AER 9.1 by Radcliffe Cardiology

Volume 9 • Issue 1 • Spring 2020

www.AERjournal.com

Mobile Health for Cardiovascular Disease: The New Frontier for AF Management: Observations from the Huawei Heart Study and mAFA-II Randomised Trial Yutao Guo and Gregory YH Lip

Electrophysiology’s Identity Crisis: What our Clinical Trials Do and Do Not Say About Us David J Callans, Matthew Reynolds and Peter J Zimetbaum

Defining Left Bundle Branch Block Patterns in Cardiac Resynchronisation Therapy: A Return to His Bundle Recordings Roderick Tung and Gaurav A Upadhyay

The Cryoballoon vs Irrigated Radiofrequency Catheter Ablation (CIRCA-DOSE) Study Results in Context Jason G Andrade, Marc W Deyell, Atul Verma, Laurent Macle and Paul Khairy; for the CIRCA-DOSE Study Investigators

Complete conduction block:

Theory of Longitu

Asynchronous cond

Intra-His or LB

AVN

Septum His

Left intrahisian block

AVN

Proximal LBBB LBBB LAF

LPF RBBB

Electrophysiologic Study in Transcatheter Aortic Valve Implantation

A Return to His Bundle Recordings

Complete Conduction Block Observed with Dedicated Electrophysiology Study of the Left Septum

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Volume 9 • Issue 1 • Spring 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

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, Indianapoli, IN

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use thereof. Published content is for information purposes only and is not a substitute for professional medical advice. Where views and opinions are expressed, they are those of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Cardiology. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS, UK © 2020 All rights reserved ISSN: 2050-3369 • eISSN: 2050–3377

Established: October 2012 | Frequency: Quarterly | Current issue: Spring 2020

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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.

The journal follows guidance from the International Committee of Medical Journal Editors and the Committee on Publication Ethics. We expect all parties involved in the journal’s publication to follow these guidelines. All authors must declare any conflicts of interest.

Structure and Format • Arrhythmia & Electrophysiology Review publishes review articles, expert opinion articles, guest editorials and letters to the editor. • The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Editorial Board.

Abstracting and Indexing Arrhythmia & Electrophysiology Review is abstracted, indexed and listed in PubMed, Crossref, Emerging Sources Citation Index, Scopus, Google Scholar and Directory of Open Access Journals. All articles are published in full on PubMed Central a month after publication. Radcliffe Group is an STM member publisher.

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Online All published manuscripts are free to read at www.AERjournal.com. They are also available at www.radcliffecardiology.com, along with articles from the other journals in Radcliffe Cardiology’s cardiovascular portfolio – Interventional Cardiology Review, Cardiac Failure Review, European Cardiology Review and US Cardiology Review.

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Contents

Foreword What Cannot Be Missed: Important Publications on Electrophysiology in 2019

Andrew Grace, Hugh Calkins, Ken Ellenbogen, Pier D Lambiase, Gregory YH Lip, Sanjiv M Narayan and Demosthenes G Katritsis DOI: https://doi.org/10.15420/aer.2020.06

Guest Editorial Mobile Health for Cardiovascular Disease: The New Frontier for AF Management: Observations from the Huawei Heart Study and mAFA-II Randomised Trial

Yutao Guo and Gregory YH Lip DOI: https://doi.org/10.15420/aer.2020.12

Electrophysiology & Ablation The Role of the Electrophysiologist in Convergent Ablation

Nadeev Wijesuriya, Nikos Papageorgiou, Edd Maclean, Bunny Saberwal and Syed Ahsan DOI: https://doi.org/10.15420/aer.2019.06

Electrophysiology’s Identity Crisis: What our Clinical Trials Do and Do Not Say About Us

David J Callans, Matthew Reynolds and Peter J Zimetbaum DOI: https://doi.org/10.15420/aer.2019.37.3

Drugs and Devices Use of Electrophysiological Studies in Transcatheter Aortic Valve Implantation

Irum D Kotadia, Steven E Williams and Mark O’Neill DOI: https://doi.org/10.15420/aer.2019.09

Cardiac Pacing Defining Left Bundle Branch Block Patterns in Cardiac Resynchronisation Therapy: A Return to His Bundle Recordings

Roderick Tung and Gaurav A Upadhyay DOI: https://doi.org/10.15420/aer.2019.12

Clinical Arrhythmias The Cryoballoon vs Irrigated Radiofrequency Catheter Ablation (CIRCA-DOSE) Study Results in Context

Jason G Andrade, Marc W Deyell, Atul Verma, Laurent Macle and Paul Khairy; for the CIRCA-DOSE Study Investigators DOI: https://doi.org/10.15420/aer.2019.13

Non-invasive Low-level Tragus Stimulation in Cardiovascular Diseases

Yunqiu Jiang, Sunny S Po, Faris Amil and Tarun W Dasari DOI: https://doi.org/10.15420/aer.2020.01

Foreword

What Cannot Be Missed: Important Publications on Electrophysiology in 2019 Andrew Grace,1 Hugh Calkins,2 Ken Ellenbogen,3 Pier D Lambiase,4 Gregory YH Lip,5 Sanjiv M Narayan6 and Demosthenes G Katritsis7 1. Royal Papworth and Addenbrooke’s Hospitals, Cambridge, UK; 2. Johns Hopkins Medical Institution, Baltimore, MD, US; 3. Virginia Commonwealth University School of Medicine, Richmond, VA, US; 4. Institute of Cardiovascular Science, University College London and Barts Heart Centre, London, UK; 5. Liverpool Centre for Cardiovascular Science, University of Liverpool, UK; 6. Stanford University Medical Center, CA, US; 7. Hygeia Hospital, Athens, Greece

Received: 14 February 2020 Accepted: 18 February 2020 Citation: Arrhythmia & Electrophysiology Review 2020;9(1):4. DOI: https://doi.org/10.15420/aer.2020.06 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.

Guidelines and Consensus Statements 1. Brugada J, Katritsis DG, Arbelo E, et al. 2019 ESC guidelines for the management of patients with supraventricular tachycardia. The Task Force for the management of patients with supraventricular tachycardia of the European Society of Cardiology (ESC). Eur Heart J 2020;41:655–720. https://doi.org/10.1093/eurheartj/ ehz467; PMID: 31504425. 2. Cronin EM, Bogun FM, Maury P, et al. 2019 HRS/EHRA/APHRS/LAHRS expert consensus statement on catheter ablation of ventricular arrhythmias Europace 2019;21:1143–4. https://doi.org/10.1093/ europace/euz132; PMID: 31075787. 3. Towbin JA, McKenna WJ, Abrams DJ, et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm 2019;16:e301–72. https://doi.org/10.1016/j.hrthm.2019.05.007; PMID: 31078652.

patients with atrial fibrillation: the CAPTAF randomized clinical trial. JAMA 2019;321:1059–68. https://doi.org/10.1001/jama.2018.15356; PMID: 30874754. 6. Cadrin-Tourigny J, Bosman LP, Nozza A, et al. A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy. Eur Heart J 2019;40:1850–8. https://doi.org/10.1093/ eurheartj/ehz103; PMID: 30915475. 7. Barra S, Duehmke R, Providencia R, et al. Very long-term survival and late sudden cardiac death in cardiac resynchronization therapy patients. Eur Heart J 2019;40:2121–7. https://doi.org/10.1093/ eurheartj/ehz238; PMID: 31046090. 8. Andrade JG, Champagne J, Dubuc M, et al. Cryoballoon or radiofrequency ablation for atrial fibrillation assessed by continuous monitoring: a randomized clinical trial. Circulation 2019;140:1779–88. https://doi.org/10.1007/s40278-019-71404-1; PMID: 31630538.

Important Clinical Trials

The Future?

1. Packer DL, Mark DB, Robb RA, et al. Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation, the CABANA randomized clinical trial. JAMA 2019;321:1261–74. https://doi. org/10.1001/jama.2019.0693; PMID: 30874766. 2. Katritsis DG, Zografos T, Siontis KC, et al. Endpoints for successful slow pathway catheter ablation in typical and atypical atrioventricular nodal re-entrant tachycardia: a contemporary, multicenter study. JACC Clin Electrophysiol 2019;5:113–9. https://doi.org/10.1016/j. jacep.2018.09.012; PMID: 30678775. 3. Kuck KH, Merkely B, Zahn R, et al. Catheter ablation versus best medical therapy in patients with persistent atrial fibrillation and congestive heart failure: the randomized AMICA trial. Circ Arrhythm Electrophysiol 2019;12:e007731. https://doi. org/10.1161/CIRCEP.119.007731; PMID: 31760819. 4. Siontis KC, Zhang X, Eckard A, et al. Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States. Circulation 2018;138:1519–29. https:// doi.org/10.1161/CIRCULATIONAHA.118.035418; PMID: 29954737. 5. Blomström-Lundqvist C, Gizurarson S, Schwieler J, et al. Effect of catheter ablation vs antiarrhythmic medication on quality of life in

1. Perez MV, Mahaffey KW, Hedlin H, et al. Large-scale assessment of a smartwatch to identify atrial fibrillation. N Engl J Med 2019;381:1909– 17. https://doi.org/10.1056/NEJMoa1901183; PMID: 31722151. 2. Guo Y, Wang H, Zhang H, et al. Mobile photoplethysmographic technology to detect atrial fibrillation. J Am Coll Cardiol 2019;74:23652375. https://doi.org/10.1016/j.jacc.2019.08.019; PMID: 31487545. 3. Willems S, Verma A, Betts T, et al. Targeting non-pulmonary vein sources in persistent atrial fibrillation identified by noncontact charge density mapping: the UNCOVER AF trial. Circ Arrhythm Electrophysiol 2019;12:e007233. https://doi.org/10.1161/ CIRCEP.119.007233; PMID: 31242746. 4. Reddy VY, Neuzil P, Koruth JS, et al. Pulsed field ablation for pulmonary vein isolation in atrial fibrillation. J Am Coll Cardiol 2019;74:315–26. https://doi.org/10.1016/j.jacc.2019.04.021; PMID: 31085321. 5. Honarbakhsh S, Hunter RJ, Ullah W, et al. Ablation in persistent atrial fibrillation using stochastic trajectory analysis of ranked signals (STAR) mapping method. JACC Clin Electrophysiol 2019;5:817–29. https://doi. org/10.1016/j.jacep.2019.04.007; PMID: 31320010. 6. Grace A, Willems S, Meyer C, et al. High-resolution noncontact chargedensity mapping of endocardial activation. JCI Insight 2019;4:e126422. https://doi.org/10.1172/jci.insight.126422; PMID: 30895945.

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Guest Editorial

Mobile Health for Cardiovascular Disease: The New Frontier for AF Management: Observations from the Huawei Heart Study and mAFA-II Randomised Trial Yutao Guo1 and Gregory YH Lip1,2,3 1. Medical School of Chinese PLA, Department of Cardiology, Chinese PLA General Hospital, Beijing, China; 2. Liverpool Centre for Cardiovascular Sciences, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, UK; 3. Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

Disclosures: The authors have no conflicts of interest to declare. Received: 27 March 2020 Accepted: 27 March 2020 Citation: Arrhythmia & Electrophysiology Review 2020;9(1):5–7. DOI: https://doi.org/10.15420/aer.2020.12 Correspondence: Gregory YH Lip, Liverpool Centre for Cardiovascular Science, William Henry Duncan Building, 6 West Derby St, Liverpool L7 8TX, UK. E: gregory.lip@liverpool.ac.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.

Cardiovascular disease (CVD) is the leading cause of death and disease globally, representing 31% of all global deaths.1 The traditional management of CVD has largely depended on the face-to-face clinic visits once the clinical events occurred. CVD contributes to and exacerbates the economic burden on households.2 However, most of these complications could be avoided with early diagnosis and effective prevention or interventions.

• ‘B’ Better symptom management with patient-centred symptomdirected shared decisions for rate or rhythm control. • ‘C’ Cardiovascular risk and comorbidity management (blood pressure, sleep apnoea etc) plus lifestyle changes (weight reduction, regular exercise, reducing alcohol/stimulants, psychological morbidity, smoking cessation etc).6,7

AF Screening Using Smart Technology With increasing advances in mobile health (mHealth), smart technology is emerging as a novel tool to improve disease prevention and management. Some exploring studies demonstrated that the alerts or text message intervention using mHealth technology might help patients in implementing changes in lifestyle behaviours or drug adherence.3 However, there are many gaps in knowledge when considering mHealth for CVD management.3,4 For example, how could wearable sensors (mobile devices) be used to improve healthcare, beside using the communication function (mobile phone) of mHealth technologies? Would mHealth-supported approaches impact on important CVD outcomes, including hospitalisations? The Mobile Health technology for improved screening and optimising integrated care in Atrial Fibrillation (the mAFA-II programme) provides some new evidence for this.5 The mAFA II programme included the pre-mAFA phase to investigate the incidence of AF with photoplethysmography (PPG)-based screening strategy among the general population, using Huawei smart devices (hence, called the Huawei Heart Study); and the AFA II trial, which was used to validate a holistic or integrated care approach, the Atrial Fibrillation Better Care pathway (ABC) pathway, supported by mHealth technology for the management of AF. The ABC (AF Better Care) Pathway simplifies the management of AF, as follows (‘easy as ABC…’): • ‘A’ Anticoagulation to avoid stroke – anticoagulation with nonvitamin K antagonist oral anticoagulant or well-managed warfarin.

The predictive ability of AF screening using smart technology would be influenced by several factors: monitoring technology PPG, single-lead ECG, the frequency of monitoring (single-point or twice a day etc), monitoring duration (7 days, 14 days etc), the type of smart devices (smart bands, ePatch or hand-held devices) and the patient population with different risk profiles. For a single-lead ECG-based approach to detect AF detection, there could also be the instability of signal quality of the wristband due to motion artefacts.8,9 A lower AF burden requires a longer monitoring time. Two large population-based smartwear studies have been published. In the Apple Heart Study: Assessment of Wristwatch-Based Photoplethysmography to Identify Cardiac Arrhythmias; (NCT03335800), 419,297 participants using Apple Watch were recruited over 8 months, and 0.52% received notifications of irregular pulse: AF was present in 34% and 84% of notifications were concordant with AF.10 In the Huawei Heart Study, a PPG algorithm and smart devices used were validated with a total of 29,485 PPG signals before starting the mAFA II programme.11,12 Both the pilot study and the Huawei Heart Study demonstrated a consistent predictive ability for AF of >91% with continuous monitoring mode in a real-world setting.12,13 In the study, about one-third of AF episodes were detected over 14 days. However, the comfort factor of monitoring should be balanced with the monitoring time and type of smart device(s) used. Nearly one-third of subjects refused to use the ECG skin adhesive patch for 14-day monitoring, and some individuals reported skin irritation, resulting in early discontinuation of structured management in one study.14 Even with a PPG technology-based wristband, more frequent monitoring

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Guest Editorial might contribute to much higher predictive ability. For example, the positive predictive value of detecting AF was 91.6% in the Huawei Heart Study with periodic measurements every 10 minutes on baseline, compared with 71.3% in the Apple Heart Study with periodic measurements every 2 hours.13,15 In the Huawei Heart Study, there were 0.23% of subjects with suspected AF using smart devices in the general population, with the highest proportion of AF episodes among the elderly, i.e. those aged over 65 years, with a prevalence of 2.78%.13 This leads to more questions, for example, whether AF screening should be a population-wide approach, with associated logistic and cost issues, or should be targeted screening of patients at high risk of developing AF or those where greater efforts should be directed towards AF detection (for example, post stroke). Not only did the Huawei Heart Study demonstrate that AF screening with wearable devices was feasible, but also that the detected patients could be entered into an integrated care AF pathway to facilitate AF management. Thus, 95% of those with identified AF from the general population entered into ABC pathway management using a mobile Atrial Fibrillation Application (mAFA), and consequently 80% of high-risk patients were anticoagulated.13

mHealth-supported AF Integrated Care and CVD Outcomes Subjects with identified AF were considered for entry into the mAFA-II clinical trial. The mAFA-II programme included an investigation of mHealth-supported AF management, and its impact on the composite of stroke/thromboembolism, all-cause death and rehospitalisation.5 Using a prospective cluster randomised trial design, the mAFA-II trial randomised AF patients to a mAFA intervention arm and usual care arm. In the mAFA intervention group, doctors used the mAFA platform to manage AF patients, providing clinical decision support tools, educational materials and patient involvement strategies with self-care protocols and structured follow-up to support implementation of the ABC pathway for AF patients.7,16 The trial showed that an integrated care approach with mAFA intervention (easy as ABC… ), supported by mobile health technology, significantly reduced the risks of rehospitalisation and the composite of stroke/thromboembolism, allcause death and rehospitalisation care (1.9% versus usual care, 6.0%; HR 0.39; 95% CI [0.22–0.67]; p<0.001).17 Rates of rehospitalisation were also lower with the mAFA intervention (1.2% versus 4.5%; HR 0.32; 95% CI [0.17–0.60]; p<0.001). The mAFA programme is the first integrated programme that links AF screening with eligible patients subsequently entered into a structured

1. W HO. Cardiovascular diseases (CVDs). Key facts. 2017. https://www.who.int/news-room/fact-sheets/detail/ cardiovascular-diseases-(cvds) (accessed 3 April 2020). 2. Murphy A, Palafox B, Walli-Attaei M, et al. The household economic burden of non-communicable diseases in 18 countries. BMJ Glob Health 2020;5:e002040. https://doi. org/10.1136/bmjgh-2019-002040; PMID: 32133191. 3. Burke LE, Ma J, Azar KM, et al. Current science on consumer use of mobile health for cardiovascular disease prevention: a scientific statement from the American Heart Association. Circulation 2015;132:1157–213. https://doi.org/10.1161/ CIR.0000000000000232; PMID: 26271892. 4. Cowie MR, Bax J, Bruining N, et al. e-Health: a position statement of the European Society of Cardiology. Eur Heart J 2016;37:63–6. https://doi.org/10.1093/eurheartj/ehv416; PMID: 26303835. 5. Guo Y, Lane DA, Wang L, et al. Mobile Health (mHealth) technology for improved screening, patient involvement and optimising integrated care in atrial fibrillation: the mAFA (mAF-

care pathway with mHealth technologies, highlighting the potential application of mHealth bridging primary care to secondary care management, as well as patient empowerment.

Integrated Care for CVD: The New Frontier Other integrated care approaches for AF management have included nurse-led integrated care, a post-discharge integrated care of home visits and 7- to 14-day Holter monitoring and AF care focused on optimising anticoagulation with trained nurses in primary care.18–20 There are growing challenges and opportunities on how best to apply mHealth technology into CVD prevention and management, for example how these novel technologies could be used to improve the quality of care without driving up costs and how mHealth technology could be applied into special populations, for example, in the management of the elderly, those with multimorbidity etc. Indeed, we need to know the advantages of smart technology in streamlining clinical management pathways, not only through better real-time communications but also with data-driven intelligent management. We have no doubt that current smart devices will increasingly improve their specifications over time, providing better-quality signals and diagnostics, long battery life and improved capability for clinical settings. These would need to be balanced against management of comorbidities, costs and clinical setting. Using PPG-based heart rate and physical activity levels, artificial intelligence and machine learning can potentially be explored to diagnose AF without recoring and documenting an ECG.21 Although there are some limitations (positive predictive value for AF episodes of 39.9%, detected AF ≥1 hour etc) in the current stage, this study highlights the potential use of artificial intelligence and smart devices in predicting the risk for subsequent AF. Nevertheless, decision-making on holistic clinical care cannot be based on only what a smart device says. Physician-patient interactions remain central to optimal clinical management, hence our challenge is to streamline the patient pathway that bridges primary and secondary care, cardiologists and non-cardiologists, and – of course – the patient. In the case of AF, patients would present to general practitioners (often asymptomatically in the setting of a health check), hospital practitioners who may be non-cardiologists (emergency room, internal medicine, stroke wards, surgeons) and cardiologists (who may or may not be arrhythmia specialists). Ultimately, the patient may get different messages on their management from all these healthcare professionals they encounter, given the perception that AF management is difficult and complex. Using the ABC pathway above, AF management can be as ‘easy as ABC…’ and, even more so, supplemented by mHealth technology.

App) II randomised trial. Int J Clin Pract 2019;73:e13352. https:// doi.org/10.1111/ijcp.13352; PMID: 31002434. 6. Lip GYH. The ABC pathway: an integrated approach to improve AF management. Nat Rev Cardiol 2017;14:627–8. https://doi. org/10.1038/nrcardio.2017.153; PMID: 28960189. 7. Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report. Chest 2018;154:1121–201. https://doi.org/10.1016/j. chest.2018.07.040; PMID: 30144419. 8. Bumgarner JM, Lambert CT, Hussein AA, et al. Smartwatch algorithm for automated detection of atrial fibrillation. J Am Coll Cardiol 2018;71:2381–8. https://doi.org/10.1016/j. jacc.2018.03.003; PMID: 29535065. 9. Tison GH, Sanchez JM, Ballinger B, et al. Passive detection of atrial fibrillation using a commercially available smartwatch. JAMA Cardiol 2018;3:409–16. https://doi.org/10.1001/ jamacardio.2018.0136; PMID: 29562087. 10. Perez MV, Mahaffey KW, Hedlin H, et al. Large-scale assessment of a smartwatch to identify atrial fibrillation.

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13.

14.

N Engl J Med 2019;381:1909–17. https://doi.org/10.1056/ NEJMoa1901183; PMID: 31722151. Fan YY, Li YG, Li J, et al. Diagnostic performance of a smart device with photoplethysmography technology for atrial fibrillation detection: pilot study (Pre-mAFA II Registry). JMIR Mhealth Uhealth 2019;7:e11437. https://doi.org/10.2196/11437; PMID: 30835243. Zhang H, Zhang J, Li HB, et al. Validation of single centre premobile atrial fibrillation apps for continuous monitoring of atrial fibrillation in a real-world setting: pilot cohort study. J Med Internet Res 2019;21:e14909. https://doi.org/10.2196/14909; PMID: 31793887. Guo Y, Wang H, Zhang H et al. Mobile photoplethysmographic technology to detect atrial fibrillation. J Am Coll Cardiol 2019;74:2365–75. https://doi.org/10.1016/j.jacc.2019.08.019; PMID: 31487545. Steinhubl SR, Waalen J, Edwards AM, et al. Effect of a homebased wearable continuous ECG monitoring patch on detection of undiagnosed atrial fibrillation: the mSToPS

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Mobile Health for Cardiovascular Disease randomized clinical trial. JAMA 2018;320:146–55. https://doi. org/10.1001/jama.2018.8102; PMID: 29998336. 15. Perez MV, Mahaffey KW, Hedlin H, et al. Large-scale assessment of a smartwatch to identify atrial fibrillation. N Engl J Med 2019;381:1909–17. https://doi.org/10.1056/NEJMoa1901183; PMID: 31722151. 16. Proietti M, Laroche C, Opolski G, et al. ‘Real-world’ atrial fibrillation management in Europe: observations from the 2-year follow-up of the EURObservational Research Programme-Atrial Fibrillation General Registry Pilot Phase. Europace 2017;19:722–33. https://doi.org/10.1093/europace/ euw112; PMID: 27194538.

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17. Guo Y, Lane DA, Wang L, et al. Mobile health technology to improve care for patients with atrial fibrillation. J Am Coll Cardiol 2020;75:1523–34. https://doi.org/10.1016/j.jacc.2020.01.052. 18. Hendriks JM, de Wit R, Crijns HJ, et al. Nurse-led care vs. usual care for patients with atrial fibrillation: results of a randomized trial of integrated chronic care vs. routine clinical care in ambulatory patients with atrial fibrillation. Eur Heart J 2012;33:2692–9. https://doi.org/10.1093/eurheartj/ehs071; PMID: 22453654. 19. Stewart S, Ball J, Horowitz JD, et al. Standard versus atrial fibrillation-specific management strategy (SAFETY) to reduce recurrent admission and prolong survival:

pragmatic, multicentre, randomised controlled trial. Lancet 2015;385:775–84. https://doi.org/110.1016/S01406736(14)61992-9; PMID: 25467562. 20. van den Dries CJ, van Doorn S, Rutten FH, et al. Integrated management of atrial fibrillation in primary care: results of the ALL-IN cluster randomized trial. Eur Heart J 2020;ehaa055. https://doi.org/10.1093/eurheartj/ehaa055; PMID: 32112556; epub ahead of press. 21. Wasserlauf J, You C, Patel R, et al. Smartwatch performance for the detection and quantification of atrial fibrillation. Circ Arrhythm Electrophysiol 2019;12:e006834. https://doi. org/10.1161/CIRCEP.118.006834; PMID: 31113234.

Electrophysiology and Ablation

The Role of the Electrophysiologist in Convergent Ablation Nadeev Wijesuriya, Nikos Papageorgiou, Edd Maclean, Bunny Saberwal and Syed Ahsan Barts Heart Centre, St Bartholomew’s Hospital, London, UK

Abstract Catheter ablation is a well-established treatment for patients with AF in whom sinus rhythm is desired. Both radiofrequency catheter ablation and cryoablation are widely performed, rapidly developing techniques. Convergent ablation is a novel hybrid technique combining an endocardial radiofrequency ablation with a minimally invasive epicardial surgical ablation. Some suggest that hybrid ablation may be more effective than lone endocardial ablation in achieving the elusive goal of maintaining sinus rhythm in patients with non-paroxysmal AF. In this article, the authors examine the safety and efficacy of catheter ablation and convergent ablation for long-standing, persistent AF. We also outline the crucial role that electrophysiologists play, not only as a procedure operator, but also as the coordinator and developer of this multidisciplinary service.

Keywords AF, convergent procedure, ablation, hybrid, multidisciplinary, surgery Disclosure: The authors have no conflicts of interest to declare. Received: 29 July 2019 Accepted: 13 January 2020 Citation: Arrhythmia & Electrophysiology Review 2020;9(1):8–14. DOI: https://doi.org/10.15420/aer.2019.06 Correspondence: Syed Ahsan, Barts Heart Centre, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, UK. E: syedahsan@nhs.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 arrhythmia and about 10% of the general population above the age of 65 years are affected by this condition.1 The mortality and morbidity of AF is well established, with a higher risk of stroke and heart failure in older patients with comorbidities.2 The pathophysiology of AF is complex and variable, making its management extremely challenging. Epidemiological studies have identified a vast array of risk factors that account for its high prevalence and the difficult implementation of primary prevention measures.3–7 Electrophysiological mapping studies over several decades have also provided us with invaluable insights. The seminal finding of spontaneous initiation of arrhythmia by ectopic focal activity in the pulmonary veins revolutionised treatment of AF; however, it is clear from recent studies that the electrophysiological substrates involved are far more heterogeneous.8 Conventional treatment for AF has focused on rate and rhythm control using anti-arrhythmic drugs (AADs), as well as anticoagulation therapy based on individual risk profile.9 Treatment can be challenging when using medical therapy alone due to a lack of atrial specific agents, modest efficacy and significant toxicities of AADs. Catheter ablation of AF is a well-established treatment for patients in which sinus rhythm is desired, such as those with refractory symptoms despite maximal medical therapy, heart failure secondary to AF and intolerance to AADs. Radiofrequency catheter ablation (RFA) of the pulmonary veins was the first and most widely performed ablation procedure and cryoablation is a newer and rapidly progressing technique which has resulted in shorter procedure times and reduced treatment costs.10 Safety and success rates of catheter ablation have improved. However, although outcomes are generally regarded as good in cases of

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paroxysmal AF (PAF defined by <7 days of continuous AF) and, in recent times, persistent AF (Pe-AF defined as >7 days AF but continuous duration <1 year), there remains a need for a more robust procedure for patients with long-standing persistent AF (LS Pe-AF defined as continuous AF >1 year).11 Convergent ablation – also known as the convergent procedure – is a hybrid technique combining an endocardial RF ablation procedure with minimally invasive epicardial surgical ablation of the posterior left atrial (LA) wall. This procedure targets the posterior wall of the LA, an area difficult to ablate effectively using a catheter-based approach. Studies have shown that in patients with longer AF durations, atrial stretch leads to structural and electrical atrial remodelling and development of vulnerable atrial substrate, particularly in the posterior LA.12 The rationale behind the convergent procedure is to target this substrate in combination with conventional endocardial pulmonary vein isolation. Significant interest in hybrid ablation began about 10 years ago. Although there have been no randomised clinical trials, several observational studies, largely from single centres, have been published describing the results of this relatively new strategy as a feasible and effective treatment approach. Some suggest that hybrid ablation may be more effective than lone endocardial ablation in achieving the highly elusive goal of maintaining sinus rhythm in patients with nonparoxysmal AF. In this article, we will review the safety and efficacy of the hybrid approach, as well as the role of the electrophysiologist in convergent ablation.

