AER 10.3

Arrhythmia & Electrophysiology Review Volume 10 • Issue 3 • Autumn 2021

Volume 10 • Issue 3 • Autumn 2021

www.AERjournal.com

Considerations for the Assessment of Substrates, Genetics and Risk Factors in Patients with Atrial Fibrillation Dominik Linz, Sander Verheule, Aaron Isaacs and Ulrich Schotten

The DAPA Trial in the Context of Previous Prophylactic ICD Landmark Trials Danielle Haanschoten and Arif Elvan

Physiology and Practicality of Left Ventricular Septal Pacing Luuk Heckman, Justin Luermans, Floor Salden, Antonius Martinus Wilhelmus van Stipdonk, Masih Mafi-Rad, Frits Prinzen and Kevin Vernooy

Impact of Catheter Ablation on Stroke, Cognitive Decline and Dementia

A Subxiphoid incision

Tyson S Burnham, Monte L Scott, Benjamin A Steinberg, Daniel L Varela, Brian Zenger and T Jared Bunch

C Endoscopic view through cannula I II III

aVR aVL

RV

aVF

LV V1

V2

Benefits of LV septal pacing 1. Compensation of slow transseptal conduction 2. Short path length of conduction 3. Fast endocardial conduction (fast-conducting endocardial, non-Purkinje fibres) 4. Faster endocardial-to-epicardial conduction than vice versa 5. Avoiding: • Phrenic nerve stimulation • Coronary sinus catheterisation • Posterolateral wall scar

V3 V4

V5

V6

Map_b

Schematic transversal overview of ventricular activation during LV septal pacing

QRS transition from non-selective LBB to LV septal capture

Surgical approach to epicardial ablation using the unipolar radiofrequency device (EPi-Sense, AtriCure, Inc.)

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Volume 10 • Issue 3 • Autumn 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

Robert Anderson

Eue-Keun Choi

Boyoung Joung

Seoul National University Hospital, Seoul, South Korea

Yonsei University, Seoul, South Korea

KR Julian Chun

Prapa Kanagaratnam

Newcastle University, Newcastle upon Tyne, UK

CardioVascular Center Bethanien, Frankfurt, Germany

Imperial College Healthcare NHS Trust, London, UK

Charles Antzelevitch

Harry Crijns

Josef Kautzner

Lankenau Institute for Medical Research, Pennsylvania, PA, US

Angelo Auricchio

Fondazione Cardiocentro Ticino, Lugano, Italy

Carina Blomström-Lundqvist Uppsala University, Uppsala, Sweden

Johannes Brachmann

Klinikum Coburg, II Med Klinik, Coburg, Germany

Josep Brugada

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

Pedro Brugada

University of Brussels, UZ-BrusselVUB, Brussels, Belgium

Maastricht University Medical Center, Maastricht, the Netherlands

Luigi Di Biase

Hospital Privado del Sur, Bahia Blanca, Argentina

Sanjay Dixit

Asklepios Klinik St Georg, Hamburg, Germany

Sabine Ernst Yutao Guo

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

Hein Heidbuchel

John M Miller

A John Camm

JW Goethe University, Frankfurt, Germany

Taipei Veterans General Hospital and National Yang Ming Chiao Tung University, Taipei, Taiwan

Shih-Ann Chen

National Yang Ming University School of Medicine and Taipei Veterans General Hospital, Taipei, Taiwan

Joseph E Marine

Chinese PLA General Hospital, Beijing, China

University of Leipzig, Leipzig, Germany

Tze-Fan Chao

Francis E Marchlinski

University of Pennsylvania Health System, Philadelphia, PA, US

Royal Brompton & Harefield NHS Foundation Trust, London, UK

David J Callans

St George’s University of London, London, UK

Karl-Heinz Kuck

University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, US

Antwerp University and University Hospital, Antwerp, Belgium

University of Pennsylvania, Philadelphia, PA, US

Roberto Keegan

Albert Einstein College of Medicine and Montefiore Medical Center, New York, NY, US

Alfred Buxton

Beth Israel Deaconess Medical Center, Boston, MA, US

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Indiana University School of Medicine, Indianapolis, IN, US

Gerhard Hindricks

Fred Morady

Cardiovascular Center, University of Michigan, MI, US

Carsten W Israel

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

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

Barts Health NHS Trust, London, UK

Afzal Sohaib

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

William G Stevenson

Vanderbilt School of Medicine, Nashville, TN, US

Neil T Srinivasan

Essex Cardiothoracic Centre, Basildon, and School of Medicine, Anglia Ruskin University, Chelmsford, Essex, UK

Richard Sutton

Andrea Natale

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

Mark O’Neill

University Medical Center Utrecht, Utrecht, the Netherlands

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

Warren Jackman

Sunny S Po

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

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

Marc A Vos

Katja Zeppenfeld

University of Bordeaux, CHU Bordeaux, France

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

Douglas Packer

Leiden University Medical Center, Leiden, the Netherlands

Roy John

Carlo Pappone

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

Pierre Jaïs

Northshore University Hospital, New York, NY, US

IRCCS Policlinico San Donato, Milan, Italy

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Volume 10 • Issue 3 • Autumn 2021

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Contents

Foreword Simple is Complicated

131

Demosthenes G Katritsis https://doi.org/10.15420/aer.2021.40

Clinical Arrhythmias Considerations for the Assessment of Substrates, Genetics and Risk Factors in Patients with Atrial Fibrillation

132

Dominik Linz, Sander Verheule, Aaron Isaacs and Ulrich Schotten https://doi.org/10.15420/aer.2020.51

Sleep Apnoea and AF: Where Do We Stand? Practical Advice for Clinicians

140

Suneet Mittal, David Golombeck and Jacqueline Pimienta https://doi.org/10.15420/aer.2021.05

Residual Stroke Risk in Atrial Fibrillation

147

Wern Yew Ding https://doi.org/10.15420/aer.2021.34

The DAPA Trial in the Context of Previous Prophylactic ICD Landmark Trials

154

Danielle Haanschoten and Arif Elvan https://doi.org/10.15420/aer.2021.23

Obesity and Atrial Fibrillation: Epidemiology, Pathogenesis and Effect of Weight Loss

159

Ahmed M Al-Kaisey and Jonathan M Kalman https://doi.org/10.15420/aer.2021.36

Cardiac Pacing Physiology and Practicality of Left Ventricular Septal Pacing

165

Luuk Heckman, Justin Luermans, Floor Salden, Antonius Martinus Wilhelmus van Stipdonk, Masih Mafi-Rad, Frits Prinzen and Kevin Vernooy https://doi.org/10.15420/aer.2021.21

ECG and Pacing Criteria for Differentiating Conduction System Pacing from Myocardial Pacingv

172

Marek Jastrzębski https://doi.org/10.15420/aer.2021.26

The Atrioventricular Conduction Axis and its Implications for Permanent Pacing

181

José-Ángel Cabrera, Robert H Anderson, Andreu Porta-Sánchez, Yolanda Macías, Óscar Cano, Diane E Spicer and Damián Sánchez-Quintana https://doi.org/10.15420/aer.2021.32

Electrophysiology & Ablation Diagnosis and Management of Complex Reentrant Arrhythmias Involving the His-Purkinje System

190

Raphael K Sung, Penelope A Boyden, Satoshi Higuchi and Melvin Scheinman https://doi.org/10.15420/aer.2021.22

Hybrid Convergent Procedure for the Treatment of Persistent and Long-standing Persistent Atrial Fibrillation

198

David B DeLurgio, Jaswinder S Gill, Syed Ahsan, Riyaz A Kaba, Kristen M Plasseraud and Michael E Halkos https://doi.org/10.15420/aer.2021.24

Impact of Catheter Ablation on Stroke, Cognitive Decline and Dementia

205

Tyson S Burnham, Monte L Scott, Benjamin A Steinberg, Daniel L Varela, Brian Zenger and T Jared Bunch https://doi.org/10.15420/aer.2021.42

The Use of Electrocardiographic Imaging in Localising the Origin of Arrhythmias During Catheter Ablation of Ventricular Tachycardia Adam J Graham and Richard J Schilling https://doi.org/10.15420/aer.2021.27

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211

Foreword

Simple is Complicated

Citation: Arrhythmia & Electrophysiology Review 2021;10(3):131. DOI: https://doi.org/10.15420/aer.2021.40 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.

