additional leadless device adjacent to the leadless pacemaker, or (b) retrieving the non-functioning leadless pacemaker and subsequently implanting a new device. Although initial studies demonstrate promising results, early experience of acute and mid-term retrieval feasibility and safety remains mixed. We suggest that the approach of leadless pacemaker retrieval is more appealing to limit the amount of non-functioning intracardiac hardware. In addition, potential risks for device–device interference, and unknown long-term complications associated with multiple intracardiac devices are prevented. The potential inability to retrieve chronically implanted leadless pacemakers limits the application of this novel technology. Therefore, long-term prospective analysis is required to define the most optimal end-of-life strategy.

Keywords Leadless pacemaker therapy, retrieval, end-of-life management, Micra Transcatheter Pacing System, Nanostim Leadless Cardiac Pacemaker, transvenous pacemaker Disclosure: Dr Beurskens has nothing to declare. Dr Tjong reports consulting fees from Boston Scientific and Abbott. Dr Knops reports consulting fees, research grants and honoraria for Boston Scientific, and consulting fees and research grants with Medtronic and Abbott. Received: 14 July 2017 Accepted: 31 July 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(3):129–33. DOI: 1015420/aer.2017:16:1 Correspondence: Dr Niek EG Beurskens, AMC Heart Center, Department of Cardiology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. E: n.e.beurskens@amc.nl

Since its introduction in 2012, leadless pacemaker (LP) therapy has developed as a therapeutic alternative to conventional transvenous pacemaker (PM) therapy to circumvent lead- and pocket-related complications.1-4 To date, two LPs are available for patients with a single-chamber pacing (VVI) indication: the Nanostim Leadless Cardiac Pacemaker (LCP; Abbott) and the Micra Transcatheter Pacing System (TPS; Medtronic). The LPs have shown to meet the pre-specified safety and performance criteria in two large prospective multicentre single-arm studies.3,4 The LPs demonstrated similar pacing performance and safety results, and exhibit high implantation success rates.5 Reynolds et al. performed a post hoc analysis of patients who received Micra TPS implantation compared with patients who underwent transvenous PM therapy in a historical control cohort. Micra TPS had fewer major complications compared to patients in the historical control cohort at 6-month follow-up: 4.0 % versus 7.4 %, respectively.3 Reddy et al. demonstrated that long-term complication rates are expected to decrease by 71 % following Nanostim LCP implantation compared to conventional transvenous PM therapy.6 Despite these promising results, there is an important challenge to consider: the end-of-life (EOL) management of LP therapy. The optimal approach at the end of service of conventional transvenous PM therapy has been studied in great detail.7,8 The subcutaneous generator is readily accessible for replacement, leaving the leads in place.7 PM lead extraction can be a high-risk procedure and is associated with serious complications, including cardiac perforation and death.8 Up to three leads can be placed intracardially, without haemodynamic compromise.7 Optimal EOL strategy of LP therapy is subject to debate. The estimated

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battery longevity of the LP ranges between 4.7 and 15 years, depending on pacing parameters.2,3,9 Therefore, selected patients might require multiple devices over their lifespan. Once the EOL of the LP approaches, there are two options for implanting physicians to address this problem. LPs were designed so that they can be programmed in a non-functional mode. The LP can be abandoned and an additional device may be implanted adjacent to the non-functional LP. Important concerns have been raised regarding the aforementioned option. Multiple devices in the heart may compromise cardiac function, or be a source of interference. The second replacement strategy is to extract the LP and subsequently implant a new device. However, extraction may not be feasible due to encapsulation of the device, and this will probably be more prevalent with more chronic use of LP therapy. Of note, there are situations where extraction of the LP may be necessary, such as in infection or dislocation. Recently, a battery advisory was distributed by Abbott stating that 7 of 1423 (0.5 %) patients had a battery malfunction that occurred more than two years after Nanostim LCP implantation. This battery dysfunction has not been shown to affect Micra TPS. With the battery advisory and the more chronic use of LPs, recommendations for EOL management become increasingly important. Therefore, an up-to-date review of available evidence on retrieval of LPs is highly clinically relevant. In this review we describe the safety, feasibility and histopathological examination of LP retrieval.

Leadless Pacemaker and Retrieval Systems Both LPs are cylindrical intracardiac devices; however, there are differences in design that merit emphasis. The Nanostim LCP is 42 mm long and 5.99 mm in diameter, whereas the Micra TPS measures

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Devices Figure 1: Characteristics of Clinically Available Leadless Pacemakers Leadless Pacemakers

Nanostim LCP

Micra TPS

Dimensions, mm

42.0 x 5.99

25.9 x 6.7

Volume, cc

0.8

Weight, g

Sheath Size, Fr

21 OD/ 18 ID

27 OD/ 23 ID

Battery Longevity, yrs

8.5 – 9.8

4.7 – 9.6

Fixation Mechanism

Helix

4 Nitinol Tines

Left: Nanostim Leadless Cardiac Pacemaker (Abbott). Right: Micra Transcatheter Pacing System (Medtronic). cc = cubic centimetre; ID = inner diameter; Fr = French; g = gram; LCP = leadless cardiac pacemaker; mm = millimetre; OD = outer diameter; TPS = transcatheter pacing system; yrs = years.

Figure 2: Retrieval of Leadless Pacemakers

towards the right atrium. The protective sleeve is retracted when positioned near the Nanostim LCP, and the single- or triple-loop snare is engaged to capture the distal cap of the LP in the RV. The snare is closed to grab the proximal docking feature of the device. After docking the Nanostim LCP, the helix can be unscrewed with two full rotations from the endocardium by turning it counter-clockwise. The protective sleeve is advanced over the total LCP, and it can be removed from the body. The Micra TPS does not have a dedicated retrieval system. It was designed with a retrieval feature at the proximal end of the LP to accommodate an off-the-shelf snare that can hold the device for removal from the myocardium. A conventional gooseneck snare alone or inserted through the delivery catheter can be used for the retrieval. The advantage of the latter option is that counter traction can be applied to the myocardium with the cup of the implant catheter. In Figure 2 the retrieval of the LP systems are illustrated.

Pre-Clinical Data on Retrieval and Multiple Implanted Leadless Pacemakers Nanostim Leadless Pacemaker

Nanostim LCP (upper) and Micra TPS (bottom). The retrieval catheter is introduced via the femoral vein towards the right atrium. The snare at the end of the retrieval catheter is engaged under fluoroscopic guidance to capture the retrieval features of the leadless pacemakers. After docking the Nanostim LCP, the helix can be unscrewed with two full rotations from the endocardium by turning it counter-clockwise. For the Micra TPS, the snare grabs the waist of the retrieval feature and the device is pulled out from the myocardium while exerting controlled counter pressure using the sheaths. LCP = leadless cardiac pacemaker; Fr = French; TPS = transcatheter pacing system. Sources: Koay, et al., 201620; Tjong and Reddy.5

25.9 mm in length and 6.7 mm in diameter. The characteristics of the devices are shown in Figure 1. Implantation of the devices is performed in the catheterization laboratory, under fluoroscopy. An introducer sheath (21F outer diameter [OD] for the Nanostim and 27F OD for the Micra TPS) is percutaneously placed in the femoral vein to deliver the device through the vena cava inferior towards the right ventricle (RV) using a steerable catheter. The Nanostim LCP uses an active helix to fixate the LP into the cardiac tissue of the RV. The Micra TPS is anchored into the right ventricular myocardium using an active fixation mechanism that is composed of four nitinol tines. Different retrieval tools are available for the Nanostim LCP and the Micra TPS. The manufacturers of the Nanostim LCP developed a dedicated steerable retrieval catheter to allow retrieval of the device. The retrieval catheter is introduced via the femoral vein through an 18F sheath. The snare (single-loop or triple-loop) and the integrated protective sleeve at the end of the retrieval catheter are engaged under fluoroscopic guidance from the vena cava inferior

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Early animal experience on retrieval of the Nanostim LCP has shown positive results. Koruth et al. evaluated the mid-term and long-term feasibility and safety of percutaneous, catheter-based retrieval of the Nanostim LCP in an ovine study.10 To evaluate mid-term retrieval capability, ten sheep underwent retrieval at a mean of 160 days, and in eight additional sheep the Nanostim LCP was extracted at a mean of 2.3 years. All mid-term and long-term retrieval attempts showed a 100 % success rate. Echocardiographic pre- and post-implant evaluation showed no signs of pericardial effusion. For the mid-term group, the time from insertion of the retrieval catheter to retrieval of the LP was 2.35 min, whereas for the long-term group this was 3.04 min. The relative short retrieval times underline the ease of the retrieval attempts. It is important to note that histological characteristics of ovine myocardium and its reaction to the device may be different compared to the human heart.