Electrophysiologist in Convergent Ablation Pathophysiology of AF Initiation and progression of AF requires vulnerable atrial substrate, with the formation of this substrate dependant upon a host of both modifiable and non-modifiable risk factors. Population-based studies have revealed increasing age, diabetes, hypertension, valvular heart disease, obesity and obstructive sleep apnoea as risk factors contributing to AF.7 The primary pathological change induced by these various diseases appears to be a final common pathway of atrial cardiomyopathy, a complex of structural, architectural, contractile and electrophysiological changes, characterised mainly by atrial dilatation and fibrosis.13 The electrophysiological mechanisms underpinning the initiation and maintenance of AF are still subject to ongoing debate. Seminal research by Haïssaguerre et al. in 1998, reported focal ectopic firing arising from the myocardial sleeves in the pulmonary veins in patients with paroxysmal AF, with ablation of these foci reducing the arrhythmia burden.8 Membrane instability due to abnormal calcium handling, complex fibre architecture and re-entry mechanisms all contribute to this abnormal ectopic activity.14 Where pulmonary vein firing has been identified as the trigger for initiation of AF, in recent years the importance of vulnerable atrial substrate and re-entry has been identified.15 Re-entry is stabilised by anatomical and electrophysiological atrial abnormalities, promoting maintenance of arrhythmia, particularly in patients with nonparoxysmal AF. There are three dominant hypotheses regarding the mechanism of the maintenance of AF: multiple independent wavelets, re-entrant rotors and the double-layer hypothesis. The multiple wavelet hypothesis was first described by Moe et al. in 1959, who postulated that the disorganised activity of AF may be due to the random propagation of multiple independent wavelets in a medium of dispersed refractoriness.16 Experimental evidence for this was provided by Allesie et al. in a dog model of AF, where several independent wavelets propagated through both atria.17 This theory was the basis of the surgical maze procedure, where the atria are compartmentalised to prevent propagation of wavelets.18 In recent years, the presence of stable spiral areas of functional reentry within the atria of patients in AF, known as ‘rotors’, have been reported. The conventional ablation for AF with or without focal impulse and Rotor Modulation (CONFIRM) trial provided clinical evidence for this theory in 2012, when it reported that rotors were mapped in 97% of 101 patients with sustained AF, and that ablation of these rotors (focal impulse and rotor modulation – FIRM) improved outcomes of AF ablation.19 However, these results have not been consistently replicated in other mapping studies.20 It is postulated that due to the low resolution of the 64-pole basket mapping catheters used in the CONFIRM study, the visualised rotor activity may have been either artefactual, or represented other forms of re-entry. In addition, the CONFIRM trial mapped patients with pacing-induced AF, which may be mechanistically different from chronic AF. In contrast to the above hypothesis, Allessie et al. demonstrated no evidence of rotor activity with simultaneous high-density endoepicardial mapping of patients with AF undergoing cardiac surgery.20 Fibrillation maps showed complex and continuously changing activation patterns by a large number of narrow fibrillation waves, separated by lines of longitudinal conduction block. They postulated that instead of AF being maintained by stable sources such as rotors,

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AF is perpetuated by two electrically dissociated layers of narrow wavelets which ‘feed’ each other via constant endo-epicardial breakthrough. The frequency of this breakthrough was seen to be four times higher in subjects with long-standing persistent AF compared with those with acute AF, possibly explaining the poor outcomes for conventional endocardial catheter ablation in this group of patients. Therefore, it is evident that the pathophysiology of AF is highly complex and not yet fully understood. This makes its management extremely challenging.

Catheter Ablation With AF being such an electrophysiologically heterogeneous entity, it is no wonder that strategies for ablation are continually developing as the search continues for optimal treatments, especially for patients with LS Pe-AF. Catheter ablation for AF was first described in 1994, and these procedures included ablation of right atrial triggering mechanisms, creation of right atrial linear lesions and attempting to recreate a surgical maze of lesions.21,22 However, these methods had limited success. The seminal finding of pulmonary vein trigger sites led to the contemporary era of pulmonary vein isolation (PVI) for AF.8 The field of PVI is constantly developing. The most widely performed procedure is RF wide antral circumferential ablation. 23 With advancements in catheter technologies, including the use of second-generation irrigated catheters and contact-force sensing catheters, the success rates of RF ablation in PAF has been reported to be about 75.7% (162 of 214 patients). 24 In recent years, the advent of cryoballoon technology has shown promise with a view to reducing procedural time. The FIRE AND ICE: Comparative study of two ablation procedures in patients with atrial fibrillation randomised control trial reported that cryoballoon ablation was non-inferior to RF ablation with respect to efficacy in treatment of patients with drug-refractory AF, with no significant difference between the methods with regards to overall safety. 25 While success rates are generally regarded as good for PAF and Pe-AF, this is not the case in the population of patients who have been in continuous AF for more than 1 year, defined as LS Pe-AF (Table 1). Data from the Hamburg Sequential Ablation Strategy reported that during 5-year follow-up of 202 patients who underwent a sequential ablation strategy for symptomatic LS Pe-AF, the single procedure success rate was 20%, rising to 45% with multiple procedures.26 Much effort has been invested in non-PVI forms of ablation, such as alternative trigger ablation and substrate modification. Reports of higher level of vulnerable atrial substrate in patients with LS Pe-AF has led researchers to hypothesise that extensive atrial ablation is superior to PVI alone for this population.27 Studies have shown that linear atrial ablation lines have improved arrhythmia-free survival in patients with Pe-AF, without increased complications.28 There has also been a great deal of interest in ablation of complex fractionated electrograms (CFAE), postulated to be areas of continuous re-entry of fibrillation waves into the same area, or overlapping of different wavelets entering the same area at different times. Nadamanee et al.. reported a 91% arrhythmia-free survival rate in a cohort of 121 patients with either PAF or Pe-AF undergoing CFAE ablation without PVI.29 However, the results from these smaller studies were not reproduced in the Substrate and Trigger Ablation for Reduction in AF Trial II (STAR AF II).30

Electrophysiology and Ablation Table 1: Efficacy and Safety of Catheter Ablation for Persistent AF Randomised Controlled Trials

Intervention

Patients

Efficacy

Follow-up

Complications

Oral et al. 200635

Extensive ablation

74%

Remote transmission

Extensive ablation

70%

Holter

6.1%

Extensive ablation

589

59%

Holter

5.9%

Extensive ablation

146

67%

Holter

6.1%

Scherr et al. 201538

Extensive ablation

150

65%

Holter

4.4%

Schreiber et al. 201539

Extensive ablation

549

56%

Holter

4.9%

Yubing et al. 201840

Extensive ablation

40%

Holter

5.8% 4.7%

Mont et al. 201436 Verma et al. 2015

Dong et al. 201537

Observational studies

Mixed strategies

202

24%

Holter

Kanagaratnam et al. 200141

PVI

21%

Holter/Reveal

5.6%

Pappone et al. 200142

PVI + AAD

68%

Holter

0.8%

Tilz et al. 2012

AAD = anti-arrhythmic drugs; PVI = pulmonary vein isolation.

This multicentre randomised clinical trial assigned patients in a 1:4:4 ratio to: PVI alone; PVI plus CFAE ablation; and PVI plus linear ablation of the LA. There was no reduction in the rate of recurrence of AF when either CFAE ablation or linear ablation was added to PVI. The procedure time and serious complication rate was higher in the two groups undergoing more extensive ablation. Catheter-based posterior wall isolation (PWI) has also been examined extensively. A non-randomised study by Aryana et al. demonstrated superiority of PVI plus PWI compared with lone PVI using a combination of cryoballoon and RFA in patients with Pe-AF.31 A systematic review of 17 studies by Thiyagarajah et al. demonstrated good outcomes for catheter-based PWI with a 12-month freedom from AF of 61.9%.32 However, randomised controlled trials comparing PWI with PVI (three studies; n=444) yielded conflicting results and could not confirm an incremental benefit to PWI. It remains unclear why there is a lack of benefit from additional ablation. One explanation is that there is significant intra-procedural heterogeneity between studies and centres when performing extensive ablation, based on operator experience. Catheter-based technology, while advancing rapidly, is still an imperfect tool to create continuous linear ablation lines, and this deficiency can leave pro-arrhythmic gaps which manifest clinically as recurrent atrial tachycardias.33 In addition, the concern of damaging the phrenic nerve, lungs or oesophagus hamper the ability to create transmural lesions with endocardial ablation, especially on the posterior wall of the LA.34 Many believe that a more robust, reproducible method of ablation will be required to treat this difficult group of patients with LS-Pe AF.

Convergent Ablation In recent years, convergent ablation – a hybrid endocardial and epicardial ablation approach – has emerged as a novel approach to treating LS-Pe AF.43 Surgical AF ablation was first described in 1987. The Cox-maze procedure involved creating linear incisions in the atrial walls which created a block against propagating wavelets and macro re-entrant circuits.44 While the procedure was efficacious, it resulted in high rates of chronotropic incompetence and pacemaker implantation. The procedure was updated to the maze II and then the maze III procedure, which used modified incisions in an attempt to maintain sinus node function. The most modern iteration, the Cox-maze IV, uses ablation rather than surgical incisions. The procedural complexity of the

maze procedures, as well as the need for median sternotomy and cardiopulmonary bypass means that it has been superseded by catheter ablation. However, it did have the advantages of creating continuous linear transmural lesions under direct vision, with reduced risk of damaging abutting organs. In recent years, studies have been conducted into the totally thoracoscopic maze procedure (TT-maze), which involves bilateral video-assisted thoracoscopic (VATS) access, and uses RF ablation to perform pulmonary vein isolation and an LA posterior box lesion.45 This procedure has shown promise but it is lengthy, extremely technically challenging and requires bilateral lung deflation. The convergent procedure was developed as a multidisciplinary twostage approach to AF ablation, involving both cardiac electro physiologists and cardiac surgical teams. The first procedure involves closed-chest access via a trans-diaphragmatic pericardial window, followed by epicardial ablation of the posterior LA. The transdiaphragmatic approach has since been abandoned in favour of a subxiphoid approach. This ablation electrically silences the posterior LA, aiming to interrupt all known AF substrates. This is followed by an endocardial catheter ablation, either at the same sitting or at a later date. During this procedure, electrical pulmonary vein isolation is confirmed, the results of the posterior wall ablation are checked and fine-tuned if necessary. The lesion set is completed by performing endocardial ablation of structures which cannot be accessed epicardially due to pericardial reflections. As yet, no data from randomised controlled trials have been published comparing convergent procedure with standard catheter ablation. Data has come from observational studies (Table 2) and meta-analyses. A multicentre study by Gersak et al. followed up 50 consecutive patients, 70% with LS Pe-AF, undergoing convergent ablation.46 It showed that 81% of the patients had less than 3% AF burden at 12 months. There was a 4% mortality in this study as two patients had fatal atriooesophageal fistulas. A study by Zembala et al. (n=90; LS Pe-AF=51) revealed similar results, with 86% of patients followed up at one year remaining in sinus rhythm and 62% being off AADs.47 This group reported three serious complications (death of unknown cause, major surgical bleeding and tamponade) in the first 27 patients, and one in the remaining 63. The

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Electrophysiologist in Convergent Ablation Table 2: Efficacy and Safety of Convergent Ablation Study

Single or Staged Setting

Patients

Efficacy

Follow-up

Complications

Kiser et al. 201160

Single setting

83%

Holter/Reveal

7.6%

Civello et al. 201361

Single setting

104

87.5%

Holter

5.7%

Gilligan et al. 201362

Single setting

95%

Holter/ECG

19%

Gehi et al. 201343

Single setting

101

70.5%

Holter

6.9%

Staged and single setting

85%

Reveal

11.8%

Staged and single setting

84.1%

Holter

8.8%

Convergent

19%

Holter

17%

Gersak et al. 2012

Zembala et al. 2017

Edgerton et al. 201664

overall serious adverse event rate was 4.5%. Luo et al. performed a meta-analysis of six observational studies examining the convergent procedure (n=478), which reported sinus rhythm maintenance at 12Â months to be 84%, but this reduced to 60.2% after two studies were trimmed according to the trim-and-fill method.48 This reported a serious complication rate of 9% and a mortality rate of 1.7%. Recent meta-analyses have also been carried out assessing the efficacy and safety of hybrid ablation with mixed results.49,50 However, these studies used the previously non-standardised definition of hybrid ablation and included patients undergoing thoracoscopic epicardial ablation. As such, the results from using convergent ablation alone cannot be extrapolated from such meta-analyses. This non-standardised definition of hybrid ablation is a limitation of existing literature outcomes. It is evident that there is considerable variability in reported efficacy and safety outcomes of convergent ablation. This probably represents the heterogeneity of interventions being analysed in observational studies.51 There has been an evolution of the surgical technique to a sub-xiphoid approach rather than trans-diaphragmatic, as well as improvements in surgical ablation equipment. This explains higher initial complication rates to some degree. Outcomes of patients undergoing convergent ablation in a single setting and a staged setting tend to be grouped together for analysis and as yet there is no clear evidence of superiority for either method compared with the other. The advantage to a singlesetting procedure is a single hospital visit and immediate endocardial mapping to confirm integrity of epicardial lesions. The caveat to this is that peri-myocyte oedema following epicardial ablation can hinder endocardial electrophysiological assessment.52 A formal comparison between the two methods will need to be undertaken to elucidate any differences in performance. The heterogeneity of existing data means that the jury is still out on convergent ablation. Randomised controlled trials with reproducible methodology and clear efficacy endpoints are needed to examine whether the procedure is superior to catheter ablation in certain patient groups. The Epi/Endo Ablation for Treatment of Persistent AF (CONVERGE; NCT01984346) trial has finished recruitment, and will hopefully answer some of these questions. The next stage in the evolution of convergent ablation may be electrical isolation of the left atrial appendage (LAA) as an adjunctive procedure, as this structure has been implicated in refractory AF.53 Potential benefits of catheter ablation of the LAA have been demonstrated, but this procedure is time-consuming and not widely performed.54 There is also ongoing concern regarding increased stroke risk caused by electromechanical

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dissociation of the post-ablation LAA leading to stasis.55 Surgical LAA exclusion or ligation at the time of open heart surgery has been in practice for several decades and retrospective studies have suggested this reduces stroke risk in patients with AF.56 Other established methods of LAA closure for stroke prevention include the Watchman (Boston Scientific) and Lariat (Willis-Knighton) devices, but a complete examination of this subject is beyond the scope of this review. There has been interest in combining the convergent procedure with a thoracoscopically delivered epicardial closure device known as the Atriclip (AtriCure). Data on this combined procedure is limited to case series.57 Outcomes from using the Atriclip combined with open heart surgery or thoracoscopic ablation have been promising. A systematic review of 922 patients reported a rate of ischaemic stroke at between 0.2â&#x20AC;&#x201C;1.5 per 100 patient years, significantly less than the predicted rate in this cohort of 2.9 per 100 patient years.58 There is a paucity of evidence assessing the effect of Atriclip on longterm arrhythmia burden. However, in a case series of patients undergoing coronary artery bypass grafting (CABG), Atriclip has been shown to provide immediate electrical LAA isolation confirmed with bidirectional block during pacing manoeuvres.59 Given the potential complications of combining Atriclip with convergent ablation, including exposing patients to single-lung ventilation in a procedure that would otherwise not require this, it is crucial that clinical trials are performed to examine its additional efficacy benefit before recommending this as standard practice.

The Role of the Electrophysiologist in Convergent Ablation Convergent ablation is a truly multidisciplinary approach to the treatment of AF. The AF heart team consists of an electrophysiologist, cardiac surgeons, specialist nurses and physiologists. The electrophysiologist is the central coordinator of this process, as they are the professional with the most experience and knowledge at managing this complex arrhythmia. Electrophysiologists play a crucial role, not only in performing the endocardial stage of the procedure, but somewhat more importantly in: establishing the service; developing safe and effective pathways and protocols; and patient selection.

Catheter Ablation and Convergent Ablation The addition of catheter ablation to epicardial ablation transforms an anatomical procedure into an electrophysiological one. When performing a staged endocardial mapping and ablation, the electrophysiologist is able to check for the electrical isolation provided

Electrophysiology and Ablation Figure 1: The Hub and Spoke Model of AF Services in the UK Secondary care: inpatient admission

Primary care: GP

Secondary care: medical/ stroke clinic/pacing clinic

Diagnosis of AF

Pharmacy screening

Electrophysiology consultant in district general hospital/ tertiary centre

General cardiology clinic: district general hospital

Standardised referral criteria to be developed

Multidisciplinary AF heart team Tertiary centre: electrophysiologist, cardiac surgeon, anaesthetist Feedback

Surgical ablation

Hybrid ablation

Catheter ablation

by the surgical lesion set, and ‘fill in the gaps’ where required, including in areas that are epicardially inaccessible beneath pericardial reflections.64 The majority of these procedures are being performed with RF ablation, however some centres are now performing cryoballoon ablation – the so-called ‘cryoconvergent’ procedure.65 Theoretically this hybrid approach has the benefits of a more robust lesion set, however there are still concerns about whether the added benefit of the catheter ablation outweighs the exposure to periprocedural complications. A recent meta-analysis reported that isolated epicardial ablation was equally efficacious to hybrid ablation (either convergent or thoracoscopic) in providing freedom from AF, with increased safety rates.49 It should be noted, however, that there were a higher proportion of patients with LS-Pe AF and increased atrial dimensions among the patients undergoing hybrid ablation in this analysis. Randomised controlled trials of patients with LS-Pe AF are needed to more reliably assess the efficacy and safety of convergent ablation compared with isolated epicardial ablation.

Establishing the Convergent Ablation Service In the UK, the majority of electrophysiology services follow a hub and spoke model with most consultant electrophysiologists having cross-site roles at both a tertiary or quaternary centre, and a district general hospital to provide outreach specialty expertise (Figure 1).66 The convergent ablation service, much like conventional ablation, follows this model, with the majority of patients having first contact at their local hospitals, followed by referral to a major cardiac hub for the procedure. 67 This form of cross-site, cross-specialty collaboration is already firmly rooted in other areas of cardiology, with joint cardiology and cardiothoracic meetings taking place in most hospitals to discuss treatments for coronary revascularisation and structural heart disease.68 The advent of the convergent procedure marks the first time that arrhythmia management will require this form of multidisciplinary decision-making.69 Electrophysiologists are crucial to the coordination

of this process, not only by establishing and facilitating this type of collaboration, but also by ensuring that information and education about the procedure is disseminated to general cardiologists, who will often have appropriate patients for this treatment under their care on the ward and in clinic.

Patient Selection Some of the challenges inherent in convergent ablation include the additional potential risks from performing a second procedure in a staged approach, the additional costs of a second procedure, and the potential need for a longer or a further stay in hospital. It is therefore critical to select the patients who would benefit most from upfront hybrid ablation as opposed to catheter ablation. Electrophysiologists are vital to this selection and decision-making process, having in-depth knowledge of AF treatments, including medical management, conventional catheter ablation or pacing plus atrioventricular node ablation. Theoretically, the patients who would benefit most from convergent ablation are those who are predicted to have poor outcomes from conventional catheter ablation. We know that duration of AF is a significant factor. Advances in radiofrequency catheter and cryoballoon technology have increased success rates in patients with PAF, and outcomes are also improving for patients with Pe-AF.25,70 Conventional ablation in patients with LS-Pe-AF currently has very poor efficacy with a single procedure.26 LA size and function is also examined closely prior to catheter ablation, with conventional theories stating that increased LA dimensions by conventional echo criteria are predictive of poor procedural efficacy outcomes.71 Observational studies and meta-analyses examining this relationship, however, have shown mixed results.72 High burden of LA structural remodelling on cardiac MRI has been demonstrated to correlate with recurrence of AF after catheter ablation, but this technology and expertise is not widely available.73 A recent metaanalysis suggested that reduction in LA strain measurement by 2D speckle tracking echocardiography may be superior to increased volumetric LA measurements in predicting long-term failure of catheter ablation.72 Further studies are required to determine whether convergent ablation is more successful in these patients. The role of convergent ablation in patients with previous failed catheter ablations has not yet been elucidated. Several observational studies included patients with previous ablations as part of their cohorts but differences in outcomes between these patients and those undergoing hybrid ablation as their first procedure have not been formally examined.47 CONVERGE-IDE recruited only de novo patients as part of the inclusion criteria. There remains scope, therefore, for future trials assessing convergent versus repeat catheter ablation in patients with AF recurrence after one procedure. Comparative cost-effectiveness studies need to be performed to determine the feasibility of convergent as a widespread ablation strategy. Using a Markov micro-simulation model, Anderson et al. concluded that convergent ablation results in superior maintenance of sinus rhythm with fewer repeat procedures compared with catheter ablation, leading to lower cost and higher quality-adjusted life-years after 5 years.74 This study was limited by the use of observational data to predict the efficacy of convergent ablation, and repeat cost-analyses should be performed after publication of clinical trial data.

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Electrophysiologist in Convergent Ablation Clinical practice with regards to patient selection for convergent ablation is highly variable worldwide. There are no standardised referral criteria for hybrid ablation even within centres, and these decisions are made based on consultant preferences. Our own practice considers convergent ablation for patients with LS-PeAF and increased LA diameter, but these criteria will need to be refined as the available data expands. After publication of randomised clinical trials, cost-analyses and further examination of predictive factors for failure of catheter ablation, we would advocate development of a scoring system to determine which patients may benefit from a hybrid approach. All patients considered for ablation who meet this threshold should be discussed with the AF heart team, as the combined expertise of electrophysiologists, surgeons and anaesthetists are needed to make these challenging and important decisions, after detailed discussions with the patient.

Pathway and Protocol Development Developing pathways for a hybrid procedure to ensure quality care and patient safety is a challenging and meticulous endeavour. The patient journey from first contact to procedure and subsequent recovery is well established in other areas of surgery and cardiology, but these models need to be transposed onto the provision of convergent ablation.75 Coordinating a two-stage procedure adds multiple layers of complexity to service protocol and patient flow. It is important that the electrophysiologist recognises this and works in collaboration with administrative and nursing staff to create a clear pathway. This involves publication of rigorous pre-assessment guidelines for convergent ablation, and liaising with anaesthetists and cardiology/cardiothoracic nursing staff regarding additional checklists and safety protocols.52,76 It involves clear communication with the bookings team and bed managers, as an overnight stay is required after the epicardial ablation. Given that convergent is a relatively novel procedure, appropriate training needs to be arranged for theatre and ward staff regarding periand post-procedural management, including common complications and complex pain needs which professionals in certain specialties may not be accustomed to treating. An area which is often neglected is rigorous follow-up and rehabilitation. Referral for cardiac rehabilitation are routine in pathways after procedures such as PCI, CABG and trans-catheter aortic valve intervention.78 Currently, this is not the case after conventional ablation. However, given that convergent ablation involves two invasive procedures, requiring at least one if not two episodes of general anaesthesia in a relatively comorbid population, it is vital that patients are educated thoroughly on the importance of exercise and risk factor

Lloyd-Jones DM. Cardiovascular health and protection against CVD: more than the sum of the parts? Circulation 2014;130:1671–3. https://doi.org/10.1161/ CIRCULATIONAHA.114.012869; PMID: 25273999. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes results from the national registry of atrial fibrillation. JAMA 2001;285:2864–70. https://doi. org/10.1001/jama.285.22.2864; PMID: 11401607. Wang TJ, Parise H, Levy D, et al. Obesity and the risk of newonset atrial fibrillation. JAMA 2004;292:2471–7. https://doi. org/10.1001/jama.292.20.2471; PMID:15562125. Benjamin EJ, Levy D, Vaziri SM, et al. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA 1994;271:840–4. https://doi. org/10.1001/jama.271.11.840; PMID: 8114238. Diouf I, Magliano DJ, Carrington MJ, et al. Prevalence, incidence, risk factors and treatment of atrial fibrillation in Australia: the Australian Diabetes, Obesity and Lifestyle

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

modification for general cardiovascular health, as well as individualised risk-based referral to cardiac rehabilitation classes. As the clinicians ultimately responsible for the management of these patients, it is important that electrophysiologists take the lead in this holistic approach to patient care.

Conclusion Convergent ablation has shown some promise as an efficacious treatment in patients with LS-PeAF. With so much uncertainty regarding the electrophysiological mechanisms of AF, convergent ablation provides a way to reliably perform reproducible linear lesions of the posterior left atrium, thus targeting all known substrates including rotors, wavelets and epicardial breakthrough. Current observational studies have provided mixed results, but as the volume and operator experience of this procedure increases, it is possible that when this procedure is perfected it will provide the best outcomes in a group of patients with LS Pe-AF who traditionally have poor results from conventional ablation. Randomised controlled trials will determine if this is the case. The electrophysiologist’s role in convergent ablation includes technical operator, manager, coordinator, leader and spokesperson in introducing this novel procedure as a safe, cost-effective, deliverable service. The success of convergent ablation will not only depend upon its efficacy and safety determined by clinical trials, but by the ability of electrophysiologists to be the glue that holds together a vast multidisciplinary team, and make the vision of widespread availability of convergent ablation a reality.

Clinical Perspective • Convergent ablation shows promise in improving the treatment of long-standing persistent AF, where conventional catheter ablation has generally poor efficacy outcomes. Data thus far has come from observational studies. The first randomised controlled trial, CONVERGE-IDE, has finished recruitment and results are awaited. • Convergent ablation is a truly multidisciplinary collaborative electrophysiology service. The electrophysiologist plays a crucial role, in particular with optimum patient selection, pathway development and team coordination. • Standardised criteria need to be developed for referral to the AF heart team to discuss complex patients who may benefit from alternative ablation strategies.

