AER 10.1

Volume 10 • Issue 1 • Spring 2021

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Arrhythmias and Conduction Disturbances in Autoimmune Rheumatic Disorders Sotiris C Plastiras and Haralampos M Moutsopoulos

Electrophysiological Substrate in Patients with Barlow’s Disease Pasquale Vergara, Savino Altizio, Giulio Falasconi, Luigi Pannone, Simone Gulletta and Paolo Della Bella

Conduction System Pacing for Cardiac Resynchronisation Parikshit S Sharma and Pugazhendhi Vijayaraman

Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy Ryan Wallace and Hugh Calkins

Electrocardiographic criteria for differentiating between the RVOT and LVOT

Activation mapping used to target the earliest pre-potential bipolar activity or Purkinje-like potentials

Supraventricular arrhythmias are frequently seen in systemic sclerosis as a result of focal myocardial fibrosis

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Volume 10 • Issue 1 • Spring 2021

Official journal of

Editor-in-Chief Demosthenes G Katritsis

Hygeia Hospital, Athens, Greece and Johns Hopkins University School of Medicine, Baltimore, MD, US

Section Editor – Clinical Electrophysiology and Ablation Hugh Calkins

Section Editor – Arrhythmia Risk Stratification Pier D Lambiase

Johns Hopkins Medicine, Baltimore, MD, US

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

Section Editor – Implantable Devices Ken Ellenbogen

Section Editor – Atrial Fibrillation Gregory YH Lip

Virginia Commonwealth University School of Medicine, Richmond, VA, US

Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool, UK

Section Editor – Arrhythmia Mechanisms / Basic Science Andrew Grace

Section Editor – Imaging in Electrophysiology Sanjiv M Narayan

Royal Papworth and Addenbrooke’s Hospitals, Cambridge, UK

Stanford University Medical Center, CA, US

Editorial Board Joseph G Akar

Yale University School of Medicine, New Haven, CT, US

Charles Antzelevitch

Hein Heidbuchel

Antwerp University and University Hospital, Antwerp, Belgium

Gerhard Hindricks

Lankenau Institute for Medical Research, Pennsylvania, PA, US

University of Leipzig, Leipzig, Germany

Angelo Auricchio

JW Goethe University, Frankfurt, Germany

Carina Blomström-Lundqvist

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

Fondazione Cardiocentro Ticino, Lugano, Italy Uppsala University, Uppsala, Sweden

Johannes Brachmann

Klinikum Coburg, II Med Klinik, Coburg, Germany

Josep Brugada

Carsten W Israel

Warren Jackman Pierre Jaïs

University of Bordeaux, CHU Bordeaux, France

Roy John

Andrea Natale

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

Mark O’Neill

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

Douglas Packer

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

Carlo Pappone

IRCCS Policlinico San Donato, Milan, Italy

Sunny S Po

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

Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain

Northshore University Hospital, New York, NY, US

Pedro Brugada

Yonsei University, Seoul, South Korea

Alfred Buxton

Imperial College Healthcare NHS Trust, London, UK

Barts Health NHS Trust, London, UK

David J Callans

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Roberto Keegan

Imperial College London and Barts Health NHS Trust, London, UK

University of Brussels, UZ-Brussel-VUB, Brussels, Belgium Beth Israel Deaconess Medical Center, Boston, MA, US University of Pennsylvania, Philadelphia, PA, US

Boyoung Joung

Prapa Kanagaratnam Josef Kautzner

A John Camm

Hospital Privado del Sur, Bahia Blanca, Argentina

Shih-Ann Chen

Asklepios Klinik St Georg, Hamburg, Germany

St George’s University of London, London National Yang Ming University School of Medicine and Taipei Veterans General Hospital, Taipei, Taiwan

KR Julian Chun

CardioVascular Center Bethanien, Frankfurt, Germany

Harry Crijns

Maastricht University Medical Center, Maastricht, the Netherlands

Sabine Ernst

Royal Brompton & Harefield NHS Foundation Trust, London, UK

Yutao Guo

Chinese PLA General Hospital, Beijing, China

Karl-Heinz Kuck Cecilia Linde

Karolinska University, Stockholm, Sweden

Francis E Marchlinski

University of Pennsylvania Health System, Philadelphia, PA, US

Joseph E Marine

Johns Hopkins University School of Medicine, Baltimore, Maryland, US

John M Miller

Indiana University School of Medicine, Indianapolis, IN, US

Fred Morady

Cardiovascular Center, University of Michigan, MI, US © RADCLIFFE CARDIOLOGY 2021 Access at: www.AERjournal.com

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Edward Rowland

Barts Heart Centre, St Bartholomew’s Hospital, London, UK

Frédéric Sacher

Bordeaux University Hospital, Electrophysiology and Heart Modelling Institute, Bordeaux, France

Richard Schilling Afzal Sohaib

William G Stevenson

Vanderbilt School of Medicine, Nashville, TN, US

Richard Sutton

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

Panos Vardas

Heraklion University Hospital, Heraklion, Greece

Marc A Vos

University Medical Center Utrecht, Utrecht, the Netherlands

Katja Zeppenfeld

Leiden University Medical Center, Leiden, the Netherlands

Douglas P Zipes

Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, US

Volume 10 • Issue 1 • Spring 2021

Official journal of

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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.

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Volume 10 • Issue 1 • Spring 2021

Ethics and Conflicts of Interest

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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.

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.

• Arrhythmia & Electrophysiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field.

• Arrhythmia & Electrophysiology Review provides comprehensive updates on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

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expert opinion pieces, guest editorials and letters to the editor.

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• Peer review – conducted by experts appointed for their experience and knowledge of a specific topic.

• An experienced team of editors and technical editors.

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Arrhythmia & Electrophysiology Review is an online publication. Articles are published on www.AERjournal.com. The journal is free to read online and PDF downloads are available for registered users. Print subscriptions are available upon request.

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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.

of the Editorial Board and Publisher.

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Contents

Foreword What Cannot Be Missed: Important Publications on Electrophysiology in 2020 Sanjiv M Narayan, Hugh Calkins, Andrew Grace, Ken Ellenbogen, Gregory YH Lip, Pier D Lambiase and Demosthenes G Katritsis https://doi.org/10.15420/aer.2021.02

Guest Editorial Atrial Fibrillation and Oral Health Amaar Hassan, Gregory YH Lip, Laurent Fauchier and Rebecca V Harris https://doi.org/10.15420/aer.2021.09

Clinical Arrhythmias Electrocardiographic Criteria for Differentiating Left from Right Idiopathic Outflow Tract Ventricular Arrhythmias

Marco V Mariani, Agostino Piro, Domenico G Della Rocca, Giovanni B Forleo, Naga Venkata Pothineni, Jorge Romero, Luigi Di Biase, Francesco Fedele and Carlo Lavalle https://doi.org/10.15420/aer.2020.10

Arrhythmias and Conduction Disturbances in Autoimmune Rheumatic Disorders Sotiris C Plastiras and Haralampos M Moutsopoulos https://doi.org/10.15420/aer.2020.43

Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy Ryan Wallace and Hugh Calkins https://doi.org/10.15420/aer.2020.39

Electrophysiology & Ablation Electrophysiological Substrate in Patients with Barlow’s Disease Pasquale Vergara , Savino Altizio, Giulio Falasconi, Luigi Pannone, Simone Gulletta and Paolo Della Bell https://doi.org/10.15420/aer.2020.29

Dynamic High-density Functional Substrate Mapping Improves Outcomes in Ischaemic Ventricular Tachycardia Ablation: Sense Protocol Functional Substrate Mapping and Other Functional Mapping Techniques Nikolaos Papageorgiou and Neil T Srinivasan https://doi.org/10.15420/aer.2020.28

Cardiac Pacing Leadless Left Ventricular Endocardial Pacing and Left Bundle Branch Area Pacing for Cardiac Resynchronisation Therapy Baldeep S Sidhu, Justin Gould, Mark K Elliott, Vishal Mehta, Steven Niederer and Christopher A Rinaldi

https://doi.org/10.15420/aer.2020.46

Conduction System Pacing for Cardiac Resynchronisation Parikshit S Sharma and Pugazhendhi Vijayaraman https://doi.org/10.15420/aer.2020.45

© RADCLIFFE CARDIOLOGY 2021 Access at: www.AERjournal.com

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Foreword

What Cannot Be Missed: Important Publications on Electrophysiology in 2020 Sanjiv M Narayan,1 Hugh Calkins,2 Andrew Grace,3 Ken Ellenbogen,4 Gregory YH Lip,5,6,7 Pier D Lambiase8,9 and Demosthenes G Katritsis10 1. Stanford University Medical Center, Palo Alto, CA, US; 2. Johns Hopkins Medical Institution, Baltimore, MD, US. 3. Royal Papworth and Addenbrooke’s Hospitals, Cambridge, UK; 4. VCU School of Medicine, Richmond, VA, US; 5. Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool, UK; 6. Liverpool Heart and Chest Hospital, Liverpool, UK; 7. Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 8. UCL Institute of Cardiovascular Science, University College London, UK; 9. Barts Heart Centre, London, UK; 10. Hygeia Hospital, Athens, Greece

Citation: Arrhythmia & Electrophysiology Review 2021;10(1):5–6. DOI: https://doi.org/10.15420/aer.2021.02 Correspondence: Demosthenes Katritsis, Hygeia Hospital, 4 Erythrou Stavrou St, Athens 15123, Greece. E: dkatrits@dgkatritsis.gr Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Guidelines and Consensus Documents

Andrade JG, Wells GA, Deyell MW, et al. Cryoablation or drug therapy for initial treatment of atrial fibrillation. N Engl J Med 2021;384:305–15. https://doi.org/10.1056/NEJMoa2029980; PMID: 33197159.

Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). Eur Heart J 2021;42:373–498. https://doi.org/10.1093/ eurheartj/ehaa612; PMID: 32860505.

Wazni OM, Dandamudi G, Sood N, et al. Cryoballoon ablation as initial therapy for atrial fibrillation. N Engl J Med 2021;384:316–24. https://doi.org/10.1056/NEJMoa2029554; PMID: 33197158.

Basic Science

Voskoboinik A, Gerstenfeld EP, Moss JD, et al. Complex re-entrant arrhythmias involving the His-Purkinje system: a structured approach to diagnosis and management. JACC Clin Electrophysiol 2020;6:1488– 98. https://doi.org/10.1016/j.jacep.2020.06.009; PMID: 33213808.

Cabrera JÁ, Anderson RH, Macías Y, et al. Variable arrangement of the atrioventricular conduction axis within the triangle of Koch: implications for permanent His bundle pacing. JACC Clin Electrophysiol 2020;6:362–77. https://doi.org/10.1016/j.jacep.2019.12.004; PMID: 32327069.

Stiell IG, Sivilotti MLA, Taljaard M, et al. Electrical versus pharmacological cardioversion for emergency department patients with acute atrial fibrillation (RAFF2): a partial factorial randomised trial. Lancet 2020;395:339–49. https://doi.org/10.1016/S0140-6736(19)32994-0; PMID: 32007169.

Anderson RH, Sanchez-Quintana D, Mori S, et al. Re-evaluation of the structure of the atrioventricular node and its connections with the atrium. Europace 2020;22:821–30. https://doi.org/10.1093/europace/ euaa031; PMID: 32304217.

Clinical Trials

Knops RE, Olde Nordkamp LRA, Delnoy PHM, et al. Subcutaneous or transvenous defibrillator therapy. N Engl J Med 2020;383:526–36. https://doi.org/10.1056/NEJMoa1915932; PMID: 32757521.

Graham AJ, Orini M, Zacur E, et al. Evaluation of ECG imaging to map hemodynamically stable and unstable ventricular arrhythmias. Circ Arrhythm Electrophysiol 2020;13:e007377. https://doi.org/10.1161/ CIRCEP.119.007377; PMID: 31934784.

Pascale P, Hunziker S, Denis A, et al. The ‘double transition’: a novel electrocardiogram sign to discriminate posteroseptal accessory pathways ablated from the right endocardium from those requiring a left-sided or epicardial coronary venous approach. Europace 2020;22:1703–11. https://doi.org/10.1093/europace/euaa200; PMID: 32984869.

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; PMID: 32241367.

Kirchhof P, Camm AJ, Goette A, et al. Early rhythm-control therapy in patients with atrial fibrillation. N Engl J Med 2020;383:1305–16. https://doi.org/10.1056/NEJMoa2019422; PMID: 32865375.

Briceño DF, Santangeli P, Frankel DS, et al. QRS morphology in lead V1 for the rapid localization of Idiopathic ventricular arrhythmias originating from the left ventricular papillary muscles: a novel electrocardiographic criterion. Heart Rhythm 2020;17:1711–8. https:// doi.org/10.1016/j.hrthm.2020.05.021; PMID: 32454219.

Poole JE, Bahnson TD, Monahan KH, et al. Recurrence of atrial fibrillation after catheter ablation or antiarrhythmic drug therapy in the CABANA trial. J Am Coll Cardiol 2020;75:3105–18. https://doi. org/10.1016/j.jacc.2020.04.065; PMID: 32586583.

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Foreword Valderrábano M, Peterson LE, Swarup V, et al. Effect of catheter ablation with vein of Marshall ethanol infusion vs catheter ablation alone on persistent atrial fibrillation: the Venus randomized clinical trial. JAMA 2020;324:1620–8. https://doi.org/10.1001/jama.2020.16195; PMID: 33107945.

DeLurgio DB, Crossen KJ, Gill J, et al. Hybrid convergent procedure for the treatment of persistent and long-standing persistent atrial fibrillation: results of CONVERGE clinical trial. Circ Arrhythm Electrophysiol.2020;13:e009288. https://doi.org/10.1161/ CIRCEP.120.009288; PMID: 33185144.

Voskoboinik A, Kalman JM, De Silva A, et al. Alcohol abstinence in drinkers with atrial fibrillation. N Engl J Med 2020;382:20–8. https:// doi.org/10.1056/NEJMoa1817591; PMID: 31893513.

The Future?

Tavares L, Lador A, Fuentes S, et al. Intramural venous ethanol infusion for refractory ventricular arrhythmias: outcomes of a multicenter experience. JACC Clin Electrophysiol 2020;6:1420–31. https://doi. org/10.1016/j.jacep.2020.07.023; PMID: 33121671.

Essayagh B, Sabbag A, Antoine C, et al. Presentation and outcome of arrhythmic mitral valve prolapse. J Am Coll Cardiol 2020;76:637–49. https://doi.org/10.1016/j.jacc.2020.06.029; PMID: 32762897.

Reddy VY, Anic A, Koruth J, et al. Pulsed field ablation in patients with persistent atrial fibrillation. J Am Coll Cardiol 2020;76:1068–80. https://doi.org/10.1016/j.jacc.2020.07.007; PMID: 32854842.

Bhatla A, Mayer MM, Adusumalli S, et al. COVID-19 and cardiac arrhythmias. Heart Rhythm 2020;17:1439–44. https://doi.org/10.1016/j. hrthm.2020.06.016; PMID: 32585191.

Choudry S, Mansour M, Sundaram S, et al. RADAR: a multicenter Food and Drug Administration investigational device exemption clinical trial of persistent atrial fibrillation. Circ Arrhythm Electrophysiol 2020;13:e007825. https://doi.org/10.1161/CIRCEP.119.007825; PMID: 31944826.

Willems S, Tilz RR, Steven 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;141:1057–67. https://doi.org/10.1161/ CIRCULATIONAHA.119.043400; PMID: 32000514.

Tung R, Raiman M, Liao H, et al. Simultaneous endocardial and epicardial delineation of 3D reentrant ventricular tachycardia. J Am Coll Cardiol 2020;75:884–97. https://doi.org/10.1016/j.jacc.2019.12.044; PMID: 32130924.

Haanschoten DM, Elvan A, Ramdat Misier AR, et al. Long-term outcome of the randomized DAPA trial. Circ Arrhythm Electrophysiol 2020;13:e008484. https://doi.org/10.1161/CIRCEP.120.008484; PMID: 33003972.

Rogers AJ, Selvalingam A, Alhusseini MI, et al. Machine learned cellular phenotypes predict outcome in ischemic cardiomyopathy. Circ Res. 2021;128:172–84. https://doi.org/10.1161/circresaha.120.317345; PMID: 33167779.

Kotecha D, Bunting KV, Gill SK, et al. Effect of digoxin vs bisoprolol for heart rate control in atrial fibrillation on patient-reported quality of life: the RATE-AF randomized clinical trial. JAMA 2020;324:2497–508. https://doi.org/10.1001/jama.2020.23138; PMID: 33351042.

Okumura K, Akao M, Yoshida T, et al. Low-dose edoxaban in very elderly patients with atrial fibrillation. N Engl J Med 2020 29;383:1735– 45. https://doi.org/10.1056/NEJMoa2012883; PMID: 32865374.

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Guest Editorial

Atrial Fibrillation and Oral Health Amaar Hassan ,1 Gregory YH Lip ,2,3 Laurent Fauchier

4

and Rebecca V Harris

1

1. Department of Public Health, Policy and Systems, Institute of Population Health, University of Liverpool, Liverpool, UK; 2. Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK; 3. Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 4 Service de Cardiologie, Centre Hospitalier Universitaire Trousseau Faculté de Médecine, Université François Rabelais, Tours, France

Disclosure: The authors have no conflicts of interest to declare.

Received: 17 February 2021 Accepted: 24 February 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(1):7–9. DOI: https://doi.org/10.15420/aer.2021.09 Correspondence: Gregory YH Lip, Liverpool Centre for Cardiovascular Science, Faculty of Health and Life Sciences, University of Liverpool, Foundation Building, Brownlow Hill, Liverpool L69 7TX, 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 non-commercial purposes, provided the original work is cited correctly.

AF, although this study has significant limitations as it did not assess for potential confounders.8

AF is becoming increasingly common and confers a major healthcare burden.1 The exact pathophysiological causes of AF have attracted much interest, but inflammation is thought to be an essential underlying aetiological mechanism implicated in the development of AF.2,3 Raised levels of biomarkers, such as C-reactive protein (CRP), interleukin (IL-1 and IL-6) and tumour necrosis factor (TNF), can lead to valvular changes resulting in atrial dilation and deposition of signalling molecules, such as matrix metalloproteinases (MMPs), leading to fibrosis of the atria.2 Identified risk factors for incident AF include smoking and alcohol intake, hypertension, obesity, diabetes and renal failure, along with acute conditions such as severe sepsis.2,4,5 One possible sepsis-related link with a risk factor that has hitherto received little attention is that of poor oral heath.

A suggested biological mechanism involved is an interplay between periodontal pathogens, vascular endothelial damage and atherogenesis from systemic inflammation, as indicated by chronically elevated inflammatory markers IL-6 and CRP found during the periodontal disease process and new-onset AF.8 The occurrence of atrial dilation and AF pathophysiology involves fibrosis and deposition of connective tissue, alongside platelet and coagulation activation, suggesting that inflammatory pathways may lead to the development of AF and thromboembolic events, such as stroke.2

It is now being recognised that poor dental health is implicated as a causal factor in a range of systemic illnesses, which includes cardiovascular disease (CVD). The relationship between CVD and periodontitis – a common chronic inflammatory disease of the gingivae (gums) that causes the destruction of the supporting bone around teeth – has been extensively researched. A recent report from the European Federation of Periodontology and the American Academy of Periodontology in 2020 reviewed the literature relating to periodontitis and CVD.6 It suggested substantial associations and concluded that effective periodontal therapy leads to improved endothelial function and reduction of chronic inflammatory markers. Bacteraemia is thought to play a role in the development of AF as it may trigger an inflammatory and autoimmune response and CRP distributed following the invasion of bacteria potentially plays a role in oxidative stress and the development of CVD.6

The role in CVD of oral bacteria entering the circulation has also been considered. There have been no studies exploring oral bacteraemia and incidence of AF, although lack of tooth-brushing and dental treatment have been associated with bacteraemia and some studies have shown evidence of cardiovascular complications and AF.9,10 One of the studies investigated almost 30,000 individuals from a Taiwanese database and found that individuals who had at least one dental scaling procedure per year for at least 3 years had a lower incidence of new-onset AF (HR 0.671; 95% CI [0.524–0.859]; p=0.002).9 However, the potential status of certain risk factors for AF, such as smoking, were not considered, and AF was only diagnosed using electronic records and not through validated methods like ECGs. Another observational study comprising 161,286 individuals from a Korean database found that improved oral hygiene and dental scaling also had a reduced risk for incidence of new-onset AF.10 Although this study had more additional information included and adjusted for analysis like smoking status, exercise, and physical weight, there were still no validated methods used for diagnosis of AF and periodontal disease, with confirmation obtained only from electronic records. Authors of another study proposed that bacteraemia, rather than inflammatory oral diseases, may also have a role in the development of new-onset AF. The study comprising 247,696 participants free of any CVD found that individuals with higher incidence of tooth decay also had an increased risk of AF-related diseases such as MI, heart failure, stroke and cardiovascular death.11

There is emerging evidence linking periodontitis with AF.6 In a recent study, 5,958 patients had a periodontal assessment of severity and were monitored for AF.7 Severe periodontitis was found to have higher associations with AF (multivariable adjusted HR 1.31; 95% CI [1.06–1.62]).

This study has significant strengths as it assessed periodontal disease using full-mouth clinical periodontal measurements with comprehensive measurements and followed up participants longitudinally for over 17 years. Incident AF was assessed using comprehensive assessments, such as 12-lead ECGs. A further retrospective cohort study in a large Taiwanese database has reported a positive association between periodontitis and

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Atrial Fibrillation and Oral Health Figure 1: Proposed Mechanisms Linking Poor Oral Health with AF

Atrial dilation Fibrosis Remodelling of the heart Valvular changes Bacterial response Streptococcus mutans

Tooth decay Crown of tooth

Inflammation

IL-1 Porphyromonas gingivalis Chronic IL-8 CRP

Root canal system

Periodontitis

Gingivae (gums) Alveolar bone

Fusobacterium

Chronic

Porphyromonas endodontalis Prevotella

Root of tooth

Apical periodontitis

TNF IL-1 Dental sepsis

MMPs

Acute

Apex of tooth CRP = C-reactive protein; IL = interleukin; MMP = matrix metalloproteinase; TNF = tumour necrosis factor.

as it is not clear how many of those are hospitalised and what percentage have dental sepsis.14

Apical periodontitis – infection of the root canal system – could also play a part in the development of AF. A retrospective observational study found a link between apical periodontitis and AF, although the study had significant limitations as it did not consider other potential confounders.12 Again, a suggested biological mechanism for the relationship was localised inflammatory response to bacterial infections and cell mediators related to CVD and AF such as IL-1.12 Interestingly, the study proposed that apical periodontitis and CVD have common sequences. They are both of connective tissue origin with an inflammatory disease process involving vasodilation, an influx of cellular metabolism, biomarkers and a breakdown of cell structure.12

In summary, there is a growing body of scientific evidence and research suggesting a connection between oral diseases and AF. Figure 1 illustrates the potential biological mechanisms underlying the bacterial and inflammatory oral disease processes highlighted in this article. The relationship of the arrhythmia with oral health can provide a unique model for understanding the impact of different diseases processes (inflammatory and bacterial) associated with the development of AF. Many oral health interventions have been retrospective, following a report that cites barriers to creating prospective trials because of ethical and financial considerations.15 However, Zimmerman et al. recently investigated the effects of a mouth care programme for reducing pneumonia in nursing homes residents using a randomised trial, illustrating that prospective studies with oral health interventions that assess systemic disease are feasible.16 Lengthy prospective longitudinal studies, such as the one by Sen et al., with a duration of 17 years are not always required to assess the relationship of oral health and AF.

A recent systematic review has explored the possible link between acute oral diseases and new-onset AF, but as the authors found only two related case reports in the last 50 years, it is evident that further study in this area is necessary.13 The presence of different Gram-positive and Gram-negative oral bacteria in the bloodstream during severe dental infection may induce cytokines like IL-1, TNF and MMPs causing a dysfunctional response which in some cases can lead to sepsis – a serious complication resulting from damaging microorganisms in the blood or other tissues and the body’s response to their presence, potentially leading to the failure of various organs, and in some cases mortality.4,13 Dental sepsis arising from acute oral diseases may still lead to consequential effects, even after the infection is cleared, as it is recognised that sepsis survivors are at a greater risk of developing new-onset AF even after hospitalisation.4 Acute dental problems are common in England, as 0.7% of all emergency attendances are dental related, but more research is needed in this area 1. Burdett P, Lip GYH. Atrial fibrillation in the United Kingdom: predicting costs of an emerging epidemic recognising and forecasting the cost drivers of atrial fibrillation-related costs.

Eur Heart J Qual Care Clin Outcomes 2020. https://doi. org/10.1093/ehjqcco/qcaa093; PMID: 33346822; epub ahead of press.

2. Kornej J, Apostolakis S, Bollmann A, Lip GY. The emerging role of biomarkers in atrial fibrillation. Can J Cardiol 2013;29:1181–93. https://doi.org/10.1016/j.cjca.2013.04.016;

Future research can include shorter prospective studies that are able to investigate recurrence of AF following cardiac ablation or cardioversion.

The occurence of post-operative AF after cardiac surgery is also common and incidence during hospital stay can be monitored following an oral health intervention.7 Oral health should be part of the comprehensive evaluation and characterisation of AF, with an integrated or holistic approach to managing this common cardiac arrhythmia.17,18

PMID: 23962731.

3. Guo Y, Lip GY, Apostolakis S. Inflammation in atrial fibrillation. J Am Coll Cardiol 2012;60:2263–70. https://doi. org/10.1016/j.jacc.2012.04.063; PMID: 23194937.

4. Walkey AJ, Hammill BG, Curtis LH, Benjamin EJ. Long-term outcomes following development of new-onset atrial fibrillation during sepsis. Chest 2014;146:1187–95. https://doi.org/10.1378/chest.14-0003; PMID: 24723004.

5. Lane DA, Skjøth F, Lip GYH, et al. Temporal trends in

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incidence, prevalence, and mortality of atrial fibrillation in primary care. J Am Heart Assoc 2017;6. https://doi.org/10.1161/ JAHA.116.005155; PMID: 28455344.

6. Sanz M, Marco Del Castillo A, Jepsen S, et al. Periodontitis and cardiovascular diseases: consensus report. J Clin Periodontol 2020;47:268–88. https://doi.org/10.1111/ jcpe.13189; PMID: 32011025.

7. Sen S, Redd K, Trivedi T, et al. Periodontal disease, atrial fibrillation and stroke. Am Heart J 2021;235:36–43.

Atrial Fibrillation and Oral Health https://doi.org/10.1016/j.ahj.2021.01.009; PMID: 33503409.

8. Chen DY, Lin CH, Chen YM, Chen HH. Risk of atrial fibrillation or flutter associated with periodontitis: a nationwide, population-based, cohort study. PloS One 2016;11:e0165601. https://doi.org/10.1371/journal. pone.0165601; PMID: 27798703.

9. Chen SJ, Liu CJ, Chao TF, et al. Dental scaling and atrial fibrillation: a nationwide cohort study. Int J Cardiol 2013;168:2300–03. https://doi.org/10.1016/j. ijcard.2013.01.192; PMID: 23453452.

10. Chang Y, Woo HG, Park J, et al. Improved oral hygiene care is associated with decreased risk of occurrence for atrial fibrillation and heart failure: a nationwide population-based cohort study. Eur J Prev Cardiol 2020;27:1835–45. https://doi. org/10.1177/2047487319886018; PMID: 31786965.

11. Park SY, Kim SH, Kang SH, et al. Improved oral hygiene care attenuates the cardiovascular risk of oral health disease: a population-based study from Korea. Eur Heart J 2019;40:1138–45. https://doi.org/10.1093/eurheartj/ehy836; PMID: 30561631.

12. Messing M, Souza LC, Cavalla F, et al. Investigating potential correlations between endodontic pathology and cardiovascular diseases using epidemiological and genetic approaches. J Endod 2019;45:104–10. https://doi. org/10.1016/j.joen.2018.10.014; PMID: 30661725.

13. Hassan A, Lip GYH, Harris RV. Atrial fibrillation and cardiac arrhythmia associated with acute dental infection: a systematic literature review and case report. Int J Clin Pract 2020:e13875. https://doi.org/10.1111/ijcp.13875; PMID: 33253465.

14. Currie CC, Stone SJ, Connolly J, Durham J. Dental pain in the medical emergency department: a cross-sectional study.

J Oral Rehabil 2017;44:105–11. https://doi.org/10.1111/ joor.12462; PMID: 27896841.

15. Tonetti MS, Van Dyke TE. Periodontitis and atherosclerotic cardiovascular disease: consensus report of the joint EFP/ AAP workshop on periodontitis and systemic diseases. J Periodontol 2013;84(4 Suppl):S24–9. https://doi.org/10.1902/ jop.2013.1340019; PMID: 23631582.

16. Zimmerman S, Sloane PD, Ward K, et al. Effectiveness of a

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mouth care program provided by nursing home staff vs standard care on reducing pneumonia incidence: a cluster randomized trial. JAMA Netw Open 2020;3:e204321. https://doi.org/10.1001/jamanetworkopen.2020.4321; PMID: 32558913.

17. Potpara TS, Lip GYH, Blomstrom-Lundqvist C, et al. The 4S-AF scheme (stroke risk; symptoms; severity of burden; substrate): a novel approach to in-depth characterization (rather than classification) of atrial fibrillation. Thromb Haemost 2021;121;270–8. https://doi. org/10.1055/s-0040-1716408; PMID: 32838473.

18. Yoon M, Yang PS, Jang E, et al. Improved population-based clinical outcomes of patients with atrial fibrillation by compliance with the simple ABC (atrial fibrillation better care) pathway for integrated care management: a nationwide cohort study. Thromb Haemost 2019;119:1695– 703. https://doi.org/10.1055/s-0039-1693516; PMID: 31266082.

Clinical Arrhythmias

Electrocardiographic Criteria for Differentiating Left from Right Idiopathic Outflow Tract Ventricular Arrhythmias Marco V Mariani ,1 Agostino Piro,1 Domenico G Della Rocca,2 Giovanni B Forleo,3 Naga Venkata Pothineni,4 Jorge Romero,5 Luigi Di Biase,5 Francesco Fedele1 and Carlo Lavalle1 1. Department of Cardiovascular, Respiratory, Nephrology, Anaesthesiology and Geriatric Sciences, Sapienza University of Rome, Italy; 2. Texas Cardiac Arrhythmia Institute, St David’s Medical Center, Austin, TX, US; 3. Department of Cardiology, Luigi Sacco Hospital, Milan, Italy; 4. Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia, PA, US; 5. Department of Cardiology, Montefiore Medical Center, New York, NY, US

Abstract

Idiopathic ventricular arrhythmias are ventricular tachycardias or premature ventricular contractions presumably not related to myocardial scar or disorders of ion channels. Of the ventricular arrhythmias (VAs) without underlying structural heart disease, those arising from the ventricular outflow tracts (OTs) are the most common. The right ventricular outflow tract (RVOT) is the most common site of origin for OT-VAs, but these arrhythmias can, less frequently, originate from the left ventricular outflow tract (LVOT). OT-VAs are focal and have characteristic ECG features based on their anatomical origin. Radiofrequency catheter ablation (RFCA) is an effective and safe treatment strategy for OT-VAs. Prediction of the OT-VA origin according to ECG features is an essential part of the preprocedural planning for RFCA procedures. Several ECG criteria have been proposed for differentiating OT site of origin. Unfortunately, the ECG features of RVOT-VAs and LVOT-VAs are similar and could possibly lead to misdiagnosis. The authors review the ECG criteria used in clinical practice to differentiate RVOT-VAs from LVOT-VAs.

Keywords

Idiopathic ventricular arrhythmia, ventricular outflow tract, catheter ablation, electrocardiogram Disclosure: The authors have no conflicts of interest to declare.

Received: 17 March 2020 Accepted: 18 November 2020 Citation: Arrhythmia & Electrophysiology Review 2021;10(1):10–6. DOI: https://doi.org/10.15420/aer.2020.10 Correspondence: Marco Valerio Mariani, Viale del Policlinico 155, 00161, Rome, Italy. E: marcoval.mariani@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 non-commercial purposes, provided the original work is cited correctly.

ablation lesions.7 Indeed, catheter ablation is accepted as a highly successful first-line therapy for OT-VAs originating from the RVOT (class I recommendation), and a treatment for VAs from endocardial and epicardial LVOT when anti-arrhythmic medication is ineffective, not tolerated or not the patient’s preference (class IIa recommendation).7

Idiopathic ventricular arrhythmias (IVAs) comprise a spectrum of arrhythmias (the mechanisms of which are presumably not related to myocardial scar or ion channel disorders), that can, occasionally, occur in patients with structural heart disease.1 The most common forms of IVA come from the right ventricular outflow tract (RVOT) and the left ventricular outflow tract (LVOT) in 60% and 20% of patients, respectively, but there are other sites of origin such as the atrioventricular annuli, papillary muscles1,2 and moderator band,3 which account for approximately 20% of IVAs.

OT-VA has a focal origin and displays a single dominant QRS morphology.

The surface ECG pattern reflects anatomical origin and can help to differentiate OT-VAs from the RVOT and LVOT: RVOT-VAs usually have left bundle branch block (LBBB) morphology and inferior QRS axis; conversely, LVOT-VAs can display different morphologies in relation to the position of the arrhythmogenic focus in the LVOT.8

In the RVOT, the septum is a more common site of OT-VA origin than the free wall. The LVOT-VAs originate from structures in close anatomical proximity: the aorto-mitral continuity (AMC), the anterior sites around the mitral annulus (MA), the aortic sinus cusp (ASC) and the epicardium.4,5

During the past decades, numerous ECG criteria have been proposed to preoperatively differentiate the site of origin of OT-VAs, because the ECG determination of site of origin has important implications for patient counselling and procedure planning. For example, the procedural risk profile and the success rate associated with aortic root ablation in the LVOT are different to those encountered in the RVOT (e.g., risk of stroke or coronary artery damage). Moreover, if LVOT-VA is suspected, retrograde aortic access and coronary angiography should be planned preoperatively.

The IVAs are considered benign ventricular arrhythmias, but OT-VA can lead to serious adverse sequelae such as premature ventricular contraction (PVC)-induced cardiomyopathy, impaired quality of life, incessant ventricular tachycardia (VT) and sudden cardiac death.6 Usually these VAs are asymptomatic but sometimes patients report palpitations, chest pain, presyncope and, rarely, syncope. In view of the origin from a single ventricular site, these arrhythmias can be treated using discrete

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Idiopathic Outflow Tract Ventricular Arrhythmias Figure 1: Activation Map of Ventricular Arrhythmias Originating from the Posteroseptal Right Ventricular Outflow Tract Site

RVOT

LVOT

direction. The proximal part of the RVOT, near the tricuspid valve, is to the right of the aortic root; the main body of the RVOT wraps itself around the LVOT and is then situated anterior and to the left of the aortic root (Figure 1). The RVOT has two opposing surfaces: an anterior or ‘free wall’ surface and a posterior or ‘septal’ surface. The pulmonary valve is located 1–2 cm superior to the aortic valve and attaches at the sinotubular junction. Because the RVOT and pulmonary valve are positioned more cranially than their LV counterparts, the posterior (septal) wall of the RVOT borders the right coronary cusp (RCC) and a slight portion of the left coronary cusp (LCC; Figure 2). The interleaflet fibrous trigone between the LCC and RCC is directly posterior relative to the RVOT (LCC/RCC commissure).9 Due to this close anatomical relationship, ECG features of VAs from these two regions are nearly identical and may lead to misdiagnosis of the site of origin.

RVOT

LVOT

Recently, Liang et al. highlighted the anatomical features of the OT region associated with challenging situations during mapping and ablation of OTVAs.10 First, the myocardial network in the OT region is complex and results in preferential conduction of the depolarisation wavefront across the interventricular outflow septum, resulting in multiple breakthrough sites from a single arrhythmogenic focus. This is the anatomical substrate responsible for the QRS morphology shift during ablation, requiring mapping and ablation in the adjacent cardiac chamber in 65% of cases. Second, OTVAs may originate from the LV summit, that is, the more superior, septal and epicardial aspect of the LV. Due to the close proximity of the coronary arteries and the epicardial fat, ablation in the coronary venous system (great cardiac vein or anterior interventricular vein) or a direct epicardial approach may be precluded and an anatomical approach may be required,11 targeting the arrhythmogenic focus from the closest adjacent locations. The close anatomical relationship between the LVOT and RVOT enables suppression of LV summit VA ablation, not only from the LV endocardium or aortic cusp region, but also from the septal aspect of the RVOT.

Anteroposterior (left) and laterolateral (right) projections showing the 3D relationship between the right and left ventricular outflow tracts (RVOT and LVOT, respectively). Red dots, surrounding the area of earliest activation, represent ablation sites, and the left and right coronary cusps are shown in pink and green, respectively. The main body of the RVOT wraps itself around the LVOT and then becomes situated anterior and to the left of the aortic valve. LVOT = left ventricular outflow tract; RVOT = right ventricular outflow tract.

Figure 2: Intracardiac Echocardiography Showing the Relationship Between the Right Coronary Cusp and Right Ventricular Outflow Tract

Current ECG Criteria for Differentiating LVOT from RVOT Origin

Although VA site of origin is determined using an electroanatomical mapping system during invasive electrophysiological study,7 preoperative analysis of the 12-lead ECG of the spontaneous OT-VAs is commonly used as the basic tool for eliminating unlikely sites of origin and for distinguishing LVOT VAs from RVOT VAs. Moreover, different ECG features have been described to identify discrete OT-VA sources (ASC, AMC, LV summit, RVOT walls) and, despite some limitations, may help in defining the successful ablation site (Figures 3 and 4).4,12–17

The RCC is situated adjacent to the distal portion of the septal wall of the right ventricular outflow tract. AO = aorta; PA = pulmonary artery; RCC = right coronary cusp.

Due to the orientation of depolarising vectors on the horizontal plane axis, anterior structures close to lead V1 will produce an LBBB pattern, while more posterior structures, far from the anterior chest, will produce an RBBB pattern.

Therefore, RVOT-VAs will usually be associated with LBBB owing to the anterior position relative to the LVOT (Figure 3). OT-VAs from the LVOT may have RBBB as well as atypical LBBB morphology depending on the position of the site of origin in the LVOT (Figure 4). For example, the RCC is immediately posterior to the septal or posterior RVOT wall, so that RCC VAs have an LBBB pattern (Figure 4A). Moving more posteriorly from the RVOT to the lateral MA produces earlier precordial transition, and the QRS morphology shifts from an LBBB pattern to an RBBB pattern (Figure 4B).5 This is the reason why, in the presence of LBBB and inferior QRS axis, a BBB pattern alone does not enable the distinction between LVOT and RVOT site of origin.

Unfortunately, the accuracy and reliability of these ECG algorithms are affected by the individual orientation of VOTs relative to the surrounding chest structures, cardiac rotation, chest wall anatomy and lead placement.7 Furthermore, close-proximity anatomical structures produce similar VA morphologies, therefore prediction of the VA site of origin could be challenging. A deep knowledge of the OT anatomy, with a focus on the gross relationship and orientation of OTs in the chest, is of paramount importance in this review of the current ECG criteria for differentiating RVOT and LVOT site of origin.

Anatomy of Ventricular Outflow Tracts: Implications for Diagnosis and Management

In the area of the OTs, several cardiac structures lie in close proximity: the RVOT and LVOT, aortic root, pulmonary artery and epicardium. From the tricuspid annulus, the RVOT projects in a superior, anterior and leftward

VA with LBBB QRS morphology and inferior axis represents a challenge because distinguishing LVOT from RVOT origin is difficult. Previously,

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Idiopathic Outflow Tract Ventricular Arrhythmias Figure 3: 12-lead ECG of Ventricular Arrhythmias Arising from Right Ventricular Outflow Tract Anterior, Middle and Posterior Sites

several algorithms have been proposed to correctly diagnose OT-VA origin in these patients.

Ouyang et al. first addressed this issue when they studied 15 patients with VAs with LBBB and inferior QRS axis.12 In eight patients the successful ablation site was the RVOT, and in seven patients it was the ASC. By retrospectively analysing surface ECG, they found that the ASC, due to the posterior and rightward location relative to the RVOT, had a higher and wider R wave in leads V1 and V2 than RVOT VAs, and proposed the indexes of R wave duration and R/S wave amplitude as criteria for differentiating RVOT from LVOT VAs. The R/S wave amplitude ratio in leads V1 and V2 is calculated as a proportion, using the amplitudes of the QRS complex from the peak (R wave) and from the nadir (S wave) to the isoelectric line, and the R/S wave amplitude index is defined as the greater of the R/S wave amplitude ratios in leads V1 and V2; the R wave duration index is measured by dividing the longer of the R wave durations in leads V1 and V2 by the QRS complex duration. An R/S amplitude index <0.3 and R wave duration index <0.5 suggest an RVOT VA.

I

II

III

aVR

aVL

aVF

V1

By correlating the ECG findings with the catheter ablation site in 80 patients with OT-VAs, Ito et al. proposed an ECG algorithm to identify the discrete origin of IOT-VAs.18 Four indices were used in the stepwise algorithm for differentiating RVOT and LVOT site of origin: the precordial R wave transition, QRS morphology in lead I, the R/S wave amplitude index in leads V1 or V2 and the R wave duration index. This algorithm was further evaluated in a prospective cohort of 88 patients with an overall sensitivity of 88% and specificity of 95%. No patients with right-sided VAs were misclassified as having left-sided VAs, whereas two patients with LVOT-VAs were misdiagnosed as having RVOT-VAs. Although prospectively tested with considerable results in term of sensitivity and specificity, this algorithm may appear cumbersome to use, due to the complex stepwise design and its reliance on QRS morphology in lead I. Indeed, QRS morphology may be affected by factors such as variation in positional relationship of OT and chest wall, body habitus, ventricular hypertrophy, chest wall deformities and chronic obstructive pulmonary disease (COPD).

V2

V3

V4

V5

V6

Posterior site

Middle site

Anterior site

Right ventricular outflow tract (RVOT) ventricular arrhythmias usually present left bundle branch block with late precordial transition and inferior QRS axis. Of note, Q wave amplitude in lead aVR becomes progressively larger moving from anterior to posterior RVOT sites; conversely, Q wave amplitude in lead aVL is smaller in posterior than in anterior RVOT sites. This is due to the caudocephalic spiral orientation of the RVOT, which wraps around the left ventricular outflow tract and is situated progressively anterior and to the left of the aortic root.