“Y

ou always write saying simple, simple, simple, and I do my best to oblige… but simple is complicated!” This was Ludwig van Beethoven’s response to the Scottish music publisher George Thomson who commissioned folksong arrangements from the great composer – but often requested that they be simplified.

Biventricular pacing has been the cornerstone of an invasive approach for the treatment of patients with heart failure and left bundle branch block. The procedure has proven efficacy but it is technically demanding, time-consuming and has inherent limitations especially concerning the pacing thresholds of the coronary sinus lead. Selective His bundle and left bundle pacing have emerged as potential alternatives providing equal if not better haemodynamic improvements.1–3 However, these approaches may be cumbersome and demand a far from negligible learning curve.

Furthermore, infra-Hisian block or peripheral intraventricular conduction delay and long-term durability of the pacing lead may hinder successful His-bundle or left-bundle pacing.

Theoretically, a mid-septal position should also be an optimum pacing site in the normal ventricle, and simple septal pacing appears to be a user-friendly, widely applicable solution, as Heckman et al. claim in this issue of the journal.4–6 This could be the answer to the quest not only for cardiac resynchronisation, but also for ‘physiological’ pacing, especially in young patients with congenital heart block who may need lifelong pacing on the left ventricle.

Is this solution too simple not to be complicated? The differences between selective and non-selective His bundle pacing and the potential caveats of a non-selective approach have been well addressed by the pioneers of the technique and are also discussed by Heckman et al.6 Further, although theoretically a mid-septal position should be the optimum site in the normal ventricle, no benefit over apical pacing has been shown in randomised studies, but there has been no long-term follow-up, especially in the paediatric population.4,5,7,8 Last but not least, the effectiveness of a septal approach for patients with extensive septal scars post-infarct is questionable if not unattainable. I remember Mark Josephson in our morning rounds teaching us that after an anteroseptal infarct, any attempt to ‘normalise’ pacing is detrimental.

We are entering a new, exciting era where the normal activation mode is being replicated using physiological pacing. However, we have a long way to go before reaching our goal. Simple is always complicated.

Demosthenes G Katritsis Editor-in-Chief, Arrhythmia & Electrophysiology Review Hygeia Hospital, Athens, Greece Johns Hopkins School of Medicine, Baltimore, MD, US 1. Arnold A, 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.

2. Su L, Wang S, Wu S, et al. Long-term safety and feasibility of left bundle branch pacing in a large single-center study. Circ Arrhythm Electrophysiol 2021;14:e009261. https:// doi.org/10.1161/CIRCEP.120.009261; PMID: 33426907.

3. Sharma PS, Vijayaraman P. Conduction system pacing for cardiac resynchronisation. Arrhythm Electrophysiol Rev 2021;10:51–8. https://doi.org/10.15420/aer.2020.45; PMID: 33936744.

4. Shimony A, Eisenberg MJ, Filion KB, Amit G. Beneficial effects of right ventricular non-apical vs. apical pacing: a systematic review and meta-analysis of randomizedcontrolled trials. Europace 2012;14:81–91. https://doi. org/10.1093/europace/eur240; PMID: 21798880.

5. Weizong W, Zhongsu W, Yujiao Z, et al. Effects of right ventricular nonapical pacing on cardiac function: a metaanalysis of randomized controlled trials. Pacing Clin Electrophysiol 2013;36:1032–51. https://doi.org/10.1111/ pace.12112; PMID: 23438131.

Heckman L, Luermans J, Salden F, et al. Physiology and practicality of left ventricular septal pacing. Arrhythm

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Electrophysiol Rev 2021;10:165–71. https://doi.org/10.15420/ aer.2021.21.

6. Janousek J, van Geldorp IE, Krupickova S, et al.

Permanent cardiac pacing in children: choosing the optimal pacing site: a multicenter study. Circulation 2013;127:613–23. https://doi.org/10.1161/ CIRCULATIONAHA.112.115428; PMID: 23275383.

7. Kaye GC, Linker NJ, Marwick TH, et al. Effect of right ventricular pacing lead site on left ventricular function in patients with high-grade atrioventricular block: results of the Protect-Pace study. Eur Heart J 2015;36:856–62. https:// doi.org/10.1093/eurheartj/ehu304; PMID: 25189602.

Atrial Fibrillation

Considerations for the Assessment of Substrates, Genetics and Risk Factors in Patients with Atrial Fibrillation Dominik Linz ,1,2,3,4 Sander Verheule ,5 Aaron Isaacs

5

and Ulrich Schotten

5

1. Department of Cardiology, Cardiovascular Research Institute Maastricht, Faculty of Health, Medicine and Life Sciences, Maastricht University and Maastricht University Medical Center+, Maastricht, the Netherlands; 2. Department of Cardiology, Radboud University Medical Centre, Nijmegen, the Netherlands; 3. Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; 4. Centre for Heart Rhythm Disorders, University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia; 5. Department of Physiology, Cardiovascular Research Institute Maastricht, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands

Abstract

Successful translation of research focussing on atrial arrhythmogenic mechanisms has potential to provide a mechanism-tailored classification and to support personalised treatment approaches in patients with AF. The clinical uptake and clinical implementation of new diagnostic techniques and treatment strategies require translational research approaches on various levels. Diagnostic translation involves the development of clinical diagnostic tools. Additionally, multidisciplinary teams are required for collaborative translation to describe genetic mechanisms, molecular pathways, electrophysiological characteristics and concomitant risk factors. In this article, current approaches for AF substrate characterisation, analysis of genes potentially involved in AF and strategies for AF risk factor assessment are summarised. The authors discuss challenges and obstacles to clinical translation and implementation into clinical practice.

Keywords

Atrial fibrillation, mechanisms, risk factors, substrate, genes Disclosure: The authors have no conflicts of interest to declare.

Received: 5 January 2021 Accepted: 16 June 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(3):132–9. DOI: https://doi.org/10.15420/aer.2020.51 Correspondence: Ulrich Schotten, Department of Physiology, Cardiovascular Research Institute Maastricht, Faculty of Health, Medicine and Life Sciences, Maastricht University; PO Box 616 6200 MD Maastricht, the Netherlands. E: schotten@maastrichtuniversity.nl 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.

In AF patients, the initiation and progression of AF depend on the underlying arrhythmogenic substrates, genetics and concomitant risk factors, which may impact the clinical presentation of the arrhythmia and manifestation in different characteristic AF patterns. Current research projects focus on the development of several diagnostic techniques for the assessment of arrhythmogenic substrates in patients with AF (diagnostic translation). Additionally, multidisciplinary teams (collaborative translation) try to describe genetic mechanisms, molecular pathways, electrophysiological characteristics and concomitant risk factors with the goal to provide a more mechanism-tailored classification of AF with the potential to improve AF treatment in subgroups of patients.

that AF is a self-perpetuating arrhythmia because it causes proarrhythmic remodelling of the atria, both electrical and structural.1 Electrical remodelling is a relatively fast process, complete within 1–2 days of AF onset.2 It is characterised by a shortening of the atrial action potential and a corresponding reduction in the atrial refractory period, allowing higher fibrillation frequencies. As such, it is a pivotal factor in the early stabilisation of AF, when anti-arrhythmic drugs are still effective. Structural remodelling, which is thought to be responsible for the further progression of AF, develops over a much slower time course of months to years and is typified by myocyte hypertrophy, deposition of fibrous tissue and expansion of adipocytes.3,4

However, despite emerging evidence of the prognostic value of several new techniques and the potential utility to guide AF management, most of these strategies have not yet been implemented in the clinic. In this article, current approaches for AF substrate characterisation, analysis of genes potentially involved in AF and strategies for AF risk factor assessment are summarised. We discuss challenges and obstacles to clinical translation and implementation into clinical practice.