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J Am Coll Cardiol 2012;60:1921–9. https://doi.org/10.1016/j.jacc.2012.04.060; PMID:23062545. Oral H. Pulmonary vein isolation for paroxysmal and persistent atrial fibrillation Circulation 2002;105:1077–81. https://doi. org/10.1161/hc0902.104712; PMID: 11877358. Fassini G, Riva S, Chiodelli R, et al. Left mitral isthmus ablation associated with PV isolation: long-term results of a prospective randomized study. J Cardiovasc Electrophysiol 2005;16:1150–6. https://doi.org/10.1111/j.1540-8167.2005. 50192.x; PMID: 16302895. 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. Verma A, Jiang CY, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015;372:1812–2. https://doi.org/10.1056/NEJMoa1408288; PMID: 25946280. Aryana A, Baker J H, Espinosa Ginic MA, et al. Posterior wall isolation using the cryoballoon in conjunction with pulmonary vein ablation is superior to pulmonary vein isolation alone in patients with persistent atrial fibrillation: a multicenter experience. Heart Rhythm 2018;15:1121–9. https://doi. org/10.1016/j.hrthm.2018.05.014; PMID: 30060879. Thiyagarajah A, Kadhim K, Lau DH, et al. Feasibility, safety, and efficacy of posterior wall isolation during atrial fibrillation ablation. Circ Arrhythm Electrophysiol 2019;12:e007005. https:// doi.org/10.1161/CIRCEP.118.007005; PMID: 31401853. Shah AJ, Jadidi A, Liu X, et al. Atrial tachycardias arising from ablation of atrial fibrillation: a proarrhythmic bump or an antiarrhythmic turn? Cardiol Res Pract 2010:950763. https://doi. org/10.4061/2010/950763; PMID: 20379387. Romero J, Avendano R, Grushko M, et al. Oesophageal injury during AF ablation: techniques for prevention. 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36. Mont L, Bisbal F, Hernandez-Madrid A, et al. Catheter ablation vs. antiarrhythmic drug treatment of persistent atrial fibrillation: a multicentre, randomized, controlled trial (SARA study). Eur Heart J 2014;35:501–7. https://doi.org/10.1093/ eurheartj/eht457; PMID: 24135832. 37. Dong JZ, Sang CH, Yu RH, et al. Prospective randomized comparison between a fixed ‘2C3L’ approach vs. stepwise approach for catheter ablation of persistent atrial fibrillation. Europace 2015;17:1798–806. https://doi.org/10.1093/europace/ euv067; PMID: 25957039. 38. Scherr D, Khairy P, Miyazaki S, et al. Five-year outcome of catheter ablation of persistent atrial fibrillation using termination of atrial fibrillation as a procedural endpoint. Circ Arrhythm Electrophysiol 2015;8:18–24. https://doi.org/10.1161/ CIRCEP.114.001943; PMID:25528745. 39. Schreiber D, Rostock T, Fröhlich M, et al. Five-year follow-up after catheter ablation of persistent atrial fibrillation using the stepwise approach and prognostic factors for success. Circ Arrhythm Electrophysiol 2015;8:308–17. https://doi.org/10.1161/ CIRCEP.114.001672; PMID: 25744570. 40. Yubing W, Yanping X, Zhiyu L, et al. Long-term outcome of radiofrequency catheter ablation for persistent atrial fibrillation. Medicine (Baltimore) 2018;97:e11520. https://doi. org/10.1097/MD.0000000000011520; PMID: 30024535. 41. Kanagaratnam L, Tomassoni G, Schweikert R, et al. Empirical pulmonary vein isolation in patients with chronic atrial fibrillation using a three-dimensional nonfluoroscopic mapping system: long-term follow-up. Pacing Clin Electrophysiol 2001;24:1774–9. https://doi.org/10.1046/j.1460-9592. 2001.01774.x; PMID: 11817811. 42. Pappone C, Oreto G, Rosanio S, et al. Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: efficacy of an anatomic approach in a large cohort of patients with atrial fibrillation. Circulation 2001;104:2539–44. https://doi.org/10.1161/hc4601.098517; PMID: 11714647. 43. Gehi AK, Mounsey JP, Pursell I, et al. Hybrid epicardialendocardial ablation using a pericardioscopic technique for the treatment of atrial fibrillation. Heart Rhythm 2013;10:22–8. https://doi.org/10.1016/j.hrthm.2012.08.044; PMID: 23064043. 44. Ruaengsri C, Schill MR, Khiabani AJ, et al. The Cox-maze IV procedure in its second decade: still the gold standard? Eur J Cardiothorac Surg 2018;53(Suppl 1):i19–25. https://doi. org/10.1093/ejcts/ezx326; PMID: 29590383. 45. Geuzebroek GS, Bentala M, Molhoek SG, et al. Totally thoracoscopic left atrial Maze: standardized, effective and safe. Interact Cardiovasc Thorac Surg 2016;22:259–64. https://doi. org/10.1093/icvts/ivv358; PMID: 26705300. 46. Gersak B, Pernat A, Robic B, Sinkovec M. Low rate of atrial fibrillation recurrence verified by implantable loop recorder monitoring following a convergent epicardial and endocardial ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2012;23:1059–66. https://doi. org/10.1111/j.1540-8167.2012.02355.x; PMID: 22587585. 47. Zembala M, Filipiak K, Kowalski O, et al. Staged hybrid ablation for persistent and longstanding persistent atrial fibrillation effectively restores sinus rhythm in long-term observation. Arch Med Sci 2017;13:109–117. https://doi.org/10.5114/ aoms.2015.53960; PMID: 28144262. 48. Luo X, Li B, Zhang D, et al. Efficacy and safety of the convergent atrial fibrillation procedure: a meta-analysis of observational studies. Interact Cardiovasc Thorac Surg 2019;28:169–76. https:// doi.org/10.1093/icvts/ivy203; PMID: 30052976. 49. Pearman CM, Poon SS, Bonnett LJ, et al. Minimally invasive epicardial surgical ablation alone versus hybrid ablation for atrial fibrillation: a systematic review and meta-analysis. Arrhythm Electrophysiol Rev 2017;6:202–9. https://doi. org/10.15420/aer/2017.29.2; PMID: 29326836. 50. Jiang YQ, Tian Y, Zeng LJ, et al. The safety and efficacy of hybrid ablation for the treatment of atrial fibrillation: A meta-analysis. PLoS One 2018;13:e0190170. https://doi.org/10.1371/journal. pone.0190170; PMID: 29298352. 51. Giannopoulos G, Deftereos S. Hybrid approach for atrial fibrillation ablation: the jury is still out. Arrhythm Electrophysiol Rev 2018;7:65. https://doi.org/10.15420/aer.2017.7.1.L3; PMID: 29636976. 52. Umbrain V, Verborgh C, Chierchia GB, et al. One-stage approach for hybrid atrial fibrillation treatment. Arrhythm Electrophysiol Rev 2017;6:210–6. https://doi.org/10.15420/2017.36.2; PMID: 29326837. 53. Di Biase L, Burkhardt JD, Mohanty P, et al. 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56. Friedman DJ, Piccini JP, Wang T, et al. Association between left atrial appendage occlusion and readmission for thromboembolism among patients with atrial fibrillation undergoing concomitant cardiac surgery. JAMA 2018;319:365–74. https://doi.org/10.1001/jama.2017.20125; PMID: 29362794. 57. Lee LS. Subxiphoid minimally invasive epicardial ablation (convergent procedure) with left thoracoscopic closure of the left atrial appendage operative techniques in thoracic and cardiovascular surgery. Operative Techniques in Thoracic Cardiovascular Surgery 2018;23:152–65. https://doi. org/10.1053/j.optechstcvs.2019.04.002. 58. Toale C, Fitzmaurice G, Eaton D, et al. Outcomes of left atrial appendage occlusion using the AtriClip device: a systematic review. Interact Cardiovasc Thoracic Surg 2019;29:655–62. https://doi.org/10.1093/icvts/ivz156; PMID: 31292605. 59. Starck CT, Steffel J, Emmert MY, et al. 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ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Electrophysiology and Ablation

Electrophysiology’s Identity Crisis: What our Clinical Trials Do and Do Not Say About Us David J Callans,1 Matthew Reynolds2 and Peter J Zimetbaum3 1. Electrophysiology Section, Cardiovascular Division, Perelman School of Medicine, University of Pennsylvania. Philadelphia, PA, US; 2. Electrophysiology Section, Cardiovascular Division, Lahey Hospital and Medical Center, Burlington, MA, US; 3. Electrophysiology Section, Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, MA, US

Abstract Although it has not always been this way, the impact of large, randomised clinical trials in electrophysiology is limited, at least compared with other disciplines in cardiology. This has been particularly true regarding procedural aspects of our field: successful randomised trials are rare and observational trials are small and typically without a proper active control group. In this article, the authors examine the reasons behind this circumstance, which include underinvestment from funding sources; lack of consensus on procedural endpoints; lack of consensus on techniques; and a therapeutic bias in favour of procedural intervention that stands in the way of investigator equipoise. Together, these factors have created a scientific culture dominated by small-scale, siloed, observational research and unwillingness to collaboratively advance the field with consensus and prospective trials. The authors feel that it is increasingly urgent to improve the scientific basis for clinical practice and explore strategies to accomplish this goal.

Keywords Randomised clinical trial, catheter ablation, ventricular tachycardia, AF, Kaplan–Meier analysis, healthy responder bias Disclosure: The authors have no conflicts of interest to declare. Received: 20 December 2019 Accepted: 17 March 2020 Citation: Arrhythmia & Electrophysiology Review 2020;9(1):15–9. DOI: https://doi.org/10.15420/aer.2019.21 Correspondence: David Callans, 3400 Spruce St, Founders 9.126, Philadelphia, PA 19104, US. E: david.callans@uphs.upenn.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.

There was a joke years ago that no one understood electrophysiologists, or even wanted to, and that suited us just fine. We were happy to be isolated in our labs working on largely academic problems. Fast forward to now, and the monumental advances in our ability to map and ablate arrhythmias and in new strategies for implantable device therapy have thrust us into the realm of high-volume interventional operators. Our enthusiasm for providing a procedural answer to our patients has not always been accepted by our referring colleagues. In truth there is often great reluctance from many cardiologists to refer patients for ablation. The Catheter Ablation versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial, although enormously valuable, brought a firestorm of criticism.1,2 In fact, this scepticism is healthy and requires us as a specialty to look more critically at the value of our interventions. Much like the emerging question of the value of percutaneous coronary intervention (PCI) compared with optimised medical therapy for stable coronary heart disease,3,4 it is fair to ask whether we are helping patients with procedural interventions, particularly early in the course of disease. This inability to make our point convincingly has created in effect an ‘identity crisis’ that has many contributing factors. In this article, we explore several themes related to clinical trial interpretation that complicate the ability of cardiologists and patients to understand the impact of our interventions. We hypothesise that our difficulties in performing large randomised clinical trials and our loose interpretations of observational

studies is a large part of the problem; in addition, it is the only part that we completely control.

The Curse of the Kaplan–Meier Survival Curve Not to single out a specific trial but consider the Catheter Ablation of Stable Ventricular Tachycardia before Defibrillator Implantation in Patients with Coronary Heart Disease (VTACH) trial.5 One hundred and seven patients with healed infarction, reduced left ventricular ejection fraction (LVEF; ≤50%) and stable ventricular tachycardia (VT) were randomised to catheter ablation or not prior to ICD implantation. The primary endpoint was time to first recurrence of VT or VF. At its inception, this was no doubt viewed as the ‘lowest hanging fruit’ for ablation. We understand much more about VT in healed infarction than other clinical situations, and hemodynamically tolerated VT allows precise mapping and elegant ablation. In fact, the trial was designed with the expectation that VT/VF recurrence would occur in 20% of the ablation group and in 50% of controls at 2 years. Mean follow-up was 22.5 months. The primary outcome occurred after a median of 18.6 months in the ablation group and of 5.9 months in the control group (p=0.045; Figure 1). VT recurrence was observed in 51% and in 76% of the ablation and control groups, respectively, despite use of amiodarone in 35% of patients. Furthermore, in an exploratory analysis examining the effect of LVEF, the advantage from ablation was erased in patients with EF ≤30%. Although a positive trial, many were

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Electrophysiology and Ablation

Survival free from VT or VF (%)

Figure 1: Kaplan–Meier Curves of Survival Free of Ventricular Tachycardia or VF in the VTACH Study 100

Ablation group

Control group

80 70 60 50 40 30 20 10

p=0.045

subjects with implanted devices), but probably more applicable from a patient point of view. Despite this demonstrated failure of catheter ablation in the VTACH trial, the number of appropriate ICD shocks was 0.6/year in the ablation group versus 2.4/year in the control group (p=0.015). For most patients, avoidance of ICD shocks is a major goal. A similar outcome is demonstrated in the Kaplan–Meier versus burden analysis of the Substrate Modification Study (SMS).6 The meaningful impact of this intervention is exceptionally difficult to reconcile with what happens in real-world analyses. In one observational trial of patients with VT in the setting of healed infarction, patients were referred only after suffering through a mean of 5.8 ICD shocks in the preceding month: 58% were in VT storm and 68% were prescribed more than 400 mg of amiodarone daily at the time of referral.7

0 6

3 4

0 0

Time (months)

Number at risk Ablation group 52 Control group 55

34 26

28 21

21 12

9 8

Although rates of recurrent VT/VF were high in both the ablation and control groups, VT burden was significantly reduced in the ablation group compared with the control. VT = ventricular tachycardia. Source: Kuck et al. 2010.5 Reproduced with permission from Elsevier.

Figure 2: Kaplan–Meier Curves of Transplantfree Survival in Patients without (Blue) and with (Red) Ventricular Tachycardia Recurrence

Transplant-free survival probability

1.0

0.9

No VT recurrence

0.8

0.7

rather sobering 53.9% and 52.2% (in the two cryoballoon groups) and 51.7% (in the RF group). However, the AF burden in all groups was reduced by >98%.

VT recurrence

0.6

0.5 0 Number at risk: 1,525 536

Months after ablation 1,278 445

1,241 415

1,194 387

1,134 363

1,087 346

1,024 321

Figures such as this are often (incorrectly) used to support the hypothesis that successful VT ablation improves survival. VT = ventricular tachycardia. Source: Tung et al. 2015.11 Reproduced with permission from Elsevier.

astonished at the unexpectedly high rate of recurrence in the ablation group. As is even more apparent in trials of AF ablation, our expectations are often falsely optimistic when based on the results of uncontrolled, single-centre observational trials; prospective randomised trials are often sobering by comparison. The Kaplan–Meier survival curve is the preferred statistical method for analysing time-to-event data, in large part because of its ability to handle censoring due to subject withdrawal, competing risks (e.g. death) and other causes of uneven follow-up duration. Despite these advantages, the Kaplan–Meier method imposes a binary definition of success/failure, which makes perfect sense in survival trials, but may not be pertinent (particularly to patients) when measuring time to first recurrent arrhythmia; an outcome that may be more meaningful is VT/ VF burden before and after intervention. This is more difficult statistically (particularly in AF, where event counting is less complete except in

A similar theme is present in trials of AF ablation, but with two additional considerations. The first is the difficulty imposed by guideline-directed assessment of recurrence defined as ≥30 seconds of AF. In the Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF II) Trial 589 patients with persistent AF were randomised to pulmonary vein isolation (PVI) alone, PVI plus ablation of complex fractionated electrograms or PVI plus linear ablation (roof and mitral lines).8 Freedom from documented recurrence of AF (≥30 s) on Kaplan– Meier analysis was 59%, 49% and 46% in the three groups, respectively. However, AF burden in all three groups was substantially reduced, from >80% to approximately 5% at 18 months (Atul Verma, unpublished obseration, 2019). Similarly, a very recent randomised trial comparing cryoballoon ablation (with two dosing strategies) with contact forceguided radiofrequency (RF) ablation in 348 patients with paroxysmal AF evaluated freedom from AT/AF following a 3-month blanking period using implantable monitors.9 Freedom from AT/AF recurrence was a

The second new consideration is that many of the benefits of ablation are not dependent on elimination of AF but are earned with reduction in burden. The Catheter Ablation versus Standard Treatment in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF) Trial demonstrated that catheter ablation, even without total elimination of AF, significantly reduced the primary endpoint of death or heart failure (HF) hospitalisation (28.5% versus 44.6%, p=0.007).10 Although the mean AF burden after ablation varied between 20 and 30% in the ablation group (as compared with 50–60% in the control group), clinically important outcomes were improved.

Our Obsession with Mortality Benefit in Ventricular Tachycardia Ablation Trials Small randomised trials have not demonstrated a mortality benefit to VT ablation. We seem to expect this, given that successful ablation reduces/eliminates ICD shocks and potentially harmful anti-arrhythmic medications. We have even processed observational trial data to arrive at this conclusion, albeit falsely. The International VT Collaborative Center Study Group provided retrospective, observational data on 2,081 patients with VT in the setting of structural heart disease treated with ablation.11 As seen in Figure 2, patients without VT recurrence had a significantly higher transplant-free survival that those with VT recurrence. This is often touted as a demonstration that VT ablation improves survival, but this is incorrect. The implication, apparently, is that if we were better at ablation, all patients would have successful outcomes. The initial logical error is that all patients received ablation

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Clinical Trials in Electrophysiology (even the ones with recurrent VT). More importantly, the two groups are different: patients with recurrence had lower EF, higher New York Heart Association (NYHA) class, higher incidence of VT storm, and were more likely to have had failure of ≥2 anti-arrhythmic drugs (AADs) prior to ablation than patients without recurrence. In addition, the groups are different because of the healthy responder bias: a relatively well patient is more likely to respond to a therapy than a sicker patient. This is a powerful (and often unconsidered) confounding principle in considering uncontrolled results. Perhaps the best demonstration of this phenomenon was presented by Goldstein et al., using the Cardiac Arrhythmia Survival Trial (CAST I and II) data.12 They hypothesised that patients who had easily suppressed premature ventricular complexes (PVCs; first AAD, first dose) would have better outcomes than patients who required further drug titration/additional drug trials or those who never had PVCs suppressed. Patients with easily suppressed PVCs had less risk of arrhythmic and total mortality in follow-up. This occurred despite a higher likelihood of being treated with active drug therapy (50% versus 35%), which was shown to cause harm in the randomised trial. Ease of arrhythmia suppression remained a significant predictor of arrhythmic deaths even after multivariate analysis. Response to any therapy (even a harmful one!) selects a population of patients that is likely to do relatively well.

Outcome After Ablation is More About the Patient Than the Procedure It follows from the discussion above that outcome after VT ablation, both in terms of recurrence and survival, may have more to do with patient than procedural characteristics. This would explain the nearly universal association of freedom from VT recurrence and survival, but not in the way it is usually put forward. Muser et al. examined the performance of eight (largely HF) prognostic risk scores applied to 282 consecutive patients with non-ischemic cardiomyopathy who underwent catheter ablation for VT.13 After a median follow up of 48 months, 43 patients (15%) died, 24 (9%) underwent heart transplantation, and 58 (21%) had VT recurrence. Of the eight models, two performed particularly well: the Seattle Heart Failure Model; and the Chronic Obstructive Pulmonary Disease, Age >60 years, Ischemic cardiomyopathy, NYHA Functional Class III or IV, EF <25%, Presentation With VT Storm, Diabetes Mellitus (PAINESD) score. Both scores had high predictive values for both VT recurrence and transplant-free survival, strongly suggesting that these two outcomes are associated with patient-related (and not procedure-related) variables. It is tempting to hypothesise that things would work out differently if we intervened earlier: before the relentless march of progressive HF, probably assisted by ICD shocks and AAD toxicity in our VT patients, before atrial fibrosis and remodelling is too established in our AF patients. Two recent trials examined the effect of early intervention in patients with VT in structural heart disease. The Leipzig VT study was an observational study of 300 patients divided into three groups based on time to referral for VT ablation from the first occurrence of VT: group 1 (n=75), <30 days; group 2 (n=84), 1 month to 1 year; and group 3 (n=141), >1 year.14 The groups were different from each other. Group 1 patients had higher EF, lower VT burden and fewer VT morphologies induced with programmed stimulation. At 2 years, VT recurred in 37.3%, 61.9% and 64.5% in groups 1–3, respectively (p<0.0001). However, no survival benefit was observed between the three groups. On multivariate analysis, recurrent VT was a significant risk for mortality. The Preventative or Deferred Ablation of Ventricular Tachycardia in Patients with Ischemic Cardiomyopathy and Implantable Defibrillator (BERLIN

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

VT) randomised patients with healed infarction, EF 30–50% and sustained VT to ablation before ICD implantation (preventative strategy) or after the third appropriate ICD shock (deferred strategy). The primary outcome was a composite of all-cause death and unplanned hospitalisation for VT or HF. The study was stopped for futility after 394 days and enrolment of 169 patients. Mortality occurred in six versus two patients, hospital admission for HF in eight versus two patients, and hospital admission for VT in 15 versus 21 patients in the preventative and deferred groups, respectively.15 It seems that mortality in patients with advanced structural heart disease treated with ICD therapy is determined by the inexorable progression of HF, not the consequences of ventricular arrhythmias. Early intervention may make sense in AF, at least in patients who do not have the additive pathophysiologic factors of obesity, sleep apnoea and poorly controlled hypertension that seem to confound our best efforts. This hypothesis was not enthusiastically supported by the Medical Antiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation (MANTRA-PAF) trial, which randomised 246 patients with paroxysmal AF to ablation or first ever exposure to Class IC or III AADs. There was no significant difference in cumulative AF burden or burden measured at 3, 6, 12 or 18 months; at 24 months AF freedom was lower in the ablation group (90th percentile, 9% versus 18%; p=0.007), and more patients in the ablation group were free from any AF (85% versus 71%, p=0.004). This trial was limited by cross-over to ablation in 36% of the anti-arrhythmic group and by a non-standard endpoint for PVI. Mortality was not addressed in that small trial. In relatively young and healthy patients a mortality trial would require a substantial period of post-intervention observation, which is difficult to imagine given current funding structures.

Barriers to a Robust Evidence Base in Electrophysiology In interventional cardiology, almost every important clinical decision is supported by at least a small amount of high-quality evidence. Seemingly, every stent, antiplatelet drug, or combination of drugs has been the subject of one or more randomised trials. By comparison, the amount of high-quality evidence supporting interventions in cardiac electrophysiology (EP) is limited. Why is this? There are five main reasons: distraction caused by the rapid evolution of technology; underinvestment; lack of consensus on procedural endpoints; lack of consensus on techniques; and a therapeutic bias in favour of ablation that stands in the way of equipoise. Together, these factors have created a scientific culture dominated by small-scale, siloed, observational research and unwillingness to collaboratively advance our field with consensus and prospective trials. Electrophysiologists are u and new technologies are developed at a frenetic pace. First-in-human experiences with promising new technologies and short-term clinical follow up are embraced by journals and readership alike. Performing such a study is surely faster and easier than designing a hypothesis-driven randomised clinical trial; in addition, the time commitment required comes with the risk that the methods used at the outset become archaic by the time of reporting. Newer is not always better; and these early experiences, although necessary and exciting, seldom contribute to the larger questions that we need to answer. Generating high-quality clinical evidence is expensive. Unfortunately, the usual sources of funding for clinical research have historically provided limited support for EP topics. Manufacturers of ablation and

Electrophysiology and Ablation cardiac implantable electronic device (CIED) technologies have generally taken a bare-minimum approach, investing in the least burdensome studies required by regulators for market entry. For AF ablation, this meant trials of <250 patients randomised to drugs or ablation;16,17 for VT ablation, this meant an observational registry;18 for devices it is the ICD-NCDR. In the US, scientific gaps left by industry and academia have traditionally been addressed by the National Institutes of Health (NIH). However, for all of clinical EP, funding from NIH has been limited to approximately 1–2 significant randomised controlled trials per decade. Conversely, and attesting to the need for continued governmental support, the Canadian Institutes of Health Research, which funded the Ventricular Tachycardia Ablation versus Escalation of Antiarrhythmic Drugs (VANISH) trial,19 has had more impact in the field of VT ablation than the NIH and industry combined. Part of the issue here is scale: ablation and CIED implants are 1–2 orders of magnitude smaller in volume than PCI at its peak. Times are changing, however, and EP interventions should no longer be flying under the radar. While lack of funding has limited the size and scope of EP research studies, other barriers are more intrinsic to the EP community itself. As described in the preceding paragraphs, we have struggled to define and agree upon endpoints that matter to patients. In clinical practice, we are strongly (and rightly) influenced by a desire to improve our patient’s symptoms, functioning, and quality of life. Yet, we have limited tools for assessing these important outcomes in research studies, with a few reasonable disease-specific qualities of life scales for AF patients, and none at all for patients with VT. We default to endpoints that are easy and relatively inexpensive to measure (e.g. ICD therapies or time to first symptomatic atrial arrhythmia) rather than choosing more meaningful although challenging ones (e.g. AF burden). Then, when studies are completed, we are disappointed when they do not clearly answer critical questions. EP research is further hampered by a lack of consensus on procedural techniques. EP is loaded with remarkably talented and creative individuals who have achieved incredible things in the service of patients. Nonetheless, things seem to evolve in EP much like they do in the art world, with the avant-garde promoting one or another new technique, and others rushing to follow, trying things out on patients without truly knowing if they are making a difference. For example, with persistent AF, there is some agreement that PVI alone is insufficient for many patients. There is a long (and growing) list of adjunctive ablation techniques, (all of which received a IIb recommendation in the AF ablation consensus statement20) or new technologies (electroporation, radiotherapy), which are all too often rushed through small observational studies into practice without accurate demonstration of safety or comparative efficacy. In the US, we have five EP-focused specialty journals, all with an impact factor <5, publishing an endless number of small observational studies, some of which are technical marvels, but collectively do not seem to move us forward very quickly.

Packer DL, Mark DB, Robb RA, et al. Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA 2019;321:1261–74. https://doi.org/10.1001/jama.2019.0693; PMID: 30874766. Packer M. The CABANA Trial: an honourable view. Eur Heart J 2018;39:2770. https://doi.org/10.1093/eurheartj/ehy381; PMID: 30107428.

A final barrier to the execution of high-quality randomised trials in clinical EP is a pervasive bias towards intervention. For many electrophysiologists, managing patients with medication in the office is anathema to the preferred clinical activity of doing procedures in an EP lab. Optimal medical therapy for HF is not pursued according to guidelines prior to primary prevention ICD therapy. This behaviour is not unique to electrophysiologists. A recent registry analysis of guideline-directed pharmacologic treatments for patients with HF with reduced EF demonstrated that medication doses were not titrated in >80% of patients; and at 12 months, <1% of patients were receiving target doses of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor–neprilysin inhibitors and mineralocorticoid receptor antagonists.21 To many, the benefits of invasive therapies are taken as a given, before careful studies are completed. Randomising patients in clinical trials requires equipoise. Too often in EP, we think we know the answer ahead of time, and if we are too proud to admit that the answer is not known, then we will not randomly allocate patients to alternative treatments to find out. To channel our hero Mark Josephson, we are acting like ablationists and defibrillationists, not physician scientists.

Moving Forward If we are correct that some of the aforementioned issues serve as major impediments to progress in our field, then perhaps we can begin to work through them. We have little doubt that more investment is needed in EP research, both intellectually and financially. It is not enough simply to meet regulatory requirements to bring products to market. We need to ask and answer questions about clinical strategies with our existing therapies to improve clinical decision-making and outcomes for patients. Arguably, what we need most is to improve our ability to collaborate. We spend too much time trying to perfect our own techniques, and not enough time cooperating to test hypotheses with uniform approaches and patient-centred outcomes. There are examples to point the way, including the development of expert consensus documents on AF ablation that not only made clinical recommendations, but also suggested approaches for future research.20 We should focus on improving the scientific support of our craft as if our field depended on it, because in the near-term future, it likely will.

Clinical Perspective • We find ourselves having trouble communicating the benefits of our procedures to referring physicians and patients. • Some of this is related to the lack of high-quality randomised clinical trials. • Some of this is related to poor messaging of the meaning of results in observational trials. • The ethos of the physician scientist in clinical electrophysiology needs to change in order to reestablish the scientific basis for our clinical practice.

Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–16. https://doi.org/10.1056/ NEJMoa070829; PMID: 17387127. Maron DJ, Hochman JS, O’Brien SM, et al. International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial: rationale and design. Am Heart J 2018;201:124–35. https://doi.org/10.1016/j.ahj.2018.04.011; PMID: 29778671.

Kuck KH, Schaumann A, Eckardt L, et al. Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): a multicentre randomised controlled trial. Lancet 2010;375:31–40. https://doi. org/10.1016/S0140-6736(09)61755-4; PMID: 20109864. Kuck KH, Tilz RR, Deneke T, et al. Impact of substrate modification by catheter ablation on implantable cardioverterdefibrillator interventions in patients with unstable ventricular arrhythmias and coronary artery disease: results from the

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Clinical Trials in Electrophysiology multicenter randomized controlled SMS (Substrate Modification Study). Circ Arrhythm Electrophysiol 2017;10:e004422. https://doi. org/10.1161/CIRCEP.116.004422; PMID: 28292751. 7. Frankel DS, Mountantonakis SE, Robinson MR, et al. Ventricular tachycardia ablation remains treatment of last resort in structural heart disease: argument for earlier intervention. J Cardiovasc Electrophysiol 2011;22:1123–8. https://doi. org/10.1111/j.1540-8167.2011.02081.x; PMID: 21539642. 8. Verma A, Jiang CY, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015;372:1812–22. https://doi.org/10.1056/NEJMoa1408288; PMID: 25946280. 9. Andrade JG, Champagne J, Dubuc M, et al. Cryoballoon or radiofrequency ablation for atrial fibrillation assessed by continuous monitoring: a randomized clinical trial. Circulation 2019;140:1779–88. https://doi.org/10.1161/ CIRCULATIONAHA.119.042622; PMID: 31630538. 10. Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 2018;378:417–27. https://doi.org/10.1056/NEJMoa1707855; PMID: 29385358. 11. Tung R, Vaseghi M, Frankel DS, et al. Freedom from recurrent ventricular tachycardia after catheter ablation is associated with improved survival in patients with structural heart disease: an International VT Ablation Center Collaborative Group study. Heart Rhythm 2015;12:1997–

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12.

