AER 9.2 by Radcliffe Cardiology

Arrhythmia & Electrophysiology Review Volume 9 • Issue 2 • Summer 2020

Volume 9 • Issue 2 • Summer 2020

www.AERjournal.com

Percutaneous Left Atrial Appendage Occlusion: A View From the UK Wern Yew Ding and Dhiraj Gupta

The Convergent AF Ablation Procedure: Evolution of a Multidisciplinary Approach to AF Management Karan Wats, Andy Kiser, Kevin Makati, Nitesh Sood, David DeLurgio, Yisachar Greenberg and Felix Yang

Hybrid Catheter-Based and Surgical Techniques for Ablation of Ventricular Arrhythmias Fouad Khalil, Konstantinos Siontis, Gabor Bagameri and Ammar M Killu

LCx

LAD

LAD Ablation catheter tip

Ablation catheter tip

Axillary artery

LCx

Axillary vein

Short-axis view

The Progression of Atrial Myopathy and Fibrillation

Externally-Irrigated Ablation Catheter Tip

Differentiating the Axillary Artery from the Axillary Vein

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Volume 9 • Issue 2 • Summer 2020

www.AERjournal.com Official journal of

Editor-in-Chief Demosthenes G Katritsis Hygeia Hospital, Athens

Section Editor – Clinical Electrophysiology and Ablation

Section Editor – Arrhythmia Mechanisms / Basic Science

Section Editor – Atrial Fibrillation

Johns Hopkins Medicine, Baltimore, MD

Royal Papworth and Addenbrooke’s Hospitals, Cambridge

Section Editor – Implantable Devices

Section Editor – Arrhythmia Risk Stratification

Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool

Pier D Lambiase

Section Editor – Imaging in Electrophysiology

Virginia Commonwealth University School of Medicine, Richmond, VA

Institute of Cardiovascular Science, University College London, and Barts Heart Centre, London

Stanford University Medical Center, CA

Hugh Calkins

Ken Ellenbogen

Andrew Grace

Gregory YH Lip

Sanjiv M Narayan

Editorial Board Joseph G Akar

Carsten W Israel

Douglas Packer

Yale University School of Medicine, New Haven, CT

JW Goethe University, Frankfurt

Mayo Clinic, St Mary’s Campus, Rochester, MN

Charles Antzelevitch

Warren Jackman

Carlo Pappone

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

IRCCS Policlinico San Donato, Milan

Sunny Po

Pierre Jaïs

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

Lankenau Institute for Medical Research, Pennsylvania, PA

Angelo Auricchio Fondazione Cardiocentro Ticino, Lugano

Carina Blomström-Lundqvist Uppsala University, Uppsala

Johannes Brachmann Klinikum Coburg, II Med Klinik, Coburg

Josep Brugada Hospital Sant Joan de Déu, University of Barcelona, Barcelona

Pedro Brugada

University of Bordeaux, CHU Bordeaux

Roy John Northshore University Hospital, New York, NY

Prapa Kanagaratnam

Edward Rowland Barts Heart Centre, St Bartholomew’s Hospital, London

Frédéric Sacher

Imperial College Healthcare NHS Trust, London

Bordeaux University Hospital, Electrophysiology and Heart Modelling Institute, Bordeaux

Josef Kautzner

Richard Schilling

Institute for Clinical and Experimental Medicine, Prague

Barts Health NHS Trust, London

University of Brussels, UZ-Brussel-VUB

Roberto Keegan

Afzal Sohaib

Alfred Buxton

Hospital Privado del Sur, Bahia Blanca, Argentina

Imperial College London and Barts Health NHS Trust, London

Beth Israel Deaconess Medical Center, Boston, MA

Karl-Heinz Kuck

William Stevenson

Asklepios Klinik St Georg, Hamburg

Vanderbilt School of Medicine, Nashville, TN

Cecilia Linde

Richard Sutton

David J Callans University of Pennsylvania, Philadelphia, PA

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

Shih-Ann Chen National Yang Ming University School of Medicine and Taipei Veterans General Hospital, Taipei

Harry Crijns Maastricht University Medical Center, Maastricht

Sabine Ernst

National Heart and Lung Institute, Imperial College London, London

Karolinska University, Stockholm

Francis Marchlinski University of Pennsylvania Health System, Philadelphia, PA

John Miller Indiana University School of Medicine, Indiana, IN

Fred Morady Cardiovascular Center, University of Michigan, MI

Royal Brompton & Harefield NHS Foundation Trust, London

Andrea Natale

Hein Heidbuchel Antwerp University and University Hospital, Antwerp

Texas Cardiac Arrhythmia Institute, St David’s Medical Center, Austin, TX

Gerhard Hindricks

Mark O’Neill

University of Leipzig, Leipzig

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

Panos Vardas Heraklion University Hospital, Heraklion

Marc A Vos University Medical Center Utrecht, Utrecht

Hein Wellens University of Maastricht, Maastricht

Katja Zeppenfeld Leiden University Medical Center, Leiden

Douglas P Zipes Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN

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• Arrhythmia & Electrophysiology Review is an international, English language, peer-reviewed, open access quarterly journal that publishes articles on www.AERjournal.com. • Arrhythmia & Electrophysiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in heart failure. • 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.

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Contents

Foreword The Human Atrioventricular Node: Oedipus and the Riddle of the Sphinx

Demosthenes G Katritsis DOI: https://doi.org/10.15420/aer.2020.30

Clinical Arrhythmias Atrial Tachycardias After Atrial Fibrillation Ablation: How to Manage?

Yuan Hung, Shih-Lin Chang, Wei-Shiang Lin, Wen-Yu Lin and Shih-Ann Chen DOI: https://doi.org/10.15420/aer.2020.07

Atrial Myopathy Underlying Atrial Fibrillation

Harold Rivner, Raul D Mitrani and Jeffrey J Goldberger DOI: https://doi.org/10.15420/aer.2020.13

Applications of Machine Learning in Cardiac Electrophysiology

Rahul G Muthalaly and Robert M Evans DOI: https://doi.org/10.15420/aer.2019.19

Cardiac Pacing Ultrasound-guided Axillary Vein Puncture in Cardiac Lead Implantation: Time to Move to a New Standard Access?

Ana Paula Tagliari, Adriano Nunes Kochi, Bernardo Mastella, Rodrigo Petersen Saadi, Andres di Leoni Ferrari, Luiz Henrique Dussin, Leandro de Moura, Márcio Rodrigo Martins, Eduardo Keller Saadi and Carisi Anne Polanczyk DOI: https://doi.org/10.15420/aer.2020.17

Devices Percutaneous Left Atrial Appendage Occlusion: A View From the UK

Wern Yew Ding and Dhiraj Gupta DOI: https://doi.org/10.15420/aer.2020.08

Electrophysiology and Ablation The Convergent Atrial Fibrillation Ablation Procedure: Evolution of a Multidisciplinary Approach to Atrial Fibrillation Management

Karan Wats, Andy Kiser, Kevin Makati, Nitesh Sood, David DeLurgio, Yisachar Greenberg and Felix Yang DOI: https://doi.org/10.15420/aer.2019.20

Hybrid Catheter-Based and Surgical Techniques for Ablation of Ventricular Arrhythmias

Fouad Khalil, Konstantinos Siontis, Gabor Bagameri and Ammar M Killu DOI: https://doi.org/10.15420/aer.2020.08

Cryoballoon Ablation of Atrial Fibrillation in Octogenarians

104

Tauseef Akhtar, Ronald Berger, Joseph E Marine, Usama Daimee, Hugh Calkins and David Spragg DOI: https://doi.org/10.15420/aer.2020.18

Foreword

The Human Atrioventricular Node: Oedipus and the Riddle of the Sphinx

Citation: Arrhythmia & Electrophysiology Review 2020;9(2):52–3. DOI: https://doi.org/10.15420/aer.2020.30 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

ardiac pathologists and electrophysiologists have studied the atrioventricular (AV) node for more than 100 years, since 1906, when Tawara first described the inferior extensions of the AV node in the human heart.1 Still, this important cardiac

structure remains “a riddle wrapped up in a mystery, inside an enigma”, to recall the famous Churchill quotation. Perhaps the same can be said about atrioventricular nodal re-entrant tachycardia (AVNRT): it represents the most common regular tachycardia in humans; since 1973 it has been associated with re-entry within or around the node;2 and still, its exact circuit remains elusive.3–5

Apart from the seminal publication by Moe et al. on the duality of AV conduction, and that by Inoue and Becker on the inferior nodal extensions, not much human anatomical data on the detailed structure of the human AV node have been collected.6,7 Recently, a group of eminent cardiac pathologists presented exciting new data on the structure of the human AV node and the potential implications for the AVNRT mechanism.8 This important report provides valuable insights into cardiac pathology, and addresses several unanswered questions about the exact circuit of this fascinating arrhythmia. We learn that considerable variation exists not only in the shape of the node, but also in the inferior nodal extensions, the potential anatomic substrate of the slow pathway. This might explain, therefore, why not all humans have AVNRT, although these structures are universal findings in the normal human heart. It seems that re-entrant tachycardia is not caused simply by the presence of inferior extensions capable of facilitating it; instead, the size and, perhaps, the orientation of these structures in the vicinity of the triangle of Koch need to satisfy particular requirements in order for the electrophysiological conditions for re-entry to occur. Unfortunately, the relevant heart specimens were not obtained from patients with clinically documented AVNRT.8 However, the considerable variation even in the apparently normal heart suggests a clearly probabilistic phenomenon. More importantly, we now have evidence for the anatomical substrate of the so-called ‘fast pathway’. Discrete tracts that constitute insulated pathways have not been histologically demonstrated in humans, but it has been speculated that superior atrio-nodal inputs may exist, consisting of atrial myocardial cells that descend onto the node and connect via a rim of transitional cells.9 Animal studies have demonstrated histological and electrophysiological evidence of multiple atrial inputs to the AV node.10–13 In humans, there has been electrophysiological evidence of atrio-nodal and atrio-Hisian connections, but their role in the AVNRT circuit was not obvious.14–16 Furthermore, histological proof of their existence was lacking. Thus, it had been proposed that the superior atrial inputs consist of loose transitional fibres, not identifiable tracts, and may play a role in fast pathway conduction in humans.17 It should be noted that in 1975 Anderson et al. identified an important connection of the transitional zone between atrial myocardium and compact node to the left side of the interatrial septum.18 Anderson et al. have also recently provided solid evidence for the anatomical substrate of the fast pathway, by identifying ubiquitous connections to the compact node through the working myocardium of the atrial septum.8 Connections were composed of ordinary myocardium. Transitional cells as forming the bridge between the septum and the body of the node were identified in only a minority of the hearts examined. The myocardial connections, and especially the last one before the node becomes insulated as the His bundle, were usually provided by the leftsided, or deep, layer of the septum, but they could also originate from the superficial, or rightward, side of the septum. These

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Human Atrioventricular Node

variations may well explain the retrograde atrial conduction patterns during slow–fast AVNRT, which may display earliest activation either in the right or the left aspect of the interatrial septum.19 Are we close to unravelling the mysteries of the AVNRT circuit? I think that several questions remain. First, this elegant work was conducted in apparently normal human hearts. We do not know exactly what happens in patients who develop the arrhythmia. Second, the identification of this last connection was not supported by electrophysiological evidence of its significance by means of participation in the circuit. And last, but not least, conventional histology may not be sufficient to disclose the whole truth. Staining and genotyping of connexins (Cx), i.e. the gap junctional proteins that are particularly expressed in the AV junction, have been used in order to characterise the different conduction properties of the node and its extensions. A connexin genotyping study in four human hearts has identified the right inferior extension as an area of high Cx43 expression and, consequently, faster conduction than the node and the left extension where Cx43 expression was low,20 although the location of the presumed left inferior extension in that study was closer to the node itself rather than that of the left extension as described in pathology studies.7,8 Nevertheless, the important message of this approach was to demonstrate the potential for different conduction characteristics of the atrial inputs to the node. Still, data are scarce, and exist only for Cx43, one of the four connexins that have been described to date.21 The human AV node, as well as the re-entrant tachycardia associated with it, remain enigmas. More data will be necessary for Oedipus to solve the riddle of the Sphinx. Demosthenes G Katritsis Editor-in-Chief, Arrhythmia and Electrophysiology Review Hygeia Hospital, Athens, Greece

Tawara S. Das Reitzleitungssystem des Saugetierherzens: Eine anatomisch-histologische Studie uber das Atrioventrikularbundel und die Purkinjeschen Faden. Jena, Germany: Gustav Fischer, 1906. Denes P, Wu D, Dhingra RC, et al. Demonstration of dual AV nodal pathways in patients with paroxysmal supraventricular tachycardia. Circulation 1973;48:549– 55. https://doi.org/10.1161/01.CIR.48.3.549; PMID: 4726237. Katritsis DG, Becker A. The atrioventricular nodal reentrant tachycardia circuit: a proposal. Heart Rhythm 2007;4:1354–60. https://doi.org/10.1016/j. hrthm.2007.05.026; PMID: 17905343. Katritsis DG, Camm AJ. Atrioventricular nodal reentrant tachycardia. Circulation 2010;122:831–40. https://doi. org/10.1161/CIRCULATIONAHA.110.936591; PMID: 20733110. Katritsis DG, Josephson ME. Classification of electrophysiological types of atrioventricular nodal re-entrant tachycardia: a reappraisal. Europace 2013;15:1231–40. https://doi.org/10.1093/europace/ eut100; PMID: 23612728. Moe GK, Preston JB, Burlington H. Physiologic evidence for a dual A-V transmission system. Circ Res 1956;4:357–75. https://doi.org/10.1161/01.RES.4.4.357; PMID: 13330177. Inoue S, Becker AE. Posterior extensions of the human compact atrioventricular node: a neglected anatomic feature of potential clinical significance. Circulation 1998;97:188–93. https://doi.org/10.1161/01. CIR.97.2.188; PMID: 9445172. Anderson RH, Sanchez-Quintana D, Mori S, et al. Re-evaluation of the structure of the atrioventricular node and its connections with the atrium. Europace 2020;22:821–30. https://doi.org/10.1093/europace/

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ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

euaa031; PMID: 32304217. Anderson RH, Ho SY, Becker AE. Anatomy of the human atrioventricular junctions revisited. Anat Rec 2000;260:81–91. https://doi.org/10.1002/10970185(20000901)260:1<81::AID-AR90>3.0.CO;2-3; PMID: 10967539. Wu J, Wu J, Olgin J, et al. Mechanisms underlying the reentrant circuit of atrioventricular nodal reentrant tachycardia in isolated canine atrioventricular nodal preparation using optical mapping. Circ Res 2001;88:1189–95. https://doi.org/10.1161/ hh1101.092187; PMID: 11397786. Antz M, Scherlag BJ, Otomo K, et al. Evidence for multiple atrio-AV nodal inputs in the normal dog heart. J Cardiovasc Electrophysiol 1998;9:395–408. https://doi. org/10.1111/j.1540-8167.1998.tb00927.x; PMID: 9581955. Hirao K, Scherlag BJ, Poty H, et al. Electrophysiology of the atrio-AV nodal inputs and exits in the normal dog heart: radiofrequency ablation using an epicardial approach. J Cardiovasc Electrophysiol 1997;8:904–15. https://doi.org/10.1111/j.1540-8167.1997.tb00852.x; PMID: 9261717. Toshida N, Hirao K, Yamamoto N, et al. Ventricular echo beats and retrograde atrioventricular nodal exits in the dog heart: multiplicity in their electrophysiologic and anatomic characteristics. J Cardiovasc Electrophysiol 2001;12:1256–64. https://doi. org/10.1046/j.1540-8167.2001.01256.x; PMID: 11761413. Anselme F, Papageorgiou P, Monahan K, et al. Presence and significance of the left atrionodal connection during atrioventricular nodal reentrant tachycardia. Am J Cardiol 1999;83:1530–6. https://doi.org/10.1016/ S0002-9149(99)00142-3; PMID: 10363866. Gonzalez MD, Contreras LJ, Cardona F, et al.

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Demonstration of a left atrial input to the atrioventricular node in humans. Circulation 2002;106:2930–4. https://doi.org/10.1161/01. CIR.0000041000.94343.28; PMID: 12460874. Otomo K, Suyama K, Okamura H, et al. Participation of a concealed atriohisian tract in the reentrant circuit of the slow-fast type of atrioventricular nodal reentrant tachycardia. Heart Rhythm 2007;4:703–10. https://doi. org/10.1016/j.hrthm.2007.02.013; PMID: 17556188. Mazgalev TN, Ho SY, Anderson RH. Anatomicelectrophysiological correlations concerning the pathways for atrioventricular conduction. Circulation 2001;103:2660–7. https://doi.org/10.1161/01. CIR.103.22.2660; PMID: 11390334. Anderson RH, Becker AE, Brechenmacher C, et al. The human atrioventricular junctional area. A morphological study of the A-V node and bundle. Eur J Cardiol 1975;3:11–25. https://doi.org/10.15420/ AER.2016.18.2; PMID: 27617092. Katritsis DG, Josephson ME. Classification, electrophysiological features and therapy of atrioventricular nodal reentrant tachycardia. Arrhythm Electrophysiol Rev 2016;5:130–5. https://doi. org/10.15420/AER.2016.18.2; PMID: 27617092. Hucker WJ, Sharma V, Nikolski VP, Efimov IR. Atrioventricular conduction with and without AV nodal delay: two pathways to the bundle of His in the rabbit heart. Am J Physiol Heart Circ Physiol 2007;293:H1122–30. https://doi.org/10.1152/ajpheart.00115.2007; PMID: 17496219. Katritsis DG, Efimov IR. Cardiac connexin genotyping for identification of the circuit of atrioventricular nodal re-entrant tachycardia. Europace 2019;21:190–1. https://doi.org/10.1093/europace/euy099; PMID: 29860485.

Clinical Arrhythmias

Atrial Tachycardias After Atrial Fibrillation Ablation: How to Manage? Yuan Hung,1 Shih-Lin Chang,2,3 Wei-Shiang Lin,1 Wen-Yu Lin1 and Shih-Ann Chen2,3 1. Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 2. Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 3. Institute of Clinical Medicine, and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan

Abstract With catheter ablation becoming effective for non-pharmacological management of AF, many cases of atrial tachycardia (AT) after AF ablation have been reported in the past decade. These arrhythmias are often symptomatic and respond poorly to medical therapy. Post-AF-ablation ATs can be classified into the following three categories: focal, macroreentrant and microreentrant ATs. Mapping these ATs is challenging because of atrial remodelling and its complex mechanisms, such as double ATs and multiple-loop ATs. High-density mapping can achieve precise identification of the circuits and critical isthmuses of ATs and improve the efficacy of catheter ablation. The purpose of this article is to review the mechanisms, mapping and ablation strategy, and outcome of ATs after AF ablation.

Keywords AF, ablation, atrial tachycardia, atrial flutter Disclosure: The authors have no conflicts of interest to declare. Received: 21 February 2020 Accepted: 12 April 2020 Citation: Arrhythmia & Electrophysiology Review 2020;9(2):54–60. DOI: https://doi.org/10.15420/aer.2020.07 Correspondence: Shih-Ann Chen, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, No 201, Section 2, Shih-Pai Rd, Taipei, Taiwan. E: epsachen@ms41.hinet.net Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

AF is the most common clinical arrhythmia that causes severe adverse cardiovascular events, such as ischaemic stroke and acute heart failure.1 Triggers from the pulmonary vein (PV) have been identified as crucial ectopic sources that initiate AF and pulmonary vein isolation (PVI) is the cornerstone for catheter ablation of AF.2,3 Per the European and US AF guidelines, catheter ablation of AF is currently recommended as the firstline therapy if anti-arrhythmic agents fail to maintain sinus rhythm.4–6 The recent advances in mapping and ablation techniques have provided more efficient non-pharmacological therapies for AF. In the Catheter Ablation Versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial, the catheter ablation group had superior quality of life compared with the anti-arrhythmic drug group and less AF recurrence after blanking through intention-to-treat analysis.7,8 Hence, catheter ablation has become widely used for treating symptomatic drug-refractory AF, even though the recurrence rates of AF ablation remain high, especially in persistent AF and longstanding persistent AF. Therefore, although several multicentre randomised trials showed no difference between PVI alone and additional ablation within the left atrium (LA), various methods, including linear ablation and substrate modification, have been introduced to achieve favourable results.9–12 However, atrial tachycardia (AT) occurring after AF ablation is often symptomatic, complex and poorly controlled by antiarrhythmic agents.13 Notably, this AT can be classified into the following three categories: focal, macroreentrant and microreentrant AT.14–16 Therefore, the question of how these ATs can be effectively ablated has become a crucial issue in the era of AF ablation. In this review, we summarise the incidence, mechanism, mapping and ablation techniques, and outcomes of AT after AF ablation.

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Incidence The incidence of AT after AF ablation varies from less than 5% to 40% and is associated with the index ablation strategy and duration of AF.15,17–20 ATs after PVI can be due to a focal or macroreentrant mechanism. Karch et al. reported that compared with segmental isolation (2%), circumferential PVI resulted in higher incidence of ATs (18%).21 Focal ATs have frequently been observed from reconnected PVs after a segmental or circumferential PVI and account for up to 80% of AT occurrences,17,22 whereas macroreentrant ATs have been noted after extensive LA ablation.23–25 Linear ablation combined with PVI may result in reentrant ATs because of conduction gaps and non-transmural lesions caused by ablation lesions.26,27 One cohort study conducted in the US demonstrated that ATs after PVI might be single AT or multiple ATs, and nearly 90% were reentrant and associated with gaps in the previous ablation line.28 Chugh et al. reported that nearly 60% of ATs after PVI had critical isthmus that localised to the mitral isthmus.20 Complex atrial fractionated electrogram (EGM)-based ablation is associated with high AT incidence (26–36%).10,29 This indicates that more aggressive and extensive LA ablation lesions might easily produce ATs after the index procedure. Cryoballoon ablation (CBA) for PVI has safety and efficacy similar to those of radiofrequency catheter ablation (RFCA).30 In one study, the incidence of ATs after CBA was 3–11% and more than half of ATs were macroreentrant.31–36 Chang et al. reported that in the second procedure, higher LA flutter occurred in the CBA group than in the RFCA group (54.5% versus 12.5%).37 The possible explanation is that CBA produced

ATs After AF Ablation Figure 1: Three Common Mechanisms of Atrial Tachycardia

A: Focal atrial tachycardia (AT). B: Macroreentrant AT. C: Microreentrant AT. Representative 3D electroanatomic maps of focal AT (D), macroreentrant AT (E) and microreentrant AT (F). Both focal and microreentrant ATs have centrifugal atrial activation, whereas macroreentrant AT has circuits spread through more than one atrial segment. LAA = left atrial appendage; LIPV = left inferior pulmonary vein; LSPV = left superior pulmonary vein; MV = mitral valve. Source: Chang et al. 2009.48 and Chang et al. 2011.52 Adapted with permission from Wiley.

more extensive low LA voltage areas than RFCA, which might have contributed to LA macroreentrant ATs.37 Of all the LA macroreentrant ATs in CBA, perimitral flutter (45.5%) is the most common type, followed by roof flutter (27.3%) and septal flutter (9%). Surgical AF ablation is an alternative treatment for drug-refractory or even catheter ablation-refractory AF and ATs are often observed after surgical AF ablation. Gopinathannair et al. reported that ATs originated more frequently in the LA (69%) than the right atrium (RA; 31%) and the most common arrhythmia mechanism was reentrant AT (70%). The three most common forms of macroreentrant AT after surgery were cavotricuspid isthmus (CTI)-dependent ATs (24%), perimitral ATs (18%) and roof-dependent ATs (16%).38

Classification and Mechanism In 2001, experts at the European Society of Cardiology and North American Society of Pacing and Electrophysiology reached a consensus and defined the two typical classifications of AT as focal AT and macroreentrant AT.16 PVI, linear ablation and substrate modification during AF ablation might contribute to the abnormal substrate and possible conduction gaps that could enhance the development of ATs.13 Microreentrant ATs were described later by Jais et al. as a novel mechanism beyond the previous definition of the expert committee.39 These three types of AT possess different electrophysiological characteristics. Comprehensive understanding of the mechanisms of AT after AF ablation could help rapid diagnosis and improve the efficacy

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and efficiency of catheter ablation (Figure 1). The mechanisms and electrophysiological characteristics are summarised in Table 1.

Atrial Tachycardias Caused by Focal Activation Focal AT caused by abnormal automaticity is an arrhythmia arising from the distinctive site of earliest activation and propagating centrifugally to the rest of the atrium. The two major mechanisms of AT with abnormal automaticity are triggered activity and enhanced automaticity. Both these mechanisms of AT can be induced by catecholamines, but AT with triggered activity can be induced or terminated through programmed stimulation and is easily terminated by adenosine injection.40 Conversely, AT with enhanced automaticity can only be transiently suppressed through an adenosine injection and cannot be induced by programmed pacing.15 Focal AT has been found to account for 22.2% of ATs after PVI,41 and, in that study, all focal ATs were terminated by RF ablation at the site with earliest atrial activation, which were related to the conduction gaps around the PV ostium.41

Macroreentrant Atrial Tachycardia Macroreentrant AT is the most common form of AT after AF ablation. Rostock etÂ al. stated that 72% of ATs after ablation in persistent AF were macroreentrant.42 Moreover, Pascale etÂ al. reported that more than half of recurrent arrhythmias were macroreentrant.43 The incidence of AT after AF ablation varies, mainly depending on the ablation strategy and lesions in the index procedure. These ATs may be easily induced but are difficult to terminate because of atrial

Clinical Arrhythmias Table 1: Electrophysiological Characteristics of Atrial Tachycardia Classification

Focal AT Abnormal automaticity

Macroreentrant AT Microreentrant AT

Mechanism

Triggered activity

Enhanced automaticity

Localised reentry

Macroreentry

Induced and terminated by PES

–

Catecholamine facilitation

Response to adenosine

Termination

Transient suppression

Insensitive

Ablation target

Earliest activation site

Conduction isthmus (often fractionated EGM)

Conduction isthmus

AT = atrial tachycardia; EGM = electrogram; PES = programmed electrical stimulation.

Figure 2: P-wave Morphology of Primary Focal Atrial Tachycardia from Different Pulmonary Veins RSPV

RIPV

LSPV

LIPV

I II III AVR AVL AVF V1 V2 V3 V4 V5 V6 P-wave morphology of atrial tachycardia from left pulmonary veins is often bifid positive in leads II and V1 and isoelectric or negative in lead I, whereas P-wave morphology of atrial tachycardias from the right pulmonary vein is positive in leads V1–V6 and also positive in lead I. LIPV = left inferior pulmonary vein; LSPV = left superior pulmonary vein; RIPV = right inferior pulmonary vein; RSPV = right superior pulmonary vein. Source: Kistler et al. 2006.50 Adapted with permission from Elsevier.

anisotropy, scarring or gaps in previous ablation lesions, and multiloop reentrant circuits during AT. Atrial structural or electrical remodelling, both AF and ablation related, can lead to small amplitude EGMs, an obscure isoelectric line and undulating P-wave morphology, which make differentiating the origin of macroreentrant ATs difficult. Unlike focal ATs, macroreentrant ATs are insensitive to adenosine infusion.44

Microreentrant Atrial Tachycardias After PVI Microreentrant ATs, also referred to as ‘localised reentry’ ATs, were described initially by Jais et al. and have since been reported by other groups.45,46 This subtype of AT was later defined as a circuit with the entire AT cycle length (CL) within a single atrial segment smaller than 2–3 cm, spreading centrifugally from the area of activation.39 This arrhythmia is noted predominantly in regions previously ablated or in those that contain extremely slow conduction allowing an extremely

small circuit. Unlike focal ATs caused by abnormal automaticity, microreentrant ATs are insensitive to adenosine.47

Pulmonary Vein-Gap Reentrant Atrial Tachycardias Another remarkable form of AT is PV-gap reentrant AT (PV-gap RATs), which is observed after PVI and is difficult to identify using conventional mapping. The circuits of PV-gap RATs involve both macroreentrant and microreentrant ATs and are associated with the prior ablation strategy. A case series determined that local reentrant ATs at the PV ostium after PVI were observed mostly in the right PV.41 Chang et al. showed that 70% of gap-related ATs after PVI were reentry ATs, with most of them related to the left PV.48 A multicentre study found that PV-gap RATs constituted 7% of all ATs after AF ablation.49 Using ultra-high-density mapping, PV-gap RATs were divided into the following three groups in the study: two gaps in one PV, two gaps in the ipsilateral superior and inferior PVs, and two separate gaps in one PV and the contralateral PVs with a long circuit. The P-wave morphology of PV-gap RATs indicated a positive or RS pattern in the lead V1 and an isoelectric interval in all leads, due to approximately 50% of the tachycardia CL being within the PV slow conduction zones. Ablation towards either the exit or entrance gap effectively terminated the PV-gap RAT.

Mapping and Ablation Atrial Tachycardias Caused by Focal Activation Kistler et al. determined in their large cohort study that more ATs due to abnormal automaticity arose from the RA than from the LA (73% versus 27%) in patients with primary focal ATs.50 The three most common locations of focal AT were found to be the crista terminalis (31%), tricuspid annulus (22%) and PV (19%).50 In that study, ATs arising from PVs were often present with a positive P wave throughout the precordial leads and inferiorly directed.50 Leads I, II and V1 are crucial for differentiating left and right PV origin. Amplitudes in leads II, III and aVF help distinguish between superior and inferior PVs. ATs from left PVs show a bifid-shape P wave in V1 (M shape) and negative P wave in lead aVL, whereas those from right PVs have a late-peaking positive P wave in lead V1 and flat or biphasic P waves in lead aVL (Figure 2). Conversely, Gerstenfeld et al. reported that the most common site of focal ATs after AF ablation was the previously isolated PV.17 Their findings were concordant with those of Ouyang et al., who found that PV tachycardia activated the atrium after continuous circular lesions.22 Generally, multipolar diagnostic catheters, such as decapolar or spiral catheters, can be used to determine the earliest activation site, with the earliest activation often preceding the onset of the P wave by 30 ms or more and with the unipolar EGMs indicated a QS pattern. Mohamed et al. reported the role of atrial overdrive pacing (AOP) in localising focal atrial tachycardia.51 In that small but elegant study, they found that the

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ATs After AF Ablation difference between post-pacing interval (PPI) and tachycardia CL (TCL; PPI-TCL) of focal ATs has a direct relationship to proximity of the pacing site to the tachycardia focus.51 Given that there was little perifocal tissue of focal ATs as compared with the sinus node, the PPI-TCL at the AT focus was usually less than 20 ms while the difference between PPI and sinus CL was above 80 ms. This manoeuvre is very useful in distinguishing AT close to the sinus node, such as ATs from the superior crista terminalis or lower superior vena cava, from sinus tachycardia.51 Electroanatomical mapping is also a useful tool for identifying the origin of focal ATs, which demonstrate centrifugal activation from a discrete point source. Additionally, it provides the information of substrate remodelling after previous ablations and helps electrophysiologists recognise gaps along the previous ablation line. Catheter ablation can be performed at the earliest activation site using a non-irrigated or irrigated radiofrequency catheter. Acceleration of tachycardia during ablation suggests that the site is an excellent target. Regarding focal ATs from PVs conducting through gaps along the isolation line, which were typical origins after PVI, reisolation of a PV antrum with a bidirectional block has been suggested. Although focal ATs, which have the earliest site near the ostium, can be directly ablated, this procedure might increase the risk of PV stenosis. In regions close to the atrioventricular (AV) node, cryoablation is an alternative method to preventing AV block.