Atrial electrical and structural remodelling occur not only as a result of AF, but also due to factors increasing the risk for AF. Atrial remodelling has been studied in large animal models of, e.g. congestive heart failure (CHF), valvular disease, hypertension, sleep apnoea and obesity.5–9 In a goat model of ‘lone AF’, increased complexity of fibrillatory conduction and a loss of efficacy of anti-arrhythmic drugs was associated with the development of endomysial fibrosis, i.e. increased thickness of collagen septa between myocytes within bundles (also called reactive or interstitial fibrosis) and typically occurring in the absence of myocyte death.10,11 In contrast, a dog model of heart failure did show myocyte death and a corresponding pattern of replacement fibrosis.12 In a direct comparison

AF Pathogenesis

Large-animal models of AF have been of great importance in understanding the pathogenesis of AF. Seminal early studies demonstrated

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Assessment of Substrates, Genetics and Risk Factors Figure 1: Obstacles to Translation of Results from Large-animal Models of AF A

animal models inflammation stretch

AF patients

translational gap AF

pathogenic factor

ischaemia

time span, contributing to the ‘translational gap’ between insights from animal model and clinical practice (Figure 1).19 One important aspect of AF pathogenesis in patients that has not been replicated in animal models is the occurrence of spontaneous AF episodes originating in the pulmonary vein region. Whether this results from differences in anatomy, tissue architecture, or pathogenesis, as mentioned above, is currently unclear, but the lack of large animal models showing spontaneous AF paroxysms limits our understanding of the underlying mechanisms of this important manifestation of AF in patients.

?

?

?

atrial muscle

AF

The ‘translational gap’ between animal studies on AF pathogenesis and patient studies extends to diverging methods used for electrophysiological mapping of the AF substrate. Most mapping studies in animals were performed in open chest situations with epicardial arrays of unipolar electrodes. Although some mapping studies in patients implemented similar techniques during cardiac surgery, most were performed using either bipolar endocardial electrodes or non-contact mapping.20,21 Unipolar electrograms allow more precise determination of local activation times and provide information on the degree of fractionation without sensitivity to the direction of propagation.22,23 Moreover, epicardial access provides higher spatiotemporal resolution and, therefore, more accuracy in the reconstruction of the complex fibrillation patterns that are associated with AF progression.

AF

B perimysial

endomysial

85x

C

replacement

42x

Atrial DE

42x Voltage Map

In animal models, tissue samples for the detailed analysis of structural remodelling can be obtained under controlled conditions at different time points. In general, studies in human atrial samples remain essential to study the consequences of clinically relevant disease-related remodelling in patients. For example, recent work identified the proarrhythmic molecular and cellular mechanisms contributing to AF in patients with heart failure and sleep apnoea.24–26 However, human atrial samples are only available from patients undergoing cardiac surgery, who likely have a risk factor profile that is dominated by ischaemic heart disease and/or valve disease and may not be representative for all AF patients. Furthermore, atrial samples are often restricted to right or left atrial appendages, which may undergo remodelling distinct from regions that are considered more relevant for AF maintenance (e.g. the pulmonary veins and the left-atrial free wall).

Nonetheless, right-atrial sources for AF are increasingly reported.27,28 Most importantly, human atrial samples can only provide a single snapshot of the cumulative effect of all AF risk factors, ignoring their complex temporal dynamics.29

A: In animal models, pathogenic stimuli are applied at high intensity for a relatively short duration to young healthy animals. AF patients are often elderly and have an extensive history of underlying risk factors for AF. B: In animal studies, the availability of tissue samples allows detailed characterisation of tissue properties, including the distribution of various types of fibrosis. In patients, delayed enhancement imaging of the thin atrial wall has been used to visualise the distribution of fibrosis as a binary parameter (scar versus normal myocardium).11,33 C: In open-chest animal studies, high-density epicardial mapping of unipolar electrograms has allowed detailed reconstruction of complex fibrillation patterns, whereas (sequential) voltage mapping using bipolar electrograms in patients offers a less detailed view.33,95 DE = delayed enhancement.

Sources: B: Adapted from Weber et al. 1989.11 Used with permission from Elsevier.

B and C: Adapted from Chen et al. 2019.33 Used with permission from Oxford University Press.

C: Adapted from Verheule et al. 2010.95 Used with permission from Wolters Kluwer Health.

with a dog model of lone AF, the CHF model showed relatively simple fibrillation patterns and a higher efficacy of pharmacological cardioversion.13 This strongly suggests that the exact pattern of fibrosis, rather than the overall amount of fibrous tissue, determines AF complexity and stability, in a manner reminiscent of the relationship between fibrosis pattern and conduction abnormalities observed in the ventricle.14,15 In aggregate, evidence from diverging studies illustrates the complex interplay between anatomy, fibre architecture, patterns of fibrosis and other types of structural remodelling and their effect on AF pattern. For example, larger areas of (replacement) fibrosis may serve as an ‘anchor point’ for spiral waves and other macroreentrant patterns, whereas endomysial fibrosis with loss of side-to-side connections may precipitate microreentry or ‘zig-zag’ conduction even in relatively small tissue areas.16–18

As an alternative to histological analysis, several surrogate parameters have been developed for imaging of atrial tissue characteristics. These methods have an intrinsically lower resolution and are limited by the thinness of the atrial wall. Thus, imaging of fatty deposits does not allow the distinction of epicardial fat from intramyocardial fatty infiltrates.30 As a measure for fibrosis, imaging of regions with delayed enhancement of gadolinium has been used increasingly in recent years.31,32 Although this method has been validated histologically for large infarct scars in the thick ventricular wall, direct histological validation of delayed enhancement imaging in the atrium has been very limited.33 Therefore, the exact type and distribution of fibrous tissue (i.e. reactive versus replacement fibrosis) detected using this technique remains uncertain. Nevertheless, areas with delayed enhancement have been correlated to regions with lowvoltage electrograms, and are predictive of clinical outcome.34,35 Most notably, patient-specific mathematical models incorporating information from delayed enhancement imaging have been successfully used to guide ablation strategies.35

Obstacles to Clinical Translation Related to the Description of AF Pathogenesis

In contrast to the controlled circumstances and limited duration of pathogenic stimuli in animal models, AF patients often have several risk factors (including ageing) that may have progressed over a prolonged

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Assessment of Substrates, Genetics and Risk Factors Another strategy might be collection of blood biomarkers, representing different pathological pathways to evaluate the progression of atrial cardiomyopathy.36 Although not specific to atrial myocardial disease, various biomarkers characterising myocyte injury, inflammation and fibrosis have been linked to the occurrence and outcomes in AF. From an electrophysiological and pathophysiological point of view, biomarkers that characterise the atrial substrate may be more indicative of AF burden rather than the seemingly random time point at which AF is first documented.37

these can be used to successfully predict a person’s risk of developing AF.58 The authors of that study suggest that, “the identification of individuals at high risk should facilitate the design of efficient naturalhistory studies to discover early markers of disease onset and clinical trials to test prevention strategies.”

However, direct translation of GWAS data, outside of this domain has been complicated by a number of factors. These include the difficulty in determining the causal variant and the gene it affects, at most loci due to the effects of linkage disequilibrium, the fact that most GWAS variants are intergenic and the cost, in terms of both money and manpower, of following up on the large number of GWAS findings.

AF Genetics

Over the previous few decades, tremendous strides were made in elucidating the genetic underpinnings of AF.38 Family-based methods, primarily linkage and fine-mapping successfully detected numerous loci leading to Mendelian forms of AF. At least eighteen forms of monogenetic AF are described, including those resulting from mutations in genes that code for potassium voltage gated channels (KCNQ1, KCNE2, KCNA5 and KCNJ2) and sodium voltage-gated channel subunits (SCN1B, SCN2B, SCN3B, SCN4B and SCN5A), natriuretic peptides (NPPA), gap junctions (GJA5), nucleoporins (NUP155), ATP binding cassette transporters (ABCC9) and myosin light chains (MYL4).39–41 Causal genes have not been located for a number of other implicated regions.42 These findings generally involve rare, highly penetrant mutations with large effect sizes, but small population level risk.

These problems are exacerbated by the typically small effect sizes of these variants, which complicates the task of prioritisation for follow-up.