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2007. https://doi.org/10.1016/j.hrthm.2015.05.036; PMID: 26031376. Goldstein S, Brooks MM, Ledingham R, et al. Association between ease of suppression of ventricular arrhythmia and survival. Circulation 1995;91:79–83. https://doi.org/10.1161/01. CIR.91.1.79; PMID: 7805221. Muser D, Liang JJ, Castro SA, et al. Performance of prognostic heart failure models in patients with nonischemic cardiomyopathy undergoing ventricular tachycardia ablation. JACC Clin Electrophysiol 2019;5:801–13. https://doi. org/10.1016/j.jacep.2019.04.001; PMID: 31320008. Dinov B, Arya A, Bertagnolli L, et al. Early referral for ablation of scar-related ventricular tachycardia is associated with improved acute and long-term outcomes: results from the Heart Center of Leipzig ventricular tachycardia registry. Circ Arrhythm Electrophysiol 2014;7:1144–51. https://doi. org/10.1161/CIRCEP.114.001953; PMID: 25262159. Willems S, Tilz RR, Stevens D, et al. Preventive or deferred ablation of ventricular tachycardia in patients with ischemic cardiomyopathy and implantable defibrillator (BERLIN VT): A multicenter randomized trial. Circulation 2020;141:1057–1067. https://doi.org/10.1161/CIRCULATIONAHA.119.043400; PMID: 32000514. Wilber DJ, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a

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randomized controlled trial. JAMA 2010;303:333–40. https:// doi.org/10.1001/jama.2009.2029; PMID: 20103757. Packer DL, Kowal RC, Wheelan KR, et al. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front (STOP AF) pivotal trial. J Am Coll Cardiol 2013;61:1713–23. https://doi. org/10.1016/j.jacc.2012.11.064; PMID: 23500312. Stevenson WG, Wilber DJ, Natale A, et al. Irrigated radiofrequency catheter ablation guided by electroanatomic mapping for recurrent ventricular tachycardia after myocardial infarction: the multicenter thermocool ventricular tachycardia ablation trial. Circulation 2008;118:2773–82. https://doi. org/10.1161/CIRCULATIONAHA.108.788604; PMID: 19064682. Sapp JL, Wells GA, Parkash R, et al. Ventricular tachycardia ablation versus escalation of antiarrhythmic drugs. N Engl J Med 2016;375:111–21. https://doi.org/10.1056/ NEJMoa1513614; PMID: 27149033. 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. Heart Rhythm 2017;14:e275–444. https://doi.org/10.1016/j. hrthm.2017.05.012; PMID: 28506916. Greene SJ, Fonarow GC, DeVore AD, et al. Titration of medical therapy for heart failure with reduced ejection fraction. J Am Coll Cardiol 2019;73:2365–83. https://doi.org/10.1016/j. jacc.2019.02.015; PMID: 30844480.

Drugs and Devices

Use of Electrophysiological Studies in Transcatheter Aortic Valve Implantation Oholi Tovia-Brodie,1 Yoav Michowitz2 and Bernard Belhassen3 1. Department of Cardiology, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; 2. Department of Cardiology, Jesselson Integrated Heart Center, Shaare Zedek Medical Center, Jerusalem, Israel; 3. Heart Institute, Hadassah University Hospital, Jerusalem, Israel

Abstract New conduction disturbances requiring permanent pacemaker implantation remain common complications following transcatheter aortic valve implantation (TAVI). It has been suggested that electrophysiological studies could help identify patients who will require permanent pacemaker implantation after TAVI. This article summarises contemporary data on the use of electrophysiological studies in patients undergoing TAVI.

Keywords Electrophysiological study, transcatheter aortic valve implantation, His–ventricular interval, pacemaker, conduction disturbances, left bundle branch block Disclosure: The authors have no conflicts of interest to declare. Received: 20 May 2019 Accepted: 12 February 2020 Citation: Arrhythmia & Electrophysiology Review 2020;9(1):20–7. DOI: https://doi.org/10.15420/aer.2019.38.3 Correspondence: Oholi Tovia-Brodie, Department of Cardiology, Soroka University Medical Center, PO Box 151, Beer Sheva 8410101, Israel. E: toholi@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.

Transcatheter aortic valve implantation (TAVI) has become the standard therapy in patients with symptomatic severe aortic stenosis and an intermediate or high surgical risk.1,2 Recent promising reports suggest that it will also become standard therapy in low-risk patients.3,4 New conduction disturbances following the procedure requiring permanent pacemaker implantation (PPI) have been well described.5,6 Although mortality and major complication rates have decreased with the newer-generation valves, the rate of pacemaker implantation and conduction disturbances remains high with both self-expandable (SE) and balloon-expandable (BE) valves.7–11 Furthermore, there are reports of the development of delayed conduction abnormalities and late complete atrioventricular block (CAVB).12–15 Recent studies have shown that PPI after TAVI was associated with a lower risk of sudden cardiac death (SCD) at 1 year follow-up.16,17 The use of implantable loop recorders (ILR) revealed that 20% of patients with new-onset persistent left bundle branch block (LBBB) after TAVI had severe bradyarrhythmias, with half of them requiring PPI during the 1-year follow-up.18 An early discharge approach (≤72 hours) after TAVI is increasingly being used, including continuous ECG monitoring <48 hours that may lead to underdiagnosis of conduction and rhythm abnormalities.19–24 Tools to identify the subgroup of patients at higher risk of developing late conduction disturbances are needed. Whereas guidelines for PPI are relatively straightforward for patients with documented second degree or higher atrioventricular (AV) conduction disorders, there is no consensus for PPI in patients who develop new-onset LBBB with or without PR prolongation after TAVI.25,26 The lack of guideline recommendations in patients with relative indications such as LBBB with or without PR prolongation has led to a centre-based approach, which varies significantly among different centres and ranges from

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PPI to a watchful waiting strategy, with some centres performing further evaluation with electrophysiological studies (EPS) or ILRs.24 The value of the His–ventricular (HV) interval in assessing the risk of developing high-degree AV block (AVB) in patients with chronic degenerative conduction disease and bundle branch block was described by Scheinman et al. in 1982; an HV interval ≥70 ms was found to carry a fourfold increased risk of developing CAVB, whereas HV ≥100 ms identified a subgroup at particularly high risk (25%).27 Katritsis and Josephson found that approximately 70% of patients with HV intervals ≥100 ms develop second- or third-degree infra-His block within the next 2 years.28 Currently, there are on-going clinical trials evaluating the utility of EPS in patients undergoing TAVI.29 This review summarises contemporary data on the use of EPS as a predictor of PPI and as a tool for decision making regarding the need for PPI in patients undergoing TAVI. Tables 1 and 2 summarise the studies and their results; Figures 1 and 2 are examples of EPS results demonstrating normal and abnormal atrium–His (AH) and HV intervals in patients with post-TAVI new conduction disturbances.

Predictive Value of Electrophysiological Studies Before and After TAVI Without Analysis of Predictors of Permanent Pacemaker Implantation Several studies have assessed EPS results before and after TAVI. Rubín et al. reported the results of 18 patients who underwent EPS immediately before and immediately after CoreValve (Medtronic, Minneapolis, MN,

EPS in TAVI Patients Rubín et al.30

Study

No. No. EPS Valve patients type

Yes

Table 1: Summary of the Studies Reviewed and Their Results

Akin et al.37

EPS EPS EPS after before immediately TAVI TAVI after TAVI

Eksik et al.31

EPS timing (days after TAVI) 7

No: baseline only

N/A

HV interval Sensitivity (%), P-value HV interval Safety of Pacemaker dependency (ms) predictive specificity (%) (ms) as PPI strategy (LBBB+HV prolongation) of HB indication

N/A

Yes

N/A

Only CHB

N/A

1 of 1

0.01

N/A

Yes

0.0006

0.03

75, 78

N/A

0.08

1 of 3

83, 82

Yes

75, 67

1 of 7

>54, baseline

>52, baseline

>65

In 6 patients 4 days–20 months

N/A

Yes

N/A

CV 5 ± 2, ES 3 ± 2 No

Yes

CV (85%), ES (15%)

Yes

ES XT Lotus

N/A

137

Yes

100 ± Yes procainamide

Mixed

N/A

Shin et al.32

Mixed

N/A

CV (85%), ES (15%)

CV, 1 Lotus

Yes

137

7 No

Rivard et al.34

Kostopoulou et al.33 48

López-Aguilera et al.36

Tovia-Brodie et al.39 81

Eksik et al.35

24 Mixed

100, 84

Badenco et al.38

No: baseline only

Makki et al.41 95

Delta HV ≥13 ms

Rogers et al.40

CHB = complete heart block; CV = CoreValve; EPS = electrophysiological study; ES = Edwards SAPIEN; HB = heart block; LBBB = left bundle branch block; PPI = permanent pacemaker implantation; TAVI = transcatheter aortic valve implantation.

Study

135.5 ± 45

97 (70–123)

AH before

153.6 ± 43.4 (day 7)

115 (96–135)

AH after

0.021

Delta AH HV before p-value (no PPI)

HV before PPI 58.5 ± 12.5

60 (50–70)

HV after

0.002

56.8 ± 8.5

Delta HV HV after p-value (no PPI)

81.7 ± 18 (day 7)

HV after PPI

<0.05

Delta HV after p-value

0.045

52 (42–55)

Delta HV before HV before p-value <0.05

77 ± 20

0.02

<0.001

58 ± 8

67 ± 24

55.9 ± 11.5

54 ± 13

47.3 ± 7.8

Table 2: Summary of Available Electrophysiological Study Results Before and After Transcatheter Aortic Valve Implantation

Rubín et al.30

119.1 ± 32.9

48.7 ± 6.9

Akin et al.37 81.8 ± 16.9

59 ± 13 (LBBB) <0.001

0.25

Eksik et al.31

52 ± 14

53 ± 14.1 (25–85) <0.005

66 ± 23

<0.03 135 ± 43 (LBBB)

54 ± 10

62.1 ± 13

125 ± 49

<0.01

49.2 ± 12.9

Rivard et al.34

108 ± 41

62 ± 13

64 ± 13 Lotus <0.001

Shin et al.32

95 ± 39

52 ± 12

52 ± 9

0.001

< 0.01

López-Aguilera et al.36

0.002 0.048

104 ± 25

60 ± 15

113 ± 30

49 ± 10

90 ± 19

55–90

71 ± 21 (HV2)

61.4 ± 15.1

100 ± 25

56 ± 10

Eksik et al.35

80–120

171.9 ± 51.7

Kostopoulou et al.33 Tovia-Brodie et al.39 Badenco et al.38 Makki et al.41

Values are presented in milliseconds as the mean ± SD, with or without the range in parentheses, or as median (interquartile range). AH = atrium–His interval; HV = His–ventricular interval; HV2 measured 15 minutes after valve deployment; LBBB = left bundle branch block.

Rogers et al.40

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Drugs and Devices Figure 1: Example of Results of an Electrophysiological Study Performed in a Patient With New Left Bundle Branch Block After Transcatheter Aortic Valve Implantation

Lifesciences). 31 In these patients, the HV interval increased significantly after the procedure. Conduction disturbances were observed in EPS and ECG immediately after the procedure in 10.7% of patients, but these disturbances recovered before discharge.31 Moreover, the conduction defects were mainly infranodal and temporary. Only one patient with right bundle branch block (RBBB) and left anterior hemiblock required PPI (3.6%); in this patient, the HV interval increased from 45 to 75 ms. Predictors of AV conduction problems could not be analysed because of the small sample size and low PPI rate.31

Electrophysiological Studies Before TAVI III

Studies Predicting Permanent Pacemaker Implantation Shin et al. reported the results of 25 patients who received a CoreValve prosthesis.32 EPS was performed before and after TAVI if no CAVB occurred. Patients developing CAVB had a significantly longer HV interval at baseline than patients with no indication for PPI. Furthermore, an HV interval >54 ms at baseline showed a predictive value for the development of CAVB after TAVI with a sensitivity of 75% and a specificity of 82.4% (95% CI [0.542–0.902]), reaching statistical significance (p=0.009).

aVR

aVL 41 ms

aVF

His

His P

118 ms 1:53:00 P

Shown are 12-lead ECG with left bundle branch block morphology and intracardiac His bundle recordings. A–H and H–V intervals were measured within the normal range (118 and 41 ms, respectively). A = atrium; H = His; His P = His proximal; V = ventricular.

US) prosthesis implantation: the HV interval was significantly prolonged after TAVI.30 On follow-up, one patient who developed a new LBBB after TAVI and had a post-TAVI prolonged HV interval (76 ms) experienced recurrent syncope after discharge; paroxysmal CAVB was documented in this patient 10 days after TAVI, and a permanent pacemaker was implanted. All four patients who underwent PPI after TAVI had a normal pre-TAVI EPS. However, the study had no statistical power to identify predictors of AVB because of its small sample size.30 Eksik et al. reported the results of 28 patients who underwent EPS immediately before the initial balloon valvuloplasty and immediately after implantation of an Edwards SAPIEN prosthesis (Edwards

Kostopoulou et al. reported the results of 48 patients who underwent a CoreValve implantation and were randomised to ECG plus EPS evaluation or to ECG evaluation only.33 Thirty patients in the EPS group underwent a baseline EPS followed by TAVI and a second EPS 48 hours after the procedure. The indication for PPI was the combination of new LBBB with infrahisian conduction delay, which was defined as an HV interval >70 ms. Five of the 30 patients in the EPS group developed CAVB immediately after TAVI and therefore did not undergo repeat EPS. Patients with baseline conduction abnormalities (HV interval >50 ms) were at higher risk of developing post-TAVI CAVB. In the two patients who developed CAVB relatively late (after day 2) and underwent a post-TAVI EPS, the HV interval increased significantly (to >70 ms). Receiver operating characteristic (ROC) analyses indicated an HV interval of 52 ms (sensitivity 75%, specificity 67%) as a cut-off value that showed a trend for PPI (HR 4.054, 95% CI [0.816–20.138]; p=0.087). Of the 14 patients with complete new LBBB, only one needed PPI. This patient developed first-degree AVB and LBBB on day 2, which progressed to CAVB on day 7. All patients with new LBBB were in the non-EPS group. Univariate but not multivariate analysis identified prolonged baseline HV interval as a significant factor associated with PPI after TAVI, whereas delta HV was not significantly associated with PPI. There were no patients with a normal post-TAVI EPS who underwent PPI over the long-term follow-up.33

Studies Not Predicting Permanent Pacemaker Implantation López-Aguilera et al. reported the results of 137 patients who underwent CoreValve prosthesis implantation and were studied by EPS before and 30 min after valve implantation. 36 Mean AH and HV intervals increased significantly (p<0.01). Furthermore, baseline intracardiac intervals did not predict the need for post-TAVI PPI within 72 hours. Post-TAVI EPS results were not included in the analysis. 36 Six patients required an additional repeat EPS after valve implantation, which was performed between day 4 and 20 months after TAVI. Two patients experienced considerable deterioration in AV conduction after valve implantation that returned to normal on repeat EPS 5 and 7 days after TAVI. Three patients experienced symptoms during the long-term follow-up. Repeat EPS showed highdegree AVB with considerable AH interval prolongation at 16 months of follow-up in one patient, and sick sinus syndrome in the remaining

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

EPS in TAVI Patients two patients 1 and 20 months after TAVI. The remaining six patients had sinus rhythm with first-degree AVB and significant prolongation of AH and HV intervals. During the first 24 hours, paroxysmal CAVB was observed. Repeat EPS 4 days after TAVI showed complete infrahisian AVB and a permanent pacemaker was implanted.36 Akin et al. reported the results of 45 patients who underwent CoreValve implantation.37 EPS was performed prior to valve implantation, immediately after valve implantation and at the 7-day follow-up. PPI was indicated in the presence of new LBBB in combination with HV interval prolongation ≥75 ms. Patients who underwent PPI (n=23; 51%) had significantly longer PQ, AH and HV intervals in all EPS. Eighteen of 22 patients with first-degree AVB had a prolonged HV interval (13 of 22 [59%] with HV prolongation ≥75 ms). The HV interval increased from baseline to immediately after TAVI, and further at 7 days after TAVI (mean ± SD 58.5 ± 12.5, 74.0 ± 13.5 and 81.7 ± 17.8 ms, respectively) and was significantly higher in patients receiving PPI than in those not.37 A multivariate analysis to identify predictors for high-grade AVB revealed new LBBB immediately (within 60 minutes) after TAVI (OR 24.85, 95% CI [1.57–392.57], p=0.023), PQ interval >200 ms (OR 11.37, 95% CI [1.138–97.620[, p=0.02) and QRS interval >120 ms (OR 14.28. 95% CI [1.50–135.88]. p=0.021) as predictors for high-grade AVB. Other clinical parameters and baseline ECG parameters (e.g. AH interval >100 ms, HV interval >75 ms, QRS interval >120 ms and PQ interval >200 ms) had no ability to predict critical conduction delay.37 Post-TAVI EPS data were not included in this analysis.

Figure 2: Example of Results of an Electrophysiological Study Performed in a Patient With New Left Bundle Branch Block and PR Prolongation After TAVI

III

aVR 170 ms aVL –100 ms aVF

His d A

Summary and Interpretation The predictive value of pre-TAVI EPS has shown mixed results. Although two studies did not find a correlation between baseline HV interval and PPI,36,37 another two studies found baseline HV intervals of 52 and 54 ms to be predictive of higher risk for PPI.32,33 These values are still within the normal HV interval range, and the implementation of these cut-off values as a strategy for PPI would result in a high rate of PPI, the majority of which are not needed.

H V

Predictive Value of Electrophysiological Studies Before and After TAVI Studies Predicting Permanent Pacemaker Implantation

Predictive Value of Delta His–Ventricular Interval Rivard et al. reported the results of 75 patients who were implanted with CoreValve (85%) or Edwards SAPIEN (15%) valves and underwent EPS at baseline and after TAVI (at a median of 4 days after the procedure).34 In patients with new-onset LBBB, there was a significant increase in both AH and HV intervals after compared with before TAVI. In multivariate analysis, the delta HV interval was the only factor independently associated with CAVB (HR 1.152 per ms, 95% CI [1.063– 1.248]; p=0.0006). ROC analysis revealed that the sensitivity and speciﬁcity for predicting CAVB were 100% and 84.4%, respectively, for a delta HV interval of ≥13 ms and 83.3% and 81.6%, respectively, for an HV interval of ≥65 ms after TAVI. Negative and positive predictive values were 100% and 70%, respectively, for a delta HV interval of ≥13 ms and 82% and 62%, respectively, for an HV interval of ≥65 ms after TAVI. Excluding the EPS results before TAVI from multivariate analysis, the only factor independently associated with CAVB was delta QRS duration (HR 1.060 per ms, 95% CI [1.024–1.097]; p=0.001). A delta QRS duration of ≥38 ms was associated with a sensitivity and speciﬁcity of 88.9% and 76.3%, respectively. In patients with new-onset LBBB, the HV interval after TAVI and the delta HV interval, but not delta QRS duration or delta PR interval, were associated with CAVB in univariate analysis. The delta

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Shown are 12-lead ECG with left bundle branch block morphology and intracardiac His bundle recordings. A–H and H–V intervals were significantly prolonged (170 and 100 ms, respectively), with an abnormal His. A = atrium; H = His; His d = His distal; V = ventricular.

HV interval was the only factor independently associated with AVB (HR 1.152 per ms, 95% CI [1.063–1.248]; p=0.007) in multivariate analysis.34

Predictive Value of Electrophysiological Studies After TAVI Eksik et al. reported the results of 55 patients who were randomised to implantation of an Edwards SAPIEN XT or Lotus (Boston Scientiﬁc) prostheses.35 EPS before and immediately after valve implantation was performed. The AH and HV intervals increased significantly after Lotus implantation. In the case of Edwards SAPIEN XT implantation, post-TAVI

Drugs and Devices HV intervals were similar to those before the procedure. However, both the post-TAVI QRS duration (mean ± SD 138 ± 26 versus 116 ± 28 ms; p=0.004) and HV interval (mean ± SD 64 ± 13 versus 55 ± 11 ms; p=0.02) were significantly longer in the Lotus than SAPIEN XT group. In multivariate analysis, a significant association was noted between preTAVI AV conduction disorders and post-TAVI HV interval and the adjusted risk of PPI (post-TAVI HV OR 1.156, 95% CI [1.012–1.319]; p=0.033). Rivard et al.34 also performed multivariate analysis without including the pre-TAVI EPS results and found that the HV interval after TAVI was the only predictor of CAVB (HR 1.081 per ms, 95% CI [1.014–1.152]; p=0.0163) with a sensitivity and speciﬁcity of 80.0% and 77.8%, respectively, for a cut-off value of ≥65 ms.

Electrophysiological Studies Not Predicting Permanent Pacemaker Implantation Badenco et al. reported the results of 84 patients implanted with CoreValve (66.7%) or Edwards SAPIEN (33.3%) prostheses. EPS was performed immediately before TAVI (defined as ‘HV1’) and 15 minutes after valve deployment (‘HV2’). A third EPS was performed after TAVI (3 ± 2 days for Edwards SAPIEN, and 5 ± 2 days for CoreValve) in 64 patients (‘HV3’).38 A PPI was implanted if HV3 was >80 ms regardless of ECG conduction disturbances. The mean HV2 interval was significantly prolonged compared with HV1. In all, 19 patients experienced highdegree AVB before discharge: nine patients with persistent CAVB during TAVI and 10 patients with new AVB from day 2 to day 6 (eight CoreValve, two Edwards SAPIEN). All these patients had perioperative conduction disturbances, including transient CAVB (n=4) or new LBBB (n=6). Neither HV1, HV2 interval nor delta HV2–HV1 were correlated with CAVB after TAVI. Pre-existing RBBB and perioperative persistent CAVB were the main factors predicting early postoperative CAVB in univariate analysis (p=0.001 and p<0.001, respectively) and only perioperative persistent CAVB remained statistically significant in multivariate analysis (p=0.001). The mean HV3 interval decreased to 63 ± 14 ms (p=0.002). HV3 >70 ms and the delta HV3–HV1 (mean 13 ± 5.5 ms) were not correlated with delayed AVB (p=0.84 and p=0.4, respectively). In 14 patients studied on days 4–7, HV measured 70–100 ms, but no AVB developed. Nine of these 14 patients were implanted for HV3 >80 ms, of whom four had no conduction disturbances, two had transient periprocedural AVB and only three had new LBBB. Conversely, three patients developed high-degree AVB (on days 2, 4 and 7) when their HV3 interval remained unchanged from HV1 and HV2, below 80 ms.

Summary and Interpretation The available studies are relatively small, with differences in valve type and EPS timing. All studies demonstrated a significant increase in HV interval after TAVI. When a third EPS was performed during hospitalisation (the second EPS being immediately after TAVI), the results varied from a further increase to a partial decrease in HV interval.37,38 These differences may be explained by different valve types, the timing of EPS and earlier versus later experience with TAVI. The predictive value of pre- and post-TAVI EPS and delta HV has shown more consistent results in predicting the need for PPI, except for one study. That study found that delta HV was the only factor independently associated with CAVB (HR 1.152 per ms).34 In addition, delta HV ≥13 ms (sensitivity and speciﬁcity 100% and 84%, respectively) and HV interval ≥65 ms (sensitivity and speciﬁcity 83% and 82%, respectively) predicted PPI. When excluding the pre-TAVI EPS results from the analysis, a post-

TAVI HV interval of ≥65 ms (HR 1.081 per ms; sensitivity and speciﬁcity 80.0% and 77.8%, respectively) predicted PPI.34 Another study found post-TAVI HV interval to be predictive of PPI with an OR of 1.156.35 Conversely, another study found no correlation between HV interval or delta HV and PPI using three EPS.38 The differences in results may be explained by the different timing of the EPS. The mechanism of AVB development after TAVI is thought to be the direct compression of the prosthesis on the His bundle and AV node.42 Hence, the design and expansion properties of the valve have a direct effect on the risk and timing of the development of new conduction disturbances. The self-expanding property of the CoreValve’s prosthesis led to the maintenance of a steady radial force on the annular and subendocardial tissue, presumably for several days after implantation.43,44 The mechanically expanded Lotus valve has a braided Nitinol frame and a polyurethane/polycarbonate outer seal, and has demonstrated similar effects on the conduction system.35,45,46 The new-generation Edwards SAPIEN 3 valve has an adaptive external polyethylene terephthalate fabric seal designed to minimise paravalvular leaks.9 All these designs result in continuation of the radial pressure caused by the prosthesis over a time period exceeding the TAVI procedure. Combining these valve mechanisms with the occurrence of late conduction disturbances after TAVI and the finding that conduction disturbances continue to progress during the first few days after the procedure, and begin to recover after days 4–6,47,48 have led to two main recommendations:39 • All patients should be evaluated with a daily ECG. • The EPS should be performed only after the conduction disturbances in the ECG have stabilised, preferably prior to discharge.

Post-TAVI Electrophysiological Study-guided Permanent Pacemaker Implantation Strategy Tovia-Brodie et al. presented the results of 81 patients with conduction abnormalities after TAVI with either BE or SE valves.39 A total of 26 of these patients underwent post-TAVI EPS. Indications for PPI were severe infranodal conduction disturbances, such as greater than first-degree intra-His block, HV interval >75 ms and the occurrence of seconddegree infranodal block during incremental atrial pacing at a cycle length >400 ms. Multilevel conduction disturbances involving the AV node (n=19; 73.1%) and the His (n=3; 11.5%) and infra-His system (n=4; 15.4%) were found. Eight patients (30.8%) in the EPS group received PPI. There were five (9%) deaths and three (5.5%) PPIs after discharge among patients who did not undergo EPS, and none in the EPS group. The cause of death was SCD in three patients, heart failure in one patient and an unknown reason in another patient. The reason for PPI was CAVB in two patients and syncope associated with new LBBB with PR prolongation in one patient. The pacemakers were implanted 29, 96 and 252 days (mean 126 ± 114.4 days) after the procedure. Accordingly, undergoing an EPS was independently associated with prolonged event-free survival (defined as PPI or death; 100% versus 85.4%; p=0.04), but not overall survival (100% versus 90.9%; p=0.12). Rogers et al. reported EPS results of 95 patients who underwent TAVI with either BE or SE valves and developed conduction disturbances without an absolute indication for PPI.40 If a subject had intra- or infrahisian block, or the HV interval was >100 ms at baseline, the EPS was considered positive. Otherwise, patients were challenged with IV procainamide (dose ranging from 500 mg to 1 g) administered over 10 minutes. If the HV interval increased to >100 ms or if the patient

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

EPS in TAVI Patients developed intrahisian or greater than second-degree infrahisian block with procainamide challenge, the EPS was considered positive. The final decision to implant a permanent pacemaker was left to the discretion of the electrophysiologist. The only significant difference between patients who had a positive EPS and underwent a PPI to those with a negative EPS was the mean post-TAVI HV interval (67 ± 24 versus 54 ± 13 ms; p=0.02). There was no significant difference in 30-day and 1-year mortality between patients who received a permanent pacemaker and those who did not.40 After an initial cautious implementation, the number of EPS procedures performed increased significantly. This increase corresponded with a decline in the overall PPI rate. Hospital length of stay in patients with a negative EPS and no PPI was equivalent to that in patients with no conduction disturbance. None of the patients with a negative EPS required PPI after hospital discharge during the 1-year follow-up after TAVI, whereas 2% of patients who had no conduction abnormalities after TAVI (and therefore did not undergo an EPS) needed PPI at 1-year follow-up. Rogers et al. concluded that an EPS-guided PPI strategy is safe for the management of conduction disturbance after TAVI.40 In patients with equivocal indication for pacing after TAVI, EPS avoided PPI in over 70% of patients.

Summary and Interpretation The available studies are relatively small and different HV intervals were used as an indication for PPI. Only one study reported the occurrence of high-degree AVB in three patients after the decision was made not to implant a pacemaker based on post-TAVI EPS during follow-up.38 That study used a relatively high cut-off of HV interval >80 ms as an indication for PPI, without the use of a drug challenge for stressing the conduction system. The three cases occurred on days 2, 4 and 7 after the procedure, and no details were provided as to valve type, the timing of the EPS (possibly too early if CoreValve was used and the EPS was done prior to the development of the block) or whether the HV interval measured was normal (HV <55 ms) or prolonged (HV 55–79 ms), making the interpretation of these results difficult. In two studies, the only two patients needing PPI due to a relative indication demonstrated significant infranodal conduction disturbances in combination with HV interval ≥75 ms.30,31 In the remaining four studies that reported the results of long-term follow-up and the need for PPI in patients, with the decision made not to implant based on post-TAVI EPS results, no SCD occurred and none of the patients needed a PPI during at least 1 year of follow-up.33,34,39,40 Even though event-free survival (including late PPI or SCD) was 100% in the EPS-guided PPI group and few events occurred in the patient group discharged without an EPS, the difference in mortality and PPI rate did not reach statistical significance. This can be explained by the relatively small number of patients and low event rates. Based on these studies, when using EPS-guided PPI strategy, the cut-off value for HV interval should be in the range 65–75 ms (when a drug challenge is not used) or 100 ms with a drug challenge.

follow-up of at least 3 months.41 PPI was indicated in the presence of LBBB with an abnormal HV interval >55 ms or elicitation of CAVB at EPS. Seven patients were implanted due to LBBB and an abnormal HV interval on EPS. The HV interval ranged from 55 to 90ms. The single patient with the borderline HV (55 ms) who developed CAVB during EPS was the only patient of the seven to remain pacemaker dependent at follow-up. Pacemaker dependency was defined as >50% pacing upon device interrogation, underlying complete heart block, underlying asystole >5 seconds or symptoms in the setting of bradycardia (rate <50 BPM). Badenco et al. reported on pacemaker dependency.38 AVB was assessed in the pacemaker memory with a specific AVB management algorithm and the rate of ventricular pacing (a rate of 2% was considered relevant for analysis). During follow-up, high-degree AVB persisted in 12 of 17 patients implanted for perioperative AVB and in one of nine patients implanted prophylactically due to an increased HV3 interval. Six of these nine patients were implanted without persisting new conduction disturbances after the procedure based on HV interval measurements only. Kostopoulou et al. reported the follow-up results of pacemaker interrogation at 1 month after TAVI.33 Nine patients were implanted due to CAVB and one was implanted due to LBBB with an HV interval of 70 ms. The devices were programmed in an endogenous preference mode to be able to evaluate pacemaker dependency and the percentage of pacing on the next assessment of the device. Pacemaker dependency was defined as asystole or complete heart block with or without escape rhythm after cessation of pacing. Four of 10 patients (25% of ﬁrst-year implantations) remained pacemaker dependent, including the one patient implanted because of LBBB with HV prolongation. Two of three patients with documented infrahisian conduction delay with an HV interval >70 ms underwent PPI and remained pacemaker dependent throughout follow-up.