Macroreentrant Atrial Tachycardias ECG features of a flutter wave remain a useful tool helping clinical electrophysiologists evaluate the possible mechanisms of and plan an ablation strategy for macroreentrant ATs. Chang et al. reported a stepwise algorithm for differentiating between focal and macroreentrant ATs after AF ablation (Figure 3).52 In that study, focal ATs had higher positive amplitudes of P or flutter waves in V6 and longer tachycardia CLs than macroreentrant ATs. Negative P or flutter waves that appeared in at least one precordial lead were more commonly seen in the RA than in the LA.52 Pascale et al. presented some ECG characteristics to help recognition of macroreentrant ATs.53 A negative P wave in the lead V1 suggested peritricuspid ATs. The precordial transition from upright to negative flutter waveforms identified anticlockwise peritricuspid ATs. A negative or negative– positive P wave in any of the leads V2–V6 in the absence of a precordial transition suggested perimitral ATs.53 Regarding the analysis of intracardiac EGMs during AT, the coronary sinus (CS) activation pattern is always the first step because it provides pertinent information on macroreentrant circuits. Simultaneous CS activation is a typical characteristic of roof-dependent ATs.43 Kim et al. reported that a CS activation time <45 ms combined with entrainment pacing from the roof and posterior wall both help in the differentiation between roof-dependent ATs and perimitral and CTI-dependent ATs.54 Casado Arroyo et al. stated that a CS activation time ≤39 ms can assist in the diagnosis of roof-dependent ATs with a sensitivity of 100% and specificity of 97%.55 Entrainment is a classical manoeuvre that can clarify whether sites participate in the circuits of ATs. Entrainment pacing from two or more different atrial segments, such as the CTI and proximal and distal CS, should be conducted initially to confirm whether the RA is involved in the circuit. If LA macroreentrant ATs are suspected, entrainment pacing should be performed from two opposite segments, namely the septal and mitral isthmus for perimitral ATs and the anterior and posterior walls for roof-dependent ATs. A PPI-TCL within 30 ms

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Figure 3: Algorithms for Differentiating Atrial Tachycardias After AF Ablation A

V6 ≥0.9 mV Yes

Flat flutter/P wave in V6

AT CL ≥265 ms Yes

Focal AT

Yes

Reentry AT

AT CL ≥290 ms Yes

Focal AT

Reentry AT

Negative flutter wave in any of precordial leads Yes

RA reentrant AT

LA reentrant AT

A: Stepwise approach to differentiating focal ATs from macroreentrant ATs after AF ablation. B: Algorithm for differentiating RA and LA macroreentrant ATs. AT = atrial tachycardia; CL = cycle length; LA = left atrial; RA = right atrial. Source: Chang et al. 2011.52 Adapted with permission from Wiley.

confirms that the site is in the circuit. Downstream overdrive pacing (DOP) and the identification of intracardiac concealed fusion (ICF), as reported by Barbhaiya et al., can help electrophysiologists locate the suspected reentrant circuits rapidly and facilitate catheter ablation.56 Initial DOP from the CS catheter was performed to confirm whether arrhythmias were perimitral ATs. If ICF was not identified during the DOP from the CS catheter, further DOP from the LA roof was achieved to clarify whether the circuit was roof dependent. Additional DOP from the posterior LA wall, anterior LA wall, LA appendage, LA septum and LA floor supported the further diagnosis of locally reentrant ATs and focal ATs. Approximately 80% of ATs could be accurately diagnosed after seven DOP attempts. Although entrainment and overdrive pacing can help clinicians identify the circuit and critical isthmus of macroreentrant ATs, several limitations restrict their application. Sometimes, the entrainment pacing easily interrupts the ATs or transforms them into other tachycardias. Moreover, rapid burst pacing in the diseased myocardium can cause rate-dependent conduction delay, thereby misleading the clinician through a lengthy PPI.57 Detailed mapping of tachycardia circuits with the entire CL using electroanatomic systems can assist in verifying the mechanism of macroreentrant ATs. Missing segments of the entire tachycardia CL imply that areas of slow conduction with extremely low amplitude or fractionated EGMs are not annotated, or that part of the circuit is involved in another atrial segment or epicardial conduction through the CS.58–60 More recently, the novel ultra-high-density mapping technique has helped in identification of the mechanisms underlying complex arrhythmias. This technique allows a lower scar threshold setting and identifies critical isthmuses with less noise on the bipolar EGMs. Frontera et al. presented an excellent work regarding the EGM characteristics related to different electrophysiological mechanisms.59 In their study, EGMs at low conduction were of low amplitude, of long

Clinical Arrhythmias duration and fractionated, whereas those at wavefront collision had high amplitude, short duration and double or triple deflections with less fractionation. Gaps along the ablation line had narrowly spaced potentials with fractionation in between. The pivot sites consisted of pivot points with high-amplitude, short-duration and multiple-deflection EGMs, and friction sites presented with double potentials with lowamplitude and fractionated EGMs. Furthermore, Takigawa et al. delicately delineated the circuits of macroreentrant ATs after AF ablation using ultra-high-density mapping.61 They determined that the three conventional subtypes of macroreentrant ATs (i.e. peritricuspid, perimitral and roof-dependent ATs) could be further divided into different subgroups according to their propagation circuits. For example, perimitral ATs could be classified as the following three subgroups: type A, the circuit is equal to the entire mitral annulus (MA); type B, the circuit is larger than the entire MA with all MA included; and type C, the circuit is larger than the entire MA without the entire MA included. More than 90% of the practical isthmuses in type A (typical type) were on mitral isthmuses. However, only 50% of the practical isthmuses in types B and C were on mitral isthmuses. These critical regions included the septum, anterior wall, posterior wall, CS, ridge between the left PV and LA appendage, and CTI. Anatomic isthmuses used as ablation targets were significantly longer than the true, practical isthmuses exposed using high-density mapping. Linear ablations between anatomical or electrical barriers, which interrupt the circuit, remain the essential tool in the management of macroreentrant AT ablation. Therefore, the atrial geometry, tachycardia reentrant circuits and gaps from the previous ablation should be clearly identified.13 Perimitral ATs are the most common reentrant ATs after AF ablation. They may be clockwise or anticlockwise along the MA, which is the anatomical obstacle for the reentrant circuit. The most common ablation line for the mitral isthmus is from the lateral MA to the left inferior PV. Because of the unstable catheter contact during mitral isthmus ablation, a deflectable long sheath is often used during the procedure. Some cases require epicardial ablation in the CS opposite the endocardial line to achieve a complete mitral isthmus block. Roof-dependent ATs are the second most common LA macroreentrant AT after AF ablation. The roof line can be achieved by ablating between the left and right superior PVs. In selected cases presenting with a figure-of-eight reentrant circuit around the mitral isthmus and through the roof, both mitral and roof lines should be performed. Another linear ablation strategy is LA anterior line, which connects the anterior mitral annulus to roof line or right superior PV, and it might be considered in cases of extensively diseased anterior LA with low amplitudes and conduction that could prompt small anterior re-entrant circuits.62 Because incomplete ablation lesions can lead to ATs in the future and should be avoided, a bidirectional conduction block must be confirmed after every linear ablation. Differential pacing, double potentials along the ablation line, or reobtaining the activation map after ablation can help confirm the existence of the bidirectional conduction block.62,63

Microreentrant Atrial Tachycardias After PVI Conventional linear multielectrode catheters and 3D mapping systems provide limited information regarding microreentrant ATs because of

their low resolution. Using ultra-high-density mapping, Frontera etÂ al. identified localised atrial reentrant circuits with multiple slow conduction isthmuses in low-voltage areas. These circuits were around a fixed scar or line of conduction block.64 However, wavefront collision or artefacts can mimic microreentrant ATs, thereby leading to misinterpretation of the tachycardia circuit.65 Entrainment pacing from at least two separate points along the circuit should be performed to confirm whether these microreentrant ATs are active or passive in the atrial arrhythmias. Successful ablation can be performed towards the long-duration and low-voltage fractionated EGMs in the circuit, which might be the sites of slow conduction isthmuses.59 However, not every slow conduction site lies in the critical isthmus. For example, EGMs of friction areas near the pivot point or wavefront collision also present a fractionated pattern and were found to be passively involved in the tachycardias.59 Therefore, careful interpretation of intracardiac EGMs and accurate delineation of tachycardia circuits are mandatory before ablation.

Procedure Outcome After Catheter Ablation The mechanisms of AT, duration of AF and abnormal substrates, such as prior ablation lesions or existing atrial scars, affect the acute success and recurrence rates of catheter ablation of ATs. In focal ATs without previous AF ablation, the acute success rate has been found to be higher than 80% and the recurrence rate to be 4â&#x20AC;&#x201C;14%;66,67 however, recurrent atrial arrhythmias after ablation of isolated LA ATs were not uncommon in one study and half of them were AF.68 Chae et al. reported that acute procedural success was achieved in 86% of ATs after circumferential PVI.28 Furthermore, catheter ablation was effective in terminating 96 of 116 macroreentrant ATs (83%), 18 of 18 focal ATs (100%) and 20 of 21 microreentrant ATs (95%). However, 27% of patients developed recurrent AT during follow up and approximately 40% had perimitral or roof-dependent ATs.28 In addition, similar results were reported in another study; despite using ultra-high-density mapping, a significant recurrence rate (26%) of macroreentrant ATs after AF ablation was observed and reconnection across the roof line and mitral isthmus was noted in most of the cases.61

Conclusion Catheter ablation has become the most common non-pharmacological therapy of AF in the last decade and has increased the incidence of ATs after AF ablation, causing severe clinical problems because these ATs are typically symptomatic and drug refractory. Preventing unnecessary ablation lesions in the index procedure could prevent creation of a substrate for arrhythmogenesis. Because prior AF ablation, atrial remodelling and existing atrial myopathy alter the normal conduction of atria, limitations exist when using ECG features, intracardiac tracings or entrainment pacing to identify the circuit and accurately localise the critical isthmus. With the development of ultrahigh-density mapping and novel annotation systems of electroanatomic mapping systems, clinical electrophysiologists can derive detailed information regarding the abnormal substrate and critical circuits of ATs and effectively perform ablations without causing iatrogenic arrhythmias.

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ATs After AF Ablation

Clinical Perspective • There are three mechanisms of atrial tachycardia (AT) after AF ablation: AT caused by focal activation (triggered activity or enhanced automaticity), macroreentrant AT and microreentrant AT. These mechanisms are associated with previous catheter ablation strategy, surgical intervention and abnormal atrial substrates, such as scars. • Macroreentrant ATs are the most common ATs after AF ablation. A complete bidirectional block across the ablation line at the conduction isthmus is mandatory to prevent iatrogenic tachycardias in the future. • Microreentrant ATs are not uncommon after AF ablation and can sometimes be misinterpreted as focal ATs because of abnormal automaticity. Entrainment pacing can help confirm whether the circuit is active in the AT. • Ultra-high-density mapping can help electrophysiologists recognise the tachycardia circuit and locate the critical isthmus accurately. Although long-duration and low-amplitude electrograms represent slow conduction in the circuit, not all of them are within the isthmus. • Pulmonary vein-gap reentrant ATs are interesting iatrogenic tachycardias after pulmonary vein isolation. They can be cured using ablation targeting the entrance or exit gaps with the assistance of high-density mapping.

10.

11.

12.

13.

14.

15.

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29. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044–53. https://doi.org/10.1016/j.jacc.2003.12.054; PMID: 15172410. 30. Kuck KH, Brugada J, Furnkranz A, et al. Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation. N Engl J Med 2016;374:2235–45. https://doi.org/10.1056/ NEJMoa1602014; PMID: 27042964. 31. Mikhaylov EN, Bhagwandien R, Janse PA, et al. Regular atrial tachycardias developing after cryoballoon pulmonary vein isolation: incidence, characteristics, and predictors. Europace 2013;15:1710–7. https://doi.org/10.1093/europace/eut129; PMID: 23689485. 32. Hermida A, Kubala M, Traulle S, et al. Prevalence and predictive factors of left atrial tachycardia occurring after second-generation cryoballoon ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2018;29:46–54. https://doi.org/ 10.1111/jce.13364; PMID: 29024212. 33. Guhl EN, Siddoway D, Adelstein E, et al. Efficacy of cryoballoon pulmonary vein isolation in patients with persistent atrial fibrillation. J Cardiovasc Electrophysiol 2016;27:423–7. https://doi.org/10.1111/jce.12924; PMID: 26757058. 34. Lyan E, Yalin K, Abdin A, et al. Mechanism, underlying substrate and predictors of atrial tachycardia following atrial fibrillation ablation using the second-generation cryoballoon. J Cardiol 2019;73:497–506. https://doi.org/10.1016/j. jjcc.2019.02.006; PMID: 30878353. 35. Julia J, Chierchia GB, de Asmundis C, et al. Regular atrial tachycardias following pulmonary vein isolation for paroxysmal atrial fibrillation: a retrospective comparison between the cryoballoon and conventional focal tip radiofrequency techniques. J Interv Card Electrophysiol 2015;42:161–9. https://doi.org/10.1007/s10840-014-9961-4; PMID: 25597847. 36. Akerstrom F, Bastani H, Insulander P, et al. Comparison of regular atrial tachycardia incidence after circumferential radiofrequency versus cryoballoon pulmonary vein isolation in real-life practice. J Cardiovasc Electrophysiol 2014;25:948–52. https://doi.org/10.1111/jce.12423; PMID: 24698206. 37. Chang TY, Lo LW, Te ALD, et al. The importance of extrapulmonary vein triggers and atypical atrial flutter in atrial fibrillation recurrence after cryoablation: insights from repeat ablation procedures. J Cardiovasc Electrophysiol 2019;30:16–24. https://doi.org/10.1111/jce.13741; PMID: 30230088. 38. Gopinathannair R, Mar PL, Afzal MR, et al. Atrial tachycardias after surgical atrial fibrillation ablation: clinical characteristics, electrophysiological mechanisms, and ablation outcomes from a large, multicenter study. JACC Clin Electrophysiol 2017;3:865– 74. https://doi.org/10.1016/j.jacep.2017.02.018; PMID: 29759784. 39. Jais P, Matsuo S, Knecht S, et al. A deductive mapping strategy for atrial tachycardia following atrial fibrillation ablation: importance of localized reentry. J Cardiovasc Electrophysiol 2009;20:480–91. https://doi.org/10.1111/j.1540-8167. 2008.01373.x; PMID: 19207747. 40. Markowitz SM, Stein KM, Mittal S, et al. Differential effects of adenosine on focal and macroreentrant atrial tachycardia. J Cardiovasc Electrophysiol 1999;10:489–502. https://doi. org/10.1111/j.1540-8167.1999.tb00705.x; PMID: 10355690. 41. Gerstenfeld EP, Callans DJ, Sauer W, et al. Reentrant and nonreentrant focal left atrial tachycardias occur after pulmonary vein isolation. Heart Rhythm 2005;2:1195–202. https://doi.org/10.1016/j.hrthm.2005.08.020; PMID: 16253909. 42. Rostock T, Drewitz I, Steven D, et al. Characterization, mapping, and catheter ablation of recurrent atrial tachycardias after stepwise ablation of long-lasting persistent atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:160–9. https://doi. org/10.1161/CIRCEP.109.899021; PMID: 20133933. 43. Pascale P, Shah AJ, Roten L, et al. Pattern and timing of the

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coronary sinus activation to guide rapid diagnosis of atrial tachycardia after atrial fibrillation ablation. Circ Arrhythm Electrophysiol 2013;6:481–90. https://doi.org/10.1161/ CIRCEP.113.000182; PMID: 23629735. Iwai S, Markowitz SM, Stein KM, et al. Response to adenosine differentiates focal from macroreentrant atrial tachycardia: validation using three-dimensional electroanatomic mapping. Circulation 2002;106:2793–9. https://doi.org/10.1161/01. CIR.0000040587.73251.48; PMID: 12451005. Jais P, Sanders P, Hsu LF, et al. Flutter localized to the anterior left atrium after catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2006;17:279–85. https://doi. org/10.1111/j.1540-8167.2005.00292.x; PMID: 16643401. Lim TW, Koay CH, McCall R, et al. Atrial arrhythmias after single-ring isolation of the posterior left atrium and pulmonary veins for atrial fibrillation: mechanisms and management. Circ Arrhythm Electrophysiol 2008;1:120–6. https://doi.org/10.1161/ CIRCEP.108.769752; PMID: 19808402. Markowitz SM, Nemirovksy D, Stein KM, et al. Adenosineinsensitive focal atrial tachycardia: evidence for de novo micro-re-entry in the human atrium. J Am Coll Cardiol 2007;49:1324–33. https://doi.org/10.1016/j.jacc.2006.11.037; PMID: 17394965. Chang SL, Lin YJ, Tai CT, et al. Induced atrial tachycardia after circumferential pulmonary vein isolation of paroxysmal atrial fibrillation: electrophysiological characteristics and impact of catheter ablation on the follow-up results. J Cardiovasc Electrophysiol 2009;20:388–94. https://doi. org/10.1111/j.1540-8167.2008.01358.x; PMID: 19017332. Yamashita S, Takigawa M, Denis A, et al. Pulmonary vein-gap re-entrant atrial tachycardia following atrial fibrillation ablation: an electrophysiological insight with high-resolution mapping. Europace 2019;21:1039–47. https://doi.org/10.1093/ europace/euz034; PMID: 30891597. Kistler PM, Roberts-Thomson KC, Haqqani HM, et al. P-wave morphology in focal atrial tachycardia: development of an algorithm to predict the anatomic site of origin. J Am Coll Cardiol 2006;48:1010–7. https://doi.org/10.1016/j. jacc.2006.03.058; PMID: 16949495. Mohamed U, Skanes AC, Gula LJ, et al. A novel pacing maneuver to localize focal atrial tachycardia. J Cardiovasc Electrophysiol 2007;18:1–6. https://doi.org/10.1111/j.1540-8167.

2006.00664.x; PMID: 17081203. 52. Chang SL, Tsao HM, Lin YJ, et al. Differentiating macroreentrant from focal atrial tachycardias occurred after circumferential pulmonary vein isolation. J Cardiovasc Electrophysiol 2011;22:748–55. https://doi.org/10.1111/j.1540-8167. 2010.02002.x; PMID: 21235680. 53. Pascale P, Roten L, Shah AJ, et al. Useful electrocardiographic features to help identify the mechanism of atrial tachycardia occurring after persistent atrial fibrillation ablation. JACC Clin Electrophysiol 2018;4:33–45. https://doi.org/10.1016/j. jacep.2017.07.018; PMID: 29600784. 54. Kim KH, Nam GB, Jin ES, et al. Coronary sinus activation pattern in the differential diagnosis of regular atrial tachyarrhythmias during catheter ablation of atrial fibrillation. Circ J 2013;77:619–25. https://doi.org/10.1253/circj.CJ-12-0753; PMID: 23196754. 55. Casado Arroyo R, Latcu DG, Maeda S, et al. Coronary sinus activation and ECG characteristics of roof-dependent left atrial flutter after pulmonary vein isolation. Circ Arrhythm Electrophysiol 2018;11:e005948. https://doi.org/10.1161/ CIRCEP.117.005948; PMID: 29858383. 56. Barbhaiya CR, Baldinger SH, Kumar S, et al. Downstream overdrive pacing and intracardiac concealed fusion to guide rapid identification of atrial tachycardia after atrial fibrillation ablation. Europace 2018;20:596–603. https://doi.org/10.1093/ europace/euw405; PMID: 28339750. 57. Vollmann D, Stevenson WG, Luthje L, et al. Misleading long post-pacing interval after entrainment of typical atrial flutter from the cavotricuspid isthmus. J Am Coll Cardiol 2012;59:819–24. https://doi.org/10.1016/j.jacc.2011.11.023; PMID: 22361402. 58. Nakashima T, Denis A, Nakatani Y, et al. A figure-of-eight atrial tachycardia using the coronary sinus as an epicardial bridge connection. J Cardiovasc Electrophysiol 2019;30:2113–4. https:// doi.org/10.1111/jce.14098; PMID: 31379047. 59. Frontera A, Takigawa M, Martin R, et al. Electrogram signature of specific activation patterns: analysis of atrial tachycardias at high-density endocardial mapping. Heart Rhythm 2018;15:28– 37. https://doi.org/10.1016/j.hrthm.2017.08.001; PMID: 28797676. 60. Latcu DG, Bun SS, Viera F, et al. Selection of critical isthmus in scar-related atrial tachycardia using a new automated

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ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Clinical Arrhythmias

Atrial Myopathy Underlying Atrial Fibrillation Harold Rivner, Raul D Mitrani and Jeffrey J Goldberger Cardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, US

Abstract While AF most often occurs in the setting of atrial disease, current assessment and treatment of patients with AF does not focus on the extent of the atrial myopathy that serves as the substrate for this arrhythmia. Atrial myopathy, in particular atrial fibrosis, may initiate a vicious cycle in which atrial myopathy leads to AF, which in turn leads to a worsening myopathy. Various techniques, including ECG, plasma biomarkers, electroanatomical voltage mapping, echocardiography, and cardiac MRI, can help to identify and quantify aspects of the atrial myopathy. Current therapies, such as catheter ablation, do not directly address the underlying atrial myopathy. There is emerging research showing that by targeting this myopathy we can help decrease the occurrence and burden of AF.

Keywords AF, atrial myopathy, atrial fibrosis, cardiac MRI, strain echocardiography Disclosure: JJG and RDM receive funding from the Miami Heart Research Institute and Grant 1R01HL145165-01 from the National Heart, Lung, and Blood Institute. HR has no conflicts of interest to declare. Received: 27 March 2020 Accepted: 14 May 2020 Citation: Arrhythmia & Electrophysiology Review 2020;9(2):61–70. DOI: https://doi.org/10.15420/aer.2020.13 Correspondence: Jeffrey J Goldberger, Cardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, Room 1124, 1120 NW 14th Street, Miami, FL 33136, US. E: j-goldberger@miami.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

AF is the most common sustained cardiac rhythm disturbance.1 Worldwide, there is an estimated 33.5 million people with AF as of 2010.2 While there are multiple estimates, the yearly incidence in the US is expected to grow, for example, from 1.2 million cases in 2010 to 2.6 million cases in 2030 and upwards of 6–12 million cases by 2050.1,3 It is associated with increased morbidity and mortality4 and diminished quality of life.5 AF is associated with structural heart disease, but it may also occur in a structurally normal heart. The clinical evaluation of patients with AF predominantly focuses on upstream risk factors, such as: hypertension, diabetes, heart failure (reduced or preserved ejection fraction), valvular heart disease, and other cardiopulmonary pathology such as pulmonary embolism.6,7 Despite being the site of origin for this arrhythmia, the atria are not typically evaluated in any systematic manner except for atrial size and/or volume, typically evaluated on echocardiography. Furthermore, atrial size and left atrial (LA) appendage (LAA) morphology have not been incorporated into clinical decisions such as starting anticoagulation in patients with AF.7 For example, the guideline-recommended and widely used CHA2DS2-VASc score for the evaluation of stroke risk does not include atrial size or any measure of atrial pathophysiology.8 Ample data have shown that the atria are diseased in many patients with AF.9,10 In this paper, we will explore the pathophysiology of atrial myopathy, the clinical evaluation of atrial fibrosis, the relationship of atrial fibrosis with thromboembolic events, and finally potential treatment approaches that might affect this atrial myopathy.

Pathophysiology of Atrial Myopathy The development of atrial myopathy is complex with multiple factors contributing to its development. Here, we will discuss the development

of atrial fibrosis, the role of obesity, the interaction of autonomic dysfunction and comorbidities on atrial myopathy, and the link between AF and atrial myopathy.

Development of Fibrosis Fibrosis is a common pathway to injury and failure in multiple organs. Four steps in the fibrogenic cascade have been identified: initiation of the body’s response to the initial injury; activation of effector cells; elaboration of extracellular matrix (ECM); and finally the development of fibrosis with organ failure from this matrix.11 Tissue damage initially leads to both a regenerative phase where tissue is replaced by normal tissue cells with no permanent damage, and a fibrosis stage in which normal parenchyma is replaced with fibroconnective tissue.12 This second phase is regulated by a complex pro-inflammatory cytokineand cell-mediated system in which fibroblasts and myofibroblasts synthesise fibrotic tissue.11,12 This process of fibrosis after injury is well characterised, for example, in the development of ischemic ventricular cardiomyopathy after MI. The resultant necrosis from an initial MI triggers the innate immune pathway activation of nuclear factor (NF)-kB.13 In addition, growth factors such as transforming growth factor-beta 1 (TGF-beta1), endothelin 1, and angiotensin II will cause the proliferation of fibroblasts and myofibroblasts. These processes drive the inflammatory response and lead to ECM deposition and fibrosis.11,14 Two types of fibrosis occur in the heart: reactive fibrosis, which occurs in the perivascular space and is similar to the fibrosis seen in other tissues; and replacement fibrosis, which occurs at the site of prior myocyte loss. This fibrotic

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Clinical Arrhythmias remodelling of the heart leads to the systolic and diastolic dysfunction seen in heart failure.15,16 There is a similar role for fibrosis in the development of atrial myopathy. The TGF-beta1/Smad signalling pathway has been identified as a key pathway in the development of atrial fibrosis. TGF-beta1 is a member of the cytokine family responsible for tissue repair and the generation of fibrosis. Smad is an additional family of proteins that can both attenuate and inhibit TGF-beta1 to help regulate this pathway.17 In the rapid pacing animal model for AF, activated TGF-beta1 phosphorylates Smad, to form complexes that translocate into the nucleus of myofibroblasts to upregulate the production of fibrin with resultant atrial fibrosis. In addition, overexpression of TGF-beta1 decreases the production of Smad7, which is responsible for the inhibitory feedback loop of the TGF-beta1/Smad pathway.17,18 The renin–angiotensin–aldosterone system (RAAS) has also been implicated in the development of atrial fibrosis. Studies of transgenic mice with overexpression of angiotensinconverting enzyme (ACE) have noted marked atrial dilation and fibrosis.19,20 Furthermore, the rapid pacing of atrial myocytes has been shown to cause the expression of microRNA that alter fibroblasts to increase ECM production.21 As discussed later in this paper, these various proteins integral to the development of atrial fibrosis can serve as both serum biomarkers and therapeutic targets.

Role of Obesity Obesity in general has been linked to a higher incidence of the development of AF.22–24 More specifically, epicardial adipose tissue (EAT), which refers to the layer of adipose tissue overlying the myocardium,25 has the potential to directly affect the atrial myocardium via the release of adipokines that promote inflammation and fibrosis.26,27 EAT has been shown to secrete activin A (a member of the TGF-beta family) that promotes the development of atrial fibrosis via a paracrine effect.28 EAT can also serve as a source of progenitor cells that can differentiate into the myofibroblasts that are responsible for the creation of ECM and fibrosis.29 A link between EAT and AF can be seen clinically. Patients with AF have been found to have higher levels of EAT compared with controls;30 furthermore, subjects with chronic AF are more likely to have a higher volume of EAT than those with paroxysmal AF.30 On multivariate analysis there was an independent association between EAT and LA volume even when controlling for BMI.30 Obese patients have increased low-voltage areas (13.9% versus 3.4%, p<0.001) and low-voltage areas correspond to the location of EAT on MRI.31 Furthermore, EAT has been shown to be a predictor of the success of AF ablation and the risk of recurrence.32–35 EAT has also been shown to be an independent risk factor for AF-associated stroke.36

Other Components of Atrial Myopathy The occurrence of atrial fibrosis in AF is clear. While this may play a critical part in the pathogenesis of AF via conduction slowing and the facilitation of re-entry, it is important to acknowledge that there are also other components of the atrial myopathy that may also be implicated. For example, there are autonomic innervation changes that occur after rapid pacing. Arora et al. showed that in the canine model, after rapid pacing, there is an increase in both sympathetic and parasympathetic fibres in the posterior LA and pulmonary veins. These autonomic changes cause regional shortening of the atrial effective refractory period, creating a substrate for re-entry and AF.37–39 These changes in innervation of the cardiac autonomic ganglia are present in AF patients and are an integral part of the atrial myopathy and have been suggested as a target for ablation.40

The systemic diseases incorporated in the CHA2DS2-VASc score, such as hypertension, heart failure, and diabetes, have been associated with increased risk for AF and may also play a role in the development of atrial myopathy.10 These comorbidities have been associated with increased LA pressure in AF patients.41 Hypertension is associated with abnormalities in the RAAS with high circulating levels of angiotensin II, ACE, and aldosterone. In addition to the fibrotic mechanism previously discussed, these components contribute to atrial myopathy by affecting ion channel structure and function and cause pro-inflammatory effects on the LA.42 Furthermore, left ventricular hypertrophy as the result of longstanding hypertension has been associated with both LA thrombus and increased risk of stroke.43–46 Heart failure (both preserved and reduced ejection fraction) causes increased LA pressure, increased LA size, and upregulation of RAAS.46 Patients with diabetes have increased angiotensin II levels, TGF-beta signalling, adipose tissue, and systemic inflammation.47 Patients with abnormal glucose metabolism have larger atrial sizes, lower atrial voltage, and higher AF recurrence after ablation.48 It is clear that multiple pathophysiologic pathways may be implicated in the formation of the atrial myopathy depending on the upstream initiators. Patients with atrial myopathy have been found to have endothelial dysfunction leading to increased hypercoagulability.49 Rapid atrial pacing of pigs has been shown to increase the levels of the endothelial nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA).50 Furthermore, in patients with persistent AF, there are higher levels of ADMA.50 ADMA leads to endothelial dysfunction and increases the risk of stroke.51 Additionally, von Willebrand factor levels have been associated with both AF and the risk of ischemic stroke.52,53 These prothrombotic factors are accentuated in patients with comorbid hypertension, heart failure, and diabetes by increased oxidative stress.40

AF and Atrial Myopathy Cardiac fibrosis is a key anatomic mediator creating the electrophysiologic substrate for arrhythmias.11,54–56 This has been illustrated in the animal model in which selective creation of atrial fibrosis via overexpression of TGF-beta1 has been shown to lead to increased inducibility of AF.57,58 Likewise, fibrosis creates a heterogenous milieu that slows intercellular conduction.39,59–61 There is an alteration in cell–cell connections, gap junctions, and anisotropy that contributes to re-entrant pathways.40 In patients undergoing catheter ablation for AF, atrial tissue conduction velocities were decreased in fibrotic areas defined by low voltage.62 These areas of slowed conduction velocity were predictive of sites in which ablation either terminated AF or slowed the AF cycle length by at least 30 ms (sensitivity 72.0% with 95% CI [50.6–87.9%] and specificity 78.1% with 95% CI [71.3–80.9%]).62 Furthermore, atrial fibrosis allows for the formation of multiple re-entry circuits that are thought to perpetuate both left-sided atrial tachycardia and AF.61,63 Fibrosis and fatty infiltrates upregulate pro-inflammatory cytokines to enhance the pro-inflammatory state of the atrium, which in turn increases the likelihood of recurrent AF.64,65 These processes lead to higher AF burden and further fibrosis. AF burden has been correlated with the degree of fibrosis found in postmortem tissue: those with persistent AF had a higher degree of fibrosis than those with paroxysmal AF.66 The degree of atrial fibrosis has been associated with AF burden, AF recurrence after ablation, and cardioembolic events (as discussed later here). The rapid atrial pacing model of AF simulates the rapid atrial rates seen in AF. In this model, animals undergo persistent rapid atrial

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Atrial Myopathy Underlying AF Figure 1: Progression of Atrial Myopathy and AF

No disease

Early disease not detectable

Mediators: Ageing Epicardial adipose tissue Oxidative stress Inflammation Pressure overload Volume overload

Fibrosis

Pre-clinical detectable substrate

Manifest clinical disease

Atrial fatty infiltrates Extracellular matrix Inflammatory markers Autonomic changes in atrium

Pre-clinical AF substrate

Normal atrium

Mechanical atrial dysfunction

Disruption of myocyte repolarisation Re-entry circuits Inducibility

Increased thrombogenicity

Stroke

pacing with atrial rates up to 900 BPM to induce AF. After a sustained period of time (6 weeks–180 days), the atrium remains in persistent AF once pacing is stopped.65,67 Morillo et al. first showed that sustained rapid atrial pacing led to atrial myopathy with a dilated LA.68 It is hypothesised that persistent atrial tachycardia leads to increased expression of the TGF-beta1/Smad signalling pathway with resultant atrial fibrosis as previously discussed.17 Furthermore, there are mRNA changes that lead to an activated fibroblast phenotype that leads to increased ECM.17,21 In a study of 26 sheep who underwent rapid atrial pacing with induction of AF, there was a significantly greater development of fibrotic fatty infiltrative tissue in the atria compared with those who received sham treatment.65 The development of atrial fibrosis has been noted in the rabbit and canine rapid atrial pacing models, but not uniformly.17,21,59 These findings demonstrate how persistent rapid atrial rates such as in AF may lead to atrial fibrosis. Atrial biopsies from humans with AF show similar fibrotic and fatty infiltrative changes as seen in the rapid pacing model.69–71 After multivariate analysis of clinical risk factors in subjects with atrial fibrosis, only history of AF was a significant predictor of atrial fibrosis.65 Furthermore, the degree of fibrosis was associated with AF burden.65 Rapid pacing has also been shown to induce electrical remodelling with increases in dominant frequency and ion channel density.72 These changes persisted despite mitigation of fibrosis and atrial dilation by eplerenone.72 It has long been accepted that "AF begets AF".73 Due to the cyclic nature of atrial myopathy and AF, it is difficult to ascertain which develops first. However, there is a clear association between the two with a resultant positive feedback loop with downstream effects (Figure 1).74

ECG Analysis of the surface ECG during sinus rhythm is a readily available tool to predict the development of atrial myopathy and AF. The terminal force of the P wave during sinus rhythm in lead V1 (PTFV1) has been shown to correlate with LA abnormalities, such as enlargement and conduction defects (Figure 2).75,76 In a large cohort study, PTFV1 >0.06 mm/s was associated with an increased risk for the development of AF (HR 1.91; 95% CI: [1.34–2.73]; p<0.001) and with mortality (HR 1.91; 95% CI [1.34–2.73]; p<0.001).77 Ishida et al. found similar predictive abilities of PTFV1.78 Furthermore, PTFV1 has been shown to be independently associated with cryptogenic, cardioembolic, and ischemic strokes.79,80 PTFV1 ≥0.04 mm/s, along with P-wave duration ≥125 ms and P-wave dispersion ≥40 ms, have been shown to be predictors of AF recurrence after ablation.81 The fibrillatory f wave itself has been shown to correlate with the degree of LA enlargement and myopathy. The f wave amplitude has been shown to correlate with LA size and chronicity of AF (i.e. large f waves in persistent AF).82 Likewise, patients with coarse AF were more likely to have spontaneous contrast in the LAA and/or thrombus on echocardiogram.83 In addition, patients with fine AF are less likely to have AF recurrence after cardioversion compared with coarse AF.84 Frequency analysis and signal processing techniques of f waves can be predictive of clinical AF outcomes, such as response to anti-arrhythmic drugs, cardioversion, and ablation.10,85,86 Furthermore, higher f wave dominant frequency has been found in patients with persistent AF compared with paroxysmal AF, although this may be due to electrophysiologic and/or structural remodelling as AF persists.87 A recent study of patients presenting to the emergency room with a first episode of AF found no difference in dominant frequency between AF types.88 Further research is needed to establish a role for fibrillatory wave analysis.

Clinical Evaluation of Myopathy A variety of techniques have been studied to help define the atrial myopathy, including ECG, biomarkers, intracardiac voltage mapping, echocardiographic evaluation of the LA, and cardiac MRI. Here, we will explore how they can be utilised clinically to identify myopathy and potentially predict morbidity from AF and recurrence after intervention.

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Biomarkers Biomarkers, although not necessarily specific to atrial pathology, have been studied both for their association with AF and AF related outcomes.45 The underlying pathophysiology represented by these biomarkers may provide an insight into the atrial myopathy.

Clinical Arrhythmias Figure 2: ECG Demonstrating P Terminal Force in V1

Circled P waves show a large terminal force in V1.

Pro-inflammatory and cardiac injury biomarkers such as C-reactive protein (CRP), interleukin-6, TGF-beta1, troponin, and N-terminal pro-Btype natriuretic peptide (NT-proBNP) have been found to be associated with the development of AF.89–92 Serum TGF-beta1, which was previously discussed as part of the fibrotic pathway, has a strong positive correlation with areas of low endocardial atrial voltage consistent with fibrosis (r2=0.93; p<0.001).93 In addition, TGFbeta1 expression is specifically upregulated in patients with extensive low-voltage areas undergoing ablation.94 Serum TGF-beta1 has been shown to be an independent risk factor for AF recurrence after ablation in both paroxysmal and persistent AF.93,95 Interestingly, Kishima et al. found lower concentrations of TGF-beta1 in patients with recurrence after ablation.96 They suggested that the discrepancy may be related to the inflammatory state of the patient. The authors concluded that in the early fibrotic phase and inflammatory stage, TGF-beta1 is higher but begins to decrease once the atrium is more heavily fibrotic.96 Additionally, high levels of the inflammatory cytokine CRP have been associated with higher risk of recurrence after cardioversion.97 Decreased aldosterone concentration has been associated with longer maintenance of sinus rhythm after cardioversion.98,99 This may reflect a reduction in the RAAS system that drives the myopathy. Elevated levels of troponin and NT-proBNP can highlight the existence of myopathy. Post-hoc analysis of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study, showed that patients with persistent elevation of troponin and NT-proBNP were at a higher risk for cardiovascular events and mortality during the follow-up period. Likewise, data from the Aristotle trial showed that troponin levels were significantly associated with higher risk of stroke and systemic embolism.100 A recent study of circulating biomarkers associated with increased myocardial interstitial fibrosis noted a correlation with both the development of AF and recurrence after AF ablation.101

Furthermore, when added to conventional risk scoring systems, biomarkers may enhance predictive value.100,102 For example, the age, biomarkers and clinical history (ABC) stroke score calculates risk based on age, troponin/NT-proBNP levels, and prior stroke. In a validation cohort, this scoring system had a higher C-statistic of 0.65 compared with 0.60 for the CHA2DS2-VASc score.102 While not an exhaustive list, these initial studies of cardiac biomarkers highlight clinical associations that may serve as additional tools for risk stratification of patients with AF.