The seminal finding that LVOT VAs, due to the posterior position of the site of origin relative to RVOT VAs, result in a mean depolarisation vector directed towards V1 and V2, led to the development of new algorithms based on the site of the R wave transition in the precordial leads.

In the study by Betensky et al., precordial transition, defined as the single precordial lead in which the R wave amplitude exceeds the S wave amplitude, was used to distinguish VA origin:20 a precordial transition later than lead V4 or later than SR transition indicated an RVOT origin (LVOT origin excluded with 100% accuracy), while a precordial transition in lead V3 or earlier than SR could not rule out an RVOT origin.11 In the latter case a new criterion, the V2 transition ratio, was evaluated to differentiate RVOT from LVOT origin. It was derived in a retrospective ECG analysis of 40 OT-VAs that were successfully ablated, and was calculated by dividing the percentage R wave during VT, (R/[R + S])VT, by the percentage R wave in SR, (R/[R + S])SR.20 In 21 prospective cases, a V2 transition ratio >0.6 predicted an LVOT origin (sensitivity, 95%; specificity, 100%; accuracy, 91%), whereas a V2 transition ratio <0.6 predicted an RVOT origin.

Yoshida et al. developed the transition zone (TZ) index, in the assessment of surface ECGs of OT-VAs with LBBB morphology and inferior axis in 112 patients who had successful ablation in the RVOT (n=87) and ASC (n=25).19 The TZ was defined as the precordial lead in which the R wave and S wave have equal amplitudes, and the lead number is used as the score.

The chest leads involved in the score are those with an R/S wave amplitude ratio between 0.9 and 1.1. The TZ index is calculated as the TZ score in OT-VA minus the TZ score in sinus rhythm (SR). Relative to a normal TZ of lead V3–V4 in SR, Yoshida et al. reported in their case series that approximately 35% of patients had a shift of the precordial TZ in SR, defined as counterclockwise rotation (CCWR) if TZ score in SR was <V3 and clockwise rotation (CWR) if TZ score in SR was >V4. That study showed that the site of TZ of OT-VAs is affected by cardiac rotation and that both RVOT VAs and LVOT VAs have a lower TZ score in CCWR than in CWR. Meanwhile, the TZ during SR is affected by the cardiac rotation too.

Hence, Yoshida et al. compared TZ score during OT-VAs and SR to obtain a novel cardiac rotation-corrected index. A TZ index cut-off <0 predicted an ASC origin with 88% sensitivity and 82% specificity.

Similarly, Yoshida et al. studied OT-VAs with an LBBB pattern and inferior QRS axis morphology in 207 patients who underwent successful catheter ablation in the RVOT (n=154 patients) and LVOT (n=53).21 They proposed the V2S/V3R index, calculated from the S wave amplitude in lead V2 divided by the R wave amplitude in lead V3 during the OT-VA, to reliably differentiate between RVOT and LVOT VA origin. A V2S/V3R index ≥1.5 predicted an RVOT site of origin; in contrast, a V2S/V3R index ≤1.5

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Idiopathic Outflow Tract Ventricular Arrhythmias Figure 4: 12-lead ECG of Ventricular Arrhythmias Arising from Different Left Ventricular Outflow Tract Sites A

RCC

R–L junction

LCC

NCC

B

I

I

II

II

III

III

aVR

aVR

aVL

aVL

aVF

aVF

V1

V1

V2

V2

V3

V3

V4

V4

V5

V5

V6

V6

LVS

AMC

AMV

A: 12-lead ECG of ventricular arrhythmias originating from the aortic root. The RCC is immediately posterior of the septal right ventricular outflow tract wall, so that RCC ventricular arrhythmias exhibits a left bundle branch block pattern. The LCC is leftward, posterior and superior relative to the other coronary cusps and presents with a right bundle branch block pattern. B: Shift in QRS morphology from a left bundle branch block pattern to a right bundle branch block pattern, as the site of origin moves posteriorly from the coronary cusps to the aorto-mitral continuity and lateral mitral annulus, producing an earlier precordial transition. AMV = anterior mitral valve; LCC = left coronary cusp; LVS = left ventricular summit; NCC = non-coronary cusp; R–L junction = right–left coronary cusp junction; RCC = right coronary cusp.

curve (AUC) of 0.931. In the validation cohort of 37 patients, V1–V3 index had 95% accuracy in predicting an RVOT origin. However, the algorithm was developed from a population in whom only a minority of VAs came from the LVOT (19.7%); therefore, the accuracy of the algorithm by Di et al.24 should be confirmed in a population with a larger series of LVOT-VAs. Moreover, the algorithm was tested only for OT-VAs with precordial transition in lead V3, thus its utility in clinical daily practice is limited to this subgroup of OT-VAs.

indicated an LVOT site of origin with a specificity of 94% and sensibility of 89%. The rationale for this index lies in the direct anatomical relationship between RVOT, LVOT and the lead V3 position, which is close to the RVOT and records a smaller R wave in RVOT-VAs.21 Kaypakli et al. proposed the S-R difference in leads V1 and V2 (V1–2 SRd), calculated using this formula on the 12-lead surface ECG: (V1S amplitude + V2S amplitude) – (V1R amplitude + V2R amplitude).22 Owing to its anterior position, the RVOT is closer to leads V1 and V2 than the LVOT, and therefore RVOT VAs will produce a deeper S wave and smaller R wave in these leads; conversely, the LVOT is further from leads V1 and V2 relative to the RVOT, and therefore LVOT VAs will give rise to a higher R wave and smaller S wave in these leads. Thus, V1-2 SRd is lower in LVOT sites of origin than in RVOT sites of origin, and the cut-off proposed by Kaypakli et al. is 1.625 mV (sensitivity, 95.1%; specificity, 85.5%).

More recently, the diagnostic value of the ECG posterior and right leads has been evaluated in OT-VAs. Zhang et al. studied the usefulness of the modification of lead V5 to V8 (at the inferior point of the scapula) in 134 patients undergoing ablation of PVCs.25 They found that PVCs successfully ablated from the left side had a statistically significantly higher V4/V8 R wave ratio compared with right-sided PVCs. When normalised to SR by dividing the OT-VA V4/V8 ratio by SR V4/V8, PVCs successfully ablated from the left side had a statistically significantly higher V4/V8 index compared with right-sided PVCs. They validated this new criterion in a prospective validation cohort of 40 patients. V4/V8 R wave ratio >3 had a sensitivity of 75%, specificity of 82%, negative predictive value (NPV) of 89% and positive predictive value (PPV) of 64% for left-sided locations. A cut-off >2.28 for V4/V8 index had a sensitivity of 67%, specificity of 96%, PPV of 89%, and NPV of 87% for left-sided origins. Normalising the V4/V8 ratio to the patient’s SR resulted in improved specificity (100%) and PPV (100%) for PVCs with a V3 precordial transition (n=19 patients) compared with VAs with precordial transition other than lead V3.

He et al. studied a cohort of 488 patients with idiopathic PVCs or VT with LBBB and inferior QRS axis.23 They developed an ECG diagnostic model consisting of two ECG algorithms, the TZ index and V2S/V3R index, with a cut-off ≥−0.76 predicting an LVOT site of origin. This model was prospectively validated in a cohort of 207 patients and yielded a sensitivity of 90% and a specificity of 87%.

Di et al. developed the V1–V3 transition index for differentiating RVOT and LVOT VAs with precordial transition in lead V3.24 This novel electrocardiographic criterion was derived from an analysis of 147 consecutive patients successfully ablated in RVOT (n=118) or LVOT (n=29), and was defined as the sum of the S wave in leads V1 and V2 during PVC divided by the S wave amplitude in the same leads during SR, minus the sum of R wave amplitude in leads V1, V2, V3 during PVC divided by the R wave amplitude in the same leads during SR; that is, [(SPVC/SSR)V1 + (SPVC/SSR) V2] − [(RPVC/RSR)V1 + (RPVC/RSR)V2 + (RPVC/RSR)V3]. RVOT sites of origin had significantly larger V1–V3 index values than LVOT sites. A cut-off > −1.60 predicted an RVOT origin with 93% sensitivity and 86% specificity, and on receiver operating characteristic (ROC) analysis it had an area under the

Finally, Cheng et al. developed a new criterion for differentiating LVOT from RVOT VAs, by replacing leads V5 and V6 with leads V3R and V7.26 Lead V3R was placed at the corresponding right-hand side to lead V3, and V7 was placed at the left posterior axillary line of the fifth intercostal space. In the analysis of OT-VA morphologies successfully ablated in 97 consecutive patients (74 with RVOT origin and 23 with LVOT origin), R wave amplitudes in lead V3R and S wave amplitudes in lead V7 were significantly larger for LVOT origin than RVOT origin. Furthermore, the QS pattern in lead V3R was found only in patients with RVOT sites of origin,

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Idiopathic Outflow Tract Ventricular Arrhythmias Table 1: Published Algorithms and Their Predictive Value for Differentiating Left Ventricular Outflow Tract from Right Ventricular Outflow Tract Ventricular Arrhythmia Author

n

Algorithm Used

Predictive Value

Ouyang et al. 2002

15

R/S amplitude index (>0.5) and R duration index (>0.3) predict LVOT

Statistically significant difference between LVOT and RVOT origins

Ito et al. 200318

168

Precordial R wave transition, QRS morphology in lead I, R wave duration index, R/S wave amplitude index in V1, V2

Sensitivity 88% Specificity 95%

Yoshida et al. 201119

112

TZ index <0 predicts LVOT

Sensitivity 88% Specificity 82%

Betensky et al. 201120

61

V2 transition ratio ≥0.6 predicts LVOT origin

Sensitivity 95% Specificity 100%

Yoshida et al. 201421

207

V2S/V3R index ≤1.5 predicts LVOT origin

Sensitivity 89% Specificity 94%

Kaypakli et al. 201722

123

V1−V2 S-R difference = (V1S + V2S) − (V1R + V2R). If >1.625, predicts RVOT origin

Sensitivity 95% Specificity 85%

He et al. 201823

695

Combined TZ index and V2S/V3R, Y = −1.15 × TZ − 0.494 × (V2S/V3R). If ≥ −0.76, predicts LVOT origin

Sensitivity 90% Specificity 87%

Di et al. 201924

184

V1–V3 transition index > −1.60 predicts RVOT origin

Sensitivity 93% Specificity 86%

Zhang et al. 201725

174

V4/V8 index >2.28 predicts LVOT origin

Sensitivity 67% Specificity 96%

Cheng et al. 201826

191

V3R/V7 ≥0.85 predicts LVOT origin

Sensitivity 87% Specificity 96%

12

LVOT = left ventricular outflow tract; RVOT = right ventricular outflow tract; TZ = transition zone.

central aorta, the infravalvular portion of the RVOT becomes located to the left of the aortic root. Therefore, misdiagnosis can be due to the underestimation of the complex 3D anatomical relationship between OTs when analysed only in the horizontal plane. Third, the precordial transition lead depends on the cardiac electrical axis in the horizontal plane. The electrical axis of the heart is strongly related to the cardiac anatomic orientation in the chest, which varies greatly between individuals. As a result, the precordial transition lead varies with cardiac anatomic orientation in each patient. Yoshida et al. reported that approximately 35% of patients have a shift of the TZ in SR, and consequently during OT-VAs, due to cardiac electrical axis rotation in the horizontal plane.19 This variability influences the QRS morphology in the anterior leads and in the precordial transition zone, and accounts for the misleading identification of the OT-VA site of origin when ECG criteria are used solely with regard to the horizontal axis of the heart.

and the S wave in lead V7 was detected only in patients with LVOT sites of origin. This led to the development of the V3R/V7 index, calculated as the ratio of R wave amplitudes in leads V3R and V7 during VA. V3R/V7 index ≥0.85 predicted an LVOT origin with 87% sensitivity and 96% specificity in the development cohort. In the validation cohort, consisting of 74 patients successfully ablated from RVOT and 20 patients from LVOT, the V3R/V7 index correctly predicted the successful ablation site in 94.7%. Published algorithms and their predictive value in differentiating RVOT and LVOT VAs are listed in Table 1.

Current ECG Criteria: Relevance to Anatomy

The ECG features of OT-VAs rely strongly on the position of the LVOT and RVOT relative to the exploratory leads. The RVOT is to the right of the aortic root and, due to the close anatomical relationship with leads V1–V3, RVOT sites of origin result in lower R-wave amplitude in these precordial leads and delayed precordial transition compared with LVOT. This finding is crucial for the understanding of the ECG criteria based on R and S wave amplitudes in the precordial leads and in the OT-VA precordial transition lead, such as the indexes of R wave duration and R/S wave amplitude by Ouyang et al., the TZ index and V2S/V3R index by Yoshida et al., the ECG prediction model by He et al., the V2 transition ratio by Betensky et al. and the V1–V3 transition index by Di et al.12, 19,2021,2324

As a result, horizontal plane analysis has limited accuracy and reliability in differentiating left from right OT. This concept was first demonstrated by Tanner et al., who showed that both RVOT origin and LVOT origins (ASCs, coronary sinus, epicardium) could display a similar precordial transition in lead V3 and QRS morphology in the horizontal plane due to the close anatomic relationships between OTs.27 To address the ECG criteria pitfalls related to the variability of cardiac anatomic orientation, body habitus and chest features, Betensky et al. compared the VA with SR QRS morphology, and normalised the VA ECG features of each patient with respect to the SR.20 Their V2 transition ratio outperforms traditional criteria and is the only index to be prospectively validated.

These criteria, although based on electroanatomical considerations, have various limitations that can possibly lead to misdiagnosis. First, QRS morphology in leads V1–V3 reflects the cardiac anatomical orientation in the horizontal plane, resulting from the depolarising vector moving towards or away from the anterior chest wall. Due to the close relationship between the RVOT and LVOT, and between the OTs and the anterior chest wall, the anterior leads might not always show a significant difference between RVOT and LVOT in the relative S and R wave amplitudes on vector analysis, especially in the presence of COPD or pericardial effusion. Second, although the proximal part of the RVOT is to the right of the aortic root, as the RVOT rotates and wraps around the

In consideration of the limitation of horizontal axis analysis, in recent years the OT-VAs have been studied on the sagittal axis, through the use of right precordial and posterior leads. As noted here, the complex anatomic relationship between OTs cannot be defined only in terms of right and left structures because the RVOT rotates, becoming situated anterior and to the left of the LVOT. Due to the anteroposterior intertwining

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Idiopathic Outflow Tract Ventricular Arrhythmias of the anatomic relationship between OTs, OT-VAs moving away from the LVOT are expected to produce taller R waves in the anterior leads and deeper S waves in the posterior leads, compared with RVOT-VAs.

Jamil-Copley et al. prospectively assessed the accuracy of NIECM in periprocedurally predicting OT-VA site of origin in 24 patients, and compared NIECM performance with that of three published ECG algorithms.32 NIECM successfully identified OT-VA site of origin in 23/24 patients (96%), outperforming the former published algorithms, which had an accuracy of 50–88%. Similar NIECM accuracy has been reported by Erkapic et al., who noted an advantage in terms of radiofrequency energy applications and time to ablation compared with conventional 12-lead ECG-guided mapping and ablation.33

Zhang et al. first addressed this issue and proposed the V4/V8 ratio, with the modification of lead V5 to V8.25 Increasing values of mean V4/V8 ratio were reported as the VA site of origin moved from anterior to posterior, due to the electrical propagation along the posteroanterior axis.

Normalisation of the V4/V8 ratio with the V4/V8 ratio in SR, produced the V4/V8 index, which had increased NPV, PPV and specificity relative to V4/ V8 ratio for left-sided OT-VAs. Moreover, in a subgroup of patients in the prospective validation cohort with V3 precordial transition, the V4/V8 index had 100% specificity and PPV. Overall, the anteroposterior ratio, V4/ V8, outperformed previously reported criteria with a demonstrated diagnostic accuracy >90%.

Recently, Mountantonakis et al. tested the accuracy of NIECM in distinguishing IOT-VAs arising from the septal RVOT, ASC region and LV summit in a cohort of 31 consecutive patients.34 The non-invasive electroanatomic mapping analysis showed that all three origins had close breakthrough sites, resulting in similar QRS morphology in 12-lead ECGs, which accounts for the frequent misdiagnosis of IOT-VAs coming from this anatomically complex region. Conversely, based on the electrical propagation pattern and the activation timing of the basal lateral MA and superior basal septum, NIECM had 100% accuracy in correctly identifying the three sites of origin. Although future studies are needed to confirm these results, NIECM appears to be a promising tool for prognostication and planning of mapping and ablation of IOT-VAs.

Cheng et al. noted similar results for the V3R/V7 index, which had a higher accuracy, as measured using AUC on ROC analysis (0.954), than that of previously reported criteria, including V2S/V3R (0.896; p=0.353), V2 transition ratio (0.792; p=0.035) and TZ index (0.666; p=0.001).26 In the validation cohort, the V3R/V7 index was able to correctly predict the site of successful ablation in 94.7%, and a cut-off ≥0.85 ruled out an RVOT origin with 98.6% accuracy. Additionally, the V3R/V7 index had 97% specificity and NPV for patients with R/S transition in lead V3, and 100% specificity and PPV for patients with cardiac rotation. Although a direct comparison between these two indexes has not been conducted, the V4/ V8 index and V3R/V7 index have similar diagnostic accuracy, although the V3R/V7 index is not normalised to SR. This lack of difference between the two indexes is hypothesis generating, and may be related to the parallel orientation of the axis formed by the V3R and V7 leads through the chest with the axis of electrical propagation between the RVOT (anterior and rightward) and LVOT (posterior and leftward). Being more in line with the electrical depolarising vector, these leads may record a higher wave amplitude and more significant differences.

Limitations

Of note, the currently used criteria have several limitations. First, these criteria were developed using small cohorts, and only the V2 transition ratio, the V4/V8 index and the V3R/V7 index have been prospectively tested. Hence, these criteria should be further validated in larger populations. Second, inter-individual variability in lead placement could have affected the development of the criteria.35 Finally, in all the studies, the successful ablation site determined the location of the arrhythmogenic focus. The site of successful ablation, however, may not represent the real focus but may represent only the breakthrough site, and preferential conduction across the ventricular outflow septum can affect the predictive accuracy of algorithms.36 Indeed, some patients with VAs originating from the ASCs have shared myocardial connections bridging LVOT and RVOT with early breakout at RVOT, thus affecting the accuracy of ECG predictive algorithms in the OTs. Moreover, due to the close relationship of the anatomical structures in the OTs, the same arrhythmia can be successfully ablated from different sites, particularly the arrhythmias from the LV summit and from the posterior RVOT-RCC.37

Overall, the study of the relative amplitudes of the electrical cardiac vector moving in an anteroposterior dimension is supported by anatomical reasons. Anteroposterior ECG configurations maximise the differences in vector ratios and provide added diagnostic value and predictive accuracy for differentiating LVOT from RVOT VAs, regardless of cardiac rotation and R/S transition lead, because the sagittal plane analysis is less affected by these variables. However, as reported in recent reviews, algorithm accuracy is limited, and it is preferable to use a combined model consisting of different algorithms, to account for the limitations of each individual ECG-based criterion.28–30

Clinical Perspective

• Ventricular outflow tracts are the most common sites of origin of idiopathic ventricular arrhythmias.

Beyond 12-Lead ECG: Non-invasive ECG Mapping

• Ventricular outflow tract arrhythmias have focal origin and

The diagnostic accuracy of current ECG algorithms in distinguishing RVOT from LVOT VAs is affected by several factors, such as body habitus, heart orientation in the chest and variability in precordial lead placement.

Moreover, 12-lead ECGs cannot provide information on the activation sequence during VAs. To overcome these limitations, non-invasive ECG mapping (NIECM) systems have been proposed, which have shown promising results. With a vest embedded with 252 electrodes at torso level, the patient undergoes thoracic CT to obtain heart–torso anatomic data, and data on the anatomic relationship between electrodes on the vest, and the heart. Subsequently, the NIECM system reconstructs the unipolar electrograms recorded by each electrode and merges body surface electrical data with the anatomical CT heart–torso images, providing 3D colour-coded, isopotential, voltage and activation maps.31

display a single dominant QRS morphology. The distinction between right and left outflow tract origin carries important clinical and prognostic implications.

• Although several ECG criteria have been developed to distinguish right from left outflow tract origin, their accuracy and reliability are affected by individual orientation of ventricular outflow tracts relative to the surrounding chest structures, cardiac rotation, chest wall anatomy and leads placement.

• This review of currently used ECG algorithms to differentiate the site of origin of ventricular arrhythmias is useful to clarify the advantages and disadvantages of each algorithm and to assist electrophysiologists in daily clinical practice.

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Idiopathic Outflow Tract Ventricular Arrhythmias Conclusion

predicting VA site of origin, and have led to the development of a multitude of ECG-based algorithms and new promising non-invasive electroanatomic mapping systems.

Idiopathic OT-VAs represent an intriguing clinical challenge due to the many ECG features resulting from heterogeneous sites of origin.

Predicting an RVOT origin rather than an LVOT site of origin is of pivotal importance in improving patient counselling and procedure planning, and in reducing unnecessary arterial or venous access, radiation exposure, ablation duration and risk of complications. Several morphological, electrophysiological and individual factors hamper the accuracy of ECG in 1. Yamada T, Doppalapudi H, McElderry HT, et al. Idiopathic ventricular arrhythmias originating from the papillary muscles in the left ventricle: prevalence, electrocardiographic and electrophysiological characteristics, and results of the radiofrequency catheter ablation. J Cardiovasc Electrophysiol 2010;21:62–9. https://doi. org/10.1111/j.1540-8167.2009.01594.x; PMID: 19793147.

2. Crawford T, Mueller G, Good E, et al. Ventricular arrhythmias originating from papillary muscles in the right ventricle.

Heart Rhythm 2010;7:725–30. https://doi.org/10.1016/j. hrthm.2010.01.040; PMID: 20206325.

3. Sadek MM, Benhayon D, Sureddi R, et al. Idiopathic ventricular arrhythmias originating from the moderator band: electrocardiographic characteristics and treatment by catheter ablation. Heart Rhythm 2015;12:67–75. https://doi. org/10.1016/j.hrthm.2014.08.029; PMID: 25240695.

4. Yamada T. Idiopathic ventricular arrhythmias: relevance to the anatomy, diagnosis and treatment. J Cardiol 2016;68:463–71. https://doi.org/10.1016/j.jjcc.2016.06.001; PMID: 27401396.

5. Hutchinson MD, Garcia FC. An organized approach to the localization, mapping, and ablation of outflow tract ventricular arrhythmias. J Cardiovasc Electrophysiol 2013;24:1189–97. https://doi.org/10.1111/jce.12237; PMID: 24015911.

6. Lerman BB. Mechanism, diagnosis, and treatment of outflow tract tachycardia. Nat Rev Cardiol 2015;12:597–608. https:// doi.org/10.1038/nrcardio.2015.121; PMID: 26283265.

7. 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.

8. Kumagai K. Idiopathic ventricular arrhythmias arising from the left ventricular outflow tract: tips and tricks. J Arrhythm 2014;30:211–21. https://doi.org/10.1016/j.joa.2014.03.002.

9. Ho SY. Structure and anatomy of the aortic root. Eur J Echocardiogr 2009;10:i3–10. https://doi.org/10.1093/ ejechocard/jen243; PMID: 19131496.

10. Liang JJ, Shirai Y, Lin A, Dixit S. Idiopathic outflow tract ventricular arrhythmia ablation: pearls and pitfalls. Arrhythm Electrophysiol Rev 2019;8:116–21. https://doi.org/10.15420/ aer.2019.6.2; PMID: 31114686.

11. Shirai Y, Santangeli P, Liang JJ, et al. Anatomical proximity dictates successful ablation from adjacent sites for outflow tract ventricular arrhythmias linked to the coronary venous system. Europace 2019;21:484–91. https://doi.org/10.1093/ europace/euy255; PMID: 30535322.

12. Ouyang F, Fotuhi P, Ho SY, et al. Repetitive monomorphic ventricular tachycardia originating from the aortic sinus cusp: electrocardiographic characterization for guiding catheter ablation. J Am Coll Cardiol 2002;39:500–8. https:// doi.org/10.1016/s0735-1097(01)01767-3; PMID: 11823089.

13. Yamada T, Litovsky SH, Kay GN. The left ventricular ostium: an anatomic concept relevant to idiopathic ventricular arrhythmias. Circ Arrhythm Electrophysiol 2008;1:396–404. https://doi.org/10.1161/CIRCEP.108.795948; PMID: 19808434.

14. Bala R, Garcia FC, Hutchinson MD, et al.

Electrocardiographic and electrophysiologic features of ventricular arrhythmias originating from the right/left

Nonetheless, the interpretation of 12-lead ECG morphology of VA using an anatomically based approach and alternative ECG configurations may be a useful tool for differentiating LVOT from RVOT VAs, and improving the safety of radiofrequency catheter ablation procedures.

coronary cusp commissure. Heart Rhythm 2010;7:312–22. https://doi.org/10.1016/j.hrthm.2009.11.017; PMID: 20097621.

15. Enriquez A, Malavassi F, Saenz LC, et al. How to map and ablate left ventricular summit arrhythmias. Heart Rhythm 2017;14:141–8. https://doi.org/10.1016/j.hrthm.2016.09.018; PMID: 27664373.

16. Lin D, Ilkhanoff L, Gerstenfeld E, et al. Twelve-lead electrocardiographic characteristics of the aortic cusp region guided by intracardiac echocardiography and electroanatomic mapping. Heart Rhythm 2008;5:663–9. https://doi.org/10.1016/j.hrthm.2008.02.009; PMID: 18452867.

17. Santangeli P, Marchlinski FE, Zado ES, et al. Percutaneous epicardial ablation of ventricular arrhythmias arising from the left ventricular summit: outcomes and electrocardiogram correlates of success. Circ Arrhythm Electrophysiol 2015;8:337–43. https://doi.org/10.1161/CIRCEP.114.002377; PMID: 25637596.

18. Ito S, Tada H, Naito S, et al. Development and validation of an ECG algorithm for identifying the optimal ablation site for idiopathic ventricular outflow tract tachycardia. J Cardiovasc Electrophysiol 2003;14:1280–86. https://doi. org/10.1046/j.1540-8167.2003.03211.x; PMID: 14678101.

19. Yoshida N, Inden Y, Uchikawa T, et al. Novel transitional zone index allows more accurate differentiation between idiopathic right ventricular outflow tract and aortic sinus cusp ventricular arrhythmias. Heart Rhythm 2011;8:349–56. https://doi.org/10.1016/j.hrthm.2010.11.023; PMID: 21078412.

20. Betensky BP, Park RE, Marchlinski FE, et al. The V2 transition ratio: a new electrocardiographic criterion for distinguishing left from right ventricular outflow tract tachycardia origin. J Am Coll Cardiol 2011;57:2255–62. https://doi.org/10.1016/j. jacc.2011.01.035; PMID: 21616286.

21. Yoshida N, Yamada T, McElderry HT, et al. A novel electrocardiographic criterion for differentiating a left from right ventricular outflow tract tachycardia origin: the V2S/ V3R index. J Cardiovasc Electrophysiol 2014;25:747–53. https://doi.org/10.1111/jce.12392; PMID: 24612087.

22. Kaypakli O, Koca H, Sahin DY, et al. S-R difference in V1-V2 is a novel criterion for differentiating the left from right ventricular outflow tract arrhythmias. Ann Noninvasive Electrocardiol 2017;3:e12516. https://doi.org/10.1111/anec.12516; PMID: 29226502.

23. He Z, Liu M, Yu M, et al. An electrocardiographic diagnostic model for differentiating left from right ventricular outflow tract tachycardia origin. J Cardiovasc Electrophysiol 2018;29:908–15. https://doi.org/10.1111/jce.13493; PMID: 29608235.

24. Di C, Wan Z, Tse G, et al. The V1-V3 transition index as a novel electrocardiographic criterion for differentiating left from right ventricular outflow tract ventricular arrhythmias.

J Interv Card Electrophysiol 2019;56:37–43. https://doi. org/10.1007/s10840-019 00612-0; PMID: 31478158.

25. Zhang F, Hamon D, Fang Z, et al. Value of a posterior electrocardiographic lead for localization of ventricular outflow tract arrhythmias: the V4/V8 ratio. JACC Clin Electrophysiol 2017;3:678–86. https://doi.org/10.1016/j. jacep.2016.12.018; PMID: 29759536.

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26. Cheng D, Ju W, Zhu L, et al. V3R/V7 index: a novel electrocardiographic criterion for differentiating left from right ventricular outflow tract arrhythmias origins. Circ Arrhythm Electrophysiol 2018;11:e006243. https://doi. org/10.1161/CIRCEP.118.006243; PMID: 30571180.

27. Tanner H, Hindricks G, Schirdewahn P, et al. Outflow tract tachycardia with R/S transition in lead V3: six different anatomic approaches for successful ablation. J Am Coll Cardiol 2005;45:418–23. https://doi.org/10.1016/j. jacc.2004.10.037; PMID: 15680722.

28. Anderson RD, Kumar S, Parameswaran R, et al.

Differentiating right- and left-sided outflow tract ventricular arrhythmias: classical ECG signatures and prediction algorithms. Circ Arrhythm Electrophysiol 2019;12:e007392. https://doi.org/10.1161/CIRCEP.119.007392; PMID: 31159581.

29. Tzeis S, Asvestas D, Yen Ho S, Vardas P. Electrocardiographic landmarks of idiopathic ventricular arrhythmia origins. Heart 2019;105:1109–16. https://doi. org/10.1136/heartjnl-2019-314748; PMID: 31092549.

30. Condori Leandro HI, Lebedev DS, Mikhaylov EN. Discrimination of ventricular tachycardia and localization of its exit site using surface electrocardiography. J Geriatr Cardiol 2019;16:362–77. https://doi.org/10.11909/j.issn.16715411.2019.04.008; PMID: 31105757.

31. Cakulev I, Sahadevan J, Arruda M, et al. Confirmation of novel noninvasive high-density electrocardiographic mapping with electrophysiology study: implications for therapy. Circ Arrhythm Electrophysiol 2013;6:68–75. https://doi. org/10.1161/CIRCEP.112.975813; PMID: 23275263.

32. Jamil-Copley S, Bokan R, Kojodjojo P, et al. Noninvasive electrocardiographic mapping to guide ablation of outflow tract ventricular arrhythmias. Heart Rhythm 2014;11:587–94. https://doi.org/10.1016/j.hrthm.2014.01.013; PMID: 24440381.

33. Erkapic D, Greiss H, Pajitnev D, et al. Clinical impact of a novel three-dimensional electrocardiographic imaging for non-invasive mapping of ventricular arrhythmias: a prospective randomized trial. Europace 2015;17:591–7. https://doi.org/10.1093/europace/euu282; PMID: 25349226.

34. Mountantonakis SE, Vaishnav AS, Jacobson JD, et al.

Conduction patterns of idiopathic arrhythmias from the endocardium and epicardium of outflow tracts: new insights with noninvasive electroanatomic mapping. Heart Rhythm 2019;16:1562–9. https://doi.org/10.1016/j.hrthm.2019.04.026; PMID: 31004776.

35. Anter E, Frankel DS, Marchlinski FE, Dixit S. Effect of electrocardiographic lead placement on localization of outflow tract tachycardias. Heart Rhythm 2012;9:697–703. https://doi.org/10.1016/j.hrthm.2011.12.007; PMID: 22155770.

36. Yamada T, Murakami Y, Yoshida N, et al. Preferential conduction across the ventricular outflow septum in ventricular arrhythmias originating from the aortic sinus cusp. J Am Coll Cardiol 2007;50:884–91. https://doi. org/10.1016/j.jacc.2007.05.021; PMID: 17719476.

37. Lavalle C, Mariani MV, Piro A, et al. Electrocardiographic features, mapping and ablation of idiopathic outflow tract ventricular arrhythmias. J Interv Card Electrophysiol 2020;57:207–18. https://doi.org/10.1007/s10840-019-006179; PMID: 31650457.

Clinical Arrhythmias

Arrhythmias and Conduction Disturbances in Autoimmune Rheumatic Disorders Sotiris C Plastiras1 and Haralampos M Moutsopoulos2 1. Echocardiography Unit, Bioiatriki SA, Bioiatriki Healthcare Group, Athens, Greece; 2. Medical Sciences/Immunology, Academy of Athens, Athens, Greece

Abstract

Rhythm and conduction disturbances and sudden cardiac death are important manifestations of cardiac involvement in autoimmune rheumatic diseases (ARD), which have a serious impact on morbidity and mortality. While the underlying arrhythmogenic mechanisms are multifactorial, myocardial fibrosis plays a pivotal role. It accounts for a substantial portion of cardiac mortality and may manifest as atrial and ventricular arrhythmias, conduction system abnormalities, biventricular cardiac failure or sudden death. In patients with ARD, myocardial fibrosis is considered to be the hallmark of cardiac involvement as a result of inflammatory process or to coronary artery occlusive disease. Myocardial fibrosis constitutes the pathological substrates for reentrant circuits. The presence of supraventricular extra systoles, tachyarrhythmias, ventricular activity and conduction disturbances are not uncommon in patients with ARDs, more often in systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, inflammatory muscle disorders and anti-neutrophil cytoplasm antibody-associated vasculitis. In this review, the type, the relative prevalence and the underlying mechanisms of rhythm and conduction disturbances in the emerging field of cardiorheumatology are provided.

Keywords

Autoimmune systemic disorders, heart involvement, arrhythmias, conduction disturbances Disclosure: The authors have no conflicts of interest to declare.

Acknowledgements: The authors thank Evangelia Zampeli for reading the manuscript and correcting mistakes and/or omissions.

Received: 30 October 2020 Accepted: 29 December 2020 Citation: Arrhythmia & Electrophysiology Review 2021;10(1):17–25. DOI: https://doi.org/10.15420/aer.2020.43 Correspondence: Sotiris C Plastiras, Cardiologist, Echocardiography Unit, Bioiatriki SA, Bioiatriki Healthcare Group, Kifisias St 132, 11527, Athens, Greece.

E: splastiras@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 non-commercial purposes, provided the original work is cited correctly.

idiopathic inflammatory myopathies (IIM), and small-size vessel vasculitis and in particular the anti-neutrophil cytoplasmic antibody (ANCA)associated vasculitides (AAV). The relative prevalence of the different types of arrhythmias in patients with ARD (Table 1) has emerged from a limited number of small clinical studies.8

Autoimmune rheumatic diseases (ARD) encompass a heterogeneous group of diseases affecting not only the musculoskeletal system but also multiple organs or systems.1 Among them, the heart and the cardiovascular system may be affected through different pathophysiological mechanisms including myocardial inflammation and/or fibrosis, vasculitis, thromboembolic events or premature atherosclerosis. All these mechanisms can lead to an increased incidence of altered automaticity and reentry phenomena in patients with ARD.2–5

Supraventricular Arrhythmias and Tachyarrhythmias in ARD

Supraventricular arrhythmias (SA) are commonly observed in patients with ARD.9 The reported frequency of SA is variable, depending on diagnostic methods and patient selection.10

Conduction disorders occur mainly during flares of ARD and are in general more frequent than rhythm disturbances.6 Rhythm disorders in patients with ARD have different, and not fully understood, underlying pathophysiological mechanisms with myocardial inflammation and fibrosis being the most important ones. Inflammatory processes and oxidative stress lead to cardiomyocyte necrosis with subsequent electrical and structural remodelling. Chronic inflammation leads to autonomic dysfunction, namely sympathetic overactivation and decreased parasympathetic function. Autoantibody-mediated and drug-induced arrhythmias are also frequently observed among patients with ARD.7

Systemic Lupus Erythematosus

SLE is a prototype autoimmune disease characterised by a plethora of autoantibodies directed against circulating, cytoplasmic or nuclear autoantigens and a wide spectrum of clinical, laboratory and histopathological manifestations from the affected organs including the joints, skin, kidneys, lungs, nervous system and the heart.11 In some patients, the disease runs an indolent course, while in others it can threaten the function of the affected organs and even the patient’s life.11

Although all heart structures can be affected in patients with systemic ARD, in this review we will focus on rhythm and conduction disturbances occurring in patients with systemic ARD, such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA),

The underlying mechanisms of SA in SLE have not been extensively investigated and are probably numerous. Sinus tachycardia, AF and atrial ectopic beats are the most frequent arrhythmias seen in patients with

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Autoimmune Systemic Diseases and the Heart Table 1: Relative Frequency of Conduction Disturbances and Arrhythmias in Autoimmune Systemic Diseases Autoimmune Systemic Disease

Typical Arrhythmias (Relative Frequency)

Systemic lupus erythematosus

• Sinus tachycardia (15–50%) • Premature atrial contractions (63.4%) • AF (2.8%) • Ventricular ectopy (45.8%) • QT prolongation (15.3%) • Increased QT dispersion (38.1%) • Conduction disturbances (34–70%) • AF (0.8–18.3%) • Ventricular arrhythmias (unknown prevalence) • Atrioventricular block (rare, unknown prevalence) • Congenital heart block (0.1%) • AF, atrial flutter and supraventricular paroxysmal

Rheumatoid arthritis

Systemic sclerosis

and complex pathogenesis, its main feature being the excessive production and accumulation of collagen leading to fibrosis of the affected organs.11 Scleroderma can be divided into two forms – localised scleroderma or systemic sclerosis – based on clinical and serological criteria. These two forms can further be classified as either limited cutaneous SSc or diffuse cutaneous SSc. Localised scleroderma is a disease of the skin and subcutaneous tissue and it is not associated with internal organ involvement or with increased mortality. However, SSc is associated with specific autoantibody positivity, systemic manifestations, internal organ involvement and increased mortality. The organs most frequently affected by scleroderma are the skin, gastrointestinal tract, lungs, kidneys, skeletal muscle and heart.11 SA are frequently seen in patients with SSc as a result of focal myocardial fibrosis (Figures 1 and 2).18–24 AF, atrial flutter and supraventricular paroxysmal tachycardia have been reported in 20–30% of patients.2,23 Patients with SSc have been found to have a higher mean heart rate (81 ± 11 BPM), with more cases of sinus tachycardia reported in limited SSc than in diffuse SSc.19,21–23 Myocardial fibrosis that disrupts the normal electrical connectivity of cardiac tissue, left atrial dilation secondary to a higher prevalence of pulmonary hypertension, and more severe mitral and tricuspid regurgitation, have been proposed as possible underlying mechanisms for SA in SSc.19

tachycardia (20–30%)

• Ventricular arrhythmias (67%) • Sudden cardiac death (21%) • First-degree heart block (6–10%) • Second- or third-degree atrioventricular block (<2%)

Idiopathic inflammatory myopathies

• Left anterior fascicular block (7–16%) • Right bundle branch block (3–6%) • Left bundle branch block (3–6%) • Premature atrial contractions, atrial tachycardia,

Atrial fibrosis, a common feature of clinical AF and a hallmark of arrhythmogenic structural remodelling, is directly related to the degree of left atrial (LA) dilation that accompanies left ventricular (LV) diastolic dysfunction in patients with SSc. In those with LV diastolic dysfunction, LA myocyte hypertrophy, LA areas of fibrosis, elevated LA pressure and LA dilation constitute the basis for the occurrence of AF and have been associated with a poor prognosis.

AF (reported with unknown prevalence)

• Ventricular arrhythmias, sudden cardiac death (reported with unknown prevalence)

• Left anterior hemiblock (13%) • Right bundle branch block (9.1%), • Left bundle branch block (3.1%) • Fascicular block (1%) • First-, second-, or third-degree atrioventricular

Rheumatoid arthritis (RA) is a systemic inflammatory disease affecting mainly the synovial tissue of small and large joints. Autoantibodies to immunoglobulins (rheumatoid factors) and citrullinated proteins are frequently found in the patients’ sera and the pleural cavity, the lung parenchyma and the heart can be affected in about one-quarter of the patients.11 The incidence of AF in patients with RA is 40% higher than in the general population and can occur any time during the disease course, although it can be the first disease manifestation.25 Although the pathophysiology of AF in RA is complex and poorly understood, several lines of evidence support that systemic inflammation causing increased circulating concentrations of inflammatory proteins, ischaemic heart disease and heart failure are important factors for the initiation and recurrence of AF in this patient group.25–27

block and sick sinus syndrome (reported with unknown prevalence)

ANCA-associated vasculitis

• ECG abnormalities (66%) • AF, extrasystoles, ventricular arrhythmias (unknown prevalence)

• Heart block (3%) Data source: Gawałko et al. 2020.8

SLE.9–14 SA are often transient and may be related to lupus myocarditis and exacerbations of SLE with fever, volume depletion and congestive failure.