Summary and Interpretation

As emphasised previously, the authors do not recommend the use of ajmaline or flecainide as substitutes for procainamide in the drug challenge during EPS in post-TAVI patients.39 These patients frequently have severe left ventricular hypertrophy or dysfunction and may be at high risk of developing complications, especially life-threatening proarrhythmic events, following administration of ajmaline or flecainide.49

Not surprisingly, pacemaker dependency in patients implanted for a relative indication (LBBB plus prolonged HV interval) is lower than in patients implanted due to CAVB, involving three of 11 patients (27%), combining data from all studies (Table 1). However, the interpretation of device interrogation data regarding PPI necessity is problematic. Pacemaker dependency definition varied between studies. Many studies rely on the percentage of ventricular pacing as a surrogate for heart block and pacemaker dependency. However, devices are not always programmed meticulously to prefer intrinsic rhythm conduction, nor can a ventricular pacing rate <1% exclude short episodes of CAVB, because most devices implanted do not use an algorithm to identify the underlying rhythm. In addition, most device interrogations are performed 1-month after TAVI; hence, the exact timing of the recovery of intrinsic rhythm is not known. Considering all of this, it is the authors’ opinion that PPI in this subgroup of patients with new conduction disturbances and a prolonged HV interval cannot be avoided in order to try to prevent SCD in these patients, while acknowledging not all SCD are necessarily the result of bradyarrhythmias that could have been avoided by pacing. The authors’ proposed management algorithm for post-TAVI conduction disturbances, without an absolute indication for PPI, is shown in Figure 3.

Pacemaker Dependency

Conclusion

Makki et al. reported the results of 24 patients who underwent inhospital PPI after TAVI (mainly with CoreValve prostheses) and had a

As the indications for TAVI are expanding, more patients will experience post-procedural conduction disturbances and the dilemma of PPI will be

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Drugs and Devices Figure 3: Proposed Management Algorithm for Post-transcatheter Aortic Valve Implantation Conduction Disturbances

Repeat daily until stable ECG

LBBB HV interval ≥70 ms

RBBB+LAHB New slow AF Daily ECG

>48 h after TAVI

No resolution

PR prolongation >20 ms Transient high-degree AVB

TAVI procedure

Stable ECG?

Infranodal block

PPI

EPS Intra-His block HV interval <70 ms

Yes

2’ AVB Resolution

No PPI

Consider ILR or remote monitoring

Observation 24 h

Daily ECGs are recommended after the procedure. If ECG demonstrates new conduction disturbances, such as LBBB, RBBB with LAHB, new slow AF, PR prolongation >20 ms, transient high-degree AVB or second-degree (2’) AVB, we recommend watchful waiting with daily ECG for at least 48 hours after the procedure because of the dynamic nature of post-TAVI conduction disturbances. If the conduction disturbances resolve, continue observation for 24 hours and repeat the ECG prior to discharge to confirm no recurrence of conduction disturbances. If the conduction disturbances do not resolve and no changes are noted in the daily ECG (in QRS morphology and width and the measured PR interval), we recommend an EPS. If the EPS diagnoses infranodal block (HV interval >70 ms) or intra-His block, a permanent pacemaker should be implanted. If EPS demonstrates no significant infranodal disease, we do not recommend PPI. Consideration should be given to implanting a loop recorder or performing remote monitoring for longer time periods in patients with abnormal EPS results not meeting the above criteria (i.e. HV interval 60–70 ms) or significantly abnormal ECG (i.e. QRS width >160 ms). AVB = atrioventricular block; EPS = electrophysiological study; HV = His–ventricular; ILR = implantable loop recorder; LAHB = left anterior hemiblock; LBBB = left bundle branch block; PPI = permanent pacemaker implantation; RBBB = right bundle branch block; TAVI = transcatheter aortic valve implantation.

encountered more frequently. EPS may be a useful tool for evaluating these patients. There is a general agreement that the HV interval increases after TAVI, especially in patients with new conduction disturbances. The use of a post-TAVI EPS-guided PPI strategy in patients with new conduction disturbances is the one presently adopted by the authors. HV interval cut-off values for PPI ranging from 65 to 75 ms (or 100 ms with procainamide drug challenge) appear to be safe. The timing of EPS should depend on the stabilisation of the conduction disturbances on the ECG. Further large-scale studies including the various newergeneration valve types are needed to further validate this approach.

Footnote A comprehensive review on the management of conduction disturbances associated with TAVI has recently been published by Rodés-Cabau et al. 50 In that review, the use of EPS is suggested as an option for the management of patients with new LBBB or aggravation of pre-TAVI conduction disturbances. Infra-His block or

Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or transcatheter aortic-valve replacement in intermediate-risk patients. N Engl J Med 2017;376:1321–31. https://doi. org/10.1056/NEJMoa1700456; PMID: 28304219. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. https://doi.org/10.1056/ NEJMoa1103510; PMID: 21639811. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aorticvalve replacement with a balloon-expandable valve in low-risk patients. N Engl J Med 2019;380:1695–705. https://doi. org/10.1056/NEJMoa1814052; PMID: 30883058. Popma JJ, Deeb GM, Yakubov SJ, et al. Transcatheter aorticvalve replacement with a self-expanding valve in low-risk patients. N Engl J Med 2019;380:1706–15. https://doi. org/10.1056/NEJMoa1816885; PMID: 30883053. van der Boon RM, Nuis RJ, Van Mieghem NM, et al. New conduction abnormalities after TAVI – frequency and causes. Nat Rev Cardiol 2012;9:454–63. https://doi.org/10.1038/ nrcardio.2012.58; PMID: 22547171. Auffret V, Puri R, Urena M, et al. Conduction disturbances after transcatheter aortic valve replacement: current status and future perspectives. Circulation 2017;136:1049–69. https:// doi.org/10.1161/CIRCULATIONAHA.117.028352; PMID: 28893961. Popma JJ, Reardon MJ, Khabbaz K, et al. Early clinical outcomes after transcatheter aortic valve replacement using a novel self-expanding bioprosthesis in patients with

an HV interval >100 ms (without drug challenge) are suggested as indications for PPI. Importantly, however, this cut-off value was not used in any of the studies using EPS-guided PPI strategy in postTAVI patients.

Clinical Perspective • Conduction disturbances remain a frequent complication after transcatheter aortic valve implantation (TAVI), especially with newer-generation valve prostheses. • Prolongation of the His–ventricular interval after TAVI was predictive of permanent pacemaker implantation in several studies. • Based on the results of relatively small studies, electrophysiological studies may be useful for evaluating patients who develop postTAVI conduction disturbances.

severe aortic stenosis who are suboptimal for surgery: results of the Evolut R U.S. Study. JACC Cardiovasc Interv 2017;10:268–75. https://doi.org/10.1016/j.jcin.2016.08.050; PMID: 28183466. 8. Ben-Shoshan J, Konigstein M, Zahler D, et al. Comparison of the Edwards SAPIEN S3 versus Medtronic Evolut-R devices for transcatheter aortic valve implantation. Am J Cardiol 2017;119:302–7. https://doi.org/10.1016/j.amjcard.2016.09.030; PMID: 28029363. 9. Webb J, Gerosa G, Lefevre T, et al. Multicenter evaluation of a next-generation balloon-expandable transcatheter aortic valve. Am J Coll Cardiol 2014;64:2235–43. https://doi. org/10.1016/j.jacc.2014.09.026; PMID: 25456759. 10. Barbanti M, Buccheri S, Rodes-Cabau J, et al. Transcatheter aortic valve replacement with new-generation devices: a systematic review and meta-analysis. Int J Cardiol 2017;245:83– 9. https://doi.org/10.1016/j.ijcard.2017.07.083; PMID: 28760396. 11. Nomura T, Maeno Y, Yoon SH, et al. Early clinical outcomes of transcatheter aortic valve replacement in left ventricular outflow tract calcification: new-generation device vs earlygeneration device. J Invasive Cardiol 2018;30:421–27. PMID: 30373952 12. Saji M, Murai T, Tobaru T, et al. Autopsy finding of the Sapien XT valve from a patient who died suddenly after transcatheter aortic valve replacement. Cardiovasc Interv Ther. 2013;28:267– 71. https://doi.org/10.1007/s12928-012-0153-9; PMID: 23277347.

13. Greason KL, Friedman PA, Brown DR, Mathew V. Aborted episode of sudden death due to delayed heart block after transcatheter aortic valve insertion. J Thorac Cardiovasc Surg 2015;149:639–40. https://doi.org/10.1016/j.jtcvs.2014.09.126; PMID: 25451484. 14. De-Torres-Alba F, Kaleschke G, Vormbrock J, et al. Delayed pacemaker requirement after transcatheter aortic valve implantation with a new-generation balloon expandable valve: should we monitor longer? Int J Cardiol 2018;273:56–62. https://doi.org/10.1016/j.ijcard.2018.07.131; PMID: 30104033. 15. McCaffrey JA, Alzahrani T, Datta T, et al. Outcomes of acute conduction abnormalities following transcatheter aortic valve implantation with a balloon expandable valve and predictors of delayed conduction system abnormalities in follow-up. Am J Cardiol 2019;123:1845–52. https://doi.org/10.1016/j. amjcard.2019.02.050; PMID: 30922540. 16. Auffret V, Webb JG, Eltchaninoff H, et al. Clinical impact of baseline right bundle branch block in patients undergoing transcatheter aortic valve replacement. JACC Cardiovasc Interv 2017;10:1564–74. https://doi.org/10.1016/j.jcin.2017.05.030; PMID: 28734885. 17. Urena M, Webb JG, Tamburino C, et al. Permanent pacemaker implantation after transcatheter aortic valve implantation: impact on late clinical outcomes and left ventricular function. Circulation 2014;129:1233–43. https://doi.org/10.1161/ CIRCULATIONAHA.113.005479; PMID: 24370552. 18. Rodés-Cabau J, Urena M, Nombela-Franco L, et al. Arrhythmic burden as determined by ambulatory continuous cardiac

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EPS in TAVI Patients

19.

20.

21.

22.

23.

24.

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monitoring in patients with new-onset persistent left bundle branch block following transcatheter aortic valve replacement: the MARE Study. JACC Cardiovasc Interv 2018;11:1495–505. https://doi.org/10.1016/j.jcin.2018.04.016; PMID: 30031719. Serletis-Bizios A, Durand E, Cellier G, et al. A prospective analysis of early discharge after transfemoral transcatheter aortic valve implantation. Am J Cardiol 2016;118:866–72. https://doi.org/10.1016/j.amjcard.2016.06.035; PMID: 27453514. Barbanti M, van Mourik MS, Spence MS, et al. Optimising patient discharge management after transfemoral transcatheter aortic valve implantation: the multicentre European FAST-TAVI trial. EuroIntervention 2019;15:147–54. https://doi.org/10.4244/EIJ-D-18-01197; PMID: 30777842. Alkhalil A, Lamba H, Deo S, et al. Safety of shorter length of hospital stay for patients undergoing minimalist transcatheter aortic valve replacement. Catheter Cardiovasc Interv 2018;91:345–53. https://doi.org/10.1002/ccd.27230; PMID: 28836345. Durand E, Eltchaninoff H, Canville A, et al. Feasibility and safety of early discharge after transfemoral transcatheter aortic valve implantation with the Edwards SAPIEN-XT prosthesis. Am J Cardiol 2015;115:1116–22. https://doi. org/10.1016/j.amjcard.2015.01.546; PMID: 25726383. Généreux P, Demers P, Poulin F. Same day discharge after transcatheter aortic valve replacement: are we there yet? Catheter Cardiovasc Interv 2016;87:980–2. https://doi. org/10.1002/ccd.26059; PMID: 26198465. Cerrato E, Nombela-Franco L, Nazif TM, et al. Evaluation of current practices in transcatheter aortic valve implantation: the WRITTEN (WoRldwIde TAVI ExperieNce) survey. Int J Cardiol 2017;228:640–7. https://doi.org/10.1016/j.ijcard.2016.11.104; PMID: 27883975. Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on Cardiac Pacing and Resynchronization Therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace 2013;15:1070–118. https://doi.org/10.1093/europace/eut206; PMID: 23801827. Kappetein AP, Head SJ, Genereux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. Am J Coll Cardiol 2012;60:1438–54. https://doi.org/10.1016/j.jacc.2012.09.001; PMID: 23036636. Scheinman MM, Peters RW, Suavé MJ, et al. Value of the H–Q interval in patients with bundle branch block and the role of prophylactic permanent pacing. Am J Cardiol 1982;50:1316–22. https://doi.org/10.1016/0002-9149(82)90469-6; PMID: 7148708. Katritsis DG, Josephson ME. Electrophysiological testing for the investigation of bradycardias. Arrhythm Electrophysiol Rev

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2017;6:24–8. https://doi.org/10.15420/aer.2016:34:2; PMID: 28507743. Massoullié G, Bordachar P, Irles D, et al. Prognosis assessment of persistent left bundle branch block after TAVI by an electrophysiological and remote monitoring risk-adapted algorithm: rationale and design of the multicentre LBBB-TAVI Study. BMJ Open 2016;6:e010485. https://doi.org/10.1136/ bmjopen-2015-010485; PMID: 27797979. Rubín JM, Avanzas P, del Valle R, et al. Atrioventricular conduction disturbance characterization in transcatheter aortic valve implantation with the CoreValve prosthesis. Circ Cardiovasc Interv 2011;4:280–6. https://doi.org/10.1161/ CIRCINTERVENTIONS.111.961649; PMID: 21540440. Eksik A, Gul M, Uyarel H, et al. Electrophysiological evaluation of atrioventricular conduction disturbances in transcatheter aortic valve implantation with Edwards SAPIEN prosthesis. J Invasive Cardiol 2013;25:305–9. https://doi.org/10.1093/ eurheartj/eht310.P5404; PMID: 23735359. Shin DI, Merx MW, Meyer C, et al. Baseline HV-interval predicts complete AV-block secondary to transcatheter aortic valve implantation. Acta Cardiol 2015;70:574–80. https://doi. org/10.1080/AC.70.5.3110518; PMID: 26567817. Kostopoulou A, Karyofillis P, Livanis E, et al. Permanent pacing after transcatheter aortic valve implantation of a CoreValve prosthesis as determined by electrocardiographic and electrophysiological predictors: a single-centre experience. Europace 2016;18:131–7. https://doi.org/10.1093/europace/ euv137; PMID: 26060209. Rivard L, Schram G, Asgar A, et al. Electrocardiographic and electrophysiological predictors of atrioventricular block after transcatheter aortic valve replacement. Heart Rhythm 2015;12:321–9. https://doi.org/10.1016/j.hrthm.2014.10.023; PMID: 25446155. Eksik A, Yildirim A, Gul M, et al. Comparison of Edwards Sapien XT versus Lotus valve devices in terms of electrophysiological study parameters in patients undergoing TAVI. Pacing Clin Electrophysiol 2016;39:1132–40. https://doi.org/10.1111/ pace.12917; PMID: 27418419. López-Aguilera J, Segura Saint-Gerons JM, Mazuelos Bellido F, et al. Atrioventricular conduction changes after CoreValve transcatheter aortic valve implantation. Rev Esp Cardiol (Engl Ed) 2016;69:28–36. https://doi.org/10.1016/j.recesp.2015.02.026; PMID: 26215663. Akin I, Kische S, Paranskaya L, et al. Predictive factors for pacemaker requirement after transcatheter aortic valve implantation. BMC Cardiovasc Disord 2012;12:87. https://doi. org/10.1186/1471-2261-12-87; PMID: 23035864. Badenco N, Chong-Nguyen C, Maupain C, et al. Respective role of surface electrocardiogram and His bundle recordings to assess the risk of atrioventricular block after transcatheter aortic valve replacement. Int J Cardiol 2017;236:216–20. https:// doi.org/10.1016/j.ijcard.2017.02.029; PMID: 28237734.

39. Tovia-Brodie O, Ben-Haim Y, Joffe E, et al. The value of electrophysiologic study in decision-making regarding the need for pacemaker implantation after TAVI. J Interv Card Electrophysiol 2017;48:121–30. https://doi.org/10.1007/s10840016-0218-2; PMID: 27987072. 40. Rogers T, Devraj M, Thomaides A, et al. Utility of invasive electrophysiology studies in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation. Am J Cardiol 2018;121:1351–7. https://doi.org/10.1016/j. amjcard.2018.02.015; PMID: 29598854. 41. Makki N, Dollery J, Jones D, et al. Conduction disturbances after TAVR: Electrophysiological studies and pacemaker dependency. Cardiovasc Revasc Med 2017;18(5S1):S10–S13. https://doi.org/10.1016/j.carrev.2017.03.009; PMID: 28377313. 42. Moreno R, Dobarro D, Lopez de Sa E, et al. Cause of complete atrioventricular block after percutaneous aortic valve implantation: insights from a necropsy study. Circulation 2009;120:e29–30. https://doi.org/10.1161/ CIRCULATIONAHA.109.849281; PMID: 19652115. 43. Kawashima T, Sato F. Visualizing anatomical evidences on atrioventricular conduction system for TAVI. Int J Cardiol 2014;174:1–6. https://doi.org/10.1016/j.ijcard.2014.04.003; PMID: 24750717. 44. Jilaihawi H, Chin D, Spyt T, et al. Prosthesis–patient mismatch after transcatheter aortic valve implantation with the Medtronic–Corevalve bioprosthesis. Eur Heart J 2010;31:857– 64. https://doi.org/10.1093/eurheartj/ehp537; PMID: 20037145. 45. Alasti M, Rashid H, Rangasamy K, et al. Long-term pacemaker dependency and impact of pacing on mortality following transcatheter aortic valve replacement with the LOTUS valve. Catheter Cardiovasc Interv 2018;92:777–82. https://doi. org/10.1002/ccd.27463; PMID: 29314625. 46. Keßler M, Gonska B, Seeger J, et al. Predictors of permanent pacemaker implantation after transfemoral aortic valve implantation with the Lotus valve. Am Heart J 2017;192:57–63. https://doi.org/10.1016/j.ahj.2017.07.011; PMID: 28938964. 47. Bjerre Thygesen J, Loh PH, Cholteesupachai J, et al. Reevaluation of the indications for permanent pacemaker implantation after transcatheter aortic valve implantation. J Invasive Cardiol 2014;26:94–9. 48. Haworth P, Behan M, Khawaja M, et al. Predictors for permanent pacing after transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2010;76:751–6. https:// doi.org/10.1002/ccd.22457; PMID: 20927783. 49. Wellens HJ, Bar FW, Vanagt EJ. Death after ajmaline administration. Am J Cardiol 1980;45:905. https://doi. org/10.1016/0002-9149(80)90139-3; PMID: 7189088. 50. Rodés-Cabau J, Ellenbogen KA, Krahn AD, et al. Management of conduction disturbances associated with transcatheter aortic valve replacement: JACC Scientific Expert Panel. Am J Coll Cardiol 2019;74:1086–106. https://doi.org/10.1016/j. jacc.2019.07.014; PMID: 31439219.

Cardiac Pacing

Defining Left Bundle Branch Block Patterns in Cardiac Resynchronisation Therapy: A Return to His Bundle Recordings Roderick Tung and Gaurav A Upadhyay Center for Arrhythmia Care, Pritzker School of Medicine, University of Chicago, Chicago, IL, US

Abstract Left bundle branch block (LBBB) is associated with improved outcome after cardiac resynchronisation therapy (CRT). One historical presumption of LBBB has been that the underlying pathophysiology involved diffuse disease throughout the distal conduction system. The ability to normalize wide QRS patterns with His bundle pacing (HBP) has called this notion into question. The determination of LBBB pattern is conventionally made by assessment of surface 12-lead ECGs and can include patients with and without conduction block, as assessed by invasive electrophysiology study (EPS). During a novel extension of the classical EPS to involve left-sided recordings, we found that conduction block associated with the LBBB pattern is most often proximal, usually within the left-sided His fibres, and these patients are the most likely to demonstrate QRS correction with HBP for resynchronisation. Patients with intact Purkinje activation and intraventricular conduction delay are less likely to benefit from HBP. Future EPS are required to determine the impact of newer approaches to conduction system pacing, including intraseptal or left ventricular septal pacing. Left-sided EPS has the potential to refine patient selection in CRT trials and may be used to physiologically phenotype distinct conduction patterns beyond LBBB pattern.

Keywords Cardiac resynchronisation therapy, left bundle branch block, His bundle, septal activation, conduction block, biventricular pacing, electrophysiology Disclosure: RT has received speaking or consulting fees from Abbott, Biotronik and Boston Scientific. GAU has received speaking or consulting fees from Abbott, Biotronik, Medtronic and Zoll Medical. Received: 16 October 2019 Accepted: 16 February 2020 Citation: Arrhythmia & Electrophysiology Review 2020;9(1):28–33. DOI: https://doi.org/10.15420/aer.2019.12 Correspondence: Roderick Tung, Center for Arrhythmia Care, University of Chicago Medicine, 5841 South Maryland Ave, MC 6080, Chicago, IL 60637, US. E: rodericktung@uchicago.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.

In 1970, Durrer et al. recorded the total excitation of the human heart with 870 electrodes and confirmed the first 10 ms of left ventricular (LV) activation as trifascicular in nature.1 The rapid and synchronous activation of the LV through the specialised His–Purkinje network is highly intricate and efficient, preserving normal physiological coupling between electrical excitation and mechanical contraction. When normal transit through the His–Purkinje system is disrupted, stereotypic conduction block patterns are manifested on the 12-lead surface ECG (e.g. fascicular blocks or bundle branch blocks). These abnormal electrical activation patterns, particularly the left bundle branch block (LBBB) pattern, are associated with the presence, development or worsening of cardiomyopathy, and leads to increased risk of subsequent morbidity and mortality. Cardiac resynchronisation therapy (CRT) via biventricular pacing has been established as the mainstay electrical pacing modality to reverse the deleterious effects of electromechanical dyssynchrony, with significant reductions in mortality and heart failure (HF) hospitalisation for patients with wide QRS, as shown in multiple randomised controlled trials.2–7 However, despite these significant benefits, up to one-third of patients do not improve after biventricular pacing, and

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the overall rate of response from traditional biventricular pacing has remained stagnant despite technical improvements in lead delivery and site selection.8–10 During the past decade, we have gained a deeper mechanistic understanding of the benefits of biventricular pacing. Research has shown that patients with LBBB are the most likely to benefit from CRT, and that patients without significant LV conduction delay, particularly those with right bundle branch (RBBB) or non-specific intraventricular conduction delay (IVCD), derive little to no benefit from biventricular pacing.11–14 Nonresponse is not necessarily a failure of biventricular pacing, but rather a failure in appropriate patient selection. The physiology of conduction system disease is highly individualised and requires therapy directed at the patient’s underlying pathophysiology; traditional LV lead placement into an available tributary of the coronary sinus might not meet the needs of an individual patient. Indeed, the goal of CRT more broadly should be complete physiological resynchronisation utilising the His–Purkinje system, if possible. Identifying patients who might achieve physiological resynchronisation, however, can be challenging. In this review, we discuss the need to return to the ‘renaissance’ of electrophysiology (EP) when His bundle and electrical conduction system recordings were the focus of invasive study.15 In CRT, a precise

Defining LBBB Patterns in CRT diagnosis of the level and extent of conduction system pathology could improve technology selection, lead delivery and outcomes of physiological pacing.

Recruitment of the Conduction System: His Bundle Pacing Biventricular pacing achieves resynchronisation via non-physiological fusion of a right ventricular apical-paced wavefront and an epicardial wavefront from the basal lateral LV (and some newer techniques attempt left-sided fusion with native right-sided His-Purkinje activation). His bundle pacing (HBP) is a promising method to achieve electromechanical resynchronisation, as pacing utilising this strategy recruits the intrinsic specialised conduction system.16,17 Relative to traditional dual-chamber or biventricular pacing, HBP has been shown to preserve intrinsic activation in patients with narrow QRS,18 as well as restore a narrow QRS in patients with LBBB and RBBB patterns.19–21 Until recently, the underlying mechanism of how HBP (delivered proximally in the conduction system) corrects LBBB patterns (a distal defect) had not been well understood. Based on fine anatomic dissection studies of human and animal hearts in the 1960s and early 1970s, James and Sherf proposed a concept of sinoventricular conduction, in which impulses originating in the sinus node were predestined to specific locations in the ventricle.22 They also identified longitudinal separation of Purkinje strands with collagen within the His bundle, and introduced the concept that proximal lesions might impact more distal conduction.23 In the late 1970s, Narula demonstrated normalisation of LBBB patterns with stimulation of the distal His bundle, and based on James and Sherf’s work, interpreted these findings to prove the existence of longitudinally dissociated fibres with asynchronous conduction due to a discrete lesion or altered refractoriness within the His bundle.24 At the same time, ElSherif et al. provided further experimental and clinical observations of the normalisation of wide QRS (both RBBB and LBBB) with distal HBP, which was also interpreted as evidence of functional longitudinal dissociation of conduction from a pathological His bundle resulting in distal asynchronous conduction.25 However, these seminal observations and studies did not investigate the left-sided conduction system distal to the His bundle. It is important to emphasise that, according to this 40-year-old theory of functional longitudinal dissociation of the His bundle, conduction through the left bundle branch was theoretically proposed as remaining intact without actual conduction block, as the lesion within the His itself is sufficient to create sufficient conduction delay to create a bundle branch block pattern.

Variability in LBBB Pattern Definitions Historically, wide (≥120 ms) QRS patterns with dominant S-waves in lead V1 have been aggregated into the broad categorisation of LBBB pattern. However, not all conduction block patterns seen on the surface ECG are indicative of the same pathology. As such, LBBB patterns include both subtypes of those without discrete conduction block and those with ‘true’ or complete conduction block into or within the left bundle. In this regard, ‘block’ is a semantic error, as many patients might have intact activation of the Purkinje system. A prevailing definition of the LBBB pattern was developed by the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology/American College of Cardiology Foundation/Heart Rhythm Society (AHA/ACCF/HRS) in 2009.

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The LBBB pattern required a QRS ≥120 ms with a broad notched or slurred R-wave in leads I, aVL, V5 and V6.26 The cut-off of 120 ms was primarily historical and was revisited by Strauss and colleagues in 2011, who proposed a cut-off of ≥140 ms in men and ≥130 ms in women, along with the requirements of a QS or RS in leads V1–V2, and mid-QRS notching or slurring in two or more of leads V1, V2, V5, V6, I and aVL.27 The outcomes of CRT via biventricular pacing have been shown to vary based on how left LBBB is defined,28–30 which illustrates the need to optimise the phenotyping of patients with wide QRS eligible for CRT. Multiple ECG criteria have been assessed, but without a ‘gold standard’ of determination of whether or not block was present. The interpretation of notching and slurring within the QRS is also highly subjective.