Micra Transcatheter Pacing System Early pre-clinical animal experience demonstrated successful retrievals in three out of four ovines up to 28 months after Micra TPS implantation.11 The unsuccessful attempt was due to full encapsulation of the device. It has been suggested that a new LP can be placed adjacent to the abandoned non-functional LP. However, two important issues arise: (1) the maximum number of LPs the RV can accommodate anatomically; and (2) the effect of multiple intracardiac devices on RV function. Therefore, Omdahl et al. evaluated the number of Micra TPS that could be placed in human cadaver hearts.12 Seven hearts were successfully implanted with three Micra TPS in traditional pacing locations using standard implantation procedures. They concluded that the RV was able to accommodate three Micra TPS without physical interaction, even in a small RV of 35 cc. However, mechanical or electric interactions between intracardiac Micra TPS may be different in contracting human hearts. To assess the effect of multiple LPs on the RV cardiac function, Chen et al. sequentially implanted two Micra TPS within 1 month in 14 pigs.13 Of all pigs that underwent implantation procedures, five animals died prior to the end of the 6-month follow-up. Echocardiography was performed at baseline, at second implantation, and at the end of the 6-month follow-up. Chen and co-workers showed no significant changes in cardiac proportions based on echocardiography and no observation of injury to the tricuspid valve.

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End-of-life Management of Leadless Cardiac Pacemakers Table 1: Overview of Retrieval Data of Leadless Pacemaker Therapy Study Type

Leadless

Year of

Pacemaker

Publication

First Author

Pre-clinical Nanostim 2014 Koruth

Number 10 8

Time LP in situ

Extraction

Reason Unsuccessful

(mean)

Success Rate

Extraction

160 days 2.3 years

100 % 100 %

N/A N/A

Micra TPS 2014 Bonner 4 28 months 75 % (3)

Complete encapsulation of device

Clinical

N/A

Nanostim

2016

Jung

506 days

100 %

Nanostim 2016 Reddy 5 <6 weeks 100 % 11 >6 weeks 91 % (10)

The docking feature could not be reached.

Nanostim 2017 Lakkireddy 73 1.7 years 90.4 % (66)

The docking button could not be reached in six cases. In one case, the docking button detached.

Micra TPS 2017 Tjong and Reddy 10 229 and 259 days* 80 % (8)

Unable to be removed due to fluoroscopy malfunction

Micra TPS

2016

Karim

3 weeks

100 %

N/A

Micra TPS

2016**

Giocondo

228 days

0 %

Unknown

Micra TPS

2016

Koay

1 month

100 %

N/A

Micra TPS

2016

Gerdes

Intraprocedural

100 %

N/A

LP = leadless pacemaker; N/A = not applicable; TPS = transcatheter pacing system. *In unsuccessful attempt cases used source: Micra Transcatheter Pacing System, 2016.17 **Heart Rhythm Society, 2016.19

Clinical Data on Leadless Pacemaker Retrieval Nanostim Leadless Pacemaker Jung et al. described a case of successful retrieval of a Nanostim LCP 506 days post-implant.14 The reason for extraction was because the patient had an indication for cardiac resynchronisation therapy. Reddy et al. performed a multicentre study, wherein they evaluated feasibility and safety of retrieval before and after 6 months post-Nanostim LCP implantation in 16 patients.15 The mean time from LCP implantation to retrieval attempt was 240 days. The indications for retrieval were elevated pacing thresholds (n=8), deterioration of heart failure (n=5), pacing failure (n=1), defibrillator implantation (n=1) and elective explantation (n=1). The success-rate was 94 % (15 of 16 patients). For the unsuccessful retrieval attempt, the device had been implanted for 103 days. The docking feature could not be reached due to its location near the tricuspid valve. A new Nanostim LCP was implanted adjacent to the initial LCP, and no procedure-related adverse events were reported. In a study by Lakkireddy et al., the worldwide experience on battery failure and Nanostim retrieval was evaluated.16 An attempt for retrieval was performed in 73 patients following Nanostim LCP implantation. The time that the Nanostim LCP was implanted in the heart ranged from 0.2 to 4.0 years. In 66 of these cases the retrieval attempts were successful (i.e. 90.4 %). Another 115 patients received an additional LP or conventional transvenous PM adjacent to the abandoned Nanostim LCP due to the advisory. No adverse haemodynamic, mechanical or electrical interactions were reported. In two cases a serious adverse occurred related to the Nanostim LCP retrieval. In one case an atriovenous fistula developed and in one case the docking button detached and migrated into the pulmonary artery.

Micra Transcatheter Pacing System Tjong and Reddy reported that 13 patients who underwent Micra TPS implantation required a system revision.5 The indications for revision were due to pacemaker syndrome, elevated thresholds, upgrade to biventricular pacing, and device infection. In 8 of 10 patients the attempt for retrieval was successful. For the unsuccessful attempts, the Micra TPS were 229 and 259 days in situ.17 One of these Micra devices was snared but was unable to be removed due

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to fluoroscopy malfunction. In the three remaining patients who required system revision, retrieval was not attempted and the device was abandoned. Karim et al. reported the first successful extraction of a Micra TPS in a patient 3 weeks after initial device implantation.18 The Micra TPS had elevated capture thresholds. The automated capture management algorithm consequently increased the pacing output. Since the expected battery longevity would decline substantially, the physicians decided to retrieve the Micra TPS and subsequently implant a new LP. In contrast, one case was presented at the 37th Heart Rhythm Society Scientific Sessions (San Francisco, CA, USA) that demonstrated an unsuccessful retrieval of the device implanted after 228 days.19 Koay et al. was the first investigator who described the extraction of an infected Micra TPS.20 The patient developed symptoms of infection 1 month after Micra TPS implantation. Transoesophageal echocardiography demonstrated a vegetation attached to the proximal part of the device. Device interrogation demonstrated elevated capture threshold and increased pacing output. Therefore, it was decided to extract the Micra TPS and this proceeded uneventfully. Gerdes et al. described a case of Micra TPS retrieval after tether removal, while no standard correctly dimensioned snare was available.21 A steerable sheath (Agilis, St Jude Medical) was engaged into the introducer; however, incongruent proportions led to blood leakage from the introducer. After manually solving this problem, a standard 6F 20-mm snare kit (Amplatz Goose Neck) was inserted to withdraw the Micra TPS. Subsequently, a new Micra TPS was successfully implanted. An overview on retrieval data of LP therapy is displayed in Table 1.

Histopathological Examination Occurrence of encapsulation and histopathological evaluation of the LP is highly relevant as it may influence LP retrieval management. Fibrous tissue formation might complicate the recapture of the device. Therefore, multiple pre-clinical studies and case reports have been published addressing this topic.

Nanostim Leadless Pacemaker Koruth et al. performed pathological examination of the Nanostim LCP in an ovine study in which devices had been implanted for a

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Devices mean of 2.3 years.10 They showed that there was no visible tissue on the body of the LCP. There was little fibrous tissue located at the proximal docking feature, and distal helix. Some subendocardial haemorrhage was observed at the implant site in the RV apex. In the study by Reddy et al., 16 patients with a Nanostim LCP underwent a retrieval attempt at a mean of 240 days.15 Although no pathological evaluation was performed, visual inspection showed that in 10 of 16 (63 %) patients, fibrous tissue was present on the docking knob or helix, and in 1 there was near-complete device encapsulation. Tjong et al. described a patient’s postmortem histological examination at 19 months after Nanostim LCP implant.22 The evaluation revealed partial (i.e. approximately 60 %), ongoing myofibrocellular encapsulation around the Nanostim LCP.