Intracardiac Electroanatomical Voltage Mapping In patients undergoing electrophysiology studies, in particular those undergoing ablation procedures, electroanatomical voltage mapping can help identify the substrate for tachyarrhythmias. For AF, 3D electroanatomical voltage maps can help identify low-voltage areas that may represent areas of fibrosis (Figure 3).103 Voltage mapping can be performed in patients in sinus rhythm or AF.104 Patients with AF had significantly lower voltage in both the right atrium and LA compared with control patients with left-sided accessory pathways (right atrium: 1.7 ± 0.4 mV versus 2.9 ± 0.4 mV; LA: 1.7 ± 0.7 mV versus 33. ± 0.7 mV; p<0.001).105 Studies have shown that patients with persistent AF have a higher burden of low-voltage areas compared with those with paroxysmal AF.106 Furthermore, these low-voltage areas can be directly targeted with radiofrequency (RF) ablation to perform substrate modification. This has been reported to improve ablation success rates.106–108 Patients with a higher burden of low-voltage areas found on preablation mapping are more likely to have recurrence after ablation.109–112 Vlachos et al. showed that patients with paroxysmal AF who have voltage less than 0.4 mV over more than 10% of the LA area were more likely to have recurrence after pulmonary vein isolation.113

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Atrial Myopathy Underlying AF Figure 3: Left Atrial Voltage Map

Voltage maps of a patient in persistent AF before ablation (posteroanterior and right anterior oblique views). Red corresponds to low voltage (<0.1 mV) and purple to normal voltage (>0.45 mV).

Similar results were seen for both paroxysmal and persistent AF after ablation when using a cut-off of 0.5 mV (HR 5.89; 95% CI [2.16–16.0]; p=0.001).114–116 Low-voltage area burden has been associated with traditional thromboembolic risk factors such as age, female gender and LA surface area and volume.110,117 The mean LA voltage is significantly lower in patients with higher CHA2DS2-VASc scores than in those with lower scores.118 Furthermore, patients with a larger area of low voltage were more likely to have had previous stroke.119

Echocardiogram Echocardiography allows for easy quantification of LA parameters such as diameter, area, volume, and volume index. These measurements can be used as an initial tool but they offer only a limited ability to predict the development of AF and recurrence after treatment.120–122 Furthermore, LA diameter on M-mode echocardiography did not predict stroke (RR 1.02/mm; p=0.10).123 Post-hoc analysis of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial showed no association between LA size and the risk of stroke.124 AF patients have also been found to have LA dysfunction despite normal size.125 Therefore, current guidelines do not include LA size in the decision to start anticoagulation.7 Other echocardiographic markers are now being investigated. Diastolic early transmitral flow velocity/mitral annular velocity (E/E’; a noninvasive surrogate marker for LA end-diastolic pressure) has been found to correlate with low-voltage areas on mapping and recurrence after ablation.126 Additional information that can be obtained from transoesophageal echocardiography include LAA velocity measured on Doppler and spontaneous echocardiographic contrast, which can be predictive of future LA thrombus formation.127,128 Speckle tracking echocardiography (STE) has been proposed as a noninvasive tool to better predict atrial fibrosis.129 STE is a non-Doppler echocardiographic method to quantify atrial deformation by calculating both the atrial strain and longitudinal strain rate of atrial segments.130

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Reduced atrial strain, as calculated using STE, has been correlated with reduced atrial compliance and increased fibrosis.130 Furthermore, histological analysis of patients undergoing mitral valve surgery for severe mitral valve regurgitation found a high inverse correlation between peak longitudinal atrial strain and LA fibrosis (r= −0.82, p<0.001).131 LA strain correlates with the risk of both the development of new onset AF and recurrence after treatment. In a study of patients after STelevation MI, multivariate analysis showed global longitudinal strain to be an independent predictor of the development of AF (HR 1.12; 95% CI [1–1.25]; p=0.042, per 1% decrease).132 Furthermore, when stratified into tertiles of longitudinal strain, patients in the lowest tertile had twice the risk as compared with the highest tertile (HR 2.10; 95% CI [1.04– 4.25]).132 Patients with lower LA total strain and global strain were found to have a higher recurrence of AF after ablation (OR 0.81; 95% CI [0.73– 0.89]; p<0.0001).133 LA strain on STE correlates with the CHADS2 score.134 Moreover, there was an improvement in the prediction of hospitalisation and mortality when LA strain and indexed LA volume were combined with the CHADS2 score (p=0.003).134 In patients with permanent AF, peak strain had an independent negative correlation with prior stroke when controlling for age, LA volume index, and ejection fraction.135 Overall, these examples of STE highlight the interplay between atrial fibrosis and AF given that lower strain has been consistently correlated with AF severity and morbidity.

Cardiac MRI Delayed contrast-enhanced cardiac MRI (DE-cMRI) has been applied to the assessment of atrial fibrosis.136 Although its use in the left ventricle for scar detection is widespread, it is much more challenging to apply to the atrium due to its thinner wall and the limited resolution of MRI.130,137 Cardiac MRI is performed by analysing the distribution of gadolinium contrast agent 10–15 minutes after it is administered. In normal cardiac tissue, the contrast agent quickly washes out. However, in fibrotic tissue it accumulates in the ECM.136,138 A positive correlation

Clinical Arrhythmias Figure 4: Stages of Left Atrial Tissue Fibrosis on Cardiac MRI

Cardiac MRI showing atrial fibrosis in four patients with increasing percentages of atrial fibrosis. Normal left atrial myocardium is shown in blue; fibrosis is represented by green. AP = anteroposterior; PA = posteroanterior. Source: Mahnkopf et al. 2010.140 Reproduced with permission from Elsevier.

Table 1: Summary of Suggested Methods to Assess Atrial Myopathy ECG: • Sinus rhythm: P terminal force in V1 • AF: f wave amplitude • AF: frequency analysis of f waves Biomarkers: • CRP • Interleukin-6 • Troponin • NT-proBNP • TGF-beta1 Electroanatomical voltage mapping: • Voltage

Utah I, 32.6% (95% CI [24.3–42.9%]) in Utah II, 45.9% (95% CI [35.5– 57.5%]) in Utah III, and 51.1% (95% CI [32.8–72.2%]) in Utah IV (Figure 4).141 Similar results have been found when using DE-cMRI to evaluate fibrosis to predict thromboembolic risk. A recent retrospective study of more than 1200 patients who had undergone DE-cMRI evaluated the association of Utah stage atrial fibrosis with cerebrovascular events. It found a significant association between higher late gadolinium enhancement and the rate of cerebrovascular events (HR 3.94; 95% CI [1.72–8.98]).142 An additional analysis of the Utah dataset found that women had a higher rate of fibrosis than men (17.5% versus 15.3%; p<0.01) which may explain the increased stroke risk in women with AF (prior stroke prevalence 15.8% versus 6.5%; p<0.001).143 Moreover, in a prospective study of 111 patients with ischemic stroke, patients with a cryptogenic stroke after extensive stroke workup were found to have a statistically significantly higher percentage of LA fibrosis than patients with a known cause excluding AF (LA fibrosis percentage: median 18%, IQR 16% versus median 10.5%, IQR 16%; p=0.03). Patients with an unknown cause had a similar percentage of fibrosis compared with those with AF as cause (median 18%, IQR 16% versus median 25%, IQR 21%; p=0.22).144 Additionally, 4D flow cardiac MRI, in which 3D images are processed over time, allows for the quantification of LA velocities.145 Subjects with AF had lower velocities than age-matched controls, and those imaged in AF had lower velocities than AF patients imaged in sinus rhythm.145 While not a direct assessment of fibrosis, 4D flow MRI provides a surrogate index for the extent of the atrial myopathy. Reduced LA velocities have been associated with increased stasis and increased CHA2DS2-VASc score (p<0.043).146–148

• Left atrial strain

Future directions for cMRI include 3D segmentation, quantification, and visualisation of LA fibrosis and T1 mapping of the LA to measure extracellular volume as a surrogate marker for LA fibrosis.149,150 However, further research needs to be done to validate these techniques and their clinical utility (Table 1).

Cardiac MRI: • DE-cMRI

Guiding Therapies to Target Fibrosis

Echocardiogram: • Left atrial dimension/volume • Left atrial appendage velocity

• 4D flow CRP = C-reactive protein; DE-cMRI = delayed contrast-enhanced cardiac MRI; NTproBNP = N-terminal pro-B-type natriuretic peptide; TGF = transforming growth factor.

has been shown between areas of delayed enhancement and areas of low voltage in pre-ablation atrial mapping (r2=0.61).139 A similar association between cardiac MRI and voltage mapping was seen by Spragg et al.137 The Utah classification scheme has been proposed to quantify LA fibrosis using DE-cMRI. Based on this system, patients are assigned to 4 groups: Utah I, defined as ≤5% LA wall enhancement; Utah II, 5–20%; Utah III, 20–35%; and Utah IV, >35%. This schema has been shown to be useful in predicting recurrence of AF after catheter ablation in both lone AF and non-lone AF.140,141 The DE-MRI Determinant of Successful Radiofrequency Catheter Ablation of Atrial Fibrillation (DECAAF) study is a large multicentre prospective trial that analysed the ability of the Utah criteria to predict recurrence after ablation.141 This study showed an independent association between MRI-detected atrial fibrosis and recurrent arrhythmia. The hazard ratio was 1.06 (95% CI [1.03–1.08]) for every 1% increase in LA fibrosis. Furthermore, cumulative incidence of recurrence after 325 days based on Utah score was 15.3% (95% CI [7.6–29.6%]) in

Current therapies such as anti-arrhythmic drugs and catheter ablation do not target the atrial myopathy that serves as the substrate for AF. Although catheter ablation of the pulmonary veins has a Class I indication for symptomatic AF,7 extensive RF ablation generates additional scar in the atrium. While this scar tissue may remove arrhythmogenic areas, new extensive scarring may have untoward effects. Patients after RF ablation often have decreased LA area and volume, which may be the result of scar formation with resultant decreased compliance.151,152 Alternatively, this may be due to reverse remodelling of the atrial myopathy. Using cardiac MRI, a correlation was seen between both the number of ablation procedures (r=0.58, p=0.002) and RF duration with the degree of post-ablation atrial scar (r=0.56, p=0.003). Additionally, post-ablation LA scar was negatively correlated with LA compliance and active LA ejection fraction.153 Similar findings were seen in a study by Wylie et al.154 Those authors concluded that scar will lead to a further decrease in LA compliance, which can lead to “stiff LA” syndrome.154 Conversely, prevention of progression and even regression of atrial myopathy has been reported after catheter ablation. There has been some evidence of atrial remodelling following catheter ablation in patients with baseline cardiomyopathies. In a subset of patients from

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Atrial Myopathy Underlying AF the Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction (CAMERA-MRI) study, repeat electroanatomical mapping after pulmonary vein and posterior wall isolation by ablation showed an increase in right atrial voltage on repeat electroanatomical mapping at a mean time of 23.4 months after index ablation (from 1.6 mV ± 0.1 mV to 1.9 ± 0.1 mV; p=0.04). This along with reduction in atrial size and complex fractionated electrograms (21.7 ± 3.5% to 8.3 ± 1.8%; p=0.002) may indicate possible reversal of the atrial myopathy.155 This reverse remodelling may be the result of maintenance of sinus rhythm after ablation.

mechanism is unclear, improvements in atrial volume on echocardiography suggest that it may be due to reversal of the underlying cardiomyopathy.165 As a result, the latest ACC/AHA guidelines for AF recommend weight loss in obese patients with a Class I indication.7 Additionally, Kunamalla et al. demonstrated the use of targeted gene-based reduction of TGF-beta signalling to decrease fibrosis and AF in the canine model.166 Other potential targets of gene therapy include modification of ion channels, gap junctions, autonomic innervation, and fibrosis.167

Conclusion There are preliminary results suggesting that therapies such as weight loss, angiotensin receptor blockers, aldosterone inhibitors, and statins may be able to reduce fibrosis to prevent and decrease AF burden.156–161 For example, patients treated with angiotensin II receptor antagonists were found to have lower levels of TGF-beta1 than those not treated.162 Clinically, the Routine Versus Aggressive Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure (RACE III) trial randomised patients with persistent AF and mild–moderate heart failure to aldosterone antagonist, ACE inhibitors, statins, and cardiac rehab versus conventional therapy. At 1 year, sinus rhythm was present in 75% of the intervention group compared with 63% in the control group (OR 1.765; p=0.042).163 There was also a decrease in markers of myopathy such as NT-proBNP. Similarly, in the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASISHF) trial, patients with systolic heart failure randomised to eplerenone had decreased incidence of new-onset AF (2.7% versus 4.5%; HR 0.58; 95% CI [0.35–0.96]; p=0.034).164 Eplerenone has been shown in the sheep model to reduce atrial fibrosis and dilation, AF inducibility, and progression to persistent AF without preventing AF-induced electrical remodelling.72 In the Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation (ARREST-AF), patients were randomised to risk factor modification guidelines as recommended by the American Heart Association/American College of Cardiology (AHA/ACC) versus conventional care. The treatment arm had an increase in arrhythmia-free survival rates as compared with the control (32.9% versus 9.7%; p<0.001) with HR of 2.3 (p<0.001). While the

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This review highlights the complex interplay between atrial myopathy and AF incidence, recurrence, burden, and stroke risk. Atrial myopathy consists of multiple changes to the atrium including increased fibrosis, pressure overload, autonomic derangement, endothelial dysfunction, and alterations in prothrombotic factors. While there are currently multiple modalities to assess atrial myopathy, they are not being utilised routinely when making decisions regarding therapy including anticoagulation. The additional use of these modalities may allow us to better predict outcomes and tailor therapy. Creating novel therapies that address inflammation, EAT, the autonomic nervous system and molecular pathways of atrial fibrosis are an exciting new paradigm for future AF treatment. Reducing and even reversing atrial myopathy may serve as a more durable method to treat AF and reduce its significant morbidity. Further research is needed to develop these novel strategies to address atrial fibrosis as the precursor to atrial myopathy, AF, and cardioembolic stroke.

Clinical Perspective • AF and atrial myopathy form a complex cycle in which each contributes to the other. • Current risk stratification schema and management strategies do not consider the underlying myopathy of AF. • By identifying atrial myopathy, we may be able to better risk stratify and treat patients with AF.

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org/10.11909/j.issn.1671-5411.2017.03.008; PMID: 28592962. 131. Cameli M, Lisi M, Righini FM, et al. Usefulness of atrial deformation analysis to predict left atrial fibrosis and endocardial thickness in patients undergoing mitral valve operations for severe mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol 2013;111:595–601. https://doi. org/10.1016/j.amjcard.2012.10.049; PMID: 23211360. 132. Olsen FJ, Pedersen S, Jensen JS, et al. Global longitudinal strain predicts incident atrial fibrillation and stroke occurrence after acute myocardial infarction. Medicine 2016;95:e5338. https:// doi.org/10.1097/MD.0000000000005338; PMID: 27858918. 133. Yasuda R, Murata M, Roberts R, et al. Left atrial strain is a powerful predictor of atrial fibrillation recurrence after catheter ablation: study of a heterogeneous population with sinus rhythm or atrial fibrillation. Eur Heart J Cardiovasc Imaging 2015;16:1008–14. https://doi.org/10.1093/ehjci/jev028; PMID: 25750193. 134. Saha SK, Anderson PL, Caracciolo G, et al. Global left atrial strain correlates with CHADS2 risk score in patients with atrial fibrillation. J Am Soc Echocardiogr 2011;24:506–12. https://doi. org/10.1016/j.echo.2011.02.012; PMID: 21477990. 135. Shih J-Y, Tsai W-C, Huang Y-Y, et al. Association of decreased left atrial strain and strain rate with stroke in chronic atrial fibrillation. J Am Soc Echocardiogr 2011;24:513–9. https://doi. org/10.1016/j.echo.2011.01.016; PMID: 21353469. 136. Siebermair J, Kholmovski EG, Marrouche N. Assessment of left atrial fibrosis by late gadolinium enhancement magnetic resonance imaging: methodology and clinical implications. JACC Clin Electrophysiol 2017;3:791–802. https://doi. org/10.1016/j.jacep.2017.07.004; PMID: 29759774. 137. Spragg DD, Khurram I, Zimmerman SL, et al. Initial experience with magnetic resonance imaging of atrial scar and co-registration with electroanatomic voltage mapping during atrial fibrillation: success and limitations. Heart Rhythm 2012;9:2003–9. https://doi.org/10.1016/j.hrthm.2012.08.039; PMID: 23000671. 138. Bucciarelli-Ducci C, Baritussio A, Auricchio A. Cardiac MRI anatomy and function as a substrate for arrhythmias. Europace 2016;18: iv130–5. https://doi.org/10.1093/europace/euw357; PMID: 28011840. 139. Oakes RS, Badger TJ, Kholmovski EG, et al. Detection and quantification of left atrial structural remodeling with delayed-enhancement magnetic resonance imaging in patients with atrial fibrillation. Circulation 2009;119:1758–67. https://doi.org/10.1161/CIRCULATIONAHA.108.811877; PMID: 19307477. 140. Mahnkopf C, Badger TJ, Burgon NS, et al. Evaluation of the left atrial substrate in patients with lone atrial fibrillation using delayed-enhanced MRI: implications for disease progression and response to catheter ablation. Heart Rhythm 2010;7:1475– 81. https://doi.org/10.1016/j.hrthm.2010.06.030; PMID: 20601148. 141. Marrouche NF, Wilber D, Hindricks G, et al. Association of atrial tissue fibrosis identified by delayed enhancement MRI and atrial fibrillation catheter ablation: the DECAAF Study. JAMA 2014;311:498–506. https://doi.org/10.1001/jama.2014.3; PMID: 24496537. 142. King JB, Azadani PN, Suksaranjit P, et al. Left atrial fibrosis and risk of cerebrovascular and cardiovascular events in patients with atrial fibrillation. J Am Coll Cardiol 2017;70:1311–21. https://doi.org/10.1016/j.jacc.2017.07.758; PMID: 28882227. 143. Akoum N, Mahnkopf C, Kholmovski EG, et al. Age and sex differences in atrial fibrosis among patients with atrial fibrillation. Europace 2018;20:1086–92. https://doi.org/10.1093/ europace/eux260; PMID: 29016990. 144. Fonseca AC, Alves P, Inácio N, et al. Patients with undetermined stroke have increased atrial fibrosis: a cardiac magnetic resonance imaging study. Stroke 2018;49:734–7. https://doi.org/10.1161/STROKEAHA.117.019641; PMID: 29371431. 145. Fluckiger JU, Goldberger JJ, Lee DC, et al. Left atrial flow velocity distribution and flow coherence using fourdimensional FLOW MRI: a pilot study investigating the impact of age and pre- and postintervention atrial fibrillation on atrial hemodynamics. J Magn Reson Imaging 2013;38:580–7. https:// doi.org/10.1002/jmri.23994; PMID: 23292793. 146. Markl M, Carr M, Ng J, et al. Assessment of left and right atrial 3D hemodynamics in patients with atrial fibrillation: a 4D flow MRI study. Int J Cardiovasc Imaging 2016;32:807–15. https://doi. org/10.1007/s10554-015-0830-8; PMID: 26820740. 147. Markl M, Lee DC, Furiasse N, et al. Left atrial and left atrial appendage 4D blood flow dynamics in atrial fibrillation. Circ Cardiovasc Imaging 2016;9:e004984. https://doi.org/10.1161/ CIRCIMAGING.116.004984; PMID: 27613699. 148. Lee DC, Markl M, Ng J, et al. Three-dimensional left atrial blood flow characteristics in patients with atrial fibrillation assessed by 4D flow CMR. Eur Heart J Cardiovasc Imaging 2016;17:1259– 68. https://doi.org/10.1093/ehjci/jev304; PMID: 26590397. 149. Ravanelli D, dal Piaz EC, Centonze M, et al. A novel skeleton based quantification and 3-D volumetric visualization of left atrium fibrosis using late gadolinium enhancement magnetic resonance imaging. IEEE Trans Med Imaging 2014;33:566–76. https://doi.org/10.1109/TMI.2013.2290324; PMID: 24239989. 150. Beinart R, Khurram IM, Liu S, et al. Cardiac magnetic resonance T1 mapping of left atrial myocardium. Heart Rhythm

Clinical Arrhythmias 2013;10:1325–31. https://doi.org/10.1016/j.hrthm.2013.05.003; PMID: 23643513. 151. Gibson DN, Di Biase L, Mohanty P, et al. Stiff left atrial syndrome after catheter ablation for atrial fibrillation: clinical characterization, prevalence, and predictors. Heart Rhythm 2011;8:1364–71. https://doi.org/10.1016/j.hrthm.2011.02.026; PMID: 21354332. 152. Kim YG, Shim J, Oh S-K, et al. Different responses of left atrium and left atrial appendage to radiofrequency catheter ablation of atrial fibrillation: a follow up MRI study. Sci Rep 2018;8:7871. https://doi.org/10.1038/s41598-018-26212-y; PMID: 29777140. 153. Cochet H, Scherr D, Zellerhoff S, et al. Atrial structure and function 5 years after successful ablation for persistent atrial fibrillation: an MRI study. J Cardiovasc Electrophysiol 2014;25:671– 9. https://doi.org/10.1111/jce.12449; PMID: 24798070. 154. Wylie JV Jr, Peters DC, Essebag V, et al. Left atrial function and scar after catheter ablation of atrial fibrillation. Heart Rhythm 2008;5:656–62. https://doi.org/10.1016/j.hrthm.2008.02.008; PMID: 18452866. 155. Sugumar H, Prabhu S, Voskoboinik A, et al. Atrial remodeling following catheter ablation for atrial fibrillation-mediated cardiomyopathy: long-term follow-up of CAMERA-MRI study. JACC Clin Electrophysiol 2019;5:681–8. https://doi.org/10.1016/j. jacep.2019.03.009; PMID: 31221354. 156. Schneider MP, Hua TA, Böhm M, et al. Prevention of atrial

fibrillation by renin-angiotensin system inhibition a metaanalysis. J Am Coll Cardiol 2010;55:2299–307. https://doi. org/10.1016/j.jacc.2010.01.043; PMID: 20488299. 157. Da˛browski R, Szwed H. Antiarrhythmic potential of aldosterone antagonists in atrial fibrillation. Cardiol J 2012;19:223–9. https:// doi.org/10.5603/CJ.2012.0043; PMID: 22641540. 158. Fauchier L, Clementy N, Babuty D. Statin therapy and atrial fibrillation: systematic review and updated meta-analysis of published randomized controlled trials. Curr Opin Cardiol 2013;28:7–18. https://doi.org/10.1097/HCO.0b013e32835b0956; PMID: 23160338. 159. Parviz Y, Iqbal J, Pitt B, et al. Emerging cardiovascular indications of mineralocorticoid receptor antagonists. Trends Endocrinol Metab 2015;26:201–11. https://doi.org/10.1016/j. tem.2015.01.007; PMID: 25707577. 160. Nalliah CJ, Sanders P, Kottkamp H, et al. The role of obesity in atrial fibrillation. Eur Heart J 2016;37:1565–72. https://doi. org/10.1093/eurheartj/ehv486; PMID: 26371114. 161. Liu T, Korantzopoulos P, Shao Q, et al. Mineralocorticoid receptor antagonists and atrial fibrillation: a meta-analysis. Europace 2016;18:672–8. https://doi.org/10.1093/europace/ euv366; PMID: 26705563. 162. Zhao S, Li M, Ju W, et al. Serum level of transforming growth factor beta 1 is associated with left atrial voltage in patients with chronic atrial fibrillation. Indian Pacing Electrophysiol J 2018;18:95–9. https://doi.org/10.1016/j.ipej.2017.11.001;

PMID: 29155027. 163. Rienstra M, Hobbelt AH, Alings M, et al. Targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent atrial fibrillation: results of the RACE 3 trial. Eur Heart J 2018;39:2987–96. https://doi.org/10.1093/ eurheartj/ehx739; PMID: 29401239. 164. Swedberg K, Zannad F, McMurray JJV, et al. Eplerenone and atrial fibrillation in mild systolic heart failure: results from the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) Study. J Am Coll Cardiol 2012;59:1598–1603. https://doi.org/10.1016/j.jacc.2011.11.063; PMID: 22538330. 165. Pathak RK, Middeldorp ME, Lau DH, et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. J Am Coll Cardiol 2014;64:2222–2231. https://doi.org/10.1016/j. jacc.2014.09.028; PMID: 25456757. 166. Kunamalla A, Ng J, Parini V, et al. Constitutive expression of a dominant-negative TGF-β type ii receptor in the posterior left atrium leads to beneficial remodeling of atrial fibrillation substrate. Circ Res 2016;119:69–82. https://doi.org/10.1161/ CIRCRESAHA.115.307878; PMID: 27217399. 167. Hucker WJ, Hanley A, Ellinor PT. Improving atrial fibrillation therapy: is there a gene for that? J Am Coll Cardiol 2017;69:2088–95. https://doi.org/10.1016/j.jacc.2017.02.043; PMID: 28427583.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Clinical Arrhythmias

Applications of Machine Learning in Cardiac Electrophysiology Rahul G Muthalaly and Robert M Evans Monash Health, Melbourne, Australia

Abstract Artificial intelligence through machine learning (ML) methods is becoming prevalent throughout the world, with increasing adoption in healthcare. Improvements in technology have allowed early applications of machine learning to assist physician efficiency and diagnostic accuracy. In electrophysiology, ML has applications for use in every stage of patient care. However, its use is still in infancy. This article will introduce the potential of ML, before discussing the concept of big data and its pitfalls. The authors review some common ML methods including supervised and unsupervised learning, then examine applications in cardiac electrophysiology. This will focus on surface electrocardiography, intracardiac mapping and cardiac implantable electronic devices. Finally, the article concludes with an overview of how ML may impact on electrophysiology in the future.

Keywords Machine learning, artificial intelligence, surface electrocardiography, ablation, big data, neural network, cardiac devices Disclosure: The authors have no conflict of interests to declare. Received: 11 December 2019 Accepted: 29 April 2020 Citation: Arrhythmia & Electrophysiology Review 2020;9(2):71–7. DOI: https://doi.org/10.15420/aer.2019.19 Correspondence: Rahul G Muthalaly, Monash Medical Centre, 246 Clayton Rd, Melbourne, VIC 3168, Australia. E: rahul.muthalaly@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Artificial intelligence (AI) has recently become a popular term in the technological world. AI refers to the simulation of human intelligence with the capacity for achieving goals within computers. Machine learning (ML) – a subtype of AI – refers to a statistical model that is able to independently learn to make inferences on new data based on data it has previously analysed. ML has markedly improved efficiency in multiple analytic domains including voice recognition, handwriting recognition, targeted marketing and robotics.1 ML is a broad term that includes a family of methods extending from decision tree models to neural networks. Each method has different attributes that relate to their suitability for a given task. Interestingly, despite their recent popularity, neural networks have been in existence since at least the 1950s, when Marvin Minsky used an artificial neural network to solve a maze.2 However, only in recent times has computing power sufficiently improved to allow the wider application of computationally intensive ML methods.

associations and phenotypic subgroups.4,5 Rajpurkar et al. used a convolutional neural network to develop a model that detected 14 different pathologies from a total of 420 frontal chest radiographs at a much faster rate than board-certified radiologists (1.5 minutes versus 240 minutes for all 420 radiographs). Their model was trained from a database of over 100,000 chest radiographs and could also anatomically localise where the pathologies (including pneumonia, effusions, masses and nodules) were present.6 As an example of unsupervised learning, Horiuchi et al. identified three phenotypic groups of acute heart failure patients that significantly predict mortality and re-hospitalisation.7 Within cardiac electrophysiology, near-term applications of novel data sources have begun appearing. Many of these are driven by industry–academic–healthcare partnerships, the most famous example of which is the Apple Heart study.8 However, significant late stage and outcomes data remain to be seen. These early studies demonstrate some applications of ML in healthcare.9 Updating prior understanding and clinical practice developed over years will take time, but ML has the potential to improve disease definitions, classification and management.

Aside from computing power, the other major development extending the reach of ML has been data acquisition and storage – an essential component to ML. Big data is a term used to describe the increasingly large and more complex datasets that form the basis for ML models.

Big Data

Modern times have seen increasing accessibility and use of large volumes of data. This is apparent in medicine with the advent of electronic health records (EHRs), implantable electronic devices and advanced wearable monitors, all of which record unprecedentedly large volumes of biological data every second.3 ML has already contributed to healthcare advances in a number of specialties. This has taken various forms from assisting imaging and pathological diagnoses, to identifying novel disease risk factor

Data are a core requirement of ML methods. Theoretically, ML methods can be applied to datasets of any size. However, ML methods often benefit from large datasets as they provide more experience on which to train a model. ‘Features’ are components of a dataset that describe characteristics of the observations being studied. These features are fed into computational models that can then provide insight into the observations, for example clustering of similar observations into groups or prediction of outcomes. Large datasets used in this context are

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Clinical Arrhythmias referred to collectively as big data. There are many sources of big data in modern healthcare including EHRs, biobanks, clinical trial data and imaging datasets. The advent of ML methods has allowed enhanced insight into these resources.

The Three Vs of Big Data There are three attributes that delineate the attributes of big data. The first V refers to volume of data. The larger the volume, the more features and experience a model can be trained and tested on. The second V refers to the velocity of data, which describes the speed at which the data is generated. With a higher velocity of data, models can remain more clinically relevant as they are retrained on current experience. The third V refers to variety, which reflects the diversity of the types of data contained in a dataset. Diverse data allows more features that can, in turn, increase generalisability and potentially the accuracy of the model.10 As a general rule, an increase in any of these attributes create a larger demand on the hardware and complexity of the method used to generate a model.

Potential Pitfalls of Big Data The issues with big data can be related to the abovementioned Vs. High volume and velocity data requires significant computer processing power to analyse. Typically it is not an isolated volume or velocity issue, but a combination of the two together. This need for computational efficiency is one of the reasons novel ML methods outperform traditional statistical methods. The extent of resources required to store and analyse data can be prohibitive. This limits the translation of data into clinical investigation and clinical practice. This is relevant in electrophysiology where cardiac devices create large volumes of data each second. Another issue with big data is that it is often poorly organised and managed. This problem, also observed in small datasets, is amplified on a larger scale. Inaccurate data can be inappropriately included or not recognised for its limitations. Thus, the problem of inaccurate data producing inaccurate models remains. Data sharing is an increasingly popular concept made easier with improvements in technological infrastructure.11â&#x20AC;&#x201C;13 Much of this is currently used for subgroup analyses, validation of prior work or the exploration of new hypotheses using trial data. Sharing of data will allow future researchers larger volumes of data to train and test models on. Many models exist for effective data sharing. Federated database systems allow geographically separate databases to be connected via networks. Thus, without merging the databases, researchers can submit queries to the federated database that interfaces with each individual database and provides results from all of them. This method allows the individual databases to remain heterogeneous and distinct. In contrast to this, distributed learning is a method that allows an ML algorithm to be trained using separate datasets. A central ML model is created and updated based on the training performed in each dataset. This model allows maintenance of data security and privacy whilst still harnessing the size of multiple datasets. However, opinions on data sharing as regards privacy and intellectual property, particularly in the medical industry sector, may remain a barrier to the spread of data sharing.14

training dataset with subsequent validation of that model on an evaluation dataset (both of which are often subsets of an original large database). The model is then often run on a test dataset to provide an unbiased evaluation of its performance. The training dataset is used to fit the weights of a model, which detail the relationship between inputs and outcomes in a way specific to the chosen model. The validation dataset is then used to fine tune the model hyperparameters and evaluate the model. Once validated, models can be improved by being re-trained on new data. After re-training, models need to be validated again. These can increase the generalisability of the model across different populations/ datasets. This allows the on-going improvement of the model with rapid responses to changing epidemiological or clinical patterns.

Machine Learning Computational Approaches/Algorithmic Principles The overarching principle of ML is the use of training, evaluation and test datasets to create a valid model.15 ML methods are broadly categorised as supervised, unsupervised or reinforcement learning. Reinforcement learning aims to refine a strategy in a controlled environment stochastically. Reinforcement learning is outside the scope of this article. Knowing which machine learning technique to apply is essential to achieving the objective, analogous to choosing an appropriate statistical technique in traditional methods or choosing an appropriate study design in epidemiology.

Supervised Learning Methods Supervised learning (SL) algorithms aim to classify input data to the correct outputs based on prior input-output pairs that are correctly labelled. The need for labelling can be time consuming. However, the methods are very effective at classification using large datasets. Examples of ML techniques used in SL include traditional linear and logistic regression, artificial neural networks (ANNs), support vector machines (SVMs), decision trees and random forests (RFs).15,16 Pictorial representations of common ML approaches are shown in Figure 1. ANNs and SVMs are among the most common SL methods. They require intensive computational power and time and are prone to over fitting (where the model fits well for the training data but poorly for any new data). However, they are flexible regarding assumptions about the data and offer significant improvements in large datasets where traditional statistical methods struggle.17 ANNs can be layered and altered in order to offer more efficiency in dealing with complex and large data. Decision trees and RFs are closely related. Decision trees are useful with smaller and simpler datasets. They classify data in a binary fashion along a chain of steps. Each branch following a step then has further classification at the next level. This then spreads out until an outcome is reached based on the series of steps taken to get there. The pictorial representation gives the shape to which decision trees are named. RFs are an extrapolation of decision trees where multiple decision trees are combined and each tree is independently trained and verified. They also have the ability to exclude individual trees or components leaving them robust to outliers in meta-analysis and less prone to selection bias.