In a study by Texeira et al. that included 317 patients with SLE, Holter monitoring abnormalities were observed in about 85% of patients with SLE, including supraventricular ectopy (63.4%), bradycardia (31.7%), atrial tachycardia (15.5%) and AF (2.8%).15

It has been shown that the rate of successful cardioversion is lower in patients with RA who have AF and high inflammatory burden with persistently increased serum inflammatory indices.27–29 Increased P wave dispersion in electrocardiography, which is considered to be a predictor of AF, also occurs more frequently in patients with RA and seems to be highly associated with the level of systemic inflammation.30

In other studies, sinus tachycardia was found to occur in 50% of patients with SLE and was the only cardiac manifestation of SLE, which resolves with corticosteroid treatment.14 Vasculitis-induced myocardial fibrosis or accelerated coronary atherosclerosis have been proposed as underlying mechanisms of SA in SLE through ectopic automatism, triggered activity or reentry.14–17

Autonomic nervous system (ANS) dysfunction due to the neurotoxic effect of chronic systemic inflammatory process associated with RA and the sideeffects of therapeutic agents, is evident in about 60% of patients with RA. ANS dysfunction is considered a possible pathogenetic cause of SA.31 The main pattern of ANS deregulation is impairment of cardiovascular reflexes and altered heart rate variability, indicative of reduced cardiac parasympathetic activity and elevated cardiac sympathetic activity

Systemic Sclerosis

Systemic sclerosis (SSc) is a rare connective tissue disorder of unknown

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Autoimmune Systemic Diseases and the Heart Figure 1: Arrhythmias in Scleroderma Heart Disease: MRI Findings

manifesting as atrial ectopic beats, impaired heart rate control and inappropriate atrial tachycardia.32

Idiopathic Inflammatory Myopathies

IIM are rare autoimmune systemic disorders characterised primarily by muscle (polymyositis) and/or skin (dermatomyositis) inflammation.10,11 Lung and cardiac involvement can be seen in this patient population and they affect survival.33–36 Recent non-invasive diagnostic modalities suggest that cardiac involvement in patients with IIM ranges from 9–72% based on different selection criteria for patients in studies.37 Myocarditis, focal fibrosis, vasculitis, intimal proliferation or medial sclerosis of vessels have been proposed as possible mechanisms of abnormal electrical activity based on abnormal automaticity.38 Studies of patients with IIM based on ECG and Holter monitoring showed frequent premature atrial beats, atrial tachycardia, paroxysmal AF and multiple focal right atrial tachycardia mainly caused by abnormal automaticity rather than triggered activity or reentry.38,39

Anti-neutrophil Cytoplasmic Antibody-associated Vasculitides

AAV are a group of disorders characterised by inflammation of blood vessels, endothelial injury and tissue damage. Although any tissue can be involved in AAV, the upper and lower respiratory tract, the kidneys, the skin and the peripheral nervous system are most commonly and severely affected more frequently rather than the central nervous system.11

Delayed enhanced MRI of a patient with scleroderma in short-axis plane shows linear mid-wall enhancement (arrowheads, A) at the medial segments of the interventricular septum. MRI in four-chamber plane shows linear mid-wall enhancement (arrowheads, B) at portions of basal and at the medial segments of the free wall, as well at the medial segment of the interventricular septum. Delayed enhanced MRI in vertical long axis plane shows linear mid-wall enhancement (arrowheads, C) in the majority of the extent of the anterior wall. Resting ECG at the intensive care unit showing paroxysmal AF with rapid ventricular response (right panel). Holter monitoring in the same patient showing isolated supraventricular and ventricular premature extrasystoles.

The three types of AAV are granulomatosis with polyangiitis (GPA; previously known as Wegener’s granulomatosis), microscopic polyangiitis (MPA) and eosinophilic GPA (EGPA; previously known as Churg–Strauss syndrome). Autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) are typically present, depending on the type of AAV.11 Clinically significant cardiac involvement is a rare complication in systemic AAV, but it can be life-threatening.40,41

Dilated cardiomyopathy with normal coronary arteries can be seen in patients with SLE.49 Although VA are infrequent among these patients, the Systemic Lupus International Collaborating Clinics Registry revealed a high prevalence of QT prolongation (15.3%) and increased QT dispersion (38.1%), both of which are recognised as independent risk factors for the development of complex VA.46 Myocardial scar due to ischaemic or nonischaemic heart disease is the main cause of VA in SLE.

Since many cardiac manifestations are clinically silent, at least during their early stages, heart function should be systematically evaluated by ECG and echocardiography. AAV is significantly associated with AF which confers independently worse survival rates.

Myocardial inflammation, either isolated or as part of the systemic inflammation, is another important cause of VA in SLE.46–49 In addition, chronic use of antimalarial drugs, which are a common therapeutic modality for SLE, may also lead to VT.49 Sympathetic hyperactivity as shown by the elevated norepinephrine levels can play an aetiological factor for VA.6

Several plausible explanations for the association between vasculitis and AF have been proposed; blood vessel wall inflammation results in increased arterial stiffness and decreased vascular distensibility leading to vascular damage and end-organ ischaemia, all of which are considered important mechanisms for atrial tachyarrhythmias in this particular group of patients.41–43 Alteration in microvascular circulation is another possible haemodynamic mechanism.41 Delay in atrial emptying due to impaired diastolic distensibility that increases pressure and wall stretch within the atria and pulmonary veins is also an important mechanism for altered atrial electrical properties that promotes AF development.

Previous studies have reported a decrease in parasympathetic activity due to the autoantibodies against the Sjögren syndrome-related antigen A (Ro/SSA) and M3 muscarinic receptors.15 The presence of anti-Ro/SSA antibodies in patients with SLE have been associated with prolongation of the corrected QT interval (QTc).49 Lazzerini et al. reported that in addition to the high prevalence of QTc prolongation, anti-Ro/SSA-positive patients also have reduced heart rate variability and a high incidence of ventricular late potentials.49

Ventricular Arrhythmias in ARD

Although supraventricular tachycardia is the most common finding in SLE, ventricular arrhythmias (VA) can occur and are mainly due to coronary artery disease (CAD).44,45 VA in SLE can also be the result of inflammatory cardiomyopathy, causing structural and electrical heart disease which may have a serious impact on the patient’s outcome.46,47 Acute myocarditis in SLE may present with ventricular tachycardia (VT) as an initial manifestation.48 Figure 3 is a representative case of lupus myocarditis detected with cardiac magnetic resonance (CMR) in our department presenting with frequent ventricular extrasystoles.

VA are common among patients with asymptomatic SSc and may be associated with poor outcome.2 Patchy or linear myocardial fibrosis provides an ideal substrate for VA dependent on reentrant circuits (Figure 1). VA in patients with SSc can also develop due to overproduction of anti-β1-adrenergic receptor autoantibodies which lead to autonomic dysfunction. This usually precedes the development of myocardial fibrosis.50,51

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Autoimmune Systemic Diseases and the Heart Figure 2: Hypertrophic Cardiomyopathy in Scleroderma

A: 12-lead electrocardiogram in a scleroderma patient revealing sinus rhythm with left axis deviation, left atrial enlargement and LV hypertrophy fulfilling voltage criteria, along with deep symmetric T-wave inversions in the precordial leads. T-wave inversions were also noted in the lateral leads (left), suggestive of apical hypertrophic cardiomyopathy. 24-hour Holter ECG monitoring revealing periods of AF (middle), runs of supraventricular tachycardia and frequent couplets of supraventricular extra-systoles (right). B: Transthoracic echocardiogram in the same scleroderma patient revealed increased LV wall thickness with asymmetric involvement of the apex, mid-interventricular septum and the mid-posterior wall (parasternal long-axis view arrows). C: The observed mid-cavity obstruction was due to the systolic apposition of hypertrophied papillary muscle and LV wall, at the level of the mid-LV, producing two distinct LV chambers. D: High Doppler velocities with the characteristic colour turbulent flow, indicating a mid-cavity gradient, were recorded at the level of the papillary muscle. E and F: End-diastole and end-systole, respectively. Cardiac MRI showed hypertrophy of the LV most prominent at the medial wall segments with a spade-like configuration of the LV cavity causing two separate chambers.

resembling arrhythmogenic RV dysplasia, as well as aneurysms of the RV and RV outflow tract were more commonly seen in patients with SSc with malignant VA than in those without arrhythmias (Figure 4). The extent to which this indicates a causal relationship requires further electrophysiological confirmation. In our unpublished data on 44 consecutive SSc patients with no history of ischaemic cardiomyopathy or risk factors for CAD, delayed enhanced CMR revealed functional and morphological abnormalities in the majority of patients (84%) (Figure 5). Myocardial fibrosis in the RV myocardium which was detected in a small percentage of patients with SSc (6%) by delayed enhanced CMR was associated with poor survival due to the high incidence of malignant VA (Figure 5).

VA have been demonstrated in 67% and non-sustained ventricular tachycardia (VT) in 7–13% of unselected patients with SSc.23,50 Patients with frequent premature ventricular contractions had 50% mortality during 33 months of follow-up, in contrast to 8% in SSc patients without frequent ectopy.51 Bulkley et al. noted sudden cardiac death (SCD) in 21% of patients with SSc, in contrast to the study by Lee et al. in which no SCD was observed in 61 deaths of 275 patients with SSc.51,52 In the study by Follansbee et al., SCD was confirmed in 5% of the 1,258 patients with SSc.53 VA and SCD occur in patients with both skeletal muscle disease and myocardial involvement.

In our study, 63% of patients with SSc had premature ventricular contractions, while 10.5% had non-sustained VT.20 SSc patients with VA documented by Holter were more likely to have pulmonary hypertension, decreased LV ejection fraction (LVEF), increased RV diameter and LA distention documented by Doppler echocardiography; they also had a greater number of enhancing myocardial segments suggestive of myocardial fibrosis in delayed enhanced CMR.20

The most common cause of SCD in patients with RA is atherosclerotic CAD that may lead to acute coronary syndrome and VT.2 Although the underlying mechanisms accounting for the pro-arrhythmogenic substrate in RA are probably intricate, the leading role seems to be played by chronic systemic inflammatory activation as it is able to promote arrhythmias both indirectly by accelerating the development of ischaemic heart disease and congestive heart failure, and directly by affecting cardiac electrophysiology.6 Furthermore, there is evidence that the inflammatory cytokines, mainly tumour necrosis factor (TNF)-α,

Involvement of the LV basal infero-septal segment and right ventricular (RV) dysfunction with hypokinetic and dyskinetic areas involving the RV free wall

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Autoimmune Systemic Diseases and the Heart Figure 3: Ventricular Arrhythmias in Lupus Myocarditis

Figure 4: Arrhythogenic Right Ventricular Cardiomyopathy in Scleroderma: MRI Findings

Representative delayed-enhanced MRI in a patient with systemic lupus erythematosus from our records, in four-chamber plane (A), short-axis plane (B) and phase-sensitive inversion recovery image (C), showing thinning and akinesia of the LV lateral wall due to lupus myocarditis (arrowheads). Resting ECG (D) showing sinus rhythm with marked left axis deviation, occasional ventricular premature complexes, poor R-wave progression in the anterior precordial leads and mild ST-segment upsloping in the inferior leads.

interleukin-1 and interleukin-6, can modulate the expression and function of ion channels both by directly acting on cardiomyocytes.6 VT has also been described in patients with RA as a consequence of giant cell myocarditis, a rare but fatal cardiac disease complication characterised by degeneration and necrosis of myocardial fibres.54 VT has also been described in patients with RA related to treatment with methotrexate and infliximab.55,56 Increased sympathetic and decreased parasympathetic activity can play a crucial role in the development of VT in patients with RA.57

Left panel: Images of the right ventricle (RV) long axis at end diastole (A) and at end systole (B) show the irregular shape of the RV free wall (black and dark grey areas), with aneurysms (arrows) bulging during diastole and systole in a patient with scleroderma. A delayed contrast-enhanced MRI in the short-axis plane (C) shows increased enhancement (white and light grey areas) of the RV myocardium (arrows) and the interventricular septum (arrowhead) caused by myocardial fibrosis.

Right panel: four-chamber (A) and short-axis views (B) of cine MRI show thinning of the RV free wall with aneurysm formation (arrows) in a patient with scleroderma. Mild flattening of the interventricular septum is also present. Linear enhancement (C, arrows) corresponding to the aneurysmal area, as well as subtle patchy enhancements (arrowheads) in the lower RV insertion point and the anteroseptal medial segment of the left ventricular (LV) myocardium on the delayed-enhancement MR image. The fibrosis in the RV insertion point was suggestive of pulmonary arterial hypertension. RV end-diastolic volume was markedly increased while RV systolic function was impaired with an RV ejection fraction of about 45%. LV systolic function was normal.

VT and SCD have also been described in people with IIM, although their incidence has not been precisely defined.58–60 Cardiac involvement with histological evidence of myocarditis is well documented in patients with IIM and may be the most usual cause of VA. The histopathology of the myocarditis resembles inflammation in the skeletal muscles including active myocarditis, focal fibrosis, vasculitis, intimal proliferation and medial sclerosis of vessels.

VA triggered by active vasculitis is uncommonly observed and rarely reported. In AAV infrequently, less than 10%, any cardiac tissue can be affected, with varied clinicopathological syndromes including pericarditis, myocarditis, coronary arteritis, valvulopathy and intracavitary cardiac thrombosis all of which can lead to VA.40

positive develop complete heart block.61,62 Autopsy studies have revealed focal inflammatory cell infiltrates or, more often, fibrous scarring of the conduction system.61,62 Small vessel vasculitis and the infiltration by fibrous or granulation tissue are major causes of the dysfunction of sinus or atrioventricular (AV) nodes in SLE. Conduction abnormalities in SLE may regress when the disease is in remission.

Conduction Disturbances in ARD

Conduction defects have been frequently diagnosed in patients with SLE (34–70%) and may be the result of active or past myocarditis.17 Firstdegree heart block may be seen and is often transient. Higher degrees of heart block are unusual in adults and are associated with the presence in the patient’s serum of anti-U1-nuclear ribonuclear protein antibodies, but not with anti-Ro/SSA or anti-La/SSB antibodies, as in the case of newborns of mothers with these autoantibodies.6

Anti-Ro/SSA antibodies in adults with SLE may be associated with an increased likelihood of a prolonged QTc, which has been shown in patients without SLE to be a risk factor for VA and SCD.63–65 The clinical significance of this observation is unclear, given the low threshold (QTc ≥440 msec) used to define prolongation in these studies. However, patients with anti-Ro/SSA antibodies may benefit from having ECGs and receiving appropriate counselling if a prolonged QTc is detected.

Neonatal lupus is a rare syndrome caused by the trans-placental passage of autoantibodies from mothers positive to anti-Ro/SSA (and/or anti-La/ SSB) to their newborns. About 3% of infants whose mothers are antibody-

Conduction system disease is common in patients with SSc and is present in about 25% of patients with SSc at the resting ECG.66–68 It is likely to be the result of myocardial and conduction system fibrosis.20,68 Most frequent

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Autoimmune Systemic Diseases and the Heart Figure A 5: Right Ventricular Involvement Detected by MRI on Probability Number of patients % of Survival in Patients with Systemic Sclerosis RV global function

B

19 11 7 6 5 15 13 27

19 6 11 5 7 15 13 6 27 5 15 13 27

% 43 25 16 14 11 34 29 61

43 25 % 16

90

No myocardial enhancement

80 C 70 100 100 90 90 60

C

43 14 25 11 16 34 29 14 61 11 34 29 61

100

Survival probability (%) Survival probability (%)

19 11 Number of patients Number of patients 7

Survival probability (%)

Normal A Mildly reduced A Severely reduced RV global function RV global function RV regional WMA Normal Normal RVOT Mildly reduced MildlyApex reduced Severely reduced Severely Freereduced wall RV regional RV regional WMA WMA Subtricuspid area RVOT RVOTIVS (Flattening) Apex Apex Free wall Free wall Subtricuspid Subtricuspid area area IVS (Flattening) IVS (Flattening)

C

80

70 60 50 40 30 20

No myocardial No myocardial enhancement enhancement

80 50 70 40

Myocardial enhancement

60 30 50 20 40 10 30 0

20 20 10

p=0.001 Myocardial Myocardial enhancement enhancement 30

40

50

60

70

80

Time (months) elapsed from MRI p=0.001 p=0.001

10 PAH No PAH 0 0 55.28 ± 10.7 57.18 ± 9 0.55 Age, yrs 20 20 30 30 40 40 50 50 60 60 70 70 80 80 13/3 26/2 0.33 Sex, F/M Time (months) elapsed from MRI Time (months) elapsed from MRI B Disease subtype(D/L) NS 9/7 14/14 B No PAH PAH9.6PAH No PAH 10.6 ± 8.1 ± 6.9 0.67 Disease duration, yrs 55.28 ± 10.7 57.18 ± 9 0.55 Age, yrs 55.28 ±10.8 10.7± 7.99 57.18 16.4 ± 9 ± 10.1 0.55 NS Age, yrs Raynaud’s duration, Sex, F/M 13/3 13/3 26/2 26/2 0.33 0.33 Sex, F/M yrs Disease subtype(D/L) NS NS Disease subtype(D/L) 9/746.89/7 14/14 14/14 ± 0.2 PAH, mmHg ± 8.1 9.6 ± 6.9 0.67 Disease duration, 10.6 ± 10.6 8.1 9.6 ± 6.9 0.67 0.03 Disease duration, yrs yrs 15 (94) 17 (61) Pulmonary fibrosis, n 10.8 ± 7.99 16.4 ± 10.1 NS Raynaud’s duration, 10.8 ± 7.99 16.4 ± 10.1 NS Raynaud’s duration, (%) yrs yrs 0.27 65.4 ± 17.7 RVEDVi, ml/m2 59.2 ± 14.5 46.8 0.2 PAH, mmHg -26.4 ±- 7.32 46.8 ±32.2 0.2 ±± 15.5 PAH, mmHg 0.14 RVESVi, ml/m2 15 (94) 17 (61) Pulmonary fibrosis, n 15 (94) 17 (61) 0.03 0.03 Pulmonary fibrosis, n 0.71 54.1 ± 10.1 53.1 ± 12.4 RVEF (%) (%) (%) Enhancement, 4 (18.8) 0.12 2 (7.1) n (%) 0.27 65.4 ± 17.7 RVEDVi, ml/m2 59.2 ± 14.5 0.27 0.39 65.4 ±22 17.7 RVEDVi, ml/m2 59.2 ± 14.5 (78.5%) 15 (94%) WMA (%) 0.14 ± 7.32 ± 15.5 RVESVi, 0.14 0.12 26.4 ±26.4 7.32 32.2 ±32.2 15.5 RVESVi, ml/m2nml/m2 Deaths, (%) 3 (18.8) 1 (3.5) 0.71 0.71 54.1 ± 54.1 10.1 ± 10.1 53.1 ± 53.1 12.4 ± 12.4 RVEF RVEF (%) (%) Enhancement, 4 (18.8)4 (18.8) 0.12 0.12 2 (7.1) 2 (7.1) Enhancement, n (%) n (%) A: Right analysis in a cohort of scleroderma patients. B. Clinical and MR findings of scleroderma patients with or without 22 (78.5%) 15 (94%)of kinematic abnormalities WMA 0.39 0.39 22 (78.5%) 15 MRI (94%) WMAventricular (%) (%)systolic function and regional pulmonary arterial C: Kaplan-Meier analysis of influence of RV myocardial enhancement detected MRI on probability of survival in patients with systemic sclerosis. D = diffuse; F = Deaths, n (%) 3 (18.8) Deaths, n (%) hypertension.

3 (18.8) 1 (3.5) 1 (3.5) 0.12by0.12 female; IVS = interventricular septum; L = limited; M = male; NS = non-significant; PAH = pulmonary arterial hypertension; RV = right ventricular; RVEDVi = right ventricle end-diastolic volume index; RVEF = right ventricular ejection fraction; RVESVi = right ventricle end-systolic volume index; RVOT = right ventricular outflow tract; WMA = wall motion abnormalities.

conduction abnormalities are first-degree heart block (6–10%), left anterior fascicular block (7–16%), right (3–6%) and left (3–6%) bundle branch block and non-specific intra-ventricular conduction defects (2–3%).21 Second- or third-degree AV block is uncommon (<2%).66–68 Dysfunctional AV node due to fibrotic changes and a linear pattern of myocardial fibrosis with sparing of the subendocardial layer have been proposed as mechanisms responsible for conduction system disorders in patients with SSc.21,66

ANCA vasculitis has been associated with bundle branch blocks and all grades of heart block. These are believed to be from granulomatous inflammation involving the AV node or the bundle of His.75 While cardiac involvement is not usual in GPA, conduction abnormalities and accelerated atherosclerosis may occur during the disease course.76,77

AV block is rare in patients with RA, but usually complete.69–71 Ahern et al. described congenital complete heart block in 0.1% of RA patients, especially in women, and concluded that it is more common in patients with subcutaneous nodules.69 Rheumatoid granuloma, CAD and nonspecific inflammatory lesions are considered to be responsible for conduction disturbances in RA patients.70,71

It is of great importance that an early and accurate diagnosis of cardiac arrhythmias and conduction disturbances is established in patients with ARD, given the fact that the heart involvement can be subclinical.1,2,7,19,78–86 These manifestations in this patient group should be the object of a careful investigation by rheumatologists and cardiologists for all patients with ARD aiming to prevent serious complications including sudden cardiac death.

Diagnostic Algorithm of Cardiac Arrhythmias in Patients with ARD

Several types of conduction abnormalities are detectable in patients with IIM, including bundle branch block, fascicular block, first-, secondand third-degree AV block and sick sinus syndrome.33,72,73 Complete AV block is extremely rare.72 Direct involvement of the conduction system either due to myositis with contraction band necrosis or due to focal myocardial fibrosis (as a final result of myocarditis or myocardial ischaemia related to coronary vasculitis) have been proposed as possible causal mechanisms.73

Classic and newer diagnostic modalities are useful for assessing cardiac function and detecting myocardial involvement and CAD, which are the major substrate for arrhythmias and conduction disturbances in patients with ARD. Clinical, 12-lead electrocardiogram and conventional transthoracic echocardiographic evaluation is the first approach. Newer echocardiographic modalities including 2D/3D speckle-tracking imaging and global longitudinal strain should be used for the early diagnosis of global and regional kinetic disorders of the ventricles, diastolic dysfunction, LV hypertrophy and valvulopathies. However, while a normal echocardiography cannot rule out heart involvement in patients with ARD, PET and CMR can provide reliable diagnostic information about inflammation and scar by performing tissue characterisation.

While the proposed diagnostic algorithm for autoimmune inflammatory cardiomyopathy using PET includes non-ischaemic cardiomyopathy with

In an electrophysiology study in four patients with IIM and bifascicular block, the site of block was localised distally to the His bundle suggesting that the conduction disturbances observed in this particular group of patients are mainly related to a direct involvement of the intraventricular conduction system.74

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Autoimmune Systemic Diseases and the Heart resynchronisation pacing.90,91 The need for ICDs should be carefully evaluated in patients with ARD with proven malignant VA and it will often require further electrophysiological confirmation.

LVEF <50%, documented monomorphic/polymorphic VT, ventricular fibrillation or frequent premature ventricular contractions and patchy focal or focal on diffuse fluorodeoxyglucose uptake on PET imaging, there is no specific algorithm for arrhythmia-induced cardiomyopathies using CMR.

Radiofrequency ablation is an effective approach to many types of arrhythmias.92–98 The role of radiofrequency ablation in patients with ARD has not yet been well evaluated but seems to be promising.

However, an expert consensus proposed that CMR provides strong evidence of myocardial inflammation with increasing specificity, if the CMR scan demonstrates the combination of myocardial oedema with other CMR markers of inflammatory myocardial injury.87 This is based on at least one T2-based criterion including global or regional increase of myocardial T2 relaxation time or an increased signal intensity in T2weighted CMR images, with at least one T1-based criterion such as increased myocardial T1, extracellular volume, or late gadolinium enhancement. CMR is able to provide a more realistic and more accurate visualisation of the ventricles than other conventional imaging methods.

Catheter ablation seems to be safe in drug-resistant AF in patients with SLE and RA.2,99,100 This approach might be considered as the first-line therapy in patients with AF and systemic disorders, especially in those patients with ARD in whom the use of antiarrhythmic drugs is either contraindicated, scarcely effective, or associated with more adverse effects. Recurrence or persistence of AF after ablation has been attributed to peri-procedural inflammation. Thus, therapies targeting the procedurerelated inflammation may reduce the risk of AF recurrence.99–101

Endomyocardial biopsy is considered the gold standard to diagnose myocarditis and/or inflammatory cardiomyopathy. However, it is an invasive method with excellent specificity but poor sensitivity due to sampling error given the patchy distribution of myocardial involvement in the majority of patients with ARD and the lack of agreement between specialists regarding interpretation of specimens.

Catheter ablation for atrial tachyarrhythmias, refractory premature ventricular contractions and ventricular tachycardia has been successfully applied in patients with IIM SSc and RA.38,102–105 ARD patients considered for RF catheter ablation for AF or VT are those with symptomatic, sustained, monomorphic VT when these are drug resistant, the patient is drug intolerant or does not desire long-term drug therapy.

Coronary angiography is the gold standard for the diagnosis of CAD. Using 24/48-hour Holter monitoring of cardiac rhythm can show specific and nonspecific findings, including any type of arrhythmias, changes of PQ and ST interval, prolongation of QRS complex, rhythm disorders and the presence of Q waves. Electrophysiology studies may be warranted to evaluate persistent palpitations, presyncope or syncope and complex supraventricular and ventricular extrasystoles as assessed in Holter studies in patients with ARD.

Pacemaker implantation is the method of choice for the treatment of complete heart block and other serious conduction abnormalities.

Sophisticated pacing modalities and programmability as well as lowenergy circuity and new battery designs have increased device longevity and enabled wide clinical application.

Conclusion

Early and accurate diagnosis of heart involvement and rhythm disorders in patients with ARD is crucial and affects their overall mortality. Mounting evidence indicates that the increased risk of arrhythmias in patients with ARD is the combined result of the increased prevalence of structural changes (fibrosis) and electrical changes (gap junction impairment and intracellular calcium-handling abnormalities) caused by inflammatory cytokines, particularly tumour necrosis factor α, interleukin-6 and 1, and C-reactive protein. These phenomena promote arrhythmogenesis, by both conduction slowing and increasing ectopic activity, thus impairing the homogeneity of impulse propagation throughout the cardiac tissue.104,105

Treatment

Optimal immunosuppressive therapy of the underlying systemic disease and management of the arrhythmias based on the international treatment guidelines and evidence-based medicine with respect to the special feature of each disease remains the cornerstone of the correct approach in these patients.85,86 Unfortunately, there are few randomised controlled trials evaluating anti-arrhythmic therapies specifically for use in patients with ARD. Therefore, therapy should be tailored for each individual patient. Drug selection should be based on their electrophysiological effects and the type of arrhythmia. Non-dihydropyridine calcium channel blockers are preferred for the treatment of SA and may improve cardiac perfusion and ventricular function, potentially reducing the burden of arrhythmias.88,89

Given the complex nature and course of these diseases, anti-arrhythmic treatment should be based on international guidelines. However, current guidelines contain scant information for the treatment of cardiac arrhythmias in patients with ARD with mainly class C recommendations.104–106 Therefore, there is a need to update guidelines in collaboration with cardiologists and rheumatologists with simultaneous conduction of a large-scale registry that could improve the treatment of patients with ARD.

Digoxin can be used to decrease ventricular response in AF and in endstage heart failure but is contraindicated in those patients with impaired renal function. The treatment of sinus tachycardia and supraventricular and ventricular extrasystoles is generally carried out by β-blockers, taking into account that they may worsen the symptomatology of severe Raynaud’s phenomenon. In these patients, a cardioselective β-blocker, such as bisoprolol, metoprolol and nebivolol, appears to be safe.

Amiodarone should be avoided in patients with ARD particularly in those with interstitial lung disease.

Understanding the mechanisms producing arrhythmias in ARD and combining newer diagnostic modalities that will guide new therapeutic strategies would probably improve the quality of life and the survival of patients. Electrophysiology studies may also be warranted to evaluate persistent palpitations, presyncope or syncope and complex supraventricular and ventricular extrasystoles as assessed by Holter studies in patients with ARD.

Medically intractable life-threatening VT are treated with ICDs. These have been proven to decrease mortality in patients with dilated cardiomyopathy and are regarded as a treatment of choice for patients with heart failure and advanced LV dysfunction in combination with

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Autoimmune Systemic Diseases and the Heart Even after the diagnosis of the arrhythmia, the electrophysiological evaluation of the arrhythmia substrate can be performed in the electrophysiology laboratory using 3D mapping systems. A detailed voltage mapping can reveal areas with low potential due to extensive fibrosis involved in reentrant circuits in the atria and ventricles.

Clinical Perspective

• Autoimmune rheumatic disorders (ARD) are inflammatory • •

Current research is focused on improving mapping techniques, developing new imaging modalities, creating new catheter designs for enhanced RF energy delivery and evaluating new energy sources for catheter ablation.

Together, these efforts will undoubtedly extend the indications and improve the efficacy of catheter ablation. The integration of CMR data sets in 3D mapping systems could also greatly facilitate electrophysiology procedures.

•

•

Further technical and procedural improvements are warranted to bring these techniques to broader clinical practice for patients with ARD.

1. Wahren-Herlenius M, Dörner T. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet 2013;382:819–31. https://doi.org/10.1016/S01406736(13)60954-X; PMID: 23993191.

2. Seferović PM, Ristić AD, Maksimović R, et al. Cardiac arrhythmias and conduction disturbances in autoimmune rheumatic diseases. Rheumatology (Oxford) 2006;45:iv39–42. https://doi.org/10.1093/rheumatology/kel315; PMID: 16980722.

3. Lee HC, Huang KT, Wang XL, Shen WK. Autoantibodies and cardiac arrhythmias. Heart Rhythm 2011;8:1788–95. https:// doi.org/10.1016/j.hrthm.2011.06.032; PMID: 21740882.

4. Giannelou M, Mavragani CP. Cardiovascular disease in systemic lupus erythematosus: a comprehensive update. J Autoimmun 2017;82:1–12. https://doi.org/10.1016/j. jaut.2017.05.008; PMID: 28606749.

5. Theodorou E, Nezos A, Antypa E, et al. B-cell activating factor and related genetic variants in lupus related atherosclerosis. J Autoimmun 2018;92:87–92. https://doi. org/10.1016/j.jaut.2018.05.002; PMID: 29859654.

6. Lazzerini PE, Capecchi PL, Guideri F, et al. Connective tissue diseases and cardiac rhythm disorders: an overview.

Autoimmun Rev 2006;5:306–13. https://doi.org/10.1016/j. autrev.2005.11.002; PMID: 16782554.

7. Seferovic PM, Ristic AD, Maksimovic R, et al. Cardiac arrhythmias and conduction disturbances in autoimmune rheumatic diseases. Rheumatology 2006;45:39–42. https:// doi.org/10.1093/rheumatology/kel315; PMID: 16980722.

8. Gawałko M, Balsam P, Lodziński P, et al. Cardiac arrhythmias in autoimmune diseases. Circ J 2020;84:685–94. https://doi. org/10.1253/circj.CJ-19-0705; PMID: 32101812.

9. Eisen A, Arnson Y, Dovrish Z, et al. Arrhythmias and conduction defects in rheumatological diseases-a comprehensive review. Semin Arthritis Rheum 2009;39:145– 56. https://doi.org/10.1016/j.semarthrit.2008.05.001; PMID: 18585758.

10. Knockaert DC. Cardiac involvement in systemic inflammatory diseases. Eur Heart J 2007;28:1797–804. https://doi.org/10.1093/eurheartj/ehm193; PMID: 17562669.

11. Moutsopoulos HM, Zampeli E, eds. Immunology and Rheumatology in Questions. 2nd ed. Cham, Switzerland: Springer Nature, 2021. https://doi.org/10.1007/978-3-03056670-8.

12. Abu-Shakra M, Urowitz MB, Gladman DD, Gough J. Mortality studies in systemic lupus erythematosus. Results from a single center. II. Predictor variables for mortality. J Rheumatol 1995;22:1265–70; PMID: 7562756.

13. Hejtmancik MR, Wright JC, Quint R, Jennings FL. The cardiovascular manifestations of systemic lupus erythemtosus. Am Heart J 1964;68:119–30. https://doi. org/10.1016/0002-8703(64)90248-0; PMID: 14193537.

14. Estes D, Christian CL. The natural history of systemic lupus erythematosus by prospective analysis. Medicine (Baltimore) 1971;50:85–95. https://doi.org/10.1097/00005792197103000-00001; PMID: 4109481.

15. Teixeira RA, Borba EF, Bonfá E, Martinelli Filho M. Arrhythmias in systemic lupus erythematosus. Rev Bras Reumatol 2010;50:81–9. https://doi.org/10.1590/S048250042010000100008; PMID: 21125143.

16. Guzmán J, Cardiel MH, Arce-Salinas A, Alarcón-Segovia D. The contribution of resting heart rate and routine blood tests to the clinical assessment of disease activity in systemic lupus erythematosus. J Rheumatol 1994;21:1845–8;

conditions frequently affecting the blood vessels and the heart.

Symptoms of arrhythmias or conduction defects are frequently reported in patients with ARD. The exact prevalence of cardiac arrhythmias in ARD is unclear, due to the small size and heterogeneity of patient populations.

Rhythm disorders may have several origins related to primary heart involvement, coronary artery disease, pericardial disease, valvulopathies or pulmonary arterial hypertension and may increase morbidity and mortality.

Further prospective large-scale studies are warranted to explore the pathogenesis and to improve the early diagnosis of cardiac rhythm disorders in patients with ARD.

PMID: 7837148.

17. Mandell BF. Cardiovascular involvement in systemic lupus erythematosus. Semin Arthritis Rheum 1987;17:126–41. https:// doi.org/10.1016/0049-0172(87)90035-7; PMID: 3334284.

18. Bourré-Tessier J, Urowitz MB, Clarke AE, et al.

Electrocardiographic findings in systemic lupus erythematosus: data from an international inception cohort.

Arthritis Care Res (Hoboken) 2015;67:128–35. https://doi. org/10.1002/acr.22370; PMID: 24838943.

19. Mavrogeni S, Gargani L, Pepe A, et al. Cardiac magnetic resonance predicts ventricular arrhythmias in scleroderma: the Scleroderma Arrhythmia Clinical Utility Study (SAnCtUS).

Rheumatology (Oxford) 2020;59:1938–48. https://doi. org/10.1093/rheumatology/kez494; PMID: 31764972.

20. Tzelepis GE, Kelekis NL, Plastiras SC, et al. Pattern and distribution of myocardial fibrosis in systemic sclerosis: a delayed enhanced magnetic resonance imaging study.

Arthritis Rheum 2007;56:3827–36. https://doi.org/10.1002/ art.22971; PMID: 17968945.

21. Rokas S, Mavrikakis M, Agrios N, et al. Electrophysiologic abnormalities of cardiac function in progressive systemic sclerosis. J Electrocardiol 1996;29:17–25. https://doi. org/10.1016/S0022-0736(96)80107-5; PMID: 8808521.

22. Biełous-Wilk A, Poreba M, Staniszewska-Marszałek E, et al.

Electrocardiographic evaluation in patients with systemic scleroderma and without clinically evident heart disease.

Ann Noninvasive Electrocardiol 2009;14:251–7. https://doi. org/10.1111/j.1542-474X.2009.00306.x; PMID: 19614636.

23. Kostis JB, Seibold JR, Turkevich D, et al. Prognostic importance of cardiac arrhythmias in systemic sclerosis. Am J Med 1988;84:1007–15. https://doi.org/10.1016/00029343(88)90305-1; PMID: 3376974.

24. Borowiec A, Dabrowski R, Wozniak J, et al. Cardiovascular assessment of asymptomatic patients with juvenile-onset localized and systemic scleroderma: 10 years prospective observation. Scand J Rheumatol 2012;41:33–8. https://doi.org/ 10.3109/03009742.2011.609489; PMID: 22103465.

25. Tłustochowicz W, Piotrowicz R, Cwetsch A, et al. 24-h ECG monitoring in patients with rheumatoid arthritis. Eur Heart J 1995;16:848–51. https://doi.org/10.1093/oxfordjournals. eurheartj.a061005; PMID: 7588930.

26. Wisłowska M, Sypuła S, Kowalik I. Echocardiographic findings and 24-h electrocardiographic Holter monitoring in patients with nodular and non-nodular rheumatoid arthritis.

Rheumatol Int 1999;18:163–9. https://doi.org/10.1007/ s002960050079; PMID: 10399790.

27. Engelmann MD, Svendsen JH. Inflammation in the genesis and perpetuation of atrial fibrillation. Eur Heart J 2005;26:2083–92. https://doi.org/10.1093/eurheartj/ehi350; PMID: 15975993.

28. Issac TT, Dokainish H, Lakkis NM. Role of inflammation in initiation and perpetuation of atrial fibrillation: a systematic review of the published data. J Am Coll Cardiol 2007;50:2021–8. https://doi.org/10.1016/j.jacc.2007.06.054; PMID: 18021867.

29. Liu T, Li G, Li L, Korantzopoulos P. Association between C-reactive protein and recurrence of atrial fibrillation after successful electrical cardioversion: a meta-analysis. J Am Coll Cardiol 2007;49:1642–8. https://doi.org/10.1016/j. jacc.2006.12.042; PMID: 17433956.

30. Guler H, Seyfeli E, Sahin G, et al. P wave dispersion in patients with rheumatoid arthritis: its relation with clinical and echocardiographic parameters. Rheumatol Int

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW Access at: www.AERjournal.com

24

2007;27:813–8. https://doi.org/10.1007/s00296-007-0307-8; PMID: 17431630.

31. Schwemmer S, Beer P, Schölmerich J, et al. Cardiovascular and pupillary autonomic nervous dysfunction in patients with rheumatoid arthritis – a cross-sectional and longitudinal study. Clin Exp Rheumatol 2006;24:683–9; PMID: 17207385.

32. Sheldon RS, Grubb BP 2nd, Olshansky B, et al. 2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.

Heart Rhythm 2015;12:e41–63. https://doi.org/10.1016/j. hrthm.2015.03.029; PMID: 25980576.

33. Bohan A, Peter JB, Bowman RL, Pearson CM. Computerassisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine (Baltimore) 1977;56:255–86. https://doi.org/10.1097/00005792-197707000-00001; PMID: 327194.

34. Stern R, Godbold JH, Chess Q, Kagen LJ. ECG abnormalities in polymyositis. Arch Intern Med 1984;144:2185–9. https://doi. org/10.1001/archinte.144.11.2185; PMID: 6497519.

35. Gonzalez-Lopez L, Gamez-Nava JI, Sanchez L, et al. Cardiac manifestations in dermato-polymyositis. Clin Exp Rheumatol 1996;14:373–9; PMID: 8871835.

36. Taylor AJ, Wortham DC, Burge JR, Rogan KM. The heart in polymyositis: a prospective evaluation of 26 patients. Clin Cardiol 1993;16:802–8. https://doi.org/10.1002/ clc.4960161110; PMID: 8269658.

37. Zhang L, Wang GC, Ma L, Zu N. Cardiac involvement in adult polymyositis or dermatomyositis: a systematic review. Clin Cardiol 2012;35:686–91. https://doi.org/10.1002/clc.22026; PMID: 22847365.

38. Yazaki K, Enta K, Kataoka S, et al. Focal right atrial tachycardia with three foci in a patient with polymyositis. J Cardiol Cases 2017;16:134–7. https://doi.org/10.1016/j. jccase.2017.06.003; PMID: 30279817.

39. Lundberg IE. Cardiac involvement in autoimmune myositis and mixed connective tissue disease. Lupus 2005;14:708– 12. https://doi.org/10.1191/0961203305lu2205oa; PMID: 16218472.

40. Miloslavsky E, Unizony S. The heart in vasculitis. Rheum Dis Clin North Am 2014;40:11–26. https://doi.org/10.1016/j. rdc.2013.10.006; PMID: 24268007.

41. Gayraud M, Guillevin L, le Toumelin P, et al. Long-term followup of polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: analysis of four prospective trials including 278 patients. Arthritis Rheum 2001;44:666–75. https://doi.org/10.1002/1529-0131(200103)44:3<666::AIDANR116>3.0.CO;2-A; PMID: 11263782.

42. Lane SE, Watts RA, Shepstone L, Scott DG. Primary systemic vasculitis: clinical features and mortality. QJM 2005;98:97– 111. https://doi.org/10.1093/qjmed/hci015; PMID: 15655098.

43. Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum 1999;42:421–30. https://doi. org/10.1002/1529-0131(199904)42:3<421::AIDANR5>3.0.CO;2-6; PMID: 10088763.

44. Miner JJ, Kim AH. Cardiac manifestations of systemic lupus erythematosus. Rheum Dis Clin North Am 2014;40:51–60. https://doi.org/10.1016/j.rdc.2013.10.003; PMID: 24268009.

45. Hashkes PJ, Wexler LF, Passo MH. Coronary artery disease in systemic lupus erythematosus: risk factors, assessment, and prevention. J Clin Rheumatol 1997;3:203–10. https://doi.

Autoimmune Systemic Diseases and the Heart org/10.1097/00124743-199708000-00005; PMID: 19078188.

46. Gawałko M, Balsam P, Lodziński P, et al. Cardiac arrhythmias in autoimmune diseases. Circ J 2020;84:685–94. https://doi. org/10.1253/circj.CJ-19-0705; PMID: 32101812.

47. Huang CN, Yu HH, Chiu SN, et al. Acute myocarditis and ventricular fibrillation as initial presentation of pediatric systemic lupus erythematosus. Rheumatol Int 2013;33:1093– 6. https://doi.org/10.1007/s00296-011-2240-0; PMID: 22119942.

48. Mavrogeni SI, Sfikakis PP, Dimitroulas T, et al. Prospects of using cardiovascular magnetic resonance in the identification of arrhythmogenic substrate in autoimmune rheumatic diseases. Rheumatol Int 2018;38:1615–21. https:// doi.org/10.1007/s00296-018-4110-5; PMID: 30043238.

49. Lazzerini PE, Acampa M, Guideri F, et al. Prolongation of the corrected QT interval in adult patients with anti-Ro/SSApositive connective tissue diseases. Arthritis Rheum 2004;50:1248–52. https://doi.org/10.1002/art.20130; PMID: 15077308.

50. Ferri C, Bernini L, Bongiorni MG, et al. Noninvasive evaluation of cardiac dysrhythmias, and their relationship with multisystemic symptoms, in progressive systemic sclerosis patients. Arthritis Rheum 1985;28:1259–66. https:// doi.org/10.1002/art.1780281110; PMID: 4063000.

51. Bulkley BH, Ridolfi RL, Salyer WR, Hutchins GM. Myocardial lesions of progressive systemic sclerosis. A cause of cardiac dysfunction. Circulation 1976;53:483–90. https://doi. org/10.1161/01.CIR.53.3.483; PMID: 1248080.

52. Lee P, Langevitz P, Alderdice CA, et al. Mortality in systemic sclerosis (scleroderma). Q J Med 1992;82:139–48; PMID: 1620814.

53. Follansbee WP, Zerbe TR, Medsger TA Jr. Cardiac and skeletal muscle disease in systemic sclerosis (scleroderma): a high risk association. Am Heart J 1993;125:194–203. https:// doi.org/10.1016/0002-8703(93)90075-K; PMID: 8417518.

54. Rosenstein ED, Zucker MJ, Kramer N. Giant cell myocarditis: most fatal of autoimmune diseases. Semin Arthritis Rheum 2000;30:1–16. https://doi.org/10.1053/sarh.2000.8367; PMID: 10966208.

55. Borek G, Jenzer HR, Frey LD, Locher JT. Repetitive exercise induced ventricular tachycardia in a patient with rheumatoid arthritis taking low dose methotrexate. J Rheumatol 1992;19:1004–5; PMID: 1404112.