LP, the potential risk for device–device interference is mitigated, as well as unknown long-term risks associated with multiple devices in situ. In addition, the option of retrieval may result in a more accessible RV in case re-implantation of an additional device is indicated. Several strategies should be implemented to prevent early battery depletion. It is recommended to avoid relatively high pacing thresholds as they inversely affect battery longevity of the LP. Economic programming of the LP may positively influence battery longevity, especially in non-pacemaker dependent patients. In these patients, pacemaker outputs can be programmed close to the pacing threshold. Therefore, Micra TPS has an automatic capture management to ensure pacing outputs remain at safe levels while adapting outputs to maximise battery longevity.

Micra Transcatheter Pacing System In a swine study performed by Chen et al., nine animals reached the endpoint with a mean follow-up of 215 days.13 Necropsy and histopathological examination showed little fibrous tissue around the extracted Micra TPS, and there were no observations of tricuspid valve injury. Complete encapsulation of the Micra TPS has been observed during autopsy of a patient 1 year after Micra TPS implantation.23 This Micra TPS was adherent to the adjacent papillary muscle and immunohistochemistry revealed signs of chronic inflammation around the Micra TPS. In a pre-clinical study, one of four Micra TPS was not retrievable at 28 months following implantation.11 Necropsy analysis of the unsuccessful retrieval attempt demonstrated the device was fully encapsulated. In a case report by Koay et al., the infected Micra TPS that was successfully extracted was covered with a thin layer of fibrous tissue firmly attached to all the fixation tines.20 The histopathological examination demonstrated fibrous tissue with infiltration of neutrophils and histiocytes, confirming the existence of inflammation.

Recommendations and Perspectives Strategies to replace LPs reaching end of service remain an unsettled concern. One option is to abandon a non-functional LP and place an additional device in the RV. The volume of the LPs (0.8–1.0 cc) occupies less than 2 % of the normal RV volume,24 consequently causing negligible hemodynamic compromise. In a study by Lakkireddy et al. no devicedevice related adverse events were reported in 115 patients in whom a new device was implanted adjacent to the abandoned Nanostim LCP.16 Electrical interaction between the functioning and non-functioning device is unlikely; however, there is currently no long-term evidence to confirm this assumption. In selected cases, one can assume that attempting extraction of a fully encapsulated LP may have higher risk than leaving the device in place. Progressive encapsulation over time might even make retrieval impossible without open-heart surgery. Although the aforementioned clinical scenarios show that there are valid arguments for this EOL strategy, we suggest that the approach of extracting the LP is more appealing to limit the amount of nonfunctioning intracardiac hardware. By extracting the non-functioning

eddy VY, Knops RE, Sperzel J, et al. Permanent R leadless cardiac pacing: results of the LEADLESS trial. Circulation 2014;129:1466–71. DOI: 10.1161/ CIRCULATIONAHA.113.006987; PMID: 24664277. Reddy VY, Exner DV, Cantillon DJ, et al. LEADLESS II Study Investigators. Percutaneous implantation of an entirely intracardiac leadless pacemaker. N Engl J Med 2015;373: 1125–35. DOI: 10.1056/NEJMoa1507192; PMID: 26321198. Reynolds D, Duray GZ, Omar R, et al. Micra Transcatheter Pacing Study Group. A leadless intracardiac transcatheter pacing system. N Engl J Med 2016;374:533–41. DOI: 10.1056/ NEJMoa1511643; PMID: 26551877. Knops RE, Tjong FV, Neuzil P, et al. Chronic performance of a leadless cardiac pacemaker: 1-year follow-up of the

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It is evident that incorporating a long-life self-rechargeable battery, or even no battery, would provide a major improvement in cardiac pacing therapy. A permanent PM system capable of self-recharging would circumvent disadvantages related to PM replacement, and eliminate its related risks. It was shown in a pre-clinical study that lead- and batteryless pacing was feasible using its own heart motion.25 In another pre-clinical study, a batteryless PM was developed that was powered by a solar module that converted transcutaneous light into electrical energy.26 This PM was able to provide pacing therapy continuously at a rate of 125 BPM for 1.5 months in the dark. Retrieval of the LP remains an essential consideration for patients who are potentially eligible for leadless VVI pacing therapy. The potential inability to retrieve chronically implanted devices may limit the application of this novel technology in selected cases. Although initial studies have demonstrated promising results, early experience on retrieval feasibility and safety of LP therapy is mixed. Therefore, longterm prospective analysis is required to define the most optimal EOL strategy concerning LP therapy. n

Clinical Perspective • There are two strategies to address end-of-life management of leadless pacemakers: (1) placing an additional leadless device adjacent to the non-functioning leadless pacemaker and (2) retrieving the non-functioning leadless pacemaker and subsequently implanting a new device. • There are clinical scenarios that have valid arguments for both aforementioned end-of-life strategies. • We suggest that the approach of LP retrieval is more appealing to limit the amount of non-functioning intracardiac hardware, mitigate risk for device interference, and limit unknown longterm complications associated with multiple chronic implanted leadless pacemakers.

LEADLESS trial. J Am Coll Cardiol 2015;65:1497–1504. DOI: 10.1016/j.jacc.2015.02.022; PMID: 25881930. Tjong FV, Reddy VY. Permanent Leadless cardiac pacemaker therapy: a comprehensive review. Circulation 2017;135:1458–70. DOI: 10.1161/CIRCULATIONAHA.116.025037; PMID: 28396380. Reddy VY, Cantillon DJ, John IP, et al. A comparative study of acute and mid-term complications of leadless vs transvenous pacemakers. Late-Breaking Clinical Trials II. Presented at Heart Rhythm Society 2016, San Francisco, CA, 6 May 2016. Abstract LBCT02–04. Wilkoff BL, Love CJ, Byrd CL, et al. Transvenous lead extraction: Heart Rhythm Society expert consensus on facilities, training, indications, and patient management: this document was endorsed by the American Heart Association

(AHA). Heart Rhythm 2009 Jul;6:1085–104. DOI: 10.1016/ j.hrthm.2009.05.020; PMID: 19560098. 8. Hauser RG, Katsiyiannis WT, Gornick CC, et al. Deaths and cardiovascular injuries due to device-assisted implantable cardioverter-defibrillator and pacemaker lead extraction. Europace 2010;12:395–401. DOI: 10.1093/europace/eup375; PMID: 19946113. 9. Micra Transcatheter Pacing System: MC1VR01. Product Specifications. http://www.medtronic.com/content/dam/ medtronic-com/products/ cardiac-rhythm/pacemakers/ micra-pacing-system/documents/2016-04-micraspecification-sheet.pdf (accessed 29 September 2016). 10. Koruth JS, Rippy MK, Khairkhahan A, et al. Percutaneous retrieval of implanted leadless pacemakers: feasibility at

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End-of-life Management of Leadless Cardiac Pacemakers

2.5 years post-implantation in an in vivo ovine model. JACC Clin Electrophysiol 2015;1:563–70. DOI: 10.1016/j.jacep.2015.07.013. 11. B onner MD, Neafus N, Byrd CL, et al. Extraction of the Micra Transcatheter Pacemaker System. Heart Rhythm 2014;11:S342. 12. Omdahl P, Eggen MD, Bonner MD, et al. Right ventricular anatomy can accommodate multiple Micra Transcatheter Pacemakers. Pacing Clin Electrophysiol 2016;39:393–7. DOI: 10.1111/pace.12804; PMID: 26710918. 13. Chen K, Zheng X, Dai Y, et al. Multiple leadless pacemakers implanted in the right ventricle of swine. Europace 2016;18:1748–52. DOI: 10.1093/europace/euv418; PMID: 26830889. 14. Jung W, Sadeghzadeh G, Kohler J, et al. Successful retrieval of an active fixation leadless pacemaker in a 74-year-old woman 506 days post-implant. Europace 2016; DOI: 10.1093/ europace/euw196; PMID: 27371661; epub ahead of press. 15. Reddy VY, Miller MA, Knops RE, et al. Retrieval of the leadless cardiac pacemaker: A multicenter experience. Circ Arrhythm Electrophysiol 2016;9:e004626. DOI: 10.1161/ CIRCEP.116.004626; PMID: 27932427. 16. Lakkireddy D, Knops R, Atwater B, et al. A worldwide experience of the management of battery failures and chronic device retrieval of the Nanostim Leadless

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17.

18.

19.

20.

21.