Direct Recordings of Activation Patterns During LBBB: A New Gold Standard? To further investigate the theory of longitudinal dissociation in the His bundle, we commenced EP testing to delineate the activation patterns of the proximal left conduction system with multielectrode catheters in patients presenting for cardiac resynchronisation or substrate mapping for ventricular tachycardia ablation.31 Prior mapping studies performed to characterise LBBB patterns focused on myocardial breakout locations.32–34 We hypothesised that lesions within the His bundle could be more evident with bilateral His recordings, where the left-sided His might have discrepant or delayed timing relative to the right-sided His bundle activation (presenting as a ‘split-His’ with observable interhisian delay). To our surprise, we did not observe any differences in the His bundle activation recorded from the right and left side, and split His electrograms were rarely observed in patients with LBBB pattern. Rather, these findings were only present in patients who served as narrow QRS complex controls. Importantly, we observed complete disruption and absence of conduction in the left bundle with detailed contact mapping with multielectrode catheters. Of note, the conduction block site was frequently proximal to the left bundle, as the last recorded pre-potential was consistent with block within the left-sided His, and timing coincided with right-sided His activation with a local atrial component (Figure 1). To the best of our knowledge, this was the first observation of the focal ‘left intrahisian’ conduction block, where the central pathology exposed was a conduction defect into the left bundle, rather than within the left bundle. In contrast, in patients with either narrow QRS or RBBB pattern, intact Purkinje activation (IPA) was noted on the left side of the septum. In our study, 11 patients with narrow QRS and five patients with RBBB served as controls for patients with LBBB pattern at baseline. The absolute difference between the earliest and latest recorded ventricular maximum peak electrogram on our left septal recording catheter (ΔLV time) and transseptal conduction time for patients with narrow QRS or RBBB was similar to that of patients with IVCD, and in marked contrast to patients with complete conduction block and ‘true’ LBBB. The findings of complete conduction block at the level of the left-sided His fibres or the proximal LBBB are consistent with the theory of longitudinal dissociation, in that the inferred site of pathology is a proximal lesion within the branching His bundle, but differs significantly from this proposed theory because left bundle activation was not asynchronous relative to the right bundle, but completely blocked (Figure 2). Importantly, we observed presystolic recruitment of latent Purkinje potentials in patients with complete conduction block in the left bundle

Cardiac Pacing Figure 1: Left Intrahisian Left Bundle Branch Block 100 ms

I II V1

L His basal His

LVS basal

V V

A LB

LAO

LVS apical

V PP

apical

â&#x20AC;&#x153;left intra-hisianâ&#x20AC;? LBBB Narrow QRS (98ms): Normal H-P activation

Wide QRS (135ms): Intact Purkinje activation

Wide QRS (190ms): Complete Conduction Block

Intracardiac subclassification of LBBB patterns with intact Purkinje activation evidenced by continuous presystolic activation of specialised conduction system potentials with apical to basal ventricular activation in contrast to complete conduction block proximal to the left bundle at the level of the left-sided His recording. An atrial component is recorded at the site of the conduction block, indicating high and proximal pathology location. The ventricular activation is non-physiological, with basal to apical passive activation. LAO = left anterior oblique; LBBB = left bundle branch block; LVS = left ventricular septum; RV = right ventricle. Source: Upadhyay et al. 2019.31 Reproduced with permission from Wolters Kluwer Health. The Creative Commons license does not apply to this content. Use of the material in any format is prohibited without written permission from the publisher, Wolters Kluwer Health. Please contact permissions@lww.com for further information.

Figure 2: Comparing Theory of Longitudinal Dissociation with Finding of Conduction Block Complete conduction block:

Theory of Longitudinal Dissociation: Asynchronous conduction without block

Intra-His or LB

AVN

Septum His

Left intrahisian block

AVN

Septum

At the time of study conception, it was not known if IVCD would fare better or worse with HBP, and therefore, a broad definition of LBBB pattern (according to the 2009 AHA/ACCF/HRS consensus criteria) was used for inclusion. With a large crossover rate (48% from His CRT to biventricular pacing), the intention-to-treat outcomes were comparable between the two groups with regard to echocardiographic response, and His corrective pacing failed to reach statistical superiority, defined as a difference of 10% in ejection fraction.

Proximal LBBB LBBB LAF

LPF RBBB Comparison of complete conduction block observed with dedicated electrophysiology study of the left septum compared to the theory of longitudinal dissociation with intact distal conduction (green arrows), but asynchronous conduction. In both models, the site of the conduction system disease is focal and localised to the His fibres, but complete conduction block is not a component of the theory of functional delay from longitudinal dissociation of the His bundle. AD = anterior division of left bundle; AVN = atrioventricular node; LB = left bundle; LBBB = left bundle branch block; RBBB = right bundle branch block; LAF = left anterior fascicle; LPF = left posterior fascicle.

during His corrective pacing (Figure 3). These findings provide direct evidence of the mechanism of QRS narrowing with HBP, where complete conduction block is circumvented by a pacing stimulus that sufficiently captures the conduction system distal to the site of discrete block. Similar to the controls or RBBB patients noted earlier, patients without complete conduction block were observed to have IPA, and these patients uniformly failed attempts at His corrective pacing (Figure 4).

In a post-hoc analysis, 50% of patients (n=5) who crossed over to biventricular pacing from His pacing had IVCD patterns that could not be corrected by HBP.36 Perhaps the most important lesson learned from the His-SYNC pilot trial was that patients with IVCD should be excluded from enrolment in future HBP and conduction system pacing studies for CRT. Indeed, these patients appear to be best suited to traditional biventricular devices, although outcomes for patients with IVCD are known to be less favourable than those of patients with LBBB. Confirmation of intact Purkinje activation with left-sided conduction system mapping would potentially assist in patient selection to exclude patients with IVCD and apparent LBBB pattern on surface ECG. In addition, contact mapping can also afford assessment of His corrective thresholds prior to lead deployment. Indeed, even for patients with complete conduction block beyond the left-sided His fibres and in the proximal left bundle branch, higher outputs are generally required to achieve QRS correction. We found that patients with complete conduction block within the left bundle had lower rates of QRS correction compared to those with left intrahisian block (62% versus 94%, respectively; Figure 5).

Lessons from the His-SYNC Trial

Routine Left-sided Electrophysiological Testing for CRT

The His-SYNC pilot trial was the first multicentre randomised trial to evaluate corrective HBP in direct comparison with biventricular pacing.35

The most rigorous and physiological method to evaluate corrective HBP prospectively would be to invasively confirm disease within the left-sided

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Defining LBBB Patterns in CRT His fibres or proximal LBBB with EP prior to randomisation. The attendant risk of a retrograde transaortic approach needs to be carefully assessed prior to implementing routine left-sided EP. Although this risk is unlikely to be higher than a routine diagnostic left heart catheterisation with coronary angiography (stroke <1%), there could be greater risk in patients with extensive aortic arch atheromatous calcification or disease.37

Figure 3: Complete Conduction Block with Recruitment of Latent Purkinje Potentials During His Bundle Pacing with QRS Correction NS 121ms QRS 180ms

I V1

The diagnostic duodecapolar catheter that we use (Livewire, 2-2-2; Abbott) is routinely employed for substrate mapping during ventricular tachycardia ablation, and should theoretically carry less risk for thromboembolism than catheters used for diagnostic angiography, as there is no lumen. Systemic heparinisation should be considered in patients with extended LV dwell time, and could also be associated with increased risk of pocket haematoma during implantation. Emerging data suggest that patients could safely undergo device implantation during uninterrupted anticoagulation, including warfarin or non-vitamin K antagonists (e.g. apixaban, rivaroxaban or dabigatran), and singledose heparin to facilitate EP could be beneficial.38,39 With regard to non-invasive evaluation, there is a need to develop novel criteria to determine the presence of complete conduction block into the left bundle, as these patients are more likely to benefit from resynchronisation strategies (either biventricular pacing or HBP). The Strauss criteria has widely been recognised to be associated with better outcome prognostication after biventricular pacing. However, we found that 39% of patients with intact Purkinje activation demonstrated by left septal mapping met the Strauss criteria.40 The most helpful surface ECG criterion identified was the presence of mid-QRS notching, which had an excellent negative prediction value of 100%. It is worth noting that the observation of notching could be associated with a degree of subjectivity. Indeed, the literature often uses the terms ‘slurring’ and ‘notching’ interchangeably, when these likely reflect distinct underlying EP phenomena. Also not explicitly mentioned in the guidelines are patients demonstrating a ‘plateau’ within the QRS complex or whether this is a comparable observation to notching or slurring. Future work should be directed towards analysing the specific features of the QRS complex, which are most likely to be associated with underlying complete conduction block, and contemporary articulation of the guidelines should incorporate direction on how to classify based on these features more explicitly. There are recent reports that have successfully utilised artificial intelligence to detect subtle patterns in digitally acquired ECG data.41 While these techniques appear quite promising, approaches, such as convolutional neural networks, require large datasets (ideally in the hundreds of thousands) for algorithm training and robustness, and availability of this gold standard set of patients remains limited. Indeed, surface ECG recordings might always have limitations that will yield a diagnostic accuracy that falls short of direct recordings, as broadly applied criteria might not account for variability in chamber size, wall thickness, anatomic rotation and scar location. More recently, the development of high-density surface ECG assessment utilising either a vest or a belt has been proposed as a means to overcome some of the conventional limitations of the 12 lead.42,43 Septal activation, however, cannot be directly assessed with either technique, as both approaches predominantly utilise epicardial voltage assessment to construct activation maps. Theoretically, patients with significant leftsided IVCD could be miscategorised as having LBBB. These patients might still benefit from biventricular pacing, but would be unlikely to

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

L His

V PP

basal

PP PP

apical Complete conduction block at the level of the left-sided His without any left bundle recordings suggestive of block proximal to the left bundle. The PP are retrograde and passive after ventricular activation. With His bundle stimulation, QRS narrowing from 180 to 121 ms is observed. Non-selective His bundle capture is demonstrated by presystolic recruitment of the latent PP immediately after the pacing impulse. Normal physiological activation of the local ventricular electrograms is restored from apical to basal. NS = non-selective; PP = Purkinje potentials.

Figure 4: Failure to Correct QRS in Patient with Intact Purkinje Activation During Right or Left-sided His Bundle Pacing QRS 135ms

Right-sided His pacing

Left-sided His pacing

I II III aVR aVL aVF V1 V2 V3 V4 V5 V6 R His p R His d LV 19,20 LV 17,18 LV 15,16 LV 13,14 LV 11,12 LV 9,10 LV 7,8 LV 5,6 LV 3,4 LV 1,2

Intact Purkinje Activation

Selective

Non-selective

Selective

No QRS correction Inability to correct wide QRS in a patient with LBBB with intact Purkinje activation with pacing from both right- and left-side His bundle recording sites. Selective and non-selective stimulation of the His bundle fails to narrow the QRS width of 135 ms. LV = left ventricular. Source: Upadhyay et al. 2019.31 Reproduced with permission from Wolters Kluwer Health. The Creative Commons license does not apply to this content. Use of the material in any format is prohibited without written permission from the publisher, Wolters Kluwer Health. Please contact permissions@lww.com for further information.

respond to HBP for resynchronisation. With the proposed His-SYNC II trial, patients with IVCD will be specifically excluded, and the role of left-sided His recordings and invasive diagnostic EP testing remains to be determined in the planned protocol. Echocardiography-based measures of electromechanical delay, including apical rocking, systolic stretch index or septal flash, might also be beneficial. The integration of echocardiography with ECG measures in future studies is of ongoing interest and debate.

Cardiac Pacing Figure 5: Sites of Conduction Block in Patients with Left Bundle Branch Block Pattern with Rate of Response to Corrective His Bundle Pacing

Left intrahisian block 46% (n=33) QRS correction: 94% Left bundle branch block 18% (n=13) QRS correction: 62% His

L His

AVN

LAF

Sept

LBBB

Intact Purkinje activation 36% (n=26) QRS correction: 0%

RBBB

LPF

In this schematic of the proximal conduction system, the distribution of septal conduction among patients with LBBB patterns is shown, along with the location of block, if present. The septum is shown (dashed) to represent the location of the right-sided His fibres as they penetrate the central fibrous body, which then give rise to the left-sided His fibers (distal portion and branching bundle). In patients with complete conduction block (CCB), block was localised to the left-sided His fibres most commonly, and this location was most amenable to corrective His bundle pacing. Less commonly, CCB was found distal to the His recording site, at locations in which an atrial electrogram was not recorded. These locations were less amenable to corrective His bundle pacing and were anatomically consistent with block in the distal branching bundle or proximal left bundle-branch. The remainder of the patients with LBBB pattern did not demonstrate CCB. Assessment of local ventricular electrograms showed intact Purkinje activation, and the QRS was wide, most likely because of conduction slowing more distally. AVN = atrioventricular node; LBBB = left bundle branch block; LPF = left posterior fascicle; RBBB = right bundle branch block. Photograph courtesy of the University of California, Los Angeles, Cardiac Arrhythmia Center, Wallace A McAlpine, MD, collection; reproduced with permission from K Shivkumar, MD, PhD. Source: Upadhyay et al. 2019.31 Reproduced with permission from Wolters Kluwer Health. The Creative Commons license does not apply to this content. Use of the material in any format is prohibited without written permission from the publisher, Wolters Kluwer Health. Please contact permissions@lww.com for further information.

Predictions and Future Studies The evolution and re-emergence of HBP provides more options for CRT and marks a return to much needed emphasis on the physiology and pathophysiology of the conduction system. Much remains to be learned about the complex nature of the highly specialised His–Purkinje network. In patients with RBBB who traditionally do not benefit from biventricular pacing, we believe that HBP might emerge as a first-line therapy. Preliminary data are promising and prospective studies are necessary to confirm these findings.20 In patients with IVCD, it is our opinion that HBP and conduction system pacing for resynchronisation should not be considered as a monotherapeutic option, and diagnostic EP could be helpful to quickly exclude a patient’s candidacy, thereby minimising crossovers in future trials. Importantly, HBP and conduction system pacing for resynchronisation are currently used in the case of failed biventricular pacing or in the setting of a clinical study, as traditional biventricular pacing has been clearly shown to have improved survival, which has not yet been demonstrated in randomised controlled trials of HBP.19 Intraseptal or LV septal fixation techniques could have the potential to correct distal conduction block in the left bundle or in cases where HBP for resynchronisation is associated with high pacing output.44–46 Presently, more data are available on patients with narrow QRS utilising these approaches, and consensus in definitions

of intraseptal pacing with and without left conduction system capture is needed.47–51 In addition, invasive EP diagnostic recordings to delineate left septal activation during intraseptal pacing are likely to provide deeper physiological insights into these and other emergent strategies for conduction system pacing.

Clinical Perspective • Left bundle branch (LBBB) is well recognised to be associated with favorable outcome after CRT. • The mechanism of benefit for LBBB with CRT is through addressing lateral left ventricular delay by biventricular pacing, or through corrective His bundle pacing which engages latent His–Purkinje fibres and restores physiologic activation. • LBBB is usually identified through use of surface 12-lead ECG, which lacks specificity in identifying patients with complete conduction block. • Invasive electrophysiology (EP) study can quickly ascertain the presence of conduction block through evaluation of left ventricular septal activation patterns. • There may be utility in pursuing left-sided EP study to better differentiate conduction patterns in order to tailor therapy selection.

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35. Upadhyay GA, Vijayaraman P, Nayak HM, et al. His corrective pacing or biventricular pacing for cardiac resynchronization in heart failure. J Am Coll Cardiol 2019;74:157–9. https://doi. org/10.1016/j.jacc.2019.04.026; PMID: 31078637. 36. Upadhyay GA, Vijayaraman P, Nayak HM, et al. On-treatment comparison between corrective His bundle pacing and biventricular pacing for cardiac resynchronization: a secondary analysis of His-SYNC. Heart Rhythm 2019;16:1797– 807. https://doi.org/10.1016/j.hrthm.2019.05.009l; PMID: 31096064. 37. de Bono D. Complications of diagnostic cardiac catheterisation: results from 34,041 patients in the United Kingdom confidential enquiry into cardiac catheter complications. The Joint Audit Committee of the British Cardiac Society and Royal College of Physicians of London. Br Heart J 1993;70:297–300. https://doi.org/10.1136/hrt.70.3.297; PMID: 8398509. 38. Birnie DH, Healey JS, Wells GA, et al. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med 2013;368:2084–93. https://doi.org/10.1056/NEJMoa1302946; PMID: 23659733. 39. Birnie DH, Healey JS, Wells GA, et al. Continued vs. interrupted direct oral anticoagulants at the time of device surgery, in patients with moderate to high risk of arterial thromboembolic events (BRUISE CONTROL-2). Eur Heart J 2018;39:3973– 9. https://doi.org/10.1093/eurheartj/ehy413; PMID: 30462279. 40. Tung S, Lemaitre J. His bundle pacing: in pursuit of the “sweet spot”. Pacing Clin Electrophysiol 2015;38:537–9. https://doi. org/10.1111/pace.12604; PMID: 25640169. 41. Attia ZI, Kapa S, Lopez-Jimenez F, et al. Screening for cardiac contractile dysfunction using an artificial intelligence-enabled electrocardiogram. Nat Med 2019;25:70–4. https://doi. org/10.1038/s41591-018-0240-2; PMID: 30617318. 42. Ploux S, Lumens J, Whinnett Z, et al. Noninvasive electrocardiographic mapping to improve patient selection for cardiac resynchronization therapy: beyond QRS duration and left bundle branch block morphology. J Am Coll Cardiol 2013;61:2435–43. https://doi.org/0.1016/j.jacc.2013.01.093; PMID: 23602768. 43. Johnson WB, Vatterott PJ, Peterson MA, et al. Body surface mapping using an ECG belt to characterize electrical heterogeneity for different left ventricular pacing sites during cardiac resynchronization: relationship with acute hemodynamic improvement. Heart Rhythm 2017;14:385–91. https://doi.org/10.1016/j.hrthm.2016.11.017; PMID: 27871987. 44. Huang W, Su L, Wu S, et al. A novel pacing strategy with low and stable output: pacing the left bundle branch immediately beyond the conduction block. Can J Cardiol 2017;33:1736e1–3. https://doi.org/10.1016/j.cjca.2017.09.013; PMID: 29173611. 45. Rademakers LM, van Hunnik A, Kuiper M, et al. A possible role for pacing the left ventricular septum in cardiac resynchronization therapy. JACC Clin Electrophysiol 2016;2:413– 22. https://doi.org/10.1016/j.jacep.2016.01.010; PMID: 29759859. 46. Huang W, Chen X, Su L, et al. A beginner’s guide to permanent left bundle branch pacing. Heart Rhythm 2019;16:1791–6. https://doi.org/10.1016/j.hrthm.2019.06.016; PMID: 31233818. 47. Mafi-Rad M, Luermans JG, Blaauw Y, et al. Feasibility and acute hemodynamic effect of left ventricular septal pacing by transvenous approach through the interventricular septum. Circ Arrhythm Electrophysiol 2016;9:e003344. https://doi. org/10.1161/CIRCEP.115.003344; PMID: 26888445. 48. Vijayaraman P, Subzposh FA, Naperkowski A, et al. Prospective evaluation of feasibility, electrophysiologic and echocardiographic characteristics of left bundle branch area pacing. Heart Rhythm 2019;16:1774–82. https://doi. org/10.1016/j.hrthm.2019.05.011; PMID: 31136869. 49. Zhang W, Huang J, Qi Y, et al. Cardiac resynchronization therapy by left bundle branch area pacing in patients with heart failure and left bundle branch block. Heart Rhythm 2019;16:1783–90. https://doi.org/10.1016/j.hrthm.2019.09.006; PMID: 31513945. 50. Li X, Li H, Ma W, et al. Permanent left bundle branch area pacing for atrioventricular block: feasibility, safety, and acute effect. Heart Rhythm 2019;16:1766–73. https://doi.org/10.1016/j. hrthm.2019.04.043; PMID: 31048065. 51. Li Y, Chen K, Dai Y, et al. Left bundle branch pacing for symptomatic bradycardia: implant success rate, safety, and pacing characteristics. Heart Rhythm 2019;16:1758–65. https:// doi.org/10.1016/j.hrthm.2019.05.014; PMID: 31125667.

Clinical Arrhythmias

The Cryoballoon vs Irrigated Radiofrequency Catheter Ablation (CIRCA-DOSE) Study Results in Context Jason G Andrade,1,2 Marc W Deyell,2 Atul Verma,3 Laurent Macle1 and Paul Khairy;1 for the CIRCA-DOSE Study Investigators 1. Montreal Heart Institute, Department of Medicine, University of Montreal, Montreal, Canada; 2. Heart Rhythm Services, Department of Medicine, University of British Columbia, Canada; 3. Southlake Regional Health Center, Newmarket, Canada

Abstract The Cryoballoon vs Irrigated Radiofrequency Catheter Ablation: Double Short vs Standard Exposure Duration (CIRCA-DOSE) study was a multicentre, randomised, single-blinded trial that compared contact-force radiofrequency ablation and two different regimens of cryoballoon ablation. All patients received an implantable cardiac monitor for the purpose of continuous rhythm monitoring, with all arrhythmia events undergoing independent adjudication by a committee blinded to treatment allocation. The study demonstrated there were no significant differences between contact-force radiofrequency ablation and cryoballoon ablation with respect to recurrence of any atrial tachyarrhythmia, symptomatic atrial tachyarrhythmia, asymptomatic AF, symptomatic AF or AF burden. While the results of the CIRCA-DOSE study are reviewed here, this article focuses on considerations around the design of the study and places the observed outcomes in context.

Keywords AF, ablation, cryoablation, pulmonary vein isolation, radiofrequency, implantable cardiac monitor, implantable loop recorder Disclosure: The CIRCA-DOSE study was funded by a peer-reviewed grant from the Heart and Stroke Foundation of Canada (grant number G-13-0003121), with additional financial support from Medtronic. The funding sources had no role in the design of the study nor during its execution, analyses or interpretation of the data. JGA receives grants and personal fees from Medtronic, grants from Baylis and personal fees from Biosense-Webster. MWD receives grants from Biosense-Webster. AV receives grants and personal fees from Medtronic and Biosense-Webster; LM receives personal fees from Medtronic, and grants and personal fees from St Jude Medical/Abbott and Biosense-Webster. PK is supported by the André Chagnon research chair in electrophysiology and congenital heart disease. Acknowledgements: The authors thank Dominique Aubin, Angel Khaznadjian and Isabelle Robert for coordinating the trial, and Sylvie Levesque at the Montreal Health Innovations Coordinating Centre for statistical expertise, as well as the collaborating centres and study investigators for their support. Received: 23 October 2019 Accepted: 6 January 2020 Citation: Arrhythmia & Electrophysiology Review 2020;9(1):34–9. DOI: https://doi.org/10.15420/aer.2019.13 Correspondence: Jason Andrade, 2775 Laurel St, Vancouver BC V5Z 1M9, Canada. E: Jason.andrade@vch.ca 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 chronic, progressive disease, characterised by exacerbations and remissions. Over the past 10–15 years, multiple large-scale observational studies and randomised controlled trials have demonstrated that catheter ablation is superior to anti-arrhythmic drug (AAD) therapy in maintaining sinus rhythm and improving AF-related symptoms, exercise capacity and quality of life.1–7 The results of catheter ablation can be limited by arrhythmia recurrence, which is most often secondary to a failure to effectuate a durable contiguous circumferential transmural myocardial lesion around the pulmonary veins.6,8,9 In response, considerable effort has been directed towards developing technologies to achieve safer and more durable pulmonary vein isolation (PVI). The two most significant advances in recent years have centred on the integration of real-time quantitative assessment of catheter contact force into focal radiofrequency (RF) ablation catheters, and the development of dedicated catheters capable of achieving PVI with a single ablation lesion (e.g. Arctic Front Cryoballoon, Medtronic).

Access at: www.AERjournal.com

While the results of the Cryoballoon vs Irrigated Radiofrequency Catheter Ablation: Double Short vs Standard Exposure Duration (CIRCA-DOSE) study are reviewed here, this article focuses on considerations around the design of the study and places the observed outcomes in context.10,11

Study Design The CIRCA-DOSE study was a pragmatic clinical trial, designed to evaluate two separate clinically relevant questions. The Cryoballoon vs Irrigated Radiofrequency Catheter Ablation (CIRCA) study was designed to compare the effectiveness of PVI performed by advanced generation catheter ablation technologies (contact force guided RF ablation and second-generation cryoballoon-based ablation), and the Double Short vs Standard Exposure Duration study (DOSE) was designed to assess optimal cryotherapy dosing. The most cost-effective manner to address these two questions was in the context of a single three-arm trial (Figure 1). The study was a multicentre, prospective, parallel-group, singleblinded randomised clinical trial, with blinded end-point

CIRCA-DOSE in Context Figure 1: Randomisation and Patient Flow in the CIRCA-DOSE Study 353 patients implanted with implantable cardiac monitor 30–90 days before ablation 6 did not undergo ablation 1 withdrawn 346 patients were randomised 7–14 days before ablation

CIRCA

DOSE

115 randomised to CF-RF CF-RF group

CRYO groups

• Power 20–35 W • Contact force target of 20 g (range 10–40 g) • Minimum FTI of 400 g/s per lesion

115 completed study

116 randomised to CRYO-2

115 randomised to CRYO-4

0 death 1 protocol violation 0 withdrew 0 lost to follow-up

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• Lesion abandoned if TTI >60 s or temperature warmer than −35°C at 60 s • Bonus lesion delivered after PVI

0 death 1 protocol violation 1 withdrew 0 lost to follow-up

114 completed study

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1 death 0 protocol violation 1 withdrew 0 lost to follow-up

116 included in primary analysis

Two protocol violations occurred; one patient in the CF-RF group received CRYO-4 ablation, and one patient in the CRYO-4 group underwent CF-RF ablation. Patients were analysed according to their randomised group by the intention-to-treat principle. CF-RF = standard RF ablation guided by tissue contact-force; CRYO-4 = 4-minute cryoballoon ablation duration; CRYO-2 = 2-minute cryoballoon ablation duration; FTI = force time interval; PVI = pulmonary vein isolation. Source: Andrade et al. 2019.11 Adapted with permission from Wolters Kluwer Health.

ascertainment conducted at eight clinical centres in Canada. The study included a total of 346 patients with AF refractory to at least one class I or class III AAD. Patients were randomised in a 1:1:1 ratio to: contact force radiofrequency ablation (CF-RF); short 2-minute cryoballoon ablation duration (CRYO-2); or standard 4-minute cryoballoon ablation duration (CRYO-4). Patients were blinded to their randomisation assignment. All patients received an implantable cardiac monitor (ICM) for continuous rhythm monitoring, with all arrhythmia events undergoing independent adjudication by a committee blinded to treatment allocation.

was 79.1% with CF-RF, 78.2% with CRYO-4 and 73.3% with CRYO-2; p=0.26. Compared to the pre-ablation monitoring period, the burden or time in AF was reduced by a median of 99.3% (IQR 67.8–100.0%) with CF-RF, 99.9% (IQR: 65.3–100.0%) with CRYO-4, and 98.4% (IQR 56.2–100.0%) with CRYO-2 (p=0.36; Figure 2B).

Safety Outcomes The absolute rate of complication within the CIRCA-DOSE study was low. Serious adverse events occurred in three patients (2.6%; six events) in the CF-RF arm, six patients (5.2%; seven events) in the CRYO4 arm, and seven patients (6.0%; 8 events) in the CRYO-2 arm, with no significant difference between the groups (p=0.24).

Endpoints The primary endpoint of CIRCA-DOSE was time to the first recurrence of any symptomatic or asymptomatic atrial tachyarrhythmia (AF, atrial flutter [AFL] or atrial tachycardia [AT]) after a single ablation procedure and 90-day blanking period, as detected by continuous cardiac rhythm monitoring. Symptomatic AF/AFL/AT and total atrial arrhythmia burden were considered secondary endpoints.

Rhythm Outcomes At 12 months, there was no difference in the arrhythmia endpoints between the three randomised groups (Figure 2A). The 1-year freedom from any atrial tachyarrhythmia, measured using continuous rhythm monitoring, was 53.9% with CF-RF, 52.2% with CRYO-4 and 51.7% with CRYO-2; p=0.87. The 1-year freedom from symptomatic atrial tachyarrhythmia, assessed using by continuous rhythm monitoring,

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

The most common complication was pericarditis (1.7% overall), with vascular access complications, pericardial effusion, tamponade, thromboembolism and phrenic nerve injury all individually occurring in <1% of patients.

Procedural Outcomes Procedure duration and left atrial access time were both significantly longest in the CF-RF group (164.5 and 143 minutes, respectively), intermediate in the CRYO-4 group (143 and 116.5 minutes, respectively) and shortest in the CRYO-2 group (130.5 and 104.5 minutes, respectively). Conversely, the median total fluoroscopy time was significantly shorter in the CF-RF group than in either of the cryoballoon groups (5.2 minutes with CF-RF versus 17.2 and 19.0 minutes in the CRYO-4 and CRYO-2 groups, respectively).