However, it is worth noting that variants with small effects may implicate genes which may be potent therapeutic targets. An excellent example is the 3-hydroxy-3-methylglutaryl-coA reductase (HMGCR) gene. Common GWAS variants in this gene are associated with LDL cholesterol levels, albeit with a comparatively modest effect size of ~0.06 mmol/l.59 The statin drugs, which act by inhibiting the protein product of the HMGCR gene, on the other hand, have large effects on serum LDL.60 This example – and others – suggests that validation and functional characterisation of GWAS findings may provide both mechanistic and clinically actionable insights into AF.

The mutations identified in family-based studies demonstrate the fundamental importance of two ion handling groups of proteins that can influence AF aetiology through a variety of related molecular mechanisms.

The potassium handling family of genes, for example, is involved in multiple facets of potassium induced current flows, particularly delayed rectifier outward currents (KCNQ1, KCNE2, KCNA5) and inward rectifier currents (KCNJ2, ABCC9).43,44 Mutations in β subunits of the voltage-gated sodium channels (SCN1B, SCN2B, SCN3B, SCN4B) have often been associated with decreases in sodium current density and/or late sodium currents, while those in α subunits, including SCN5A, lead to decreased channel expression and inactivation abnormalities and are associated with a considerable degree of phenotypic variability.45,46 Variants in the genes coding for both protein families alter cardiac action potentials.

Moreover, the value of GWAS, as well as genome- and exome-wide DNA sequencing studies, can be further exploited in several ways. The first is to use more precisely defined clinical phenotypes to discern genetic variants that may be associated with etiologically distinct forms of AF. The second is to perform genome-wide studies on novel endophenotypes, such as tissue characteristics (i.e. fibrosis, capillary rarefaction and fatty infiltration), sequential voltage mapping, unexplored ECG parameters, etc. Although it may not be feasible to ascertain sample sizes on the same scale as previously studied traits, these studies may yield findings that help to elucidate the genetic complexities of AF. Other forms of analysis may also shed light on AF. An important branch of emerging research examines the transcriptomics involved, either causally or in response to AF. Previous studies have suggested that transcriptional profiles are associated with AF; however, these studies have typically been hampered by the use of microarrays, in lieu of next-generation RNA sequencing, small sample sizes, limited analysis of selected transcripts and lack of replication.61 On-going studies, involving large numbers of atrial biopsies and state-of-the-art RNA sequencing methods, will allow unprecedented opportunities to evaluate the transcriptional landscape of AF, related endophenotypes (such as PR interval and P wave characteristics), markers of atrial remodelling and AF risk factors. As evidence continues to accumulate implicating the crucial role of noncoding RNA (including long non-coding RNA, microRNA, circular RNA, small nucleolar RNA and other species) on transcriptional regulation, RNA sequencing should yield considerable insight into not just genes involved in AF but the mechanisms of their control. These analyses will provide valuable information on the causes and consequences of AF, AF aetiology and AF biomarkers.

Genome-wide association studies (GWAS) of AF, by contrast, delineated numerous common polymorphisms with generally small effect sizes, but affecting larger segments of the population in individuals of European ancestry and others.47–55 These GWAS have been supplemented by whole exome sequencing and exome-chip analyses that have identified additional pertinent loci.56,57

Obstacles to Clinical Translation Related to AF Genetics

Despite the success of these studies in locating a large number of loci associated with AF and AF endophenotypes, substantial progress in translating this information into clinically relevant knowledge has largely not been realised to date. In familial settings, characterising mutations in currently unaffected individuals may lead to the prospective identification of cases. These data have also proven useful in terms of helping to characterise mechanisms that contribute to the development of AF. Nevertheless, given the rarity of these mutations, family-based data typically finds limited applicability in the general population.

RNA sequencing data will also provide valuable clues to the role of AFassociated genetic variants.62 Moreover, the integration of genomic and transcriptomic data will allow for more precise classification of AF patients – a goal considered crucial in the field.63 The application of machine-

GWAS, in contrast, has identified many common genetic AF susceptibility variants throughout the genome. Polygenic risk scores derived from

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Assessment of Substrates, Genetics and Risk Factors Figure 2: Leveraging Data Analysis and Integration to Elucidate AF Mechanisms and Classify Patients

sleep apnoea and endurance exercise, in particular, are separately mentioned.64 For all these modifiable AF risk factors, meta-analyses of observational studies or randomised intervention studies support the recommendations for clinical management of these conditions.65–69 Aggressive management of AF risk factors combined with lifestyle changes has been shown to control sinus rhythm in AF patients.65 Despite these described positive responses to risk factor management programmes in AF, other studies could not confirm these beneficial effects, suggesting, that there are potentially non-weight responsive forms of AF in some patients.70–73

AF

Clinical Features

Endophenotypes

Previous work showed that idiopathic AF patients develop cardiovascular disease more often, at a younger age and with a more severe disease profile compared to healthy sinus rhythm controls, suggesting the presence of subclinical comorbidities.74 Similarly, in a recent retrospective study of young AF patients (mean age 46 years), only 11% of patients were free of AF risk factors or comorbidities, whereas 44% had hypertension and 25% had a family history of AF.75

Genomics

Transcription

Despite the available evidence and the recommendations in current AF guidelines, the optimal approach to assess AF risk factors and specific lifestyle components remains unclear. In clinical practice, the presence of AF risk factors is generally considered a binary variable. However, AF risk factors (with the exception of the genetic component) may be dynamic, which results in a temporally variable exposure of the organism to arrhythmogenic conditions that may contribute to variability in the frequency, duration and timing of paroxysmal AF episodes.76 In addition to the structural remodelling process, which generally develops and progresses slowly, the exposure to variable AF risk factors may also contribute to temporal patterns of paroxysmal AF episodes by transient acute arrhythmogenic mechanisms.77 This may result in fluctuations in triggers and components of the substrate that can be rapidly modified such as post-translational modifications of proteins or autonomic nervous system activation, etc.19 The concept of a dynamic substrate for AF is summarised in Figure 3.

Other-omics

Machine learning/PRS/ Bioinformatics/etc

Genetic, transcriptomic and other -omic studies generate enormous quantities of data on AF, as well as important clinical characteristics and endophenotypes. Using machine learning approaches, bioinformatics and polygenic risk scores will help to create new phenotypic classes and stratify patients based on molecular mechanisms. These groupings can then serve as inputs to subsequent rounds of analysis in an iterative fashion to elucidate increasingly refined mechanistic underpinnings of AF, which may, in turn, lead to personalised medicine with different treatment modalities for specific subgroups of patients. PRS = polygenic risk scores.

Increasing arrhythmia risk

Figure 3: A Complex and Dynamic Substrate for AF Impacting AF Patterns Paroxysmal AF Pattern: Transient AF-promoting components Triggering paroxysmal AF episodes

Each AF risk factor has different dynamic components with distinct time courses. Advancing age is a slowly progressive AF-risk factor. Long-term untreated hypertension also has a strong progressive component.

Frequent alcohol intake is an important risk factor for new-onset AF. Furthermore, binge drinking, can also trigger paroxysmal AF episodes, known as the ‘holiday heart syndrome’.78

Arrhythmia risk

AF progression: Long-term exposure to risk factors Progressive AF substrate Time (several months to years)

Intense activity, sleep apnoea, excessive alcohol intake and surgery have major transient AF-promoting components that are due to modulation of systemic regulators such as activation of the autonomic nervous system in the case of exercise, intrathoracic pressure changes in sleep apnoea or inflammation following cardiac surgery. 8,79,80 These transient effects are partially or fully reversible and are modulated by variability in risk-factor severity.

Long-term exposure to risk factors result in a structural arrhythmogenic substrate and AF progression (red line). Transient AF-promoting components (e.g. individual sleep apnoea episodes, binge drinking, extensive sport activities, heart failure decompensation, surgeries, etc; blue lines) can trigger paroxysmal AF episodes by reaching a stage of high arrhythmia risk (dashed black line) if structural remodelling is present.

learning methods, such as random forests, will also yield more precise phenotypes for further genomic and transcriptomic discovery (Figure 2).