Pacemaker. Heart Rhythm 2017. pii: S1547-5271(17)30846-9. DOI: 10.1016/ j.hrthm.2017.07.004; PMID: 28705736; epub ahead of press. Micra Transcatheter Pacing System (TPS). FDA Panel Pack for Circulatory Systems Devices Panel, 18 February 2016. http://www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials/ MedicalDevices/MedicalDevicesAdvisoryCommittee/ CirculatorySystemDevicesPanel/UCM485094.pdf (accessed 29 September 2016). Karim S, Adbelmessih M, Marieb M, et al. Extraction of a Micra Transcatheter Pacing System: first-in-human experience. Heart Rhythm Case Reports 2016;2:60–2. DOI: 10.1016/j.hrcr.2015.10.001; PMID: 28491633. Giocondo. Unsuccessful extraction of a Medtronic Micra Leadless Pacemaker. 37th Heart Rhythm Society 2016, San Francisco, CA, 4-7 May 2016. Koay A, Khelae S, Kok Wei K, et al. Treating an infected transcatheter pacemaker system via percutaneous extraction. Heart Rhythm Case Reports 2016;2:360–2. DOI: 10.1016/j.hrcr.2016.04.006; PMID: 28491710. Gerdes C, Nielsen JC. Retrieval of Medtronic Micra Transcatheter Pacing System after tether removal. Europace 2016 Aug;18:1202. DOI: 10.1093/europace/euv444; PMID:

26851811. 22. T jong FV, Stam OC, van der Wal AC, et al. Postmortem histopathological examination of a leadless pacemaker shows partial encapsulation after 19 months. Circ Arrhythm Electrophysiol 2015;8:1293–5. DOI: 10.1161/CIRCEP.115.003101; PMID: 26487626. 23. Kypta A, Blessberger H, Lichtenauer M, et al. Complete encapsulation of a leadless cardiac pacemaker. Clin Res Cardiol 2016;105:94. DOI: 10.1007/s00392-015-0929-x; PMID: 26493306. 24. Tamborini G, Marsan NA, Gripari P, et al. Reference values for right ventricular volumes and ejection fraction with real-time three-dimensional echocardiography: evaluation in a large series of normal subjects. J Am Soc Echocardiogr 2010;23:109–15. DOI: 10.1016/j.echo.2009.11.026; PMID: 20152691. 25. Zurbuchen A, Haeberlin A, Bereuter L, et al. The Swiss approach for a heartbeat-driven lead- and batteryless pacemaker. Heart Rhythm 2017;14:294–9. DOI: 10.1016/j. hrthm.2016.10.016; PMID: 27756706. 26. Haeberlin A, Zurbuchen A, Walpen S, et al. The first batteryless, solar-powered cardiac pacemaker. Heart Rhythm 2015 Jun;12:1317–23. DOI: 10.1016/j.hrthm.2015.02.032; PMID: 25744612.

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Mechanisms of Arrhythmias

Ventricular Arrhythmia after Acute Myocardial Infarction: ‘The Perfect Storm’ Justine Bhar-Amato, William Davies and Sharad Agarwal Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge, United Kingdom

Abstract Ventricular tachyarrhythmias (VAs) commonly occur early in ischaemia, and remain a common cause of sudden death in acute MI. The thrombolysis and primary percutaneous coronary intervention era has resulted in the modification of the natural history of an infarct and subsequent VA. Presence of VA could independently influence mortality in patients recovering from MI. Appropriate risk assessment and subsequent treatment is warranted in these patients. The prevention and treatment of haemodynamically significant VA in the post-infarct period and of sudden cardiac death remote from the event remain areas of ongoing study.

Keywords Acute myocardial infarction, ventricular arrhythmias, risk assessment, management Disclosure: The authors have no conflicts of interest to declare. Received: 30 July 2017 Accepted: 17 August 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(3):134–9. DOI:10.15420/aer.2017.24.1 Correspondence: Sharad Agarwal, consultant cardiologist and electrophysiologist, Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge CB23 3RE. E: sharad.agarwal@nhs.net

Ventricular tachyarrhythmias (VAs) most commonly occur early in ischaemia, and patients presenting with an acute MI and ventricular arrhythmias are a group that has a significantly increased risk of mortality.1,2 Thrombolysis primary percutaneous coronary intervention (PCI) and use of beta-blockers, while resulting in the modification of the natural history of an infarct, have also reduced the incidence of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) occurring within 48 hours of the onset of an acute coronary syndrome (ACS), over the past decades.3 The prevention and treatment of haemodynamically significant VA in the post-infarct period, and of sudden cardiac death (SCD) remote from the event, remain areas of ongoing study. Prompt revascularisation and drug therapy, including anti-platelets, statins, angiotensin converting enzyme (ACE)-inhibitors and betablockers, have markedly reduced the incidence of VA.4–8 Nevertheless, approximately 10% of post-MI survivors remain at high risk of dying in the first months or years following hospital discharge (mortality >25% at 2 years).9 Sudden death secondary to sustained VT or VF accounts for about 50% of all deaths in these high-risk patients.10 There remain three vulnerable classes of patients: patients presenting after a long period of chest pain, patients who have undergone only partial revascularisation and those with a pre-existing arrhythmogenic substrate.11 VA is seen more often in those with cardiogenic shock, related to the size of the infarct. A genetic predisposition to VA in the context of ischaemia may also exist. The finding of early repolarisation (ER) changes being more prevalent in idiopathic VF survivors and their relatives, and on the ECGs of patients with coronary artery disease and ST-segment elevation MI (STEMI) who experience VA perhaps alludes to this.12,13 There is a temporal distribution to VA post-acute MI: an early, or acute phase, of up to 48–72 hours, which is a time of very dynamic ischaemia and reperfusion. From 72 hours to a few weeks up to a

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month post event, and a more chronic phase beyond that, where remodelling continues to occur. Premature ventricular contractions (PVCs) are common in the early phase. The significance of these and the occurrence of non-sustained or sustained VA in terms of shortand long-term prognosis have been debated over the years. It appears there needs to exist a combination of biochemical, electrophysiological, autonomic and, as yet unknown, genetic factors culminating in a so-called ‘perfect storm’ resulting in arrhythmia in the post-MI period. Patients who develop sustained VF or VT >48 hours after their index MI have a significantly higher rate of all-cause mortality; however, the relationship between early (within 48 hours of the index MI) VF/VT and mortality remains controversial. Some data have suggested that sustained ventricular arrhythmias during the early post-MI period may be associated with increased 30-day mortality, but without a protracted risk over the long term.14–16 Non-sustained VT in the early-phase post-MI does not contribute to risk assessment in this group of patients.17 The prognostic implication of VA post PCI was studied in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONSAMI) Trial. In this, 5.2% patients developed VA post primary PCI with 85% of the VA happening in the first 48 hours. They reported that sustained VT/VF after primary PCI was not significantly associated with 3-year mortality or major adverse clinical events.18

Mechanisms of Ischaemic Arrhythmogenesis: From the Cell Upwards Acute MI is characterised histopathologically by coagulative necrosis of the myocardium. In a non-reperfused MI, this is seen within 30 to 40 minutes of sustained ischaemia, with the changes only visible at the resolution electron microscopy. From 2 weeks, scar develops from the periphery to the centre, and its formation is complete after the second month.19 Any attempt at reperfusion potentially alters this process.