Machine Learning Methods ML algorithms use and require significant datasets in order to create models and test them. The foundation of ML is creation of a model on a

SL has its limitations including over fitting, the requirement of training and validation and the requirement for accurately labelled data, which

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Machine Learning in Cardiac Electrophysiology Figure 1: Pictorial Representations of Common Machine Learning Techniques

C HIDDEN LAYERS

OUTPUT Sinus rhythm

INPUT

DATA

A: Linear regression where a line of best fit is estimated that allows future predictions to be made given new variables; B: Cluster analysis that separates observations into groups based on their similarity. In this case three groups have been determined; C: An artificial neural network demonstrating an input (ECG) that is fed through a number of connected nodes to match to an output (sinus rhythm); D: A decision tree diagram where values are determined at each branch until a final output is determined.

can be laborious.16 SL models can have poor generalisability and struggle transferring experiences to new data owing to over fitting whereby the model is very well fit only for the original dataset. As a result different models are often required for data from different populations. Each model requires large volumes of labelled data to train and then validate. Importantly, SL does not necessarily overcome prior

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

human biases in classification owing to the labelling step, which is often performed by humans and thus translates those biases into the model. This has had important implications in algorithms overweighting the importance of correlations as causation. This was the case with the Correctional Offender Management Profiling for Alternative Sanctions tool that analysed recidivism and was found to be using race as a

Clinical Arrhythmias predictor in its algorithm.18 Each of these limitations result in varying degrees of bias, impacting on the data and future results.

data that consists of 25 ECG recordings that are 10 hours long.24–26 Importantly, this should herald caution in the assessment of diagnostic accuracy in such studies given the small sample sizes.

Unsupervised Learning Methods Unsupervised learning (UL) has a different goal to SL. In this method, the algorithm attempts to find patterns in the data without prior labelling. For example, in clustering the algorithm creates an unbiased set of categories without human intervention based on similarities between observations (e.g. creating groups of people based on their similarities). There are a variety of techniques included in UL, such as clustering, autoencoders and principal component analysis.15–17 UL is particularly useful when the dataset is very complex or if there is no natural fit to the data. In medicine, it is increasingly being used to identify disease phenotypes in heterogeneous conditions. This could suggest new classifications or stratifications that lead to more sophisticated treatment allocations. It can also be used in less established diseases, where data or literature are poorly developed or pathophysiology is not completely understood. As an example, Shah et al. clustered heart failure with preserved ejection fraction into phenotypic subtypes based on cardiometabolic, cardio-renal and biochemical features.19 UL can produce multiple cluster schemes after analysis. Choosing which cluster scheme is most accurate or appropriate can be difficult and requires clinical interpretation. Importantly, just because a model defines clusters within a disease does not mean these clusters have any clinical relevance. For this to be successful sometimes it is necessary for UL to be combined with follow-up studies assessing the relevance and utility of these clusters. For example, Ahmad et al. identified differing mortality risks after clustering groups of patients with chronic systolic heart failure.20

Machine Learning Applications in Cardiac Electrophysiology ML is gradually expanding its utility in medicine, particularly in cardiology. Cardiac electrophysiology is particularly suitable for ML methods given its big data use and need for more accurate disease phenotype definitions and risk prediction. Returning to the three Vs, through implantable electronic devices, intracardiac mapping and wearable devices, high volume, velocity and variety data are produced. ML methods provide an opportunity to extract maximum clinical and public health benefit from this data.

Surface Electrocardiography Surface ECGs can provide non-invasive, cheap and detailed information regarding arrhythmias. Importantly, because of these attributes, improving ECG interpretation could have substantial public health benefits. There is a bulk of research involving ML and ECGs. While computer analysis of ECGs has been available on most machines for many years, these are often inaccurate because of the quality of ECG recorded. Traditional methods have relied on examining R-R intervals and P-wave presence. However, newer ML-based models have undertaken more sophisticated feature extraction to analyse a variety of rhythms.21 Research on ML in ECG began with basic improvements in pre-processing such as noise reduction or extraction of features such as P-wave or QRS complex characteristics.22,23 This initial work laid the foundation for future research to use these algorithms to create features that could be fed into classifiers such as ANNs and SVMs to further analyse ECGs. Much of the work performed in this area uses the MIT-BIH publicly available classified

Many investigators have attempted to optimise the detection of AF using differing methods, duration of recordings and leads. Models differ by analysing either P-wave absence, R-R intervals or a combination of many ECG features. Ladavich and Ghoraani created a ‘rate-independent’ model that was able to identify AF using only a single cardiac cycle in order to overcome difficulties associated with detection of AF with rapid ventricular response. After feature extraction from the surface ECGs, an expectation-maximisation algorithm was used to train a model. The ultimate model had a sensitivity of 89.37% and specificity of 89.54% for detection of AF using just a single cardiac cycle.24 Longer duration analysis has also been used to provide higher accuracy in the detection of AF. He et al. used a convolutional neural network on time-frequency features (as opposed to P-wave absence or R-R intervals) to train a model for AF detection.26 The final model had an accuracy of 99.23%. Notably, the ECGs still required significant preprocessing before being classified using the convolutional neural network, which limits the potential for clinical use. Other authors have used differing algorithms to train AF detection models. Kennedy et al. used RFs to train a model based on R-R intervals using their own database.27 They later tested this model on the MIT-BIH database. The RF model had a specificity of 98.3% and sensitivity 92.8%, which is comparatively less than seen in many of the neural-network-based approaches. However, their training database was also considerably smaller and further direct comparisons of RF and ANN models are needed to determine their comparative accuracy in AF detection. In contrast to ANNs and RFs, Asgari et al. used an SVM to train a model for detection of AF based on wavelet transformation.28 The use of wavelet transformation obviates the need for pre-processing of P or R-waves that is required by many algorithms. However, this method still required feature extraction prior to classification with the SVM. The authors tested their model on the MIT-BIH database and found an area under the curve (AUC) of 0.995, which outperformed both a naïve Bayesian classifier and logistic regression based method. There is less literature available on identification of ventricular arrhythmias. Mjahad et al. demonstrated that time-frequency analysis using a variety of models (logistic regression, ANN, SVM and bagging classifier) accurately identifies ventricular tachycardia (VT) and ventricular fibrillation (VF) on 12-lead ECG.25 This method required pre-processing of the ECG signal for both noise reduction and computation of time windows. On testing, all models performed similarly, with ANNs having a 98.19% accuracy for VF and 98.87% accuracy for detection of VT. Huang et al. demonstrated the ability of ANNs to localise atrioventricular accessory pathways in patients undergoing ablation.29 Using features of delta wave polarity and R-wave duration as a proportion of the QRS complex, an ANN generated model trained on 90 cases correctly identified the site of accessory pathways in 58/60 test cases. In the two cases of misclassification, the accessory pathway was located in a contiguous region to the identified area. The aforementioned studies have generally required significant preprocessing of the ECG signal prior to classification as well as involving

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Machine Learning in Cardiac Electrophysiology models trained for a specific arrhythmia. Hannun et al. created their own test and validation database.21 This included 91,232 single lead ECGs from the Zio patch-based electrode device. These ECGs were then fed to an ANN to create a model for classifying 12 different output rhythms (10 arrhythmias, sinus rhythm and noise). Importantly, their method did not require significant feature extraction or ECG signal preprocessing. The authors validated their findings against a committee of cardiologists who had classified the test dataset. The ANN achieved an AUC of 0.91 across all rhythms. Additionally, they compared their model to that of ‘average’ cardiologists outside the adjudication committee and found that the model outperformed cardiologists across every rhythm. This work represents a significant step forward in ECG classification as it demonstrates end-to-end machine learning, where raw data is inputted and diagnostic probabilities are outputted without the use of extensive data manipulation or pre-processing. UL methods have, thus far, had more limited application in the analysis of surface ECG. Donoso et al. used a k-means clustering algorithm to separate AF on ECG into five different types based on frequency values. However, this work is yet to be validated by examination of the clinical significance of the five different types of AF.30 AliveCor uses ML software built into their app to work in combination with an electrode band and phone or smartwatch.31 Their model is one of the first that has the ability to analyse the rhythm and diagnose AF in almost real time, as well as other ML models they have developed to identify long QT and hyperkalaemia off ECG.32,33 Twice weekly ECGs using their devices has been shown to be 3.9 times more likely to identify AF in high risk patients aged >65 years than routine monitoring.31 Additionally, recent work has examined the sensitivity of an AliveCor convolutional neural network using the Apple Watch heart rate, activity and ECG sensors as inputs compared to traditional implantable cardiac monitors for the detection of AF.3 The results suggest that the wearable monitor provides excellent sensitivity (97.5%) for detecting AF episodes lasting >1 hour but poor positive predictive value (39.9%). Given the excellent sensitivity, this strategy may help define those who would benefit from an implantable cardiac monitor post cryptogenic stroke. Continual progress is being made in ML-based surface ECG analysis. With the advent of wearable technology, the availability of training data on which to improve models will increase and the quality of the raw data may also improve alongside the technology. However, these data will still require labelling for the implementation of SL methods, which represents a major resource barrier. External validation of the abovementioned models on larger datasets will be required before more sophisticated conclusions about the utility of such models can be made.

Intracardiac Mapping ML is gradually emerging as a tool to improve the understanding and efficacy of ablation. Preclinical and early clinical work has focused on stratifying and classifying electrogram morphology to guide electrogram-based AF ablation. In attempt to improve complex fractionated atrial electrogram (CFAE) based AF ablation, Schilling et al. created four classes of CFAEs based on patient data. They established classes that increased in complexity from class 0 to class 3.34 They used a variety of features in order to create their complexity classes, including time domain descriptors, phase space descriptors, wavelet based descriptors, similarity of

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active segments and amplitude based-descriptors. Once defined, they employed a fuzzy-decision tree (similar in methodology to a standard decision tree) to classify electrograms from 11 patients undergoing AF ablation. This algorithm had 81% accuracy for defining the CFAE class of an electrogram. The fuzzy decision tree model imparted the advantage of applying a probability that an electrogram belonged to a certain class unlike other algorithms. Duque et al. later validated and improved these CFAE classes by using a genetic algorithm (that optimised the included features) to further define the four classes.35 After the initial consolidation of the classes, they used a k-nearest neighbour SL algorithm to classify electrograms. They demonstrated 92% accuracy for classification of CFAE class and performed simulation to demonstrate that the more complex CFAE classes were associated with rotor locations in a simulated model. Orozco-Duque et al. similarly tried to improve classification of CFAEs using four features (two time-domain morphology based and two nonlinear dynamic based) to separate four classes of fractionation.36 They used a semi-supervised clustering algorithm to validate these classes on partially labelled data. They then went on to apply those classes to an unlabelled dataset and created clusters with reasonable separation. This work suggests that ML may be able to separate subtle differences in recorded electrograms and possibly provide feedback about areas most likely to result in AF termination after ablation. McGillivray et al. used an RF classifier to identify re-entrant drivers of AF in a simulated model where the ‘true’ location of the re-entrant circuits were known.37 This model used electrogram features to assess the rhythm, predict the location and reassess the predictions until focused on the source of the driver. The model correctly identified 95.4% of drivers whether one or more were present in the simulation. Muffoletto et al. simulated AF ablation in a 2D model of atrial tissue using three different methods – pulmonary vein isolation, fibrosis-based and rotor-based ablation.38 They were able to model the outcomes of these ablation strategies and use the outcome as labelled data for a ANN. Using different patterns in their AF simulation, the model was able to identify the successful ablation strategy in 79% of the simulations. This work serves as a proof-of-concept for ML prediction of optimal ablation strategies, but the difficulty of identifying the ‘correct’ ablation strategy amongst a number of options in vivo makes the possibility of clinical translation daunting. Computer modelling of AF is becoming more complex with the advancement of cell-level, tissue-level and organ-level models.39,40 These models have provided crucial insights into the relationships driving AF including the nature of automatic and rotational foci, the role of fibrosis and the effect of channel-types. ML may prove a useful tool in integrating the significant high-dimensional data produced by computer modelling. Possibilities include the definition of phenotypes using UL or the prediction of AF rotors based on patient-specific attributes, thus guiding ablation strategy using SL. In an abstract presented at the American Heart Association 2018 scientific meeting, Alhusseini et al. described the use of a convolutional neural network to identify organised AF drivers that acutely terminate with ablation in persistent AF based on features extracted from spatial phase maps.41 They reported 95.2% accuracy for determining organised sites of activity that terminate AF upon ablation. These early results suggest another possibility for real-time ML-guided ablation strategies. However, the long-term efficacy of such an approach remains unclear.

Clinical Arrhythmias ML is gradually entering the field of ablation and has the opportunity to integrate the significant volume of data generated by electroanatomical mapping systems and guide electrophysiologists to appropriate sites and methods of ablation. The use of SL in this way will face challenges given the significant data load and difficulties of creating labelled datasets, though the ultimate goal of machine-guided ablation may be achieved. However, UL methods may provide more insight into the patterns of arrhythmia seen during procedures.

Cardiac Implantable Electronic Devices Cardiac implantable electronic devices (CIEDs) are an ideal target for ML methods given the high volume and velocity of data they produce. ML applications have allowed for risk stratification, improved arrhythmia localisation and streamlined remote monitoring which may significantly reduce the workload faced by electrophysiologists.42–44 CRT is an effective component of heart failure management in selected patients.45 Benefit is restricted to those who meet current guideline criteria based on trial data. ML models may provide a more sophisticated method of identifying those likely to respond to CRT. Kalscheur et al. used multiple SL methods on data from the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial to construct a model capable of predicting outcomes with CRT.42 They employed an RF, decision tree, naïve Bayesian classifier and SVM with 48 features available in the clinical trial. They found that the RF model produced the best results, demonstrating an AUC of 0.74 for predicting outcomes. The quartile of highest risk predicted by the model had an eightfold difference in survival in comparison to the lowest risk quartile. When using traditional factors of QRS duration and morphology there was no significant association with outcomes. The features used in their model are easily clinically available. Cikes et al. employed UL for a similar purpose, seeking to identify high- and low-risk phenotypes for those likely to respond to CRT.46 Using data from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) trial, they employed a k-means clustering algorithm to create groups with similar characteristics based on echocardiographic and clinical parameters. Of the four phenotypes they identified, two were associated with a better effect of CRT on heart-failure-free survival (HR 0.35 and HR 0.36 compared to non-significant). The advantage of using UL in this instance was the ability to identify the phenotypic aspects associated with CRT benefit. This is often not possible in SL owing to the nature of how the algorithms create associations, referred to as the ‘black-box’ problem. Recognising the potential clinical difficulty of employing such models, Feeny et al. attempted to predict improved left ventricular ejection fraction with CRT using only nine features selected to optimise model performance. 47 These nine variables were employed in multiple ML models (including an SVM, RF, logistic regression, an adaptive boosting algorithm and a naïve Bayesian classifier). They found that the Bayesian classifier performed best demonstrating an AUC of 0.70, which was significantly better than guideline-based prediction. To demonstrate the clinical adaptability of their approach they generated a publicly available online calculator. The above studies are clinically relevant examples of using both UL and SL to risk stratify patients and help with decision making around significant interventions. The benefits of UL as regards transparency are observed, as well as the potential difficulties around clinical adaptation of complex models.

Rosier et al. examined the potential for ML to automate monitoring of alerts from CIEDs.44 They used natural language processing to examine EHR data to determine the significance of AF alerts from CIEDs. The natural language processing algorithm was able to calculate CHA2DS2VASc scores and anticoagulant status for each patient and thus, classify the importance of the AF alert. Their algorithm correctly stratified CHA2DS2-VASc scores of 0, 1 and ≥2 97% of the time. As a result of this, 98% of AF alerts were correctly classified with regard to their importance and the remaining misclassified alerts were overclassified, allowing for human review. This study highlights the ability of ML to act as an assistant to electrophysiologists by guiding attention to where it is needed. In a similar vein of aiding electrophysiological intervention, SanrománJunquera et al. used ICD electrograms to localise exit sites during pace mapping for VT ablation.43 Using implanted RV leads as sensors, they employed multiple algorithms including ANNs, SVMs and regression methods to identify left ventricular exit sites. Their SVM model produced the best results, localising the exit site to one eighth of the heart 31.6% of the time (where a random model would produce results of 12.5%). This work serves as a proof of concept for ML based ablation localisation, especially where a 12-lead ECG of the tachycardia may not be available. However, significant improvements are required before such methods are clinically applicable. In an application of RF models, Shakibfar et al. used only ICD data without clinical variables to predict risk of electrical storm.48 They developed 37 ICD electrogram-based features found during the four consecutive days prior to the onset of electrical storm (defined using device detection). They found that their RF model had an AUC of 0.80 for predicting electrical storm. The most relevant features were percentage of pacing and reduced daytime activity. These results are limited by the use of device-defined ventricular arrhythmias, however, they signify promise for the increasing use of the high dimensional data produced by CIEDs.

Conclusion ML in electrophysiology is nascent. However, early work suggests the potential use that ML may have in stratification, diagnosis and therapy for arrhythmia. These methods may also affect the nature of the electrophysiologist’s role into the future with increasing data sources and methods of analysis to add to each patient’s data profile. As data derived from the use of wearable devices increases, consideration needs to be given to how these technologies will be implemented to ensure patient safety and appropriate use. In particular, the risk of overdiagnosis will need to be considered as wearable monitors become more commonplace.

Clinical Perspective • Big data, easily collected from electronic health records and cardiac devices, allows the use of sophisticated models to generate new insights. • Machine learning models can accurately diagnose multiple rhythms from short segments of surface electrocardiographs in almost real time. • Optimisation of intra-cardiac mapping and implantable device analysis are areas that can significantly gain from increased machine learning integration owing to the large volume of data created in these fields.

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20. Ahmad T, Pencina MJ, Schulte PJ, et al. Clinical implications of chronic heart failure phenotypes defined by cluster analysis. J Am Coll Cardiol 2014;64:1765–74. https://doi.org/10.1016/j. jacc.2014.07.979; PMID: 25443696. 21. Hannun AY, Rajpurkar P, Haghpanahi M, et al. Cardiologist-level arrhythmia detection and classification in ambulatory electrocardiograms using a deep neural network. Nat Med 2019;25:65–9. https://doi.org/10.1038/s41591-018-0268-3; PMID: 30617320. 22. Ochoa-Brust A, Mena L, Felix V. Noise-tolerant neural network approach for electrocardiogram signal classification. Proceedings of the International Conference on Compute and Data Analysis 2017:277–82. https://doi.org/10.1145/ 3093241.3093269. 23. Pourbabaee B, Lucas C. Automatic detection and prediction of paroxysmal atrial fibrillation based on analyzing ECG signal feature classification methods. Presented at Cairo International Biomedical Engineering Conference 2008, Cairo, Egypt, 18–20 December 2008. https://doi.org/10.1109/ CIBEC.2008.4786068. 24. Ladavich S, Ghoraani B. Rate-independent detection of atrial fibrillation by statistical modeling of atrial activity. Biomed Signal Process Control 2015;18:274–81. https://doi.org/10.1016/j. bspc.2015.01.007. 25. Mjahad A, Rosado-Munoz A, Bataller-Mompean M, et al. Ventricular fibrillation and tachycardia detection from surface ECG using time-frequency representation images as input dataset for machine learning. Comput Methods Programs Biomed 2017;141:119–27. https://doi.org/10.1016/j.cmpb.2017.02.010; PMID: 28241963. 26. He R, Wang K, Zhao N, et al. Automatic detection of atrial fibrillation based on continuous wavelet transform and 2D convolutional neural networks. Front Physiol 2018;9:1206. https://doi.org/10.3389/fphys.2018.01206; PMID: 30214416. 27. Kennedy A, Finlay DD, Guldenring D, et al. Automated detection of atrial fibrillation using R-R intervals and multivariate-based classification. J Electrocardiol 2016;49:871–6. https://doi.org/10.1016/j.jelectrocard.2016.07.033; PMID: 27717571. 28. Asgari S, Mehrnia A, Moussavi M. Automatic detection of atrial fibrillation using stationary wavelet transform and support vector machine. Comput Biol Med 2015;60:132–42. https://doi. org/10.1016/j.compbiomed.2015.03.005; PMID: 25817534. 29. Huang D, Yamauchi K, Inden Y, et al. Use of an artificial neural network to localize accessory pathways of Wolff-ParkinsonWhite syndrome with 12-lead electrocardiogram. Med Inform Internet Med 2005;30:277–86. https://doi.org/10.1080/ 14639230500367670. PMID: 16531354. 30. Donoso FI, Figueroa RL, Lecannelier EA, et al. Clustering of atrial fibrillation based on surface ECG measurements. Conf Proc IEEE Eng Med Biol Soc 2013;2013:4203–6. https://doi. org/10.1109/EMBC.2013.6610472; PMID: 24110659. 31. Halcox JPJ, Wareham K, Cardew A, et al. Assessment of remote heart rhythm sampling using the Alivecor heart monitor to screen for atrial fibrillation: the REHEARSE-AF Study. Circulation 2017;136:1784–94. https://doi.org/10.1161/ CIRCULATIONAHA.117.030583; PMID: 28851729. 32. Karacan M, Celik N, Gul EE, et al. Validation of a smartphonebased electrocardiography in the screening of QT intervals in children. Northern Clin Istanb 2019;6:48–52. https://doi. org/10.14744/nci.2018.44452; PMID: 31180383. 33. Galloway CD, Valys AV, Shreibati JB, et al. Development and validation of a deep-learning model to screen for hyperkalemia from the electrocardiogram. JAMA Cardiol 2019;4:428–36. https://doi.org/10.1001/jamacardio.2019.0640; PMID: 30942845. 34. Schilling C, Keller M, Scherr D, et al. Fuzzy decision tree to classify complex fractionated atrial electrograms. Biomed Tech (Berl) 2015;60:245–55. https://doi.org/10.1515/bmt-2014-0110;

PMID: 25781659. 35. Duque SI, Orozco-Duque A, Kremen V, et al. Feature subset selection and classification of intracardiac electrograms during atrial fibrillation. Biomedical Signal Process Control 2017;38:182–90. https://doi.org/10.1016/j. bspc.2017.06.005. 36. Orozco-Duque A, Bustamante J, Castellanos-Dominguez G. Semi-supervised clustering of fractionated electrograms for electroanatomical atrial mapping. Biomed Eng Online 2016;15:44. https://doi.org/10.1186/s12938-016-0154-5; PMID: 27117088. 37. McGillivray MF, Cheng W, Peters NS, et al. Machine learning methods for locating re-entrant drivers from electrograms in a model of atrial fibrillation. R Soc Open Sci 2018;5:172434. https://doi.org/10.1098/rsos.172434; PMID: 29765687. 38. Muffoletto M, Fu X, Roy A, et al. Development of a deep learning method to predict optimal ablation patterns for atrial fibrillation. Presetned at IEEE Conference on Computational Intelligence in Bioinformatics and Computational Biology (CIBCB) 2019, Siena, Italy, 9–11 July 2019. https://doi. org/10.1109/CIBCB.2019.8791475. 39. Aronis KN, Ali RL, Liang JA, et al. Understanding AF mechanisms through computational modelling and simulations. Arrhythm Electrophysiol Rev 2019;8:210–9. https:// doi.org/10.15420/aer.2019.28.2; PMID: 31463059. 40. Ciaccio EJ, Wan EY, Saluja DS, et al. Addressing challenges of quantitative methodologies and event interpretation in the study of atrial fibrillation. Comput Methods Programs Biomed 2019;178:113–22. https://doi.org/10.1016/j.cmpb.2019.06.017; PMID: 31416540. 41. Alhusseini M, Abuzaid F, Swerdlow M, et al. Sites where ablation terminated atrial fibrillation identified by machine learning models. Presented at American Heart Association Scientific Sessions 2018, Chicago, IL, 10–12 November 2018. Abstract 13161. 42. Kalscheur MM, Kipp RT, Tattersall MC, et al. Machine learning algorithm predicts cardiac resynchronization therapy outcomes. Circ Arrhythm Electrophysiol 2018;11:e005499. https://doi.org/10.1161/CIRCEP.117.005499; PMID: 29326129. 43. Sanromán-Junquera M, Mora-Jiménez I, Almendral J, et al. Automatic supporting system for regionalization of ventricular tachycardia exit site in implantable defibrillators. PLoS One 2015;10:e0124514. https://doi.org/10.1371/journal. pone.0124514; PMID: 25910170. 44. Rosier A, Mabo P, Temal L, et al. Personalized and automated remote monitoring of atrial fibrillation. Europace 2016;18:347–52. https://doi.org/10.1093/europace/euv234; PMID: 26487670. 45. Bristow MR, Saxon LA, Boehmer J, et al. Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140–50. https://doi.org/10.1056/NEJMoa032423; PMID: 15152059. 46. Cikes M, Sanchez-Martinez S, Claggett B, et al. Machine learning-based phenogrouping in heart failure to identify responders to cardiac resynchronization therapy. Eur J Heart Fail 2019;21:74–85. https://doi.org/10.1002/ejhf.1333; PMID: 30328654. 47. Feeny AK, Rickard J, Patel D, et al. Machine learning prediction of response to cardiac resynchronization therapy: Improvement versus current guidelines. Circ Arrhythm Electrophysiol 2019;12:e007316. https://doi.org/10.1161/ CIRCEP.119.007316; PMID: 31216884. 48. Shakibfar S, Krause O, Lund-Andersen C, et al. Predicting electrical storms by remote monitoring of implantable cardioverter-defibrillator patients using machine learning. Europace 2019;21:268–74. https://doi.org/10.1093/europace/ euy257; PMID: 30508072.

Cardiac Pacing

Ultrasound-guided Axillary Vein Puncture in Cardiac Lead Implantation: Time to Move to a New Standard Access? Ana Paula Tagliari,1,2,3 Adriano Nunes Kochi,1,4,5 Bernardo Mastella,6 Rodrigo Petersen Saadi,6 Andres di Leoni Ferrari,2 Luiz Henrique Dussin,2,6 Leandro de Moura,2,6 Márcio Rodrigo Martins,2,6 Eduardo Keller Saadi2,6 and Carisi Anne Polanczyk1,7 1. Postgraduate Program in Cardiology and Cardiovascular Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 2. Cardiovascular Surgery Department, Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil; 3. University Hospital of Zurich, University of Zurich, Cardiac Surgery Department, Zurich, Switzerland; 4. Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil; 5. Centro Cardiologico Monzino, Heart Rhythm Center, Milan, Italy; 6. Cardiovascular Surgery Department, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; 7. Cardiology Department, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

Abstract Cardiac stimulation therapy has evolved significantly over the past 30 years. Currently, cardiac implantable electronic devices (CIED) are the mainstream therapy for many potentially lethal heart conditions, such as advanced atrioventricular block or sustained ventricular tachycardia or fibrillation. Despite sometimes being lifesaving, the implant is surgical and therefore carries all the inevitable intrinsic risks. In the process of technology evolution, one of the most important factors is to make it safer for the patient. In the context of CIED implants, complications include accidental puncture of intrathoracic structures. Alternative strategies to intrathoracic subclavian vein puncture include cephalic vein dissection or axillary vein puncture, which can be guided by fluoroscopy, venography or, more recently, ultrasound. In this article, the authors analyse the state of the art of ultrasound-guided axillary vein puncture using evidence from landmark studies in this field.

Keywords Cardiac implantable electronic devices, permanent pacemaker implantation, ICD, ultrasound, axillary vein Disclosure: APT has received funds from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES; Finance Code 001) for scientific research. All other authors have no conflicts of interest to declare. Received: 18 April 2020 Accepted: 19 May 2020 Citation: Arrhythmia & Electrophysiology Review 2020;9(2):78–82. DOI: https://doi.org/10.15420/aer.2020.17 Correspondence: Ana Paula Tagliari, Cardiovascular Surgery Department, Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul, Ipiranga Ave, 6690, 90619-900 Porto Alegre, Brazil. E: anapaulatagliari@yahoo.com.br Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Cardiac implantable electronic devices (CIEDs), including permanent pacemakers (PPMs), ICD and CRT devices, are the mainstream therapy for many potentially lethal heart conditions, such as advanced atrioventricular block or sustained ventricular tachycardia or fibrillation. CIEDs can be implanted through endovascular or epicardial routes, with the former used the most because it is less invasive and provides better pacing thresholds.1–3

Cephalic access has been used as a route for endocardial lead implantation since 1960. 7,8 Despite its relative safety, by avoiding central venous puncture, the method is associated with high failure rates and longer procedure times.9 Cardiac lead insertion is also highly dependent on venous anatomy, trajectory, calibre and operator skills,10 which culminates in failure rates ranging from 10% to 70%.11–15

Since the first successful insertion of a temporary transvenous endocardial lead through the brachial vein by Furman and Schwedel in 1959,4 many technical advancements have been described, culminating in the widespread use of the procedure.5 It is projected that the global number of PPMs implanted annually will be 1.43 million by 2023.6

Conversely, subclavian vein puncture is a highly successful approach, but requires central venous puncture, the complications of which, although uncommon, can be potentially fatal.16,17 In addition, leads implanted through subclavian puncture are more susceptible to longterm dysfunction secondary to subclavian crush syndrome.18–22

A European Heart Rhythm Association survey showed that cephalic vein dissection and blind subclavian vein puncture are the preferred techniques for the implantation of CIED leads in European centres.5 However, these two techniques are associated with variable success and complications rates that can be reduced by using imaging guidance.

To address these problems, punctures guide d by fluoroscopy, venography and ultrasound (US) have emerged as feasible and reproducible alternatives to increase procedure success and safety.7,23–28 Another relatively new method that has received increasing attention is axillary vein puncture, the first application of which in CIED implantation was described by Byrd in 1993.29

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Ultrasound-guided Axillary Vein Puncture in Lead Implantation By anatomical definition, the axillary vein is a continuation of the brachial vein, originating at the lower margin of the teres major muscle and terminating at the lateral margin of the first rib. The extrathoracic location of the axillary vein and its distance from the first rib explain the lower rates of pneumothorax, haemothorax, inadvertent arterial puncture and subclavian crush syndrome following axillary vein puncture. In addition, the axillary vein has a large calibre, allowing multiple punctures or multiple lead insertions through the same puncture.18

resolution image. If a more medial puncture is desired, a microconvex linear array probe with a smaller footprint may be an alternative to deal with the acoustic shadowing from the overlying clavicle.43 A more medial puncture offers a less deep and steep puncture angle and reduces the risk of brachial plexus injury, the incidence of which in axillary puncture varies from 0% to 1.3%.44 Symptoms related to brachial plexus injury can be attributed to direct trauma of the nerve by the needle due to repeated puncture attempts in a too lateral position or to brachial plexus block induced by lignocaine.44

Despite these benefits, lead insertion using the axillary vein remains uncommon in many centres, primarily due to the lack of proper training and concerns with a supposed long learning curve.

Compared with fluoroscopy and venography, US-guided puncture has some advantages, such as a faster effective learning process and no requirement for extra X-ray exposure, additional peripheral access or contrast injection. These features may potentially avoid renal function impairment, allergic reactions and venous spasm related to the use of contrast.45 Furthermore, the use of venography for axillary vein puncture is limited by the inability to estimate the depth of the puncture with this method.

Ultrasound-guided Venous Puncture US-guided puncture allows direct visualisation of the vessels and surrounding structures. Therefore, the puncture is safer and less time consuming.30,31 Since 2001, US-guided central catheter placement has been recommended by the Agency for Healthcare Research and Quality as one of the 11 fundamental practices to improve procedural safety.32 However, this recommendation applies mostly to the jugular vein, because there was not enough evidence supporting USguided axillary vein puncture, especially during CIED implantation.33–35 The first description of US-guided axillary vein location was reported by Shregel et al. in 1994.36 This was followed by the first real-time US-guided axillary vein puncture, initially using the short axis, by Nash et al. in 1998 and, posteriorly, using the long axis by Sandhu in 2004.25,37 Subsequently, many reports have suggested that this method is associated with a short time to obtain central venous access, a reduced number of puncture attempts and low complication rates.25,31,38–40 Some ultrasound characteristics make the axillary vein easily distinguishable from the axillary artery and feasible for clinical use, such as the lack of pulsation, a more medial and superficial position and external pressure compressibility (Figure 1). Ultrasound scanning also allows evaluation of vein patency prior to pocket creation, which may be useful in patients with prior thoracic surgery, radiotherapy exposure or dialysis catheters.39 Another particularly relevant advantage of US is the detection of complications, such as pneumothorax, earlier than with radiological control. Whereas the presence of pleural sliding is the most important finding in a normal aerated lung (‘seashore sign’ using the M-mode), the lack of pleural sliding and the presence of parallel horizontal lines above and below the pleural line (‘barcode’ or ‘stratosphere sign’ using the M-mode) are indicative of pneumothorax.41 In terms of the US-guided axillary puncture, clear needle visualisation is a crucial step to enable proper puncture, avoiding damage to adjacent structures such as vessels, nerves and pleura. In crosssectional images, the needle tip can be seen as a highly echogenic spot with surrounding artefacts caused by the scattering of the ultrasound beam, which is less easily visible within the heterogeneous appearance of body tissue. In the out-of-plane needle approach, the needle shaft is not visualised, and indirect evidence of vein compression may be seen (Figure 2).42 The probe most used to guide axillary vein puncture is the vascular highfrequency linear array probe (5–10 MHz), which provides a high-

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Scientific Evidence Comparing CIED Lead Insertion Through Axillary Vein Puncture With Other Techniques Calkins et al. were one the first groups, in 2001, to undertake a randomised clinical trial evaluating venography-guided extrathoracic subclavian puncture versus cephalic vein dissection in 200 participants who had undergone PPM or ICD lead implantation.46 The extrathoracic subclavian group had higher success (99% versus 64%; p<0.001), shorter time to obtain central venous access (mean ± SD: 10 ± 8 minutes versus 25 ± 17 minutes; p<0.01), shorter total procedural time (86 ± 22 minutes versus 98 ± 35 minutes; p<0.01) and lower blood loss (55 ± 13 ml versus 115 ± 107 ml; p<0.01), but there was no significant difference in early complication rates between the two groups (6% versus 11%; p=0.2).46 In 2016, Lui et al. published the results of another randomised control trial comparing fluoroscopy-guided axillary vein puncture to standard blind subclavian vein puncture in 247 CIEDs.47 Comparisons of axillary and subclavian punctures revealed similar first-puncture attempt success (68.4% versus 66.1%, respectively; p=0.597) and overall success rate (95.7% versus 96%, respectively; p=0.845). Despite these similarities, the time to perform the puncture was shorter in the subclavian puncture group (46 ± 14 versus 28.7 ± 14 s; p<0.001), but, over a mean follow-up period of 24.1 ± 7.4 months, the complication rate was lower in the axillary puncture group (1.6% versus 8.2%; p=0.016). In terms of severe complications, three cases of pneumothorax and two of subclavian crush syndrome were reported with subclavian access.47 In 2018, Liccardo et al. compared PPM and ICD lead insertion through US-guided axillary vein puncture to anatomical landmark-guided subclavian puncture in 174 participants.38 Before starting the comparative study, a training phase (60 axillary cases) was performed, during which an axillary success rate of 69% was achieved. During the randomised phase, no difference in success rate was reported (91.4% versus 94.8% in the axillary and subclavian groups, respectively). Over a mean follow-up period of 18 ± 6 months, lead complications were similar in both groups (2.6% versus 5.2%; p=0.664), with two cases of pneumothorax (3.4%) requiring thorax drainage and longer hospitalisation length of stay in the subclavian group. Axillary puncture was considered a safe and efficient alternative to the standard subclavian access for CIED implantation.38

Cardiac Pacing Figure 1: 2D Ultrasound Image of the Right Axillary Vein and Artery in Short-Axis View

Axillary artery

Axillary vein

Short-axis view The probe marker is pointing cranially. Compressibility, lack of pulsation and a more medial and superficial position differentiate the axillary artery from the axillary vein.