The VARIOSA-AF study is an example how transient AF-promoting factors can influence AF patterns: there is considerable night-to-night variability in sleep apnoea severity, which impacts AF risk associated with sleep apnoea severity in the preceding night.81,82 Additionally, over time these variable risk factors may also promote progressive structural remodelling processes. In rats, cumulative exposure to transient sleep apnoea-related conditions resulted in AF-substrates and was associated with increased AF-susceptibility.83 Of note, AF risk is not just determined by risk factors with clinical manifestation but also by variability in sub-clinical risk factors.

AF Risk Factors

Several cardiovascular risk factors contribute to AF initiation and progression (see the AF Pathogenesis section). In the current guidelines of the European Society of Cardiology for AF diagnosis and management, the importance of identification and management of established AFpromoting risk factors and unhealthy lifestyle is addressed and clearly recommended.63 In addition to non-modifiable factors such as advancing age and sex, hypertension, obesity, excessive alcohol consumption,

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Assessment of Substrates, Genetics and Risk Factors

Nutritional status

Lifestyle components

Physical activity

Figure 4: mHealth Technology Infrastructure and Assessment of Lifestyle Components

mHealth technologies Sleep quality

• Longitudinal data • Objectively measured • Behaviour-changing

Time Questionnaires • Spot assessments • Baseline only • Recall bias mHealth technologies could provide a promising infrastructure for a more objective and longitudinal assessment of lifestyle components.

In AF patients without overt risk factors, the inter-visit variability of metabolic parameters showed a close association with AF risk.84 Additionally, the combination of risk factors may be important as well. For example, rats with spontaneous hypertension and obesity show more pronounced structural remodelling and AF susceptibility than lean hypertensive rats.85

assessed once by questionnaires. Lifestyle, though, may vary (such as seasonal variation), again resulting in a dynamic exposure to lifestylerelated conditions which may critically impact the timepoint and extent of incident AF episodes (Figure 4).

Risk factor assessment, therefore, requires a longitudinal and remote structured monitoring infrastructure. Additionally, longitudinal documentation of risk factors during a modification programme may allow monitoring of the response to the intervention and adaptation and guidance, as required, to optimise the results. Recent technological advances have considerably expanded the options for non-invasive, longitudinal assessment of AF and potential underlying risk factors.

Implantable loop recorders and a variety of wearables enable longitudinal or (near) continuous AF monitoring, making it possible to directly link specific clinical conditions to the occurrence of AF. Furthermore, longitudinal risk factor monitoring is becoming increasingly feasible. For example, some pacemakers can perform continuous monitoring of sleep disordered breathing, and implantable pulmonary arterial pressure monitors provide haemodynamic information that is used in remote monitoring of HF patients.74,87 Finally, some blood-based biomarkers have been associated with AF.37 Repeated biomarker collection could potentially provide information about progressive atrial remodelling, although at present there are no biomarkers that specifically reflect individual AF mechanisms.

A binary assessment of AF risk factors, as currently practised clinically, may not adequately reflect the contribution of the respective risk factor on AF mechanisms and progression. Under circumstances of variable risk factors, the development of the AF substrate will depend critically on the cumulative exposure to the arrhythmogenic conditions (the risk factor burden represents the time exposed to a particular risk factor).

Despite convincing evidence of the need for risk factor management in AF patients, it remains unclear how best to assess substrates and risk factors and guide treatment, risk factor management and lifestyle modification.64 Established risk factors are often assessed only once in a structured way at the time point when patients present for the first time in the AF-clinic (spot-assessment of risk factors). However, several AF risk factors may show a high visit-to-visit or even day-to-day variability and lifestyle components, such as physical activity, diet and sleep behaviours, may be variable over time. Therefore, clinically relevant risk factors will be missed if the assessment is only performed once. Importantly, this variability does not just complicate the detection of AF risk factors but may also have a prognostic implication. High visitto-visit variability in risk factors is associated with increased risk of incident new-onset AF, worse cardiovascular outcome and increased mortality.86 Additionally, lifestyle components are often self-reported or

mHealth apps and smart technologies, such as activity trackers, Bluetoothlinked balances, blood pressure devices and apps to assess diet, may allow a widespread and affordable infrastructure for longitudinal risk factor identification and monitoring (Figure 4).88 Several mHealth

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Assessment of Substrates, Genetics and Risk Factors Figure 5: Translation from Experimental and Clinical Research to Mechanism-tailored AF Treatment Experimental Research Animal models

EP Mechanisms Reentry Ectopy

Clinical Investigation Cells/organoids

Human atrial tissue

Molecular pathways Fibrosis Ion channel function

Leading AF mechanisms

Biomarkers Genetics

Individual clinical features

Patients

- Clinical signs/symptoms - ECG/ECG imaging - Imaging - AF pattern/burden

Diagnostic Translation

Collaborative Translation

Mechanistic classification of AF based on clinical presentation of AF patients

Mechanism-tailored AF treatment Diagnostic and collaborative translation as important steps towards mechanism-tailored treatment of AF. EP = electrophysiology.

applications are available for the management of AF.89 In addition to the assessment of risk factors, mHealth infrastructures and apps can also be helpful in applying dedicated in-app coaching to improve lifestyle and control risk factors by behavioural changes.90–93

Diagnostic translation involves development of clinical diagnostic tools allowing the identification of mechanisms of AF. Examples are biomarkers for fibrosis or non-invasive electrophysiological markers of the degree of electrophysiological changes in the atria. Additionally, several large ongoing studies are attempting to establish associations between the clinical profile of AF patients derived from deep phenotyping with leading AF mechanisms identified on the tissue level.

This approach requires multidisciplinary teams studying genetic mechanisms, molecular pathways and electrophysiological characteristics on the tissue level in clinically well characterised patients (collaborative translation). Such approaches recently became feasible with advances in non-invasive or minimally invasive characterisation of AF patients (non-invasive electrophysiology, longitudinal risk factor assessment, AF-burden and patterns using mHealth technologies, wearables or implantable loop recorders) and the development of high throughput histological techniques and -omics approaches, such as RNA sequencing.

Obstacles to Clinical Translation Related to AF Risk Factors

Implementation of infrastructure for longitudinal assessment of variables such as risk factors, lifestyle components, or rate and rhythm information require adaptation of existing care coordination and clinical pathways.94 An important element for embedding mHealth in clinical practice is the accessibility of the recordings by other healthcare professionals. For this, a connection with the patients’ electronic healthcare record is crucial.

Additionally, many available devices and apps lack scientific validation and are written at excessively high reading-grade levels challenging users with limited health literacy.

Although technologies for longitudinal monitoring of lifestyle components and AF risk factors are available and may represent an interesting tool in future research projects, legal considerations and missing reimbursement models are still blocking wide implementation in existing clinical pathways.

A multidisciplinary effort by regulatory agencies, healthcare organisations and app sellers is required to improve relevance, scientific validity and readability of AF apps for AF patients. Additionally, discussions with insurance companies about reimbursement of mHealth infrastructures and with different stakeholders to agree on security and privacy regulations are initiated in different countries.

The development of a new mechanism-tailored classification AF will be essentially an iterative process, where particular investigational steps informed by initial outcomes are repeated to refine the classification. The application of machine learning methods will result in more precise phenotypes for further clinical investigations. This will, in turn, lead to a more exact AF taxonomy. Both diagnostic and collaborative translation aim at the development of a mechanism-based subclassification of AF potentially allowing for better treatment of subclasses of AF patients.

Supplementing these efforts with other current technological innovations, such as epigenetic sequencing, proteomics, metabolomics and microbiomics, will further the goal of developing mechanistic insights into AF pathology. The implementation of these methods, especially in conjunction with genomic and transcriptomic data, will further aid efforts to define molecular sub-types of AF aetiology and pathology.

Bridging the Translation Gap

Successful translation to develop a mechanism-tailored classification of AF with the potential to improve treatment in subgroups of patients will require translational research approaches on various levels (Figure 5).

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Clinical Perspective

• The best way how to assess substrates, genetics and risk factors in patients with AF remains unclear.

• A successful translation of research focussing on atrial arrhythmogenic mechanisms has the potential to provide a mechanism-tailored classification and to support personalised treatment approaches in patients with AF.

• The clinical uptake and clinical implementation of new diagnostic techniques and treatment strategies require translational research approaches.