Clinical Arrhythmias Figure 2A: Tachyarrhythmia and EventFree Survival After Ablation 100 Freedom from symptomatic atrial tachyarrhythmia

Blanking period

79.1% CF-RF

78.2% CRYO-4

Event-free survival (%)

73.3% CRYO-2 Freedom from any atrial tachyarrhythmia

53.9% CF-RF 52.2% CRYO-4 51.7% CRYO-2 40

demonstrated that these outcomes were consistent across the evaluated technologies. Specifically, there was no significant difference between contact-force RF ablation and cryoballoon ablation with respect to recurrence of any atrial tachyarrhythmia, symptomatic atrial tachyarrhythmia, asymptomatic AF, symptomatic AF or AF burden. Similarly, there was no difference in the frequency of complications between randomised groups. Finally, the 53% time-to-first recurrence success rate corresponded to a >99% AF burden reduction, suggesting that the use of a binary time-to-event outcome may underestimate clinical benefits to patients.

How Do the Results Compare to Other Contact Force Radiofrequency Ablation Studies?

CRYO-2

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CF-RF

0 0

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Kaplan-Meier curves of freedom from symptomatic (top) and any (bottom) atrial tachyarrhythmia (AF/atrial flutter/atrial tachycardia) after a single ablation procedure. CF-RF = standard RF ablation guided by tissue contact-force; CRYO-4 = 4-minute cryoballoon ablation duration; CRYO-2 = 2-minute cryoballoon ablation duration. Source: Andrade et al. 2019.11 Adapted with permission from Wolters Kluwer Health.

Figure 2B: AF Burden Before and After Ablation 40

In contrast to the two largest multicentre trials evaluating contact-force RF technology (TactiCath Contact Force Ablation Catheter Study for Atrial Fibrillation [TOCCASTAR] and THERMOCOOL® SMARTTOUCH™ Catheter for the Treatment of Symptomatic Paroxysmal Atrial Fibrillation [SMART-AF]) the CIRCA-DOSE study protocol pre-specified the contact force and lesion delivery parameters.12,13 For CIRCA-DOSE, the prespecified target contact force of 20 g (acceptable range 10–40 g) with a minimum individual target lesion duration of 400 gram-seconds forcetime integral (FTI) was based on data derived from the TactiCath® Prospective Effectiveness Pilot Study (EFFICAS I and II) and Touch+™ for Catheter Ablation (TOCCATA) studies, which were the best data available when the CIRCA-DOSE study was initiated.14–17

Percent time in AF

Within this context, the observed freedom from symptomatic AF/AT/ AFL of 79.1% in the CF-RF group in CIRCA-DOSE is numerically greater than that observed in the SMART-AF and TOCCASTAR trials (72.5%, and 66% respectively).12,13 However, the results in CIRCA-DOSE are comparable to those observed in SMART-AF when operators were working in their selected CF-ranges ≥80% of the time.

0 Pre

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Pre-ablation AF burden

1.57 (0.08–16.09)

3.71 (0.22–13.78)

1.46 (0.09–9.17)

Post-ablation AF burden

0.00 (0.00–0.11)

0.00 (0.00–0.24)

0.01 (0.00–0.34)

Median reduction in AF burden from baseline

99.34% (67.76–100.00)

99.93% (65.31–100.00)

98.40% (56.24–100.00)

AF burden before and after ablation by randomised group. Data in the table are presented as median (IQR). Plots demonstrates the 10th, 25th, 50th, 75th, and 90th percentile. CF-RF = standard RF ablation guided by tissue contact-force; CRYO-4 = 4-minute cryoballoon ablation duration; CRYO-2 = 2-minute cryoballoon ablation duration; IQR = interquartile range. Source: Andrade et al. 2019.11 Adapted with permission from Wolters Kluwer Health.

Quality of Life Outcomes At baseline, disease-specific and generic health-related quality of life (HRQOL) were moderately to severely impaired. For each of the randomised groups, there was a significant improvement in HRQOL and AF symptom scores at 6 months’ follow-up. This improvement was sustained at 12 months.

What does the CIRCA-DOSE Study Tell Us? First and foremost, the CIRCA-DOSE study convincingly demonstrates the efficacy of PVI for patients with paroxysmal AF. The observed substantial (>99%) reduction in AF burden was significant and clinically relevant, given that the major indication for PVI is to alleviate symptoms associated with recurrent arrhythmia episodes. Second, the study

While it is possible that the high success in CIRCA-DOSE reflects the value of prospectively targeting pre-specified CF parameters such as FTI, it is difficult to know how these results may have differed with the use of novel ablation lesion quality markers such as ablation index, which incorporates contact force, time and power into a weighted formula.6,13,18

Why Was Any Atrial Tachyarrhythmia the Primary Endpoint? Given that the CIRCA-DOSE study was designed as a comparative technology evaluation, we felt that a determination of the true efficacy of AF ablation required the inclusion of both symptomatic and asymptomatic arrhythmia episodes, as detected by continuous rhythm monitoring. While freedom from AF-related symptoms may be the most important endpoint from a patient perspective, contemporary evidence suggests a poor correlation between symptoms and AF burden.19,20 Moreover, studies reporting ablation success based on freedom from symptomatic arrhythmia have a tendency to overestimate treatment success (defined by the absence of detected AF) by 20% or more, which is consistent with the difference observed in CIRCA-DOSE (i.e., a 21.6–26.0% difference between symptomatic and any AF/AFL/AT).2,6,12,13,18,21,22 Including AT and AFL within the primary endpoint recognises that iatrogenic tachyarrhythmias can be caused by incomplete scar formation secondary to the ablation procedure itself. This is relevant to our study design because previous studies have suggested that CF-RF may be associated with a higher rate of atypical flutter/tachycardia than cryoballoon ablation.23

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CIRCA-DOSE in Context Finally, while some studies permitted multiple ablation procedures within the periprocedural blanking period “without penalty with regard to the primary efficacy endpoint”, we felt this would overestimate treatment success.3,12,13,24 As such, we considered a repeat ablation procedure at any time to constitute a treatment failure.

Why Were Implantable Cardiac Monitors Used to Document Arrhythmia Recurrence? While non-invasive intermittent rhythm monitoring remains the most widely used method of ascertaining ablation efficacy, it lacks sensitivity in detecting sporadic arrhythmias such as paroxysmal AF. This would be expected to result in recurrences being underdetected, inflating estimates of arrhythmia-free survival and introducing misclassification errors that could potentially impact the accuracy and precision of comparative risk estimates.25–27 This imprecision associated with intermittent arrhythmia monitoring confers a significant risk of a type II error, which makes non-invasive intermittent rhythm monitoring inappropriate for outcome ascertainment in a trial designed to evaluate the efficacy of different therapeutic interventions. In addition to optimising arrhythmia detection, the use of an ICM optimises adherence through automated home monitoring (CareLink, Medtronic). For the reasons set out above, non-adherence to rhythm monitoring protocols can result in under-detection of recurrences, and consequent misclassification errors. Unfortunately, compliance with non-invasive rhythm monitoring has been reported to be as low as 59% in contemporary AF ablation studies.28 Finally, using an ICM provided an accurate quantification of AF burden or the proportion of time an individual is in AF.22,25,26,29 While time to first AF recurrence has been considered the gold standard for reporting the efficacy of AF ablation procedures, these dichotomous endpoints considers AF as a binary condition, which provides an incomplete assessment of ablation outcomes.22,29 Virtually no other chronic cardiac condition, such as heart failure or angina, is considered in similar binary terms. In evaluating AF burden with ICMs, we were able to consider AF as a quantitative entity on a continuous scale, which provides a more comprehensive evaluation of treatment effect of ablation.22

Why Were 2-minute Freezes Chosen for the Short Duration Group? The optimal duration of freezing – how long the tissue should be kept in a frozen state – is not well established. The previous recommendation was for cryoablation dosing at 240 seconds for each application. This recommendation was derived from studies of an early focal cryocatheter. In these early cryofocal studies, it was observed that the effect of a cryoablation lesion reached a plateau of 3 minutes after the onset of ablation. Thereafter, “prolongation of exposure time beyond 3 minutes did not result in any further increase in lesion dimension or volume”.30,31 Since then, the cryocatheter has evolved from a rigid focal catheter to a semicompliant balloon, which meant the cryorefrigerant delivery mechanisms had to be redesigned. Moreover, the refrigerant itself has changed from slow-cooling to more efficacious gases. Before undertaking the CIRCA-DOSE clinical study, we completed two randomised pre-clinical studies examining the immediate and delayed effects of shorter cryoablation times. In the first study, a focal cryocatheter was used. This study demonstrated no difference in ablation lesion surface area (167.8 ± 21.6 mm2 versus

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

194.3 ± 22.6 mm2; p=0.40), maximum depth (4.4 ± 0.2 mm versus 4.5 ± 0.2 mm; p=0.71) and volume (125.7 ± 69.5 mm3 versus 141.0 ± 83.5 mm3; p=0.25) between 2-minute and 4-minute freezes, as assessed by three-dimensional morphometric analyses.32 This study concluded that single 2-minute and 4-minute applications result in catheter ablation lesions of a similar size using the modern cryoablation system with nitrous oxide as a refrigerant. The second study examined a single 2- versus 4-minute cryoballoon application, specifically assessing PVI efficacy.33 In this study, 32 dogs underwent cryoballoon ablation with a 23 mm cryoballoon catheter. PVI procedures were randomised to a 2-minute versus a 4-minute cryoballoon application. Although 4-minute lesions were associated with a thicker neointima than 2-minute lesions (223.8 μm versus 135.6 μm; p=0.007), no differences were observed in the rates of procedural PVI or in the achievement of complete circumferentially transmural lesions at 30 days (78% overall; 86.2% for 2-minute versus 70% for 4-minute lesions; p=0.285). However, fewer late pulmonary vein (PV) strictures were observed in the 2-minute group (6/30 PVs with strictures in the 4-minute freeze duration versus 0/29 PVs with strictures in the 2-minute freeze duration; p=0.024). As such, the CIRCA-DOSE study was designed to evaluate whether an abbreviated 2-minute cryoablation lesion would have a similar efficacy to a cryoablation lesion of a standard duration. While clinical practice has moved to 3-minute cryoablation durations, it is important to recognise that the evidence supporting the use of a 3-minute lesion is derived from non-randomised studies, where 3-minute cryoablation durations were compared to historical controls.34,35 Even though we did not specifically study 3-minute cryoapplications, it is reasonable to interpret the results of the CIRCADOSE study in supporting the use of a 3-minute cryolesion, given that the study demonstrated similar efficacy in the primary endpoint for both the 2-minute and 4-minute cryoablation groups.

Why Were Time to Isolation and Time to Effect Not Used? Time to isolation (TTI) and time to effect (TTE) are physiological intraprocedural predictors of lesion durability, with a short time to effect associated with a higher likelihood of delivering an efficacious lesion.36 As TTI can be evaluated in real time during the index ablation procedure, there has been a recent trend for protocols to incorporate assessment of real-time PVI into cryoablation dose-titration algorithms.37 While the CIRCA-DOSE study did not explicitly titrate the cryoablation lesion duration on the basis of the observed TTI, the study did prospectively incorporate TTI assessment into the cryoablation protocol. Specifically, a key focus of the study was on determining if shorter cryoballoon ablation durations were as efficacious as standard cryoablation durations. As the permanence of cryoablation lesions are a function of catheter tissue contact, tissue temperature and freezing duration, we were concerned that late PVI (occurring >60 seconds after freezing onset) would disproportionately affect the short cryoablation group (CRYO-2). To avoid this, we prospectively mandated that lesions that fail to isolate the vein after 60 seconds of ablation onset be terminated. In patients where real-time PV monitoring could not be achieved, we employed a temperature cut-off of −35°C at 60 seconds as a surrogate for lesion efficacy. This combination ensured that the lesion would be as efficacious as possible.

Clinical Arrhythmias Figure 3: Fluoroscopy Duration Fluoroscopy duration 50 RF 40

CRYO

19.6%

Time in minutes

64.7% 69.0%

74.6% 22.7%

84.1% 69.7%

88.5%

60.0%

52.0%

CRYO versus RF study

FIRE AND ICE study

CIRCA-DOSE

Site A

Site B

Site C

Site D

Site E

Site F

Site G

CIRCA-DOSE study sites Fluoroscopy duration in the CRYO vs RF Study, the FIRE AND ICE Study, and the CIRCA-DOSE study, as well as by site in the CIRCA-DOSE. CRYO = cryoballoon ablation; RF = radiofrequency ablation.

Figure 4: AF Reduction but Failed Primary Outcome Feb 2016

P = program

Apr 2016

Jun 2016

Aug 2016

Oct 2016

Dec 2016

Feb 2017

I = interrogate _ = remote S = symptom(s)

AT/AF (total hours/day)

24 20 16 12 8 4 0

Pre-ablation AF burden

Post-ablation AF burden

Illustrative example of a treatment failure based on the primary outcome of the CIRCA-DOSE study. The patient had an adjudicated isolated asymptomatic recurrence of atrial tachyarrhythmia about 6 months after the index ablation, which constituted a study endpoint. However, consideration of the baseline AT/AF burden demonstrates a substantial decrease following pulmonary vein isolation. AT = atrial tachyarrhythmia.

How do Patients in CIRCA-DOSE Compare to Others? The CIRCA-DOSE study enrolled patients with highly symptomatic paroxysmal AF refractory to AADs. The patients included in the study reflected those in contemporary AF ablation trials, with the majority being men in their late 50s with normal atrial dimensions and a low CHA2DS2-VASc score.38 Two-thirds of patients were classified as having a Canadian Cardiovascular Society Severity of AF score of 3 or more, signifying that the symptoms attributable to AF were having a moderate to severe impact on their general quality of life. Likewise, both the disease-specific (AFEQT) and generic (EQ-5D) HRQOL scores were moderate-severely impaired at baseline (mean Atrial Fibrillation Effect on QualiTy-of-Life [AFEQT] score 54.2; mean EQ-5D score 0.867). The pre-ablation AF burden recorded on continuous monitoring was 1.5–3.7%, which corresponds to 1 hour of AF every 1– 3 days. Unfortunately, it is difficult to contextualise this burden, as CIRCA-DOSE is unique as continuous cardiac rhythm was monitored in the months

before the ablation procedure. Using more commonly reported surrogates of pre-ablation AF burden, the median of 4.0 AF episodes per month in CIRCA-DOSE and the observation that patients had failed a median of 2.0 AADs before enrolment are both comparable to contemporary studies.1,3,4,6,18,21,38,39

How Can We Interpret the Procedural Data? Consistent with the previous randomised comparisons, we observed a significantly shorter procedure duration but significantly longer fluoroscopy duration with cryoballoon ablation. While these results are consistent on the whole with previous randomised comparisons, it is important to note that the fluoroscopy time in CIRCA-DOSE was lower than that reported in previous comparative studies (Figure 3). Conversely, while the procedure time was longer in CIRCA-DOSE, this was likely to be a function of the mandated 20-minute post-ablation observation period in combination with the administration of adenosine for the assessment, as per protocol, and subsequent elimination of dormant conduction.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

CIRCA-DOSE in Context Interestingly, when the analysis was stratified by site, these differences became more significant. This suggests that the between-site variability resulted in significant overlap when the results were considered only by the randomised groups. Within each site, there were consistent and substantial differences in procedural and fluoroscopy times between these ablation technologies. In all study sites, the procedures with cryoablation were significantly shorter, and procedures with CF-RF used less fluoroscopy.

What Else Can We Take Away? The stark contrast between the rates of the primary endpoint (~53% success when based on AF recurrence as a dichotomous outcome) and the magnitude of reduction in AF burden (~99% compared to pre-ablation monitoring) highlights the need to reappraise the optimal endpoint for establishing the success of AF ablation procedures (Figure 4).

Conclusion The CIRCA-DOSE trial demonstrates that PVI performed by cryoballoon ablation or by contact-force guided RF ablation results in comparable

10.

11.

12.

13.

Pappone C, Augello G, Sala S, et al. A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: the APAF study. J Am Coll Cardiol 2006;48:2340–7. https://doi.org/10.1016/j. jacc.2006.08.037; PMID: 17161267. Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA 2005;293:2634–40. https://doi.org/10.1001/jama.293.21.2634; PMID: 15928285. Jais P, Cauchemez B, Macle L et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation 2008;118:2498–505. https://doi.org/10.1161/ CIRCULATIONAHA.108.772582; PMID: 19029470. Oral H, Pappone C, Chugh A , et al. Circumferential pulmonaryvein ablation for chronic atrial fibrillation. N Engl J Med 2006;354:934–41. https://doi.org/10.1056/NEJMoa050955; PMID: 16510747. Packer DL, Irwin JM, Champagne J, et al. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front STOP-AF pivotal trial. J Am Coll Cardiol 2010;55:e3015–6. https://doi. org/10.1016/j.jacc.2012.11.064; PMID: 23500312. Wilber DJ, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA 2010;303:333–40. https:// doi.org/10.1001/jama.2009.2029; PMID: 20103757. Wokhlu A, Monahan KH, Hodge DO, et al. Long-term quality of life after ablation of atrial fibrillation: the impact of recurrence, symptom relief, and placebo effect. J Am Coll Cardiol 2010;55:2308–16. https://doi.org/10.1016/j.jacc.2010.01.040; PMID: 20488300. Kobza R, Hindricks G, Tanner H, et al. Late recurrent arrhythmias after ablation of atrial fibrillation: incidence, mechanisms, and treatment. Heart Rhythm 2004;1:676–83. https://doi.org/10.1016/j.hrthm.2004.08.009; PMID: 15851239. Ouyang F, Ernst S, Chun J, et al. Electrophysiological findings during ablation of persistent atrial fibrillation with electroanatomic mapping and double Lasso catheter technique. Circulation 2005;112:3038–48. https://doi. org/10.1161/CIRCULATIONAHA.105.561183; PMID: 16275866. Andrade JG, Deyell MW, Badra M, et al. Randomised clinical trial of cryoballoon versus irrigated radio frequency catheter ablation for atrial fibrillation-the effect of double short versus standard exposure cryoablation duration during pulmonary vein isolation (CIRCA-DOSE): methods and rationale. BMJ Open 2017;7:e017970. https://doi.org/10.1136/bmjopen-2017017970; PMID: 28982836. Andrade JG, Champagne J, Dubuc M, et al. Cryoballoon or radiofrequency ablation for atrial fibrillation assessed by continuous monitoring: a randomized clinical trial. Circulation 2019;140:1779–88. https://doi.org/10.1161/ CIRCULATIONAHA.119.042622; PMID: 31630538. Reddy VY, Dukkipati SR, Neuzil P, et al. Randomized, controlled trial of the safety and effectiveness of a contact force-sensing irrigated catheter for ablation of paroxysmal atrial fibrillation: results of the TactiCath Contact Force Ablation Catheter Study for Atrial Fibrillation (TOCCASTAR) study. Circulation 2015;132: 907–15. https://doi.org/10.1161/CIRCULATIONAHA.114.014092; PMID: 26260733. Natale A, Reddy VY, Monir G, et al. Paroxysmal AF catheter ablation with a contact force sensing catheter: results of the

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22.

23.

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freedom from recurrent atrial tachyarrhythmia as assessed by continuous cardiac rhythm monitoring. Binary efficacy outcomes, such as AF recurrence, appear to underestimate the treatment effect of AF ablation.

Clinical Perspective • Arrhythmia outcomes are comparable after pulmonary vein isolation using the cryoballoon ablation and contact forceguided radiofrequency energy, suggesting that either procedure can be performed depending on operator preference and skill. • Shorter cryoballoon ablation durations (freezing for 2 minutes instead of 4 minutes) significantly reduce procedural duration without compromising arrhythmia efficacy. • Binary arrhythmia efficacy outcomes underestimate the clinical impact of catheter ablation, with a 53% time-to-first-recurrence success rate corresponding to a >99% AF burden reduction.

prospective, multicenter SMART-AF trial. J Am Coll Cardiol 2014;64:647–56. https://doi.org/10.1016/j.jacc.2014.04.072; PMID: 25125294. Neuzil P, Reddy VY, Kautzner J, et al. Electrical reconnection after pulmonary vein isolation is contingent on contact force during initial treatment: results from the EFFICAS I study. Circ Arrhythm Electrophysiol 2013;6:327–33. https://doi.org/10.1161/ CIRCEP.113.000374; PMID: 23515263. Kautzner J, Neuzil P, Lambert H, et al. EFFICAS II: optimization of catheter contact force improves outcome of pulmonary vein isolation for paroxysmal atrial fibrillation. Europace 2015;17:1229– 35. https://doi.org/10.1093/europace/euv057; PMID: 26041872. Kuck KH, Reddy VY, Schmidt B, et al. A novel radiofrequency ablation catheter using contact force sensing: Toccata study. Heart Rhythm 2012;9:18–23. https://doi.org/10.1016/j. hrthm.2011.08.021; PMID: 21872560. Reddy VY, Shah D, Kautzner J, et al. The relationship between contact force and clinical outcome during radiofrequency catheter ablation of atrial fibrillation in the TOCCATA study. Heart Rhythm 2012;9:1789–95. https://doi.org/10.1016/j. hrthm.2012.07.016; PMID: 22820056. Macle L, Khairy P, Weerasooriya R, et al. Adenosine-guided pulmonary vein isolation for the treatment of paroxysmal atrial fibrillation: an international, multicentre, randomised superiority trial. Lancet 2015;386:672–9. https://doi.org/10.1016/S01406736(15)60026-5; PMID: 26211828. Nergardh A, Frick M. Perceived heart rhythm in relation to ECG findings after direct current cardioversion of atrial fibrillation. Heart 2006;92:1244–7. https://doi.org/10.1136/hrt.2005.082156; PMID: 16547207. Verma A, Champagne J, Sapp J, et al. Discerning the incidence of symptomatic and asymptomatic episodes of atrial fibrillation before and after catheter ablation (DISCERN AF): a prospective, multicenter study. JAMA Intern Med 2013;173:149–56. https:// doi.org/10.1001/jamainternmed.2013.1561; PMID: 23266597. Packer DL, Kowal RC, Wheelan KR, et al. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front (STOP AF) pivotal trial. J Am Coll Cardiol 2013;61:1713–23. https://doi. org/10.1016/j.jacc.2012.11.064; PMID: 23500312. 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. Heart Rhythm 2017;14:e275–444. https://doi.org/10.1016/j. hrthm.2017.05.012; PMID: 28506916. Cardoso R, Mendirichaga R, Fernandes G, et al. Cryoballoon versus radiofrequency catheter ablation in atrial fibrillation: a meta-analysis. J Cardiovasc Electrophysiol 2016;27:1151–9. https://doi.org/10.1111/jce.13047; PMID: 27422848. 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. Chen LY, Chung MK, Allen LA, et al. Atrial fibrillation burden: moving beyond atrial fibrillation as a binary entity: a scientific statement from the American Heart Association. Circulation 2018;137:e623–44. https://doi.org/10.1161/ CIR.0000000000000568; PMID: 29661944. Charitos EI, Ziegler PD, Stierle U, et al. Atrial fibrillation burden estimates derived from intermittent rhythm monitoring are unreliable estimates of the true atrial fibrillation burden. Pacing Clin Electrophysiol 2014;37:1210–8. https://doi.org/10.1111/ pace.12389; PMID: 24665972.

27. Ziegler PD, Koehler JL, Mehra R. Comparison of continuous versus intermittent monitoring of atrial arrhythmias. Heart Rhythm 2006;3:1445–52. https://doi.org/10.1016/j.hrthm.2006.07.030; PMID: 17161787. 28. Kuck KH, Furnkranz A, Chun KR, et al. Cryoballoon or radiofrequency ablation for symptomatic paroxysmal atrial fibrillation: reintervention, rehospitalization, and quality-of-life outcomes in the FIRE AND ICE trial. Eur Heart J 2016;37:2858– 65. https://doi.org/10.1093/eurheartj/ehw285; PMID: 27381589. 29. Steinberg JS, O’Connell H, Li S, et al. Thirty-second gold standard definition of atrial fibrillation and its relationship with subsequent arrhythmia patterns: analysis of a large prospective device database. Circ Arrhythm Electrophysiol 2018;11:e006274. https://doi.org/10.1161/CIRCEP.118.006274; PMID: 30002065. 30. Dubuc M, Roy D, Thibault B, et al. Transvenous catheter ice mapping and cryoablation of the atrioventricular node in dogs. Pacing Clin Electrophysiol 1999;22:1488–98. https://doi. org/10.1111/j.1540-8159.1999.tb00353.x; PMID: 10588151. 31. Dubuc M, Talajic M, Roy D, et al. Feasibility of cardiac cryoablation using a transvenous steerable electrode catheter. J Interv Card Electrophysiol 1998;2:285–92. https://doi. org/10.1023/A:1009797206514; PMID: 9870024. 32. Bessiere F, Dubuc M, Andrade J, et al. Focal transcatheter cryoablation: Is a four-minute application still required? J Cardiovasc Electrophysiol 2017;28(5):559-563. https://doi. org/10.1111/jce.13193; PMID: 28233925. 33. Andrade JG, Dubuc M, Guerra PG, et al. Pulmonary vein isolation using a second-generation cryoballoon catheter: a randomized comparison of ablation duration and method of deflation. J Cardiovasc Electrophysiol 2013;24:692–8. https:// doi.org/10.1111/jce.12114; PMID: 23489648. 34. Miyazaki S, Hachiya H, Nakamura H, et al. Pulmonary vein isolation using a second-generation cryoballoon in patients with paroxysmal atrial fibrillation: one-year outcome using a single big-balloon 3-minute freeze technique. J Cardiovasc Electrophysiol 2016;27:1375–80. https://doi.org/10.1111/ jce.13078; PMID: 27534931. 35. Ciconte G, Sieira-Moret J, Hacioglu E, et al. Single 3-minute versus double 4-minute freeze strategy for second-generation cryoballoon ablation: a single-center experience. J Cardiovasc Electrophysiol 2016;27:796–803. https://doi.org/10.1111/ jce.12986; PMID: 27063442. 36. Andrade JG, Khairy P, Dubuc M. Catheter cryoablation: biology and clinical uses. Circ Arrhythm Electrophysiol 2013;6:218–27. https://doi.org/10.1161/CIRCEP.112.973651; PMID: 23424224. 37. Su W, Aryana A, Passman R, et al. Cryoballoon best practices II: Practical guide to procedural monitoring and dosing during atrial fibrillation ablation from the perspective of experienced users. Heart Rhythm 2018;15:1348–55. https://doi.org/10.1016/j.hrthm.2018.04.021; PMID: 29684571. 38. Calkins H, Reynolds MR, Spector P, et al. Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: two systematic literature reviews and meta-analyses. Circ Arrhythm Electrophysiol 2009;2:349–61. https://doi.org/10.1161/ CIRCEP.108.824789; PMID: 19808490. 39. Pappone C, Vicedomini G, Augello G, et al. Radiofrequency catheter ablation and antiarrhythmic drug therapy: a prospective, randomized, 4-year follow-up trial: the APAF study. Circ Arrhythm Electrophysiol 2011;4:808–14. https://doi. org/10.1161/CIRCEP.111.966408; PMID: 21946315.

Clinical Arrhythmias

Non-invasive Low-level Tragus Stimulation in Cardiovascular Diseases Yunqiu Jiang,1 Sunny S Po,2 Faris Amil3 and Tarun W Dasari2 1. Cardiac Arrhythmias Section, Heart Center, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China; 2. Cardiovascular Section, Department of Internal Medicine, Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, US; 3. College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, US

Abstract Low-level tragus stimulation (LLTS) is a non-invasive approach of transcutaneous vagus nerve stimulation. LLTS has applications in diseases of multiple systems, including epilepsy, depression, headache and potentially several cardiovascular diseases. LLTS has shown promising results in suppressing AF, alleviating post-MI ventricular arrhythmias and ischaemia-reperfusion injury along with improving diastolic parameters in heart failure with preserved left ventricular ejection fraction (HFpEF). Preliminary pilot clinical studies in patients with paroxysmal AF, HFpEF, heart failure with reduced ejection fraction and acute MI have demonstrated promising results. The beneficial effects are likely secondary to favourable alteration of the sympathovagal imbalance. On-going exploratory work focused on underlying mechanisms of LLTS in cardiovascular disease states and larger scale clinical trials will shed more light on the non-invasive modulation of the neuro-immune axis.

Keywords Arrhythmia, autonomic nervous system, neuromodulation, tragus Disclosure: The authors have no conflicts of interest to declare. Received: 12 January 2020 Accepted: 2 March 2020 Citation: Arrhythmia & Electrophysiology Review 2020;9(1):40–6. DOI: https://doi.org/10.15420/aer.2020.01 Correspondence: Tarun W Dasari, Cardiovascular Section, Department of Medicine, 800 SL Young Blvd, COM 5400, University of Oklahoma HSC, Oklahoma City, OK 73104, US. E: tarun-dasari@ouhsc.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.