In contrast to the finding of lower success in the initial training phase noted above, Squara et al. demonstrated excellent outcomes for a selftaught axillary technique from the first case.44 That study was a prospective randomised trial comparing self-learned fluoroscopyguided axillary vein puncture with cephalic vein dissection in 74 participants undergoing PPM implantation. Similar venous access success (81.1% versus 75.7% for axillary vein puncture and cephalic vein dissection, respectively; p=0.57) and 30-day complication rates (13.5% versus 10.8%; p=0.71) were obtained, with shorter venous access time (5.7 minutes versus 12.2 minutes; p<0.001), total procedural time (34.8 minutes versus 42 minutes; p=0.043) and X-ray exposure (1,463 versus 1,013 mGy·cm2; p=0.12) in the axillary group.44 These results were quite consistent throughout the study, independent of the number of cases performed by each operator. Based on these findings, the authors highlighted that one of the particular advantages of the axillary vein is its possible use as a bail-out alternative when the cephalic vein is absent or has an unsuitable calibre, avoiding intrathoracic puncture.44 Esmaiel et al. also reported their experience with US-guided axillary vein puncture in 403 consecutive patients who underwent a PPM implantation between 2012 and 2015.48 In that study, a success rate of 99.2% was obtained, with a mean number of 1.18 venepuncture attempts per patient and a mean time of 2.24 minutes to obtain central venous access. No access-related complication was reported.48 However, because that study was a retrospective, observational, single-centre and single-operator study, its external validity could be questionable. An interesting point from the study by Esmaiel et al. is that the authors had described puncturing the vein from inside the pocket incision using a sterile covered probe.48 According to Esmaiel et al., this puncture is performed 1–2 cm medial to the deltopectoral groove, therefore more medial and slightly cranial than the standard incision for a cephalic cutdown.48 We prefer to puncture first and to create the pocket after because, with this technique: • we can incise the skin in a medial position, far from the axillary region, in a location that we judge more comfortable to the patient; • the puncture site does not get restricted to the incision area, which enables us to more easily change the position of vascular linear

probe (e.g. from the short to long-axis or from lateral to medial), scanning the entire vein; and • we avoid applying gel inside the pocket, even sterile gel, due to concern of infection. Despite these arguments, in obese patients puncturing from inside the pocket could be preferable because this technique facilitates vein visualisation by obviating imaging impairment due to the deep layer of subcutaneous fat. In our practice, in chronological order, we first puncture the vein and insert the 0.035" guidewire. Second, we make the skin incision and build the pocket in a location that we judge more comfortable to the patient. Third, we dissect the tissues until we identify the 0.035" J-wire, which we then pull to the subcutaneous or submuscular space (i.e. subcutaneously in case of subcutaneous pocket and submuscularly in case of a submuscular pocket). A 2006 prospective non-randomised study comparing PPM lead implantation by US-guided axillary puncture versus cephalic vein dissection evidenced similar success rates for the two approaches (88% versus 87%, respectively), with shorter lead placement time in the axillary group (8 minutes versus 12 minutes; p<0.05).31 It was also reported that the operators achieved lead placement times with US-guided axillary puncture that were equivalent to those for cephalic dissection after 25 cases; however, once the US-guided technique was mastered, the operators had faster lead placement times with this method than with cephalic dissection. In this analysis, independent predictors of lead placement time were BMI, operator experience, initial strategy (ultrasound versus cephalic) and number of procedures.31 Regarding predictors of late lead complication, Chan et al. reported that, over a mean follow-up period of 73.6 ± 33.1 months, subclavian vein puncture instead of axillary vein puncture was the only independent predictor of pacemaker lead failure (HR 0.26; 95% CI [0.07–0.95]; p=0.042).49 In this analysis, the success rate was significantly lower in the cephalic group (78.2%) than in the venography-guided axillary puncture or blind subclavian puncture groups (97.6% and 96.8%, respectively; p<0.001).49 In addition, over a medium-term follow-up period (mean 45 ± 10 months), ElJamili et al. showed that, even in

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Ultrasound-guided Axillary Vein Puncture in Lead Implantation Figure 2: Long-Axis Ultrasound-guided Axillary Vein Puncture

Aiming to fill the evidence gap in the comparison between US-guided axillary puncture and cephalic vein dissection, as well as to provide a strong scientific basis for the use of US-guided axillary vein puncture as the standard technique for CIED implantation, Tagliari et al. recently published the results of the first randomised clinical trial comparing these two approaches during PPM and ICD lead implantation.52 In that trial, the superiority of the US-guided axillary approach was demonstrated in terms of success rate (97.7% versus 54.5%; p<0.001), time to obtain central venous access (5 minutes versus 15 minutes; p<0.001) and total procedural time (40 minutes versus 51 minutes; p=0.010), with no increase in complication rate.52

Guidewire

Conclusion Vein

patients under oral anticoagulation or antithrombotic therapy, USguided axillary puncture presented no postoperative complications and achieved a success rate of 95.78%, with the guidewire insertion time reaching a plateau after 15 patients.50 Considering all these studies, US-guided axillary vein puncture has a success rate ranging from 80% to 99%.25,38–40 Compared with other available access routes, this rate appears better than that reported for cephalic vein dissection (64–87%)31,44,46,49 and similar to that reported for venography-guided axillary puncture (90–98%),10,28,49,51 fluoroscopyguided axillary puncture (61–98%)10,18,22,23,44,47 and even blind subclavian puncture (94–96%).23,38,47,49

Sharma AD, Guiraudon GM, Klein GJ. Pacemaker implantation techniques. In: El-Sherif N, Samet P, eds. Cardiac Pacing and Electrophysiology. Philadelphia: WB Saunders; 1991; 561–7. 2. Smyth NPD. Techniques of implantation: atrial and ventricular, thoracotomy and transvenous. Prog Cardiovasc Dis 1981;23:435–50. https://doi.org/10.1016/0033-0620(81)900086; PMID: 7232757. 3. Lawrie GM, Scale JP, Morris GC Jr, et al. Results of epicardial pacing by the left subcostal approach. Ann Thorac Surg 1979;28:561–7. https://doi.org/10.1016/S0003-4975(10)631785; PMID: 518184. 4. Furman S, Schwedel JB. An intracardiac pacemaker for Stokes–Adams seizures. N Engl J Med 1959;261:943–8. https:// doi.org/10.1056/NEJM195911052611904; PMID: 13825713. 5. Bongiorni MG, Proclemer A, Dobreanu D, et al. Preferred tools and techniques for implantation of cardiac electronic devices in Europe: results of the European Heart Rhythm Association survey. Europace 2013;15:1664–8. https://doi.org/10.1093/ europace/eut345; PMID: 24170423. 6. Statista. Global number of pacemakers in 2016 and a forecast for 2023 (in million units). 2019. https://www.statista.com/ statistics/800794/pacemakers-market-volume-in-unitsworldwide (accessed 22 June 2020). 7. Parsonnet V, Zucker R, Gilbert L, Myers GH. Clinical use of an implantable standby pacemaker. JAMA 1966;196:784–6. https://doi.org/10.1001/jama.196.9.784; PMID: 5952309. 8. King SM, Arrington JO, Dalton ML. Permanent transvenous cardiac pacing via the left cephalic vein. Ann Thorac Surg 1968;5:469–473. https://doi.org/10.1016/S00034975(10)66382-5; PMID: 5647935. 9. Aizawa Y, Negishi M, Kashimura S, et al. Predictive factors of lead failure in patients implanted with cardiac devices. Int J Cardiol 2015;199:277–81. https://doi.org/10.1016/j. ijcard.2015.07.055; PMID: 26218183. 10. Burri H, Sunthorn H, Dorsaz PA, Shah D. Prospective studies of

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11.

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CIEDs are a widely used, life-saving therapy for different heart rhythm conditions. Because of potential failures or complications of standard implant practices (i.e. cephalic dissection and subclavian vein puncture), alternative techniques have emerged. Among these, USguided axillary puncture stands out because of its high success rate, associated with a low incidence of complications and short learning curve. In addition, this techniques aligns with the new trend to use US for safer vascular access in different contexts. The article by Tagliari et al. will hopefully contribute to shedding some light on this issue, and possibly to changing standard approaches.52

Clinical Perspective • Despite not being the standard approach in many centres, axillary vein punctures guided by fluoroscopy, venography and ultrasound have emerged as feasible alternatives for the implantation of cardiac implantable electronic devices (CIEDs). • Lead insertion through axillary vein puncture is associated with a short learning curve and procedural time. • Ultrasound-guided axillary vein puncture has a high success rate with a low complication rate, which could make it the preferred approach for the implantation of CIEDs.

axillary vein puncture with or without contrast venography for pacemaker and defibrillator lead implantation. Pacing Clin Electrophysiol 2005;28(Suppl 1):S280–3. https://doi.org/10.1111/ j.1540-8159.2005.00039.x; PMID: 15683516. Furman S. Venous cutdown for pacemaker implantation. Ann Thorac Surg 1986;41:438–9. https://doi.org/10.1016/S00034975(10)62705-1; PMID: 3963922. Furman S. Subclavian puncture for pacemaker lead placement. Pacing Clin Electrophysiol 1986;9:467. https://doi. org/10.1111/j.1540-8159.1986.tb06600.x; PMID: 2426662. van Rugge FP, Savalle LH, Schalij MJ. Subcutaneous singleincision implantation of cardioverter-defibrillators under local anesthesia by electrophysiologists in the electrophysiology laboratory. Am J Cardiol 1998;81:302–5. https://doi.org/10.1016/ S0002-9149(97)00918-1; PMID: 9468072. Shmada H, Hoshino K, Yuki M, et al. Percutaneous cephalic vein approach for permanent pacemaker implantation. Pacing Clin Electrophysiol 1999;22:1499–501. https://doi.org/10.1111/j.1540-8159.1999.tb00354.x; PMID: 10588152. Ong LS, Barold SS, Lederman M, et al. Cephalic vein guidewire technique for implantation of permanent pacemakers. Am Heart J 1987;114:753–6. https://doi.org/10.1016/00028703(87)90785-x; PMID: 3661365. Aggarwal RK, Connelly DT, Ray SG, et al. Early complications of permanent pacemaker implantation: no difference between dual and single chamber systems. Br Heart J 1995;73:571–5. https://doi.org/10.1136/hrt.73.6.571; PMID: 7626359. Chauhan A, Grace AA, Newell SA, et al. Early complications after dual chamber versus single chamber pacemaker implantation. Pacing Clin Electrophysiol 1994;17:2012–5. https:// doi.org/10.1111/j.1540-8159.1994.tb03791.x; PMID: 7845809. Migliore F, Siciliano M, De Lazzari M, et al. Axillary vein puncture using fluoroscopic landmarks: a safe and effective approach for implantable cardioverter defibrillator leads. J

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Interv Card Electrophysiol 2015;43:263–7. https://doi. org/10.1007/s10840-015-0011-7; PMID: 25956478. Fyke EF. Doppler guided extrathoracic introducer insertion. Pacing Clin Electrophysiol 1995;18:1017–21. https://doi. org/10.1111/j.1540-8159.1995.tb04742.x; PMID: 7659552. Jacobs DM, Fink AS, Miller RP, et al. Anatomical and morphological evaluation of pacemaker lead compression. Pacing Clin Electrophysiol 1993;16:434–44. https://doi. org/10.1111/j.1540-8159.1993.tb01606.x; PMID: 7681195. Alt E, Völker R, Blömer H. Lead fracture in pacemaker patients. Thorac Cardiovasc Surg 1987;35:101–4. https://doi. org/10.1055/s-2007-1020206; PMID: 2440129. Antonelli D, Feldman A, Freedberg NA, Turgeman Y. Axillary vein puncture without contrast venography for pacemaker and defibrillator leads implantation. Pacing Clin Electrophysiol 2013;36: 1107–10. https://doi.org/10.1111/pace.12181; PMID: 23713786. Sharma G, Senguttuvan NB, Thachil A, et al. A comparison of lead placement through the subclavian vein technique with fluoroscopy-guided axillary vein technique for permanent pacemaker insertion. Can J Cardiol 2012;28:542–6. https://doi. org/10.1016/j.cjca.2012.02.019; PMID: 22552175. Dora S, Kumar V, Bhat A, Tharakan JA. Venogram-guided extrathoracic subclavian vein puncture. Indian Heart J 2003, 55, 637–40. PMID: 14989516. Nash A, Burrell CJ, Ring NJ, Marshall AJ. Evaluation of an ultrasonically guided venepuncture technique for the placement of permanent pacing electrodes. Pacing Clin Electrophysiol 1998;21:452–5. https://doi.org/10.1111/ j.1540-8159.1998.tb00071.x; PMID: 9507548. Belott P. How to access the axillary vein. Heart Rhythm 2006;3:366–9. https://doi.org/10.1016/j.hrthm.2005.10.031; PMID: 16500314. Jiang M, Gong XR, Zhou SH, et al. A comparison of steep and shallow needle trajectories in blind axillary vein puncture.

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Pacing Clin Electrophysiol 2013;36:1150–5. https://doi. org/10.1111/pace.12156; PMID: 23663298. Ramza BM, Rosenthal L, Hui R, et al. Safety and effectiveness of placement of pacemaker and defibrillator leads in the axillary vein guided by contrast venography. Am J Cardiol 1997;80:892–6. https://doi.org/10.1016/S0002-9149(97)005420; PMID: 9382004. Byrd C. Clinical experience with the extrathoracic introducer insertion technique. Pacing Clin Electrophysiol 1993;16:1781–4. https://doi.org/10.1111/j.1540-8159.1993.tb01810.x; PMID: 7692408. Harada Y, Katsume A, Kimata M, et al. Placement of pacemaker leads via the extrathoracic subclavian vein guided by fluoroscopy and venography in the oblique projection. Heart Vessels 2005;20:19–22. https://doi.org/10.1007/s00380004-0797-1; PMID: 15700198. Jones DG, Stiles MK, Stewart JT, Armstrong GP. Ultrasoundguided venous access for permanent pacemaker leads. Pacing Clin Electrophysiol 2006;29:852–7. https://doi. org/10.1111/j.1540-8159.2006.00451.x; PMID: 16923001. Shojania KG, Duncan BW, McDonald KM, et al. Making health care safer: a critical analysis of patient safety practices. Evid Rep Technol Assess (Summ) 2001;43:1–668. PMID: 11510252. Rupp SM, Apfelbaum JL, Blitt C, et al. Practice guidelines for central venous access: a report by the American Society of Anesthesiologists Task Force on Central Venous Access. Anesthesiology 2012;116:539–73. https://doi.org/10.1097/ ALN.0b013e31823c9569; PMID: 22307320. Lamperti M, Bodenham AR, Pittiruti M, et al. International evidence-based recommendations on ultrasound-guided vascular access. Intensive Care Med 2012;38:1105–17. https:// doi.org/10.1007/s00134-012-2597-x; PMID: 22614241. National Institute of Clinical Excellence. Guidance on the use of ultrasound locating devices for placing central venous catheters. London: NICE; 2002. http://guidance.nice.org.uk/TA49 (accessed 22 June 2020). Schregel W, Hoer H, Radtke J, Cunitz G. Ultrasonic guided cannulation of the axillary vein in intesive care patients. Anaesthesist 1994;43:674–9 [in German]. https://doi.

org/10.1007/s001010050109; PMID: 7818050. 37. Sandhu NS. Transpectoral ultrasound-guided catheterization of the axillary vein: an alternative to standard catheterization of the subclavian vein. Anesth Analg 2004;99:183–7. https://doi.org/10.1213/01.ANE.0000117283.09234.2C; PMID: 15281527. 38. Liccardo M, Nocerino P, Gaia S, Ciardiello G. Efficacy of ultrasound-guided axillary/subclavian venous approaches for pacemaker and defibrillator lead implantation: a randomized study. J Interv Card Electrophysiol 2018;51:153–60. https://doi. org/10.1007/s10840-018-0313-7; PMID: 29335840. 39. Seto AH, Jolly A, Salcedo J. Ultrasound-guided venous access for pacemakers and defibrillators. J Cardiovasc Electrophysiol 2013;24:370–4. https://doi.org/10.1111/jce.12005; PMID: 23131025. 40. Orihashi K, Imai K, Sato K, et al. Extrathoracic subclavian venipuncture under ultrasound guidance. Circ J 2005;69:1111– 5. https://doi.org/10.1253/circj.69.1111; PMID: 16127196. 41. Husain LF, Hagopian L, Wayman D, et al. Sonographic diagnosis of pneumothorax. J Emerg Trauma Shock 2012;5:76–81. https:// doi.org/10.4103/0974-2700.93116; PMID: 22416161. 42. Kim IS, Kand SS, Park JH, et al. Impact of sex, age and BMI on depth and diameter of the infraclavicular axillary vein when measured by ultrasonography. Eur J Anaesthesiol 2011;28:346– 50. https://doi.org/10.1097/EJA.0b013e3283416674; PMID: 21150632. 43. Shiloh AL, Eisen LA, Yee M, et al. Ultrasound-guided subclavian and axillary vein cannulation via an infraclavicular approach: in the tradition of Robert Aubaniac. Crit Care Med 2012;40:2922–3. https://doi.org/10.1097/ CCM.0b013e31825cea64; PMID: 22986669. 44. Squara F, Tomi J, Scarlatti D, et al. Self-taught axillary vein access without venography for pacemaker implantation: prospective randomized comparison with the cephalic vein access. Europace 2017;19:2001–6. https://doi.org/10.1093/ europace/euw363; PMID: 28064251. 45. Duan X, Ling F, Shen Y, et al. Venous spasm during contrastguided axillary vein puncture for pacemaker or defibrillator lead implantation. Europace 2012;14:1008–11. https://doi.

org/10.1093/europace/eus066; PMID: 22436615. 46. Calkins H, Ramza BM, Brinker J, et al. Prospective randomized comparison of the safety and effectiveness of placement of endocardial pacemaker and defibrillator leads using the extrathoracic subclavian vein guided by contrast venography versus the cephalic approach. Pacing Clin Electrophysiol 2001;24:456–64. https://doi.org/10.1046/j.1460-9592. 2001.00456.x; PMID: 11341082. 47. Liu P, Zhou YF, Yang P, et al. Optimized axillary vein technique versus subclavian vein technique in cardiovascular implantable electronic device implantation: a randomized controlled study. Chin Med J (Engl) 2016;129:2647–51. https:// doi.org/10.4103/0366-6999.193462; PMID: 27823994. 48. Esmaiel A, Hassan J, Blenkhorn F, Mardigyan V. The use of ultrasound to improve axillary vein access and minimize complications during pacemaker implantation. Pacing Clin Electrophysiol 2016;39:478–82. https://doi.org/10.1111/ pace.12833; PMID: 26880272. 49. Chan NY, Kwong NP, Cheong AP. Venous access and long-term pacemaker lead failure: comparing contrast-guided axillary vein puncture with subclavian puncture and cephalic cutdown. Europace 2017;19:1193–7. https://doi.org/10.1093/ europace/euw147; PMID: 27733455. 50. ElJamili M, Bun SS, Latcu DG, et al. Ultrasound-guided axillary vein puncture for cardiac devices implantation in patients under antithrombotic therapy. Indian Pacing Electrophysiol J 2020;20:21–6. https://doi.org/10.1016/j.ipej.2019.12.008; PMID: 31857214. 51. Mehrotra S, Rohit MK. Prospective study to develop surface landmarks for blind axillary vein punctures for permanent pacemaker and defibrillator lead implantation and compare it to available contrast venography guided technique. Indian Heart J 2015;67:136–40. https://doi.org/10.1016/j.ihj.2015.04.007; PMID: 26071292. 52. Tagliari AP, Kochi AN, Mastella B, et al. Axillary vein puncture guided by ultrasound versus cephalic vein dissection in pacemaker and defibrillator implant: a multicenter randomized clinical trial. Heart Rhythm 2020. https://doi.org/10.1016/j. hrthm.2020.04.030; PMID: 32360827; epub ahead of press.

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Devices

Percutaneous Left Atrial Appendage Occlusion: A View From the UK Wern Yew Ding and Dhiraj Gupta Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, UK

Abstract AF is associated with an increased risk of thromboembolic events, which is usually managed with oral anticoagulation therapy. However, despite a broad range of anticoagulant options and improved uptake in anticoagulation over the past decade, there are some limitations to this approach. Percutaneous left atrial appendage occlusion has been shown to be an effective alternative in this setting, and population data suggest a clear demand for this procedure. Over the past decade, several important changes to the commissioning and delivery of this service have occurred in the UK. In this article, the authors describe the use of percutaneous left atrial appendage occlusion in the UK and discuss the challenges that lie ahead.

Keywords Left atrial appendage, occlusion, closure, percutaneous, UK Disclosure: DG is speaker for Bayer, Bristol Myers Squibb /Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Biosense Webster and Boston Scientific, proctor for Abbott, and has research grants from Medtronic, Biosense Webster and Boston Scientific. WYD has no conflicts of interest to declare. Received: 7 February 2020 Accepted: 28 May 2020 Citation: Arrhythmia & Electrophysiology Review 2020;9(2):83–7. DOI: https://doi.org/10.15420/aer.2020.08 Correspondence: Dhiraj Gupta, Department of Cardiology, Liverpool Heart and Chest Hospital, Thomas Drive, Liverpool L14 3PE, UK. E: Dhiraj.Gupta@lhch.nhs.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

AF is associated with an increased risk of thromboembolic events.1,2 Risk scores are used to identify patients at high risk of such complications who may benefit from anticoagulation therapy.3 However, despite a broad range of anticoagulant options and improved uptake in anticoagulation over the past decade, there are limitations to this approach. First, there is a significant proportion of high-risk patients who have haematological disorders, frailty or previous major bleeding, whose high risk of bleeding precludes the use of anticoagulants.4 Second, there are patients who may continue to suffer thromboembolic events despite receiving appropriate guideline-directed anticoagulation therapy.5 Third, compliance and adherence with drug therapy may be suboptimal; discontinuation rates in randomised controlled trials (RCTs) of direct oral anticoagulants (DOACs) are between 21 and 27%.6–9 Therefore, there is the need for an alternative treatment strategy for these patients. The majority (>90%) of thrombus formation in AF has been shown to originate from the left atrial appendage (LAA).10,11 As a result, surgical closure of the LAA has been performed in an attempt to reduce stroke risk.12 More recently, less invasive techniques, such as percutaneous LAA occlusion, have been developed. In this review, we aim to discuss the provision of LAA occlusion in the UK.

Demand for Left Atrial Appendage Occlusion in the UK The Sentinel Stroke National Audit Programme (SSNAP) is a national quality improvement project that has recorded stroke data for most of the UK since 2012. In its most recent 2019 annual report (Table 1),

it found that over a third of patients with known AF were not on oral anticoagulation therapy prior to their stroke presentation (n=1,566, 36.7%). 13 Although this proportion has declined significantly compared with previous years – 61.6% in 2014 – it is still high enough to cause concern. Given that the majority of patients with AF and stroke were aged ≥70 years (68.9%) and suffered from hypertension (54.9%), it is unlikely that low perceived stroke risk was the main reason for the lack of anticoagulation among these patients. Although the exact reasons remain unclear, the report did highlight that many of these patients were not anticoagulated due to contraindications (n=421, 26.8%). This figure would chime with the observation from primary care’s Quality Outcomes Framework data that about 6% of the overall AF cohort in the UK are deemed to have contraindications to anticoagulation, although this was lower than the estimated 12% from the US.14,15 Furthermore, the SSNAP data showed that 2,705 strokes occurred in AF patients who were already receiving anticoagulation therapy (12.3% of the total cohort). A UK population-based cohort study of 11,481 patients with AF who were treated with a DOAC between January 2012 and December 2016 found that almost a third of patients had discontinued DOAC treatment within 1 year. 16 The majority of these patients (60.4%) had a gap of at least 30 days without stroke protection before eventually reinitiating treatment with a vitamin K antagonist or DOAC. However, a significant percentage (n=813, 7.1%) still remained without anticoagulation following this period. Similar discontinuation rates were reported in other non-UK cohorts.17,18 Overall, these data demonstrate that there is a clear demand for LAA occlusion therapy

Access at: www.AERjournal.com

Devices Table 1: Summary of SSNAP 2019 Annual Report Patient Variables

Prevalence

Total patients with strokes: • Infarction

n=22,068 87.3%

• Intracerebral haemorrhage

12.2%

• Unknown

0.5%

Men

52.3%

Median age (IQR)

77 years (66–85)

Prior comorbidities: • Hypertension

54.9%

• Stroke or TIA

26.0%

• Diabetes

22.4%

• Congestive heart failure

4.9%

Known AF

19.4%

Anticoagulation status: • Prescribed

n=4, 271 63.3%

• Not prescribed

26.8%

• Contraindicated

9.9%

Newly diagnosed AF

5.6%

IQR = interquartile range; SSNAP = Sentinel Stroke National Audit Programme; TIA = transient ischaemic attack. Source: Sentinel Stroke National Audit Programme (SSNAP), 2020.13 Adapted with permission from SSNAP.

among patients in whom anticoagulation is either not tolerated or is contraindicated, with a further potential role in those with anticoagulation-resistant strokes.

Service Delivery in the UK The UK population is covered by the National Health Service (NHS), a publicly funded healthcare system. The National Institute for Health and Care Excellence (NICE) is responsible for appraising evidence and providing guidelines for clinicians in England and Wales. In 2011, NICE determined that there was inadequate evidence to support percutaneous LAA occlusion as an adjunct for stroke prevention in AF.19 However, it recognised that certain patients may be unable to tolerate anticoagulation and permitted the use of LAA occlusion in those circumstances. One year later, a draft policy in the NHS revealed that there were plans to put restrictions on the routine commissioning of LAA occlusion.20 Concerns were raised from healthcare professionals and health charities about this and NHS England decided upon a multicentre observational registry using the process of Commissioning through Evaluation (CtE).21 The purpose of the single-arm CtE registry was to evaluate LAA occlusion as a possible treatment option for patients with AF at high risk of stroke who have contraindications to anticoagulation therapy. As a quid pro quo for contributing to the registry, 10 specialised centres in England with cardiac surgery facilities were granted limited funding to perform LAA occlusion between October 2014 and September 2016. After this period, there was an 18-month interval during which LAA occlusion in the NHS essentially ceased due to lack of funding while data from the CtE registry were analysed and reviewed by the specialised commissioning group. In June 2018, a decision was made by NHS England to support commissioning of LAA occlusion in selected patients with nonvalvular AF and high thromboembolic risk, defined as having a CHA2DS2-VASc score of ≥2, where there is a physician-assessed contraindication to oral anticoagulants.22 This included patients with anticoagulation-resistant strokes. Under this policy, patients who had

a Rockwood frailty score of ≥6 or a life expectancy of less than 3 years were deemed unsuitable for LAA occlusion. All procedures undertaken were to be recorded on a national registry to allow prospective evaluation of long-term outcomes. The plan was to perform 400 cases in the first year at the same 10 centres that were part of the CtE process, increasing to 1,200 a year over 5 years with the approval of additional centres following another round of selection in summer 2019. At the time of writing this review (February 2020), no more centres have been commissioned. Recently, the Scottish Health Technologies Group released a report advising that NHS Scotland should offer LAA occlusion to similar patients.23 Figure 1 shows a timeline of the LAA occlusion service delivery in the UK.

Access to Left Atrial Appendage Occlusion Broadly speaking, the eligibility and funding criteria for LAA occlusion in the UK resemble that of France, the US, Australia, Poland and Canada.24–26 The fundamental difference, however, is in the restriction in the number of centres commissioned to provide LAA occlusion in the UK set at 10 as this puts a significant constraint on the provision of this service at a population level. In Germany, provision of LAA occlusion is dependent on individual insurance providers and is not subject to restrictions. In New Zealand, there are severe restrictions imposed on LAA occlusion in the public sector, but patients with anticoagulationresistant strokes and a high risk of bleeding may be covered by private health insurance.27

Data on Left Atrial Appendage Occlusion The final report of the CtE registry was produced in early 2019 and included 525 patients with AF who underwent LAA occlusion.21 Virtually all cases were performed under general anaesthetic (99.4%) and with intraoperative transoesophageal echocardiographic imaging (99.5%). Median fluoroscopy time and procedural duration in minutes were 10 (inter quartile range [IQR] 7–15) and 75 (IQR 57–110), respectively. Overall procedural success was 89% with a periprocedural mortality risk of 1%. Median length of stay was one night with 22.4% of patients requiring an extended admission (≥2 days). No differences in outcomes were seen between the various devices used. Risk of ischaemic stroke during follow-up was significantly reduced compared with that predicted from validated risk scoring systems, affirming the role of LAA occlusion in patients with AF who have contraindications to anticoagulation therapy. Furthermore, subsequent linkage of 460 patients with two UK datasets (Hospital Episode Statistics and Office of National Statistics) produced comparable data with the registry, adding confidence to the results.21 Based on our experience at a large tertiary centre in the UK, LAA occlusion can be performed with a high procedural success rate (82/83, 98.8%) in patients with contraindications to anticoagulation therapy. 28 The procedure appeared to result in a reduction of stroke rates compared with historical cohorts with a corresponding risk profile. In those who did have a stroke despite LAA occlusion, none were disabling, and all patients made a full recovery. This finding supports the notion that LAA occlusion may be associated with fewer AF-related strokes, as well as lesser severity of strokes when they do occur. 29–32 It was our practice that all procedures were performed jointly by a consultant electrophysiologist and interventional cardiologist under transoesophageal echocardiogram and fluoroscopic guidance. Post-procedural dual antiplatelet therapy was mandated for 6 weeks, followed thereafter by single antiplatelet therapy up to 6 months. Most patients in our centre

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Percutaneous Left Atrial Appendage Occlusion were kept in for overnight monitoring and discharged the following day, with a mean length of hospital stay of one day. More recently, Williams et al. demonstrated that LAA occlusion can be performed safely as a day-case procedure with very low rates of complications and readmissions. 33

Figure 1: UK Timeline of Left Atrial Appendage Occlusion Service Delivery

2011

A retrospective registry by Betts et al. reported on outcomes from 371 patients with AF who underwent percutaneous LAA occlusion at eight centres in the UK prior to the period when the CtE registry was active.34 The follow-up period was over 24 months. Overall procedural success was 92.5% with an annual relative risk reduction based on predicted risk profiles for ischaemic stroke, thromboembolic events and major bleeding of 90.1%, 87.2% and 92.9%, respectively. The number of LAA occlusions undertaken at each centre varied significantly with a median of 40 cases (IQR 5–145). This suggests that some centres in the UK performed very few procedures during the study period, a factor which has been shown to be associated with worse outcomes.35 The UK-specific data appear broadly in agreement with that from international registries (Table 2).21,33–37 The relatively high periprocedural mortality rates reported in the CtE registry and study by Williams et al. was also observed by Tzikas et al. and may be related to an initial learning curve with the procedure.21,33,37 Overall, a direct comparison of complication rates across studies may be inaccurate due to confounders related to differences in the inclusion criteria and baseline risk factors. With this in mind, the periprocedural mortality rates found in the aforementioned studies were greater than in the Registry on WATCHMAN Outcomes in Real-Life Utilization (EWOLUTION) study (NCT01972282).38 Worse primary outcomes observed in the real-life registries compared with randomised trials may be explained by recruitment of patients with a higher risk of stroke, along with greater prevalence of comorbidities causing contraindication to oral anticoagulation.35,36 Despite evidence to support the role of LAA occlusion in patients with AF who have contraindications to anticoagulation therapy, there are several factors to be considered. About half of the cases in the UK were performed using the Amplatzer Amulet device (Abbott). However, results from RCTs are currently only available for the Watchman device (Boston Scientific).35,36 Furthermore, these trials excluded patients who were considered unsuitable for anticoagulation, thereby further limiting generalisability of their results to patients receiving LAA occlusion. In general, the use of an epicardial approach for LAA occlusion remains poorly explored. Nonetheless, this offers an interesting prospect as the relatively high periprocedural complication rates may potentially be balanced by the absence of an intracardiac device, thereby negating the need for even short-term anticoagulation and the risk of device-related thrombus.39–41 Currently, the majority of the data on LAA occlusion are derived from real-world registries that may be subject to selection and reporting bias. There are limited studies directly comparing LAA occlusion to placebo and additional welldesigned RCTs are needed. There are two ongoing RCTs that may provide some insight on the matter – Prevention of Stroke by Left Atrial Appendage Closure in Atrial Fibrillation Patients After Intracerebral Hemorrhage (STROKECLOSE; NCT02830152) and Assessment of the WATCHMAN™ Device in Patients Unsuitable for Oral Anticoagulation (ASAP-TOO; NCT02928497) but results are not expected for several years. It has also been suggested that LAA

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

2012

2014

NICE guidance recommends LAAO in certain patients with AF

Draft NHS policy reveals future plans to restrict LAAO therapy

Limited funding by NHS England for LAAO in 10 specialised sites using the process of CtE

CtE evaluation completed 2016

2016 – 2018

2018

Service delivery of LAAO in the NHS ceased

Decision by NHS England to continue commissioning of LAAO for selected patients

CtE = commissioning through evaluation; LAAO = left atrial appendage occlusion; NHS = National Health Service; NICE = National Institute for Health and Care Excellence.

occlusion may be feasible in patients with proven LAA thrombus although this needs further evaluation.42

Cost Efficacy of Left Atrial Appendage Occlusion In a publicly funded healthcare system, such as the NHS, the costeffectiveness of LAA occlusion is an important consideration. Using recent estimates, the cost of each procedure was about £11,600.43 This represented an increase of 78% compared with the lifetime cost of medical therapy with antiplatelets alone. However, when the higher initial cost of the procedure is balanced against a reduction in medical and social care expenditure from lower stroke rates, it is forecasted to be cost neutral over a 15-year period. When compared with the cost of medical therapy with anticoagulants, LAA occlusion was found to achieve cost parity between 4.9 years versus dabigatran and 8.4 years versus warfarin.44 The study by Panikker et al. estimated that LAA occlusion may save up to £7,194 at 10 years compared with other therapies. As such, the predicted remaining lifespan of individuals is an important factor when assessing their suitability for LAA occlusion. Similar cost benefits have also been demonstrated in studies in the US.45–47 In the current UK setting – and many other parts of the world – the majority of patients with AF are seen in primary care. This includes many patients who may be deemed unsuitable for anticoagulation by GPs. However, given the new policy changes and the unavailability of LAA occlusion until recently, many clinicians may not be aware that there exists an alternative for such patients. Estimates from NHS England predict that referral networks may require more than 5 years to become established and eventually only 10% of LAA occlusioneligible patients will be considered for this treatment.22

Devices Table 2: Comparison of Left Atrial Appendage Occlusion in the UK Compared with Rest of the World

RoW

Betts et al. 201734 (n=371)

CtE registry, 201921 (n=525)

Williams et al. PROTECT AF, 201936 201833 (n=463)1 (n=117)

PREVAIL, 201435 (n=269)*

Tzikas et al. 201637 (n=1,047)

Mean age, years (SD)

72.9 (8.3)

74.5 (8.0)

75.6 (NA)

71.7 (8.8)

74.0 (7.4)

75.0 (8.0)

Male (%)

88.9

68.7

66.7

70.4

67.7

62.0

Study population

Any indication†

AC contraindicatedAC contraindicatedAC not contraindicated

AC not contraindicated

Any indication‡

Mean follow-up, months (SD)

24.7 (16.1)

18.0 (10.0)

11.8 (5.8)

13 (NA)

CHADS2 score, mean (SD)

2.6 (1.2)

2.9 (1.3)

2.2 (NA)

2.6 (1.0)

2.8 (1.3)

CHA2DS2-VASc score, mean (SD)

4.2 (1.6)

4.3 (1.5)

4.3 (NA)

3.8 (1.2)

4.5 (1.6)

HAS-BLED score, mean (SD)

3.34 (1.17)

3.7 (1.1)

3.1 (1.2)

• Watchman

63.0

38.1

2.6

100

• Amplatzer Cardiac Plug

34.7

7.7

50.4

100

• Amplatzer Amulet

46.9

41.0

• Others

2.3

0.7

6.0

• Not specified

6.6

Procedural success (%)

92.5

89.0

99.1

91.0

95.1

97.3

Device implanted (%):

Major procedural complications‡ (%)

3.5

5.5

4.9

2.2

5.0

Periprocedural mortality (%)

0.25

0.95

0.76

• Single APT

10.8

• DAPT

50.1

39.1

100

3.0 ||

5.2 ||

2.2 ||

2.3

2.6 ||

4.7

Discharge anti-thrombotic regimen (%):

• OAC ± APT ‡

Outcome measures per 100 patient years: • Stroke, SE and mortality

9.8

• Stroke, TIA or SE

1.0

5.0

1.5

• All-cause or CV mortality

1.8

6.2

1.0 ||

LAA occlusion group only, Includes absolute and relative contraindication for AC, resistant stroke, intolerance to OAC and lifestyle choice, Includes absolute and relative contraindication for AC, resistant stroke, and drug interaction, ‡definition differs slightly between trials, ||estimates from CtE report. AC = anticoagulation; APT = antiplatelet therapy; CtE = Commissioning through Evaluation; CV = cardiovascular; DAPT = dual antiplatelet therapy; LAA occlusion = left atrial appendage occlusion; NA = not available; OAC = oral anticoagulation; RoW = rest of world; SE = systemic embolism; TIA = transient ischaemic attack. *

†

‡

Conclusion Percutaneous LAA occlusion appears to be a viable option in patients with AF who have contraindications to anticoagulation therapy, which

comprise 5-6% of the total AF population. Availability of this therapy is at present significantly restricted in the UK compared with many countries in western Europe and the US.