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51. Lee JY, Kim TH, Yang PS, et al. Korean atrial fibrillation network genome-wide association study for early-onset atrial fibrillation identifies novel susceptibility loci. Eur Heart J 2017;38:2586–94. https://doi.org/10.1093/eurheartj/ehx213; PMID: 28460022.

52. Benjamin EJ, Rice KM, Arking DE, et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet 2009;41:879–81. https://doi. org/10.1038/ng.416; PMID: 19597492.

53. Low SK, Takahashi A, Ebana Y, et al. Identification of six new genetic loci associated with atrial fibrillation in the Japanese population. Nat Genet 2017;49:953–58. https://doi. org/10.1038/ng.3842; PMID: 28416822.

54. Christophersen IE, Rienstra M, Roselli C, et al. Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. Nat Genet 2017;49:946–52. https://doi.org/10.1038/ng.3843; PMID: 28416818.

55. Nielsen JB, Thorolfsdottir RB, Fritsche LG, et al. Biobankdriven genomic discovery yields new insight into atrial fibrillation biology. Nat Genet 2018;50:1234–9. https://doi. org/10.1038/s41588-018-0171-3; PMID: 30061737.

56. Weng LC, Hall AW, Choi SH, et al. Genetic determinants of electrocardiographic p-wave duration and relation to atrial fibrillation. Circ Genom Precis Med 2020;13:387–95. https:// doi.org/10.1161/CIRCGEN.119.002874; PMID: 32822252.

57. Lin H, van Setten J, Smith AV, et al. Common and rare coding genetic variation underlying the electrocardiographic PR interval. Circ Genom Precis Med 2018;11:e002037. https:// doi.org/10.1161/CIRCGEN.117.002037; PMID: 29748316.

58. Khera AV, Chaffin M, Aragam KG, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet 2018;50:1219–24. https://doi.org/10.1038/s41588-018-0183-z; PMID: 30104762.

59. Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids.

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60. Stancu C, Sima A. Statins: mechanism of action and effects.

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61. Deshmukh A, Barnard J, Sun H, et al. Left atrial transcriptional changes associated with atrial fibrillation susceptibility and persistence. Circ Arrhythm Electrophysiol 2015;8:32–41. https://doi.org/10.1161/CIRCEP.114.001632; PMID: 25523945.

62. Hsu J, Gore-Panter S, Tchou G, et al. Genetic control of left atrial gene expression yields insights into the genetic susceptibility for atrial fibrillation. Circ Genom Precis Med 2018;11:e002107. https://doi.org/10.1161/CIRCGEN.118.002107; PMID: 29545482.

63. Fabritz L, Guasch E, Antoniades C, et al. Expert consensus document. Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment. Nat Rev Cardiol 2016;13:230–7. https://doi.org/10.1038/nrcardio.2015.194; PMID: 26701216.

64. 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.

65. Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and cardiometabolic risk factor management on

symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial. JAMA 2013;310:2050– 60. https://doi.org/10.1001/jama.2013.280521; PMID: 24240932.

66. Pathak RK, Middeldorp ME, Meredith M, et al. Longterm effect of goal-directed weight management in an atrial fibrillation cohort: a long-term follow-up study (LEGACY). J Am Coll Cardiol 2015;65:2159–69. https://doi.org/10.1016/j. jacc.2015.03.002; PMID: 25792361.

67. 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.

68. Elliott AD, Linz D, Mishima R, et al. Association between physical activity and risk of incident arrhythmias in 402 406 individuals: evidence from the UK Biobank cohort. Eur Heart J 2020;41:1479–86. https://doi.org/10.1093/eurheartj/ehz897; PMID: 31951255.

69. Linz D, McEvoy RD, Cowie MR, et al. Associations of obstructive sleep apnea with atrial fibrillation and continuous positive airway pressure treatment: a review.

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70. Mohanty S, Mohanty P, Natale V, et al. Impact of weight loss on ablation outcome in obese patients with longstanding persistent atrial fibrillation. J Cardiovasc Electrophysiol 2018;29:246–53. https://doi.org/10.1111/jce.13394; PMID: 29171116.

71. Yaeger A, Cash NR, Parham T, et al. Nurse-led limited risk factor modification program to address obesity and obstructive sleep apnea in atrial fibrillation patients. J Am Heart Assoc 2018;7:e010414. https://doi.org/10.1161/ JAHA.118.010414; PMID: 30571593.

72. Yaeger A, Keenan BT, Cash NR, et al. Impact of a nurse-led limited risk factor modification program on arrhythmia outcomes in patients with atrial fibrillation undergoing catheter ablation. J Cardiovasc Electrophysiol 2020;31:423–31. https://doi.org/10.1111/jce.14336; PMID: 31916273.

73. Yew Ding W, Kozhuharov N, Hao Chin S, et al. Feasibility of weight loss in obese atrial fibrillation patients attending a specialist arrhythmia clinic and its impact on ablation outcomes. J Arrhythm 2020;36:984–90. https://doi. org/10.1002/joa3.12432; PMID: 33335614.

74. Weijs B, de Vos CB, Tieleman RG, et al. The occurrence of cardiovascular disease during 5-year follow-up in patients with idiopathic atrial fibrillation. Europace 2013;15:18–23. https://doi.org/10.1093/europace/eus203; PMID: 22782972.

75. De With RR, Marcos EG, Van Gelder IC, et al. Atrial fibrillation progression and outcome in patients with youngonset atrial fibrillation. Europace 2018;20:1750–7. https://doi. org/10.1093/europace/euy028; PMID: 29518195.

76. Wineinger NE, Barrett PM, Zhang Y, et al. Identification of paroxysmal atrial fibrillation subtypes in over 13,000 individuals. Heart Rhythm 2019;16:26–30. https://doi. org/10.1016/j.hrthm.2018.08.012; PMID: 30118885.

77. De With RR, Erküner Ö, Rienstra M, et al. Temporal patterns and short-term progression of paroxysmal atrial fibrillation: data from RACE V. Europace 2020;22:1162–72. https://doi. org/10.1093/europace/euaa123; PMID: 32642768.

78. Linz D, Crijns HJGM. Alcohol abstinence in drinkers with atrial fibrillation. N Engl J Med 2020;382:1768. https://doi. org/10.1056/NEJMc2001512; PMID: 32348656.

79. Guasch E, Benito B, Qi X, et al. Atrial fibrillation promotion by endurance exercise: demonstration and mechanistic exploration in an animal model. J Am Coll Cardiol 2013;62:68–77. https://doi.org/10.1016/j.jacc.2013.01.091; PMID: 23583240.

80. Dobrev D, Aguilar M, Heijman J, et al. Postoperative atrial fibrillation: mechanisms, manifestations and management.

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81. Linz D, Brooks AG, Elliott AD, et al. Nightly variation in sleep

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apnea severity as atrial fibrillation risk. J Am Coll Cardiol 2018;72:2406–7. https://doi.org/10.1016/j.jacc.2018.08.2159; PMID: 30384896.

82. Linz D, Brooks AG, Elliott AD, et al. Variability of sleep apnea severity and risk of atrial fibrillation: the VARIOSA-AF study.

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83. Linz B, Hohl M, Lang L, et al. Repeated exposure to transient obstructive sleep apnea-related conditions causes an atrial fibrillation substrate in a chronic rat model. Heart Rhythm 2021;18:455–64. https://doi.org/10.1016/j. hrthm.2020.10.011; PMID: 33080392.

84. Lee SR, Choi EK, Han KD, et al. Effect of the variability of blood pressure, glucose level, total cholesterol level, and body mass index on the risk of atrial fibrillation in a healthy population. Heart Rhythm 2020; 17:12–9. https://doi. org/10.1016/j.hrthm.2019.07.006; PMID: 31299298.

85. Hohl M, Lau DH, Müller A, et al. Concomitant obesity and metabolic syndrome add to the atrial arrhythmogenic phenotype in male hypertensive rats. J Am Heart Assoc 2017;6:e006717. https://doi.org/10.1161/JAHA.117.006717; PMID: 28919580.