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Ventricular Arrhythmia after Acute MI Thus there is a temporal distribution to the occurrence and postulated mechanisms of ventricular arrhythmia in the post-MI period. In animal studies, an early, potentially reversible, phase within the first 30 minutes following epicardial coronary artery occlusion was identified. This is followed by an irreversible phase from 90 minutes to 72 hours, during which there is rapid evolution of the characteristics of the infarcted tissue.19 Reperfusion contributes to the profound electrophysiological changes. Acute ischaemia causes hypoxia, which results in an intracellular depletion of adenosine triphosphate and the consequent accumulation of adenosine diphosphate and the products of anaerobic glycolysis, leading to intracellular acidosis. This drop in pH activates the Na+/H+ and Na+/Ca++ion exchange channels, with expulsion of hydrogen ions in exchange for sodium, which passes into the cell and is then exchanged for calcium, resulting in cell swelling and calcium overload. This is accompanied by the build-up of extracellular potassium, cathecholamines and lysophosphatidylcholine. This results in depolarisation of the cell membrane and reduction of the fast inward sodium current and increase in the late sodium current initially prolonging the action potential duration (APD). Ultimately, abbreviation of the APD, seen during ischaemia, results from decreased inward calcium currents (inhibited by the acidosis) and enhanced outward ATP-sensitive potassium current due to reduction in intracellular ATP, following hypoxia. A lower reduced resting transmembrane potential, intracellular calcium mishandling and reduced functional gap junctions also result. The cessation of anaerobic glycolysis marks the next phase resulting in low glycogen and high lactic acid intracellular content, reduction of ATP levels to below 10%, sodium and calcium overload and further accumulation of extracellular potassium. Spontaneous calcium oscillations trigger early and late afterdepolarisation-induced ventricular ectopics.11,19 Surviving purkinje fibres with shortened APD or reduced amplitude, depolarised membrane potentials and reduced Vmax are thought to be the source of automatic foci for VA. The partial and temporal dispersal repolarisation contribute to a re-entrant mechanism based on regions of unidirectional conduction block, fractionation of cellular electrograms and shortened APDs.11 Tissue heterogeneity is particularly marked in the peri-infarct or ‘border zone’ and it is here that arrhythmogenesis is thought to arise.11,19 Of note, both human and animal studies have shown abnormal sympathetic activity in these border zones. These nerve terminals are more susceptible to ischaemic damage than myocytes.20 It has been well recognised that re-entry through a stable circuit involving the infarct scar tissue is the most-likely mechanism of sustained monomorphic ventricular tachycardia.21 In acute myocardial ischaemia, with no previous scar, zones of slow conduction and block may create conditions for re-entry. These patients are likely to have large infarct areas and a very large acute ischaemic zone may create the conditions for a transiently stable re-entry circuit capable of sustaining a monomorphic re-entrant tachycardia.15 Alternatively, mechanical stretching of a failing ventricle alongside high sympathetic drive associated with MI can result in VA because of focal triggers.22

Identifying those at Risk of Post-infarction Ventricular Tachyarrhythmia Various invasive and non-invasive tools have been used to identify patients most at risk of SCD following MI. Left ventricular ejection along with inducibility of VA during programmed electrical stimulation have

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been most cited as factors identifying patients most at risk. Due to the dynamic phase of repair and remodelling after the acute episode, the acute assessment of these parameters may not reliably predict longterm risk of arrhythmic death. It is estimated that around 15–20% of all AMI patients will have LVEF ≤35% at the time of revascularisation for AMI.23 However, recovery of reduced LVEF after AMI with or without immediate PCI is often unpredictable. In a study by Solomon et al., 3 months after AMI, 22% of all patients with abnormal LV function at the time of AMI recovered to normal LV function.24 Assessment of LVEF to risk stratify and subsequent implantation of ICD early (within 40 days) post-MI has not been shown to be of prognostic benefit.25,26

Left Ventricular Ejection Fraction The incidence of VA is directly proportional to the size of an infarct and inversely related to the LVEF. Late presenters, and in those whom there is failure to achieve adequate patency of the culprit artery, are the most at risk. In addition, over a third of patients with STEMI, and the majority of those with STEMI complicated by cardiogenic shock, have significant bystander coronary disease, and appear to be at increased risk of VA,11 presenting a valid argument for early full revascularisation. Transthoracic echocardiography is used routinely to assess the extent of infarct and to risk stratify patients on the basis of LVEF. When quantifying LVEF alone, there is greater operator variability in echo compared with MRI. Irrespective of the mode of LVEF determination, there are limitations in its use in identifying those at risk of VA and SCD. The multicenter automatic defibrillator implantation trial (MADIT) identified a mortality benefit from ICD in 5.6% of patients with a postinfarct LVEF of 30% or lower over 27 months from the index event.27 The sudden cardiac death in heart failure trial (SCD-HeFT) identified a mortality benefit of 7.3% over 60 months in those with an LVEF of 35% or less.28 Apart from being quite modest numbers, most patients who suffer a cardiac arrest post-MI have an LVEF higher than 35%.29 When looking at VA and SCD risk in the longer term it is worth noting that less than 20% of ICD recipients in the above-mentioned studies received appropriate ICD therapies in their respective follow-up periods.27 Additionally in the setting of chronic coronary artery disease, an analysis of the multicenter unsustained tachycardia trial (MUSTT) study would seem to advise caution in attributing risk based on LVEF alone. Those who experienced non-sustained ventricular tachycardia (NSVT), a condition of recruitment into the study, and an LVEF of anywhere between 30% and 40%, demonstrated higher risk of arrhythmic death or cardiac arrest compared with LVEF of or less than 30% when other factors were taken into account.30 The variables having the greatest prognostic impact in multivariable analysis were functional class, history of heart failure, NSVT not related to bypass surgery, EF, age, LV conduction abnormalities, inducible sustained ventricular tachycardia, enrolment as an inpatient and AF. Non-invasive assessments of scar burden, ventricular conduction and repolarisation, as well as autonomic tone, have been explored in risk prediction. Cardiac magnetic resonance is far superior at characterising infarcted tissue and assessing scar burden compared with other imaging modalities. Increased tissue heterogeneity31 and a larger peri-infarct or ‘border zone’ has been found to correlate with increased mortality risk and MRI is better able to assess these.32 Large-scale data assessing how primary prevention ICD therapy could be guided by MRI beyond LVEF assessment is lacking. A study of 48 patients with known coronary

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Mechanisms of Arrhythmias artery disease referred for PES did find that infarct surface area and mass measured by cardiac MRI more accurately identified patients with a substrate for monomorphic VT, compared with LVEF.33 The majority of patients were studied beyond a month post-MI. DETERMINE-ICD is a current large, randomised trial looking into prophylactic ICD therapy in post-MI in patients with an LVEF greater than 35% and extensive scarring assessed by MRI.

Programmed Electrical Stimulation Current data only support the use of PES in post-MI patients with LVEF of 40% or less. The timing of programmed electrical stimulation (PES) is an area of debate. In MADIT I, patients with inducible VA and LVEF of 35% or less late post-MI were found to derive most mortality benefit from an ICD.34 The same finding in beta-blocker Strategy plus Implantable Cardioverter Defibrillator (BEST+ICD) less than a month post-MI suggested that inducibility early after the event may do the same but was really unable to predict benefit.35 The Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) trial, however, found that inducible VT at 6 weeks post-MI was a strong predictor of future arrhythmic events.36 Beyond the fact that differences in stimulation protocol is one factor that can account for the variation in study findings, PES is still marred by low sensitivity demonstrated in part by the fact that more than a quarter of patients with an LVEF of 35% or less and a negative study went on to have serious events.37

Other Risk Assessment Modalities None of the non-invasive assessments of ventricular conduction and repolarisation or autonomic tone have yet been individually found to be of use in accurately predicting risk of VA or to guide ICD therapy.29 Measures of ventricular conduction include QRS duration, signal-averaged ECG and Wedensky modulation (the identification of local perturbations within the QRS following delivery of a subthreshold impulse during the ventricular refractory period). Measures of ventricular repolarisation include QT variability and dispersion, T loop morphology variations, T wave variance, the QT/RR slope and T wave alternans. Measures of autonomic tone include assessment of linear and non-linear heart rate variability (HRV), baroreflex sensitivity, heart rate turbulence and deceleration capacity. Risk Estimation following Infarction Non-invasive Estimation (REFINE)-ICD has been designed to evaluate prophylactic ICD therapy in post-MI patients with LVEF of 36% to 49% and abnormal Holter T wave alternans and heart rate turbulence.29 An increased incidence of ER on the ECG in the form of a slurring or notching in the terminal portion of the QRS complex in the inferior and/or lateral leads has been found in patients with coronary artery disease. Patel et al. compared 50 individuals with VA within the first 72 hours post-STEMI and 50 individuals without VA. Arrhythmias included sustained VT, non-sustained VT and VF. When looking at ECGs recorded 1 year prior to the MI, they found a higher prevalence of ER among those with VA, even after adjusting for creatine kinase (CK)-MB levels and LVEF.38 Another group reported a higher prevalence of ER in over 400 SCD victims ascribed to acute coronary syndrome following postmortem.39 This was in addition to the findings that more victims were male smokers with a lower BMI, higher heart rate, with prolonged QRS durations and a lower prevalence of history of cardiovascular disease. Early repolarisation syndrome (ERS) may be a marker of vulnerable substrate. The same finding of increased incidence of ER in idiopathic VF survivors40,41 and their relatives42 would suggest that there exists a phenotype with a predisposition to VA in the context of ACS.