Clinical Perspective • Percutaneous LAA occlusion is associated with a significant reduction in thromboembolic risk among patients with AF who have contraindications to anticoagulation therapy. • Patients with AF who have high thromboembolic risk and are unable to tolerate anticoagulation, including those with anticoagulationresistant strokes should be referred to a specialist for consideration of percutaneous LAA occlusion. • The procedure is associated with a high initial cost that appears to be subsequently balanced against a reduction in medical and social care expenditure from lower stroke rates over a 10–15-year period.

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47.

warfarin therapy: the PREVAIL trial. J Am Coll Cardiol 2014;64:1–12. https://doi.org/10.1016/j.jacc.2014.04.029; PMID: 24998121. Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009;374:534–42. https://doi.org/10.1016/S0140-6736(09)61343-X; PMID: 19683639. Tzikas A, Shakir S, Gafoor S, et al. Left atrial appendage occlusion for stroke prevention in atrial fibrillation: multicentre experience with the AMPLATZER Cardiac Plug. EuroIntervention 2016;11:1170–9. https://doi.org/10.4244/ EIJY15M01_06; PMID: 25604089. Boersma LV, Ince H, Kische S, et al. Efficacy and safety of left atrial appendage closure with WATCHMAN in patients with or without contraindication to oral anticoagulation: 1-Year follow-up outcome data of the EWOLUTION trial. Heart Rhythm 2017;14:1302–8. https://doi.org/10.1016/j.hrthm.2017.05.038; PMID: 28577840. Lakkireddy D, Afzal MR, Lee RJ, et al. Short and long-term outcomes of percutaneous left atrial appendage suture ligation: Results from a US multicenter evaluation. Heart Rhythm 2016;13:1030–6. https://doi.org/10.1016/j. hrthm.2016.01.022; PMID: 26872554. Bartus K, Han FT, Bednarek J, et al. Percutaneous left atrial appendage suture ligation using the LARIAT device in patients with atrial fibrillation: initial clinical experience. J Am Coll Cardiol 2013;62:108–18. https://doi.org/10.1016/j. jacc.2012.06.046; PMID: 23062528. Massumi A, Chelu MG, Nazeri A, et al. Initial experience with a novel percutaneous left atrial appendage exclusion device in patients with atrial fibrillation, increased stroke risk, and contraindications to anticoagulation. Am J Cardiol 2013;111:869–73. https://doi.org/10.1016/j.amjcard. 2012.11.061; PMID: 23312129. Sharma SP, Cheng J, Turagam MK, et al. Feasibility of left atrial appendage occlusion in left atrial appendage thrombus: a systematic review. JACC Clin Electrophysiol 2020;6:414–24. https://doi.org/10.1016/j.jacep.2019.11.017; PMID: 32327075. National Institute for Health and Clinical Excellence. Commissioning through Evaluation Project Report: Left atrial appendage occlusion (LAAO). 2018. https://www.england.nhs. uk/wp-content/uploads/2018/07/Left-Atrial-AppendageOcclusion-CtE-Report.pdf (accessed 12 June 2020). Panikker S, Lord J, Jarman JWE, et al. Outcomes and costs of left atrial appendage closure from randomized controlled trial and real-world experience relative to oral anticoagulation. Eur Heart J 2016;37:3470–82. https://doi.org/10.1093/eurheartj/ ehw048; PMID: 26935273. Reddy VY, Akehurst RL, Gavaghan MB, et al. Costeffectiveness of left atrial appendage closure for stroke reduction in atrial fibrillation: analysis of pooled, 5-year, longterm data. J Am Heart Assoc 2019;8:e011577. https://doi. org/10.1161/JAHA.118.011577; PMID: 31230500. Holmes DRJ, Doshi SK, Kar S, et al. Left atrial appendage closure as an alternative to warfarin for stroke prevention in atrial fibrillation: a patient-level meta-analysis. J Am Coll Cardiol 2015;65:2614–23. https://doi.org/10.1016/j.jacc.2015.04.025; PMID: 26088300. Reddy VY, Akehurst RL, Amorosi SL, et al. Cost-effectiveness of left atrial appendage closure with the WATCHMAN device compared with warfarin or non-vitamin k antagonist oral anticoagulants for secondary prevention in nonvalvular atrial fibrillation. Stroke 2018;49:1464–70. https://doi.org/10.1161/ STROKEAHA.117.018825; PMID: 29739915.

Electrophysiology and Ablation

The Convergent Atrial Fibrillation Ablation Procedure: Evolution of a Multidisciplinary Approach to Atrial Fibrillation Management Karan Wats,1 Andy Kiser,2 Kevin Makati,3 Nitesh Sood,4 David DeLurgio,5 Yisachar Greenberg1 and Felix Yang1 1. Maimonides Medical Center, Brooklyn, New York, NY, US; 2. St Clair Cardiovascular Surgical Associates, Pittsburgh, PA, US; 3. Tampa Cardiac Specialists, Lutz, FL, US; 4. Southcoast Health, Fall River, MA, US; 5. Emory Saint Joseph’s Hospital, Atlanta, GA, US

Abstract The treatment of AF has evolved over the past decade with increasing use of catheter ablation in patients refractory to medical therapy. While pulmonary vein isolation using endocardial catheter ablation has been successful in paroxysmal AF, the results have been more controversial in patients with long-standing persistent AF where extrapulmonary venous foci are increasingly recognised in the initiation and maintenance of AF. Hybrid ablation is the integration of minimally invasive epicardial ablation with endocardial catheter ablation, and has been increasingly used in this population with better results. The aim of this article was to analyse and discuss the evidence for the integration of catheter and minimally invasive surgical approaches to treat AF with specific focus on convergent ablation and exclusion of the left atrial appendage using a surgically applied clip.

Keywords AF, ablation, convergent procedure, AtriClip Disclosure: AK, KM, NS, DD, YG and FY received consulting fees from Atricure. All other authors have no conflicts of interest to declare. Acknowledgement: The authors contributed equally. Received: 11 December 2019 Accepted: 9 April 2020 Citation: Arrhythmia & Electrophysiology Review 2020;9(2):88–96. DOI: https://doi.org/10.15420/aer.2019.20 Correspondence: Felix Yang, Cardiology, 1st Floor Professional Building, 953 49th St, Brooklyn, NY 11219, US. E: fyang@maimonidesmed.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

AF is the most commonly encountered atrial arrhythmia in clinical practice. Restoration of normal sinus rhythm through catheter- and surgically based approaches has been increasingly used as technologies and outcomes have improved.1 Success rates for AF ablation vary greatly depending on the duration of AF (more successful for paroxysmal AF, less successful in persistent AF and even less so for long-standing persistent AF). The persistent AF population represents a challenging cohort that frequently requires multiple ablation procedures to maintain sinus rhythm.2 Additionally, the left atrial appendage (LAA) has been implicated as an independent driver of AF arrhythmogenesis, as well as a site responsible for thromboembolism, and this in turn has increased interest in LAA management.3 In this article, we discuss how the convergent AF procedure and external surgical LAA ligation can be performed through a multidisciplinary approach to manage conventional treatment-refractory persistent AF patients.

(CIRCA-DOSE) trial reported only a 51–54% freedom from atrial arrhythmias at 1 year with loop recorder data utilising the latest iterations of contact force-sensing ablation catheters and the second-generation cryoballoon. 7 If one excludes asymptomatic and shorter-lived recurrences, the successful elimination of AF increases to around 80% for both ablation devices. However, PVI alone does not address AF and other atrial arrhythmias originating from regions outside the pulmonary veins. Frequent extra-PV targets of AF ablation include the posterior left atrium, superior vena cava, ligament of Marshall, coronary sinus, crista teminalis and the left atrial appendage. 8,9

The substrate in paroxysmal AF appears to largely originate from the pulmonary veins, and as a result, pulmonary vein isolation (PVI) has demonstrated effectiveness in eliminating AF recurrence in the majority of patients.4,5 Nevertheless, the success rates for ablation of paroxysmal AF ablation still warrants improvement. The FIRE and ICE trial yielded an approximate 65% freedom from atrial arrhythmias off antiarrhythmics in both the cryoballoon and the radiofrequency ablation arms at 18 months.6

Patients with persistent AF are thought to have arrhythmogenic substrate outside the pulmonary veins, thus explaining poor outcomes in studies with ablation strategies limited to PVI. Substract and Trigger Ablation for Reduction of AF Trial Part II (STAR AF II) compared the strategies of pulmonary vein isolation, PVI with ablation of complex fractionated electrograms and PVI plus linear ablation, and the freedom from AF at 18 months was 59%, 49% and 46%, respectively.10 Freedom from any atrial arrhythmias off antiarrhythmic therapy was even lower. The pathophysiological mechanisms for persistent and also longstanding persistent AF are frequently more complex than those of paroxysmal AF.

Even more recently, the Cryoballoon versus Irrigated Radiofrequency Catheter Ablation: Double Short versus Standard Exposure Duration

Although still considered a cornerstone of persistent AF ablation, PVI alone does not sufficiently maintain normal sinus rhythm in this

Access at: www.AERjournal.com

Convergent AF Ablation population. In the post-STAR AF II era, operators have struggled to address the persistent AF population. In addition to PVI, a variety of supplemental procedures have found clinical application, such as roof and mitral isthmus lines, posterior wall isolation, rotor mapping, ablation of autonomic ganglia, ablation of low-voltage fibrotic regions, high-dose isoproterenol to elicit focal triggers, vein of Marshall alcohol ablation and left atrial appendage isolation.3,11–17 Unfortunately, no catheter-based approach has consistently yielded a high rate of success in persistent patients.

Surgical Ablation The first cut-and-sew maze procedure was performed in 1987.18 Subsequent revisions culminating in the Cox maze III and Cox maze IV have yielded high success rates, maintaining sinus rhythm in 80–90% of patients off antiarrhythmic therapy.19 However, the surgical maze procedure requires cardiopulmonary bypass and is associated with significantly higher morbidity compared with a catheter-based approach. Minimally invasive epicardial approaches have attempted to replicate the efficacy of the Cox maze procedure, but with less morbidity. In a pooled analysis of minimally invasive epicardial approaches, only 43% of patients with long-standing persistent AF maintained sinus rhythm, as compared with 75% in paroxysmal AF.20 In comparison, single-procedure freedom from atrial arrhythmias ± antiarrhythmics for catheter-based ablation of long-standing persistent AF was reported to be ~52% at 1 year by Ganesan et al., and ~37% after one or two procedures in the Hamburg experience.21,22 The advantage of surgical ablation lies in the surgeon’s ability to directly visualise and ablate the target structures of interest. In addition to endocardial access, the surgeon also has direct access to epicardial structures, such as the ligament of Marshall and ganglionated plexi, that may serve as drivers of persistent AF. Direct visualisation enables ablation while avoiding complications involving the phrenic nerve and the oesophagus.23 Moreover, the surgeon can exclude the left atrial appendage, which eliminates associated AF triggers while potentially reducing the patient’s risk of stroke.24 The AF Catheter Ablation Versus Surgical Ablation Treatment (FAST) trial compared bilateral thoracoscopic epicardial ablation with endovascular catheter ablation randomising 124 patients with drug refractory AF to either surgical PVI using a bipolar radiofrequency (RF) clamp, LAA staple with additional ganglionated plexi ablation, ligament of Marshall, and optional linear ablations lines or endovascular ablation with antral PVI and additional linear ablation. The overall freedom from AF at 12 months was 66% in the surgical arm, as compared with 37% in the catheter ablation arm. The difference was notable even in patients with persistent AF (56% versus 36%; p=0.341). The surgical arm, however, was associated with more procedural complications.25 While the cut-and-sew maze creates a definitive scar to isolate and compartmentalise the regions of the atria, less invasive iterations of the maze procedure depends on achieving transmurality, contiguity and durability of the lesions created with RF or cryothermy. Validation of the lesion set is not readily performed surgically, in contrast to that of catheter-based approaches. Additionally, the surgical environment in most institutions does not provide access to electrophysiological manoeuvres, such as comprehensive lesion validation and nonpulmonary vein trigger mapping. The lack of electrophysiological testing during surgical ablation may explain the varied and poor AF-free outcomes despite extensive lesion sets being performed.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Hybrid Ablation The desire to create durable transmural lesions, close the appendage, validate the lesions set and address additional arrhythmic substrate has led to the concept of hybrid ablation. Centres have emerged embracing this multidisciplinary approach, and integrate the expertise of electrophysiologists and surgeons. Unfortunately, much of the hybrid experience comes from single-centre observation studies that vary in surgical technique, as well as the endocardial ablation strategy.26–28 Hybrid surgical approaches predominately involve either bilateral thoracoscopy using bipolar RF clamps or a unilateral thoracoscopic approach through the right chest alone.26,27 The surgeon utilises RF energy tools to create block across linear lesions in both atria. The catheter-based portion of the procedure usually follows, validating the surgical work, and addressing additional substrate, triggers and creation of a cavotricuspid isthmus line. Mahapatra et al. first described their experience with a staged hybrid ablation for patients with persistent AF who had failed antiarrhythmic drug therapy and at least one attempt at catheter ablation.26 Using bilateral thoracoscopy, they created bilateral antral PVI lesions and isolated the superior vena cava, connected the veins with a roof line, created lesions connecting the right and left superior PVs to the noncoronary commissure of the aortic valve, and a lesion connecting the left superior PV to the LAA followed by LAA closure. Catheter ablation was performed 3–5 days later. They compared these patients with a matched catheter ablation-alone group and found higher freedom from atrial arrhythmia off antiarrhythmic drugs in the hybrid group at 20 months of follow-up (87% versus 53%; p=0.04). There were no complications in this report. Other hybrid procedures followed with single-centre observational reports using variable ablation lesions with sinus rhythm rates, off antiarrhythmic drugs, ranging from 37% to 86%.27–31

Posterior Wall Isolation With the failure of rotor mapping, complex fractionated atrial electrogram ablation and simple linear ablation, there is increasing interest in the isolation of the posterior wall. Cardiac MRI data have implicated the posterior wall as a region with a high prevalence of atrial fibrosis.32 Additionally, the varied myocardial fibre orientation of the posterior wall and the high prevalence of autonomic ganglionic plexi may also contribute to the AF substrate.33,34 Debulking of the posterior wall perhaps reduces the AF substrate to a critical level at which AF cannot sustain. This critical mass hypothesis, first suggested in observational studies by Garrey et al. more than a century ago and reproduced in animal studies more recently by Lee et al., may explain the success of ablation lesion strategies that effectively compartmentalise the atria.35,36 The current strategies for posterior wall isolation using catheter ablation include a single-ring approach, pulmonary vein isolation and box lesion set or obliteration of posterior wall potentials. The single-ring approach is similar to the Cox maze III procedure, which involves isolating the pulmonary veins and posterior wall, but has had variable success rates, and due to difficulty in achieving complete block in the roof portion of the circle, recurrent conduction can occur and compromise isolation of the posterior wall.37 Pulmonary vein isolation and a box lesion set uses double circles around the veins as anchors for posterior wall isolation, and an additional roof line to connect the superior PVs and a low posterior line to connect the inferior veins. This technique also showed only modest success rates in observational trials.38 Endocardial homogenisation of the posterior wall signals may

Electrophysiology and Ablation Figure 1: Epicardial and Endocardial Lesions of the Convergent Procedure

epicardial space. Under direct visualisation, the Epi-Sense® (Atricure, Mason, OH, US) unipolar vacuum-assisted linear RF ablation catheter uses vacuum to suck the atrial tissue into apposition with the RF coil. Saline continuously irrigates the electrode to improve energy penetration and limit char. The pericardioscopic access provides optimal access to the posterior left atrium and posterior pulmonary vein antrums. It also enables direct electrocardiogram evaluation before, during and after the procedure to help confirm a complete lesion set. This immediate and comprehensive lesion approach is more difficult with other hybrid procedures. Endocardial ablation follows the epicardial procedure to confirm lesion integrity and supplement the epicardial procedure, which can be performed during the same setting or in a staged fashion – each approach offering distinct advantages.44

A: The Epi-Sense Coagulation Device applied to the posterior left atrium. B: Posterior wall and pulmonary vein isolation with high-density endocardial mapping of the left atrium after convergent epicardial ablation and cryoballoon isolation of all four pulmonary veins. The grey colour denotes scar, while the purple colour denotes healthy atrial voltage. C: The transmural scar (red) created from the epicardial ablation. Healthy left atrial voltages are seen in purple. Endocardial pulmonary vein isolation was performed with radiofrequency ablation and creation of a lateral mitral isthmus line. The left atrial appendage was closed with an AtriClip and the vein of Marshall was epicardially ablated. D: Absence of the left atrial appendage after closure with an AtriClip is also noted in a lateral view in another patient. Source: Reproduced with permission from AtriCure.

address the shortcomings of linear ablation, but potentially increases the rate of atrioesophageal fistula.39 Concern about atrioesophageal fistula frequently limits the amount of ablation that an operator can deliver to the posterior wall. Current catheter-based strategies to address posterior wall substrate include high-power, short-duration application of radiofrequency energy to theoretically limit deep ablation; real-time temperature monitoring; oesophageal deviation; and cryoballoon across the posterior space.40 Despite the endocardial energy used, oesophageal injury during posterior wall catheter ablation can occur, and although the occurrence of an atrioesophageal fistula is of low relative frequency, the high mortality of this complication necessitates standardised ablation protocols and close post-procedural surveillance. The posterior wall of the left atrium may also have epicardial connections. This may explain the variability in success with posterior box lesion sets. Multiple reports have demonstrated the ability to have endocardial electrical isolation, yet persistent posterior wall activity.41–43 Because endocardial catheter ablation alone has limited epicardial efficacy, related to energy penetration restrictions, supplemental epicardial ablation to achieve definitive posterior wall isolation has gained attention.

Convergent Ablation The convergent procedure is a form of hybrid AF ablation that utilises a pericardioscopic approach from the upper abdomen. As such, the convergent approach distinguishes itself as a compliment to catheter ablation rather than a complex surgical procedure. The convergent procedure simplifies the lesion set to focus on an effective endocardial and epicardial posterior wall and pulmonary vein isolation (Figure 1). Involving an epicardial approach, there may also be utility in the ablation of ganglionated plexi and epicardial fat in the surgical lesion set. Pericardioscopy provides laparoscopic access to the pericardium and

A concomitant approach has the advantage of providing immediate endocardial confirmation of posterior isolation and provides timely feedback to the surgeon. The concomitant approach requires efficient schedule coordination between the surgeon, electrophysiologist and the staff to offer the patient a same-day procedure. Simultaneous epicardial mapping of the posterior wall scar utilising 3D mapping systems can be performed to demonstrate gaps and allow for surgeons to create additional epicardial lesions. During a staged procedure, the surgeon performs the epicardial procedure, which includes pulmonary vein isolation and posterior wall isolation followed by catheter ablation after days to weeks. This approach offers convenience to both the electrophysiologist and surgeon. Additionally, it gives time for reconnections to develop by the time endocardial ablation is performed, and gaps in the epicardial ablation can be addressed.

Evidence for Convergent Ablation Kiser et al. reported the initial convergent procedure experience in 28 patients with persistent or long-standing persistent AF.45 The patients underwent concomitant epicardial radiofrequency ablation and transseptal endocardial ablation to exclude the entire posterior left atrium and isolate the PVs. They reported no deaths. At ≤6 months follow-up, freedom from AF and antiarrhythmic drugs was 76%. Since then, other observational studies with ≥12 months follow-up have reported similar results of success (Table 1), with freedom from AF at 12 months ranging 73–88% and patients in sinus rhythm ranging 52–88%.46–48 Gersak et al. reported the longest follow-up on convergent procedures, with 81% of patients being free from AF at 4 years.49 Among comparison studies of convergent versus endocardial-only ablation, Edgerton et al. in 2009 initiated a prospective study that enrolled 24 patients to a hybrid approach and 35 patients to catheter ablation only.50 Their hybrid group underwent surgical ablation through a pericardioscopic approach followed immediately by endocardial catheter ablation. They used a unipolar radiofrequency device to perform PVI, posterior box, ablate the ligament of Marshall (without dissection) and the lateral right atrium. The endocardial portion entailed verification and completion of epicardial lines, ablation in the coronary sinus, isolation of the LAA, and ablation of complex fractionated atrial electrograms. At 12-month follow-up, the hybrid group had lower arrhythmia-free survival (24% versus 63%; p<0.001). The complication rates were significantly higher in the hybrid group (21% versus 3%; p=0.036), including three deaths, one tamponade and one phrenic nerve palsy in the hybrid group compared with one

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Convergent AF Ablation

Concomitant

Timing

3.7%

10%

12 months

73%

80%

–

88%

Mortality Complications Follow-up Freedom from AF Freedom from ± Antiarrhythmics any Atrial (%) Arrhythmia ± Antiarrhythmics (%)

–

83%

Table 1: Convergent Procedure Studies

65 Staged 0%

No. of Patients

Jan 2009-May 2010 27 Concomitant

Timeframe of Treatment

PAF, PsAF, LSPAF Aug 2009-Dec 2011 101

Year

2011 PsAF, LSPAF Jan 2009-Dec 2011

Type

Observational 2012 PAF, PsAF, LSPAF

Studies

Kiser et al.46 Observational 2013

Prospective

Observational

2017

2016

2014

2013

PsAF, LSPAF

PAF, PsAF, LSPAF

LSPAF

PsAF;, LSPAF

PsAF, LSPAF

Jul 2009-Dec 2014 90

Jan 2009-Jul 2013

–

May 2010-Dec 2011

Jan 2010-Dec2011 73

Jun 2010-Feb 2013

104

Concomitant

Staged

Concomitant & staged

Concomitant

1.6%

14%

7.8%

12%

16 months

12 months

48 months

24 months

12 months

6 months

12 months

72%

–

19%

73%

–

82%

81%

–

89%

87.5%

62%

69%

–

72%

Type of AF (PAF, PsAF, LSPAF)

Zembala et al.47 Observational 2013

Freedom from any Atrial Arrhythmia off Antiarrhythmics (%)

Gehi et al.48 Observational

Gersak et al.51

Observational

2017

Transabdominal without AtriClip

Civello et al.76 PAF, PsAF, LSPAF

Edgerton et al.50

Prospective

24 months

30.5 months –

52%

–

58.3%

Observational

Gersak et al.49

Observational

12.5%

Thosani et al.54

Zembala et al.55

12.9%

Kress et al.52

Jun 2010-Aug 2014

71%

–

Concomitant

76%

63%

Concomitant

–

12 months

80%

Jan 2013-Jun 2015 24

1.6%

12 months

PAF

2018

Concomitant

Randomised

–

Jan et al.77

87.5%

Oct 2013-Mar 2017

Jan 2014-Aug 2016

–

PsAF, LSPAF

Feb 2015-Sept 2017

12 months

2019

LSPAF

7.8%

Observational

2019

–

Concomitant

78%

–

PsAF, LSPAF

12 months

2019

16.7%

Aug 2016-Oct 2019

Feb 2016-May 2017

2019

PAF, PsAF, LSPAF

Gulkarov et al.78

Subxiphoid without AtriClip

Observational

Gegechkori et al.71 Observational Sabzwari et al.79

Subxiphoid with AtriClip

Observational

Gegechkori et al.71 Observational Tonks et al.72

36 (25/36 Concomitant subxiphoid, (32/36) 13/36 with AtriClip)

LSPAF = longstanding persistent AF; PAF = paroxysmal AF; PsAF = persistent AF.

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Electrophysiology and Ablation Table 2: Convergent Procedure Complications Complications Atrioesophageal fistula

6/884

0.7%

Pericardial effusion

10/884

1.1%

Pericardial tamponade

9/884

1.0%

Cardiac death

2/884

0.2%

Unexplained death

2/884

0.2%

Major bleeding

12/884

1.4%

Hematemesis

1/884

0.1%

Stroke

7/884

0.8%

TIA

2/884

0.2%

Pleural effusion

3/884

0.3%

Lung injury

1/884

0.1%

Pulmonary vein stenosis

1/884

0.1%

Transient phrenic nerve palsy

3/884

0.3%

Groin/puncture site complications

2/884

0.2%

Infection

1/884

0.1%

TIA = transient ischaemic attack.

tamponade in the catheter ablation group. The authors attributed the deaths and complications to the unipolar RF design; however, their experience was largely with the first iteration of the procedure before the epicardial lesion set was modified, before oesophageal protections were instituted, and involved an extensive endocardial lesion set. Gehi et al. reported results for a transdiaphragmatic pericardiosopic approach in 101 patients with long-standing persistent (n=37), persistent (n=47) and paroxysmal AF (n=17).48 At 12-month follow-up, 66% with single and 71% with repeat ablation were in normal sinus rhythm. The endocardial procedure was performed immediately after the epicardial portion. Gersak et al. reported both a single-centre and a multicentre pericardioscopic approach with an epicardial lesion set including pulmonary venous antrum and posterior wall followed by similar area ablation endocardially.51 In their single-centre data on 50 patients with persistent or long-standing persistent AF with implantable loop recorder monitoring, they reported 88% normal sinus rhythm at 1 year. In the multicentre data for persistent (30.1%) and long-standing persistent AF (69.1%) patients (n=73), they reported 80% normal sinus rhythm at 1-year follow-up, which was performed with Holter monitoring and implantable loop recorder. Of these, approximately half of the patients were not taking antiarrhythmic drugs at follow-up. In a retrospective study of consecutive patients, Kress et al. compared convergent ablation with endocardial-only ablation in 133 patients with persistent and long-standing AF.52 In this series, cryoballoon was primarily used for endocardial ablation in both procedures. They found the convergent group had fewer recurrences than the endocardial-only group, and 16-month AF-free survival was 72% with convergent ablation compared with 51% for endocardial-only ablation (p=0.01). Complications were not significantly different between groups (7.8% for convergent and 2.9% for endocardial-only ablation; p=0.205).

Evolution of the Convergent Procedure The first iteration of the convergent procedure emerged as a surgical epicardial ablation performed without incisions in the chest. After evaluating the original nContact ablation technology during open cardiac procedures, Kiser conceived the pericardioscopic cannula, which enabled

transabdominal access to the posterior pericardium of the beating heart.44,53 The first clinical application was a surgical procedure alone, utilising both thoracoscopy and pericardioscopy to create an epicardial lesion set for AF. The results of this pericardioscopic ex-maze procedure were similar to catheter ablation alone; however, chest incisions were still necessary. Kiser assembled a team of international experts in Krakow, Poland, and on 3 January 2009, performed the first convergent epicardial and endocardial ablation procedure.45 The early convergent procedure included surgical ablation of the anterior and posterior aspects of the pulmonary veins through a transabdominal approach (Figure 1). A left atrial roof and inferior floor line were also created by curling the catheter along the cannula guidewire. During the same setting, endocardial catheter ablation addressed gaps in the surgical lesion set at the pericardial reflections of the superior and inferior vena cava. Simultaneous catheter ablation addressed the cavotricuspid isthmus, the mitral valve annulus and any other high-frequency activity deemed clinically relevant by the operator. The hybrid catheter and surgical approach saw improved outcomes, but centres also identified oesophageal injuries and associated morbidity and mortality.49â&#x20AC;&#x201C;50,54â&#x20AC;&#x201C;56 In 2011, Kiser et al. evaluated these published and the non-published, but early reported, outcomes and complications of the convergent procedure while examining the predicate iterations of the pericardioscopic approach.45 As a result, the authors recommended, and subsequent procedural guidelines were instituted, to reduce the risk of oesophageal injury by: attentively positioning the ablation device only towards the epicardium; monitoring oesophageal temperature; using fluoroscopy to identify and avoid the oesophagus; and irrigating the pericardial space with cool saline. Improvements to the convergent procedure have reduced procedural complexity while further reducing complications (Table 2). Unlike the original description of complicated device manipulation over wires and within the transverse sinus, the procedure was modified in 2012 to keep the epicardial ablation catheter in a straight configuration. The resulting epicardial lesion set sought to homogenise the posterior LA wall rather than create a convoluted linear box lesion. (Figure 2) The procedure also moved to a subxiphoid approach in 2015 (Figure 3).57 This change eliminated the rare complication of bowel herniation into the thoracic space via the transabdominal, transdiaphragmatic approach, while still allowing the surgeon sufficient access to the posterior left atrium.58â&#x20AC;&#x201C;60 These changes have enhanced efficacy, as well as the safety profile of the procedure.

Concomitant LAA Exclusion Using the AtriClip The LAA has been implicated in the initiation and perpetuation of AF, particularly in the persistent AF population. The Effect of Empirical Left Atrial Appendage Isolation on Long-term Procedure Outcome in Patients With Persistent or Long-standing Persistent Atrial Fibrillation Undergoing Catheter Ablation (BELIEF) trial examined patients who had long-standing AF and randomised them to ablation with LAA isolation versus ablation without LAA isolation (NCT01362738). Single-procedure freedom at 12 months with LAA isolation was 56% versus 28% without isolation (p=0.001). While endocardial isolation of the LAA is possible, multiple procedures are frequently required to create lasting LAA electrical isolation. A consequence of electrical isolation appears to be an increased incidence of LAA thrombus secondary to mechanical standstill of the appendage.61 While this may be addressed with a WATCHMAN implant,

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Convergent AF Ablation Figure 2: Evolution of the Convergent Procedure

Hybrid ex-maze (2009–2011)

Convergent (2012–present)

Aorta PA

Standardised comprehensive posterior homogenisation

Posterior box lesion set

Pericardial reflections SVC

RA LA Epicardial lesions of convergent procedure

Epicardial ablation line

Endocardial lesions of convergent procedure

IVC

Endocardial ablation line Pericardial reflections Electrode curved along guidewire

Electrode kept in straight configuration

Left atrium

Epi-Sense catheter

Guidewire

The convergent procedure has evolved from the hybrid ex-maze’s (left panel) complex epicardial (blue lines) and endocardial (green lines) linear ablation set to the current convergent lesion set (right panel), which involves epicardial homogenization of the posterior wall (blue lines), followed by endocardial ablation (red dots) to complete the pulmonary vein isolation and a cavotricuspid isthmus line. IVC = inferior vena cava; LA = left atrium; PA = pulmonary artery; RA = right atrium; SVC = superior vena cava. Source: Reproduced with permission from AtriCure.