86. Linz D, Baumert M, Desteghe L, et al. Nightly sleep apnea severity in patients with atrial fibrillation: potential applications of long-term sleep apnea monitoring. Int J Cardiol Heart Vasc 2019;24:100424. https://doi.org/10.1016/j. ijcha.2019.100424; PMID: 31763438.

87. Dickinson MG, Allen LA, Albert NA, et al. Remote monitoring of patients with heart failure: a white paper from the Heart Failure Society of America Scientific Statements Committee.

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88. Hermans ANL, van der Velden RMJ, Gawalko M, et al.

On-demand mobile health infrastructures to allow comprehensive remote atrial fibrillation and risk factor management through teleconsultation. Clin Cardiol 2020;43:1232–9. https://doi.org/10.1002/clc.23469; PMID: 33030259.

89. Lane DA, McMahon N, Gibson J, et al. Mobile health applications for managing atrial fibrillation for healthcare professionals and patients: a systematic review. Europace 2020;22:1567–78. https://doi.org/10.1093/europace/ euaa269; PMID: 3285336.

90. Guo Y, Chen Y, Lane DA, et al. Mobile health technology for atrial fibrillation management integrating decision support, education, and patient involvement: mAF App trial. Am J Med 2017;130:1388-1396.e6. https://doi.org/10.1016/j. amjmed.2017.07.003; PMID: 28847546.

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Clinical Arrhythmias

Sleep Apnoea and AF: Where Do We Stand? Practical Advice for Clinicians Suneet Mittal ,1,2 David Golombeck

2

and Jacqueline Pimienta

2

1. Snyder Center for Comprehensive Atrial Fibrillation, Paramus, NJ, US; 2. Valley Health System, Ridgewood, NJ, US

Abstract

AF is the most common sustained arrhythmia encountered in clinical practice. Among the largest contributing factors to the rapid increase in the incidence of AF are aging and obesity within the global population. Obstructive sleep apnoea (OSA) is a risk factor for AF that is clearly linked to obesity. Guidelines have advocated interrogation for clinical signs of OSA in all AF patients. The aim of this article is to provide practical advice for clinicians seeking to manage patients with AF and OSA. The authors discuss questionnaires to screen for OSA, various types of tests available for the diagnosis of OSA and data to assess the impact of treatment of OSA after various treatment options in AF patients. Finally, they outline the many areas that warrant further investigation in this patient population.

Keywords

AF, continuous positive airway pressure, obstructive sleep apnoea, outcomes, treatment Disclosure: The authors have no conflicts of interest to declare.

Received: 5 February 2021 Accepted: 8 July 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(3):140–6. DOI: https://doi.org/10.15420/aer.2021.05 Correspondence: Suneet Mittal, Valley Health System, 970 Linwood Avenue, Paramus, NJ 07652, US. E: mittsu@valleyhealth.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.

AF is the most common sustained arrhythmia encountered in clinical practice. In 2010, the global AF population was 33.5 million. It is estimated that the number of AF cases will increase by approximately 5 million people per year, with annual cases likely to double by 2030.1 AF increases the risk of stroke fivefold and increases the risk of morbidity and mortality.2 Among the largest contributing factors for the rapid increase in the incidence of AF are aging and obesity.3 Risk factors independently associated with AF that are linked to obesity include hypertension, diabetes, obstructive sleep apnoea (OSA), alcohol consumption and poor cardiorespiratory fitness.4 The aim of this article is to provide practical advice for clinicians seeking to manage patients with AF and OSA.

AF in patients with OSA has been estimated to be between 3% and 5%, which is higher than the prevalence in the general population. OSA is considered an independent risk factor for AF (HR 2.18; 95% CI [1.34– 3.54]).4 Whether the risk of developing AF is proportional to the severity of OSA remains unclear. Nonetheless, the most recent European Society of Cardiology (ESC) guidelines advocate opportunistic screening for AF in patients with OSA (class of recommendation: IIa; level of evidence: C).10 The prevalence of OSA in patients with AF is 21–74%, which provides support for this recommendation.11 Current guidelines advocate addressing risk factors such as obesity and OSA in all patients with AF. In support of this, the LEGACY study demonstrated that weight loss alone can reduce the burden of AF and promote maintenance of sinus rhythm.12 In fact, weight loss ≥10% resulted in a sixfold greater probability of arrhythmia-free survival. In addition, the importance of weight maintenance was further emphasised, because patients whose weight fluctuated >5% were twice as likely to have AF recurrence.12

Obese individuals are more susceptible to repeated closure of the upper airway, known as OSA, during sleep. Additional risk factors include male sex and increasing age. Typical symptoms include snoring, fatigue, disrupted sleep and excessive daytime sleepiness. Continued nightly intermittent airway obstruction leads to large swings in negative intrathoracic airway pressure, intermittent hypoxia, repeated arousals from sleep and neurohumoral activation, all of which contribute to adverse cardiovascular events.5–7 Obstructive respiratory events result in an increased occurrence of spontaneous premature atrial contractions, which are potent triggers for AF episodes. In addition, airway obstruction promotes left atrial dilatation, slows atrial conduction and shortens the atrial effective refractory period, all of which make the atrium more susceptible to AF.7,8 OSA has also been shown to increase systemic inflammation, which may further predispose to the initiation of AF.7

With respect to OSA, before it can be treated it has to be diagnosed. Prior guidelines have advocated interrogation for clinical signs of OSA in all AF patients.4 Unfortunately, the optimal method to determine which patients require sleep testing remains undefined.

Screening Questionnaires

Numerous screening questionnaires have been developed to screen for patients at risk for OSA and determine who should be referred for polysomnography (PSG), also known as a sleep study.

Relationship Between Obstructive Sleep Apnoea and AF

There is a clear relationship between OSA and AF. Patients with OSA are two- to fourfold more likely to develop AF.9 The prevalence of nocturnal

Commonly used questionnaires include the Epworth Sleepiness Scale (ESS), the Berlin questionnaire and the STOP-BANG questionnaire

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Sleep Apnoea and AF Table 1: Screening Questionnaires for Obstructive Sleep Apnoea Questionnaire Epworth Sleepiness Scale

13

Berlin Questionnaire14

STOP-BANG Questionnaire15

Questions How likely are you to doze off or fall asleep in the following situations?

For each situation, assign ‘chance of dozing’ from 0 to 3: 0 = none; 1 = slight chance; 2 = moderate chance; 3 = high chance

Category 1 1. Do you snore? If yes: 2. Your snoring is: a. Slightly louder than breathing b. As loud as talking c. Louder than talking 1. Sitting and reading d. Very loud (can be heard outside of room) 3. How often do you snore?

2. Watching TV a. Nearly every day 3. Sitting, inactive in a public place b. 3–4 times a week 4. As a passenger in a car for an hour without a break c. 1–2 times a week 5. Lying down to rest in the afternoon when circumstances d. 1–2 times a month permit e. Rarely or never 6. Sitting and talking to someone 4. Has your snoring ever bothered people?

7. Sitting quietly after lunch without alcohol 5. Has anyone noticed that you stop breathing during 8. In a car, while stopped for a few minutes in traffic sleep? a. Nearly every day b. 3–4 times a week c. 1–2 times a week d. 1–2 times a month e. Rarely or never

1. Snoring? (Do you snore loudly enough to disturb your bed partner or be heard through a closed door?)

2. Tired? (Do you often feel tired, fatigued or sleepy during the daytime?)

3. Observed? (Has anyone observed you stop breathing or gasping/choking for air while sleeping?)

4. Pressure? (Do you have high blood pressure?)

5. BMI ≥35 kg/m2?

6. Age >50 years old?

7. Neck size large? (Neck circumference ≥43 cm in men or ≥41 cm in women?)

8. Gender = male?

Category 2 6. How often do you feel tired or fatigued after your sleep? a. Nearly every day b. 3–4 times a week c. 1–2 times a week d. 1–2 times a month e. Rarely or never 7. During your waking time, do you feel tired, fatigued or not up to par? a. Nearly every day b. 3–4 times a week c. 1–2 times a week d. 1–2 times a month e. Rarely or never 8. Have your ever nodded off or fallen asleep while driving a vehicle? If yes: 9. How often does this occur? a. Nearly every day b. 3–4 times a week c. 1–2 times a week d. 1–2 times a month e. Rarely or never Category 3 10. Do you have high blood pressure?