56. Lazzerini PE, Acampa M, Hammoud M, et al. Arrhythmic risk during acute infusion of infliximab: a prospective, singleblind, placebo-controlled, crossover study in patients with chronic arthritis. J Rheumatol 2008;35:1958–65; PMID: 18709695.

57. Schwemmer S, Beer P, Schölmerich J, et al. Cardiovascular and pupillary autonomic nervous dysfunction in patients with rheumatoid arthritis – a cross-sectional and longitudinal study. Clin Exp Rheumatol 2006;24:683–9; PMID: 17207385.

58. Jindal G, Singh S, Suri D, et al. Recurrent ventricular tachycardia in a child with juvenile dermatomyositis – an unusual association. Int J Rheum Dis 2012;15:e26–7. https:// doi.org/10.1111/j.1756-185X.2012.01701.x; PMID: 22462430.

59. Dilaveris P, Pietri P, Tsiachris D, et al. Inducible ventricular tachycardia due to dermatomyositis-related cardiomyopathy in the era of implantable cardioverter-defibrillator therapy.

Circulation 2012;125:967–9. https://doi.org/10.1161/ CIRCULATIONAHA.111.049882; PMID: 22354978.

60. Adler M, Banerjeee S, Stratton R. Ventricular tachycardia as a presenting feature of dermatomyositis. Heart 2002;88:443. https://doi.org/10.1136/heart.88.5.443; PMID: 12381621.

61. James TN, Rupe CE, Monto RW. Pathology of the cardiac conduction system in systemic lupus erythematosus. Ann Intern Med 1965;63:402–10. https://doi.org/10.7326/00034819-63-3-402; PMID: 14327506.

62. Maisch B, Ristić AD. Immunological basis of the cardiac conduction and rhythm disorders. Eur Heart J 2001;22:813– 24. https://doi.org/10.1053/euhj.2000.2186; PMID: 11350091.

63. Xiao GQ, Hu K, Boutjdir M. Direct inhibition of expressed cardiac l- and T-type calcium channels by IGG from mothers whose children have congenital heart block. Circulation 2001;103:1599–604. https://doi.org/10.1161/01.CIR.103.11.1599; PMID: 11257091.

64. Cardoso CR, Sales MA, Papi JA, Salles GF. QT-interval parameters are increased in systemic lupus erythematosus patients. Lupus 2005;14:846–52. https://doi. org/10.1191/0961203305lu2225oa; PMID: 16302681.

65. Bourré-Tessier J, Clarke AE, Huynh T, et al. Prolonged corrected QT interval in anti-Ro/SSA-positive adults with systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2011;63:1031–7. https://doi.org/10.1002/acr.20470; PMID: 21452253.

66. Roberts NK, Cabeen WR Jr, Moss J, et al. The prevalence of conduction defects and cardiac arrhythmias in progressive

systemic sclerosis. Ann Intern Med 1981;94:38–40. https://doi. org/10.7326/0003-4819-94-1-38; PMID: 7447221.

67. Janosik DL, Osborn TG, Moore TL, et al. Heart disease in systemic sclerosis. Semin Arthritis Rheum 1989;19:191–200. https://doi.org/10.1016/0049-0172(89)90032-2; PMID: 2690346.

68. Ridolfi RL, Bulkley BH, Hutchins GM. The cardiac conduction system in progressive systemic sclerosis. Clinical and pathologic features of 35 patients. Am J Med 1976;61:361–6. https://doi.org/10.1016/0002-9343(76)90373-9; PMID: 961700.

69. Ahern M, Lever JV, Cosh J. Complete heart block in rheumatoid arthritis. Ann Rheum Dis 1983;42:389–97. https:// doi.org/10.1136/ard.42.4.389; PMID: 6882034.

70. Wallberg-Jonsson S, Ohman ML, Dahlqvist SR. Cardiovascular morbidity and mortality in patients with seropositive rheumatoid arthritis in Northern Sweden. J Rheumatol 1997;24:445–51; PMID: 9058647.

71. Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003;107:1303–7. https://doi. org/10.1161/01.CIR.0000054612.26458.B2; PMID: 12628952.

72. Alyan O, Ozdemir O, Geyik B, Demirkan D. Polymyositis complicated with complete atrioventricular block – a case report and review of the literature. Angiology 2003;54:729– 31. https://doi.org/10.1177/000331970305400615; PMID: 14666964.

73. Tami LF, Bhasin S. Polymorphism of the cardiac manifestations in dermatomyositis. Clin Cardiol 1993;16:260– 4. https://doi.org/10.1002/clc.4960160319; PMID: 8444002.

74. Kehoe RF, Bauernfeind R, Tommaso C, et al. Cardiac conduction defects in polymyositis: electrophysiologic studies in four patients. Ann Intern Med 1981;94:41–3. https:// doi.org/10.7326/0003-4819-94-1-41; PMID: 7447222.

75. Kane GC, Keogh KA. Involvement of the heart by small and medium vessel vasculitis. Curr Opin Rheumatol 2009;21:29– 34. https://doi.org/10.1097/BOR.0b013e32831cb94d; PMID: 19077715.

76. de Leeuw K, Sanders JS, Stegeman C, et al. Accelerated atherosclerosis in patients with Wegener’s granulomatosis.

Ann Rheum Dis 2005;64:753–9. https://doi.org/10.1136/ ard.2004.029033; PMID: 15374854.

77. Faurschou M, Mellemkjaer L, Sorensen IJ, et al. Increased morbidity from ischemic heart disease in patients with Wegener’s granulomatosis. Arthritis Rheum 2009;60:1187–92. https://doi.org/10.1002/art.24386; PMID: 19333952.

78. England BR, Thiele GM, Anderson DR, Mikuls TR. Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications. BMJ 2018;361:k1036. https://doi.org/10.1136/bmj. k1036; PMID: 29685876.

79. Ocampo-Piraquive V, Nieto-Aristizábal I, Cañas CA, Tobón GJ. Mortality in systemic lupus erythematosus: causes, predictors and interventions. Expert Rev Clin Immunol 2018;14:1043–53. https://doi.org/10.1080/174466 6X.2018.1538789; PMID: 30338717.

80. Plastiras SC, Karadimitrakis SP, Kampolis C, et al.

Determinants of pulmonary arterial hypertension in scleroderma. Semin Arthritis Rheum 2007;36:392–6. https:// doi.org/10.1016/j.semarthrit.2006.10.004; PMID: 17204309.

81. Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis 2010;69:1809–15. https://doi.org/10.1136/ ard.2009.114264; PMID: 20551155.

82. Elhai M, Meune C, Boubaya M, et al. Mapping and predicting mortality from systemic sclerosis. Ann Rheum Dis 2017;76:1897–905. https://doi.org/10.1136/ annrheumdis-2017-211448; PMID: 28835464.

83. Gabriel SE. Cardiovascular morbidity and mortality in rheumatoid arthritis. Am J Med 2008;121:S9–14. https://doi. org/10.1016/j.amjmed.2008.06.011; PMID: 18926169.

84. Jayakumar D, Zhang R, Wasserman A, Ash J. Cardiac manifestations in idiopathic inflammatory myopathies: an overview. Cardiol Rev 2019;27:131–7. https://doi.org/10.1097/ CRD.0000000000000241; PMID: 30585794.

85. Chang C. Unmet needs in the treatment of autoimmunity: from aspirin to stem cells. Autoimmun Rev 2014;13:331–46. https://doi.org/10.1016/j.autrev.2014.01.052; PMID: 24462645.

86. Bournia VK, Vlachoyiannopoulos PG, Selmi C, et al. Recent advances in the treatment of systemic sclerosis. Clin Rev Allergy Immunol 2009;36:176–200. https://doi.org/10.1007/ s12016-008-8114-x; PMID: 19132559.

87. Ferreira VM, Schulz-Menger J, Holmvang G, et al.

Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations. J Am Coll Cardiol 2018;72:3158–76. https://doi.org/10.1016/j. jacc.2018.09.072; PMID: 30545455.

88. Desai CS, Lee DC, Shah SJ. Systemic sclerosis and the

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW Access at: www.AERjournal.com

25

heart: current diagnosis and management. Curr Opin Rheumatol 2011;23:545–54. https://doi.org/10.1097/ BOR.0b013e32834b8975; PMID: 21897256.

89. Allanore Y, Meune C, Vonk MC, et al. Prevalence and factors associated with left ventricular dysfunction in the EULAR Scleroderma Trial and Research group (EUSTAR) database of patients with systemic sclerosis. Ann Rheum Dis 2010;69:218–221. https://doi.org/10.1136/ard.2008.103382; PMID: 19279015.

90. Katritsis DG, Boriani G, Cosio FG, et al. European Heart Rhythm Association (EHRA) consensus document on the management of supraventricular arrhythmias. Europace 2017;19:465–511. https://doi.org/10.1093/europace/euw444; PMID: 28431074.

91. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary. Heart Rhythm 2018;15:e190–252. https://doi.org/10.1016/j. hrthm.2017.10.035; PMID: 29097320.

92. Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Europace 2015;17:1601–87. https://doi. org/10.1093/europace/euv319; PMID: 26318695.

93. Fragakis N, Pantos I, Younis J, et al. Surgical ablation for atrial fibrillation. Europace 2012;14:1545–52. https://doi. org/10.1093/europace/eus081; PMID: 22490369.

94. Katritsis D, Merchant FM, Mela T, et al. Catheter ablation of atrial fibrillation the search for substrate-driven end points. J Am Coll Cardiol 2010;55:2293–8. https://doi.org/10.1016/j. jacc.2010.03.016; PMID: 20488298.

95. Katritsis DG, Josephson ME. Classification, electrophysiological features and therapy of atrioventricular nodal reentrant tachycardia. Arrhythm Electrophysiol Rev 2016;5:130–5. https://doi.org/10.15420/AER.2016.18.2; PMID: 27617092.

96. Katritsis G, Calkins H. Catheter ablation of atrial fibrillation – techniques and technology. Arrhythm Electrophysiol Rev 2012;1:29–33. https://doi.org/10.15420/aer.2012.1.29; PMID: 26835026.

97. Prabhu S, Lim WH, Schilling RJ. The evolving role of catheter ablation in patients with heart failure and AF. Arrhythm Electrophysiol Rev 2019;8:47–53. https://doi. org/10.15420/aer.2019.9.2; PMID: 30918667.

98. Mahida S, Berte B, Yamashita S, et al. New ablation technologies and techniques. Arrhythm Electrophysiol Rev 2014;3:107–12. https://doi.org/10.15420/aer.2014.3.2.107; PMID: 26835075.

99. Katritsis GD, Katritsis DG. Cardiac autonomic denervation for ablation of atrial fibrillation. Arrhythm Electrophysiol Rev 2014;3:113–5. https://doi.org/10.15420/aer.2014.3.2.113; PMID: 26835076.

100. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. J Interv Card Electrophysiol 2012;33:171–257. https://doi. org/10.1007/s10840-012-9672-7; PMID: 22382715.

101. Ho KM, Tan JA. Benefits and risks of corticosteroid prophylaxis in adult cardiac surgery: a dose-response metaanalysis. Circulation 2009;119:1853–66. https://doi.org/10.1161/ CIRCULATIONAHA.108.848218; PMID: 19332460.

102. Schmidt M, Christiansen CF, Mehnert F, et al. Non-steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter: population based case-control study. BMJ 2011;343:d3450. https://doi.org/10.1136/bmj.d3450; PMID: 21727167.

103. Chatzidou S, Repasos V, Palios J, Plastiras S. Usefulness of cardiovascular magnetic resonance imaging in supraventricular tachycardia ablation in a scleroderma patient. Hellenic J Cardiol 2017;58:159–60. https://doi. org/10.1016/j.hjc.2016.10.006; PMID: 27927577.

104. Lacroix D, Brigadeau F, Marquié C, Klug D. Electroanatomic mapping and ablation of ventricular tachycardia associated with systemic sclerosis. Europace 2004;6:336–42. https:// doi.org/10.1016/j.eupc.2004.03.012; PMID: 15172658.

105. Lazzerini PE, Capecchi PL, Laghi-Pasini F. Systemic inflammation and arrhythmic risk: lessons from rheumatoid arthritis. Eur Heart J 2017;38:1717–27. https://doi.org/10.1093/ eurheartj/ehw208; PMID: 27252448.

106. Schleifer JW, Sorajja D, Shen WK. Advances in the pharmacologic treatment of ventricular arrhythmias. Expert Opin Pharmacother 2015;16:2637-2651. https://doi.org/10.1517/ 14656566.2015.1100170; PMID: 26513538.

Risk Stratification in ARVC

Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy Ryan Wallace

and Hugh Calkins

Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institute, Baltimore, MD, US

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC), also called arrhythmogenic right ventricular dysplasia or arrhythmogenic cardiomyopathy, is a genetic disease characterised by progressive myocyte loss with replacement by fibrofatty tissue. This structural change leads to the prominent features of ARVC of ventricular arrhythmia and increased risk for sudden cardiac death (SCD). Emphasis should be placed on determining and stratifying the patient’s risk of ventricular arrhythmia and SCD. ICDs should be used to treat the former and prevent the latter, but ICDs are not benign interventions. ICDs come with their own complications in this overall young population of patients. This article reviews the literature regarding the factors that contribute to the assessment of risk stratification in ARVC patients.

Keywords

Arrhythmogenic right ventricular cardiomyopathy, ventricular arrhythmia, risk stratification, right ventricular dysplasia, ICD, sudden cardiac death, cardiomyopathy Disclosure: HC is a paid consultant for Boston Scientific, Abbott Medical and Medtronic. The Johns Hopkins ARVC program receives research support from Boston Scientific. RW has no conflicts of interest to declare.

Received: 24 October 2020 Accepted: 14 December 2020 Citation: Arrhythmia & Electrophysiology Review 2021;10(1):26–32. DOI: https://doi.org/10.15420/aer.2020.39 Correspondence: Hugh Calkins, 600 N Wolfe St, Sheikh Zayed Tower 7125R, Baltimore, MD 21287, US. E: hcalkins@jhmi.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease characterised by progressive replacement of myocytes with fibrofatty tissue. These changes create a substrate prone to ventricular arrhythmia (VA) and increased risk for sudden cardiac death (SCD).

Although initially thought to affect only the right ventricle, it has since been well-recognised that left ventricular (LV) involvement is common, and sometimes predominant.1–3

old. It remains an important cause of SCD in young patients, particularly athletes.3 These factors highlight the importance of early recognition and appropriate therapy in ARVC. Many individuals diagnosed with ARVC have a family history of the disease, and it is typically transmitted through an autosomal dominant pattern.3,5 In most cases, ARVC is inherited with an autosomal dominant pattern with variable expression. Most mutations that are associated with ARVC code for desmosomal proteins. A pathogenic mutation can be found in approximately two-thirds of patients. The clinical manifestations of ARVC appear to be worse in men compared with women, and this is further discussed later in this article.

There have been significant advancements in the recognition and identification of predictive risk factors of the major outcomes of ARVC: VA and SCD. These include patient-controlled risk factors, such as exercise restriction, and unmodifiable risk factors, such as mutation status. Risk factor identification is important because it lays the foundation for stratifying an individual patient’s risk. A patient’s specific risk stratification should be used to make an informed decision regarding ICD placement, which is one of the main cornerstones of ARVC treatment. However, the decision to place an ICD must balance the potential short- and long-term complications of ICD placement with the risk for VA and SCD in the individual patient. This article will provide an overview of ARVC and examine the factors that contribute to an individual patient’s risk for VA and SCD.

Diagnosis and Management

The diagnosis of ARVC is based on the 2010 Task Force Criteria.6 These diagnostic criteria consist of major and minor diagnostic criteria pertaining to characteristics of RV dysfunction, histopathology on endomyocardial biopsy, repolarisation and depolarisation abnormalities on ECG, history of arrhythmia in the individual, and family history of ARVC or SCD. Each category has major (2 points) and minor (1 point) criteria. A score of 4 is considered definite ARVC; 3 points is borderline ARVC; 1–2 points is possible ARVC and 0 points is not ARVC.

Overview of Arrhythmogenic Right Ventricular Cardiomyopathy Epidemiology

Accurate diagnosis based on the 2010 Task Force Criteria is the first step in ARVC management. Once the diagnosis is secured, the second step of management is determination of an individual’s risk for VA and SCD. This will help to facilitate decisions regarding ICD placement, and is a large focus of this article. The other three components of this fivestep approach to ARVC management are the minimisation of ICD

The prevalence of ARVC ranges anywhere from 1 per 1,000 to 1 per 2,000, with a higher prevalence in specific regions of Italy (Padua, Venice). The mean age of first presentation in one large cohort study was 36 ± 14 years.4 The most common presentations included VA in 50% of patients and cardiac arrest in 11%. The median age at cardiac arrest was 25 years

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Inherited Arrhythmogenic Cardiac Conditions Figure 1: International Task Force Consensus Guidelines for ICD Implantation Flowchart for ICD implantation High risk

Intermediate risk

- Aborted SCD due to VF

≥1 major risk factors:*

- Sustained VT - Severe dysfunction of RV, LV or both

- Syncope

ICD indicated (Class I)

Low risk

≥1 minor risk factors*

- NSVT

- No risk factors - Healthy gene carriers

- Moderate dysfunction of RV, LV or both

ICD should be considered (Class IIa)

ICD may be considered (Class IIb)

ICD not indicated (Class III)

The 2015 ITF consensus statement guidelines categorise patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) based on their risk, to help determine ICD placement. High-risk patients have a >10% per year risk of a major arrhythmic event, while intermediate-risk patients have 1–10% per year risk, and low-risk patients have a less than 1% per year risk for major arrhythmic events. *See text for details on major and minor risk factors. LV =left ventricle; NSVT = non-sustained ventricular tachycardia; RV = right ventricle; SCD = sudden cardiac death; VT = ventricular tachycardia. Source: Corrado et al. 2015.22 Reproduced with permission from Oxford University Press.

population’s high risk for arrhythmia. Guideline-directed medical therapy for heart failure with reduced ejection fraction including β-blockers and RAAS blockade should be initiated as appropriate.16 Cardiac transplantation is required in a significant subset of patients.17 Cardiac transplantation is generally needed more than 15 years after initial presentation and is most commonly performed due to intractable right- or left-sided heart failure.17,18

therapy; prevention of disease progression; and cascade screening of family members.

Pharmacotherapy, catheter ablation, and exercise restriction are used to address the third step of ARVC management, the minimisation of ICD therapy. Pharmacotherapies include β-blockers and anti-arrhythmic drugs. β-blockers are thought to be beneficial in almost all patients with ARVC. Patients with ARVC are particularly sensitive to catecholaminergic effects.7 Beta-blockers not only prevent VAs, but are also a cornerstone of management in patients who have heart failure (Class of Recommendation [COR] I). In addition to β-blockers, sotalol (COR IIb) is the most commonly used anti-arrhythmic agent, followed by flecainide (COR IIb) and amiodarone (COR IIb).8–10

Cascade screening of family members, the fifth component of ARVC management, is discussed in the ARVC risk stratification section below.

Arrhythmogenic Right Ventricular Cardiomyopathy Risk Stratification

The approach to ARVC risk stratification has evolved considerably over time. A general guideline to follow is the more severe the disease, as assessed from an electrical and structural perspective, the greater the risk of sustained VA or SCD. This approach is based on a long list of risk markers that have been identified. These risk markers include: previous history of sustained VT or VF; premature ventricular contraction (PVC) frequency; non-sustained VT (NSVT); cardiac syncope; proband status and genetic testing; gender; degree of exercise restriction; and degree of myocardial involvement.

When anti-arrhythmic drugs fail or are not tolerated, catheter ablation becomes an important treatment option. Catheter ablation has been shown to reduce ventricular tachycardia (VT) events but does not reduce SCD risk or improve survival. Notably, a recent large study with more than 400 patients demonstrated continuing high rates of recurrence at 1 year (59%; 95% CI [44–71%]) and at 5 years (74%; 95% CI [59–84%]) despite ablation, but that overall burden of VA was reduced.11 The origin of VT is most commonly epicardial, and epicardial ablation paired with or without endocardial ablation has been shown to be safe and effective in further reducing VT events.12,13 In addition to pharmacological therapy and catheter ablation, exercise restriction is critical. We have recently reported that the tertile of patients with ARVC who reduce their exercise to the greatest degree have a 90% lower risk of developing VA (HR 0.10; 95% CI [0.02–0.43]).14

As identified in Orgeron et al., and supported by previous studies by Mazzanti et al. and Piccini et al., a history of VA predicts appropriate ICD therapy for any future VA.19–21 Corrado et al. suggested that the risk for VF is likely to be low in patients with a history of haemodynamically stable VT, but other studies have suggested that haemodynamically significant VT is still associated with an unacceptably high risk for lethal VA and SCD.22 As a result, a history of any VA is a potent risk factor. Current guidelines advise ICD implantation for all patients with ARVC who have had a previous sustained VA.23,24 However, the more critical issue concerns risk stratification in patients who have never had a sustained VA. In the following sections, we discuss some of the most important primary prevention risk markers.

The fourth component of ARVC management is the prevention of progression and development of heart failure. It has been well-established that ARVC is a progressive disease and that heart failure develops over time in more than 40% of patients.15 The risk of progression is addressed with pharmacological therapy (β-blockers and renin–angiotensin– aldosterone system [RAAS] blockade) and exercise restriction.

Management of overt heart failure symptoms is similar to any aetiology of heart failure. Diuretics should be used for congestive symptoms, and close attention should be placed on electrolyte balances given this

Electrical Instability

Electrical instability is an important risk factor in ARVC risk stratification.

PVC burden (more than 1,000 in 24 hours), NSVT or more invasive

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Inherited Arrhythmogenic Cardiac Conditions Figure 2: New Prediction Model for 5-year Event-free Survival Rate from Ventricular Arrhythmia Prediction of sustained ventricular arrhythmia in ARVC Model for 5-year risk prediction

5-year event-free survival (n=528) Overall

5-year event-free survival (n=528) Per predicted risk group

1.00

0.75

0.50

0.25

x

0.49

Age

x

–0.022

Recent syncope

x

0.66

Non-sustained VT

x

0.81

Ln(24 h PVC count)

x

0.17

Leads with T wave inv.

x

0.11

RVEF

x

–0.025

Observed event-free survival probability

Observed event-free survival probability

Predicted risk

Sex

+ 0.00

1 – 0.802exp( 0

1

2

3

Time (years)

4

)

= 5-year risk

5–15%

15–25%

25–50%

>50%

4

5

1.00

0.75

0.50

0.25

0.00 0

5

<5%

1

2

3

Time (years)

This model, which can be found at arvcrisk.com, uses sex, age, recent syncope, non-sustained ventricular tachycardia (VT), 24-hour premature ventricular contraction (PVC) count, number of T wave inversions and right ventricular ejection fraction (RVEF) to provide a predicted risk. This model treats arrhythmogenic right ventricular cardiomyopathy (ARVC) risk as a continuum, as opposed to the 2015 International Task Force consensus model in Figure 1. VA = ventricular arrhythmia. Source: Cadrin-Tourigny et al. 2019.44 Reproduced with permission from Oxford University Press.

Figure 3: Comparison of 2015 International Task Force Consensus Statement Model to ARVCrisk.com Model 6

100%

5

Proportion of total (%)

80%

Cardiac Syncope

4 60% 3 40% 2 20%

A history of syncope should raise suspicion for a previously unrecognised VA event. A detailed history of the syncopal event should be carried out to search for clues of cardiac origin (diaphoresis, shortness of breath, palpitations, severe injuries sustained from syncopal event). In 1989, Marcus et al. first recognised that previous syncope was associated with worse outcomes in ARVC, including arrhythmic death.31 Later studies confirmed this and found that syncope at first presentation was not only common but also suggestive of poor outcomes, such as SCD.32,33 One of these studies found that approximately half of patients diagnosed with ARVC after SCD had syncope prior to the event.32 In line with these findings, syncope also predicts VF/Vfl and appropriate ICD therapy.19,30 Syncope (especially when there is a high suspicion of cardiac origin) should be considered as a significant risk factor for poor outcomes in patients with ARVC.

0%

No. ICDs per VA event

evaluation with electrophysiology study can all quantify electrical instability. High PVC burden, NSVT and a positive electrophysiology study (defined as VT >30 seconds or haemodynamically significant VA requiring termination) all predict appropriate future ICD firing (for VT/VF).

Interestingly, only high PVC burden was found to be predictive of future VF or ventricular flutter (Vfl) events.19,25–29 Only one study, by Corrado et al. in 2010, found that inducibility was not predictive of future appropriate therapies, and cited a positive predictive value of programmed ventricular stimulation (PVS) of 35% for any appropriate ICD therapy, and only 20% for VF/Vfl.30 However, given the abundance of evidence suggesting an association with VA and or appropriate ICD therapy, inducibility should be considered a marker of higher risk ARVC, along with high PVC burden and history of NSVT.

1

l

Al

% % % e % % .5 .0 .5% .0% .5% .0% .5% .0 .5 .0 on >2 >5 >7 >10 >12 >15 >17 >20 >22 >25 N ICD, VA No ICD, VA

ICD, no VA No ICD, no VA

FC

0

IT

ICD:VA ITFC ICD:VA

Impact of potential 5-year VA risk thresholds for ICD implantation calculated using the new arrhythmogenic right ventricular cardiomyopathy risk model (ARVCrisk.com), versus the International Task Force consensus statement model (on the far right). The solid blue represents patients in the model who have an ICD but who are predicted to never sustain a VA event. The solid red represents those with an ICD and who are predicted to sustain a VA event. Most importantly, the striped red represents those without an ICD who are predicted to be unprotected from a VA event. The solid black triangle represents the number of ICDs required to achieve protection of one patient from VA. All = ICDs implanted in all patients; none = ICDs implanted in no patients; VA = ventricular arrhythmia. Source: Cadrin-Tourigny et al. 2019.44 Reproduced with permission from Oxford University Press.

Genetic Testing and Proband Status

and 40 years, measured at 4.0 per 100 person years.24 This suggests that children in families with ARVC should be screened for these mutations in the teenage years, prior to this period of increased LAE risk. Patients with more than one identified mutation are at an even higher risk for not only earlier onset of symptoms, but also for SCD and VA.25 The importance of

ARVC is a disease of desmosomal dysfunction. Eighty per cent of patients have a single copy mutation of the plakophilin-2 (PKP2) gene, but the less common mutation of the desmoplakin gene is associated with significantly higher rates of SCD. Importantly, the rate of first life-threatening arrhythmic event (LAE) in one study was found to be greatest between the ages of 21

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Inherited Arrhythmogenic Cardiac Conditions Figure 4: Prediction of Life-threatening Ventricular Arrhythmia and Any Sustained Ventricular Arrhythmia A

B LTVA

Any sustained VA

No prior event

Prior LTVA or unstable VT

Prior stable VT

No prior event

Prior stable VT

1.00 Event-free survival probability

1.00 Event-free survival probability

Prior LTVA or unstable VT

0.75

0.50

0.25 p=0.43

0.75

0.50

0.25 p<0.0001 0.00

0.00 0

2

4

6

8

10

12

14

16

0

2

4

Time (years) 386 104 175

291 77 146

8

10

12

14

16

Time (years)

Number at risk No prior event 529 Prior LTVA or unstable VT 129 Prior stable VT 206

6

Number at risk 203 59 119

154 48 95

109 33 76

68 30 58

44 23 45

No prior event 529 341 244 164 121 Prior LTVA or unstable VT 129 57 36 20 13 Prior stable VT 206 112 69 49 32

27 15 32

82 7 24

47 7 18

31 6 12

18 4 9

A: Prior history of any VA did not predict LTVA. B: Prior history of any VA (LTVA, unstable VT or stable VT) did predict future episodes of sustained VA. LTVA = life-threatening ventricular arrhythmia; VA = ventricular arrhythmia; VT = ventricular tachycardia. Source: Cadrin-Tourigny et al. 2021.47 Reproduced with permission from Wolters Kluwer Health.

cascade screening of family members after a proband identification is further supported by increased rates of appropriate ICD therapy in probands versus family members.34 It is likely that the lower rate of ICD therapy in family members is due to earlier initiation of appropriate treatment and exercise restriction.35

Another recent study by Gasperetti et al. reinforced these findings by showing a reduction in PVC burden through ‘detraining’ of athletes with ARVC. However, there was no improvement in RV ejection fraction (RVEF) with exercise restriction.40 An additional study by Maupain et al. further supported exercise restriction by finding an increased VA risk in those who exercised more than 6 hours per week.29 All of these findings together suggest that exercise restriction alone is not sufficient to avoid ICD placement, but it should be strongly recommended to patients with ARVC to reduce VA events. Accordingly, the current 2019 Heart Rhythm Society (HRS) Guidelines for ARVC Management recommend that those with ARVC should avoid competitive exercise and high-intensity endurance exercise.10 Exercise intensity is expressed using metabolic equivalents (METs). Low-MET activities such as yoga and walking for pleasure should be considered safe, and even encouraged. However, more intense exercises, such as running, swimming and sports, should be avoided given the deleterious effects of exercise.10 Unwillingness to restrict exercise should be considered during risk stratification and decision-making regarding ICD placement.

Gender

Despite most ARVC mutations being transmitted in an autosomal dominant fashion, male sex is a well-recognised predictor of lifetime arrhythmic risk.36 The pathophysiology of this was originally thought to be attributed to exercise, but the role that sex hormones play in ARVC is becoming wellrecognised. Akdis et al. found that higher levels of testosterone in men and lower levels of oestrogen in women were both associated with higher rates of major arrhythmic cardiovascular events in patients with ARVC.37 The underlying pathophysiology is thought to be due to testosterone promoting apoptosis and lipogenesis, while oestrogen inhibits these effects. This possibly explains why regular exercise, which is thought to lower oestrogen levels, is associated with worse outcomes in ARVC.38 Additionally, these findings may provide an explanation for the rare occurrence of ARVC before pubertal years.

Degree of myocardial involvement should be assessed as well. Extensive RV involvement, defined as RVEF ≤45% or ≥2 areas of regional dysfunction, is predictive of appropriate ICD therapy.41 Greater RV dysfunction as measured on echocardiogram is associated with an overall increase in major adverse cardiovascular events (MACEs), with VA unsurprisingly being the most common MACE.42 In addition to RV involvement, LV involvement in ARVC is also recognised.2 An early study by Wichter et al. in 2005 suggested that LV involvement showed a trend towards predicting appropriate ICD therapy.41 More recent studies have provided stronger evidence that LV involvement and dysfunction increase VA risk.29,42–44 Given the progressive nature of ARVC, we suggest that the degree of myocardial involvement is reassessed periodically to re-stratify a patient’s risk.

Other Risk Factors

Exercise has also been associated with progression and poor outcomes in patients with ARVC. Even ARVC carriers with greater exercise duration were found to be at significantly higher risk for a VA event. This suggests higher penetrance in patients who exercise more.39 This finding was similarly demonstrated in patients with definite ARVC. Athletes with definite ARVC were at higher risk for VA, VA at a younger age, and ICD placement at a younger age.6,40 Wang et al. further investigated exercise restriction and found a dose–response relationship between exercise dose (defined as intensity × duration) and reduction in VA events.14 This benefit is even greater in gene-elusive patients and those with ICDs placed for primary prevention.14 Despite this, the absolute risk of VA in that study was found to be 22% annually.

Decision-making Regarding ICD Placement

ICD placement is currently the cornerstone of treatment after a diagnosis of ARVC. However, the decision to place an ICD should be weighed

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Inherited Arrhythmogenic Cardiac Conditions Figure 5: Protection Rates When Using Life-threatening Ventricular Arrhythmia to Determine ICD Placement ICD, LTVA

No ICD, LTVA

ICD, no LTVA

No ICD, no LTVA

100%

Proportion of total (%)

80%

60%

40%

20%

0%

All

>1%

>2%

>3%

Plot area

>5%

>6%

>7%

>8%

>9%

>10%

None

Predicted 5-year risk

No LTVA, no ICD No LTVA, ICD LTVA, no ICD

All

>1%

>2%

>3%

>4%

>5%

>6%

>7%

>8%

>9%

>10%

None

0 (0%) 778

13 (1.5%) 765

57 (6.6%) 721

133 (15.4%) 645

222 (25.7%) 556

282 (32.7%) 496

341 (39.4%) 437

414 (48%) 364

468 (54.1%) 310

500 (57.8%) 278

526 (60.9%) 252

778 (90%) 0

(90%)

(88.5%) 0

(83.4%)

(74.7%)

(64.3%)

(57.4%)

(50.6%)

(42.2%)

(35.9%)

(32.2%)

(29.1%)

(0%)

1 (0.1%)

1 (0.1%)

2 (0.2%)

5 (0.6%)

10 (1.2%)

10 (1.2%)

16 (1.9%)

21 (2.4%)

23 (2.7%)

86 (10%)

0 (0%)

LTVA, ICD

86

(0%) 86

85

85

84

81

76

76

70

65

63

0

ICD, total

(10%) 864

(10%) 851

(9.8%) 806

(9.8%) 730

(9.8%) 640

(9.3%) 577

(8.8%) 513

(8.8%) 440

(8.1%) 380

(7.5%) 343

(7.3%) 315

(0%) 0

(100%)

(98.5%)

(93.3%)

(84.5%)

(74.1%)

(66.8%)

(59.4%)

(50.9%)

(44%)

(39.7%)

(36.5%)

(0%)

100%

100.0%

98.8%

98.8%

97.7%

94.2%

88.4%

88.4%

81.4%

75.6%

73.3%

0.0%

Protection rate (%)

The resulting protection rate at various rates of ICD placement based on a model that looks specifically at LTVA, instead of any ventricular arrhythmia. The red bar demonstrates patients with an ICD who are predicted to sustain an LTVA. The blue bar represents those with an ICD and who are not predicted to sustain an LTVA. The dashed red bar represents patients who are without an ICD and who will be unprotected from a predicted LTVA. All = ICDs implanted in all patients; none = ICDs implanted in no patients; LTVA = life-threatening ventricular arrhythmia. Source: Cadrin-Tourigny et al. 2021.48 Reproduced with permission from Wolters Kluwer Health..

diagnosis), number of T wave inversions, maximum 24-hour PVC count, history of NSVT, and RVEF to provide a predicted risk of sustained VA. Compared with the 2015 ITF algorithm, which treats ARVC risk as high, intermediate or low, the more recent ARVC risk calculator treats VA risk as a continuum. This new algorithm showed similar levels of benefit and protection from ICD placement at a much lower rate of ICD placement (20.6% fewer ICD implantations compared with the ITF algorithm; Figures2 and 3).45

against the short- and long-term risks of ICD placement. According to the 2015 International Task Force (ITF) consensus statement, Class I indications for ICD placement include a history of sustained VT or VF, severe RV dysfunction (fractional area change ≤17% or RVEF ≤35%), and severe LV dysfunction (LVEF ≤35%; Figure 1).23 However, this ITF consensus statement is less clear regarding ICD placement for primary prevention in ARVC patients. The ITF consensus statement provides Class IIa indications for when ICD placement should be considered in patients with ≥1 major risk factor, such as a history of syncope, NSVT, moderate RV dysfunction (RV fractional area change between 24% and 17% or RVEF 36–40%), moderate LV dysfunction (LVEF 36–45%) or biventricular dysfunction.

Class IIb indications for when ICD placement may be considered include T wave inversion in ≥3 precordial leads, male sex, inducibility on electrophysiological study, and proband status.23 These guidelines lack clarity regarding ICD placement for primary prevention in ARVC patients.

Another study comparing this new ARVC risk score with both the ITF and HRS guidelines found that an ARVC risk score >10% had the greatest net benefit compared with the guidelines.46 This new model provides the physician with a tool with which to quantify an individual patient’s risk and which can supplement clinical judgement during ICD placement decisionmaking. It is worth mentioning that this new model may underestimate non-classical forms of ARVC, such as biventricular or left dominant forms.47 Notably, this risk calculator also does not include inducibility on PVS, which is one of the discussed risk factors in the present article. Future ARVC risk calculators may include this to provide even more robust models regarding ARVC risk.

A paper by Cadrin-Tourigny et al. in 2019 attempted to provide more clarity regarding primary prevention ICD placement by creating an ARVC risk calculator (which can be found at http://www.arvcrisk.com).45 This risk calculator uses age at diagnosis, sex, cardiac syncope (<6 months prior to

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Inherited Arrhythmogenic Cardiac Conditions restriction. An individualised risk assessment is required to weigh the risks and benefits in the important decision of whether or not to proceed with ICD placement.

An even more recent study by Cadrin-Tourigny et al. specifically investigated predictive factors of life-threatening VAs (LTVAs) to serve as a closer surrogate marker for SCD risk. That study did not find that prior sustained VA predicted LTVA, but that younger age, male sex, PVC count and number of leads with T wave inversion were predictive of LTVA.48 However, that study did reinforce the predictive value of any previous sustained VA for a future sustained VA event (Figure 4).48 That study also equips clinicians with more data for shared decision-making regarding ICD placement by providing more objective measures of risk and protection rates (Figure 5).48 It may not be unreasonable to forgo ICD placement in those deemed high risk for complications, or in low-risk patients who are hesitant to have an ICD placed. Regardless of these data, current ARVC guidelines recommend ICD placement as secondary prevention in patients with a history of any VA.23.

Clinical Perspective

• Arrhythmogenic right ventricular cardiomyopathy (ARVC)

management consists of a 5-step approach that includes accurate diagnosis, determination of the need for ICD placement, minimisation of ICD therapy, prevention of disease progression and cascade screening of family members.

• ARVC risk stratification is determined by age at presentation, male sex, proband status, history of ventricular arrhythmia, history of cardiac syncope, frequency of premature ventricular contractions and non-sustained ventricular tachycardia, degree of myocardial involvement and exercise plans.

• ARVC risk calculators provide more objective measures of risk stratification and can supplement clinical judgement when weighing the risks and benefits of ICD placement.

Conclusion

Risk stratification should be carried out immediately when a diagnosis of ARVC is made. Risk factors predictive of VA and SCD include age of onset, male sex, specific genetic mutation, cardiac syncope, history of VA, degree of myocardial involvement, electrical instability, and exercise 1. Thiene G, Nava A, Corrado D, et al. Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med 1988;318:129–33. https://doi.org/10.1056/ NEJM198801213180301; PMID: 3336399.

2. Sen-Chowdhry S, Syrris P, Prasad SK, et al. Left-dominant arrhythmogenic cardiomyopathy: an under-recognized clinical entity. J Am Coll Cardiol 2008;52:2175–87. https://doi. org/10.1016/j.jacc.2008.09.019; PMID: 19095136.

3. Corrado D, Link MS, Calkins H. Arrhythmogenic right ventricular cardiomyopathy. N Engl J Med 2017;376:61–72. https://doi.org/10.1056/NEJMra1509267; PMID: 28052233.

4. Groeneweg JA, Bhonsale A, James CA, et al. Clinical presentation, long-term follow-up, and outcomes of 1001 arrhythmogenic right ventricular dysplasia/cardiomyopathy patients and family members. Circ Cardiovasc Genet 2015;8:437–46. https://doi.org/10.1161/ CIRCGENETICS.114.001003; PMID: 25820315.

5. James CA, Syrris P, van Tintelen JP, et al. The role of genetics in cardiovascular disease: arrhythmogenic cardiomyopathy. Eur Heart J 2020;41:1393–1400. https://doi. org/10.1093/eurheartj/ehaa141; PMID: 32191298.

6. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J 2010;31:806–14. https://doi.org/10.1093/eurheartj/ehq025; PMID: 20172912.

7. Denis A, Sacher F, Derval N, et al. Diagnostic value of isoproterenol testing in arrhythmogenic right ventricular cardiomyopathy. Circ Arrhythm Electrophysiol 2014;7:590–7. https://doi.org/10.1161/CIRCEP.113.001224; PMID: 24970294.

8. Marcus GM, Glidden DV, Polonsky B, et al. Multidisciplinary Study of Right Ventricular Dysplasia Investigators. Efficacy of antiarrhythmic drugs in arrhythmogenic right ventricular cardiomyopathy: a report from the North American ARVC Registry. J Am Coll Cardiol 2009;54:609–15. https://doi. org/10.1016/j.jacc.2009.04.052; PMID: 19660690.

9. Ermakov S, Gerstenfeld EP, Svetlichnaya Y, et al. Use of flecainide in combination antiarrhythmic therapy in patients with arrhythmogenic right ventricular cardiomyopathy. Heart Rhythm 2017;14:564–9. https://doi.org/10.1016/j. hrthm.2016.12.010; PMID: 27939893.

10. 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.

11. Christiansen MK, Haugaa KH, Svensson A, et al. Incidence, predictors, and success of ventricular tachycardia catheter ablation in arrhythmogenic right ventricular cardiomyopathy (from the Nordic ARVC Registry). Am J Cardiol 2020;125:803– 11. https://doi.org/10.1016/j.amjcard.2019.11.026; PMID: 31924321.

12. Philips B, te Riele AS, Sawant A, et al. Outcomes and ventricular tachycardia recurrence characteristics after epicardial ablation of ventricular tachycardia in arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Heart Rhythm 2015;12:716–25. https://doi.org/10.1016/j.

hrthm.2014.12.018; PMID: 25530221.

13. Mahida S, Venlet J, Saguner AM, et al. Ablation compared with drug therapy for recurrent ventricular tachycardia in arrhythmogenic right ventricular cardiomyopathy: results from a multicenter study. Heart Rhythm 2019;16:536–43. https://doi.org/10.1016/j.hrthm.2018.10.016; PMID: 30366162.

14. Wang W, Orgeron G, Tichnell C, et al. Impact of exercise restriction on arrhythmic risk among patients with arrhythmogenic right ventricular cardiomyopathy. J Am Heart Assoc 2018;7:e008843. https://doi.org/10.1161/ JAHA.118.008843; PMID: 29909402.

15. Gilotra NA, Bhonsale A, James CA, et al. Heart failure is common and under-recognized in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia.

Circ Heart Fail 2017;10:e003819. https://doi.org/10.1161/ CIRCHEARTFAILURE.116.003819; PMID: 28874384.

16. Morel E, Manati AW, Nony P, et al. Blockade of the reninangiotensin-aldosterone system in patients with arrhythmogenic right ventricular dysplasia: a double-blind, multicenter, prospective, randomized, genotype-driven study (BRAVE study). Clin Cardiol 2018;41:300–6. https://doi. org/10.1002/clc.22884; PMID: 29574980.