Figure 3: Transabdominal and Subxiphoid Approaches

Subxiphoid approach (2015–present)

Transabdominal approach (2009–2015)

Source: Reproduced with permission from AtriCure.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Electrophysiology and Ablation

ic n

Figure 4: AtriClip Application to Electrically and Mechanically Isolate the Appendage

Le ft p

hr en

AtriClip PRO2

LAA RO2

pP riCli

AtriClip PROV

ed en op of um i ge Ed ricard pe

Adipose tissue above pericardial sac

LAA Closed with AtriClip

LAA AtriClip placed at the base of LAA The PRO2 and PROV AtriClips are shown in the top left inset. A multilobed left atrial appendage (LAA) is shown in the bottom left inset, which is closed with a PRO2 AtriClip (right panel). Note the purple colour change of the ligated appendage (bottom right) Source: Reproduced with permission from AtriCure.

concomitant endocardial AF ablation and WATCHMAN implantation is cost prohibitive due to reimbursement constraints. The AtriClip has been utilised in >200,000 patients, predominantly in open-chest surgical procedures to close the appendage. Retrospective data demonstrate that the AtriClip closure is safe, durable and leads to a reduction in thromboembolic events.62–65 Acute and long-term closure rates have been >95% with residual stumps >10 mm in only 0–5% of cases.62,63 The AtriClip began to be placed through a left thoracoscopic approach in 2012, and convergent procedures began incorporating the AtriClip in 2017 (Figure 4).66–69 As the convergent procedure already enlists the assistance of the surgeon, the thoracoscopic addition of the AtriClip is able to be performed in the same procedure setting in a costeffective manner. The AtriClip seeks to address the LAA as an electrical source of AF triggers and the mechanical risk for stroke. Studies have demonstrated that the AtriClip achieves acute electrical isolation of the appendage, which has earned it a US Food and Drug Administration indication.70 Additional benefits of incorporating a left thoracoscopic approach to LAA management include the ability to epicardially ablate the vein of Marshall, which may allow for easier creation of a lateral mitral isthmus line. While recent reports have demonstrated favourable outcomes with the addition of the AtriClip to the convergent procedure, further studies are required.71,72 Outcomes from the LAA Ligation Adjunctive to PVI for Persistent or Longstanding Persistent AF (aMAZE) trial (NCT02513797), which investigates the antiarrhythmic effect of closing the LAA with Lariat in patients with persistent AF, are anticipated to shed further light on the importance of LAA electrical isolation.73

Future Direction The Epi/Endo Ablation For Treatment of Persistent Atrial Fibrillation (AF) (CONVERGE) trial (NCT01984346) is an investigational device-exempt, prospective, multicentre, open-label, randomised controlled pivotal study to evaluate the safety and efficacy of the Epi-Sense AF Guided Coagulation System (Atricure) for the treatment of symptomatic

persistent and long-standing persistent AF in patients refractory to medical therapy. The primary objective is to demonstrate the superiority of the convergent procedure compared with stand-alone endocardial radiofrequency catheter ablation. A total of 153 patients have been randomised in a two-to-one manner to the convergent procedure or endocardial-only ablation and followed for a minimum of 1 year. Unlike other catheter ablation trials for persistent AF, CONVERGE imposed no limits on the duration of AF and allows left atrial sizes up to 6 cm. As a result, the CONVERGE trial is the only ablation trial thus far to include a substantial portion of patients with long-standing persistent AF. The study finished enrolment in August 2018, and 12-month follow-up for primary effectiveness was completed in August 2019. The results are expected to be reported in 2020. If positive, the CONVERGE trial would mark a major milestone by confirming a superior method for ablation of persistent and long-standing persistent AF. Future trials utilising the convergent procedure are necessary to assess the use of endocardial cryoablation as an alternative to endocardial RF ablation, and to assess the incremental benefit of LAA exclusion and electrical silencing.

Conclusion The convergent procedure as practiced today has evolved from its original design as a modification of the Cox maze linear lesion set to its current lesion protocol, which prioritises homogenisation of the posterior wall substrate through the pericardium to dovetail the electrophysiologist’s endocardial wide area circumferential pulmonary vein isolation.74 With iterative procedural refinements in the epicardial access, catheter manipulation and oesophageal protection, the rate of procedural complications has significantly declined. In summary, the convergent hybrid ablation affords endocardial pulmonary vein isolation, epicardial posterior wall isolation and left atrial appendage management via external ligation in either a single or staged procedural setting.75 With a cumulative experience in >10,000 patients to date, the convergent procedure now has an established position in the vast array of procedures directed at managing non-paroxysmal AF.

Clinical Perspective • The strategy of pulmonary vein isolation alone in the treatment of patients with persistent AF has been unsatisfactory. • Isolation of the posterior wall of the left atrium is a strategy employed in open chest maze procedures, as well as hybrid AF ablations, the convergent AF procedure and endocardial approaches. Operators seek achievement of a durable posterior wall isolation in a safe manner. • The convergent AF ablation procedure was developed to achieve endocardial and epicardial isolation of the pulmonary veins and posterior wall. The epicardial portion of the procedure has evolved over time to a more simplified lesion set and from a transabdominal to a subxiphoid approach. Additional safety measures including oesophageal temperature monitoring and saline irrigation in the pericardial space have been implemented, which have minimised the complications with the procedure while maintaining a high success rate. • Convergent ablations are now increasingly performed with concomitant application of an AtriClip to electrically and mechanically isolate the left atrial appendage.

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Convergent AF Ablation 1.

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ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Electrophysiology and Ablation

Hybrid Catheter-Based and Surgical Techniques for Ablation of Ventricular Arrhythmias Fouad Khalil,1 Konstantinos Siontis,1 Gabor Bagameri2 and Ammar M Killu1 1. Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Mayo Clinic, Rochester, MN, US; 2. Department of Cardiovascular Surgery, Mayo Clinic, Rochester, MN, US

Abstract Catheter ablation is a rapidly expanding and evolving field. The advent of interventional techniques and advances in technology have allowed catheter ablation to supplant antiarrhythmic surgery for ventricular arrhythmia treatment. However, issues related to access and energy delivery limit the use of catheter ablation in some cases. Hybrid catheter-based and surgical techniques represent a novel approach to overcome these limitations. The hybrid technique combines the strengths and minimises the limitations of either catheter or surgical ablation alone. There is a growing body of evidence in the literature supporting the safety and efficacy of the hybrid surgical technique. This review aims to provide an overview of hybrid surgical-catheter ablation for ventricular arrhythmia.

Keywords Ventricular tachycardia, hybrid surgical ablation, epicardial access, subxiphoid approach, limited anterior thoracotomy, left ventricular assist device Disclosure: The authors have no conflicts of interest to declare. Received: 2 March 2020 Accepted: 6 May 2020 Citation: Arrhythmia & Electrophysiology Review 2020;9(2):97–103. DOI: https://doi.org/10.15420/aer.2020.08 Correspondence: Ammar M Killu, Mayo Clinic, 200 First Street SW, Rochester, MN 55901, US. E: killu.ammar@mayo.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

Catheter-based ablation has been a well-established tool in the treatment of ventricular tachycardia (VT). However, the effectiveness of catheter ablation may be limited by its ability to access sites of arrhythmogenic tissue and achieve adequate lesion size in target areas without risking collateral damage. Antiarrhythmic surgery would be an effective alternative in such situations. Despite the potential usefulness of arrhythmia surgery, major drawbacks include invasiveness, prolonged hospital stays, higher morbidity and potential mortality.1 These limitations have been partially overcome with the development of minimally invasive surgical approaches and the integration of surgical and catheter-based approaches. We define hybrid ablation as an approach that combines surgical intervention for access and/or ablation, along with catheter mapping and ablation. In this article, we review hybrid techniques for VT ablation, discuss the role of hybrid ablation techniques in the contemporary management of VT and review the outcomes of hybrid approaches. We specifically review issues regarding patient selection, specific procedural considerations, safety and future directions.

A Historical Perspective of Interdisciplinary Collaboration In the 1970s and 1980s, cardiac electrophysiological (EP) testing was extensively used for diagnosis and mapping of arrhythmias before or during cardiac surgery.2,3 With advancing EP knowledge and techniques, antiarrhythmic surgery was revolutionised (Figure 1). The foundation of this collaboration began with the Wolff-Parkinson-White (WPW) syndrome in which EP testing assisted in confirming the arrhythmia mechanism

and determining the number and approximate location of accessory pathways.4,5 This expanded to include the encircling endocardial ventriculotomy introduced in 1978 for post-MI VT, the subendocardial resection procedure in 1979 for recurrent VT and the right ventricular disconnection procedures developed in the early 1980s for arrhythmogenic right VT.6–8 Furthermore, the introduction of steerable catheters in the 1980s and the development of 3D navigation systems in the last two decades allowed detailed EP mapping in a shorter time, which significantly improved preoperative planning for patients undergoing surgical approaches.

Patient Selection Hybrid ablation combines the advantages of percutaneous endocardial and epicardial catheter-based procedures and those of arrhythmia surgery. In 1996, Sosa et al. initially described a subxiphoid percutaneous epicardial approach for epicardial mapping and ablation in patients with Chagas cardiomyopathy and associated VT secondary to epicardial substrates.9 The procedure has since been widely adopted in the management of ventricular arrhythmias in complex substrates. Epicardial approaches are often necessary for mapping/ablation of epicardial substrates, such as in patients with non-ischaemic cardiomyopathy including arrhythmogenic right ventricular cardiomyopathy, but also in order to provide an additional vantage point for creation of larger ablation lesions in patients with intramural substrate. However, safe percutaneous epicardial access may not be feasible in some patients. Some of the clinical scenarios where a hybrid approach may be necessary are listed below. These include situations where safe epicardial access may not be

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Electrophysiology and Ablation Figure 1: Timeline of Advances in Arrhythmia Diagnosis and Management

• Detailed description of accessory pathways and atrioventricular nodal connections using multielectrode catheters • Development of surgical antiarrhythmic techniques for Wolff-Parkinson-White syndrome and ventricular tachycardia

1970s

• Development of mapping systems to guide antiarrhythmic surgical procedures • Development of atrial arrhythmias surgery • Clinical introduction of single-chamber implantable cardioverter defibrillators (ICD) implanted via thoracotomy • Direct current catheter ablation

1980s

• Radiofrequency energy replacing direct current • Evolution in ICD systems, leads and implantation techniques which replace surgical implants

1990s

• Catheter ablation as the mainstay for invasive management of atrial and ventricular arrhythmias • Development of hybrid ablation approaches for atrial and ventricular arrhythmia • Advanced experimental modalities: needle ablation, radiotherapy and endoscopic robotic ablation

2000s

Figure 2: Coronary Angiography View Demonstrating an Externally-Irrigated Ablation Catheter Tip A

LCx

LAD

LAD Ablation catheter tip

Ablation catheter tip

LCx

The catheter tip is seen in the great cardiac vein – anterior interventricular vein junction at the site of earliest activation for the culprit ventricular arrhythmia. Note the proximity to the coronary arteries in both the right anterior oblique (A) and left anterior oblique (B) views. LAD = left anterior descending coronary artery; LCx = left circumflex coronary artery; LM = left main coronary artery.

feasible and situations where power delivery to the area of interest would be insufficient. Patients with extracardiac anatomical challenges, such as overlaying bowel loops, severe pectus deformity, rendering epicardial access prohibitively high risk. Patients with extensive adhesions from previous open-heart surgery, pericarditis or epicardial procedures.10 Even with successful

percutaneous access in patients with previous cardiac surgery, success rates are lower and the risk of complications can be significant.11 In addition to the limited catheter manipulation by adhesions, the adhesions themselves are sometimes vascular and catheter manipulation may lead to intrapericardial bleeding. The myocardial tissue that needs to be targeted is in close proximity to critical structures, particularly the proximal coronary arteries making catheter ablation too high risk (Figure 2). Need for epicardial mapping/ablation in patients with prior coronary artery bypass grafting (CABG). Even though percutaneous epicardial access in these patients is feasible, catheter manipulation and ablation carry a risk of graft disruption.12 Also, in patients with coronary artery disease, catheter manipulation during mapping and ablation can disrupt the bridging veins that traverse the pericardium to the myocardium as natural bypasses. Thus, the procedure in those patients carries a risk of infarction.12 Arrhythmogenic substrate or arrhythmia origin deep within the myocardium and below epicardial fat may not be amenable to catheter ablation via traditional percutaneous epicardial access. Direct visualisation is possible with surgical access and can permit epicardial fat dissection and surgical ‘unroofing’ of the target myocardium. Inaccessible left ventricle (LV) due to mechanical aortic and mitral valves. While percutaneous transapical, transventricular septal or atrioventricular septal puncture can be performed, these approaches are limited to endocardial mapping and ablation. Given that such patients tend to have non-ischaemic substrate with perivalvular/epicardial substrate, an approach for epicardial mapping and ablation would be desirable.13

Surgical Approach The surgical approach should be individualised and based on the likely origin/exit of the arrhythmia as determined by scar location on preprocedural imaging (typically MRI), non-invasive mapping, or prior invasive mapping. In particular, delineation of the arrhythmogenic substrate with preprocedural delayed-enhancement MRI has been associated with improved procedural and long-term outcomes in patients with non-ischaemic cardiomyopathy undergoing catheter ablation and this may also apply to hybrid procedures.14 While median sternotomy can provide wide access to the epicardial surface, this may be unnecessary and is associated with increased procedural time and morbidity (Figure 3). Therefore, in the absence of need for concomitant cardiac surgery, two main approaches are currently in use: subxiphoid window and limited anterior thoracotomy (Figure 4). Patient selection for each approach is critical due to the difference in LV epicardial exposure between the two. Soejima et al. described a subxiphoid approach for VT mapping and ablation that provides access to the inferior and inferolateral LV.15 After dissecting down to the diaphragmatic pericardial surface, the pericardium is opened and under direct visualisation, lysis of any adhesions is performed with blunt dissection to fully expose the diaphragmatic and posterior epicardium. This approach is suitable for patients with predominately inferior or basal inferolateral scars. Limited anterior thoracotomy provides access to the anterior, mid to apical anterolateral wall and the true apex. As such, it is suitable for individuals with previous scarring in the left anterior descending

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Hybrid Surgical Ablation of Ventricular Arrhythmias coronary artery territory. Typically, the procedure is performed under general anaesthesia. A limited left anterior incision is performed at the target intercostal space and extended through the subcutaneous tissue and fascia.16 The pericardium is then dissected off the LV laterally to maximally expose the area of interest.

Figure 3: Picture Demonstrating Median Sternotomy with Direct Cryoprobe Application Over an Epicardial Region of Scar in a Patient with Ventricular Tachycardia

Diaphragm

A case report described a successful VT ablation using a transabdominal endoscopic approach using an incision through the central tendon of the diaphragm with concomitant use of an Impella haemodynamic support device (Abiomed) which was felt to be less invasive than performing a subxiphoid window.17 Another minimally invasive option that provides broad access to the epicardium includes a lateral thoracoscopic approach using one-sided threeport thoracoscopy.18,19

Coronary artery

Surgical Cryoprobe

Ventricular scar

After the epicardium has been surgically exposed, the surgeon or electrophysiologist can proceed with direct catheter mapping and ablation with the guidance of a recording system and a 3D electroanatomic mapping system.

Sternal retractor

Depending on institutional practice and resources, such hybrid procedures can be performed either in the EP laboratory or in the operating room. This was demonstrated in a study of 14 patients who underwent hybrid surgical epicardial ablation with surgical access in the EP laboratory.16 However, whether this practice can be widely

The patient had undergone concomitant mitral valve repair.

adopted depends on the availability of resources and expertise.

Figure 4: Schematic Demonstration of Hybrid Surgical Ablation Via a Sub-xiphoid Window (A) and Limited Anterior Thoracotomy (B)

Electroanatomical Mapping

Surgical access allows epicardial mapping of ventricular arrhythmias during the hybrid surgical procedure. LV access could be obtained via the transseptal or retrograde aortic approach in cases of concomitant endocardial mapping. 3D electroanatomical mapping systems integrate anatomy with electrophysiology. These systems enable the display of catheter position in real time and permit geometrical reconstruction of the chamber of interest. Signals for voltage and activation mapping can be annotated simultaneously during baseline rhythm or tachycardia. Since their inception, 3D electroanatomical systems have facilitated the reconstruction of complex anatomical and EP considerations during procedures and increased safety, efficacy and efficiency of ablation compared with only using fluoroscopy.20 Of note, electroanatomic mapping and EP recording systems may not be readily available in the surgical suite. Portable systems are available but require knowledge and experience to set up and for troubleshooting.

Safety and Outcomes of Hybrid Ventricular Tachycardia Ablation

Subxiphoid

Limited anterior thoracotomy

10% of the cases (n=15). A surgical window for epicardial exposure was performed via a subxiphoid approach in 14 patients with no specific complications reported in this group.10 On follow-up, 95 of the 134 patients (71%) achieved freedom from recurrence after 23 (Âą21) months.

Several case reports and series have been published demonstrating the feasibility of the hybrid procedures.10,15,16,21 In 2004, Soejima et al. described their experience using the subxiphoid surgical window in six people with VT with prior cardiac surgery or failed percutaneous pericardial access.15 The study demonstrated the safety and feasibility of the approach. Access to the pericardium was successful in all patients. No complications were reported apart from transient chest pain consistent with pericarditis. After a follow-up period ranging from 106 to 675 days, two of the six patients had recurrent, though infrequent, VT.

A recent study involved five patients who underwent hybrid ablation for recurrent sustained VT using combined endocardial and epicardial mapping and radiofrequency ablation in a hybrid operating room. Surgical approaches included anterolateral thoracotomy, one-sided three-port lateral thoracoscopy and sternotomy. After a mean follow-up of 18 months, three patients remained VT free with two of them using antiarrhythmics. One patient with recurrent VT required increasing amiodarone dose for arrhythmia control and one patient required a redo ablation 21 months after the initial procedure. There were no periprocedural complications.18

In 2010, a multicentre study assessed the safety of epicardial VT ablation in 134 patients. Percutaneous subxiphoid approach failed in

While these published experiences demonstrate the feasibility and safety of hybrid ablation in centres with experienced operators, no

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Electrophysiology and Ablation Figure 5: Cardiac MRI Short-Axis Views Demonstrating Transmural Delayed Enhancement

assisted surgery could be used for these complex arrhythmias as they describe a successful case of resistant VT originating from the LV summit with a robotically assisted endoscopic mapping followed by a minithoracotomy and cryoablation.23 This was expanded upon by Aziz et al. with a totally endoscopic LV summit premature ventricular complex ablation performed using a duodecapolar catheter for mapping coupled with an externally irrigated radiofrequency ablation catheter.24 Such approaches allow for excellent visualisation of the coronary arteries in this sensitive area; furthermore, surgical dissection may permit the surgeon to mobilise adjacent arteries to allow safer delivery of ablative energy. This approach can offer an alternative option for targeting these challenging arrhythmias when standard approaches have failed. However, considerable operator skill and experience is required, especially if it is performed â&#x20AC;&#x2DC;off-pumpâ&#x20AC;&#x2122;.

VT Ablation in the Setting of Left Ventricular Assist Device People with advanced heart failure have a high incidence of ventricular arrhythmias. While left ventricular assist device (LVAD) implantation is associated with increased survival compared with conventional therapy in carefully selected patients, postoperative VT is common and may occur de novo in one-third of patients, which may be related to the new substrate associated with the apical core incisions but also due to preexisting substrate.25 In LVAD patients, VT is associated with increased morbidity and mortality.26 Practical considerations regarding VT ablation in LVAD patients include crossing the aortic valve in the absence of complete valve opening due to loss of significant flow across the valve, or in some cases, over-sewing of valve leaflets.27 This, however, can be largely circumvented by accessing the ventricle using a transseptal approach.

Transmural delayed enhancement involves the apical anterior and lateral walls with extension along the subendocardium in the extreme apex into the inferior wall (bottom panels). Subepicardial and mesocardial scarring is noted with subendocardial sparing along the apical septum and inferior wall. Additionally, confluent subepicardial scarring is noted involving the basal (top panel) and mid (middle panel) ventricular anterolateral and inferolateral walls, with more discrete transmural scarring involving the basal inferolateral wall.

randomised studies have assessed whether this approach is superior to traditional catheter-based ablation in terms of long-term arrhythmia control. In a propensity-matched comparison of 38 patients who underwent hybrid epicardial ablation compared with patients who underwent percutaneous epicardial ablation, there was no significant difference in long-term outcomes.22

Endoscopic Robotic Ventricular Tachycardia Ablation While robotically assisted endoscopic coronary artery bypass surgery was established as an alternative to the standard median sternotomy approach over the past two decades, its application in arrhythmia surgery had to await the evolution of technology. One of the most challenging scenarios electrophysiologists might face is the approach to arrhythmias arising from the LV summit. This region comprises the most superior portion of the LV epicardium, near the bifurcation of the left main coronary artery into the left anterior descending and left circumflex coronary artery. The complexity of the relationship between the LV summit and surrounding structures may limit the feasibility of safe ablation in this area. Access to the most basal aspect of the LV summit is also frequently limited by epicardial fat. As first described by Mulpuru et al., robotically

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While feasible, endocardial catheter ablation in patients with LVAD can be high risk. Therefore, mapping and ablation at the time of LVAD implantation surgery represent a novel approach to the management of this high-risk population. A large number of these patients have had previous endocardial mapping and this information can be used in conjunction with epicardial mapping intraoperatively. While mapping and ablation can typically be performed at the time of the surgery, often the sternum is not immediately closed after LVAD implantation.28 This period represents another opportunity for epicardial mapping and ablation in patients with suspected epicardial VT or substrate.29 Although adhesions limit percutaneous pericardial access after LVAD implantation, case reports have described ablation after LVAD implantation using lateral thoracotomy or subxiphoid approaches as has been described following nonLVAD cardiac surgery. 30,31

Procedural Considerations for Hybrid Ablation A thorough evaluation and multidisciplinary approach including cardiac electrophysiologists, cardiothoracic surgeons, anaesthesiologists, perfusionists and allied health staff are critical in the care of patients before hybrid ablation. These important procedural aspects should be considered and addressed. Preprocedural imaging is critical in order to define the distribution of the arrhythmogenic substrate (scar) and help determine the optimal hybrid approach. In most cases, cardiac MRI with delayed enhancement protocol will offer the most sensitive evaluation of the extent and location of scarring (Figure 5). Contrast cardiac CT scans can also be used.

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Hybrid Surgical Ablation of Ventricular Arrhythmias Table 1: Emerging Technologies in Ventricular Arrhythmia Ablation Procedures

Technique

Advantages

Disadvantages

Needle-based catheter ablation

Needle deployed through irrigated ablation catheter – distance determined by operator1

Targeting deep intramyocardial or epicardial substrate

Limited experience – still under investigation

Allows the delivery of high-power radiofrequency energy creating deep lesions in between the two catheters3

Trial showed higher adverse events5

Mapping and ablation via the needle tip can be performed High-power bipolar ablation

A second ablation catheter is used as the grounding connection in place of a grounding patch thereby theoretically preventing radiofrequency energy dispersal

Radiotherapy ablation Delivery of radiation with stereotactic body radiation therapy to induce myocardial cell death

Transcoronary ethanol ablation

Ethanol injection into the coronary branch supplying the arrhythmogenic substrate Retrograde venous ethanol ablation is an alternative to avoid instrumentation of coronary arteries9

Potential for extensive myocardial damage and cardiac perforation2

Reportedly achieves larger lesions and transmurality4 Non-invasive Short duration – permits outpatient therapy Useful for septal ventricular tachycardia with no endocardial origin and also in some cases of epicardial inaccessibility10

Dose-dependent adverse effects on left ventricular function6 Limited long-term studies7,8 Limited by coronary anatomy Risk of complete heart block11 Limited studies12

Table 2: Overview of Mechanical Circulatory Support Devices for Haemodynamic Support During Ventricular Tachycardia Ablation Device

Mechanism

Advantages

Disadvantages

IABP

Diastolic aortic augmentation with LV afterload reduction

• Easy insertion

• Modest haemodynamic support (0.5 l/min)

• Cheapest option

• Not ideal with VT as diastolic gating is difficult

LV to ascending aorta pump

• Better support compared with IABP

• Electromagnetic interference can impede accurate electroanatomical mapping

Impella

• Increases cardiac output by 2.5 l/min (Impella 2.5), 3.5 l/min (Impella CP) or 5 l/min (Impella 5) TandemHeart ECMO

• Greater risk of embolism and peripheral ischaemia

LA (via transseptal puncture) to femoral artery bypass

• Up to 4.0 l/min support

• Adequate RV function is required

• Can be used with very poor LV function

• Requires transseptal puncture

Cardiopulmonary bypass

• Provides biventricular and respiratory support

• Complexity necessitates expertise with a perfusionist team and resources.

• Provides >4.5 l/min

• Risk of limb-threatening vascular complications due to large cannulae with peripheral ECMO

ECMO = extra-corporeal membrane oxygenation; IABP = intra-aortic balloon pump; LV: left ventricle; RV: right ventricle; VT: ventricular tachycardia.

Patients with a history of CABG should be evaluated with CT or invasive coronary angiography to determine the vessel course to assess the anatomic relationship to the selected surgical approach. CT may be effective in excluding large vessel stenosis/occlusion such as in graft vessels. However, its diagnostic value may be more limited for native vessels and invasive coronary angiography may be required. In cases where an anterior thoracotomy is used, precordial ECG lead placement may be displaced from the standard position due to the incision line and this could affect ECG interpretation during mapping. The leads should be placed as close to the normal position as possible.With the limited anterior thoracotomy approach, single lung ventilation may be needed to allow for the appropriate exposure. Therefore, patients with severe respiratory lung disease may not be suitable candidates. With severe pericardial adhesions, the surgeon may need to re-enter the thorax at a different intercostal space to extend exposure.16 In cases using minimally invasive access, such as robotic access, air accumulation in the pericardial space may increase the defibrillation

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threshold significantly. As such, one should be ready to deliver implantable cardioverter defibrillators (ICD) shocks, if available, or to evacuate air promptly to permit external defibrillation.32 The metal retractors used for surgical access can interfere with the electroanatomic mapping systems and consequently prohibit mapping in certain areas of the heart. Ablation tools commonly used in the surgical setting use either cryoablation energy or radiofrequency. Cryothermy uses either Argon gas (CryoFlex, Medtronic) or nitrous oxide (cryoICE, AtriCure) to achieve rapid cooling temperature and deliver deep lesions. Flexible cryoprobes have the advantage of delivering tailored lesions over a wider area compared with radiofrequency. Some radiofrequency ablation devices, such as Cardioblate iRF (Medtronic) and Isolator (AtriCure) allow for mapping as well as ablation at the same time, which is not feasible with large cryoprobes. Haemodynamic decompensation from prolonged procedural time or during activation mapping of VT is a major limitation. While vasopressor and inotropic support are often used, these are frequently

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Electrophysiology and Ablation insufficient.33 Therefore, preprocedural risk stratification to assess for the need of potential mechanical circulatory support (MCS) is essential. Patients with advanced age, marked left ventricular dysfunction and comorbidities such as chronic obstructive pulmonary disease and diabetes are at particular risk for haemodynamic decompensation.34 MCS can be instituted at the beginning of the procedure, especially when activation mapping of unstable VTs is considered necessary. Alternatively, MCS may be established ad hoc, though it should be noted that the outcomes of urgent or emergent MCS for haemodynamic compromise during VT ablation procedures are poor. Short-term MCS options include intra-aortic balloon pump, Impella, TandemHeart (TandemLife) and extracorporeal membrane oxygenation (Table 2).35–37 Post-operative pain is a major issue and may be related to the route of access – such as sternotomy, intercostal access or rib retraction – tissue injury from ablation with associated inflammation and surgical drain sites. Inadequate management of post-operative pain prolongs the rehabilitation period and worsens patient-reported outcomes.38 As such, post-operative pain assessment and appropriate management are crucial.

Emerging Technologies in Ventricular Tachycardia Ablation Though hybrid surgical ablation has provided another tool for the treatment of ventricular arrhythmias, emerging techniques may reduce the reliance on this approach. These remain off label and are mainly relegated to use in tertiary referral centres. Such techniques include needle-based catheter ablation, radiotherapy ablation, bipolar ablation and transcoronary or retrograde venous ethanol ablation (Table 1).43–53

Conclusion The evolution of VT ablation techniques is associated with expanding indications. The choice should be guided primarily by the clinical scenario. Hybrid surgical ablation may be viewed as a form of synergism that combines the advantages of EP and surgery. There is now a significant body of evidence suggesting the safety and feasibility of hybrid surgical ablation of VT. Appropriate patient selection is key. Therefore, providers should be fully aware of the indications and caveats associated with this technique.

Clinical Perspective Management includes multimodal analgesia such as non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, as well as opioid and non-opioid analgesics; occasionally, regional anaesthesia may be used for refractory and prolonged pain.39 Pericarditis is also common following epicardial ablation and measures aimed at reducing pericardial inflammation should be instituted; these predominantly include NSAIDs and colchicine. In certain circumstances, intrapericardial or systemic steroid use and intrapericardial lidocaine may be used.40–42

Niebauer MJ, Kirsh M, Kadish A, et al. Outcome of endocardial resection in 33 patients with coronary artery disease: correlation with ventricular tachycardia morphology. Am Heart J 1992;124:1500–6. https://doi.org/10.1016/0002-8703(92)900632; PMID: 1462905. 2. Josephson ME, Horowitz LN, Farshidi A, et al. Recurrent sustained ventricular tachycardia. 2. Endocardial mapping. Circulation 1978;57:440–7. https://doi.org/10.1161/01. CIR.57.3.440; PMID: 624153. 3. Waspe LE, Brodman R, Kim SG, et al. Activation mapping in patients with coronary artery disease with multiple ventricular tachycardia configurations: occurrence and therapeutic implications of widely separate apparent sites of origin. J Am Coll Cardiol 1985;5:1075–86. https://doi.org/10.1016/S07351097(85)80007-3; PMID: 3989117. 4. Gallagher JJ, Pritchett EL, Sealy WC, et al. The preexcitation syndromes. Prog Cardiovasc Dis 1978;20:285–327.https://doi. org/10.1016/0033-0620(78)90015-4; PMID: 146210. 5. Josephson ME, Horowitz LN, Farshidi A, Kastor JA. Recurrent sustained ventricular tachycardia. 1. Mechanisms. Circulation 1978;57:431–40. https://doi.org/10.1161/01.CIR.57.3.431 PMID: 624152. 6. Guiraudon G, Fontaine G, Frank R, et al. Encircling endocardial ventriculotomy: a new surgical treatment for life-threatening ventricular tachycardias resistant to medical treatment following myocardial infarction. Ann Thorac Surg 1978;26:438– 44. https://doi.org/10.1016/S0003-4975(10)62923-2; PMID: 753158. 7. Josephson ME, Harken AH, Horowitz LN. Endocardial excision: a new surgical technique for the treatment of recurrent ventricular tachycardia. Circulation 1979;60:1430–9. https://doi. org/10.1161/01.CIR.60.7.1430; PMID: 498470. 8. Guiraudon GM, Klein GJ, Gulamhusein SS, et al. Total disconnection of the right ventricular free wall: surgical treatment of right ventricular tachycardia associated with right ventricular dysplasia. Circulation 1983;67:463–70. https://doi. org/10.1161/01.CIR.67.2.463 PMID: 6848239. 9. Sosa E, Scanavacca M, d’Avila A, Pilleggi F. A new technique to perform epicardial mapping in the electrophysiology laboratory. J Cardiovasc Electrophysiol 1996;7:531–6. https://doi.org/10.1111/j.1540-8167.1996.tb00559.x; PMID: 8743758. 10. Sacher F, Roberts-Thomson K, Maury P, et al. Epicardial ventricular tachycardia ablation a multicenter safety study. J

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• An increasing body of evidence suggests that hybrid surgical ablation is a safe, effective and feasible technique. • Hybrid ablation should be considered in patients with pericardial adhesions, deep myocardial substrate, proximity to critical structures, inaccessible LV and extra-cardiac anatomic challenges. • A multidisciplinary approach including cardiac electrophysiologists, cardiothoracic surgeons, anaesthesiologists, perfusionists and allied health staff is critical in the care of these patients.