Imbalance of the autonomic nervous system (sympathetic/ parasympathetic) is known to contribute to the pathophysiology of multiple cardiovascular diseases, including AF, MI (and related ventricular arrhythmias) and heart failure. The concept of neuroimmune axis has been proposed to tightly integrate the brain–heart– periphery axis, which is characterised by various pathways of the antiinflammatory properties of the vagus nerve.1,2 For instance, immune responses can activate the hypothalamic–pituitary–adrenal axis through the vagal afferents and the cholinergic anti-inflammatory pathway through the vago-parasympathetic and sympathetic reflexes.3 Modulating this neuro-immune axis could play a key role in the alleviation of several cardiovascular diseases. Several modalities have been developed to modulate this axis and restore a favourable balance between the sympathetic and parasympathetic system. A few examples of this include direct vagus nerve stimulation (VNS), baroreceptor stimulation, renal artery sympathetic denervation, low-level tragus stimulation (LLTS), cardiac sympathetic denervation and spinal cord stimulation.4 Among them, direct cervical VNS has been used in multiple diseases, including epilepsy, drug-resistant depression, migraine, angina pectoris, hypertension and impaired upper limb function after stroke.5–11 In patients with heart failure with reduced ejection fraction (HFrEF), three major clinical trials of direct VNS have yielded mixed results.12–14 One of the major drawbacks of cervical vagus stimulation is the invasive nature of this treatment with inherent surgical complications and poor patient tolerance.15

Access at: www.AERjournal.com

Designed to stimulate the auricular branch of the vagus nerve (ABVN), LLTS is a non-invasive transcutaneous technique of VNS that can modulate the autonomic function (Figure 1).16 The aim of this current review is to summarise the evidence to date pertaining to the use of LLTS in various cardiovascular disease states.

The Anatomical and Physiological Basis of Low-level Tragus Stimulation Twenty per cent of the vagus nerve fibres are efferent fibres originating from the brainstem, providing parasympathetic control of the viscera, peripheral vasculature and heart. The remaining 80% of the nerve fibres are afferent fibres that relay sensory information from the periphery to the central nervous system. The afferent fibres distribute widely in the heart, lungs, liver, adrenal medulla and the gastrointestinal tract up to the splenic flexure of the colon.17 The vagus nerve contains three fibre types: highly myelinated A fibres, which have low activation thresholds; lightly myelinated B fibres; and unmyelinated C fibres, which have high activation thresholds.18,19 The ABVN is the cutaneous branch of the vagus nerve which innervates the antihelix, tragus and cavity of the concha.20 The innervation of the auricle is shown in Figure 2. Currently, how the external auricle is innervated remains controversial. In an anatomical study, ABVN was able to be observed in 94% of cases (17/18). All of the ABVN were observed to distribute to the external acoustic meatus and auricle. Cutaneous branches from the facial nerve were observed to innervate the external acoustic meatus as well.21 The nerve branches around the auricle and the acoustic meatus have various complex

Low-level Transcutaneous Vagal Stimulation Figure 1: Low-level Tragus Stimulation communications

before

reaching

the

central

nervous

system.

which are innervated by the ABVN in 73% and 100%, respectively. 24

ABVN

Tragus stimulation

Medulla oblongata

Vagus nerve

LV remodelling

HRV

Electric impulses delivered to the tragus stimulate the auricular branch of the vagus nerve (afferent fibres). The excitation then enters the medulla oblongata at the brain stem, which excites the vagus efferent fibres to modulate cardiac function. Low-level tragus stimulation is reported to reduce AF burden, alleviate LV remodelling after MI and increase HRV. ABVN = auricular branch of the vagus nerve; HRV = heart rate variability; LV = left ventricular.

Nevertheless, ample evidence indicates that the ABVN remains the most important innervation of the external auricle and the cymba conchae.22 Brain activation patterns, based on functional MRI (fMRI) during LLTS, were associated with greater activation of the vagal centres (dorsal vagal complex) throughout cortical, subcortical and cerebellar brain regions compared to sham stimulation. 23 In one of the most cited anatomical studies, 14 ears from seven cadavers were examined. A total of 45% of the ears were shown to be innervated by the great auricular nerve (GAN), 9% by the auriculotemporal nerve (ATN) and 46% were innervated by both the GAN and ATN. However, there has been some debate on the optimal site of transcutaneous VNS (tVNS). An fMRI study recently showed that stimulation at the cymba conchae had a greater effect on the vagal pathways and the dorsal vagal complex compared to three other locations: the inner surface of the tragus, the posterior-inferior wall of the external acoustic meatus and the earlobe. 23 A recent study used the triangular fossa innervated by the GAN as the stimulation site, because it allowed stimulation for a longer period of time without interfering with patient comfort, daily hygiene requirements and sleep. Most importantly, it is located proximal to the antihelix and the concha,

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Figure 2: Innervation of the Auricular Skin Auricular branch of the vagus nerve

Helix

Auriculotemporal nerve Concha

Tragus Auriculotemporal nerve Lobule Great auricular nerve

Auricular branch of the vagus nerve Great auricular nerve

The anterior auricular branches of the auriculotemporal nerve innervates the skin overlying the tragus, as well as the adjacent part of the helix. The auricular branch of the vagus nerve innervates the ear canal, tragus and part of the auricle. The great auricular nerve innervates the skin of the lateral auricle and the skin over both the parotid gland and mastoid process. Source: Roberts 2017.58 Reproduced with permission from Elsevier.

Stimulating the effective triangular fossa was effective in suppressing postoperative AF in this study.

Clinical Arrhythmias Table 1: Summary of Preclinical Tragus Stimulation Studies Publication

Subjects n

Stimulation Parameters Frequency Pulse (Hz) Width (ms)

Amplitude

On and Off Cycle

Outcome

Side Duration Chronic/ Acute

Wang et al. 201459 MI dogs

80% below the Yes, 5 s on heart rate slowing and 5 s off threshold

Daily, 90 days

Attenuated LV remodelling in dogs with healed MI

Wang et al. 201526 MI dogs

80% below the Yes, 5 s on heart rate slowing and 5 s off threshold

Daily, 6 weeks

Improved cardiac function and attenuated cardiac remodelling in late stages after MI

Yu et al. 201627

MI dogs

80% below the Yes, 5 s on heart rate slowing and 5 s off threshold

Daily, 2 months

Reduced ventricular arrhythmia inducibility, LSG neural activity and sympathetic neural remodelling

Nasi-Er et al.

MI dogs

50% below the No heart rate slowing threshold

Every other day, Reduced spontaneous 4 weeks ventricular arrhythmias, increased ventricular electrical stability and alleviated ventricular interstitial fibrosis

Yu et al. 201738

OSA dogs

80% below the Yes, 5 s on heart rate slowing and 5 s off threshold

Left

Acute

LLTS suppressed shortening of atrial refractoriness and autonomic remodelling

Chen et al. 201528

AF dogs

80% below the No heart rate slowing threshold

Left

Acute

Left-sided LLTS exerts anti-AF effects as effectively as right-sided LLTS

Yu et al. 201337

AF dogs

80% below the No heart rate slowing threshold

Right

Acute

LLTS reversed RAP-induced atrial remodelling and inhibited AF inducibility

Zhou et al. 201925

HFpEF rats 48

0.2

2 mA

30 min

Daily, 4 weeks

Chronic intermittent LLTS ameliorated diastolic dysfunction, and attenuated cardiac inflammation and fibrosis

Zhou et al. 201660

IST dogs

80% below the No heart rate slowing threshold

Right

Acute

LLTS suppressed RSG activity and inhibited sympathetically induced sinus node acceleration

201941

Bi = bilateral; HFpEF = heart failure with preserved ejection fraction; IST = inappropriate sinus tachycardia; LLTS = low-level tragus stimulation; LSG = left satellite ganglion; LV = left ventricular; OSA: obstructive sleep apnoea; R = right; RAP = rapid atrial pacing; RSG = right stellate ganglion.

Parameters of Low-level Tragus Stimulation Currently, optimal settings of LLTS remain undetermined. Parameters of LLTS for both preclinical and clinical studies have generally been empirical (Tables 1 and 2). In a rat model of heart failure with preserved ejection fraction (HFpEF), LLTS below the threshold of heart rate reduction was applied by placing two oppositely charged magnetic electrodes over the auricular concha region at 20 Hz frequency, 0.2 ms pulse duration and 2 mA amplitude.25 In a rat MI model, LLTS at 20 Hz, 1 ms pulse wide and 80% below the threshold of slowing the sinus heart rate was used.26 The same settings were extended to a canine model of post-infarction ventricular arrhythmia.27 The majority of LLTS studies were right-sided, while one canine model study demonstrated that left-sided LLTS is also effective in suppressing AF.28 In a clinical study in patients with ST-segment elevation MI (STEMI), LLTS was set at 20 Hz, 1 ms pulse wide and 50% below the heart rate-slowing threshold with a duty cycle of 5 seconds on and 5 seconds off.29 The

same parameters were used in an AF suppression study, but in a continuous manner without the on-and-off cycle.30 To test if LLTS has a parameter-specific effect on heart rate, an exploratory study compared nine combinations of stimulating parameters (pulse width: 100 μs, 200 μs, 500 μs; frequency: 1 Hz, 10 Hz, 25 Hz) among 15 healthy volunteers.31 Essentially, the setting of 500 μs and 10 Hz had the strongest effect on heart rate reduction (−2.40 ± 0.275 BPM) during the 60 seconds of stimulation. Recently, a large clinical trial using VNS in patients with HFrEF failed to show a beneficial effect while another trial in patients with HFrEF using different stimulation parameters demonstrated efficacy, highlighting the importance of optimising stimulation parameters.13,32 Mechanistic studies have suggested that the optimal stimulation parameters for VNS are at the point at which the afferent and efferent fibres are activated in a well-balanced manner, i.e. the afferent-driven decreases in central parasympathetic drive are counteracted by direct activation of the cardiac parasympathetic efferent projections to the intrinsic cardiac autonomic nervous system,

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Low-level Transcutaneous Vagal Stimulation Table 2: Summary of Human Tragus Stimulation Studies Publication Subjects n

Stimulation Parameters Follow- Outcome Frequency Pulse Amplitude On and Side Duration Chronic/ up period (Hz) Width Off Cycle Acute (ms)

Stavrakis et al. Paroxysmal 40 AF 201530

50% below the No heart rate slowing threshold

Right

Acute

None

Suppressed AF and decreased inflammatory cytokines in patients with paroxysmal AF

HFpEF

0.2

1 mA below No uncomfortable threshold

Right

Acute

None

LLTS acutely ameliorated LV longitudinal mechanics and improved HRV

HFrEF

0.2

5–40mA

Right

Acute

None

Beneficial effect on micro-circulation and endothelial function

Yu et al. 201729 STEMI

50% below the heart rate slowing threshold

Yes, 5 s on Right and 5 s off

Acute

7 days

Reduced myocardial ischaemia-reperfusion injury in patients with STEMI

Study 1: 14

0.2

Just below the threshold of causing discomfort

15 min

Acute

None

TS increased vagal tone and was associated with greater increases in baroreflex sensitivity

Study 2: 51

Acute

None

Study 3: 29

Chronic, daily for 2 weeks

2 weeks

Tran et al. 201847

Dasari et al. 201848

Bretherton et al. 201950

Age ≥55 years

Improvements in HRV parameters, higher quality of life, better moods and sleep quality

HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; HRV = heart rate variability; LLTS = low-level tragus stimulation; LV = left ventricular; NS = not specified; STEMI = ST-segment elevation MI.

resulting in a relatively neutral heart rate response.33 Consistent with this notion, a recent study of LLTS (30 Hz,10–50 mA, 200 ms, which was slightly below the sensory threshold) in healthy volunteers showed a significant decrease in muscle sympathetic nerve activity (MSNA) without a change in heart rate.34 Recently, the works by Sclocco et al. suggested that tVNS is headed toward a more refined and sophisticated direction.35,36 Through respiratory gating and EEG-informed fMRI, the efficacy and accuracy of this therapy can be further improved.

Results in Animal Models AF It has been established that the abnormal regulation of the cardiac autonomic nervous system contributes to the initiation and perpetuation of AF. High sympathetic/vagal tone contribute to the substrate of AF while sudden changes in autonomic balance lead to AF episodes. Theoretically, suppressing either the sympathetic or parasympathetic tone could have a moderating effect on AF. There have been at least two animal models testing the acute effect of LLTS. For example, in a canine AF model, right sided LLTS reduced AF inducibility and reversed acute atrial electrical remodelling. Its antiremodelling effect was indicated by a prolonged effective refractory period and a narrowed window of vulnerability (to measure the difficulty of AF induction).37 In a canine model of obstructive sleep apnoea, LLTS suppressed shortening of atrial refractoriness and autonomic remodelling caused by obstructive sleep apnoea, thus reducing the vulnerability to AF.38

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Post MI The close relationship between ventricular arrhythmias after MI and sympathetic activation is well recognised.39,40 Suppressing the sympathetic tone and increasing the parasympathetic tone protected against post-MI ventricular arrhythmias. In a canine MI model, right-sided LLTS performed 2 hours a day for 2 months reduced left stellate ganglion activity in both frequency and amplitude.27 Both of these parameters of neural activity were significantly lower in the MI plus LLTS group than the MI group alone. Ventricular arrhythmias inducibility evaluated by ventricular programed stimulation was also suppressed by LLTS. Besides electrical remodelling, in a canine model intermittent bilateral LLTS for 4 weeks alleviated left ventricular remodelling by reducing ventricular interstitial fibrosis post MI.41 In another post-MI canine model, 6 weeks of bilateral LLTS (20 Hz, 1 ms pulse wide, 80% below the sinus slowing threshold) for 4 hours per day reduced left ventricle dilation and infarct size, improved both left ventricular contractility and diastolic function and alleviated myocardial fibrosis.26

Heart Failure with Preserved Ejection Fraction HFpEF, another clinical syndrome associated with dysregulation of the autonomic nervous system and inflammation, comprises approximately 50% of all patients with heart failure.42 Patients with HFpEF have been shown to have increases in plasma renin activity and arginine vasopressin compared with healthy controls.43 In a rat model of HFpEF (Dahl salt-sensitive rats), LLTS (20 Hz, 2 mA, 0.2 ms)

Clinical Arrhythmias attenuated the elevation of both systolic and diastolic blood pressure. Echocardiography revealed that LLTS improved left ventricular hypertrophy, circumferential strain and diastolic function as measured by E/A ratio and E/e’ ratio.25 Histological studies showed that LLTS attenuated ventricular inflammatory cell infiltration and fibrosis. Downregulation of the pro-inflammatory and profibrotic genes (interleukin [IL]-11, IL18, IL23-A and osteopontin) was seen in the LLTS group as well.25

Mechanisms of Low-level Tragus Stimulation Tragus stimulation exerts its modulating effects through an integrated nervous reflex system. The ABVN is the afferent nerve fibre while the medulla oblongata (nuclei including NTS, nucleus of the solitary tract; NSNT, nucleus spinalis of the trigeminal nerve; NA, nucleus ambiguous; DMN, dorsal motor nucleus) function as the reflex centre.44 The efferent vagus nerve then arrives at the ganglionated plexi within the epicardial fat pads to achieve the related physiological effects. Though the neuropathway of tVNS is grossly understood, the exact mechanisms underlying the various beneficial effects of LLTS are still poorly understood. The inherent sympathovagal imbalance is different in various cardiovascular states. Modulation of this tone may have variable beneficial effects and is likely directly related to the underlying pathophysiology. For example, even in heart failure, acute and chronic states exhibit a wide spectrum of sympathovagal imbalance and there are likely differential effects of non-invasive vagal modulation. In common cardiovascular disease states, vagal stimulation probably suppress arrhythmias, ischaemia and heart failure through different mechanisms. Up-regulation of c-fos (a proto-oncogene expressed within some neurons following depolarisation) and nerve growth factor (NGF) expression in left superior ganglionated plexus and the left stellate ganglion is found to contribute to autonomic remodelling of AF. LLTS suppressed AF by down-regulating both c-fos and NGF.38 Connexins (Cx) are an essential component of gap junctions and a key player in the formation of AF substrate. LLTS has been shown to suppress AF by preventing the loss of atrial Cxs (Cx40 and Cx43).28 At the cardiac remodelling and fibrosis level, downregulation of matrix metalloproteinase 9 and transforming growth factor-beta 1 was observed in LLTS treated post-MI dogs.26 Small conductance calciumactivated potassium channel type 2 (SK2) is an ion channel molecule responsible for after-hyperpolarisation that suppresses nerve discharges that are crucial to regulating neuronal excitability. In a canine MI model, LLTS down-regulated the NGF protein and upregulated the SK2 protein.27 These studies indicate that LLTS affects the pathophysiological progress on multiple levels – from neural remodelling to myocardial remodelling.

Human Studies AF Reports of tragus stimulation on human subjects are still limited. LLTS for 1 hour during ablation procedures reduced the duration of induced AF, while levels of inflammatory markers (circulatory tumour necrosis factor [TNF] alpha and C-reactive protein) were reduced.30 In patients with paroxysmal AF who received chronic LLTS for 1 h/day for 6 months, there was a 85% decrease in AF burden in the active stimulation group compared to the sham group (stimulating the earlobe).45

MI and Angina In patients with STEMI undergoing primary percutaneous coronary intervention, 2 hours of right LLTS after reperfusion attenuated

reperfusion-related ventricular arrhythmias during the first 24 hours, with smaller area under the curve of creatine kinase myocardial band, which theoretically indicated reduced infarct size.29 In addition to reduced ventricular arrhythmias and cardiac biomarkers, significant improvement in left ventricular ejection fraction and N-terminal pro–Btype natriuretic peptide was observed in the LLTS group. The wall motion index, calculated using the 16-segment model, was used to evaluate the extent of left ventricular dysfunction. The percentage of left ventricular akinetic and dyskinetic segments was significantly lower in the LLTS group than the sham group. The level of inflammatory cytokines including IL-6, IL1-beta, TNF-alpha and HMGB1 were significantly reduced. However, MRI was not conducted to accurately evaluate the infarct size and their differences between groups. It remains to be proven if chronic LLTS would improve morbidity and mortality in patients with STEMI. Alongside STEMI, the application of vagal neural stimulation for the treatment of coronary artery disease is also worth mentioning. Though conducted in a small population of patients, the clinical and histological messages in the article by Zamotrinsky et al. were impressive.46 Vagal stimulation via trans-auricular electroacupuncture showed antianginal effect that could last for 2–3 weeks after the completion of the treatments. The effects of LLTS in refractory angina deserves further study.

Heart Failure Human studies of LLTS on heart failure patients are also limited. In a prospective, randomised, double-blind, 2×2 cross-over study, 1 hour of LLTS acutely ameliorated left ventricular longitudinal mechanics and favourably altered heart rate variability (HRV) frequency domain components in patients with HFrEF.47 In a pilot, sham controlled, randomised study in patients with HFrEF, 1 hour of LLTS (20 Hz frequency and 200 μs pulse width) led to improvements in microcirculation (as assessed by flow mediated vasodilatation) and nail bed microcirculation (assessed by laser speckle contrast imaging).48

Ageing As people age, the contribution of the parasympathetic activity to the heart declines, whereas sympathetic tone increases, resulting in a less balanced autonomic function. Tragus stimulation was found to be beneficial in healthy young subjects as demonstrated by an increase in HRV.49 After preliminary LLTS studies showed its safety and efficacy as an alternative to invasive stimulation of cervical vagus nerve, Bretherton et al. applied daily LLTS at a level just below the threshold of causing discomfort (usually 2–4 mA) to people ≥55 years of age.50 Higher baroreflex sensitivity and HRV were observed by LLTS. Furthermore, it was reported in the same article that in 26 healthy adults with an average age of 64 years, daily sessions of LLTS for 14 days resulted in improvements in HRV parameters, higher quality of life questionnaire score (SF-36), better moods (measured by profile of mood states questionnaire) and better sleep quality (measured by sleep questionnaire), thus showing potential against aging.

Safety of Low-level Tragus Stimulation The non-invasive nature of tVNS granted it an impressive safety record. Drop in blood pressure and/or heart rate during stimulation is rarely observed. Some mild skin lesions were observed in the study by Stavrakis et al. and they did not recur after adjusting the tension of the medal clips delivering the stimulation.30

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Low-level Transcutaneous Vagal Stimulation A systematic review published by Redgrave et al. summarised all available literature on tVNS, not limited to cardiovascular diseases and found that local irritation (tingling/pain/redness/itching) is the most common discomfort (16.7%) that is attributable to stimulation, with headache being the second (3.3%) and nasopharyngitis (1.6%) the third.51 Dizziness and syncope was found in 20 patients across eight studies, with a prevalence of 1.4%. However, only three severe adverse events were considered tVNS-related. Conventional wisdom suggests that stimulation of the right vagus nerve exerts more prominent cardiovascular effects than stimulation of the left vagus nerve. Left vagal stimulation is therefore the preferred approach to treat epilepsy.52 This conventional wisdom has been challenged by reported side effects of left VNS studies.53,54 For noninvasive VNS, whether left and right tragus stimulation will affect the sinus node and atrioventricular node is still unknown.

Next Steps There are some limitations associated with previous studies. These include lack of a well controlled sham group, absence of longitudinal data and small sample sizes. Optimal parameters for stimulation are yet to be determined. Furthermore, the lack of a uniform stimulation parameter makes results less generalisable. Some studies used active stimulation at another site while others used sham stimulation at the same site. All of the current clinical studies are acute or short-term studies except one recent study by Stavrakis et al. reporting that chronic LLTS suppressed paroxysmal AF.45 Longitudinal data are warranted to evaluate the long-term benefit of LLTS. Lastly, there is a lack of a reliable biomarker to indicate the effectiveness of LLTS. MSNA may serve as an attractive method to determine changes in sympathetic tone with LLTS. However, this technique is time-consuming and lack of widespread availability limits its usage. Serum/plasma markers of neuroendocrine activity (such as vasostatin and catestatin) could also potentially be used to

Andersson U, Tracey KJ. Neural reflexes in inflammation and immunity. J Exp Med 2012;209:1057–68. https://doi. org/10.1084/jem.20120571; PMID: 22665702. 2. Chavan SS, Tracey KJ. Essential neuroscience in immunology. J Immunol 2017;198:3389–97. https://doi.org/10.4049/ jimmunol.1601613; PMID: 28416717. 3. Bonaz B, Sinniger V, Pellissier S. The vagus nerve in the neuro-immune axis: Implications in the pathology of the gastrointestinal tract. Front Immunol 2017;8:1452. https://doi. org/10.3389/fimmu.2017.01452; PMID: 29163522. 4. Chatterjee NA, Singh JP. Novel interventional therapies to modulate the autonomic tone in heart failure. JACC Heart Fail 2015;3:786–802. https://doi.org/10.1016/j.jchf.2015.05.008; PMID: 26364257. 5. Giordano F, Zicca A, Barba C, et al. Vagus nerve stimulation: Surgical technique of implantation and revision and related morbidity. Epilepsia 2017;58 (Suppl 1):85–90. https://doi. org/10.1111/epi.13678; PMID: 28386925. 6. Carreno FR, Frazer A. Vagal nerve stimulation for treatment-resistant depression. Neurotherapeutics 2017;14:716– 27. https://doi.org/10.1007/s13311-017-0537-8; PMID: 28585221. 7. Lendvai IS, Maier A, Scheele D, et al. Spotlight on cervical vagus nerve stimulation for the treatment of primary headache disorders: a review. J Pain Res 2018;11:1613–25. https://doi.org/10.2147/JPR.S129202; PMID: 30214271. 8. Braunwald E, Epstein SE, Glick G, et al. Relief of angina pectoris by electrical stimulation of the carotid-sinus nerves. N Engl J Med 1967;277:1278–83. https://doi.org/10.1056/ NEJM196712142772402; PMID: 5299662. 9. Annoni EM, Xie X, Lee SW, et al. Intermittent electrical stimulation of the right cervical vagus nerve in saltsensitive hypertensive rats: effects on blood pressure, arrhythmias, and ventricular electrophysiology. Physiol Rep 2015;3:e12476. https://doi.org/10.14814/phy2.12476; PMID: 26265746. 10. Meyers EC, Solorzano BR, James J, et al. Vagus nerve stimulation enhances stable plasticity and generalization of

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11.

12.

13.

14.

15.

16.

17.

18.

gauge change in neuro endocrine function, pending future data. Stimulus-driven event-related potentials and vagus-sensory evoked potentials in electroencephalogram, fMRI and HRV are potential biomarkers as well. 34,55–57 In some clinical studies, a simple reduction in heart rate is considered a marker of parasympathetic activation.29 Individual disease states may have respective biomarkers that would predict adequate response to LLTS. While HRV may sound attractive as a biomarker of response, it would be premature to state that this alone could direct this field forward. Searching for a reliable biomarker for effective LLTS should be a continued focus of future research. The aforementioned limitations show clear paths for future research studies.

Conclusion Non-invasive autonomic modulation using LLTS appears promising in its early stages. The ability to stimulate the central vagal complexes at a level below the heart-rate-lowering threshold seems very attractive. LLTS has promising data in animal models of AF, post-acute MI and heart failure. Accumulating data in humans with paroxysmal AF, post-acute MI and both systolic and diastolic heart failure may pave the way for larger clinical trials focused on demonstrating improvement in morbidity and mortality associated with such disease states. Larger trials are needed to prove the safety and efficacy of tragus stimulation.

Clinical Perspective • Tragus stimulation is an emerging therapy for non-invasive modulation of the autonomic nervous system. • Pre-clinical and clinical studies proved the potential of tragus stimulation in AF, MI and heart failure. • Though the number of clinical trials is still limited, available data point to safety and efficacy of tragus stimulation. Large-scale trials are critically warranted.

stroke recovery. Stroke 2018;49:710–7. https://doi.org/10.1161/ STROKEAHA.117.019202; PMID: 29371435. Kimberley TJ, Pierce D, Prudente CN, et al. Vagus nerve stimulation paired with upper limb rehabilitation after chronic stroke. Stroke 2018;49:2789–92. https://doi.org/10.1161/ STROKEAHA.118.022279; PMID: 30355189. Dicarlo L, Libbus I, Amurthur B, et al. Autonomic regulation therapy for the improvement of left ventricular function and heart failure symptoms: the ANTHEM-HF study. J Card Fail 2013;19:655–60. https://doi.org/10.1016/j.cardfail.2013.07.002; PMID: 24054343. Gold MR, Van Veldhuisen DJ, Hauptman PJ, et al. Vagus nerve stimulation for the treatment of heart failure: the INOVATE-HF trial. J Am Coll Cardiol 2016;68:149–58. https://doi.org/10.1016/j. jacc.2016.03.525; PMID: 27058909. De Ferrari GM, Stolen C, Tuinenburg AE, et al. Long-term vagal stimulation for heart failure: eighteen month results from the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) trial. Int J Cardiol 2017;244:229–34. https://doi.org/10.1016/j. ijcard.2017.06.036; PMID: 28663046. Akdemir B, Benditt DG. Vagus nerve stimulation: An evolving adjunctive treatment for cardiac disease. Anatol J Cardiol 2016;16:804–10. https://doi.org/10.14744/ AnatolJCardiol.2016.7129; PMID: 27723668. Deuchars SA, Lall VK, Clancy J, et al. Mechanisms underpinning sympathetic nervous activity and its modulation using transcutaneous vagus nerve stimulation. Exp Physiol 2018;103:326–31. https://doi.org/10.1113/EP086433; PMID: 29205954. Clancy JA, Deuchars SA, Deuchars J. The wonders of the wanderer. Exp Physiol 2013;98:38–45. https://doi.org/10.1113/ expphysiol.2012.064543; PMID: 22848084. Schwaber JS, Cohen DH. Electrophysiological and electron microscopic analysis of the vagus nerve of the pigeon, with particular reference to the cardiac innervation. Brain Res 1978;147:65–78. https://doi.org/10.1016/0006-8993(78)907722; PMID: 656917.

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Pulmonary vein potentials seen with Advisor™ HD Grid Mapping Catheter, Sensor Enabled™, not captured on standard mapping catheter

ADVISOR™ HD GRID MAPPING CATHETER, SE

CIRCULAR MAPPING CATHETER

Capture more data for insight into activity that may not be visible with standard configuration catheters

SEE THINGS DIFFERENTLY WITH THE ADVISOR™ HD GRID MAPPING CATHETER, SENSOR ENABLED™ LEARN MORE AT CARDIOVASCULAR.ABBOTT/CLOSETHEGAP

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. © 2019 Abbott. All Rights Reserved. 31672-SJM-ADV-0319-0072

Item approved for global use.

AER 9.1

Articles inside

Foreword

Guest Editorial