17. Tedford RJ, James C, Judge DP, et al. Cardiac transplantation in arrhythmogenic right ventricular dysplasia/ cardiomyopathy. J Am Coll Cardiol 2012;59:289–90. https:// doi.org/10.1016/j.jacc.2011.09.051; PMID: 22240135.

18. DePasquale EC, Cheng RK, Deng MC, et al. Survival after heart transplantation in patients with arrhythmogenic right ventricular cardiomyopathy. J Card Fail 2017;23:107–12. https://doi.org/10.1016/j.cardfail.2016.04.020; PMID: 27154489.

19. Orgeron GM, James CA, Te Riele A, et al. Implantable cardioverter-defibrillator therapy in arrhythmogenic right ventricular dysplasia/cardiomyopathy: predictors of appropriate therapy, outcomes, and complications. J Am Heart Assoc 2017;6:e006242. https://doi.org/10.1161/ JAHA.117.006242; PMID: 28588093.

20. Mazzanti A, Ng K, Faragli A, et al. Arrhythmogenic right ventricular cardiomyopathy: clinical course and predictors of arrhythmic risk. J Am Coll Cardiol 2016;68:2540c50. https:// doi.org/10.1016/j.jacc.2016.09.951; PMID: 27931611.

21. Piccini JP, Dalal D, Roguin A, et al. Predictors of appropriate implantable defibrillator therapies in patients with arrhythmogenic right ventricular dysplasia. Heart Rhythm 2005;2:1188–94. https://doi.org/10.1016/j. hrthm.2005.08.022; PMID: 16253908.”

22. Corrado D, Leoni L, Link MS, et al. Implantable cardioverterdefibrillator therapy for prevention of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation 2003;108:3084–91. https://doi.org/10.1161/01.CIR.00001+03130.33451.D2; PMID: 14638546.

23. Corrado D, Wichter T, Link MS, et al. Treatment of arrhythmogenic right ventricular cardiomyopathy/dysplasia: an International Task Force consensus statement. Circulation 2015;132:441–53. https://doi.org/10.1161/ CIRCULATIONAHA.115.017944; PMID: 26216213.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW Access at: www.AERjournal.com

31

24. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2018;15:190– 252. https://doi.org/10.1016/j.hrthm.2017.10.035; PMID: 29097320.

25. Bhonsale A, Groeneweg JA, James CA, et al. Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers. Eur Heart J 2015;36:847–55. https://doi.org/10.1093/ eurheartj/ehu509; PMID: 25616645.

26. Piccini JP, Dalal D, Roguin A, et al. Predictors of appropriate implantable defibrillator therapies in patients with arrhythmogenic right ventricular dysplasia. Heart Rhythm 2005;2:1188–94. https://doi.org/10.1016/j. hrthm.2005.08.022; PMID: 16253908.

27. Roguin A, Bomma CS, Nasir K. Implantable cardioverterdefibrillators in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol 2004;43:1843–52. https://doi.org/10.1016/j.jacc.2004.01.030; PMID: 15145110.

28. Saguner AM, Medeiros-Domingo A, Schwyzer MA, et al.

Usefulness of inducible ventricular tachycardia to predict long-term adverse outcomes in arrhythmogenic right ventricular cardiomyopathy. Am J Cardiol 2013;111:250–7. https://doi.org/10.1016/j.amjcard.2012.09.025; PMID: 23103200.

29. Maupain C, Badenco N, Pousset F, et al. Risk stratification in arrhythmogenic right ventricular cardiomyopathy/dysplasia without an implantable cardioverter-defibrillator. JACC Clin Electrophysiol 2018;4:757–68. https://doi.org/10.1016/j. jacep.2018.04.017; PMID: 29929669.

30. Corrado D, Calkins H, Link MS, et al. Prophylactic implantable defibrillator in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia and no prior ventricular fibrillation or sustained ventricular tachycardia.

Circulation 2010;122:1144–52. https://doi.org/10.1161/ CIRCULATIONAHA.109.913871; PMID: 20823389.

31. Marcus FI, Fontaine GH, Frank R, Gallagher JJ, Reiter MJ. Long-term follow-up in patients with arrhythmogenic right ventricular disease. Eur Heart J 1989;10(Suppl D):68–73. https://doi.org/10.1093/eurheartj/10.suppl_d.68; PMID: 2806306.

32. Gupta R, Tichnell C, Murray B, et al. Comparison of features of fatal versus nonfatal cardiac arrest in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Am J Cardiol 2017;120:111–17. https://doi.org/10.1016/j. amjcard.2017.03.251; PMID: 28506445.

33. Sadjadieh G, Jabbari R, Risgaard B, et al. Nationwide (Denmark) study of symptoms preceding sudden death due to arrhythmogenic right ventricular cardiomyopathy. Am J Cardiol 2014;113:1250–4. https://doi.org/10.1016/j. amjcard.2013.12.038; PMID: 24513468.

34. Bosman LP, Sammani A, James CA, et al. Predicting

Inherited Arrhythmogenic Cardiac Conditions arrhythmic risk in arrhythmogenic right ventricular cardiomyopathy: a systematic review and meta-analysis.

Heart Rhythm 2018;15:1097–1107. https://doi.org/10.1016/j. hrthm.2018.01.031; PMID: 29408436.

35. Nava A, Bauce B, Basso C, et al. Clinical profile and longterm follow-up of 37 families with arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol 2000;36:2226– 33. https://doi.org/10.1016/s0735-1097(00)00997-9; PMID: 11127465.

36. Rigato I, Bauce B, Rampazzo A, et al. Compound and digenic heterozygosity predicts lifetime arrhythmic outcome and sudden cardiac death in desmosomal gene-related arrhythmogenic right ventricular cardiomyopathy. Circ Cardiovasc Genet 2013;6:533–42. https://doi.org/10.1161/ CIRCGENETICS.113.000288; PMID: 24070718.

37. Akdis D, Saguner AM, Shah K, et al. Sex hormones affect outcome in arrhythmogenic right ventricular cardiomyopathy/dysplasia: from a stem cell derived cardiomyocyte-based model to clinical biomarkers of disease outcome. Eur Heart J 2017;38:1498–1508. https://doi. org/10.1093/eurheartj/ehx011; PMID: 28329361.

38. Smith AJ, Phipps WR, Thomas W, et al. The effects of aerobic exercise on estrogen metabolism in healthy premenopausal women. Cancer Epidemiol Biomarkers Prev 2013;22:756–64. https://doi.org/10.1158/1055-9965.EPI-121325; PMID: 23652373.

39. James CA, Bhonsale A, Tichnell C, et al. Exercise increases

age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathyassociated desmosomal mutation carriers. J Am Coll Cardiol 2013;62:1290–7. https://doi.org/10.1016/j.jacc.2013.06.033; PMID: 23871885.

40. Gasperetti A, Dello Russo A, Busana M, et al. Novel risk calculator performance in athletes with arrhythmogenic right ventricular cardiomyopathy. Heart Rhythm 2020;17:1251–9. https://doi.org/10.1016/j.hrthm.2020.03.007; PMID: 32200046.

41. Wichter T, Paul M, Wollmann C, et al. Implantable cardioverter/defibrillator therapy in arrhythmogenic right ventricular cardiomyopathy: single-center experience of long-term follow-up and complications in 60 patients.

Circulation 2004;109:1503–8. https://doi.org/10.1161/01.

CIR.0000121738.88273.43; PMID: 15007002.

42. Saguner AM, Vecchiati A, Baldinger SH, et al. Different prognostic value of functional right ventricular parameters in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

Circ Cardiovasc Imaging 2014;7:230–9. https://doi.org/10.1161/ CIRCIMAGING.113.000210; PMID: 24515411.

43. Liao YC, Lin YJ, Chung FP. Risk stratification of arrhythmogenic right ventricular cardiomyopathy based on signal averaged electrocardiograms. Int J Cardiol 2014;174:628–33. https://doi.org/10.1016/j.ijcard.2014.04.169; PMID: 24820746.

44. Aquaro GD, De Luca A, Cappelletto C, et al. Prognostic

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value of magnetic resonance phenotype in patients with arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol 2020;75:2753–65. https://doi.org/10.1016/j. jacc.2020.04.023; PMID: 32498802.

45. 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.

46. Aquaro GD, De Luca A, Cappelletto C, et al. Comparison of different prediction models for the indication of implanted cardioverter defibrillator in patients with arrhythmogenic right ventricular cardiomyopathy. ESC Heart Fail 2020;7:4080–8. https://doi.org/10.1002/ehf2.13019; PMID: 32965795.

47. Casella M, Gasperetti A, Gaetano F, et al. Long-term followup analysis of a highly characterized arrhythmogenic cardiomyopathy cohort with classical and non-classical phenotypes: a real-world assessment of a novel prediction model: does the subtype really matter. Europace 2020;22:797–805. https://doi.org/10.1093/europace/euz352; PMID: 31942607.

48. Cadrin-Tourigny J, Bosman LP, Wang W, et al. Sudden cardiac death prediction in arrhythmogenic right ventricular cardiomyopathy: a multinational collaboration. Circ Arrhythm Electrophysiol 2021;14:e008509. https://doi.org/10.1161/ CIRCEP.120.008509; PMID: 33296238.

Electrophysiology and Ablation

Electrophysiological Substrate in Patients with Barlow’s Disease Pasquale Vergara , Savino Altizio, Giulio Falasconi, Luigi Pannone, Simone Gulletta and Paolo Della Bella Arrhythmia Unit and Electrophysiology Laboratories, IRCCS San Raffaele Scientific Institute, Milano, Italy

Abstract

Mitral valve prolapse (MVP) is the most common valvular heart disease, affecting 2–3% of the general population. Barlow’s disease is a clinical syndrome characterised by MVP. Initially thought a benign condition, MVP is now recognised as a cause of sudden cardiac death and ventricular arrhythmias. The development of new imaging techniques has contributed recently to the identification of novel risk factors. Catheter ablation of ventricular arrhythmias in patients affected by MVP is traditionally considered challenging. In this review, the authors summarise the evidence on arrhythmogenesis in the context of MVP, along with risk stratification of sudden cardiac death and the available treatment options, including new catheter ablation techniques.

Keywords

Ventricular arrhythmias, ventricular tachycardia, premature ventricular beats, mitral valve disease, sudden cardiac death, mitral prolapse Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: SG and PDB are shared last authors.

Received: 3 July 2020 Accepted: 2 December 2020 Citation: Arrhythmia & Electrophysiology Review 2021;10(1):33–7. DOI: https://doi.org/10.15420/aer.2020.29 Correspondence: Pasquale Vergara, Arrhythmia Unit and Electrophysiology Laboratories, IRCCS San Raffaele Scientific Institute, Milano, Italy.

E: pasqualevergara@hotmail.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 non-commercial purposes, provided the original work is cited correctly.

depolarisation of transmembrane potential, with the latter being associated with both transient afterpotentials and propagated action potentials.10,11 Stretch-induced depolarisation may induce PVCs that can be the main clinical finding or the trigger for malignant arrhythmias.12,13 Furthermore, a prolongation of the ventricular functional refractory period has been demonstrated in the traction zone. Regional refractory period prolongation may cause action potential heterogeneities, demonstrated to serve both as the substrate for polymorphic VT and as the trigger for short-coupled PVCs (‘R from T mechanism’).14 In a study based on 2D and 3D simulations, large heterogeneities were implicated in the initiation of focal activity polymorphic VT and smaller heterogeneities in re-entry-type polymorphic VT.15 The final result of those action potential heterogeneities was polymorphic VTs induced both by multiple competing foci and re-entry circuits.

Mitral valve prolapse (MVP) is the most common valvular heart disease and is estimated to affect 2–3% of the general population.1 Barlow’s disease is a clinical syndrome characterised by MVP, a late systolic murmur and nonejection systolic click; the cornerstone of the disease is a fibro-myxomatous modification in the mitral leaflet tissue, with superior displacement of one or both leaflets into the left atrium.2,3 Although MVP has generally been regarded as a benign condition, several studies have reported ventricular arrhythmias (VAs) and sudden cardiac death (SCD).4–7 Basso et al. detected left ventricular (LV) fibrosis at post mortem examination at the level of the papillary muscle (PM) and/or infero-basal wall.8 LV late gadolinium enhancement (LGE) was identified by contrastenhanced cardiac magnetic resonance (CMR) in the same regions.

The aim of this article is to summarise the pathophysiology, risk stratification and available treatment options for patients with MVP and VAs.

Beyond the PM structure, the Purkinje system (PS) may be implicated as a substrate and a trigger of malignant MVP. Distal arborisations of PS are localised near the base of the PM, where Purkinje-like potentials can often be recorded.16 PS-ventricular muscle junction is a region characterised by a low safety factor for propagation. The safety factor is defined as the ratio between the upstream current and the downstream threshold current.17 A safety factor of at least 1 is necessary for conduction.

Arrhythmogenesis and Electrophysiological Substrate

Arrhythmogenesis in MVP is the result of a complex interplay between the substrate and a mechanical and electrical trigger, which goes beyond the PM anatomy. The most common arrhythmic presentation in MVP is premature ventricular complexes (PVCs), followed by non-sustained ventricular tachycardia (VT), sustained VT, polymorphic VT and VF.

A low safety factor in PS-ventricular muscle junction can be explained by the narrow curvature of the propagation wavefront in this region.18 This can lead to ‘source-sink mismatch’, propagation failure and predisposes to reentrant arrhythmias. In a 3D model of polymorphic VT, reentrant excitation was initiated in the myocardium of the LV by unidirectional propagation; the PS was demonstrated to be necessary for the maintenance of that reentry, at least in the initial stage.19 Furthermore, a ‘source-sink mismatch’ was also

Several animal models of mechanical stretch-induced arrhythmias have been proposed. These models might also provide some hints on the pathogenesis of MVP-related arrhythmias. In a canine model, Gornick et al. demonstrated that the mechanical traction of PM was associated with local premature ventricular activation.9 Other studies in cardiac tissues showed that myocardial stretch is associated with reversible

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Electrophysiological Substrate in Barlow’s Disease demonstrated in the PM region, secondary to an abrupt change of the muscular fibre orientation and also related to the electrical mass of PM, which serves as an additional sink. 20 Based on these observations, Kim et al. demonstrated in a swine model that during VF, reentrant wavefronts are often transiently anchored to the PM. Purkinje fibre potentials were recorded at the base of PM and preceded the local myocardial activation. Tissue mass reduction converted VF to VT, while PM disconnection led to the noninducibility of sustained VT.21

In a large cohort of 595 consecutive patients, 9% had severe VAs (VT ≥180 BPM and/or history of proven VT/VF), 27% had moderate VAs (VT 120–179 BPM), 8% had mild VAs (≥5% PVC and/or VT <120 BPM), and 57% had no/ trivial ectopy (<5% PVCs). Arrhythmia severity was strongly associated with adverse outcome, with mortality rates at 8 years after the diagnosis ranging from 10 ± 2% in patients with no/trivial VAs, to 15 ± 3% for mild and/or moderate and 24 ± 7% for severe arrhythmia (p=0.02). Severe VA was independently associated with mortality after adjustment for clinical covariates (adjusted HR 2.94; 95% CI [1.36–6.36]; p=0.006).30

In a series by Santoro et al., the main mechanism of VF originating from the PM was short coupled PVCs that could be preceded by Purkinje-like potentials.22 However, Purkinje-like potentials precede local ventricular activation during sinus rhythm but are bystander activated during PVCs, suggesting that PVCs originate from the ventricular PM, rather than from the conduction system.23 Thus, based on anatomical proximity, PS might be implicated in enabling and maintenance of reentrant mechanism initiated by PM.

Cardiac Imaging Characteristics

Cardiac imaging with trans-thoracic, trans-oesophageal echocardiography and CMR provides valuable support for correct risk stratification. As early as 1994, Zuppiroli et al. demonstrated the relationship between mitral valve tissue redundancy – in particular anterior mitral leaflet thickening – with the occurrence of complex VAs.31 Moreover, MVP-related regurgitation appeared as an independent predictor of VAs.29 Contradictory studies are available regarding the role of surgical treatment of mitral regurgitation in prevention of major arrhythmic events. Naksuk et al. showed that surgery did not uniformly reduce the PVC burden, but the reduction was greater in young patients, thus suggesting a possible benefit on arrhythmic burden from early surgical referral.27

Since the first description of arrhythmic MVP, a substrate could be demonstrated based on histopathology and CMR. In their seminal study on SCD in MVP, Basso et al. detected endo-perimysial and patchy replacementtype fibrosis at the level of PM in all SCD patients, and sub-endocardial/ mid-mural fibrosis in the infero-basal LV wall under the posterior mitral valve leaflet in 88% of cases. 8 In vivo CMR demonstrated LV LGE in 93% of arrhythmic MVP versus 14% of control subjects, with a regional distribution overlapping with the histopathological findings. Furthermore, in a large primary mitral regurgitation cohort, CMR LGE appeared as an important prognostic factor, with the highest arrhythmic event rate seen in MVP patients with replacement fibrosis (7.7%), followed by MVP patients without replacement fibrosis (2.7%) and non-MVP patients (0.6%).24

The presence of mitral annular disjunction (MAD), defined as the detachment of the mitral annulus compared to the ventricular myocardium during cardiac systole, and the presence of the Pickelhaube sign, defined as an high-velocity positive systolic wave at tissue Doppler evaluation of lateral mitral annulus, also characterised a cohort of patients with a high risk of malignant VAs.32–34 The clinical role of MAD is not yet fully understood. In particular, Dejgaard et al. showed that MAD was associated with VAs, even in absence of detectable MVP, thus suggesting that MAD itself is an arrhythmogenic entity.34 Arrhythmia risk increased proportionally to MAD length, suggesting a central role of MAD in the arrhythmogenic MVP.35 However, it is also possible that MAD and overt MVP are components of the same clinical spectrum.36 In 2017, Muthukumar et al. described the Pickelhaube sign. During mid-systole, the excessive movement of the prolapsing mitral valve causes traction on the myocardium of the inferior-lateral wall and on the PM; this mechanical event can cause a local electrical dysfunction, even in the absence of fibrosis detected by CMR.25,33

When considering programmed electrical stimulation and invasive electroanatomic mapping, Syed et al. found that bipolar and unipolar voltage maps were normal in all MVP patients undergoing VAs ablation; abnormal LV fascicular potentials, defined as fractionated, delayed, or mid-diastolic Purkinje electrograms, were evident in all patients with MVP and previous cardiac arrest, and in all cases of sustained VAs induced during the electrophysiological study.25

Risk Stratification

MVP is an under-recognised cause of SCD in young adults, accounting for 7% of total events and 13% in females.8 Several small cohort studies have attempted to identify patient characteristics associated with major cardiac events. However, to date, results are contradictory and a comprehensive risk stratification is not available. We will review the results of the most important studies on the topic. Risk factors are summarised in Figure 1.

Avierinos et al. suggested that female sex and young age are associated with an increased arrhythmic risk.26 Bileaflet MVP was frequently found in patients experiencing idiopathic out of hospital cardiac arrest (in the absence of ischaemia, cardiomyopathy and channelopathies). Other common characteristics in this subset of patients were the presence of isodiphasic or negative T waves in inferior leads, PVCs with outflow tract, PM or fascicular origin.27 At ECG evaluation, the presence of T wave abnormalities in the inferior leads (inverted or isodiphasic T waves) was found in >80% of the cases of MVP-related SCD.8 Wei et al. showed that a large burden of PVCs was associated with higher rate of non-sustained and sustained VT occurrence.28 Complex arrhythmias, such as pleomorphic PVCs with alternating morphology, ventricular couplets or triplets, are much more frequent in the MVP population than in the general population.29 They are a possible trigger for malignant arrhythmias.

CMR has shown an additive role to echocardiography in the risk stratification of patients with MVP. Basso et al., by histological evaluation, detected the presence of fibrosis at the level of PM and inferior-basal wall in most patients with MVP. 37 In the same cohort of patients, the presence of LGE was associated with complex VA occurrence; LGE distribution was similar to the one found by histopathological examination.37 In patients with primary mitral regurgitation, LV myocardial fibrosis is more frequent in MVP than in non-MVP patients; myocardial fibrosis appeared as an independent arrhythmic risk factor.24 This correlation was also reported by Han et al., who identified focal regions of LGE in the PM in 63% of their cohort; this finding was associated with the presence of complex VAs.36 Arrhythmic events in MVP patients were also associated with the presence of MAD detected by CMR, larger end-systolic and end-diastolic mitral annular diameters, posterior systolic curling and basal to mid LV wall thickness ratio >1.5.37 Among patients with MAD, Scheirlynck et al. found VAs in 22 (31%). The implementation of additional risk factors allowed a more appropriate stratification of patients with MAD. The risk of VAs was highest in those with LGE at the PM, high levels of soluble suppression of tumourigenicity-2 and reduced LV ejection fraction (LVEF).38 The excessive

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Electrophysiological Substrate in Barlow’s Disease Figure 1: Risk Stratification in Patients with Mitral Valve Prolapse

movement and mechanical stretching present in the pathological mitral valve systems favour LV hypertrophy, myocardial scarring and, consequently, the occurrence of VAs.

• T wave abnormalities (II, III, aVF) • Complex premature ventricular complex

• Woman • Bileaflet prolapse • No valve surgery

To date there is no shared expert consensus on the management of patients with MVP and risk of VAs. Because several grey areas still exist in risk stratification and no diagnostic methodology has been extensively validated, a multimodal evaluation becomes fundamental. Our current diagnostic practice includes the use of periodical ambulatory ECG monitoring or implantable loop recorders in MVP patients symptomatic for palpitation, in the absence of any risk factors. We tend to perform CMR before programmed electrical stimulation in patients with complex PVCs or syncope. In patients with aborted SCD, an ICD is mandatory. Catheter ablation of the documented VAs is a promising therapeutic option. However, any potential beneficial effects on patient survival have not yet been clearly documented.

Baseline characteristics

Echo

• Leaflet thickening • Mitral valve regurgitation • Pickelhaube sign

Treatment

Although the arrhythmogenic role of PM has been well known since the 1980s, catheter ablation of VAs originating from PM is a relatively recent acquisition. First experiences, dating to the late 2000s, reported PMrelated VAs both in the context of ischaemic cardiomyopathy and in normal hearts, with a spectrum of clinical presentation ranging from isolated PVCs to non-sustained VT, sustained VT and VF.22,39,40

ECG

Cardiac MRI

• Myocardial fibrosis • Mitral-annular disjunction • Systolic curling

from mitral annulus VAs, Yamada et al. proposed several ECG criteria.46 Among them, only an R/S ratio ≤1 in lead V6 in the LV anterolateral region and a QRS duration >160 ms in the LV postero-septal region were reliable predictors of PM exit. More recently, Al’Aref proposed an ECG algorithm based on QRS duration, r and R’ amplitudes in V1 and precordial transition to differentiate the three subgroups.44

Doppalapudi et al. described a cohort of seven patients out of 290 referred for the ablation of idiopathic VAs.23 Patients showed the following distinctive characteristics, which suggested the presence of a new clinical syndrome: normal baseline ECG and intracardiac conduction intervals, with normal LV systolic function; right bundle branch block and superioraxis PVC morphology; lack of VA inducibility by electrophysiological study and atrial programmed electrical stimulation; VT or PVC inducibility by intravenous isoproterenol or epinephrine; earliest ventricular activation at the base of the posterior PM in the LV; and absence of high-frequency potentials at the site of origin, thus suggesting that the PS was not directly involved. VAs originating from the anterior PM were later described by the same group.41

When clinically applying the previously cited ECG criteria, the electrophysiologist should be aware that they present some potential limitations. In fact, the criteria have not been validated in specific populations with confirmed diagnosis of MVP. Theoretically, PMs VA should share a common exit located at the base of the PM. However, several anatomical configurations have been described. PM portions might be connected with other portions of the same PM, with the opposite PM, with the ipsilateral or contralateral LV wall and bifid PMs might present a mismatch between the strands. Rivera et al. found PM connections in 62% of PMs from patients undergoing VA ablation. 47 The PM connections might be responsible for impulse propagation in areas located away from the PM base, thus providing an R/S transition in the precordial leads and/ or a QRS axis inconsistent with the site of VA origin.

Among a cohort of 597 patients treated for VAs, Enriquez et al. identified 25 patients with MVP and PVCs mapped to the PM.42 The clinical presentation was PVC-triggered VF in four of them and one patient died during follow-up.

CMR and electroanatomic maps were available in a small subset of cases (nine and 11 patients, respectively). Bipolar voltage abnormalities were identified only in three patients. Acute ablation procedure was associated with a significant reduction in PVC burden during follow-up (from 20.4% ± 10.8% to 6.3% ± 9.5%; p=0.001) and with improvement of post-ablation LV function in patients with depressed LVEF (five of six patients).

Electroanatomical Mapping and Catheter Ablation

Mapping and ablation of VA in MVP are usually performed with standard electrophysiological techniques. Nevertheless, the particular location of the substrate requires the implementation of specific arrangements.

Idiopathic PM-related VAs usually exhibit a focal, non-reentrant mechanism (automaticity or triggered activity); ventricular/atrial programmed electrical stimulation are usually not able to induce those arrhythmias.

Electroanatomic mapping of VAs originating from PM is affected by several issues, including the presence of a deep focus within the PM and possibly multiple exit points. In almost half of the patients treated by Yamada et al., PM VAs exhibited multiple QRS morphologies, often requiring radiofrequency lesions on both sides of the PM in order to completely eliminate the VAs.40 Catheter ablation guided by pace-mapping is therefore hampered by a high risk of failure. Activation mapping is the most commonly used mapping approach: the aim is to target the earliest prepotential bipolar activity (≥30 ms before the QRS onset) or Purkinje-like potentials, which can be found in about 40% of patients (Figure 2).46 Isoproterenol or epinephrine infusion and burst pacing from right ventricular apex/right atrium can be eventually useful to increase PVCs frequency. Enriquez et al. mapped 27 different PM PVCs in 25 patients.42

ECG Criteria for the Identification of the Exit Point of Premature Ventricular Complexes

When planning catheter ablation in patients with MVP, analysis of ECG morphology might help differentiating PM VAs from other arrhythmias presenting with right-bundle block morphology, i.e. LV fascicular and mitral annulus related arrhythmias.41,43,44 Typically, VAs originating from the posteromedial PM, posterior fascicle or the posterior mitral annulus exhibit a superior axis, while those originating from the anterolateral PM, anterior fascicle or the anterior part of the MA, present with an inferior axis. QRS is significantly wider in patients with PM arrhythmias compared with the fascicular ones. All fascicular arrhythmias share an rsR’ morphology pattern in lead V1, which is not present in the arrhythmias originating from the PM.45 In order to discriminate PM and LV fascicular

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Electrophysiological Substrate in Barlow’s Disease Figure 2: Activation Mapping and Ablation of Premature Ventricular Complexes Originating from the Body of the Postero-medial Papillary Muscle

The site of PVC origin was the posteromedial PM in 14 patients (56%), the anterolateral PM in eight (32%) and both PMs in three patients (12%). In sinus rhythm, a Purkinje potential was recorded at the site of successful ablation in seven cases; in the other two patients a late potential was recorded in sinus rhythm that became pre-systolic during the PVC.42

B

A I II

After the identification of the arrhythmia exit point, the ablation phase is also hampered by a series of technical difficulties. The arrhythmic focus is usually localised but deep in the myocardium. The PM is an anatomically complex 3D structure, protruding from the myocardial wall into the LV cavity, changing its position at every heartbeat. It is also in close proximity with other structures of the mitral apparatus (mitral valve chordae and leaflets), which might be damaged by radiofrequency. A trans-septal approach with steerable sheets can improve catheter stability and is usually advisable. Intracardiac echocardiography allows the direct visualisation of the PM during mapping and helps to correctly identify the anatomical localisation of the arrhythmogenic focus; during catheter ablation, it allows confirmation of contact between the ablation catheter and the target PM, avoiding damage to surrounding anatomical structures.23,48

III aVR aVL aVF V1 V2

C

V3 V4

31 ms

V5 V6 Abl-d Abl-p

A: 12-lead and ablation catheter tracing. The premature complex shows a QS complex in II, III, aVF, R complex from V1 to Ve and RS in lead V6. The ventricular electrogram at earliest activation site preceeded the QRS onset by 31 ms; B: Electroanatomical mapping showing the catheter pointing towards the body of the postero-medial papillary muscle (pink). A clipping plane was applied to the apex of the left ventricle in order to facilitate the view of the postero-medial papillary muscle; C: Ultrasound view of the postero-medial papillary muscle (light blue line) and ablation catheter (yellow arrow) placed at the earliest activation site, through a transmitral approach.

The complexity of the substrate in VAs arising from PM justifies the low acute success and high recurrence rate after catheter ablation. In a large multicentre analysis of idiopathic PVCs ablation procedures, PM-related VAs showed the second lowest acute procedural success (80%), after epicardial foci (67%). During follow-up, patients with PM-related PVCs had among the highest recurrence rate, with only 60% of patients maintaining ≥80% reduction in PVC burden without antiarrhythmic drugs.49 Small cohort studies have evaluated the predictors of successful ablation; these included the smaller size of the PMs assessed by CMR, and the presence of Purkinje potentials at the site of ablation, which may reflect a superficial location of the arrhythmogenic substrate.49

proposed in patients with arrhythmia recurrence after a standard catheter ablation procedure, showing favourable results.51 In a small cohort of patients, radiofrequency ablation with an 8 mm catheter tip was more effective than non-irrigated 4 mm tip catheter ablation.52 However, such a large bipolar dipole is not able to correctly identify lowvoltage signals; the use of small and closely spaced diagnostic electrodes on a large-tip ablation catheter might allow both the detection of low-voltage fragmented electrograms and the application of deep lesions.53 Initial reports on a circumferential ablation around the base of the PM suggested a higher success rate.54 However, we believe that this strategy requires the delivery of a significant amount of radiofrequency, which could potentially damage PM architecture and, finally, increase the risk of complications.

Cryoablation, theoretically, provides the advantage over radiofrequency catheter ablation of greater catheter stability, deeper and more homogeneous lesions. However, in the clinical setting conflicting results have been reported concerning any real benefits. In a small series by Rivera et al., the acute success rate was 100% for cryoenergy in 12 patients and 78% for radiofrequency in nine patients (p=0.08).50 The better acute results of cryoenergy were probably related to a higher catheter stability achieved with cryoenergy (100% of treated patients), than radiofrequency (25% of treated patients, p=0.001). VA recurrence at 6-month follow-up was significantly lower in patients treated with cryoablation (0%), than those treated with radiofrequency (44%; p=0.03).

Widespread application of contact-force monitoring for catheter ablation procedures significantly improved procedural endpoints and, in cases of PM-related arrhythmias, it contributed to bridge the gap with cryoenergy.

The same authors compared three techniques for ablation of PM-related arrhythmia.47 These were cryoablation with cardiac CT integration into the electroanatomical mapping system, radiofrequency ablation with non-contact-force-sensing catheters and cardiac CT integration, and contact-force-sensing radiofrequency ablation catheters with intracardiac echo-facilitated 3D electroanatomical mapping. Acute success and arrhythmia recurrence during follow-up were 100% (14 patients) and 7% (one patient), respectively, with contact-force-sensing radiofrequency ablation catheters/intracardiac echo. Cryoablation/cardiac CT achieved non-significantly different results with acute success in 100% (16 patients) and recurrence rates in 19% (three patients). Non-contact-force-sensing radiofrequency ablation was associated with a reduced acute success rate (19 patients; 83%; p=0.03) and an increased risk of clinical arrhythmia recurrence (11 patients; 48%; p=0.02). Cryoablation has also been

Conclusion

MVP is now recognised as a cause of VAs and SCD that is not to be overlooked. The increasing interest in the pathophysiology and risk stratification of MVP-related arrhythmias allows us to more precisely target the arrhythmic substrate and to individualise therapies such as ICDs and catheter ablation. The recent technological advances in the field of catheter ablation need more extensive validation in MVP patients.

Furthermore, randomised controlled clinical trials are welcomed to better understand indication, timing and outcomes of antiarrhythmic therapies in this complex but fascinating setting.

Clinical Perspective • Specific subsets of patients with mitral valve prolapse have a

significant risk of ventricular arrhythmias.

• Myocardial fibrosis and premature ventricular complexes may act as a substrate and trigger of malignant ventricular arrhythmias.

• Catheter ablation of ventricular arrhythmias in this setting is a promising therapeutic option; potential beneficial effects should be validated.

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Electrophysiological Substrate in Barlow’s Disease 1. Freed LA, Levy D, Levine RA, et al. Prevalence and clinical outcome of mitral-valve prolapse. N Engl J Med 1999;341:1–7. https://doi.org/10.1056/NEJM199907013410101; PMID: 10387935.

2. Tamura K, Fukuda Y, Ishizaki M, et al. Abnormalities in elastic fibers and other connective-tissue components of floppy mitral valve. Am Heart J 1995;129:1149–58. https://doi. org/10.1016/0002-8703(95)90397-6; PMID: 7754947.

3. Rabkin E, Aikawa M, Stone JR, et al. Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation 2001;104:2525–32. https://doi.org/10.1161/hc4601.099489; PMID: 11714645.

4. Nishimura RA, McGoon MD, Shub C, et al.

Echocardiographically documented mitral-valve prolapse: long-term follow-up of 237 patients. N Engl J Med 1985;313:1305–9. https://doi.org/10.1056/ NEJM198511213132101; PMID: 4058522.

5. Düren DR, Becker AE, and Dunning AJ. Long-term follow-up of idiopathic mitral valve prolapse in 300 patients: a prospective study. J Am Coll Cardiol 1988;11:42–7. https://doi. org/10.1016/0735-1097(88)90164-7; PMID: 3335704.

6. Marks AR, Choong CY, Sanfilippo AJ, et al. Identification of high-risk and low-risk subgroups of patients with mitralvalve prolapse. N Engl J Med 1989;320:1031–6. https://doi. org/10.1056/NEJM198904203201602; PMID: 2927482.

7. Avierinos JF, Gersh BJ, Melton LJ, et al. Natural history of asymptomatic mitral valve prolapse in the community.

Circulation 2002:106:1355–61. https://doi.org/10.1161/01.

CIR.0000028933.34260.09; PMID: 12221052.

8. Basso C, Perazzolo Marra M, Rizzo S, et al. Arrhythmic mitral valve prolapse and sudden cardiac death. Circulation 2015;132:556–66. https://doi.org/10.1161/ CIRCULATIONAHA.115.016291; PMID: 26160859.

9. Gornick CC, Tobler HG, Pritzker MC, et al. Electrophysiologic effects of papillary muscle traction in the intact heart.

Circulation 1986;73:1013–21. https://doi.org/10.1161/01.

CIR.73.5.1013; PMID: 3698223.

10. Kaufmann RL, Lab MJ, Hennekes R, et al. Feedback interaction of mechanical and electrical events in the isolated mammalian ventricular myocardium (cat papillary muscle). Pflügers Arch 1971;324:100–23. https://doi. org/10.1007/BF00592656; PMID: 5102600.

11. Spear JF, EN Moore. A comparison of alternation in myocardial action potentials and contractility. Am J Physiol 1971;220:1708–16. https://doi.org/10.1152/ ajplegacy.1971.220.6.1708; PMID: 5087820.

12. Lab MJ. Contraction-excitation feedback in myocardium.

Physiological basis and clinical relevance. Circ Res 1982;50:757–66. https://doi.org/10.1161/01.RES.50.6.757; PMID: 6282491.

13. Lab MJ. Mechanically dependent changes in action potentials recorded from the intact frog ventricle. Circ Res 1978;42:519–28. https://doi.org/10.1161/01.RES.42.4.519; PMID: 630669.

14. Liu MB, Vandersickel N, Panfilov AV, et al. R-from-T as a common mechanism of arrhythmia initiation in long QT syndromes. Circ Arrhythmia Electrophysiol 2019;12:e007571. https://doi.org/10.1161/CIRCEP.119.007571; PMID: 31838916.

15. Vandersickel N, de Boer TP, Vos MA, et al. Perpetuation of torsade de pointes in heterogeneous hearts: competing foci or re-entry? J Physiol 2016;594:6865–78. https://doi. org/10.1113/JP271728; PMID: 26830210.

16. Myerburg RJ, Nilsson K, Gelband H. Physiology of canine intraventricular conduction and endocardial excitation. Circ Res 1972;30:217–43. https://doi.org/10.1161/01.RES.30.2.217; PMID: 5061320.

17. Boyle PM, Franceschi WH, Constantin M, et al. New insights on the cardiac safety factor: unraveling the relationship between conduction velocity and robustness of propagation. J Mol Cell Cardiol 2019;128:117–28. https://doi. org/10.1016/j.yjmcc.2019.01.010; PMID: 30677394.

18. Boyle PM, Vigmond EJ. An intuitive safety factor for cardiac propagation. Biophys J 2019;98:L57–9. https://doi. org/10.1016/j.bpj.2010.03.018; PMID: 20550885.

19. Berenfeld O, Jalife J. Purkinje-muscle reentry as a mechanism of polymorphic ventricular arrhythmias in a 3-dimensional model of the ventricles. Circ Res 1998;82:1063–77. https://doi.org/10.1161/01.RES.82.10.1063; PMID: 9622159.

20. Valderrábano M, Lee MH, Ohara T, et al. Dynamics of intramural and transmural reentry during ventricular fibrillation in isolated swine ventricles. Circ Res

2001;88:839–48. https://doi.org/10.1161/hh0801.089259; PMID: 11325877.

21. Kim YH, Xie F, Yashima M, et al. Role of papillary muscle in the generation and maintenance of reentry during ventricular tachycardia and fibrillation in isolated swine right ventricle. Circulation 1999;100:1450–9. https://doi. org/10.1161/01.CIR.100.13.1450; PMID: 10500048.

22. Santoro F, Di Biase L, Hranitzky P, et al. Ventricular fibrillation triggered by PVCs from papillary muscles: clinical features and ablation. J Cardiovasc Electrophysiol 2014;25:1158–64. https://doi.org/10.1111/jce.12478; PMID: 24946987.

23. Doppalapudi H, Yamada T, McElderry HT, et al. Ventricular tachycardia originating from the posterior papillary muscle in the left ventricle: a distinct clinical syndrome. Circ Arrhythm Electrophysiol 2008;1:23–9. https://doi.org/10.1161/ CIRCEP.107.742940; PMID: 19808390.

24. Kitkungvan D, Nabi F, Kim RJ, et al. Myocardial fibrosis in patients with primary mitral regurgitation with and without prolapse. J Am Coll Cardiol 2018;72:823–34. https://doi. org/10.1016/j.jacc.2018.06.048; PMID: 30115220.

25. Syed FF, Ackerman MJ, McLeod CJ, et al. Sites of successful ventricular fibrillation ablation in bileaflet mitral valve prolapse syndrome. Circ Arrhythmia Electrophysiol 2016;9:e004005. https://doi.org/10.1161/CIRCEP.116.004005; PMID: 27103091.

26. Avierinos JF, Inamo J, Grigioni F, et al. Sex differences in morphology and outcomes of mitral valve prolapse. Ann Intern Med 2008;149:787–94. https://doi.org/10.7326/00034819-149-11-200812020-00003; PMID: 19047025.

27. Naksuk N, Syed FF, Krittanawong C, et al. The effect of mitral valve surgery on ventricular arrhythmia in patients with bileaflet mitral valve prolapse. Indian Pacing Electrophysiol J 2016;16:187–91. https://doi.org/10.1016/j. ipej.2016.10.009; PMID: 28401865.

28. Wei M, Thomas M, Do D, et al. Ventricular arrhythmias in mitral valve prolapse. J Am Coll Cardiol 2019;73(Suppl 1):493. https://doi.org/10.1016/S0735-1097(19)31101-5.

29. Kligfield P, Hochreiter C, Kramer H, et al. Complex arrhythmias in mitral regurgitation with and without mitral valve prolapse: Contrast to arrhythmias in mitral valve prolapse without mitral regurgitation. Am J Cardiol 1985;55:1545–9. https://doi.org/10.1016/00029149(85)90970-1; PMID: 4003297.

30. Essayagh B, Sabbag A, Antoine C, et al. Presentation and outcome of arrhythmic mitral valve prolapse. J Am Coll Cardiol 2020;76:637–49. https://doi.org/10.1016/j. jacc.2020.06.029; PMID: 32762897.

31. Zuppiroli A, Mori F, Favilli S, et al. Arrhythmias in mitral valve prolapse: Relation to anterior mitral leaflet thickening, clinical variables, and color Doppler echocardiographic parameters. Am Heart J 1994;128:919–27. https://doi. org/10.1016/0002-8703(94)90590-8; PMID: 7942485.

32. Widmer F. Arrhythmic mitral valve prolapse. Cardiovasc Med 2019;22:w02075. https://doi.org/10.4414/cvm.2019.02075.

33. Muthukumar L, Rahman F, Jan MF, et al. The Pickelhaube sign: novel echocardiographic risk marker for malignant mitral valve prolapse syndrome. JACC Cardiovascular Imaging 2017;10:1078–80. https://doi.org/10.1016/j.jcmg.2016.09.016; PMID: 28017396.

34. Dejgaard LA, Skjølsvik ET, Lie ØH, et al. The mitral annulus disjunction arrhythmic syndrome. J Am Coll Cardiol 2018;72:1600–9. https://doi.org/10.1016/j.jacc.2018.07.070; PMID: 30261961.

35. Carmo P, Andrade MJ, Aguiar C, et al. Mitral annular disjunction in myxomatous mitral valve disease: a relevant abnormality recognizable by transthoracic echocardiography. Cardiovasc Ultrasound 2010;8:53. https:// doi.org/10.1186/1476-7120-8-53; PMID: 21143934.

36. Han HC, Ha FJ, Teh AW, et al. Mitral valve prolapse and sudden cardiac death: a systematic review. J Am Heart Assoc 2018;7:e010584. https://doi.org/10.1161/JAHA.118.010584; PMID: 30486705.

37. Marra MP, Basso C, De Lazzari M, et al. Morphofunctional abnormalities of mitral annulus and arrhythmic mitral valve prolapse. Circ Cardiovasc Imaging 2016;9:e005030. https://doi.org/10.1161/CIRCIMAGING.116.005030; PMID: 27516479.

38. Scheirlynck E, Dejgaard LA, Skjølsvik E, et al. Increased levels of sST2 in patients with mitral annulus disjunction and ventricular arrhythmias. Open Heart 2019;6:e001016. https:// doi.org/10.1136/openhrt-2019-001016; PMID: 31168386.