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PMID: 31139299. 20. Medical Advisory Secretariat. Advanced electrophysiologic mapping systems: an evidence-based analysis. Ont Health Technol Assess Ser 2006;6:1–101. PMID: 23074499. 21. Maury P, Leobon B, Duparc A, et al. Epicardial catheter ablation of ventricular tachycardia using surgical subxyphoid approach. Europace 2007;9:212–5. https://doi.org/10.1093/europace/ eum016; PMID: 17347330. 22. Li A, Hayase J, Do D, et al. Hybrid surgical vs percutaneous access epicardial ventricular tachycardia ablation. Heart Rhythm 2018;15:512–9. https://doi.org/10.1016/j. hrthm.2017.11.009; PMID: 29132931. 23. Mulpuru SK, Feld GK, Madani M, Sawhney NS. A novel, minimally-invasive surgical approach for ablation of ventricular tachycardia originating near the proximal left anterior descending coronary artery. Circ Arrhythm Electrophysiol 2012;5:e95–7. https://doi.org/10.1161/ CIRCEP.112.975284; PMID: 23074330. 24. Aziz Z, Moss JD, Jabbarzadeh M, et al. Totally endoscopic robotic epicardial ablation of refractory left ventricular summit arrhythmia: First-in-man. Heart Rhythm 2017;14:135–8. https:// doi.org/10.1016/j.hrthm.2016.09.005; PMID: 27614027. 25. Ahmed A, Amin M, Boilson BA, et al. Ventricular arrhythmias in patients with left ventricular assist device (LVAD). Curr Treat Options Cardiovasc Med 2019;21:75. https://doi.org/10.1007/ s11936-019-0783-7; PMID: 31773322. 26. Garan AR, Iyer V, Whang W, et al. Catheter ablation for ventricular tachyarrhythmias in patients supported by continuous-flow left ventricular assist devices. ASAIO J 2014;60:311–6. https://doi.org/10.1097/ MAT.0000000000000061; PMID: 24614361. 27. Herweg B, Ilercil A, Kristof-Kuteyeva O, et al. Clinical observations and outcome of ventricular tachycardia ablation in patients with left ventricular assist devices. Pacing Clin Electrophysiol 2012;35:1377–83. https://doi. org/10.1111/j.1540-8159.2012.03509.x; PMID: 22946711. 28. Richenbacher WE, Naka Y, Raines EP, et al. Surgical management of patients in the REMATCH trial. Ann Thorac Surg 2003;75:S86–92. https://doi.org/10.1016/S0003-4975(03)004855; PMID: 12820740. 29. Patel M, Rojas F, Shabari FR, et al. Safety and feasibility of open chest epicardial mapping and ablation of ventricular tachycardia during the period of left ventricular assist device implantation. J Cardiovasc Electrophysiol 2016;27:95–101. https://

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Hybrid Surgical Ablation of Ventricular Arrhythmias doi.org/10.1111/jce.12839; PMID: 26377813. 30. Mathuria NS, Vaseghi M, Buch E, Shivkumar K. Successful ablation of an epicardial ventricular tachycardia using a surgical ablation tool. Circ Arrhythm Electrophysiol 2011;4:e84-6. https://doi.org/10.1161/CIRCEP.111.965467; PMID: 22203665. 31. Whang W, Patel MR, Iyer V, et al. Epicardial catheter ablation through subxiphoid surgical approach in a patient with implanted left ventricular assist device and cannula-related ventricular tachycardia. Circ Heart Fail 2014;7:868–9. https:// doi.org/10.1161/CIRCHEARTFAILURE.114.001487; PMID: 25228322. 32. Yamada T, McElderry HT, Platonov M, et al. Aspirated air in the pericardial space during epicardial catheterization may elevate the defibrillation threshold. Int J Cardiol 2009;135:e34–5. https://doi.org/10.1016/j.ijcard.2008.03.074; PMID: 18593642. 33. 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;58:1363–71. https://doi. org/10.1016/j.jacc.2011.06.022; PMID: 21920266. 34. Santangeli P, Muser D, Zado ES, et al. Acute hemodynamic decompensation during catheter ablation of scar-related ventricular tachycardia. Circ Arrhythm Electrophysiol 2015;8:68– 75. https://doi.org/10.1161/CIRCEP.114.002155; PMID: 25491601. 35. Peura JL, Colvin-Adams M, Francis GS, et al. Recommendations for the use of mechanical circulatory support: device strategies and patient selection. Circulation 2012;126:2648–67. https://doi.org/10.1161/CIR.0b013e3182769a54; PMID: 23109468. 36. Health Quality Ontario. Percutaneous ventricular assist devices: a health technology assessment. Ont Health Technol Assess Ser 2017;17:1-97. PMID: 28232854. 37. Hajjar LA, Teboul JL. Mechanical circulatory support devices for cardiogenic shock: state of the art. Critical Care 2019;23:76. https://doi.org/10.1186/s13054-019-2368-y; PMID: 30850001. https://doi.org/10.1186/s13054-019-2368-y; PMID: 30850001.

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38. Braun LA, Stanguts C, Casanelia L, et al. Massage therapy for cardiac surgery patients – a randomized trial. J Thorac Cardiovasc Surg 2012;144:1453–9, 1459.e1. https://doi. org/10.1016/j.jtcvs.2012.04.027; PMID: 22964355. 39. White PF. Multimodal analgesia: its role in preventing postoperative pain. Curr Opin Investig Drugs 2008;9:76–82. PMID: 18183534. 40. Dyrda K, Piers SRD, Taxis CFvHv, et al. Influence of steroid therapy on the incidence of pericarditis and atrial fibrillation after percutaneous epicardial mapping and ablation for ventricular tachycardia. Circ: Arrhythm Electrophysiol 2014;7:671–6. https://doi.org/10.1161/CIRCEP.113.001148; PMID: 24970295. 41. Weibel S, Jelting Y, Pace NL, et al. Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery in adults. Cochrane Database Syst Rev 2018;6:CD009642–CD009642. https://doi. org/10.1002/14651858.CD009642.pub3; PMID: 29864216. 42. Adler Y, Charron P, Imazio M, et al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases: The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC) endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2015;36:2921–64. https://doi. org/10.1093/eurheartj/ehv318; PMID: 26320112. 43. Sapp JL, Beeckler C, Pike R, et al. Initial human feasibility of infusion needle catheter ablation for refractory ventricular tachycardia. Circulation 2013;128:2289–95. https:// doi.org/10.1161/CIRCULATIONAHA.113.003423; PMID: 24036605. 44. Sapp JL, Beeckler C, Pike R, et al. Initial human feasibility of infusion needle catheter ablation for refractory ventricular tachycardia. Circulation 2013;128:2289–95. https://doi. org/10.1161/CIRCULATIONAHA.113.003423; PMID: 24036605. 45. Loo BW Jr, Soltys SG, Wang L, et al. Stereotactic ablative radiotherapy for the treatment of refractory cardiac ventricular arrhythmia. Circ Arrhythm Electrophysiol 2015;8:748–50. https://

doi.org/10.1161/CIRCEP.115.002765; PMID: 26082532. 46. Zei PC, Soltys S. Ablative radiotherapy as a noninvasive alternative to catheter ablation for cardiac arrhythmias. Curr Cardiol Rep 2017;19:79. https://doi.org/10.1007/s11886-0170886-2; PMID: 28752279. 47. Cuculich PS, Schill MR, Kashani R, et al. Noninvasive Cardiac Radiation for Ablation of Ventricular Tachycardia. N Engl J Med 2017;377:2325–36. https://doi.org/10.1056/NEJMoa1613773; PMID: 29236642. 48. Hohmann S, Deisher AJ, Suzuki A, et al. Left ventricular function after noninvasive cardiac ablation using proton beam therapy in a porcine model. Heart Rhythm 2019;16:1710–9. https://doi.org/10.1016/j.hrthm.2019.04.030; PMID: 31004779. 49. Sauer WH, Steckman DA, Zipse MM, et al. High-power bipolar ablation for incessant ventricular tachycardia utilizing a deep midmyocardial septal circuit. Heart Rhythm Case Rep 2015;1:397–400. https://doi.org/10.1016/j.hrcr.2015.01.018; PMID: 28491595. 50. Koruth JS, Dukkipati S, Miller MA, et al. Bipolar irrigated radiofrequency ablation: a therapeutic option for refractory intramural atrial and ventricular tachycardia circuits. Heart Rhythm 2012;9:1932–41. https://doi.org/10.1016/j. hrthm.2012.08.001; PMID: 22863684. 51. Tokuda M, Sobieszczyk P, Eisenhauer AC, et al. Transcoronary ethanol ablation for recurrent ventricular tachycardia after failed catheter ablation. Circ Arrhythm Electrophysiol 2011;4:889– 96. https://doi.org/10.1161/CIRCEP.111.966283; PMID: 21984361. 52. Kay GN, Epstein AE, Bubien RS, et al. Intracoronary ethanol ablation for the treatment of recurrent sustained ventricular tachycardia. J Am Coll Cardiol 1992;19:159–68. https://doi. org/10.1016/0735-1097(92)90068-X; PMID: 1729328. 53. Tokuda M, Sobieszczyk P, Eisenhauer AC, et al. Transcoronary ethanol ablation for recurrent ventricular tachycardia after failed catheter ablation: an update. Circ Arrhythm Electrophysiol 2011;4:889–96. https://doi.org/10.1161/CIRCEP.111.966283; PMID: 21984361.

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Electrophysiology and Ablation

Cryoballoon Ablation of Atrial Fibrillation in Octogenarians Tauseef Akhtar, Ronald Berger, Joseph E Marine, Usama A Daimee, Hugh Calkins and David Spragg Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, US

Abstract A significant proportion of AF patients with advanced age are being treated in clinical practice. Cryoballoon ablation of AF, given its shorter procedure time and comparable efficacy to radiofrequency ablation, has rapidly become a commonly used tool for AF ablation. Data regarding the outcomes of cryoballoon ablation of AF in octogenarians are limited because of the exclusion of this age group in the previous studies. The authors report outcomes of 15 octogenarian AF patients undergoing index cryoballoon ablation at a single centre. The mean age of the included patients was 83 ± 3 years. In total, 13 patients (87%) presented with paroxysmal AF, and two (13%) had long-standing persistent AF. At 6 and 12 months of follow-up, freedom from AF was 80% and 70%, respectively. None of the patients suffered any procedure-related complications. Cryoballoon ablation appears to be a safe and effective approach for treating symptomatic AF refractory to antiarrhythmic drug therapy in octogenarian patients, based on outcomes in this cohort. These findings require further validation in prospective randomised studies with larger sample sizes.

Keywords AF, cryoballoon ablation, octogenarians, radiofrequency ablation, pulmonary vein isolation, elderly, transient phrenic nerve palsy Disclosure: Funding for this research was provided in part by the Edward St John Fund for AF Research, the Roz and Marvin H Weiner and Family Foundation, the Dr Francis P Chiaramonte Foundation, the Marilyn and Christian Poindexter Arrhythmia Research Fund, Norbert and Louise Grunwald Cardiac Arrhythmia Research Fund, and the Mr & Mrs Larry Small AF Research Fund. The authors have no other conflicts of interest to declare. Received: 27 April 2020 Accepted: 27 June 2020 Citation: Arrhythmia & Electrophysiology Review 2020;9(2):104–8. DOI: https://doi.org/10.15420/aer.2020.18 Correspondence: David Spragg, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287, US. E: dspragg1@jhmi.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly.

AF is a common and clinically impactful arrhythmia. Given both the association of AF with aging and the increasing number of elderly people in the general population, it follows that many AF patients are of advanced age. The management of AF in the geriatric population is associated with several challenges, including multiple comorbidities, increased toxicity of antiarrhythmic drugs (AAD), an increased risk of complications from invasive procedures and an increased risk of stroke and bleeding complication secondary to anticoagulation use.1,2 Catheter-ablation-based pulmonary vein isolation (PVI) has become the most commonly performed procedure for the management of AF.3 Traditional radiofrequency-based point-by-point ablation has shown favourable clinical success rates, but is associated with a long learning curve, significant procedure time, and often the need for multiple procedures in order to achieve durable PVI.4,5 The use of cryoballoon ablation catheters to achieve PVI has been associated with a shorter procedure time with comparable efficacy compared to radiofrequency ablation approaches and has rapidly become a commonly used tool for AF ablation. 6 While the safety and efficacy of AF ablation have been demonstrated in many clinical trials, the outcomes of cryoballoon AF ablation in the very elderly is limited. In this case series, we report our institutional experience with second-generation cryoballoon-based PVI in octogenarian patients.

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Access at: www.AERjournal.com

Methods We describe the safety and efficacy outcomes of 15 octogenarian patients undergoing index AF ablation using the second-generation cryoballoon at the Johns Hopkins Hospital between 2012 and 2019. The study participants were non-consecutively included and derived from an institutional review board-approved, prospectively populated clinical database of AF ablation patients. Demographics, clinical history, procedural data, complications, and outcomes were recorded for each case. Patients were excluded if they had prior catheter ablation of AF, left atrial thrombus detected on pre-procedural transoesophageal echocardiography (TOE) or CT scan, and advanced comorbidities and frailty precluding catheter ablation. Arrhythmia recurrence and periprocedural complications were ascertained based on monitoring strategies described in the 2017 Heart Rhythm Society consensus document.3 Arrhythmia recurrence was defined as any AF or atrial tachyarrhythmia sustained for >30 seconds recorded by a surface ECG or rhythm-monitoring device after a 90-day blanking period. Procedurerelated complications, such as major bleeding, minor bleeding, phrenic nerve palsy, cerebral embolism, pericardial effusion/tamponade, atriooesophageal fistula or extended hospitalisation, were assessed.

Pre-procedural Management AAD management was left to the discretion of the operator. Preprocedure TOE was performed only for the patients presenting in AF at

Cryoballoon Ablation of AF in Octogenarians

Demographics

Study Population (n=15), n (%)*

Age (years)

83 ± 3

Male

9 (60)

Former smoker

5 (33)

AF duration (years)

8.9 ± 8.2

Paroxysmal/long-standing persistent

13 (87) / 2 (13)

BMI (kg/m2)

26.8 ± 5.2

CHF

2 (13)

Hypertension

12 (80)

Diabetes

3 (20)

Stroke/TIA

4 (27)

CAD

6 (40)

CHA2DS2VASc score

4.2 ± 1.7

HASBLED score

2.4 ± 0.8

Previous atrial flutter ablation

4 (27)

OSA

2 (13)

CKD

3 (20)

Hyperlipidaemia

8 (53)

Pacemaker implantation

2 (13)

Echocardiographic Parameters Left atrial diameter (cm)

4.5 ± 1.2

Left ventricular ejection fraction (%)

63.7 ± 3.5

Drugs

Figure 1: Freedom From AF During Follow-up Following Cryoballoon Ablation

100%

Blanking period

80% Freedom from AF

Table 1: Baseline Patient Characteristics

60%

40%

20%

0% 0

Follow-up duration (months) Kaplan-Meier survival curve showing the percentage of the included 15 patients free from AF after a 3-month blanking period.

direct oral anticoagulants (DOACs) underwent cessation of anticoagulation for 12–24 hours prior to the ablation procedure, with resumption 4 hours post-procedure. Anticoagulation was continued for a minimum of 3 months following ablation procedure for all patients unless contraindicated.

Ablation Strategy

Class I

0 (0)

Class III

7 (47)

Beta-blocker

11 (73)

Ca2+ channel blocker

6 (40)

*Unless otherwise specified. CAD = coronary artery disease; CHF = congestive heart failure; CKD = chronic kidney disease; OSA = obstructive sleep apnoea; TIA = transient ischaemic attack.

Table 2: Procedural Characteristics Procedure/Characteristic

Study Population (n=15)

Additional CTI ablation n (%)

2 (13)

Number of PVs isolated

Mean number of PV isolated per patient

4.07 ± 0.458

Anatomical variant of PV, n (%)

3 (20)

LSPV diameter (mm)

17.7 ± 4.6

LIPV diameter (mm)

15.5 ± 3.3

RSPV diameter (mm)

16.9 ± 7.2

RIPV diameter (mm)

17.1 ± 3.6

Mean number of freezes per patient

10.8 ± 2.1

Ablation duration per patient (s)

1,530 ± 411.6

Nadir temperature (°C)

40 ± 2.8

CTI = cavo-tricuspid isthmus; PV = pulmonary vein; LIPV = left inferior pulmonary vein; LSPV = left superior pulmonary vein; RIPV = right inferior pulmonary vein; RSPV = right superior pulmonary vein.

the time of ablation, as per the institutional practice. All patients underwent a preprocedural CT scan to assess the left atrium (LA) and pulmonary vein (PV) anatomy in detail. Catheter ablation in patients on warfarin was performed without cessation of warfarin and patients on

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

All ablation procedures were performed under general anaesthesia. Femoral site access was obtained and intravenous heparin administered to maintain activated clotting times >350 seconds. After a trans-septal puncture at the fossa ovalis, a long deflectable sheath (FlexCath Advance sheath, Medtronic) was introduced into the LA using intracardiac echocardiographic guidance. Pulmonary venous angiograms were obtained for each of the four PVs to serve as a fluoroscopic reference. An endocardial map of the LA was created via the CARTO-Biosense system (Carto 3, Biosense Webster or Ensite NavX, St Jude Medical). Right-sided phrenic nerve pacing was performed by placing a catheter against the phrenic nerve at or above the level of the superior vena cava. A second-generation cryoballoon catheter with a 23 or 28 mm balloon (Arctic Front Advance, Medtronic) and a PV mapping catheter were passed into the LA via the long sheath. Cryo lesions were targeted to the PVs after the demonstration of balloon occlusion with contrast injection. Goal temperatures were between −35°C and −55°C. Freezes were aborted if the oesophageal temperature fell below 28°C or if phrenic nerve pacing showed diminution of diaphragmatic excursion during right-sided PV lesion delivery. Following the delivery of at least two lesion sets per vein, electrical isolation of each PV was reassessed, and additional applications of cryotherapy delivered with either a 28 mm or 23 mm second-generation cryoballoon. Additional cavo-tricuspid isthmus (CTI) ablation using radiofrequency energy was performed at the discretion of the operator in patients with history of clinically documented typical atrial flutter. An endocardial map of the right atrium was created. His bundle position was identified and marked. Radiofrequency energy was delivered to create a line of electrical block along the CTI, which was verified by bidirectional, differential atrial pacing. Intracardiac electrograms and conduction were measured at rest and after ablation.

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Electrophysiology and Ablation Table 3: Safety and Efficacy Outcomes in the Included Patients Patient

Sex

CHA2DS2VASc Score

HASBLED Score

AF Type

Duration Since Prior Failed AF Diagnosis AAD (Years)

Follow-up Recurrence Complication Duration

Paroxysmal

2 years

None

Paroxysmal

Amiodarone

5 years

None

Paroxysmal

Amiodarone

1 year

Yes

None

Paroxysmal

Unknown

2 years

None

Paroxysmal

Amiodarone

2 years

None

Paroxysmal

Amiodarone

1 year

None

Paroxysmal

Amiodarone, dronederone

2 years

None

Long-standing persistent

Amiodarone

1 year

Yes

None

Paroxysmal

1 year

None

Paroxysmal

Amiodarone, dronederone, flecainide, sotalol

1 year

Yes

None

Paroxysmal

Unknown

Amiodarone

8 months

None

Paroxysmal

Amiodarone, propafenone

7 months

None

Long-standing persistent

Amiodarone, dronederone, flecainide

6 months

None

Paroxysmal

Unknown

Amiodarone

6 months

None

Paroxysmal

6 months

None

AAD = antiarrhythmic drug; NA = not applicable.

Clinical Follow-up

Ablation Procedure and Acute Outcomes

All patients were observed in the hospital for a minimum of one night post-ablation. Routine follow-up (history, exam, and electrocardiography or Holter) was performed at the outpatient clinic or by a local cardiologist at 3, 6 and 12 months and additionally, if prompted by symptoms. Status of symptoms, including AF burden and effect of ablation on quality of life, was assessed in each patient at follow-up visit. Event monitors were arranged for patients in whom symptoms suggestive of AF developed in the post-blanking phase of follow-up. AAD therapy, if present at the time of ablation, was discontinued at the 3-month follow-up visit. Outcomes were assessed via electronic health record reviews or telephone interviews.

Of the 15 patients, five (33%) had catheter ablation performed on continuous anticoagulation with warfarin and the remaining 10 (67%) underwent ablation on minimally interrupted DOAC anticoagulation. Four patients (27%) presented in AF at the time of ablation and underwent preprocedural TOE to rule out left atrial appendage thrombi before cryoballoon ablation. Table 2 describes the procedural characteristics. In all the patients, 100% of PVs were successfully isolated at the end of the procedure. Three patients had variant PV anatomy (one patient each with left common, left middle, and right middle PVs). Two patients underwent additional CTI ablation. None of the patients suffered any procedure-related complications.

Statistical Analysis

Efficacy of Ablation with Follow-up

Quantitative variables were described with measures of central tendency and dispersion (mean and standard deviation). Qualitative variables were described as frequencies. All analysis was done using SPSS Statistics Software for Windows version 23.0 (IBM).

During a mean follow-up duration of 15.8 months (range 6–60 months), AF recurred in three patients. The freedom from AF recurrence was 80% and 70% at 6 and 12 months of follow-up, respectively (Figure 1). Thirteen of the 15 patients reported significant reduction in symptoms and AF burden associated with improvement in quality of life following catheter ablation. Anticoagulation following catheter ablation was continued in all the patients at 3 months follow-up visit except in one patient who developed occult gastrointestinal bleeding secondary to gastritis. Table 3 provides patient specific safety and efficacy outcome data for all patients included in this report.

Results Patient Population The cohort comprised 15 patients between 80 and 88 years of age who underwent cryoballoon AF ablation between 2012 and 2019. The clinical characteristics of our patient cohort are shown in Table 1. The mean patient age was 83 ± 3 years and 60% of the patients were men. Of the 15 patients, 13 (87%) presented with paroxysmal AF (PAF) and two (13%) had long-standing persistent AF (PsAF). The mean time since AF was first diagnosed was 8.9 ± 8.2 years. Mean CHA2DS2-VASc score and HASBLED scores were 4.2 ± 1.7 and 2.4 ± 0.8, respectively. Mean LA diameter was 4.5 ± 1.2 cm.

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Discussion This case series describes the outcomes of cryoballoon ablation for AF in octogenarian patients. Our report reveals that secondgeneration cryoballoon ablation was a safe and effective procedure in this cohort.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Cryoballoon Ablation of AF in Octogenarians The success rate was 70% at 1 year of follow-up, and there were no complications. Our results serve to extend and confirm those of a number of prior publications that have reported the outcomes of cryoballoon ablation in elderly patients with AF.7–16 The definition of ‘elderly’ in these series included patients aged as young as 70 years, and the reported success rates range from 62 to 87%. In the aggregate, these studies have investigated safety and efficacy rates at 1 year in a total of 2,235 patients. In all the studies, no significant differences were seen in either efficacy or safety rates when comparing outcomes with nonelderly patients. The most commonly reported complication was transient phrenic nerve palsy. The reported incidence of phrenic nerve palsy with cryoballoon ablation ranges from 4 to 14%. Phrenic nerve palsy is described to occur more commonly with right superior PV (RSPV) ablation because of the proximity of the right phrenic nerve to the RSPV. Several risk factors for phrenic nerve palsy during cryoballoon ablation have been identified, including shorter distance between the RSPV and right phrenic nerve, larger ostial vein size, circular shape of pulmonary vein ostium and greater obtuse angle between the RSPV and LA.17 Our series differs from prior studies in that ours included patients of more advanced age than in most of the previously published investigations. Only one prior study, by Kanda et al., examined the outcomes of cryoballoon ablation in octogenarians.13 Their study included patients with PAF and compared cryoballoon ablation outcomes in patient cohorts of age ≥80 years versus those <80 years. Among the 49 patients aged >80 years who underwent cryoballoon ablation, the success rate was 87%. None of the patients suffered any major complication, with transient phrenic nerve palsy being the most common complication. Compared to the previous study of cryoballoon ablation in patients over the age of 80,13 the lower success rate in our report could possibly result from the inclusion of the patients with long-standing PsAF, higher CHA2DS2-VASc score, and greater LA diameter. Previous studies have reported that these factors are associated with a poor success rate of ablation procedure.18–20 In terms of safety, our findings are in line with the study by Kanda et al., with no reported major complications.13

Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:1825–33. https://doi.org/10.1056/ NEJMoa021328; PMID: 12466506. Lip GY, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/ Alcohol Concomitantly) score. J Am Coll Cardiol 2011;57:173–80. https://doi.org/10.1016/j.jacc.2010.09.024; PMID: 21111555. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. Heart Rhythm 2017;14:e445–94. https://doi. org/10.1016/j.hrthm.2017.07.009; PMID: 31631881. Ouyang F, Tilz R, Chun J, et al. Long-term results of catheter ablation in paroxysmal atrial fibrillation: lessons from a 5-year follow-up. Circulation 2010;122:2368–77. https://doi.org/ 10.1161/CIRCULATIONAHA.110.946806; PMID: 21098450. Tilz RR, Rillig A, Thum A-M, et al. Catheter ablation of longstanding persistent atrial fibrillation: 5-year outcomes of the Hamburg Sequential Ablation Strategy. J Am Coll Cardiol 2012;60:1921–9. https://doi.org/10.1016/j.jacc.2012.04.060; PMID: 23062545. Kuck K-H, Brugada J, Fürnkranz A, et al. Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation. N Engl J Med 2016;374:2235–45. https://doi.org/10.1056/ NEJMoa1602014; PMID: 27042964. Abdin A, Yalin K, Lyan E, et al. Safety and efficacy of cryoballoon ablation for the treatment of atrial fibrillation in

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10.

11.

12.

13.

14.

Additionally, we also did not observe any transient phrenic nerve palsy. This could possibly be because of effective phrenic nerve monitoring during the ablation of right PVs, with immediate cessation of ablation in the case of diminished diaphragmatic motion. Moreover, the limited sample size in our report could also underestimate the complication rate. Although limited in size, the results of our series confirm and extend the results of prior studies, which have examined the outcomes of cryoballoon ablation of AF in the elderly and demonstrate an acceptable efficacy rate with minimal complications. The findings of our report should be interpreted with attention to the associated limitations. These include the single-centre, retrospective and observational nature of the study and lack of a comparator group, the small sample and the lack of continuous ECG monitoring.

Conclusion Based on our study with a limited sample size, cryoballoon AF ablation appears to be a safe and effective strategy for treating octogenarians with symptomatic AF refractory to AAD therapy. Our findings require validation by prospective randomised studies with larger sample sizes.

Clinical Perspective • Given the association of AF with increasing age, a significant proportion of AF patients with advanced age are being treated in clinical practice. • Cryoballoon ablation of AF is associated with a shorter procedure time and comparable efficacy to radiofrequency ablation and has become the commonly used tool for AF ablation. • Data related to the outcomes of cryoballoon ablation of AF in octogenarian patients are limited because of the exclusion of this age group in previous studies. • Cryoballoon ablation appears to be a safe and effective approach for treating symptomatic AF refractory to antiarrhythmic drug therapy in octogenarian patients.

elderly patients. Clin Res Cardiol 2019;108:167–74. https://doi. org/10.1007/s00392-018-1336-x; PMID: 30187178. Abugattas J-P, Iacopino S, Moran D, et al. Efficacy and safety of the second generation cryoballoon ablation for the treatment of paroxysmal atrial fibrillation in patients over 75 years: a comparison with a younger cohort. Europace 2017;19:1798– 803. https://doi.org/10.1093/europace/eux023; PMID: 28402529. Chen C-F, Zhong Y-G, Jin C-L, et al. Comparing between second-generation cryoballoon vs open-irrigated radiofrequency ablation in elderly patients: Acute and longterm outcomes. Clin Cardiol 2020;43:500–7.https://doi.org/ 10.1002/clc.23335; PMID: 31943264. Chierchia GB, Capulzini L, de Asmundis C, et al. Cryoballoon ablation for paroxysmal atrial fibrillation in septuagenarians: a prospective study. Indian Pacing Electrophysiol J 2010;10:393–9. PMID: 20930957. Heeger CH, Bellmann B, Fink T, et al. Efficacy and safety of cryoballoon ablation in the elderly: a multicenter study. Int J Cardiol 2019;278:108–13. https://doi.org/10.1016/j.ijcard. 2018.09.090; PMID: 30287056. Ikenouchi T, Nitta J, Nitta G, et al. Propensity-matched comparison of cryoballoon and radiofrequency ablation for atrial fibrillation in elderly patients. Heart Rhythm 2019;16:838– 5. https://doi.org/10.1016/j.hrthm.2018.12.019; PMID: 30576880. Kanda T, Masuda M, Kurata N, et al. Efficacy and safety of the cryoballoon-based atrial fibrillation ablation in patients aged ≥80 years. J Cardiovasc Electrophysiol 2019;30:2242–7. https:// doi.org/10.1111/jce.14166; PMID: 31507014. Pott A, Messemer M, Petscher K, et al. Clinical outcome of 2nd

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generation cryoballoon pulmonary vein isolation in patients over 75 years of age. J Cardiol 2017;69:24–9. https://doi. org/10.1016/j.jjcc.2016.07.020; PMID: 27650097. Tscholl V, Lin T, Lsharaf AKA, et al. Cryoballoon ablation in the elderly: one year outcome and safety of the secondgeneration 28mm cryoballoon in patients over 75 years old. Europace 2017;20:772–7. https://doi.org/10.1093/europace/ eux128; PMID: 29741689. Zhang J, Ren Z, Wang S, et al. Efficacy and safety of cryoballoon ablation for Chinese patients over 75 years old: a comparison with a younger cohort. J Cardiovasc Electrophysiol 2019;30:2734–42. https://doi.org/10.1111/jce.14220; PMID: 31588616. Kulkarni N, Su W, Wu R. How to prevent, detect and manage complications caused by cryoballoon ablation of atrial fibrillation. Arrhythm Electrophysiol Rev 2018;7:18–23. https://doi. org/10.15420/aer.2017.32.1; PMID: 29636968. Clarnette JA, Brooks AG, Mahajan R, et al. Outcomes of persistent and long-standing persistent atrial fibrillation ablation: a systematic review and meta-analysis. Europace 2018;20:f366–76. https://doi.org/10.1093/europace/eux297; PMID: 29267853. den Uijl DW, Delgado V, Bertini M, et al. Impact of left atrial fibrosis and left atrial size on the outcome of catheter ablation for atrial fibrillation. Heart 2011;97:1847–51. https://doi. org/10.1136/hrt.2010.215335; PMID: 21357370. Chao TF, Cheng CC, Lin WS, et al. Associations among the CHADS2 score, atrial substrate properties, and outcome of catheter ablation in patients with paroxysmal atrial fibrillation. Heart Rhythm 2011;8:1155–9. https://doi.org/10.1016/j. hrthm.2011.03.016; PMID: 21402172.

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When you check for gaps in pulmonary vein isolation, are you seeing them all?

Acute data collection that includes both direct and indirect comparisons of the Advisor™ HD Grid Mapping Catheter, Sensor Enabled™ (SE), in standard pulmonary vein isolation (PVI) confirmation workflows suggests that the Advisor HD Grid Mapping Catheter, SE, can identify gaps that may be missed by other technologies.

C I R C U L A R MA P P I N G C ATH ETER S 1 The incidence and location of gaps following PVI were tracked utilizing either a 10-pole circular mapping catheter (CMC10), a 20-pole circular mapping catheter (CMC20) or the Advisor™ HD Grid Mapping Catheter, SE.

C MC 10 n = 30

36.7%

O F PATI E NTS H AD G APS 1

I S O L AT I O N WA S T R A C K E D ACROSS 99 CASES

Advisor™ HD Grid Mapping Catheter, SE n = 33

CMC20 n = 36

0.9

G APS/ PATI E N T 1

38.9%

O F PAT I E N T S H A D GA P S 1

81.8%

1.44

GA P S/ PAT I E N T 1

O F PAT I E N T S H A D GAP S 1 2.15 GA P S/PAT I ENT 1

C R YOA B L AT I ON 2 In a direct comparison, 18 patients received cryoablation with isolation confirmed by the Achieve‡ Mapping Catheter. Isolation was then checked again with the Advisor HD Grid Mapping Catheter, SE, revealing:

4 patients with ≥ 1 gap missed by the Achieve‡ Mapping Catheter

12 total gaps missed by the Achieve Mapping Catheter were identified by the Advisor HD Grid Mapping Catheter, SE2 Septum

Posterior Wall

Right Pulmonary Veins

PAC I N G A B L AT I ON LINE 3 In a direct comparison, 22 patients received ablation with isolation confirmed by pacing the ablation line. Isolation was then checked again with the Advisor HD Grid Mapping Catheter, SE, revealing:

15 patients with ≥ 1 gap missed by pacing3

Left Pulmonary Veins

30 total gaps missed by pacing were identified by the Advisor HD Grid Mapping Catheter, SE3 Septum

Posterior Wall

Right Pulmonary Veins

Refer to adjacent page for Important Safety Information. MAT-2001478 v1.0 | Item approved for global use.

Anterior Wall

Left Pulmonary Veins

S E E T H I N G S D I F F E R E N T LY AT

Cardiovascular.Abbott/ClosetheGap

1. Porterfield C, et al. Comparison of Gap Identification Using Three Technologies for Confirmation of Pulmonary Vein Isolation. Originally scheduled for poster presentation at EHRA 2020 Congress. Abbott. Data on File: MAT2002108 v1.0. 2. Eldadah Z, et al. Incidence and Location of PVI Gaps Identified Post-Cryoballoon Ablation for Atrial Fibrillation. Originally scheduled for poster presentation at EHRA 2020 Congress. Abbott. Data on File: MAT-2002103 v1.0. 3. Giuggia M, et al. Incidence and Location of Residual Gaps Identified by a High-Density GridStyle Mapping Catheter After PVI Is Confirmed by Pacing the Ablation Lines. Originally scheduled for poster presentation at EHRA 2020 Congress. Abbott. Data on File: MAT2002112 v1.0. CAUTION: This product is intended for use by or under the direction of a physician. Prior to use, reference the Instructions for Use, inside the product carton (when available) or at manuals.sjm.com or eifu. abbottvascular.com for more detailed information on Indications, Contraindications, Warnings, Precautions and Adverse Events. United States — Required Safety Information Indications: The Advisor™ HD Grid Mapping Catheter, Sensor Enabled™, is indicated for multiple electrode electrophysiological mapping of cardiac structures in the heart, i.e., recording or stimulation only. This catheter is intended to obtain electrograms in the atrial and ventricular regions of the heart. Contraindications: The catheter is contraindicated

for patients with prosthetic valves and patients with left atrial thrombus or myxoma, or interatrial baffle or patch via transseptal approach. This device should not be used with patients with active systemic infections. The catheter is contraindicated in patients who cannot be anticoagulated or infused with heparinized saline. Warnings: Cardiac catheterization procedures present the potential for significant x-ray exposure, which can result in acute radiation injury as well as increased risk for somatic and genetic effects, to both patients and laboratory staff due to the x-ray beam intensity and duration of the fluoroscopic imaging. Careful consideration must therefore be given for the use of this catheter in pregnant women. Catheter entrapment within the heart or blood vessels is a possible complication of electrophysiology procedures. Vascular perforation or dissection is an inherent risk of any electrode placement. Careful catheter manipulation must be performed in order to avoid device component damage, thromboembolism, cerebrovascular accident, cardiac damage, perforation, pericardial effusion, or tamponade. Risks associated with electrical stimulation may include, but are not limited to, the induction of arrhythmias, such as atrial fibrillation (AF), ventricular tachycardia (VT) requiring cardioversion, and ventricular fibrillation (VF). Catheter materials are not compatible with magnetic resonance imaging (MRI). Precautions: Maintain an activated clotting time (ACT) of greater than 300 seconds at all times during use of the catheter. This includes when the catheter is used in the right side of the heart. To prevent entanglement with concomitantly used catheters, use care when using the catheter in the proximity

of the other catheters. Maintain constant irrigation to prevent coagulation on the distal paddle. Inspect irrigation tubing for obstructions, such as kinks and air bubbles. If irrigation is interrupted, remove the catheter from the patient and inspect the catheter. Ensure that the irrigation ports are patent and flush the catheter prior to re-insertion. Always straighten the catheter before insertion or withdrawal. Do not use if the catheter appears damaged, kinked, or if there is difficulty in deflecting the distal section to achieve the desired curve. Do not use if the catheter does not hold its curve and/or if any of the irrigation ports are blocked. Catheter advancement must be performed under fluoroscopic guidance to minimize the risk of cardiac damage, perforation, or tamponade. ™ Indicates a trademark of the Abbott group of companies. ‡ Indicates a third party trademark, which is property of its respective owner. © 2020 Abbott. All Rights Reserved. MAT-2001478 v1.0 | Item approved for global use.

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