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Therapeutic Options The incidence of sustained VT and VF occurring within 48 hours of the onset of an ACS seems to have decreased over the past decade, likely due to the widespread availability of revascularisation therapy, limiting the size of infarction and to an increased use of beta-blockers.43

Anti-arrhythmic Drugs Robust evidence for anti-arrhythmic drug (AAD) use in the early dynamic phase of ischaemia and reperfusion within the first 48â€“72 hours post-MI is lacking in comparison to use in the chronic phase. Despite the availability of early revascularisation and beta-blocker use, 6% of patients in this early phase are still affected by sustained VA.44 While the immediate treatment for VA with haemodynamic collapse remains direct current cardioversion, recurrent sustained VA in the absence of need for further revascularisation and normal electrolytes usually calls for some form of drug therapy. AADs are not without their side effects in addition to their effects on transmembrane voltage and heart rate, all of which can further exacerbate instability. Beta-blockers have been effectively used in patients with acute coronary events, reducing major cardiac events including SCD.45 In a meta-analysis by Huang et al., use of beta-blockers was associated with reduction of all-cause death in patients with acute MI undergoing PCI. The benefit was restricted to those with reduced EF, low use of other secondary prevention drugs or with none STEMI. The association between the use of beta-blockers and improved survival rate was significant only in <1-year follow-up duration. They concluded there was a lack of evidence to support routine use of beta-blockers in all patients with AMI who underwent PCI.46 In the carvedilol post-infarct survival control in left ventricular dysfunction study (CAPRICORN) trial, Carvedilol was shown to have significant anti-arrhythmic effect after AMI. It suppressed both atrial and ventricular arrhythmias in these patients.47 There have been conflicting reports concerning the class Ib drug lidocaine of either a significant trend towards a lower risk of death in the early period post-MI,48,49 and less VA and a survival benefit post-cardiac arrest when used prophylactically to a neutral effect on overall mortality or a trend towards excess mortality.49,50 Prophylactic lidocaine use has largely been discouraged although it remains a potential intravenous treatment of recurrent sustained VA post-MI. The class Ic drugs like flecainide and propafenone cause significant slowing of conduction, which may exacerbate VA in the post-MI setting and should not be used.50 Amiodarone remains the most commonly used AAD post-MI and is particularly useful in the presence of severe structural disease. However, it does take time to reach therapeutic levels. Its use following out-of-hospital cardiac arrest in patients with shock refractory VF was associated with a survival benefit in comparison with lidocaine.51 In patients who survived more than 3 hours after MI, use of amiodarone was associated with increased short- (30 days) and long-term (6 months) mortality compared with lidocaine for use in the ACS setting.49 No added survival benefit has been shown with amiodarone use over and above concomitant beta-blocker therapy post-MI52 and its significant side-effect profile has been shown to increase mortality in the longer term. There are no data to support the use of dronaderone in the post-MI period. Other class III drugs, such as dofetilide, prolong cardiac repolarisation and do suppress VA,51â€“53 but there are no data showing added beneficial effects of their use. All class III drugs prolong

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Ventricular Arrhythmia after Acute MI the QT interval thus risking polymorphic VT, though the incidence of polymorphic VT is low with amiodarone.54 Ranolazine is a relatively new entry into the arena. The metabolic efficiency with ranolazine for less ischemia in non−ST-elevation acute coronary syndromes (MERLIN)-TIMI 36 trial did not show a significant difference in the combined primary endpoint of cardiovascular death, MI or recurrent ischaemia but it did significantly reduce the incidence of non-sustained VT when compared with placebo.55 More investigation is needed, including how it stacks up against current drug therapy. Similarly, eplerenone 25 mg/day, in addition to conventional therapy, significantly reduced all-cause mortality 30 days after randomisation in patients with an LVEF ≤40% and signs of heart failure. There was a 37% relative risk reduction of SCD in patients receiving epleronone.56 When considering drug therapy, the use of deep sedation must not be forgotten. In addition to the necessary use if a conscious patient is to undergo direct current cardioversion, a reduction of the sympathetic drive associated with post-MI VA afforded by it makes it a viable therapeutic option.

Overdrive Pacing If the above measures fail to suppress VA in the early post-MI period, temporary overdrive pacing may be used. An automatic focus may be captured and suppressed, or exit block achieved by making surrounding myocardium refractory. Alterations of conduction and refractoriness due to pacing may terminate a tachycardia caused by a re-entrant mechanism. This measure can be used in refractory VA to reduce the need for recurrent cardioversion while waiting for drug therapy to take effect, or prior to further revascularisation or catheter ablation.

Radiofrequency Ablation Catheter ablation for VA in the acute phase is not commonly performed. The acute success rate is in the region of 70% and carries with it a peri-procedural mortality of 3% in unstable patients, and a long-term mortality of 18% due to decompensated heart failure.57,58 Ablation is primarily subendocardial and in the border zone. The targets are the re-entrant circuits in the heterogenous myocardium and the after-depolarisations and automatic foci arising from purkinje fibres. Activation mapping can be performed in the presence of frequent PVCs. Pace mapping can be performed against prior recorded PVCs if they are less frequent. Endpoints include suppression of the triggering PVC and loss of the purkinje potential. On the occasions that PVCs are not present, routine induction manoeuvres including PES or drug provocation can be non-specific in the acute period is often unsuccessful and can be non-specific. In these situations, substrate ablation guided by voltage mapping can be undertaken.59 This cohort of patient is often haemodynamically unstable and the complexity of the procedure means it is best undertaken in highvolume centres by experienced electrophysiologists, with the use of 3D electroanatomical mapping systems and, one would argue, advanced supportive care including the ability to provide mechanical circulatory support if needed.

cardiogenic shock and acute MI, undergoing thrombolysis or primary PCI.60 Revascularisation improves survival. The use of inotropes can exacerbate VA and the amount needed can potentially be reduced if used in conjunction with mechanical support. Beyond supporting revascularisation procedures, mechanical support may help maintain cardiac output adequate for tissue perfusion in the post-MI period. The most widely used form is the intra-aortic balloon pump (IABP). This counter-pulsation device primarily reduces afterload, augments diastolic coronary perfusion and contributes towards the cardiac output. It is unable to provide support in VF, whereas other forms of mechanical support can. Use of the Impella assist device in this cohort of patients was associated with reduction of tissue hypoxia, haemodynamic stabilisation and improvement of neurological outcome.61,62 Veno-arterial extracorporeal membrane oxygenation (VA–ECMO)-assisted PCI was shown to improve survival in patients with cardiogenic shock and refractory VT/VF compared with IABP.61–63 These forms of support can act as bridges to recovery or eventual heart transplantation.

The Implantable Cardioverter-Defibrillator Current guidance advocates ICD implantation from 40 days post-MI in patients with an LVEF of 35% or less in New York Heart Association (NYHA) class 1, 2 or 3. The Defibrillator in Acute Myocardial Infarction Trial (DINAMIT) and the Immediate Risk Stratification Improves Survival (IRIS) showed that there was no survival benefit in implantation under 40 days from the event.25,26 In the DINAMIT trial, ICD implantation within 6–40 days of an acute MI (average time from MI to randomisation of 18 days) was compared with conventional medical therapy. This was a primary prevention study and excluded people who had VA post-48 hours after MI. The DINAMIT study included a measurement of HRV, with an EF of <35% as study inclusion criteria. The study demonstrated a reduction in the arrhythmic death, which was largely balanced by an increase in the non-arrhythmic cardiac death in the ICD arm when compared with the control group, but there was no reduction in the total mortality. Similarly, the IRIS trial enrolled patients, 5–31 days after MI. The inclusion criteria included a reduced LVEF (≤40%) and a heart rate of 90 or more. This was also a primary prevention study and failed to show any benefit of prophylactic ICD in this group of patients, though the rate of arhhythmic deaths was lower in patients with ICD. Though both the trials showed no significant benefit of ICD in this group of patients, they did not include people who had VA after 48 hours of the myocardial event and such patients need to be studied further. Risk stratification tools are required to assess these people who may be at a higher risk of VA. In the absence of robust risk stratification tools, wearable defibrillators may have a role in the prevention of SCD, particularly in patients with depressed LV function, but such a strategy will need to be evaluated in further randomised studies.