39. Bogun F, Desjardins B, Crawford T, et al. Post-infarction

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW Access at: www.AERjournal.com

37

ventricular arrhythmias originating in PM. J Am Coll Cardiol 2008;51:1794–802. https://doi.org/10.1016/j.jacc.2008.

01.046; PMID: 18452787.

40. Van Herendael H, Zado ES, Haqqani H, et al. Catheter ablation of ventricular fibrillation: Importance of left ventricular outflow tract and papillary muscle triggers. Heart Rhythm 2014;11:566–73. https://doi.org/10.1016/j. hrthm.2013.12.030; PMID: 24398086.

41. Yamada H, McElderry HT, Okada T, et al. Idiopathic focal ventricular arrhythmias originating from the anterior papillary muscle in the left ventricle. J Cardiovasc Electrophysiol 2009;20:866–72. https://doi. org/10.1111/j.1540-8167.2009.01448.x; PMID: 19298560.

42. Enriquez A, Shirai Y, Huang J, et al. Papillary muscle ventricular arrhythmias in patients with arrhythmic mitral valve prolapse: electrophysiologic substrate and catheter ablation outcomes. J Cardiovasc Electrophysiol 2019;30:827– 35. https://doi.org/10.1111/jce.13900; PMID: 30843306.

43. Yamada T, Doppalapudi H, McElderry HT, et al. Idiopathic ventricular arrhythmias originating from the papillary muscles in the left ventricle: prevalence, electrocardiographic and electrophysiological characteristics, and results of the radiofrequency catheter ablation. J Cardiovasc Electrophysiol 2010;21:62–9. https://doi. org/10.1111/j.1540-8167.2009.01594.x; PMID: 19793147.

44. Al’Aref SJ, Ip JE, Markowitz SM, et al. Differentiation of papillary muscle from fascicular and mitral annular ventricular arrhythmias in patients with and without structural heart disease. Circ Arrhythmia Electrophysiol 2015;8:616–24. https://doi.org/10.1161/CIRCEP.114.002619; PMID: 25925230.

45. Good E, Desjardins B, Jongnarangsin K, et al. Ventricular arrhythmias originating from a papillary muscle in patients without prior infarction: a comparison with fascicular arrhythmias. Heart Rhythm 2008;5:1530–7. https://doi. org/10.1016/j.hrthm.2008.08.032; PMID: 18984528.

46. Yamada T, Doppalapudi H, McElderry HT, et al.

Electrocardiographic and electrophysiological characteristics in idiopathic ventricular arrhythmias originating from the papillary muscles in the left ventricle relevance for catheter ablation. Circ Arrhythmia Electrophysiol 2010;3:324–31. https://doi.org/10.1161/CIRCEP.109.922310; PMID: 20558848.

47. Rivera S, Tomas L, de la Paz Ricapito M, et al. Updated results on catheter ablation of ventricular arrhythmias arising from the papillary muscles of the left ventricle. J Arrhythmia 2019;35:99–108. https://doi.org/10.1002/ joa3.12137; PMID: 30805050.

48. Seiler J, Lee JC, Roberts-Thomson KC, et al. Intracardiac echocardiography guided catheter ablation of incessant ventricular tachycardia from the posterior papillary muscle causing tachycardia-mediated cardiomyopathy. Heart Rhythm 2009;6:389–92. https://doi.org/10.1016/j.hrthm.2008.11.029; PMID: 19251217.

49. Latchamsetty R, Yokokawa M, Morady F, et al. Multicenter outcomes for catheter ablation of idiopathic premature ventricular complexes. JACC Clin Electrophysiol 2015;1:116–23. https://doi.org/10.1016/j.jacep.2015.04.005; PMID: 29759353.

50. Rivera S, de la Paz Ricapito M, Tomas L, et al. Results of cryoenergy and radiofrequency-based catheter ablation for treating ventricular arrhythmias arising from the papillary muscles of the left ventricle, guided by intracardiac echocardiography and image integration. Circ Arrhythmia Electrophysiol 2016;9:e003874. https://doi.org/10.1161/ CIRCEP.115.003874; PMID: 27069089.

51. Gordon JP, Liang JJ, Pathak RK, et al. Percutaneous cryoablation for papillary muscle ventricular arrhythmias after failed radiofrequency catheter ablation. J Cardiovasc Electrophysiol 2018;29:1654–63. https://doi.org/10.1111/ jce.13716; PMID: 30106213.

52. Latchamsetty R, Bogun F. Papillary muscle arrhythmias: to freeze or to burn, that is the question. Circ Arrhythm Electrophysiol 2016;9:e004078. https://doi.org/10.1161/ CIRCEP.116.004078; PMID: 27069092.

53. Solimene F, Schillaci V, Shopova G, et al. High-resolution mapping and ablation of recurrent left lateral accessory pathway conduction. J Arrhythmia 2017;33:328–9. https://doi. org/10.1016/j.joa.2016.12.003; PMID: 28765765.

54. Wo HT, Liao FC, Chang PC, et al. Circumferential ablation at the base of the left ventricular papillary muscles: a highly effective approach for ventricular arrhythmias originating from the papillary muscles. Int J Cardiol 2016;220:876–82. https://doi.org/10.1016/j.ijcard.2016.06.151; PMID: 27400187.

Clinical Arrhythmias

Dynamic High-density Functional Substrate Mapping Improves Outcomes in Ischaemic Ventricular Tachycardia Ablation: Sense Protocol Functional Substrate Mapping and Other Functional Mapping Techniques Nikolaos Papageorgiou

1

and Neil T Srinivasan

1,2,3

1. Department of Cardiac Electrophysiology, Barts Heart Centre, St Bartholomew’s Hospital, London, UK; 2. Institute of Cardiovascular Science, University College London, London, UK; 3. Department of Cardiac Electrophysiology, Essex Cardiothoracic Centre, Basildon, UK

Abstract

Post-infarct-related ventricular tachycardia (VT) occurs due to reentry over surviving fibres within ventricular scar tissue. The mapping and ablation of patients in VT remains a challenge when VT is poorly tolerated and in cases in which VT is non-sustained or not inducible. Conventional substrate mapping techniques are limited by the ambiguity of substrate characterisation methods and the variety of mapping tools, which may record signals differently based on their bipolar spacing and electrode size. Real world data suggest that outcomes from VT ablation remain poor in terms of freedom from recurrent therapy using conventional techniques. Functional substrate mapping techniques, such as single extrastimulus protocol mapping, identify regions of unmasked delayed potentials, which, by nature of their dynamic and functional components, may play a critical role in sustaining VT. These methods may improve substrate mapping of VT, potentially making ablation safer and more reproducible, and thereby improving the outcomes. Further large-scale studies are needed.

Keywords

Ventricular tachycardia, ablation, substrate mapping, functional substrate mapping Disclosure: NTS has received speaker fees from Abbot. NP has no conflicts of interest to declare.

Received: 29 June 2020 Accepted: 10 December 2020 Citation: Arrhythmia & Electrophysiology Review 2021;10(1):38–44. DOI: https://doi.org/10.15420/aer.2020.28 Correspondence: Neil T Srinivasan, Department of Cardiac Electrophysiology, The Essex Cardiothoracic Centre, Basildon, Essex SS16 5NL, UK. E: neil.srinivasan@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 non-commercial purposes, provided the original work is cited correctly.

the tachycardia.8 This led to the development of entrainment mapping techniques (Figure 1 ) pioneered by Stevenson et al.4,9 The process involves applying stimuli within regions of myocardium thought to be part of the VT circuit, and assessing the timing of the return cycle.

Entrainment mapping of VT remains the gold standard for identifying critical sites for ablation of VT, but this technique remains a challenge in patients in whom VT is poorly tolerated or non-sustained.4,9 Additionally, the process can be time consuming, requiring serial roving of the catheter to critical regions, pacing manoeuvres and measurement of time intervals. The challenges and limitations of this methodology have been previously reviewed.10 Commonly this technique is performed with a 3.5 mm tip ablation catheter that contains a relatively widely spaced bipole, increasing the susceptibility to far-field signals or far-field capture. Such pitfalls of entrainment are well-documented.11

In the context of ischaemic heart disease, ventricular tachycardia (VT) occurs due to reentry over what are classically thought to be fixed anatomical structures. The most common cause of a structural barrier is scar tissue, and remodelling over time within the scar results in regions of patchy and poorly coupled recovered fibres that serve as surviving electrical channels for slow conduction.1–3 These channels within the scar contain regions of slow conduction and conduction block, creating an environment in which protected isthmuses can sustain VT.1,2 Reentrant circuits most commonly involve VT traversing a circuitous, and often zigzag course through these surviving fibres before exiting from a stable location to activate the entire myocardium, before returning in diastole into the scar region.1,4,5 A single substrate region may facilitate multiple VT circuits, via multiple channels and exits, and may evolve over time to facilitate new circuits due to abnormal remodelling, resulting in recurrent VT. Treatment with anti-arrhythmic drugs, which predominantly act to delay recovery from excitation or slow conduction, often fails to prevent reentry, and largescale studies confirm their poor efficacy.6,7 Thus catheter ablation of VT remains the mainstay of treatment for patients with VT when conservative measures fail. This review summarises current VT ablation techniques as well as emerging data on functional assessment of substrate characteristics.

Activation Mapping

Activation mapping, similar to entrainment mapping of VT, relies on mapping in VT and carries similar limitations. It involves the collection of the timing points of the majority of the VT circuit, which then enables the construction of a colour map of activation, and visual classification of the critical isthmus. New high-density mapping systems may allow complete characterisation of VT circuits in suitable patients, suggesting that VT circuits may be more complex than the standard entrainment models described, with regions of slow conduction at the entrances and exits of VT isthmuses.9,12

Conventional Ablation Techniques and Outcomes Entrainment Mapping

Early catheter mapping studies were able to identify that complex signals with decremental properties are present within the diastolic pathway of

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Functional Substrate Mapping of Ventricular Tachycardia Figure 1: Ventricular Entrainment Outer loop Manifest fusion PPI ≥VTCL +30 ms

Central isthmus PPI = VTCL ±30 ms Stim-QRS = EGM-QRS Stim-QRS = 30–50% TCL

Bystander Concealed fusion PPI > +30 ms VTCL Stim-QRS > EGM-QRS

catheters favouring the delineation of higher definition near-field components.12 Another limitation is that LAVA and LPs may play a bystander or an active role in the VT circuit, and there is no clear way to differentiate between these regions. The use of new high-density mapping catheters may help to identify important electrogram features such as LPs with low amplitude and short duration, which may better delineate the VT isthmus.26

Isthmus entrance Concealed fusion PPI = VTCL ±30 ms Stim-QRS = EGM-QRS Stim-QRS = 50–70% TCL

Inner loop Concealed fusion PPI = VTCL ±30 ms Stim-QRS = EGM-QRS Stim-QRS >70% TCL

Outcomes

Outcomes from VT ablation vary, with an average freedom from appropriate ICD shock of 72% for ablation versus 60% for medical therapy in the major randomised trials.27 This highlights the fact that current ablation strategies do not decrease the mortality rates, although reduced hospitalisation, improved quality of life and greater cost-effectiveness have been noted with VT ablation.28,29 Additionally, real world outcomes may be worse than in the controlled environments of many trials: outcomes as poor as 44%, major complication rates of up to 12%, a 3.5% rate of cardiac tamponade and a rate of death of up to 2.7% at 30 days have been reported.30 Thus, there is a need for improvements in real world ablation strategies, both to improve the outcomes and safety of the procedure, and to offer patients a better standard of care. Non-inducibility at the end of ablation has been shown to be a strong predictor of outcome, but this is not always achieved in clinical practice.31,32

Isthmus exit Concealed fusion PPI = VTCL ±30 ms Stim-QRS = EGM-QRS Stim-QRS <30% TCL

Schematic diagram of ventricular tachycardia scar with a central isthmus channel within a region of ventricular scar. Ventricular tachycardia enters via a central isthmus (red), before exiting and looping around the scar. The scar contains multiple channels, some of which may not be part of the critical isthmus. Entrainment criteria to define different regions within the scar are shown. The blue area represents the inner loop or bystander regions. EGM-QRS = electrogram; PPI = postpacing interval; Stim-QRS = stimulation time to QRS on ECG; TCL = tachycardia cycle length; VTCL = VT tachycardia cycle length.

Pace-mapping

Functional Substrate Mapping Requirement for Functional Substrate Assessment

In patients in whom it is not possible to perform entrainment mapping, pace-mapping may be a strategy to identify the critical isthmus.11,13,14 This strategy involves pacing within regions of the heart, to capture regions near the critical isthmus myocardium that result in wavefront exit to the same region as the clinically documented VT, with subsequent matching of the 12-lead ECG (Figure 2). Again, this method has its limitations, including the fact that it is time consuming, that pacing rate may influence QRS morphology due to conduction changes within critical regions, that paced QRS morphology can vary over a narrow range of areas, and that pacing output and catheter size can significantly affect the region of tissue captured, resulting in bystander capture.15 Additionally, the technique is designed to identify the exit site of a reentry circuit, which may not always be the optimal site for ablation.

Classical substrate mapping techniques predominantly involve mapping ventricular scar substrate in intrinsic rhythm, however, VT circuits may be dynamic, and substrate characteristics may not be static or prevalent in intrinsic rhythm. Interrogation of VT initiation from device tracings suggests that VT is frequently triggered by extrasystolic impulses that alter the conduction and refractory properties of the tissue to enable initiation of VT.33,34 This suggests that dynamic substrate changes may unmask critical conduction changes that facilitate functional unidirectional block and reentry, as has been demonstrated in animal and computer models.35,36 In the light of this, functional substrate mapping techniques have been developed, to unmask critical substrate changes that may play a part in VT mapping.

Substrate Mapping

Existing Function Substrate Mapping Techniques Decrement-evoked Potential Mapping

In light of the limitations of the above methods, several substrate mapping and ablation methods have been developed.16,17 The goal of these strategies is to target the abnormal tissue that sustains VT. This is particularly useful when VT is non-sustained or poorly tolerated. Strategies include linear ablation within scar tissue, scar homogenisation, scar dechanneling, core isolation, ablation of late potentials (LPs) and ablation of local abnormal ventricular activity (LAVA).16,18–22 Again all have limitations, including that the definition of scar is variable (dependent on mapping technology and on the technology used to define scar such as MRI), and that the definition of abnormal potentials may be subjective.23,24 LPs are defined on electrograms as double or multiple components separated by an isoelectric or very-low-amplitude interval >50 ms.21 LAVA is defined as sharp high-frequency ventricular potentials, of low amplitude, distinct from the far-field ventricular electrogram occurring any time during or after the far-field ventricular electrogram in sinus rhythm (SR), displaying fractionation or double or multiple components separated by very-lowamplitude signals or an isoelectric interval.22 Specifically, LAVA lateness is affected by the location they are mapped to in the heart. LAVA mapping may miss critical arrhythmogenic substrate, in the septum and other earlyto-activate regions.25 Additionally, the mapping catheter used can significantly affect the substrate characterisation, with multipolar

Decrement-evoked potential (DEEP) mapping utilises drive train pacing at 600 ms (S1) from the right ventricle (RV), followed by the delivery of a single extrastimulus (S2).37,38 The process involves looking at the behaviour of LPs in response to this S1–S2 pacing protocol. If the difference between the time interval measured from surface ventricular far-field signal onset to the local LP bipolar electrogram during the S1 drive, and the same interval measured immediately after the S2 is >10 ms, the LP is defined as a DEEP. The same strategy is used for multicomponent electrograms from which DEEP are identified if their components split by >10 ms after S2. DEEP LPs were co-localised with the regions of the initiation and diastolic circuit of VT more accurately than those areas displaying non-decremental LPs. At 6-month follow up 75% of patients were free of any VT, after ablation to DEEP regions plus further ablation if VT was still inducible.37 This highlights the potential for targeted functional substrate mapping, looking specifically for functional decrement in LP, which may be the precursor to unidirectional block and VT initiation. Although promising, repeated stimuli may be time consuming, and DEEP software is not commercially available, meaning that manual measurement annotation and tagging of regions would be

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Functional Substrate Mapping of Ventricular Tachycardia Figure 2: Pace-mapping

required at present to replicate this technique. This may prolong procedure time, and repeated drive train pacing may risk worsening of heart failure in a cohort of patients who are already unwell with poor ejection fraction (EF), therefore larger scale trials are awaited.

Clinical VT 30

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Evoked Delayed Potential Mapping

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Evoked delayed potential (EDP) mapping similarly uses RV pacing to invoke functional masked substrate changes.39 Electrograms are compared during SR, RV pacing at 500 ms, and short coupled single S1–S2 stimuli. This technique uses a 3.5-mm-tip mapping catheter placed in a stable position. Electrograms are systematically analysed during SR, RV pacing at a fixed rate of 500 ms, and during the application of a single RV extrastimulus (S1–S2) with a coupling interval of 50 ms above the ventricular refractory period, over the presumed infarct area as derived from imaging data (echocardiogram and contrast-enhanced MRI) regardless of local electrogram amplitude or morphology during SR. Sites are examined manually and those exhibiting low-amplitude (<1.5 mV) near-field potentials with conduction delay >10 ms or block in response to RV extrastimuli are categorised as EDPs and annotated on the map.

Substrate modification aimed at EDP elimination is then performed. LPs (onset after QRS complex, separated by an isoelectric segment from the far-field signal >20 ms) during SR or RV pacing without additional conduction delay during RV extrastimuli are not targeted. In an initial study of patients undergoing this procedure compared with a historical cohort of patients matched for left ventricular function and electroanatomical scar area, patients in the hidden substrate group had a higher 1-year VT-free survival (89% versus 73%), suggesting that functional substrate mapping may improve outcomes compared with standard protocols.39 However, again this protocol requires accurate manual electrogram annotation/analysis, which may be time consuming, especially with the use of multi-electrode mapping catheters.

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Representative examples of good and bad pace-mapping compared with clinical VT. VT = ventricular tachycardia.

previously demonstrated dynamic conduction and repolarisation changes within myocardial scar and regions of LP.42 In light of this, we developed a short coupled single extrastimuli protocol (sense protocol; SP) to evoke maladapted conduction delay within the tissue and map these critical regions of slow conduction and hidden abnormal electrograms.43 One of the limitations of the DEEP and EDP mapping methods is the need for multiple pacing, sometimes from multiple sites, which can be time consuming, involve extensive manual annotation and measurement of electrograms, and which risks putting patients into heart failure or poorly tolerated VT through repetitive stimulation. Repetitive stimulation may also cause conduction block during pacing, which may result in failure to see critical slow conduction regions that may play a crucial role in the tachycardia mechanism.22,43 Additionally, interrogation of VT initiation from device tracings suggests that VT is frequently triggered by single extrasystolic impulses, and therefore we developed the SP to replicate the physiological substrate properties of VT initiation.33,34,43 This enables a consistent, easily reproducible functional substrate mapping technique with rapid acquisition of dynamic substrate maps.

Isochronal Late Activation Mapping

Isochronal late activation mapping involves mapping in SR or intrinsic pacing if the patient is pacing dependent.40,41 Although not strictly a dynamic form of mapping, it does endeavour to delineate functional properties within the tissue. Each abnormal electrogram is manually annotated to the offset of the local bipolar electrogram deflection in realtime, signifying the completion of local activation to incorporate the latest local activation into the map.

Mapping Technique

VT substrate maps are acquired with the EnSite Precision mapping system (Abbott) and the Advisor HD Grid Mapping Catheter, Sensor Enabled (Abbott; Figure 3), which is a multipolar mapping catheter containing 16 equally spaced electrodes in a 4 × 4 grid layout (Figure 3). A hexapolar catheter is placed in the RV apex for pacing, with the proximal pole located in the inferior vena cava blood pool to reference for unipolar signals. In view of the finding that VT is frequently triggered by extrasystolic impulses, substrate maps of bipolar voltage and LPs were obtained simultaneously during:

Isochronal crowding is analysed relative to the entire ventricular activation window, and candidate deceleration zones (DZs) are defined as regions with >3 isochrones in a 1 cm radius. Extreme conduction slowing is defined as regions of isochronal crowding with continuous local fractionated activity within the DZ. Electrograms within candidate DZs are manually confirmed to have discontinuous fractionated characteristics or split local activation. Discontinuous electrograms require verification by the operator in real time with the concordant local timing at adjacent sites within 1 cm. Abnormal electrograms without reproducibility and confirmatory neighbouring electrograms are deleted. At 12 months, 70% freedom from VT recurrence (80% in ischaemic cardiomyopathy and 63% in non-ischaemic cardiomyopathy) was achieved.40

• intrinsic or SR; and • the paced beat of a single (without drive train) sensed extrastimulus

from the RV apex (SP) at 20 ms above the effective refractory period, which is applied every fifth beat, in order to allow the conduction properties of the tissue to return to steady state.33,34

Bipolar LP substrate maps are collected using the HD Wave Solution mapping technology of the Advisor HD Grid Mapping Catheter, Sensor Enabled (Abbott), whereby bipolar recording along and across splines is enabled, with the system analysing orthogonal bipolar wavefronts and recording the highest amplitude of the two signals to negate the effect of wavefront directionality. The system is set to annotate the latest LPs identified within the diastolic window. Additionally, the system uses the

Sense Protocol Mapping Practical Considerations

Dynamic changes in conduction and repolarisation within this substrate may form a critical aspect of the tachycardia mechanism when conduction velocity slows dynamically and tissue refractory periods lengthen. We have

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Functional Substrate Mapping of Ventricular Tachycardia Figure 3: Advisor HD Grid Mapping Catheter, Sensor Enabled and Schematic Diagram of the HD Wave Solution

Along splines HD Wave

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The Advisor HD Grid Mapping Catheter, Sensor Enabled consists of 16 equally spaced electrodes arranged in a 4 × 4 grid. Bipolar wavefronts are measured both along and across the splines with the HD Wave Solution software selecting the highest amplitude signal from two orthogonal bipoles, thus combating the problem of bipolar blindness, whereby a wavefront travelling across along the splines would record a low-amplitude signal.

Figure 4: Sense Protocol Colour Maps of Late Potentials/Activation

Figure 5: Functional Behaviour of Late Potentials

A: During sinus rhythm (left), no late potentials (LPs) are seen; during sense protocol (SP) single extrastimuli pacing at this site (right), LP are seen (yellow highlighted area), with splitting of the LPs across several bipoles. B: Pacing from within this region of functional LP via poles D3-4 results in local delay and split LPs (yellow highlighted area best seen in C3-4 and A3-4), with excellent pace-match of the clinical VT (C).

window of interest is set in the mapping system that contains the entire diastolic interval, and the TurboMap feature is used to identify the latest LPs from SP pacing. This enables simultaneous mapping of SR and SP to speed up the mapping process.

For the purposes of scar/voltage delineation, normal myocardium is defined as tissue with a bipolar voltage >1.5 mV, dense scar was defined as a bipolar voltage <0.5 mV, and scar border zone was defined as a bipolar voltage 0.5–1.5 mV.

A: During sinus rhythm substrate mapping there are no late potentials (LPs). B: During single extrastimuli sense protocol mapping there is unmasking of LPs, highlighted in yellow. C: This represents a functional region of slow conduction, located over the site of entrainment (green open circle target point).

Examples From Sense Protocol Mapping

The main principle of functional substrate mapping is to expose hidden substrate and electrogram changes that are functional and which, by nature of their decrement/unmasking, may play an important role in the critical regions of slow conduction within the ventricular scar that facilitate VT. Figure 4 shows an example of a region in which there were no LPs in SR (Figure 4A), but LP were unmasked through SP mapping (Figure 4B); this region correlated with the region of best entrainment on VT mapping (Figure 4C).

Best Duplicate algorithm, which analyses orthogonal bipoles, collecting multiple electrograms beat by beat for a specific point on the map, in order to compare signal amplitude for the collected mapping data; and then automatically selects the electrogram with the highest peak-to-peak voltage in a collected region to display on the map. These features negate the effects of sampling quality, beat-to-beat changes and wavefront in relation to the bipolar orientation on the recorded electrogram. A new

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Functional Substrate Mapping of Ventricular Tachycardia Figure 6: Outcomes from Sense Protocol Mapping VT burden before and after ablation for each patient

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A: 95% reduction in 12-month ICD shock. B: Improved sensitivity and specificity from sense protocol mapping to critical regions of the ventricular tachycardia (VT) circuit defined by entrainment or pace-mapping, compared with sinus rhythm mapping. C: Kaplan–Meier curves demonstrating the probability of ICD shock with institutional protocol versus sense protocol. ATP = anti-tachycardia pacing; AUC = area under the curve; FPP = false-positive proportion; TPP = true-positive proportion. Source A and C: Srinivasan et al. 2020.43 Reproduced with permission from Elsevier under a Creative Commons (CC BY 4.0) licence.

Additionally, in response to the dynamic stress of the SP on the conduction properties, electrograms not only display delay/unmasking, but also display complex splitting of components. Figure 5A shows an example of unmasking of LP during SP mapping, with electrogram splitting and delay, with long fractionated components between them (see splines A1-2 in Figure 5A).

These are markers of functional slow conduction tissue and regional conduction block in response to SP stimuli that are not seen during SR mapping, and pace-mapping from within this region (Figures 5B and 5C) resulted in a good match for the clinical VT (Figure 5C).

is similar to the 75% freedom from VT at 6 months seen with DEEP mapping and the 89% 1-year VT-free survival of EDP mapping compared with 73% in a historical matched cohort.37,39 This may be related to the increased sensitivity and specificity of SP mapping to critical regions of the VT circuit (Figure 6B). SP mapping resulted in a lower probability of ICD shock compared with the standard institutional VT ablation protocol (Figure 6C).43 If regions that display functional changes and delay, dynamically relate to critical circuits within scar and scar border zone in ischaemic VT, this may prove to be an important step in improving success in VT ablation, by minimising the risk of mapping in VT and offering improved functional targets for substrate-guided ablation.

Outcomes of Functional Substrate Mapping

When compared with a case-matched institutional cohort (for age, sex and EF), outcomes from SP VT ablation showed a 90% freedom from VT, compared with 60% in a historical institutional cohort, using conventional mapping methods.43 VT burden was reduced by 95% (Figure 6A).43 This

Conclusion

Despite the improvement in catheter mapping technologies over the last 20 years, long-term outcomes of VT ablation continue to remain poor in real

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Functional Substrate Mapping of Ventricular Tachycardia world data.30 Activation and entrainment mapping of VT is limited in patients in whom VT is not inducible or not tolerated, and puts patients at risk of decompensation in terms of cardiac and renal function due to the neurohormonal consequences of VT. Additionally, activation/entrainment mapping fails to account for the fact that there may be several channels of tissue capable of sustaining VT, and limiting mapping to induced VTs fails to account for the potential for other regions of diseased tissue to sustain further VT in future. Better understanding of the critical substrate that may facilitate VT is needed. This may be achieved through the use of newer high-density mapping techniques that enable clearer characterisation of the substrate, and through new novel techniques of assessing dynamic substrate changes, aided by the advances in computing power of modern mapping systems.26,43,44 The majority of centres worldwide perform substrate mapping in a static state either during SR or paced rhythm. As a consequence of this, mortality improvements from VT ablation have not been demonstrated in large-scale randomised trials incorporating standard mapping techniques.45 This may be a function of a failure to significantly improve outcomes compared with medical strategies. Emerging data suggest that substrate changes are not static, and that mapping dynamic changes may improve outcomes.43 Larger scale randomised comparator trials are 1. Bakker JM de, Capelle FJ van, Janse MJ, et al. Slow conduction in the infarcted human heart. ‘Zigzag’ course of activation. Circulation 1993;88:915–26. https://doi. org/10.1161/01.CIR.88.3.915; PMID: 8353918.

2. Soejima K, Stevenson WG, Maisel WH, et al. Electrically unexcitable scar mapping based on pacing threshold for identification of the reentry circuit isthmus: feasibility for guiding ventricular tachycardia ablation. Circulation 2002;106:1678–83. https://doi.org/10.1161/01.

CIR.0000030187.39852.A7; PMID: 12270862.

3. Fenoglio JJ Jr, Pham TD, Harken AH, et al. Recurrent sustained ventricular tachycardia: structure and ultrastructure of subendocardial regions in which tachycardia originates. Circulation 1983;68:518–33. https:// doi.org/10.1161/01.CIR.68.3.518; PMID: 6223722.

4. Stevenson WG, Khan H, Sager P, et al. Identification of reentry circuit sites during catheter mapping and radiofrequency ablation of ventricular tachycardia late after myocardial infarction. Circulation 1993;88:1647–70. https:// doi.org/10.1161/01.CIR.88.4.1647; PMID: 8403311.

5. Stevenson WG, Soejima K. Catheter ablation for ventricular tachycardia. Circulation 2007;115:2750–60. https://doi. org/10.1161/CIRCULATIONAHA.106.655720; PMID: 17533195.

6. Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial. JAMA 2006;295:165–71. https://doi.org/10.1001/jama.295.2.165; PMID: 16403928.

7. Boutitie F, Boissel JP, Connolly SJ, et al. Amiodarone interaction with beta-blockers: analysis of the merged EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) databases. The EMIAT and CAMIAT Investigators. Circulation 1999;99:2268–75. https://doi.org/10.1161/01.CIR.99.17.2268; PMID: 10226092.

8. Josephson ME, Horowitz LN, Farshidi A. Continuous local electrical activity. A mechanism of recurrent ventricular tachycardia. Circulation 1978;57:659–65. https://doi. org/10.1161/01.CIR.57.4.659; PMID: 630672.

9. Stevenson WG, Friedman PL, Sager PT, et al. Exploring postinfarction reentrant ventricular tachycardia with entrainment mapping. J Am Coll Cardiol 1997;29:1180–9. https://doi.org/10.1016/S0735-1097(97)00065-X; PMID: 9137211.

10. Graham AJ, Orini M, Lambiase PD. Limitations and challenges in mapping ventricular tachycardia: new technologies and future directions. Arrhythm Electrophysiol Rev 2017;6:118–24. https://doi.org/10.15420/aer.2017.20.1; PMID: 29018519.

11. Tung R. Challenges and pitfalls of entrainment mapping of ventricular tachycardia: ten illustrative concepts. Circ Arrhythm Electrophysiol 2017;10:e004560. https://doi. org/10.1161/CIRCEP.116.004560; PMID: 28408650.

12. Martin R, Maury P, Bisceglia C, et al. Characteristics of scarrelated ventricular tachycardia circuits using ultra-highdensity mapping: a multi-center study. Circ Arrhythm

required to investigate whether functional substrate mapping techniques may improve long-term outcomes and mortality in VT ablation. Additionally, further studies of these techniques in non-ischaemic, septal, intramural and epicardial circuits are required.

Clinical Perspective

• Mapping ventricular tachycardia (VT) remains a challenge due to

the difficulties associated with haemodynamic stability and sustaining VT to enable conventional mapping and entrainment.

• Outcomes from conventional substrate mapping techniques remain poor in real world data.

• VT circuits are known to be dynamic, and emerging functional substrate mapping techniques suggest that unmasking or delay in local electrograms may represent surrogate markers for regions of conduction delay that are critical to the VT circuit.

• Further large-scale randomised studies of VT ablation comparing functional substrate mapping techniques with conventional techniques are required.

Electrophysiol 2018;11:e006569. https://doi.org/10.1161/ CIRCEP.118.006569; PMID: 30354406.

13. Chillou C de, Groben L, Magnin-Poull I, et al. Localizing the critical isthmus of postinfarct ventricular tachycardia: the value of pace-mapping during sinus rhythm. Heart Rhythm 2014;11:175–81. https://doi.org/10.1016/j.hrthm.2013.10.042; PMID: 24513915.

14. Brunckhorst CB, Delacretaz E, Soejima K, et al. Identification of the ventricular tachycardia isthmus after infarction by pace mapping. Circulation 2004;110:652–9. https://doi. org/10.1161/01.CIR.0000138107.11518.AF; PMID: 15289385.

15. Goyal R, Harvey M, Daoud EG, et al. Effect of coupling interval and pacing cycle length on morphology of paced ventricular complexes. Implications for pace mapping.

Circulation 1996;94:2843–9. https://doi.org/10.1161/01.

CIR.94.11.2843; PMID: 8941111.

16. Tzou WS, Frankel DS, Hegeman T, et al. Core isolation of critical arrhythmia elements for treatment of multiple scarbased ventricular tachycardias. Circ Arrhythm Electrophysiol 2015;8:353–61. https://doi.org/10.1161/CIRCEP.114.002310; PMID: 25681389.

17. Santangeli P, Marchlinski FE. Substrate mapping for unstable ventricular tachycardia. Heart Rhythm 2016;13:569– 83. https://doi.org/10.1016/j.hrthm.2015.09.023; PMID: 26410105.

18. Marchlinski FE, Callans DJ, Gottlieb CD, Zado E. Linear ablation lesions for control of unmappable ventricular tachycardia in patients with ischemic and nonischemic cardiomyopathy. Circulation 2000;101:1288–96. https://doi. org/10.1161/01.CIR.101.11.1288; PMID: 10725289.

19. Di Biase L, Santangeli P, Burkhardt DJ, et al. Endo-epicardial homogenization of the scar versus limited substrate ablation for the treatment of electrical storms in patients with ischemic cardiomyopathy. J Am Coll Cardiol 2012;60:132–41. https://doi.org/10.1016/j.jacc.2012.03.044; PMID: 22766340.

20. Berruezo A, Fernández-Armenta J, Andreu D, et al. Scar dechanneling: new method for scar-related left ventricular tachycardia substrate ablation. Circ Arrhythm Electrophysiol 2015;8:326–36. https://doi.org/10.1161/CIRCEP.114.002386; PMID: 25583983.

21. Arenal A, Glez-Torrecilla E, Ortiz M, et al. Ablation of electrograms with an isolated, delayed component as treatment of unmappable monomorphic ventricular tachycardias in patients with structural heart disease. J Am Coll Cardiol 2003;41:81–92. https://doi.org/10.1016/S07351097(02)02623-2; PMID: 12570949.

22. Jaïs P, Maury P, Khairy P, et al. Elimination of local abnormal ventricular activities: a new end point for substrate modification in patients with scar-related ventricular tachycardia. Circulation 2012;125:2184–96. https://doi. org/10.1161/CIRCULATIONAHA.111.043216; PMID: 22492578.

23. Takigawa M, Relan J, Kitamura T, et al. Impact of spacing and orientation on the scar threshold with a high-density grid catheter. Circ Arrhythm Electrophysiol 2019;12:e007158. https://doi.org/10.1161/CIRCEP.119.007158; PMID: 31446771.

24. Wijnmaalen AP, van der Geest RJ, van Huls van Taxis CFB, et al. Head-to-head comparison of contrast-enhanced

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW Access at: www.AERjournal.com

43

magnetic resonance imaging and electroanatomical voltage mapping to assess post-infarct scar characteristics in patients with ventricular tachycardias: real-time image integration and reversed registration. Eur Heart J 2011;32:104–14. https://doi.org/10.1093/eurheartj/ehq345; PMID: 20864488.

25. Komatsu Y, Daly M, Sacher F, et al. Electrophysiologic characterization of local abnormal ventricular activities in postinfarction ventricular tachycardia with respect to their anatomic location. Heart Rhythm 2013;10:1630–7. https://doi. org/10.1016/j.hrthm.2013.08.031; PMID: 23994727.

26. Frontera A, Melillo F, Baldetti L, et al. High-density characterization of the ventricular electrical substrate during sinus rhythm in post-myocardial infarction patients. JACC Clin Electrophysiol 2020;6:799-811. https://doi.org/10.1016/j. jacep.2020.04.008; PMID: 32703562.

27. Maskoun W, Saad M, Abualsuod A, et al. Outcome of catheter ablation for ventricular tachycardia in patients with ischemic cardiomyopathy: a systematic review and metaanalysis of randomized clinical trials. Int J Cardiol 2018;267:107–13. https://doi.org/10.1016/j.ijcard.2018.03.127; PMID: 29655948.

28. Coyle K, Coyle D, Nault I, et al. Cost effectiveness of ventricular tachycardia ablation versus escalation of antiarrhythmic drug therapy: the VANISH trial. JACC Clin Electrophysiol 2018;4:660–8. https://doi.org/10.1016/j. jacep.2018.01.007; PMID: 29798795.

29. Gula LJ, Doucette S, Leong-Sit P, et al. Quality of life with ablation or medical therapy for ventricular arrhythmias: a substudy of VANISH. J Cardiovasc Electrophysiol 2018;29:421– 34. https://doi.org/10.1111/jce.13419; PMID: 29316012.

30. Breitenstein A, Sawhney V, Providencia R, et al. Ventricular tachycardia ablation in structural heart disease: impact of ablation strategy and non-inducibility as an end-point on long term outcome. Int J Cardiol 2019;277:110–7. https://doi. org/10.1016/j.ijcard.2018.08.099; PMID: 30196998.

31. Muser D, Hayashi T, Castro SA, et al. Noninvasive programmed ventricular stimulation-guided management following ventricular tachycardia ablation. JACC Clin Electrophysiol 2019;5:719–27. https://doi.org/10.1016/j. jacep.2019.03.007; PMID: 31221360.

32. Frankel DS, Mountantonakis SE, Zado ES, et al. Noninvasive programmed ventricular stimulation early after ventricular tachycardia ablation to predict risk of late recurrence. J Am Coll Cardiol 2012;59:1529–35. https://doi.org/10.1016/j. jacc.2012.01.026; PMID: 22516442.

33. Roelke M, Garan H, McGovern BA, Ruskin JN. Analysis of the initiation of spontaneous monomorphic ventricular tachycardia by stored intracardiac electrograms. J Am Coll Cardiol 1994;23:117–22. https://doi.org/10.1016/07351097(94)90509-6; PMID: 8277069.

34. Saeed M, Link MS, Mahapatra S, et al. Analysis of intracardiac electrograms showing monomorphic ventricular tachycardia in patients with implantable cardioverterdefibrillators. Am J Cardiol 2000;85:580–7. https://doi. org/10.1016/S0002-9149(99)00815-2; PMID: 11078271.

35. Ciaccio EJ, Coromilas J, Ashikaga H, et al. Model of

Functional Substrate Mapping of Ventricular Tachycardia unidirectional block formation leading to reentrant ventricular tachycardia in the infarct border zone of postinfarction canine hearts. Comput Biol Med 2015;62:254– 63. https://doi.org/10.1016/j.compbiomed.2015.04.032; PMID: 25966920.

36. Baker LC, London B, Choi BR, et al. Enhanced dispersion of repolarization and refractoriness in transgenic mouse hearts promotes reentrant ventricular tachycardia. Circ Res 2000;86:396–407. https://doi.org/10.1161/01.RES.86.4.396; PMID: 10700444.

37. Porta-Sánchez A, Jackson N, Lukac P, et al. Multicenter study of ischemic ventricular tachycardia ablation with decrement-evoked potential (DEEP) mapping with extra stimulus. JACC Clin Electrophysiol 2018;4:307–15. https://doi. org/10.1016/j.jacep.2017.12.005; PMID: 30089555.

38. Jackson N, Gizurarson S, Viswanathan K, et al. Decrement evoked potential mapping: basis of a mechanistic strategy for ventricular tachycardia ablation. Circ Arrhythm Electrophysiol 2015;8:1433–42. https://doi.org/10.1161/

CIRCEP.115.003083; PMID: 26480929.

39. Riva M de, Naruse Y, Ebert M, et al. Targeting the hidden substrate unmasked by right ventricular extrastimulation improves ventricular tachycardia ablation outcome after myocardial infarction. JACC Clin Electrophysiol 2018;4:316–27. https://doi.org/10.1016/j.jacep.2018.01.013; PMID: 30089556.

40. Aziz Z, Shatz D, Raiman M, et al. Targeted ablation of ventricular tachycardia guided by wavefront discontinuities during sinus rhythm: a new functional substrate mapping strategy. Circulation 2019;140:1383–97. https://doi.org/10.1161/ CIRCULATIONAHA.119.042423; PMID: 31533463.

41. Irie T, Yu R, Bradfield JS, et al. Relationship between sinus rhythm late activation zones and critical sites for scarrelated ventricular tachycardia: systematic analysis of isochronal late activation mapping. Circ Arrhythm Electrophysiol 2015;8:390–9. https://doi.org/10.1161/ CIRCEP.114.002637; PMID: 25740836.

42. Srinivasan NT, Orini M, Providencia R, et al. Prolonged

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW Access at: www.AERjournal.com

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action potential duration and dynamic transmural action potential duration heterogeneity underlie vulnerability to ventricular tachycardia in patients undergoing ventricular tachycardia ablation. Europace 2018;21:616–25. https://doi. org/10.1093/europace/euy260; PMID: 30500897.

43. Srinivasan NT, Garcia J, Schilling RJ, et al. Multicenter study of dynamic high-density functional substrate mapping improves identification of substrate targets for ischemic ventricular tachycardia ablation. JACC Clin Electrophysiol 2020;6:1783–93. https://doi.org/10.1016/j.jacep.2020.06.037; PMID: 33357574.

44. Martin R, Hocini M, Haïsaguerre M, et al. Ventricular tachycardia isthmus characteristics: insights from highdensity mapping. Arrhythm Electrophysiol Rev 2019;8:54–9. https://doi.org/10.15420/aer.2018.78.2; PMID: 30918668.

45. 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.

Cardiac Pacing

Leadless Left Ventricular Endocardial Pacing and Left Bundle Branch Area Pacing for Cardiac Resynchronisation Therapy Baldeep S Sidhu ,1,2 Justin Gould ,1,2 Mark K Elliott ,1,2 Vishal Mehta ,1,2 Steven Niederer1 and Christopher A Rinaldi

1,2

1. School of Biomedical Engineering and Imaging Sciences, King’s College London, London, UK; 2. Guy’s and St Thomas’ Hospital, London, UK

Abstract

Cardiac resynchronisation therapy is an important intervention to reduce mortality and morbidity, but even in carefully selected patients approximately 30% fail to improve. This has led to alternative pacing approaches to improve patient outcomes. Left ventricular (LV) endocardial pacing allows pacing at site-specific locations that enable the operator to avoid myocardial scar and target areas of latest activation. Left bundle branch area pacing (LBBAP) provides a more physiological activation pattern and may allow effective cardiac resynchronisation. This article discusses LV endocardial pacing in detail, including the indications, techniques and outcomes. It discusses LBBAP, its potential benefits over His bundle pacing and procedural outcomes. Finally, it concludes with the future role of endocardial pacing and LBBAP in heart failure patients.

Keywords

Cardiac resynchronisation therapy, endocardial pacing, left bundle branch area pacing, WiSE-CRT Disclosure: BSS is funded by NIHR and received speaker fees from EBR Systems outside of the submitted work. JG has received project funding from Rosetrees Trust outside of the submitted work. JG, MKE and VM have received fellowship funding from Abbott outside of the submitted work. CAR receives research funding and/ or consultation fees from Abbott, Medtronic, Boston Scientific and MicroPort outside of the submitted work. SN has no conflicts of interest to declare. The study was supported by the Wellcome/EPSRC Centre for Medical Engineering (WT203148/Z/16/Z).

Acknowledgement: The authors thank Michael Lee and EBR Systems for providing images used in this manuscript.

Received: 5 December 2020 Accepted: 31 December 2020 Citation: Arrhythmia & Electrophysiology Review 2021;10(1):45–50. DOI: https://doi.org/10.15420/aer.2020.46 Correspondence: Baldeep Singh Sidhu, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital, London SE1 7EH, UK. E: baldeep.sidhu@kcl.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 non-commercial purposes, provided the original work is cited correctly.

failure to cannulate the coronary sinus.17 Therefore, given the limitations of epicardial pacing and the need to improve response rates, the role of alternative pacing strategies has become increasingly important.

Cardiac resynchronisation therapy (CRT) is an established treatment for patients with symptomatic heart failure, severe left ventricular (LV) dysfunction and electrical dyssynchrony.1,2 However, even in carefully selected patients, approximately 30% fail to respond, and this has led to the development of alternative pacing strategies to improve patient outcomes.3,4 Conduction system pacing with His bundle pacing (HBP) or left bundle branch area pacing (LBBAP) provides physiological activation using the native conduction system.5 LV endocardial pacing enables access to faster endocardial conduction and site-specific pacing, unlike conventional CRT.6–9 This article will discuss LV endocardial pacing and LBBAP in detail, including the potential benefits and risks of each intervention and future directions.

Endocardial Pacing

Endocardial pacing offers many advantages over epicardial pacing. It enables access to fast endocardial conduction, shorter path length for impulse conduction, a more physiological activation pattern by spreading from the endocardium to the epicardium, a lower pacing capture threshold and a lower risk of phrenic nerve stimulation.6–9 Endocardial pacing is less arrhythmogenic than epicardial pacing and is less affected by myocardial scar location.18 It is also less likely to result in phrenic nerve stimulation such as in epicardial pacing. The greatest potential benefit of endocardial pacing is the ability to pace anywhere inside the left ventricle, enabling the operator to select the optimal pacing site unrestricted by the coronary sinus anatomy. This is particularly attractive in patients with unfavourable characteristics, such as ischemic cardiomyopathy and transmural myocardial scar.

Transvenous Epicardial CRT

Pacing within areas of myocardial scar is associated with poorer outcomes, whereas targeting areas of latest electrical and mechanical activation leads to improved patient outcomes.10–15 Patient-specific pacing that avoids myocardial scar while targeting areas of latest activation is difficult with epicardial CRT because the pacing location is dependent on the coronary sinus anatomy, and the optimal pacing segment may not be subtended by a coronary vein or may result in phrenic nerve stimulation.

Pacing in unfavourable locations will result in inadequate resynchronisation and a suboptimal response.3,16 Furthermore, it is estimated that 8–10% of CRT procedures are unsuccessful due to anatomical constraints, such as

The haemodynamic changes with endocardial and epicardial pacing have been previously studied. In a study of eight anaesthetised dogs with experimental left bundle branch block (LBBB), endocardial pacing was associated with greater electrical resynchronisation, and increase in LV dP/dtmax and stroke work, compared with epicardial pacing.19 Similarly

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Leadless LV Endocardial Pacing and LBBAP Figure 1: Components of the WiSE-CRT System

power is supplied from a remote battery, is the only commercially available leadless LV endocardial pacing system, and will be discussed further.

WiSE-CRT System

in a study of 22 dogs, endocardial pacing resulted in better electrical resynchronisation and haemodynamic changes than epicardial pacing.20 Large human studies comparing epicardial and endocardial pacing are lacking but smaller studies demonstrate the predominant benefit of endocardial pacing, which is its ability to access the optimal pacing site.21–24

The WiSE-CRT system provides leadless LV endocardial pacing to achieve near simultaneous ventricular activation and resynchronisation. The system consists of three components: a submuscular transmitter, connected to a subcutaneous battery, and an endocardial receiver electrode (Figure 1). The system requires the patient to have a co-implant in situ that is capable of producing continuous right ventricular (RV) pacing. The transmitter and battery detect an RV pacing pulse emitted by the co-implant, and the transmitter emits a number of short ultrasound pulses to locate the electrode. Each pulse is converted into electrical energy to identify the electrode location but is of insufficient magnitude to pace the left ventricle. Once identified, the transmitter sends a focused beam of ultrasound energy to the electrode location and this is converted into electrical energy, causing LV capture and simultaneous biventricular pacing in 2–5 ms. The endocardial electrode can be placed anywhere inside the left ventricle but the energy reaching the electrode reduces with an increased angle and distance between the transmitter and electrode. Patients who have an obtuse angle between devices or increased distance, will have insufficient electrode capture, battery depletion and failure of biventricular pacing. The WiSE-CRT system is indicated in patients suitable for CRT.

Delivering Left Ventricular Endocardial Pacing

Transmitter and Battery Implantation

The WiSE-CRT system consists of three components: sub-muscular Transmitter connected to a subcutaneous Battery and an endocardial left ventricular Receiver Electrode. The system requires a co-implant in situ capable of right ventricular pacing.

LV endocardial pacing was initially delivered using leads via an atrial transseptal, transventricular septal or transventricular apical approach.

Several case series report their experience with lead-based endocardial pacing but are limited by the study design and a small patient cohort.25 The ALSYNC study was the largest prospectively collected, multicentre registry investigating the feasibility and safety of LV endocardial pacing, enrolling 138 patients with a failed conventional LV lead, suboptimal coronary sinus anatomy or CRT non-response.26 Patients were predominantly men, with non-ischaemic cardiomyopathy, LBBB, broad QRS duration and severely impaired LV systolic function. Successful procedures were achieved in 89% of patients, 82% of patients had freedom from complications related to the lead delivery system, implant procedure or lead, and 3.8% of patients had non-disabling strokes. At 6 months, the New York Heart Association (NYHA) functional class improved in 59% of patients, and 55% had a reduction in LV end-systolic volume (LVESV) ≥15%.26 Although the response rate in this difficult patient group was promising, the main limitations were the significant rate of cerebrovascular accidents, the need for lifelong anticoagulation, and the low rate of optimal lead placement (leads could be placed in the desired location in only 81% of implants).

Patients must undergo acoustic window screening to be eligible for the device. This involves placing an ultrasound probe in different intercostal spaces to determine if there is an adequate window. Acceptable windows have no lung encroachment during maximal inspiration (Figure 2) and an angle between the probe and basal posterolateral wall <45°, distance <12 cm and LV wall thickness ≥5 mm. These measurements are repeated with the patient lying supine, on their right side, and while sitting upright.

Patients often have more than one intercostal space available for transmitter implantation, enabling the operator to select the optimal site.28 Procedures are predominantly performed under general anaesthesia and can be undertaken in a single-stage or dual-stage procedure, with the latter involving implantation of the battery and transmitter, and the electrode on two separate occasions. The transmitter is always implanted first, is placed on the intercostal muscle and is secured to the costal cartilage, with the battery placed in the adjacent mid-axillary line (Figure 2). Intra-procedural confirmation of an adequate window to the left ventricle using echocardiography is advised to ensure there is no lung encroachment.

Electrode Implantation

Leadless LV pacing offers many advantages over lead-based pacing, including a reduced risk of lead-related issues (including infection), no requirement for lifelong anticoagulation, and potentially a greater selection of pacing sites. Leadless LV pacemakers need to be compact to ensure that they do not interfere with anatomical structures within the left ventricle, the endocardial wall, or outflow tract. Longer devices with broad batteries are more likely to collide with intracardiac structures, and therefore, to reduce this risk of collision while maintaining the volume for the battery, devices must be shorter and thicker.27 The current generation of leadless pacemakers used in the right ventricle are predicted to be able to be placed in only a limited number of LV endocardial sites due to their dimensions,27 highlighting the importance of optimal length/device width ratio. Currently, the WiSE-CRT system (EBR Systems), in which the

The electrode can be implanted via a retrograde aortic approach using arterial access or a transseptal approach using venous access.29 The electrode delivery system is a catheter-based system used for implanting the electrode, consisting of the electrode and delivery catheter (8 Fr) and a steerable delivery sheath (12 Fr). The delivery sheath has a diameter of 4 mm, therefore confirmation of adequate arterial access is recommended prior to the procedure, and this is possible with CT or ultrasound. Dual femoral arterial access can be used with the aid of an aortogram to ensure that the puncture site for the electrode delivery sheath is correctly sited, to reduce the risk of vascular complications. A trans-oesophageal or intracardiac echocardiogram is performed during electrode implantation to ensure that any complications are identified in a timely manner and to facilitate the implantation of the electrode.

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Leadless LV Endocardial Pacing and LBBAP Figure 2: Acoustic Window Screening and WiSE-CRT Implantation A

B

C Sk in Fa t

n Ski Fat scle

Mus

Mu

cle

Rib

Rib

Intercostal muscle

Pigtail catheter

Endothelialised

Anchored

Transmitter

F

Anchoring

Delivery sheath

Site evaluation

E

D

LV endocardium wall

A: Evaluation of the intercostal spaces using an ultrasound probe during acoustic window screening. In this example the whole left ventricle can be viewed during maximal inspiration without any lung encroachment, demonstrating that this space is viable. B–E: WiSE-CRT implantation. The transmitter and battery are implanted first (B,C). B: The transmitter is implanted in the intercostal space identified pre-procedurally. It is placed on the internal intercostal muscle and the wings are sutured onto the costal cartilage of the ribs. C: The transmitter cable is tunnelled to the battery, which is implanted in the adjacent mid-axillary line. D: The electrode is implanted using an electrode delivery system, and the delivery sheath is positioned within the left ventricle using a pigtail catheter. E: Different endocardial sites are evaluated, and the electrode is implanted in three defined stages: anchoring, electrode detachment and electrode release. F: Change in left ventricular (LV) electrogram (EGM) and current of injury (COI), highlighted in pink, during anchoring. ST elevation indicates that the electrode is being anchored into viable myocardial tissue, and fluoroscopy with contrast is required to confirm that it is fully anchored.

LV Post Market Surveillance Registry.30–32 These studies included patients who had a failed LV lead, were considered high-risk for a CRT upgrade or were non-responders to conventional CRT. The WiSE-CRT study was a first-in-man trial, published in 2014, which assessed the feasibility, safety and short-term outcomes of the system in 17 patients.30 That study was stopped early due to a high incidence of pericardial tamponade, occurring in three patients (17.6%). Consequently, the delivery sheath was redesigned to incorporate a balloon at the distal tip to reduce traumatic engagement with the LV endocardium. The feasibility of the WiSE-CRT system using the re-designed delivery sheath was investigated in the SELECT-LV study, involving 35 patients across six centres and was published in 2017.31 The recent publication of the WICS-LV Post Market Surveillance Registry in 2020 determined the safety and efficacy of the WiSE-CRT system in a real-world setting involving 90 patients from 14 European centres.32 The outcomes of the WiSE-CRT system will be discussed further in the following sections using the latter two studies, which have utilised the latest iteration of the redesigned delivery sheath.

The delivery sheath has a balloon at its distal tip, and once access has been achieved the balloon is inflated. The delivery sheath is positioned within the left ventricle and the electrode catheter is inserted. The delivery sheath is slowly advanced to the desired endocardial location. A tight seal between the balloon and the endocardium is confirmed by a flush of contrast, which should be seen coming around the sides of the balloon rather than forwards (Figure 3). The electrode is implanted in a number of defined stages, as follows: 1. Anchoring: a tight seal is maintained between the balloon and the endocardium while the electrode catheter is advanced 1 mm at a time (Figure 3). Simultaneous live fluoroscopy and contrast flushes are used to look for LV tenting. Tenting demonstrates that the electrode tines are still within the cavity of the left ventricle. The electrode is then slowly advanced until there is no tenting, demonstrating that the tines are within the endocardium. The absence of tenting should be confirmed on two orthogonal views, with no contrast beyond the electrode body (Figure 3).

2. Electrode detachment: both the delivery sheath and electrode catheter are kept stable and the electrode is detached, resulting in an indicator change on the catheter and a disturbance on the intracardiac electrogram.

3. Electrode release: under continuous fluoroscopy, the delivery sheath is slowly retracted until it is aligned with the tip of the catheter; they are then withdrawn together. Satisfactory placement of the electrode can be seen on fluoroscopy, and pacing checks are undertaken to ensure that there is appropriate RV tracking and biventricular pacing.

Procedural Success

Procedural success was reported in 34 of 35 patients (97.1%) in the SELECT-LV study, given that one patient had a ventricular arrhythmia.31 Successful procedures occurred in 85 of 90 patients (94.4%) in the WICSLV Post Market Surveillance Registry, with biventricular pacing confirmation after implantation.32 Failure to achieve procedural success was due to failing to exclude unsuitable intercostal spaces during acoustic window screening, pericardial tamponade, transmitter displacement, and implantation of the electrode within suspected myocardial scar.

Response to CRT

Outcomes of the WiSE-CRT System

Overall at 6 months, 84.8% of patients in the SELECT-LV study and 69.8% in the WICS-LV Post Market Surveillance Registry had an improvement in their clinical composite score.31,32 There was also a significant reduction in

Experience and patient outcomes have been reported in three prospective multicentre trials: the WiSE-CRT study, the SELECT-LV study and the WiCS-

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Leadless LV Endocardial Pacing and LBBAP Figure 3: Anchoring of the Endocardial Electrode

A: Good contact between the delivery sheath and endocardium, as demonstrated by the flow of contrast. B: The presence of contrast up to the tip of the electrode indicates inadequate anchoring. C: Partial tenting with contrast around the needle body caused by the five tines, which cannot be seen on fluoroscopy, and further advancement is required. D: No tenting, as indicated by the absence of contrast around the needle. This indicates that the electrode is now fully anchored. E,F: Troubleshooting during implantation of the electrode. E: The electrode has been advanced too far outside the delivery sheath and there is inadequate fluoroscopic magnification, therefore assessment of tenting cannot be reliably made. F: There is partial tenting present and the electrode is not fully anchored.

NYHA functional class, QRS duration, improvement in LV ejection fraction (LVEF) and reduction in both LV end-diastolic volume and LVESV.31,32 Overall, 52–55% of patients had a significant reduction in LVESV ≥15%.

Additionally, guiding in WiSE-CRT procedures by targeting the electrode to areas of latest activation while avoiding myocardial scar using different imaging modalities has been shown to further improve clinical and echocardiographic outcomes.33,34 In patients who fail to improve following conventional CRT and who undergo WiSE-CRT implantation, 55.6% show improvement in their clinical composite score and 66.7% have a reduction in LVESV ≥15% and/or absolute improvement in LVEF ≥5%.35

referred for pacing, 30 of whom (8.8%) required CRT, LBBAP was successful in 89% of procedures, and at 1-year follow up the pacing threshold and R waves remained stable.43 Currently, LBBAP is usually delivered using a SelectSecure 3830 pacing lead (Medtronic), and confirmation is dependent on several criteria, which are currently being updated and validated.5,36,44 The predominant complications of LBBAP relate to the risk of septal perforations and lead dislodgements. LBBAP may be affected by intrinsic conduction and programming optimal atrioventricular delays will be important.40 Several studies have shown this to be effective in improving acute haemodynamics and patient outcomes.36,43,45 Several trials have demonstrated the feasibility of LBBAP for delivering CRT.46–49 In a study of 63 patients with non-ischaemic cardiomyopathy, LVEF ≤50%, complete LBBB and who had an indication for CRT or ventricular pacing, left bundle branch pacing was successful in 97% of cases, and this resulted in a significant improvement in LVEF and NYHA functional class at 1 year.48

Complications

Procedure-related deaths occurred in three of 90 patients (3.3%), with acute complications ≤24 hours after the procedure in 4/90 patients (4.4%), intermediate complications 24 hours–1 month after the procedure in 17 of 90 patients (18.8%), and chronic complications 1–6 months after the procedure in six of 90 patients (6.7%).32 The commonest complications included arterial access complications and cardiac tamponade.

In a large international multicentre study of 325 patients with LVEF <50% and an indication for CRT or pacing, LBBAP was successful in 85% of patients, and this resulted in significant narrowing of the QRS duration, and improvement in LVEF and NYHA functional class at 6 months.49 Unsuccessful procedures were due to failure to penetrate the septum or inadequate resynchronisation; and the presence of LBBB at baseline was found to be an independent predictor of echocardiographic response.49 Additionally, biventricular pacing was compared with both LBBAP and HBP in a nonrandomised observational study of 137 patients with LVEF ≤40%, typical LBBB and referral for CRT.42 It was found that both HBP and left bundle branch pacing resulted in a significant improvement in LVEF and NYHA functional class compared with biventricular pacing at 1-year follow-up.42

Physiological Pacing and LBBAP

LBBAP and HBP restore physiological activation through the native conduction system, and LBBAP may be more feasible than HBP due to a wider target area.5,36 Although HBP has been shown to lead to narrowing of the QRS duration and cardiac resynchronisation in clinical and simulation studies, implantation can be difficult and the success rates vary from 56% to 95%.37–40 Follow-up can be problematic due to oversensing of atrial signals, undersensing of ventricular signals, lead displacement, and rising capture thresholds with premature battery depletion.36 Indeed, robust long-term data on the outcomes of HBP are currently lacking.

Novel LBBAP was developed to bypass the left bundle branch conduction block by screwing a ventricular lead into the interventricular septum to provide LV resynchronisation.41 Studies have shown it may overcome some of the limitations of HBP.36,42,43 In a prospective study of 341 patients

LV septal pacing involves pacing the LV endocardial side of the interventricular septum, and this may provide an alternative approach for cardiac resynchronisation. In a study of 27 patients undergoing CRT,

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Leadless LV Endocardial Pacing and LBBAP Conclusion

temporary LV septal pacing performed via a transaortic approach resulted in a significant reduction in QRS area and standard deviation of activation times, but similar LV dP/dtmax compared with biventricular pacing.50 LV septal pacing may prove to be especially useful in patients who have failed LBBAP, particularly given that the pacing location is relatively large.

Endocardial pacing has many advantages over conventional CRT and has the potential to improve patient outcomes. The WiSE-CRT system allows pacing at a customised location and enables areas of latest activation to be targeted while avoiding myocardial scar. It can lead to clinical improvement, and the ongoing SOLVE-CRT trial will be important in determining its efficacy and safety profile. Physiological pacing with LBBAP has shown promising results in initial trials but its role in CRT requires further investigation. In the future, leadless LBBAP may be achievable but will require technological advances.

Future Directions

LV endocardial pacing with the WiSE-CRT system in prospective registries has demonstrated reliable resynchronisation, improvement of symptoms and reversal of LV remodelling, but the risk of procedural complications requires further evaluation. The ongoing SOLVE-CRT trial is a randomised controlled multicentre trial to assess the safety and efficacy of the WiSE-CRT system, and it will provide important outcome data on the safety and efficacy of leadless LV endocardial pacing.51 In the future, completely leadless pacing and or CRT and defibrillation may be achievable with the incorporation of a Micra transcatheter pacing system (Medtronic), WiSE-CRT system and a subcutaneous ICD (Boston Scientific), but refinements in the technology will be needed before this becomes more widespread.52

Clinical Perspective • Alternative pacing approaches including left ventricular (LV)

endocardial pacing and left bundle branch area pacing (LBBAP) have the potential to provide superior resynchronisation to conventional cardiac resynchronisation therapy (CRT) and to improve response rates.

• Patients undergoing WiSE-CRT implantation should have an assessment of their peripheral arterial vasculature to reduce potential complications. Guiding the electrode to the desired endocardial location can improve patient outcomes.

• Prospective registries have shown that the WiSE-CRT system results in an improved clinical composite score in 70% of patients, and a reduction in LV end-systolic volume ≥15% in 55%.

• LBBAP has the ability to provide physiological pacing and it overcomes many of the problems with His-bundle pacing but its role in CRT requires further investigation.

LBBAP has the potential to improve outcomes in patients eligible for CRT, and future modifications to the equipment will likely further improve procedural success and patient outcomes. Data on the long-term safety profile and outcomes of heart failure patients who undergo LBBAP for CRT are needed to determine whether this will become a viable treatment intervention. Theoretically, the WiSE-CRT electrode could be targeted to achieve leadless left bundle branch stimulation from the LV endocardium, or HBP from the RV endocardium. However, it is likely that refinements of the technology, including modification of the electrode delivery system, will be required to enable targeted physiological pacing.

1. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–49. https://doi. org/10.1056/NEJMoa050496; PMID: 15753115.

2. Bristow MR, Saxon LA, Boehmer J, et al. Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140–50. https://doi.org/10.1056/NEJMoa032423; PMID: 15152059.

3. European Heart Rhythm Association, European Society of Cardiology, Heart Rhythm Society, et al. 2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management. Europace 2012;14:1236–86. https://doi.org/10.1093/europace/eus222; PMID: 22930717.

4. Sidhu BS, Gould J, Sieniewicz BJ, et al. Complications associated with cardiac resynchronization therapy upgrades versus de novo implantations. Expert Rev Cardiovasc Ther 2018;16:607–15. https://doi.org/10.1080/14779072.2018.14987 83; PMID: 29985076.

5. Arnold AD, Whinnett ZI, Vijayaraman P. His-Purkinje conduction system pacing: state of the art in 2020. Arrhythm Electrophysiol Rev 2020;9:136–45. https://doi.org/10.15420/ aer.2020.14; PMID: 33240509.

6. Singh JP, Fan D, Heist EK, et al. Left ventricular lead electrical delay predicts response to cardiac resynchronization therapy. Heart Rhythm 2006;3:1285–92. https://doi.org/10.1016/j.hrthm.2006.07.034; PMID: 17074633.

7. Bordachar P, Ploux S, Lumens J. Endocardial pacing: the wave of the future? Curr Cardiol Rep 2012;14:547–51. https:// doi.org/10.1007/s11886-012-0298-2; PMID: 22825920.

8. Huntjens PR, Walmsley J, Ploux S, et al. Influence of left ventricular lead position relative to scar location on response to cardiac resynchronization therapy: a model study. Europace 2014;16(Suppl 4):iv62–8. https://doi. org/10.1093/europace/euu231; PMID: 25362172.

9. Mendonca Costa C, Neic A, Kerfoot E, et al. Pacing in proximity to scar during cardiac resynchronization therapy increases local dispersion of repolarization and susceptibility to ventricular arrhythmogenesis. Heart Rhythm 2019;16:1475–83. https://doi.org/10.1016/j.hrthm.2019.03.027;

PMID: 30930329.

10. Bleeker GB, Schalij MJ, Van Der Wall EE, Bax JJ. Posterolateral scar tissue resulting in non-response to cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2006;17:899–901. https://doi.org/10.1111/ j.1540-8167.2006.00499.x; PMID: 16903969.

11. Chalil S, Foley PW, Muyhaldeen SA, et al. Late gadolinium enhancement-cardiovascular magnetic resonance as a predictor of response to cardiac resynchronization therapy in patients with ischaemic cardiomyopathy. Europace 2007;9:1031–7. https://doi.org/10.1093/europace/eum133; PMID: 17933857.

12. Gold MR, Birgersdotter-Green U, Singh JP, et al. The relationship between ventricular electrical delay and left ventricular remodelling with cardiac resynchronization therapy. Eur Heart J 2011;32:2516–24. https://doi.org/10.1093/ eurheartj/ehr329; PMID: 21875862.

13. Sohal M, Duckett SG, Zhuang X, et al. A prospective evaluation of cardiovascular magnetic resonance measures of dyssynchrony in the prediction of response to cardiac resynchronization therapy. J Cardiovasc Magn Reson 2014;16:58. https://doi.org/10.1186/s12968-014-0058-0; PMID: 25084814.

14. Behar JM, Mountney P, Toth D, et al. Real-Time X-MRIguided left ventricular lead implantation for targeted delivery of cardiac resynchronization therapy. JACC Clin Electrophysiol 2017;3:803–14. https://doi.org/10.1016/j. jacep.2017.01.018; PMID: 29759775.

15. Behar JM, Rajani R, Pourmorteza A, et al. Comprehensive use of cardiac computed tomography to guide left ventricular lead placement in cardiac resynchronization therapy. Heart Rhythm 2017;14:1364–72. https://doi. org/10.1016/j.hrthm.2017.04.041; PMID: 28479514.

16. Mullens W, Grimm RA, Verga T, et al. Insights from a cardiac resynchronization optimization clinic as part of a heart failure disease management program. J Am Coll Cardiol 2009;53:765–73. https://doi.org/10.1016/j.jacc.2008.11.024; PMID: 19245967.

17. Morgan JM, Delgado V. Lead positioning for cardiac resynchronization therapy: techniques and priorities.

Europace 2009;11 (Suppl 5):v22–8. https://doi.org/10.1093/ europace/eup306; PMID: 19861387.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW Access at: www.AERjournal.com

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18. Mendonca Costa C, Neic A, Gillette K, et al. Left ventricular endocardial pacing is less arrhythmogenic than conventional epicardial pacing when pacing in proximity to scar. Heart Rhythm 2020;17:1262–70. https://doi.org/10.1016/j. hrthm.2020.03.021; PMID: 32272230.

19. van Deursen C, van Geldorp IE, Rademakers LM, et al. Left ventricular endocardial pacing improves resynchronization therapy in canine left bundle-branch hearts. Circ Arrhythm Electrophysiol 2009;2:580–7. https://doi.org/10.1161/ CIRCEP.108.846022; PMID: 19843927.

20. Strik M, Rademakers LM, van Deursen CJ, et al. Endocardial left ventricular pacing improves cardiac resynchronization therapy in chronic asynchronous infarction and heart failure models. Circ Arrhythm Electrophysiol 2012;5:191–200. https:// doi.org/10.1161/circep.111.965814; PMID: 22062796.

21. Spragg DD, Dong J, Fetics BJ, et al. Optimal left ventricular endocardial pacing sites for cardiac resynchronization therapy in patients with ischemic cardiomyopathy. J Am Coll Cardiol 2010;56:774–81. https://doi.org/10.1016/j. jacc.2010.06.014; PMID: 20797490.

22. Derval N, Steendijk P, Gula LJ, et al. Optimizing hemodynamics in heart failure patients by systematic screening of left ventricular pacing sites: the lateral left ventricular wall and the coronary sinus are rarely the best sites. J Am Coll Cardiol 2010;55:566–75. https://doi. org/10.1016/j.jacc.2009.08.045; PMID: 19931364.

23. Behar JM, Jackson T, Hyde E, et al. Optimized left ventricular endocardial stimulation is superior to optimized epicardial stimulation in ischemic patients with poor response to cardiac resynchronization therapy: a combined magnetic resonance imaging, electroanatomic contact mapping, and hemodynamic study to target endocardial lead placement. JACC Clin Electrophysiol 2016;2:799–809. https://doi.org/10.1016/j.jacep.2016.04.006; PMID: 28066827.

24. Sieniewicz BJ, Behar JM, Sohal M, et al. Electrical latency predicts the optimal left ventricular endocardial pacing site: results from a multicentre international registry. Europace 2018;20:1989–96. https://doi.org/10.1093/europace/euy052; PMID: 29688340.

25. Gamble JHP, Herring N, Ginks M, et al. Endocardial left ventricular pacing for cardiac resynchronization: systematic review and meta-analysis. Europace 2018;20:73–81.

Leadless LV Endocardial Pacing and LBBAP https://doi.org/10.1093/europace/euw381; PMID: 28073886.

26. Morgan JM, Biffi M, Geller L, et al. ALternate Site Cardiac ResYNChronization (ALSYNC): a prospective and multicentre study of left ventricular endocardial pacing for cardiac resynchronization therapy. Eur Heart J 2016;37:2118–27. https://doi.org/10.1093/eurheartj/ehv723; PMID: 26787437.

27. Razeghi O, Strocchi M, Lee A, et al. Tracking the motion of intracardiac structures aids the development of future leadless pacing systems. J Cardiovasc Electrophysiol 2020;31:2431–9. https://doi.org/10.1111/jce.14657; PMID: 32639621.

28. DeFaria Yeh D, Lonergan KL, Fu D, et al. Clinical factors and echocardiographic techniques related to the presence, size, and location of acoustic windows for leadless cardiac pacing. Europace 2011;13:1760–5. https://doi.org/10.1093/ europace/eur199; PMID: 21798878.

29. Sieniewicz BJ, Gould JS, Rimington HM, et al. Transseptal delivery of a leadless left ventricular endocardial pacing electrode. JACC Clin Electrophysiol 2017;3:1333–5. https://doi. org/10.1016/j.jacep.2017.04.020; PMID: 29759633.

30. Auricchio A, Delnoy PP, Butter C, et al. Feasibility, safety, and short-term outcome of leadless ultrasound-based endocardial left ventricular resynchronization in heart failure patients: results of the Wireless Stimulation Endocardially for CRT (WiSE-CRT) study. Europace 2014;16:681–8. https:// doi.org/10.1093/europace/eut435; PMID: 24497573.

31. Reddy VY, Miller MA, Neuzil P, et al. Cardiac resynchronization therapy with wireless left ventricular endocardial pacing: the SELECT-LV Study. J Am Coll Cardiol 2017;69:2119–29. https://doi.org/10.1016/j.jacc.2017.02.059; PMID: 28449772.

32. Sieniewicz BJ, Betts TR, James S, et al. Real-world experience of leadless left ventricular endocardial cardiac resynchronization therapy: a multicenter international registry of the WiSE-CRT pacing system. Heart Rhythm 2020;17:1291–7. https://doi.org/10.1016/j.hrthm.2020.03.002; PMID: 32165181.

33. Sieniewicz BJ, Behar JM, Gould J, et al. Guidance for optimal site selection of a leadless left ventricular endocardial electrode improves acute hemodynamic response and chronic remodeling. JACC Clin Electrophysiol 2018;4:860–8. https://doi.org/10.1016/j.jacep.2018.03.011; PMID: 30025684.

34. Sidhu BS, Lee AWC, Haberland U, et al. Combined computed tomographic perfusion and mechanics with

predicted activation pattern can successfully guide implantation of a wireless endocardial pacing system.

Europace 2020;22:298. https://doi.org/10.1093/europace/ euz227; PMID: 31504436.

35. Sidhu BS, Porter B, Gould J, et al. Leadless left ventricular endocardial pacing in nonresponders to conventional cardiac resynchronization therapy. Pacing Clin Electrophysiol 2020;43:966–73. https://doi.org/10.1111/pace.13926; PMID: 32330307.

36. Padala SK, Ellenbogen KA. Left bundle branch pacing is the best approach to physiological pacing. Heart Rhythm O2 2020;1:59–67. https://doi.org/10.1016/j.hroo.2020.03.002.

37. Bhatt AG, Musat DL, Milstein N, et al. The efficacy of His bundle pacing: lessons learned from implementation for the first time at an experienced electrophysiology center. JACC Clin Electrophysiol 2018;4:1397–1406. https://doi.org/https:// doi.org/10.1016/j.jacep.2018.07.013; PMID: 30466843.

38. Vijayaraman P, Chung MK, Dandamudi G, et al. His bundle pacing. J Am Coll Cardiol 2018;72:927–47. https://doi. org/10.1016/j.jacc.2018.06.017; PMID: 30115232.

39. Sharma PS, Vijayaraman P, Ellenbogen KA. Permanent His bundle pacing: shaping the future of physiological ventricular pacing. Nat Rev Cardiol 2020;17:22–36. https:// doi.org/10.1038/s41569-019-0224-z; PMID: 31249403.

40. Strocchi M, Lee AWC, Neic A, et al. His-bundle and left bundle pacing with optimized atrioventricular delay achieve superior electrical synchrony over endocardial and epicardial pacing in left bundle branch block patients. Heart Rhythm 2020;17:1922–9. https://doi.org/10.1016/j. hrthm.2020.06.028; PMID: 32603781.

41. 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;33:1736.e1–3. https://doi.org/10.1016/j.cjca.2017.09.013; PMID: 29173611.

42. Wu S, Su L, Vijayaraman P, et al. Left bundle branch pacing for cardiac resynchronization therapy: nonrandomized on-treatment comparison with His bundle pacing and biventricular pacing. Can J Cardiol 2021;37:319–28. https:// doi.org/10.1016/j.cjca.2020.04.037; PMID: 32387225.

43. Padala SK, Master VM, Terricabras M, et al. Initial experience, safety, and feasibility of left bundle branch area pacing: a multicenter prospective study. JACC Clin Electrophysiol 2020;6:1773–82. https://doi.org/10.1016/j. jacep.2020.07.004; PMID: 33357573.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW Access at: www.AERjournal.com

50

44. 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.

45. Chen K, Li Y, Dai Y, et al. Comparison of electrocardiogram characteristics and pacing parameters between left bundle branch pacing and right ventricular pacing in patients receiving pacemaker therapy. Europace 2019;21:673–80. https://doi.org/10.1093/europace/euy252; PMID: 30462207.

46. Vijayaraman P, Subzposh FA, Naperkowski A, et al.

Prospective evaluation of feasibility and 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.

47. 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.

48. Huang W, Wu S, Vijayaraman P, et al. Cardiac resynchronization therapy in patients with nonischemic cardiomyopathy using left bundle branch pacing. JACC Clin Electrophysiol 2020;6:849–58. https://doi.org/10.1016/j. jacep.2020.04.011; PMID: 32703568.

49. Vijayaraman P, Ponnusamy S, Cano Ó, et al. Left bundle branch area pacing for cardiac resynchronization therapy: results from the International LBBAP Collaborative Study Group. JACC Clin Electrophysiol 2020. https://doi.org/10.1016/j. jacep.2020.08.015; epub ahead of press.

50. Salden F, Luermans J, Westra SW, et al. Short-term hemodynamic and electrophysiological effects of cardiac resynchronization by left ventricular septal pacing. J Am Coll Cardiol 2020;75:347–59. https://doi.org/10.1016/j. jacc.2019.11.040; PMID: 32000945.

51. Singh JP, Abraham WT, Auricchio A, et al. Design and rationale for the Stimulation Of the Left Ventricular Endocardium for Cardiac Resynchronization Therapy in nonresponders and previously untreatable patients (SOLVE-CRT) trial. Am Heart J 2019;217:13–22. https://doi.org/10.1016/j. ahj.2019.04.002; PMID: 31472360.

52. Sidhu BS, Gould J, Porter B, et al. Completely leadless cardiac resynchronization defibrillator system. JACC Clin Electrophysiol 2020;6:588–9. https://doi.org/10.1016/j. jacep.2020.02.012; PMID: 32439047.

Cardiac Pacing

Conduction System Pacing for Cardiac Resynchronisation Parikshit S Sharma

1

and Pugazhendhi Vijayaraman

2

1. Rush University Medical Center, Chicago, IL, US; 2. Geisinger Heart Institute, Wilkes-Barre, PA, US

Abstract

Conduction system pacing (CSP) is a technique of pacing that involves implantation of permanent pacing leads along different sites of the cardiac conduction system and includes His bundle pacing and left bundle branch pacing. There is an emerging role for CSP to achieve cardiac resynchronisation in patients with heart failure with reduced ejection fraction and inter-ventricular dyssynchrony. In this article, the authors review these strategies for resynchronisation and the available data on the use of CSP in overcoming dyssynchrony.

Keywords

Biventricular pacing, cardiac resynchronisation therapy, conduction system pacing, heart failure, His bundle pacing, left bundle branch block, left bundle branch pacing, right bundle branch block, ventricular dyssynchrony Disclosure: PSS has received honoraria from Medtronic and is a consultant for Abbott, Biotronik, Boston Scientific and Medtronic; PV has received honoraria and does research for Medtronic, and is a consultant for Abbott, Biotronik, Boston Scientific and Medtronic and has patented a His bundle pacing delivery tool.

Received: 3 December 2020 Accepted: 1 February 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(1):51–58. DOI: https://doi.org/10.15420/aer.2020.45 Correspondence: Pugazhendhi Vijayaraman, Geisinger Heart Institute, Geisinger Wyoming Valley Medical Center, MC 36–10, 1000 E Mountain Blvd, Wilkes-Barre, PA 18711, US. E: pvijayaraman1@geisinger.edu; pvijayaraman@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 non-commercial purposes, provided the original work is cited correctly.

Traditional Biventricular CRT

Conduction system pacing (CSP) is a therapy that involves the placement of permanent pacing leads along different sites of the cardiac conduction system with the intent of overcoming sites of atrioventricular (AV) conduction disease and delay, thereby providing a pacing solution that results in more synchronised biventricular activation. Lead placement for CSP can be targeted either at the bundle of His, known as His bundle pacing (HBP), or at the region of the left bundle branch (LBB), known as LBB pacing (LBBP). HBP was first described by Deshmukh et al. in 2000.1

BVP is the conventional form of CRT (BVP-CRT). It is as an integral part of therapy for patients with HF with depressed left ventricular ejection fraction (LVEF) and a wide QRS, which implies inter-ventricular dyssynchrony.

Several large, randomised studies have demonstrated improved quality of life, increased exercise capacity, reduced HF hospitalisation and decreased all-cause mortality with the use of traditional BVP-CRT.7–12 The patients who derive the most benefit from BVP-CRT are those with HF with reduced ejection fraction (HFrEF) and left bundle branch block (LBBB). BVP-CRT may also benefit patients who develop an RV pacing-induced cardiomyopathy (PICM), which is another form of ventricular dyssynchrony, and patients with a low LVEF undergoing implantation of a new or replacement pacemaker or ICD with an anticipated requirement for a significant percentage (>40%) of ventricular pacing.13,14

There are a number of observational studies that have demonstrated the clinical benefits of HBP over conventional right ventricular (RV) pacing.2–5 LBBP was first described by Huang et al. in 2018 and involves placement of a pacing lead through the inter-ventricular septum closer to the main trunk of the LBB, bypassing areas of AV conduction disease.6 Over the past decade, these techniques have gained significant popularity and specific tools have been designed to enhance lead delivery.

However, about 30% of patients receiving BVP-CRT do not derive a detectable clinical or echocardiographic benefit and some worsen after resynchronisation.7,9,15 Anatomical limitations such as lack of suitable venous branches and unavoidable phrenic nerve stimulation at suitable anatomic LV lead positions affect the success of coronary sinus lead implantation. Finally, certain subsets of patients, such as patients with HFrEF and RBBB or patients with a narrow QRS duration (QRSd) and need for ventricular pacing, may not derive a significant benefit and hence may not be ideal for traditional BVP-CRT.16

Cardiac resynchronisation therapy (CRT), which has traditionally been performed using biventricular pacing (BVP), in addition to guideline directed medical therapy, is the cornerstone treatment for patients with cardiomyopathy, heart failure (HF) and ventricular dyssynchrony.7 Although not a new concept, HBP and LBBP have been successful in overcoming bundle branch block (BBB) and result in ventricular synchrony, particularly in patients with more proximal disease. This has allowed the use of these strategies for CRT, either as a first-line therapy or as a rescue strategy when BVP fails.

Conduction System Pacing for CRT

Permanent HBP was first described by Deshmukh et al. for maintenance of inter-ventricular synchrony in a small series of patients with AF and cardiomyopathy undergoing AV node (AVN) ablation.1 Over the past decade, there has been a reinvigoration in the interest in HBP as more

In this paper, we provide a comprehensive review of CSP for CRT including a review of the available data on CSP among various indications for CRT.

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Conduction System Pacing for CRT Figure 1: Sites for Conduction System Pacing and Cardiac Resynchronisation Therapy

of the first series demonstrating the value of HBP for CRT but the study was limited by its observational nature, small number of participants and low success rates.

1. His bundle pacing 2. Left bundle branch pacing 3. Left septal pacing 4. LV epicardial pacing

Lustgarten et al. performed a crossover study comparing HBP versus BVPCRT in 29 patients, with successful resynchronisation in 21 (72%) cases.19 All patients received a coronary sinus LV lead and an HBP lead connected to the LV port with a Y adapter and were randomised in single patient-blinded fashion to either HBP or BVP pacing. Among the 12 patients who completed the crossover analysis, patients from both groups demonstrated significant improvements in LVEF, NYHA functional status and 6-minute walk distance.

Although this was the first randomised crossover study evaluating the value of HBP for CRT, only 12 of the 29 patients completed the study.

Possible CRT strategies: 1. HBP-CRT = site 1 2. LBBP-CRT = site 2 3. BVP-CRT = site 4 and RV endocardium 4. HOT-CRT = site 1 and 4 5. LOT-CRT = site 2 and 4 Locations for permanent lead placement along the atrioventricular conduction system and possible cardiac resynchronisation therapy strategies using conduction system pacing.

BVP: biventricular pacing; CRT: cardiac resynchronisation therapy; HBP: His bundle pacing; HOT-CRT = His optimised CRT; LBBP = left bundle branch pacing; LOT-CRT = left bundle branch pacing optimised CRT.

Ajijola et al. evaluated the value of HBP as an alternative approach to CRT in lieu of coronary sinus lead and this was successful in 16 of the 21 patients in the study (76%).20 There was a significant narrowing of the QRSd from 180 ± 23 ms to 129 ± 13 ms (p<0.0001) with an improvement in NYHA functional class from III to II (p<0.001), while the mean LVEF and LV internal dimension in diastole at a median follow-up of 12 months improved from 27 ± 10% to 41 ± 13% (p<0.001) and from 5.4 ± 0.4 cm to 4.5 ± 0.3 cm (p<0.001), respectively. This study was a small observational single-centre evaluation and only focused on patients with LBBB.

data are now available on the benefit of using HBP for patients who need ventricular pacing.2,3,17 However, given challenges with an increase in HBP lead capture thresholds and oversensing in some patients, Huang et al. first described placing a permanent pacing lead more distally along the conduction system in a patient with LBBB and HFrEF with a low capture threshold and this improved outcomes.6,17 This newer location of lead implantation along the LBB region of the conduction system has gained popularity over the past 2 years with growing data on this implant location having low left fascicular capture thresholds, better R wave sensing and potential ease of implantation (Figure 1).