Mechanical Circulatory Support

The risk of VA and consequent ICD therapy appears to reduce with increasing time from the infarct and the majority of patients fitted with a primary prevention ICD (and without further ischaemia) do not have sustained VA, implying that there might be other factors at play beyond LV function and stable scar.64

VA is common in MI complicated by cardiogenic shock and is associated with high short-term mortality. Sustained VT occurs in 17–21% and VF is seen slightly more often (24–29%) in selected patients with

An ICD prevents sudden death from VA but does not prevent VA itself. It certainly does not prevent death from progressive pump failure

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Mechanisms of Arrhythmias and may in fact just allow for change in the mode of death. Both appropriate and inappropriate shocks have been associated with increased mortality, whereas ATP-treated arrhythmias were not. The psychological impact of ICD therapy must not be underestimated. More aggressive ATP, extended detection and redetection algorithms, onset and stability criteria and morphology discrimination can help reduce the frequency of inappropriate shocks.65 Further ischaemia or infarction may precipitate an electrical storm in patients who already have an ICD. In such situations, treatment should be as for someone without an ICD but an added consideration may be to reprogramme the device to deal with increased frequency or altered characteristics of arrhythmia and perhaps even switching device therapies off in the short term in a well-monitored environment to prevent excessive or inappropriate ATP and/or shocks.

Future Directions A greater understanding of the cellular and electrophysiological mechanisms of arrhythmia in the context of acute ischaemia is needed. It is clear that risk stratification based on LVEF and PES alone is inadequate and more robust investigations used in combination are likely to be required. Current therapy is limited to drugs with significant side effects and catheter ablation techniques.

10.

11.

12.

13.

14.

Henkel DM, Witt BJ, Gersh BJ, et al. Ventricular arrhythmias after acute myocardial infarction: a 20-year community study. Am Heart J 2006;151:806–12. DOI: 10.1016/j. ahj.2005.05.015; PMID: 16569539. Khairy P, Thibault B, Talajic M, et al. Prognostic significance of ventricular arrhythmias post-myocardial infarction. Can J Cardiol 2003;19:1393–404. PMID: 14631474. Demidova MM, Smith JG, Höijer CJ, et al. Prognostic impact of early ventricular fibrillation in patients with ST-elevation myocardial infarction treated with primary PCI. Eur Heart J 2012;1:302–11. DOI: 10.1177/2048872612463553; PMID: 24062921. Califf RM, White HD, Van de Werf F, et al. One-year results from the global utilization of streptokinase and TPA for occluded coronary arteries (GUSTO I) trial. Circulation 1996;94:1233–8. PMID: 8822974. Volpi A, De Vita C, Franzosi MG, et al. Determinants of 6-month mortality in survivors of myocardial infarction after thrombolysis. Results of the GISSI-2 data base. Circulation 1993;88:416–29. PMID: 8339405. Yusuf S, Peto R, Lewis J, et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335–71. PMID: 2858114. Latini R, Maggioni AP, Fiather M, et al. ACE inhibitor use in patients with myocardial infarction. Summary of evidence from clinical trials. Circulation 1995;92:3132–7. PMID: 7586285. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–9. DOI: 10.1016/j. atherosclerosissup.2004.08.027; PMID: 15531279. Raviele A, Bonso A, Gasparini G, Themistoclakis S. Prophylactic implantation of implantable cardioverter/ defibrillator in post-myocardial infarction patients. In: Vardas PE (ed.). Cardiac arrhythmias, pacing and electrophysiology. Dordrecht: Kluger Academic Publishers, 1998;305–10. Uretsky BF, Sheahan RG. Primary prevention of sudden cardiac death in heart failure: will the solution be shocking? J Am Coll Cardiol 1997;30:1589–159. PMID: 9385881. Gorenek B, Blomström Lundqvist C, Brugada Terradellas J, et al. Cardiac arrhythmias in acute coronary syndromes: position paper from the joint EHRA, ACCA and EAPCI task force. EuroIntervention 2015;10:1095–108. DOI: 10.4244/ EIJY14M08_19; PMID: 25169596. Haïssaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008;358:2016–23. DOI: 10.1056/NEJMoa071968; PMID: 18463377. Tikkanen JT, Wichmann V, Junttila J, et al. Association of early repolarization and sudden cardiac death during an acute coronary event. Circ Arrhythm Electrophysiol 2012;5:714–8. DOI: 10.1161/CIRCEP.112.970863. Askari AT, Shishehbor MH, Kaminski MA, et al. The association between early ventricular arrhythmias, reninangiotensin-aldosterone system antagonism, and mortality in patients with ST-segment-elevation myocardial infarction: Insights from Global Use of Strategies to Open coronary arteries (GUSTO) V. Am Heart J 2009;1582:238–43. DOI: 10.1016/j.ahj.2009.05.023; PMID: 19619700.

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The concept of a genetic predisposition and therapies targeted at autonomic modulation are fascinating and warrant further research. Timely and thorough revascularisation appears to be a strategy to prevent death due to VA but it cannot be achieved in all patients presenting post-infarct. Perhaps the future for some does lie in molecular and stem cell therapy, with the potential to regenerate lost or damaged myocardium.66 Stem cell therapy has been used to treat heart failure. In early trials in an animal model (rat), and subsequently in humans, stem cell therapy was shown to increase propensity to ventricular arrhythmias (ventricular ectopics and non-sustained VA), perhaps due to lack of effective integration to the connexin network.67,68 Though further studies using stem cell therapies in the animal model and subsequently in the humans have been reported to either reduce propensity for cardiac arrhythmias or show no change in incidence of sustained ventricular arrhythmias, further studies are required.69,70 Ventricular arrhythmias in patients with acute coronary syndrome could influence the immediate and long-term mortality in these patients. Appropriate risk assessment is needed to identify patients at risk of further risk of VA and sudden cardiac death, and research is needed in this field. n

15. Mont L, Cinca J, Blanch P, et al. Predisposing factors and prognostic value of sustained monomorphic ventricular tachycardia in the early phase of acute myocardial infarction. J Am Coll Cardiol 1996;28:1670–6. DOI: 10.1016/S07351097(96)00383-X; PMID: 8962550. 16. Al-Khatib SM, Stebbins AL, Califf RM, et al. Sustained ventriculararrhythmias and mortality among patients with acute myocardialinfarction: results from the GUSTO-III trial. Am Heart J 2003;145:515–21. DOI: 10.1067/mhj.2003.170; PMID: 12660676. 17. Hohnloser SH, Klingenheben T, Zabel M, et al. Prevalence, characteristics and prognostic value during long-term follow-up of nonsustained ventricular tachycardia after myocardial infarction in the thrombolytic era. J Am Coll Cardiol 1999;33:1895–902. PMID: 10362190. 18. Mehta RH, Yu J, Piccini JP, et al. Prognostic significance of postprocedural sustained ventricular tachycardia or fibrillation in patients undergoing primary percutaneous coronary intervention.from the HORIZONS-AMI Trial. Am J Cardiol 2012;109:805–12. DOI: 10.1016/j.amjcard.2011.10.043; PMID: 22196782. 19. Di Diego JM, Antzelevitch C. Ischaemic ventricular arrhythmias: Experimental models and their clinical relevance. Heart Rhythm 2011;8:1963–68. DOI: 10.1016/j. hrthm.2011.06.036; PMID: 21740880; PMCID: PMC3222739. 20. Sasano T, Roselle Abraham M, Chang K, et al. Abnormal sympathetic innervations of viable myocardium and the substrate of ventricular tachycardia after myocardial infarction. J Am Coll Cardiol 2008;51:2266–75. DOI: 10.1016/j. jacc.2008.02.062; PMID: 18534275. 21. Marchlinski FE, Waxman HL, Buxton AE, et al. Sustained ventricular tachyarrhythmias during the early postinfarction period: electrophysiologic findings and prognosis for survival. J Am Coll Cardiol 1983;2:240–50. PMID: 6863760. 22. Wit AL, Rosen MR. After depolarizations and triggered activity: distinction from automaticity as an arrhythmogenic mechanism. In: Fozzard HA, Haber E, Jennings RF, et al. (eds). The Heart and Cardiovascular System. New York: Raven, 1991;2113–63. 23. Klein HU, Goldenberg I, Moss AJ. Risk stratification for implantable cardioverter defibrillator therapy: the role of the wearable cardioverter-defibrillator. Eur Heart J 2013;34:2230– 42. DOI: 10.1093/eurheartj/eht167; PMID: 23729691. 24. Solomon SD, Glynn RJ, Greaves S, et al. Recovery of ventricular function after myocardial infarction in the reperfusion era: the healing and early afterload reducing therapy study. Ann Intern Med 2001;134:451–8. PMID: 11255520. 25. Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of implantable cardioverter defibrillator after acute myocardial infarction. N Engl J Med 2004;351:2481–8. DOI: 10.1056/ NEJMoa041489; PMID: 15590950. 26. Steinbeck G, Andresen D, Seidl K, et al. Defibrillator implantation early after myocardial infarction. N Engl J Med 2009;361:1427–36. DOI: 10.1056/NEJMoa0901889; PMID: 19812399. 27. Moss AJ, Zareba W, Jackson Hall W, et al. Prophylactic implantation of defibrillator in patients with myocardial infarction and reduced ejection fraction. N Eng J Med 2002;346:877–83. DOI: 10.1056/NEJMoa013474; PMID: 11907286.

28. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37. DOI: 10.1056/NEJMoa043399; PMID: 15659722. 29. Exner DV, Kavanagh KM, Slawnych MP, et al. Noninvasive risk assessment early after myocardial infarction. The REFINE study. J Am Coll Cardiol 2007;50:2275–84. DOI: 10.1016/j. jacc.2007.08.042; PMID: 18068035. 30. Buxton AE, Lee KL, Hafley GE, et al. Limitations of ejection fraction for prediction of sudden death risk in patients with coronary artery disease: lessons from the MUSTT study. J Am Coll Cardiol 2007;50:1150–7. DOI: 10.1016/j. jacc.2007.04.095; PMID: 17868806. 31. Schmidt A, Azevedo CF, Cheng A, et al. Infarct tissue heterogeneity by magnetic resonance imaging identifies enhanced cardiac arrhythmia susceptibility in patients with left ventricular dysfunction. Circulation 2007;115:2006 14. DOI: 10.1161/CIRCULATIONAHA.106.653568; PMID: 17389270; PMCID: PMC2442229. 32. Yan AT, Shayne AJ, Brown KA, et al. Characterisation of the per-infarct zone by contrast-enhanced cardiac magnetic resonance imaging is a powerful predictor of postinfarct mortality. Circulation 2006;114:32–9. DOI: 10.1161/ CIRCULATIONAHA.106.613414; PMID: 16801462. 33. Bello D, Fieno DS, Kim RJ, et al. Infarct morphology identifies patients with substrate for sustained ventricular tachycardia. J Am CollCardiol 2005;45:1104–8. DOI: 10.1016/j. jacc.2004.12.057; PMID: 15808771. 34. Moss AJ, Jackson Hall W, Cannom DS, et al. Improved survival with an implantable defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 1996;335:1933–40. DOI: 10.1056/NEJM199612263352601; PMID: 8960472. 35. Raviele A, Bongiorni MG, Brignole M, et al. Early EPS/ICD strategy in survivors of acute myocardial dysfunction on optimal beta-blocker treatment. The Beta-blocker Strategy plus ICD trial. Europace 2005;7:327–37. PMID: 16028343. 36. Bloch Thomsen PE, Jons C, Pekka Raatikainen MJ, et al. Longterm recording of cardiac arrhythmias with an implantable cardiac monitor in patients with reduced ejection fraction after acute myocardial infarction. The Cardiac Arrhythmias in Risk Stratification after acute Myocardial infarction (CARISMA) study group. Circulation 2010;121:1258–64. DOI: 10.1161/CIRCULATIONAHA.109.902148; PMID: 20837897. 37. Daubert JP, Zareba W, Hall WJ, et al. Predictive value of ventricular arrhythmia inducibility for subsequent ventricular tachycardia or ventricular fibrillation in Multicentre Automatic Defibrillator Implantation Trial (MADIT) II patients. J Am Coll Cardiol 2006;47:98–107. DOI: 10.1016/j. jacc.2005.08.049; PMID: 16386671. 38. Patel RB, Ilkanoff L, Ng J, et al. Clinical characteristics and prevalence of early repolarisation associated with ventricular arrhythmias following acute ST-elevation myocardial infarction. Am J Cardiol 2021;110:615–20. DOI: 10.1016/j. amjcard.2012.04.042; PMID: 22658503. 39. Tikkanen JT, Wichmann V, Junttila J, et al. Association of early repolarisation and sudden cardiac death during an acute coronary event. Circ Arrhythm Electrophysiol 2012;5:714–8. DOI: 10.1161/CIRCEP.112.970863; PMID: 22730409.

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40. Haïssaguerre M, Derval N, Sacher F. Sudden cardiac arrest associated with early repolarisation. N Engl J Med 2008;358:2016–23. DOI: 10.1056/NEJMoa071968; PMID: 18463377. 41. Rosso R, Kogan E, Belhassen B, et al. J-point elevation in survivors of primary ventricular fibrillation and matched control subjects: incidence and clinical significance. J Am Coll Cardiol 2008;52:1231–8. DOI: 10.1016/j.jacc.2008.07.010; PMID: 18926326. 42. Nunn LM, Bhar-Amato J, Lowe MD, et al. Prevalence of J-point elevation in sudden arrhythmic death syndrome families. J Am Coll Cardiol 2011;58:286–90. DOI: 10.1016/j. jacc.2011.03.028; PMID: 21737021. 43. 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 in patients presenting without persistent ST-segment elevation of the European Society of Cardiology. Eur Heart J 2011;32:2999– 3054. DOI: 10.1093/eurheartj/ehr236; PMID: 21873419. 44. Alexander JH, Granger CB, Sadowski Z, et al. The GUSTO-I and GUSTO-IIb Investigators. Prophylactic lidocaine use in acute myocardial infarction: incidence and outcomes from two international trials. Am Heart J 1999;137:799–805. PMID: 10220627. 45. Kernis SJ, Harjai KJ, Stone GW, et al. Does beta-blocker therapy improve clinical outcomes of acute myocardial infarction after successful primary angioplasty, J Am Coll Cardiol 2004;43:1773–9. DOI: 10.1016/j.jacc.2003.09.071; PMID: 15145098. 46. Huang BT, Huang FY, Zuo ZL, et al. Meta-analysis of relation between oral b-blocker therapy and outcomes in patients with acute myocardial infarction who underwent percutaneous coronary intervention. Am J Cardiol 2015;115:1529–38. DOI: 10.1016/j.amjcard.2015.02.057; PMID: 25862157. 47. McMurray J, Køber L, Robertson M, et al. Antiarrhythmic effect of carvedilol after acute myocardial infarction results of the carvedilol post-infarct survival control in left ventricular dysfunction.CAPRICORN) Trial. J Am Coll Cardiol 2005;45:525–30. PMID: 15708698; DOI: 10.1016/j. jacc.2004.09.076. 48. Piccini JP, Schulte PJ, Pieper KS, et al. Antiarrhythmic drug therapy for sustained ventricular arrhythmias complicating acute myocardial infarction. Crit Care Med 2011;39:78–83. DOI: 10.1097/CCM.0b013e3181fd6ad7; PMID: 20959785; PMCID: PMC3010352. 49. The Cardiac Arrhythmia Suppression Trial Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomised trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321:406–12. DOI: 10.1056/NEJM198908103210629; PMID: 2473403. 50. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006

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

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

In partnership with

or for free online access to the journal, please visit:

www.AERjournal.com

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

www.radcliffecardiology.com

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

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H eart R hythm C ongress

Heart Rhythm Congress

www.heartrhythmcongress.org

1 - 4 October 2017 International Convention Centre (ICC) Birmingham UK www.heartrhythmcongress.org info@heartrhythmcongress.org.uk

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Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

www.radcliffecardiology.com A free-to-access community supporting best practice in cardiovascular care

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C Academy C Webinars www.AERjournal.com

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Radcliffe Cardiology

Published on Aug 23, 2017

AER 6.3

Arrhythmia & Electrophysiology Review Volume 6 Issue 3 Autumn 2017

AER 6.3

Published on Aug 23, 2017

Arrhythmia & Electrophysiology Review Volume 6 Issue 3 Autumn 2017

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