Sharma et al. reported a multi-centre study of HBP for CRT in 106 patients including HBP as a primary or rescue strategy and reported an overall success rate of 90%.21 BBB was present in 45% of the patients while 39% cases had a paced rhythm. During a mean follow-up of 14 months, both groups demonstrated significant narrowing of QRS from 157 ±33 ms to 117 ± 18 ms (p=0.0001), increase in LVEF from 30 ± 10% to 43 ± 13% (p=0.0001) and improvement in NYHA class with HBP. His capture and BBB correction thresholds were 1.4 ± 0.9 V and 2.0 ± 1.2 V at 1 ms, respectively. Leadrelated complications occurred in seven patients. Although this study was multicentre and included patients with all indications for CRT, the retrospective nature of this study was a limitation.

Over the past few years, these two sites for pacing along the cardiac conduction system have become attractive as potential alternatives to BVP-CRT with the demonstration of resynchronised ventricular activation in various studies.18–27 CSP has been used as a primary strategy when CSP is attempted as the first-line therapy for CRT or as a rescue strategy in cases where coronary venous anatomy limits the ability to successfully place an LV epicardial lead.

Data on Conduction System Pacing for CRT

Upadhyay et al. conducted a multicentre randomised pilot study evaluating the value of HBP for CRT compared with BVP-CRT in 41 patients with CRT indications.28 Of the 41 patients in the study, 35 had an underlying LBBB. Although the crossover rate was high, QRSd was significantly shorter in those that received His-CRT compared to those that received BVP-CRT (125 ± 22 ms versus 164 ± 25 ms; p<0.001). The median change in LVEF was higher for His-CRT compared to BVP-CRT, but this difference was not statistically significant (+7.2% [5.0–16.9%] versus +5.9% [1.5– 11.3%], p=0.17). A trend toward higher rates of echocardiographic response (80% versus 57%, p=0.14) was similarly observed. This was the first multicentre randomised pilot study evaluating His-CRT versus BVP-CRT. Some of the conclusions were limited due to the high crossover rates and the inclusion of patients with intraventricular conduction delay (IVCD) QRS patterns that do not always respond to HBP for CRT.

Multiple studies have been published on the benefit of HBP and LBBP as a CRT strategy. However, it is important to recognise that the majority of these studies are observational and non-randomised, with only two pilot studies randomising HBP compared with BVP with a limited number of patients (Table 1 ). Below we review the available data on CSP based on indication for CRT. Figure 1 highlights some pacing locations with possible strategies for CRT.

Patients with Left Bundle Branch Block and HFrEF

It is well recognised that the patients who derive the most benefit from traditional BVP-CRT are those with LBBB. CSP with HBP and LBBP can recruit and narrow typical LBBB and provide an ideal resynchronisation option. Case examples of HBP and LBBP are demonstrated in Figures 2 and 3. Most of the available data on CSP for CRT focuses on this patient population and this is summarised in Table 1.

Huang et al. published data on HBP for CRT in 74 patients with nonischaemic cardiomyopathy and LBBB.27 Permanent HBP was successful in 75.7% of the patients (n=56). Over a median follow-up of 3 years, LVEF increased from 32.4 ± 8.9% at baseline to 55.9 ± 10.7% (p<0.001) and NYHA class improved from 2.73 ± 0.58 to 1.03 ± 0.18 (p<0.001). LBBB correction threshold remained stable with an acute threshold of 2.13 ± 1.19 V/0.5 ms and 2.29 ± 0.92 V/0.5 ms at 3-year follow-up (p>0.05). The high superresponder rate in this study was likely due to its highly selective study population of patients with typical LBBB and non-ischaemic cardiomyopathy.

Barba-Pichardo et al. first described their experience with HBP in failed CRT cases in 2013.18 HBP was attempted in 16 patients with cardiomyopathy and failed BVP-CRT. Temporary pacing at the HB corrected LBBB in 13 patients (81%). Successful permanent HBP for CRT was achieved in 69% of the patients (n=9). Mean QRSd decreased from 166 ± 8 ms to 97 ± 9 ms.

New York Heart Association (NYHA) functional class improved from III to II and there was an improvement in LVEF and LV dimensions. This was one

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Conduction System Pacing for CRT Table 1: Study Summary for Conduction System Pacing and Cardiac Resynchronisation Therapy Study

Design

Indication

n

Success Follow- Echocardiographic ECG/QRSd and Haemodynamic Rate up (Months) (mean results)

Outcomes

56%

31

LVEF 29–36% LVEDD 6.6 to 6.0 cm LVESD 5.5 to 5.1 cm

QRSd 166 to 97 ms

Improved NYHA III to II

His Bundle Pacing in Left Bundle Branch Block BarbaPinchardo et al. 201318

Single centre Prospective Observational

HBP in CRT with dilated 16 LV, LBBB, no coronary venous access

HBP for CRT Lustgarten et Multicentre Prospective -97% LBBB al. 201519 Crossover of HBP versus BV

29

59%

6

LVEF baseline 26% HBP 32% BVP 31%

QRSd Baseline 169 ms NSHBP 160 ms SHBP 131 ms BV 165 ms

Improved NYHA class Improved 6-min walk Improved quality of life

Single centre Prospective Observational

HBP for CRT

21

76%

12

LVEF 27–41% LVEDD 5.4 to 4.5 cm

QRSd 180 to 129 ms

NYHA III to II

HBP for CRT after BVP failure or primary HBP 45% BBB 39% paced 16% AVB

106 90%

14

LVEF 30–44% LVEF 25–40% (LVEF ≤35%) LVEDD 55 to 54 mm

QRSd 157 to 118 ms

NYHA 2.8 to 1.8 Demonstrates HBP feasibility and safety as an alternative to CRT

41

76%

12

LVEF 26–32%

QRSd 172 to 144 ms

Demonstrates feasibility and safety of HBP as an alternative to CRT

HBP in LBBB, NYHA 74 II–IV with CRT or pacing indication

76%

37

LVEF 31–57% LVESV 140 to 65 ml

QRSd Baseline 171 ms HBP 113 ms SHBP 173 to 105 ms NSHBP 161 to 140 ms

NYHA 2.8 to 1.0 HBP corrected LBBB in most patients with HF and typical LBBB

95%

15

LVEF 31–39% LVEF 26 to 34% (LVEF ≤35%) 19% super-responders

QRSd 158 to 127 ms

NYHA 2.8 to 2.0 HBP appears to be a reasonable therapy for patients with RBBB and depressed LVEF

Ajijola et al.

201720

Sharma et al. Multicentre Prospective 201821 Observational

Upadhyay et al. 201928

Multicentre HBP for CRT in LBBB Prospective Randomised crossover trial

Huang et al.

201927

Single centre Prospective Observational

His Bundle Pacing in Right Bundle Branch Block Sharma et al. Multicentre 201822 Retrospective Observational

HBP in RBBB QRSd ≥120 ms NYHA class II–IV LVEF ≤50%

39

Left Bundle Branch Pacing Vijayaraman et al. 201924

Single centre Prospective Observational

LBBP for bradycardia or 100 93% CRT (11%) if CS lead or HBP failed LBBB 24% RBBB 25% IVCD 8% AV block 61%

3

n/a

QRSd LBBP feasible 133 to 136 ms Low thresholds observed QRSd 162 to 137 ms for LBBB subgroup

Huang et al.

202026

Multicentre Prospective Observational

Non-ischaemic cardiomyopathy LBBB LVEF <50%

63

12

LVEF 33–55% LVESV 123 to 67 ml

QRSd Baseline 169 ms LBBP 118 ms

NYHA 2.8 to 1.4 LBBP may be a reasonable therapy for patients with LBBB and non-ischaemic cardiomyopathy

Wu et al.

202029

Prospective Observations Case control

CRT with BVP, HBP or LBBP in LVEF <40%, LBBB

137 100%

12

∆LVEF 24%

QRSd Baseline 166 ms LBBP 111 ms

Echo outcomes were similar to HBP and significantly greater than BVP

Vijayaraman et al. 202125

Multicentre Retrospective Observational

CRT pacing LVEF <50%

325 85%

6

LVEF 33–44% LVEDD 56 to 54 mm LVESV 114 to 83 ml LVEF 27–40% (LVEF ≤35%) Response 73% Super-response 31%

QRSd 152 to 137 ms LBBB Subgroup 162 to 133 ms

NYHA 2.7 to 1.8 LBBB (OR 3.96, p<0.01) LVEDD (OR 0.62, p<0.01) were independent predictors of response LBBP may be a reasonable CRT alternative

12

LVEF 24–38% LVEDD 65 to 59 mm LVEDV 225 to 200 ml LVESV 171 to 138 ml Super-response 28%

QRSd Baseline 183ms BV 162 ms HBP 151 ms HOT-CRT 120 ms

NYHA 3.3 to 2.0 Reduced HF hospitalisations Reduced loop diuretic and aldosterone antagonist doses

97%

His-Optimised Cardiac Resynchronisation Therapy Vijayaraman et al. 201923

Multicentre Retrospective Observational

HOT-CRT in LBBB and 27 IVCD with QRS ≥140 ms or AV block with LBBB type escape

93%

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Conduction System Pacing for CRT Table 1: Cont Study

Design

Indication

n

Deshmukh 202040

Retrospective Single centre Observational

HOT-CRT in LBBB and 21 non-LBBB. HBP without BBB correction

Success Follow- Echocardiographic ECG/QRSd rate up and haemodynamic (months) (mean results) 30

• LVEF 27–41% • LVEDV 172 to 147 ml • ∆EF 10% in 76%

Outcomes

QRSd NYHA 3.1 to 2.1 Baseline 171 ms Reduced HF hospitalisations BVP 141 ms HBP 157 ms HOT-CRT 110 ms QRS area from 78.1 to 35.5 μV/s

AV = atrioventricular; AVB = atrioventricular block; BBB = bundle branch block; BVP = biventricular pacing; CRT = cardiac resynchronisation therapy; CS = coronary sinus; EF = ejection fraction; HBP = His bundle pacing; HOT-CRT = His-optimised CRT; ICD = implantable cardioverter defibrillator; IVCD = intraventricular conduction delay; LBBP = left bundle branch pacing; LV = left ventricle; LVEDD = left ventricular end diastolic diameter; LVEF = left ventricular ejection fraction; LVESD = left ventricular end systolic diameter; LVESV = left ventricular end systolic volume; NSHBP = non-selective HIS bundle pacing; NYHA = Hew York Heart Association; QRSd = QRS diameter; RBBB = right bundle branch block; SBP = systolic blood pressure; SHBP = selective His bundle pacing; ∆ = change in EF. Source: Herweg et al. 2020.39 Adapted with permission from Oxford University Press.

Figure 2: His Bundle Pacing for Cardiac Resynchronisation Therapy in Left Bundle Branch Block B

A

E

Q-LV 70ms AHV C

D

S-HBP with LBBB recruitment, Paced QRSd 88ms The patient is a 67-year-old woman with a history of non-ischaemic cardiomyopathy, LVEF 15–20% and NYHA class III. She has a baseline LBBB and QRSd of 152 ms (A), with the distal His location on an right anterior oblique fluoroscopic view (B) and a noted His-ventricular interval of 48 ms (B). A guide wire is placed in a lateral coronary sinus branch through a coronary sinus guide to measure the Q LV interval (B). HBP results in selective His capture with LBBB recruitment resulting in narrow paced QRS with a Q LV of 70 ms and loss of capture threshold of 1 V at 1 ms. (D). Final paced ECG with complete recruitment and selective His bundle pacing with a paced QRSd of 88 ms (E). HBP = His bundle pacing; LBBB = left bundle branch block; LVEF = left ventricular ejection fraction.

Vijayaraman et al. reported a single centre observational series evaluating the feasibility of LBBP in 100 patients about 24% of whom had LBBB and 11% of total cases had a CRT indication.24 In patients with LBBB, the QRSd could be significantly narrowed from 162 ± 21 ms at baseline to 137 ± 19 ms during LBBP (p<0.001). At 3-month follow-up (n=68), the pacing thresholds and sensing remained stable at 0.68 ± 0.21 V at 0.5 ms (p=0.51) and 12.3 ± 5.7 mV (p=0.21), respectively. Only 11% of cases in this study had a CRT indication which limited the evaluation of LBBP for CRT.

(123 ± 61 ml versus 67 ± 39 ml; p<0.001) and an improvement in NYHA functional class from 2.8 ± 0.6 at baseline to 1.4 ± 0.6 at 1 year. Again, the selective study population – patients with typical LBBB and non-ischaemic cardiomyopathy – likely resulted in a high rate of super-responders.

Wu et al. compared LBBP with HBP and BVP in a non-randomised observational study including 137 patients with non-ischaemic cardiomyopathy (49 HBP, 32 LBBP and 54 BVP).29 Mean paced QRSd was 100.7 ± 15.3 ms, 110.8 ± 11.1 ms and 135.4 ± 20.2 ms during HBP, LBBP, and BVP, respectively. HBP and LBBP demonstrated a similar absolute increase (Δ) in LVEF (+23.9% versus +24%, p= 0.977) and rate of normalised final LVEF (74.4% versus 70.0%, p=0.881) at 1-year follow-up. This was significantly higher than in the BVP group (Δ LVEF +16.7% and 44.9% rate of normalised final LVEF, p< 0.005). HBP and LBBP also demonstrated greater improvements in NYHA class compared with BVP. LBBP was associated with higher R-wave amplitude (11.2 ± 5.1 mV versus 3.8 ± 1.9

Huang et al. reported a 97% success rate with LBBP in a prospective multicentre study involving 63 patients with non-ischaemic cardiomyopathy and LBBB.26 QRSd narrowed from 169 ± 16 ms to 118 ± 12 ms (p<0.001).

Pacing threshold and R wave amplitude remained stable at 1-year followup (0.5 ± 0.15 V/0.5 ms versus 0.58 ± 0.14 V/0.5 ms and 11.1 ± 4.9 mV versus 13.3 ± 5.3 mV, respectively). LVEF increased significantly (33 ± 8% versus 55 ± 10%; p<0.001), with a reduction in left ventricular end systolic volume

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Conduction System Pacing for CRT Figure 3: Left Bundle Branch Pacing for Cardiac Resynchronisation Therapy A

B

E

AHV Q-LV 100ms

C

D

LBBB with LBBB recruitment, Paced QRSd 106ms The patient is a 55-year-old man with a history of non-ischaemic cardiomyopathy, LVEF 15–20% and NYHA class III. He has a baseline LBBB and QRSd of 180 ms (A). The distal His location on a right anterior oblique fluoroscopic view (B) and a noted HV interval of 60 ms with corresponding His bundle injury (B). A guide wire is placed in a lateral coronary sinus branch to measure the Q-LV interval (B).

His bundle pacing results in non-selective His capture with LBBB recruitment but with a high threshold of 3 V at 1 ms. Hence, LBBP is performed resulting in paced QRS of 129 ms with a Q-LV of 100 ms (D).

D also shows the left anterior oblique fluoroscopic view of the LBBP site (arrow). Final paced ECG with bipolar LBBP and adjusted atrioventricular delay demonstrating a final a paced QRSd of 106 ms (E).

HBP = His bundle pacing; LBBB = left bundle branch block; LBBP = left bundle branch pacing; LVEF = left ventricular ejection fraction.

narrowing of QRS from 158 ± 24 ms to 127 ± 17 ms (p=0.0001), with an improvement in LVEF (31 ± 10% to 39 ± 13%) (p=0.004) and NYHA functional class from 2.8 ± 0.6 to 2 ± 0.7 (p=0.0001) was noted with HBP. His capture and BBB correction thresholds were 1.1 ± 0.6V and 1.4 ± 0.7 V at 1 ms, respectively. An increase in capture threshold occurred in three patients.

This was the first multicentre observational analysis signaling that HBP might be an ideal strategy for CRT in patients with RBBB and HFrEF.

mV, p< 0.001) and lower pacing threshold (0.49 ± 0.13 V/0.5 ms versus 1.35 ± 0.73 V/0.5 ms, p<0.001) compared with HBP. Although non-randomised, this study demonstrated that both HBP and LBBP may be superior to BVP when evaluating echocardiographic response.

The largest retrospective multicentre study assessing the feasibility of LBBP for CRT was published by Vijayaraman et al in 2021.25 LBBB pattern was noted in 39% of this cohort, RBBB in 17% and intraventricular conduction defect in 15%. CRT was successfully achieved by LBBP in 277 of the 325 patients (85%) in which it was attempted and resulted in a significant reduction in QRSd from 152 ± 32 ms to 137 ± 22ms (p<0.01).

LVEF improved from 33 ± 10% to 44 ± 11% (p<0.01) and was noted in both ischaemic and non-ischaemic patients. The lead threshold and R wave amplitude (0.6 ± 0.3 V at 0.5 ms and 10.6 ± 6 mV at implantation) remained stable during follow-up of 6 ± 5 months. Clinical response was noted in 72% and echocardiographic response in 73% of patients while 31% of patients were super-responders.

Patients with Pacing-Induced Ventricular Dyssynchrony and HFrEF

Conventional RV apical pacing leads to ventricular dyssynchrony which can predispose to PICM in a subset of patients. Recent data suggest that this risk can be as high as one in five patients among patients with an RV pacing burden ≥20%.30 CSP can help resynchronise ventricular activation thereby resulting in resolution of cardiomyopathy. Most of the studies evaluating this indication have evaluated HBP as an option for CRT. The multicentre findings on HBP for CRT by Sharma et al. included 31 patients with PICM with successful HBP in 81% patients (25 of 31).21 There was a significant decrease in QRSd from 177 ± 19 ms to 125 ± 15 ms (p=0.0001) and the LVEF increased from 32 ± 11% to 45 ± 13% (p=0.0001) in this subset.

Patients with Right Bundle Branch Block and HFrEF

It has been demonstrated that BVP-CRT benefits patients with LBBB more than patients with RBBB or IVCD patterns. In patients with typical isolated RBBB, it is the RV that contracts asynchronously with normal LV activation.

Hence, BVP-CRT may not correct this delayed RV activation and may not improve outcomes in patients with RBBB. On the other hand, in patients with correction of RBBB with HBP, delayed RV activation can be overcome while maintaining near normal LV activation.

Shan et al. demonstrated a success rate of 89% among the 18 patients undergoing attempted HBP upgrade, 11 of which were patients with PICM.31 In this study, the QRSd decreased from 157 ± 22 ms to 107 ± 17 ms, p<0.01. During a 1-year follow-up, left ventricular end-diastolic dimensions decreased from baseline 62 ± 7 mm to 56 ± 8 mm (p<0.01) and LVEF increased from 36 ± 8% to 53 ± 10% (p<0.01).

Sharma et al. reported their multicentre findings with HBP in RBBB. HBP was attempted in patients with HFrEF and RBBB, with an overall success rate of 95% (37 of 39 patients) including complete correction of RBBB in 78% of cases.22 Over a mean follow-up of 15 months, a significant

Vijayaraman et al. published a multicentre observational study with HBP in patients with longstanding AVB and chronic RV pacing and/or PICM in

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Conduction System Pacing for CRT functional class.31 Although these are interesting findings, the small sample size in these studies and the varied definition of non-response to BVP-CRT, this sub-group of patients needs further careful evaluation before CSP can be considered a standard approach.

need of CRT.32 HBP was successful in 79 of 85 patients (93%) with chronic RV pacing. QRSd increased from 123 ± 31 ms at baseline to 177 ± 17 ms (p<0.001) during RV pacing and decreased to 115 ± 20 ms with HBP (p<0.001). HBP threshold was 1.47 ± 0.9 V at 1 ms at implant and 1.9 ± 1.3 V at 1 ms over a mean 2-year follow-up. In 60 patients with PICM in whom LVEF decreased from 54 ± 7.7% at baseline to 34.3 ± 9.6% (p<0.001) with RV pacing, there was an improvement of 48.2 ± 9.8% (p<0.001) after HBP.

Patients with Intraventricular Conduction Delay and HFrEF

Most IVCD patterns with QRSD <150 ms typically represent intramyocardial cell-to-cell conduction delay and may not benefit from CSP given the lack of focal disease within the AV conduction system. However, in patients with advanced cardiomyopathy and dilated ventricles, AV conduction disease such as LBBB and intramyocardial delay may coexist.

In these circumstances, resynchronisation may be more complete with pacing at the level of both the specialised conduction system (distal to site of AV delay) in conjunction with sequential LV pacing in areas of delayed myocardial activation, referred to as His-optimised CRT (HOT-CRT).

Patients Undergoing Atrioventricular Node Ablation and HFrEF

Intuitively, CSP may be the best strategy for maintenance of ventricular synchrony in patients with permanent AF, narrow QRSd at baseline and HFrEF undergoing an AVN ablation. In patients with intact distal AV conduction, BVP-CRT creates dyssynchrony by activating endocardial RV and epicardial LV after an AVN ablation. On the other hand, CSP preserves synchronised ventricular activation by pacing the intact native conduction system distal to the site of AVN ablation.

HOT-CRT was evaluated in a small series of patients by Vijayaraman et al.23 In this study, 27 patients with LBBB/IVCD in whom only partial or no QRS narrowing was achieved by HBP alone, underwent an LV epicardial lead implantation in addition to HBP. HOT-CRT resulted in improved electrical resynchronisation when compared with conventional BVP or HBP alone and was felt to be the best clinical option for these patients.

The QRSd reduced from 183 ± 27 ms at baseline to 120 ± 16 ms (34%) with HOT-CRT compared to 162 ± 18 ms (11%) by conventional BVP (p<0.05).

There was an observed significant echocardiographic and clinical improvement in 95% of patients with advanced HF treated with HOT-CRT.

Vijayaraman et al. published their initial findings of HBP among 42 patients undergoing AVN ablation and demonstrated a 95% success rate.33 HBP threshold at implant was 1 ± 0.8 V at 1 ms and increased to 1.6 ± 1.2 V at 1 ms during a mean follow-up of 19 ± 14 months. Patients with LVEF ≤40% at baseline demonstrated a significant improvement in LVEF (33 ± 7% to 45 ± 9%, p<0.001) while those with an LVEF >40% at baseline, demonstrated a preserved LVEF (56 ± 5% to 57 ± 7%, p=0.5) during follow-up.

Huang et al. similarly evaluated HBP with AVN ablation in 52 patients, half of whom had HFrEF.34 HBP and AVN ablation was successful in 42 patients (80.8%). Over a median follow-up of 20 months, the LVEF increased significantly from baseline in patients with HFrEF (n=20). NYHA functional status improved 2.9 ± 0.6 to 1.4 ± 0.4 after HBP in patients with a low LVEF. The number of patients who required diuretics for HF decreased significantly (p<0.001).

Left Bundle Branch Pacing Versus Left Ventricular Septal Pacing

LBBP and LV septal pacing may be able to overcome more distal conduction disease, such as intrahisian disease, proximal BB disease, and might provide a better opportunity for synchronised LV activation than HBP in such cases. However, LV septal pacing alone versus LBBP (which involves capture and engagement of the left fascicular system) are mechanistically different in LV activation. How this affects resynchronisation, particularly in patients with LBBB and the need for CRT has been evaluated acutely in two studies.

Wang et al. evaluated 86 consecutive patients with persistent AF and HF who had indications for ICD implantation and split them into patients receiving HBP/LBBP with ICD and AVN ablation (n=52) and the remaining patients underwent ICD implantation only (n=31).35 During follow-up, patients with HBP/LBBP and AVN ablation had a lower incidence of inappropriate shocks (15.6% versus 0%, p<0.01) and adverse events (p=0.011) and a higher improvement in LVEF and reduction in LV endsystolic volume (15% versus 3%, p<0.001; and 40 ml versus 2 ml, p<0.01, respectively).

The effects of temporary LV septal pacing without left fascicular system capture were studied in a canine model with LBBB and a human study with LBBB by the Maastricht group.36,37 Electrocardiography measuring QRSd, vectorcardiography measuring QRS area, and multielectrode body surface mapping, measuring standard deviation of activation times, were used to assess electrical resynchronisation. LV septal pacing resulted in a larger reduction in QRSd/area and LV activation time when compared to BVP or LV septal and RV pacing.37 Basal, mid- and apical LV septal pacing positions resulted in similar results, indicating that within the LV septum, the position of the pacing electrode is not critical. Changes in QRS area, LV activation time and LVdP/dtmax were comparable between LV septal and HBP suggesting that electrical resynchronisation and haemodynamic improvement with LV septal pacing may be as good as that with BVP or HBP in the short term.37

The above studies have highlighted that HBP and LBBP are reasonable options for CRT for patients undergoing AVN ablation. However, the observational nature and lack of randomisation to conventional BVP-CRT are limitations of these studies.

Non-responders to Biventricular Cardiac Resynchronisation Therapy

Limited data exists on CSP in patients who have not responded to traditional BVP-CRT. In our multicentre study on HBP for CRT, we had eight patients who were deemed non-responders to BVP-CRT that underwent a successful upgrade to HBP.21 Six patients (75%) had an echocardiographic response with HBP with an average increase in LVEF from 30 ± 10% to 38 ± 13% (p=0.07).

Anecdotally, LV septal capture might be reasonable for patients with normal or mildly depressed LVEF, but whether it truly adds value as a strategy for CRT in patients with HFrEF, particularly in those with severely depressed LVEF and a dilated LV cavity remains unknown. The long-term clinical benefit of LV septal pacing compared to HBP or LBBP, particularly in the CRT-indicated patient still needs further systematic evaluation.

Similarly, in the study by Shan et al. there were five patients who had successful upgrade to HBP with improvements in LVEF and NYHA

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Conduction System Pacing for CRT Figure 4: Schematic for Cardiac Resynchronisation Therapy

RBBB

HBP

BVP

HBP

BVP

HBP or correction threshold >1.5 V

No/partial correction HBP+RV

IVCD

LBBB

LBBP

HOT/LOT CRT

HOT/LOT CRT

Optimal resychronisation

Proposed schematic for achieving the best electrical resynchronisation using BVP or CSP. RBBB HBP No/partial correction HBP+RV BVP LBBB HBP HBP or correction threshold >1.5 V LBBP HOT/LOT CRT Optimal resychronisation BVP IVCD HOT/LOT CRT. BVP: biventricular pacing; CRT: cardiac resynchronisation therapy; HBP: His bundle pacing; HOT-CRT = His optimised CRT; IVCD = intraventricular conduction delay; LBBB: left bundle branch block; LBBP: left bundle branch pacing; LOT-CRT = left bundle branch pacing optimised CRT; RBBB: right bundle branch block.

During LBBP and LV septal pacing, RBBB delay pattern is often seen in varying degrees due to late activation of the RV. The implications of RV dyssynchrony likely induced by this RBBB pattern in patients undergoing CRT is unclear. However, this RBBB delay/dyssynchrony can be minimised by fusing with native RBB conduction using AV optimisation, bipolar pacing with anodal capture of RV septum, or fusion with RV or RBB pacing using another lead.

In recent studies reported above, CSP has been reported to achieve successful CRT in 76–97% of cases. HBP may be associated with an increase in capture thresholds or loss of BBB recruitment thresholds in follow-up.

For instance, in the multicentre study on HBP for CRT by Sharma et al., an increase in HB capture threshold (defined as a >2 V increase in capture threshold from implant or capture threshold >5 V at 1 ms) was noted in seven (7.4%) cases, three of which resulted in loss of BBB recruitment.21 All of these occurred late during follow-up (>6 months postimplant) due to progressive increase in His capture threshold. Repeat procedures were needed in three patients (HBP extraction with manual traction and replacement with LV lead). Whether these increases are related to progression in conduction disease, microdislodgement of the lead (with cardiac motion) or lead-related properties remains unanswered. With LBBP, although thresholds have been reported to be stable during followup, long-term issues such as loss of LBB capture, lead dislodgement and the rarely reported complication of late LV septal perforation (into the LV cavity) have been reported.38

Proposed Algorithm for Conduction System Pacing

Figure 4 summarises a proposed algorithm for CRT using CSP. As noted above, BVP may not be the ideal resynchronisation strategy for patients with HFrEF and RBBB, and HBP likely provides the best option for biventricular activation. In cases with incomplete or no correction of RBBB pattern with HBP, RV pacing can be combined with HBP to pre-excite the RV and provide resynchronisation. BVP still remains the gold standard for CRT for patients with LBBB and HFrEF. CSP with HBP may be considered as a primary or rescue strategy in such cases. If HBP results in correction of LBBB with a correction threshold ≥ 1.5 V at 1 ms, LBBP should be considered. If HBP or LBBP result in partial correction, HOT/LOT-CRT may be performed by combining CSP with LV pacing. Similarly, for patients with an IVCD pattern, combining CSP with LV pacing may be an option. AV delay optimisation with any of these above strategies, particularly with LBBP, can result in further narrowing of the QRS width and help with RV activation.

Future Directions

HBP and LBBP may provide a true physiological pacing strategy in patients with an intact distal His-Purkinje system. The above data suggest there is a potential value of this form of pacing for cardiac resynchronisation. CSP offers a promising alternative to BVP in non-responders or as a rescue strategy in those who fail BVP. While preliminary data from small, randomised, crossover studies suggest an equivalent response, it is important to emphasise that there have been no published large-scale randomised trials comparing the effectiveness of HBP or LBBP for CRT in comparison to BVP-CRT.

Challenges with Conduction System Pacing

Despite a significant benefit and evolving indications for traditional BVPCRT, limitations during implant such as the lack of suitable coronary sinus venous branches and unavoidable phrenic nerve stimulation at ideal anatomic LV lead positions can result in failure to achieve optimal CRT. CS lead dislodgement or increasing thresholds (if the lead is placed close to areas of scarring) can be issues in follow-up.

There are other unanswered questions to be considered:

• What is the degree of correction necessary to achieve electrical and mechanical resynchronisation with HBP or LBBP?

• Are there patient or ECG characteristics that can help predict patients

Similarly, both HBP and LBBP may not be successful in achieving CRT in all cases given the level of conduction system disease, presence of IVCD (myocardial conduction delay) and many cases with significant LV remodelling (with mixed conduction disease and myocardial delay).

who will achieve successful HBP and will respond to this therapy?

• Is one of these sites for CSP better than the other when looking at clinical outcomes?

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Conduction System Pacing for CRT • Is LBBP with left fascicular capture better/necessary for

resynchronisation or is LV septal capture alone enough to improve outcomes in patients with HFrEF and LBBB?

Clinical Perspective

• Conduction system pacing (CSP) which includes His bundle pacing and the left bundle branch pacing is a promising tool for patients who need ventricular pacing.

• CSP can also overcome bundle branch block patterns and thereby alleviate ventricular dyssynchrony.

• There are a number of studies demonstrating the clinical benefit of CSP in patients with heart failure, depressed LV function and known ventricular dyssynchrony.

• CSP might provide an additional modality for cardiac resynchronisation therapy in addition to conventional biventricular pacing.

Larger, multicentre, randomised studies are needed to evaluate the clinical efficacy of these strategies and help answer some of these questions.

Conclusion

CSP is a promising technique for ventricular pacing and helps maintain synchronous ventricular contraction. It can correct ventricular dyssynchrony in some patients and more data are emerging on the potential benefit of CSP for CRT. Larger randomised controlled trials and registry data can help realise the true benefit of CSP in comparison to BVP-CRT. 1. Deshmukh P, Casavant DA, Romanyshyn M, et al.

Permanent, direct His-bundle pacing: a novel approach to cardiac pacing in patients with normal His-Purkinje activation. Circulation 2000;101:869–77. https://doi. org/10.1161/01.CIR.101.8.869; PMID: 10694526.

2. Sharma PS, Dandamudi G, Naperkowski A, et al. Permanent His-bundle pacing is feasible, safe, and superior to right ventricular pacing in routine clinical practice. Heart Rhythm 2015;12:305–12. https://doi.org/10.1016/j.hrthm.2014.10.021; PMID: 25446158.

3. Abdelrahman M, Subzposh FA, Beer D, et al. Clinical outcomes of His bundle pacing compared to right ventricular pacing. J Am Coll Cardiol 2018;71:2319–30. https:// doi.org/10.1016/j.jacc.2018.02.048; PMID: 29535066.

4. Sharma PS, Ellenbogen KA, Trohman RG. Permanent His bundle pacing: the past, present, and future. J Cardiovasc Electrophysiol 2017;28:458–65. https://doi.org/10.1111/ jce.13154; PMID: 28032941.

5. Zanon F, Ellenbogen KA, Dandamudi G, et al. Permanent His-bundle pacing: a systematic literature review and metaanalysis. Europace 2018;20:1819–26. https://doi.org/10.1093/ europace/euy058; PMID: 29701822.

6. 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;33:1736.e1–1736.e3. https://doi.org/10.1016/j. cjca.2017.09.013; PMID: 29173611.

7. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–49. https://doi. org/10.1056/NEJMoa050496; PMID: 15753115.

8. Bristow MR, Saxon LA, Boehmer J, et al. Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140–50. https://doi.org/10.1056/NEJMoa032423; PMID: 15152059.

9. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–53. https://doi.org/10.1056/NEJMoa013168; PMID: 12063368.

10. Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA 2003;289:2685–94. https://doi.org/10.1001/ jama.289.20.2685; PMID: 12771115.

11. Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873– 80. https://doi.org/10.1056/NEJM200103223441202; PMID: 11259720.

12. Auricchio A, Stellbrink C, Sack S, et al. Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J Am Coll Cardiol 2002;39:2026– 33. https://doi.org/10.1016/s0735-1097(02)01895-8; PMID: 12084604.

13. Kiehl EL, Makki T, Kumar R, et al. Incidence and predictors of right ventricular pacing-induced cardiomyopathy in patients with complete atrioventricular block and preserved left ventricular systolic function. Heart Rhythm 2016;13:2272–8. https://doi.org/10.1016/j.hrthm.2016.09.027; PMID: 27855853.

14. Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart

Association Task Force on Practice Guidelines. J Am Coll Cardiol 2012;60:1297–313. https://doi.org/10.1016/j. jacc.2012.07.009; PMID: 22975230.

15. Singh JP, Klein HU, Huang DT, et al. Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) trial. Circulation 2011;123:1159–66. https://doi.org/10.1161/CIRCULATIONAHA.110.000646; PMID: 21382893.

16. Moss AJ, Hall WJ, Cannom DS, et al. Cardiacresynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1329–38. https://doi. org/10.1056/NEJMoa0906431; PMID: 19723701.

17. Vijayaraman P, Naperkowski A, Subzposh FA, et al.

Permanent His-bundle pacing: long-term lead performance and clinical outcomes. Heart Rhythm 2018;15:696–702. https://doi.org/10.1016/j.hrthm.2017.12.022; PMID: 29274474.

18. Barba-Pichardo R, Manovel Sanchez A, Fernandez-Gomez JM, et al. Ventricular resynchronization therapy by direct His-bundle pacing using an internal cardioverter defibrillator. Europace 2013;15:83–8. https://doi.org/10.1093/ europace/eus228; PMID: 22933662.

19. Lustgarten DL, Crespo EM, Arkhipova-Jenkins I, et al. Hisbundle pacing versus biventricular pacing in cardiac resynchronization therapy patients: A crossover design comparison. Heart Rhythm 2015;12:1548–57. https://doi. org/10.1016/j.hrthm.2015.03.048; PMID: 25828601.

20. Ajijola OA, Upadhyay GA, Macias C, et al. Permanent Hisbundle pacing for cardiac resynchronization therapy: Initial feasibility study in lieu of left ventricular lead. Heart Rhythm 2017;14:1353–61. https://doi.org/10.1016/j.hrthm.2017.04.003; PMID: 28400315.

21. Sharma PS, Dandamudi G, Herweg B, et al. Permanent Hisbundle pacing as an alternative to biventricular pacing for cardiac resynchronization therapy: A multicenter experience. Heart Rhythm 2018;15:413–20. https://doi. org/10.1016/j.hrthm.2017.10.014; PMID: 29031929.

22. Sharma PS, Naperkowski A, Bauch TD, et al. Permanent His bundle pacing for cardiac resynchronization therapy in patients with heart failure and right bundle branch block.

Circ Arrhythm Electrophysiol 2018;11:e006613. https://doi. org/10.1161/CIRCEP.118.006613; PMID: 30354292.

23. Vijayaraman P, Herweg B, Ellenbogen KA, et al. Hisoptimized cardiac resynchronization therapy to maximize electrical resynchronization. Circ Arrhythm Electrophysiol 2019;12:e006934. https://doi.org/10.1161/CIRCEP.118.006934; PMID: 30681348.

24. 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.

25. Vijayaraman P, Ponnusamy SS, Cano O, et al. Left bundle branch pacing for cardiac resynchronization therapy: results from International LBBP Collaborative Study Group. JACC Clin Electrophysiol 2021;7:135–47. https://doi.org/10.1016/j. jacep.2020.08.015; PMID: 33602393.

26. Huang W, Wu S, Vijayaraman P, et al. Cardiac resynchronization therapy in patients with nonischemic cardiomyopathy using left bundle branch pacing. JACC Clin Electrophysiol 2020;6:849–58. https://doi.org/10.1016/j. jacep.2020.04.011; PMID: 32703568.

27. Huang W, Su L, Wu S, et al. Long-term outcomes of His bundle pacing in patients with heart failure with left bundle branch block. Heart 2019;105:137–43. https://doi.org/10.1136/

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW Access at: www.AERjournal.com

58

heartjnl-2018-313415; PMID: 30093543.

28. 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.

29. Wu S, Su L, Vijayaraman P, et al. Left bundle branch pacing for cardiac resynchronization therapy: nonrandomized on-treatment comparison with His bundle pacing and biventricular pacing. Can J Cardiol 2021;37:319–28. https:// doi.org/10.1016/j.cjca.2020.04.037; PMID: 32387225.

30. Khurshid S, Epstein AE, Verdino RJ, et al. Incidence and predictors of right ventricular pacing-induced cardiomyopathy. Heart Rhythm 2014;11:1619–25. https://doi. org/10.1016/j.hrthm.2014.05.040; PMID: 24893122.

31. Shan P, Su L, Zhou X, et al. Beneficial effects of upgrading to His bundle pacing in chronically paced patients with left ventricular ejection fraction <50. Heart Rhythm 2018;15:405– 12. https://doi.org/10.1016/j.hrthm.2017.10.031; PMID: 29081396.

32. Vijayaraman P, Herweg B, Dandamudi G, et al. Outcomes of His bundle pacing upgrade after long-term right ventricular pacing and/or pacing-induced cardiomyopathy: insights into disease progression. Heart Rhythm 2019;16:1554–61. https:// doi.org/10.1016/j.hrthm.2019.03.026; PMID: 30930330.

33. Vijayaraman P, Subzposh FA, Naperkowski A. Atrioventricular node ablation and His bundle pacing.

Europace 2017;19:iv10-iv6. https://doi.org/10.1093/europace/ eux263; PMID: 29220422.

34. Huang W, Su L, Wu S, et al. Benefits of permanent His bundle pacing combined with atrioventricular node ablation in atrial fibrillation patients with heart failure with both preserved and reduced left ventricular ejection fraction. J Am Heart Assoc 2017;6:e005309. https://doi.org/10.1161/ jaha.116.005309; PMID: 28365568.

35. Wang S, Wu S, Xu L, et al. Feasibility and efficacy of His bundle pacing or left bundle pacing combined with atrioventricular node ablation in patients with persistent atrial fibrillation and implantable cardioverter-defibrillator therapy. J Am Heart Assoc 2019;8:e014253. https://doi. org/10.1161/jaha.119.014253. PMID: 31830874.

36. 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.

37. Salden F, Luermans J, Westra SW, et al. Short-term hemodynamic and electrophysiological effects of cardiac resynchronization by left ventricular septal pacing. J Am Coll Cardiol 2020;75:347–59. https://doi.org/10.1016/j. jacc.2019.11.040; PMID: 32000945.

38. Ravi V, Hanifin JL, Larsen T, et al. Pros and cons of left bundle branch pacing: a single-center experience. Circ Arrhythm Electrophysiol 2020;13:e008874. https://doi. org/10.1161/CIRCEP.120.008874; PMID: 33198496.

39. Herweg B, Welter-Frost A, Vijayaraman P. The evolution of cardiac resynchronization therapy and an introduction to conduction system pacing: a conceptual review. Europace 2020;Nov28:euaa264. https://doi.org/10.1093/europace/ euaa264; PMID: 33247913.

40. Deshmukh A, Sattur S, Bechtol T, Heckman LIB, Prinzen FW, Deshmukh P. Sequential His bundle and left ventricular pacing for cardiac resynchronization. J Cardiovasc Electrophysiol 2020;31:2448–54. https://doi.org/10.1111/ jce.1467; PMID: 32666630.

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.

Abbott One St. Jude Medical Dr., St. Paul, MN 55117 USA, Tel: 1 651 756 2000 Abbott.com ‡ Indicates a third party trademark, which is property of its respective owner. © 2021 Abbott. All Rights Reserved.

MAT-2102119 v1.0 | Item approved for global use.

© RADCLIFFE CARDIOLOGY 2021 Access at: www.AERjournal.com

THE POWER TO

REDUCE AF REDO PROCEDURES1 A manuscript published in the Journal of Atrial Fibrillation compares LONG-TERM OUTCOMES OF AF PROCEDURES using a circular mapping catheter (CMC) to those using the ADVISOR™ HD GRID MAPPING CATHETER, SENSOR ENABLED™.

The use of the Advisor HD Grid Mapping Catheter, SE resulted in A STATISTICALLY SIGNIFICANT IMPROVEMENT 1 IN BOTH: 12-MONTH FREEDOM FROM ATRIAL ARRHY THMIA S

87%

Advisor™ HD Grid Mapping Catheter, SE

75% CMC

REDUC TION IN REDO PROCEDURE S

6%

vs.

Redo rate when Advisor HD Grid Mapping Catheter, SE was used

20% Redo rate when CMC was used

Learn more about how the Advisor HD Grid Mapping Catheter, SE gives you the POWER TO SEE THINGS DIFFERENTLY › cardiovascular.abbott/hdgrid

1.

Day, J. D., Crandall, B., Cutler, M., Osborn, J., Miller, J., Mallender, C., & Lakkireddy, D. (2020). High Power Ultra Short Duration Ablation with HD Grid Improves Freedom from Atrial Fibrillation and Redo Procedures Compared to Circular Mapping Catheter. Journal of Atrial Fibrillation, 13(2).