Scoring System Add ‘chance of dozing’ score for each question together Add points for each category individually Category 1 Q1 and Q4: ‘yes’ = 1 point each Q2: ‘c’ or ‘d’ = 1 point Q3 and Q5: ‘a’ or ‘b’ = 1 point each

Each question answered ‘yes’ is given 1 point; then, sum the number of points

Category 2 Q6 and Q7: ‘a’ or ‘b’ = 1 point each Q8: ‘a’ = 1 point

Score Interpretation Normal = 0–9 points Significant daytime sleepiness ≥10 points

Category 1: ‘positive’ if score ≥2 Category 2: ‘positive’ if score ≥ 2 Category 3: ‘positive’ if Q10 ‘yes’ and/or BMI ≥30 kg/m2 Low risk = none or one positive category High risk = two or all positive categories

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Low risk = 0–2 points Intermediate risk = 3–4 points High risk ≥5 points

Sleep Apnoea and AF Table 2: Types of Sleep Studies Level I

Standard PSG, includes EEG (frontal, central and occipital derivations), EOG, chin EMG, ECG and recordings of airflow, respiratory effort, oxygen saturation, and limb EMG; a technician is in constant attendance

Level II

Comprehensive portable PSG is the same as Level I except that a heart rate monitor can replace the ECG and a technician is not in constant attendance

Level III

Modified portable sleep apnoea testing is a cardiorespiratory study that includes ventilation (at least two channels of respiratory movement or respiratory movement and airflow), heart rate or ECG, and oxygen saturation

Level IV

Continuous (single or dual) bioparameter recordings where devices that measure a minimum of one parameter, usually oxygen saturation, are used

EMG = electromyogram; EOG = electrooculogram; PSG = polysomnography. Source: Jafari et al.16

(Table 1).13-15 Unfortunately, the sensitivity and specificity of these questionnaires in AF patients remain poorly defined. Ideally, all patients with AF would undergo PSG; however, in the US, this is usually not possible due to constraints imposed by insurance coverage regulations.

In our own experience of consecutive patients undergoing PSG, 85% had OSA and approximately 50% had moderate to severe OSA.

negative test result or underestimate the severity of OSA compared with in-laboratory PSG.17 PSG allows one to grade the severity of sleep apnoea based on the apnoea–hypopnoea index (AHI). An apnoea or hypopnoea event is counted if it lasts at least 10 seconds.18 Obstructive and central apnoeas are differentiated by looking at the thoracoabdominal band readings to determine whether there was persistent or absent respiratory effort.

Obstructive apnoeas show movement, indicating that respiratory effort was present, whereas central apnoeas demonstrate no movement, so no respiratory effort was measured.

Epworth Sleepiness Scale

The ESS is a self-reported scale that evaluates the level of daytime sleepiness. Patients are asked to rate their ‘chance of dozing’ on a scale of 0–3 (0, would never dose; 1, slight chance of dozing; 2, moderate chance of dozing; 3, high chance of dozing) in eight different situations that are commonly encountered in daily life. The sum of the eight ratings gives the ESS score, which ranges from 0 to 24. ESS scores ≥10 suggest significant daytime sleepiness and would warrant a sleep study.13

Conversely, hypopnoeas are more difficult to define. The current American Academy of Sleep Medicine recommended definition for hypopnoeas includes a minimum 10-second duration and a ≥30% airflow reduction associated with ≥3% oxygen desaturation and arousal.19 The acceptable definition of hypopnoeas used by the Centers for Medicare & Medicaid Services is a minimum 10 s duration and ≥30% airflow reduction associated with ≥4% oxygen desaturation; there is no requirement to demonstrate arousal.20 Based on the AHI, patients are categorised as having no OSA (AHI <5), mild OSA (5 ≤ AHI < 15), moderate OSA (15 ≤ AHI <30) or severe OSA (AHI ≥30).

Berlin Questionnaire

The Berlin questionnaire incorporates history of snoring, degree of tiredness, witnessed apnoeas, history of hypertension and obesity. Each question is within one of three categories, and each category has its own point system. The first category asks questions regarding snoring and witnessed apnoeas; the second category examines the level of tiredness; and the third category asks whether a patient has high blood pressure and incorporates their BMI. For this questionnaire, a BMI ≥30 kg/m2 is considered high risk. A patient is categorised as being low risk for OSA if they have one or no categories with a positive score and high risk if two or more categories are positive.14

Alternative methods to at-home PSG have been proposed. In recent years, there has been increased use of WatchPAT (PAT = peripheral arterial tonometry) as a method of home sleep testing. The system is grounded on a wrist-worn device with a finger probe that obtains PAT signals and oxygen saturation levels, a snoring and body position sensor that is positioned under the sternal notch and an accelerometer that is embedded in the wrist unit.21 The device’s algorithm detects respiratory (apnoea/hypopnoea) events and sleep–wake status, and determines sleep stages. The ability to differentiate sleep stages is an important improvement over more conventional methods of home sleep testing.22,23 A recent study assessed the simultaneous use of a WatchPAT device in AF patients undergoing in-laboratory PSG, finding very high correlation between the two.21

STOP-BANG Questionnaire

The STOP-BANG questionnaire consists of eight questions that are answered with either a ‘yes’ or a ‘no.’ The questions evaluate the presence of loud snoring, tiredness, observed apnoeas, BMI ≥35 kg/m2, age >50 years, large neck circumference (≥43 cm in men and ≥41 cm in women) and male sex. Each question answered ‘yes’ is given 1 point; thus, the aggregate score ranges from 0 to 8. A person with a score of 0–2 is considered to be at low risk of OSA, whereas those with a score of 3–4 are considered to be at moderate risk and those with scores ≥5 are considered to be at high risk.15

The diagnostic utility of overnight oximetry in AF patients has been evaluated as a means to provide a more accessible and cost-effective tool for the diagnosis of sleep disordered breathing (SDB). Among 439 patients with AF, overnight oximetry was used in combination with a novel automated computer algorithm to calculate the oxygen desaturation index (ODI; number of desaturations/hour).24 The ODI scores for these patients were subsequently compared to AHI scores obtained from an in-laboratory PSG. An ODI cut-off of 4.1 events/h had 91% sensitivity and 83% specificity for identifying patients with an AHI ≥15; similarly, an ODI cut-off of 7.6 events/hour had 89% sensitivity and 83% specificity for identifying patients with an AHI ≥30.24 Conversely, the negative predictive value for exclusion of OSA by oximetry was >95%.24 Thus, it may be

Diagnosing Obstructive Sleep Apnoea

The gold standard for the diagnosis of sleep apnoea is PSG, which uses various methods to simultaneously and continuously record neurophysiological, cardiopulmonary and other physiological parameters over the course of several hours, usually during an entire night.16 There are four types of sleep studies available, depending on the number of physiological variables being recorded (Table 2). In patients with AF, athome PSG has largely replaced in-laboratory testing given issues of patient compliance, underlying costs and insurance constraints. However, clinicians should be aware that a home sleep test (HST) may yield a false

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Sleep Apnoea and AF Table 3: Approach to Treatment of Obstructive Sleep Apnoea

significant variability in nightly RDI (absolute SD of ±6.3 events/hour; range 2–14 events/hour). The nights with the highest RDI were associated with a higher likelihood of experiencing >5 minutes, >1 hour or >12 hours of AF on the same day.26 These data suggest that symptomatic patients who test negative for OSA may benefit from repeated testing due to the day-to-day variability in respiratory events.

Sleep Modifications Positional therapy • Advantages: non-invasive, reduces snoring • Disadvantages: uncomfortable

Treatment of Obstructive Sleep Apnoea in AF Patients

Dental appliances • Advantages: reduce snoring • Disadvantages: uncomfortable, cost

There has been great interest in treating OSA in patients with AF. Treatment has focused on modifications during sleep, lifestyle modifications, institution of positive airway pressure (PAP) and implantable device therapy (Table 3). Current guidelines state that optimal management of OSA may be considered to reduce AF incidence, AF progression, AF recurrences and symptoms.27 However, this carries only a Class IIb level of recommendation with Level C evidence, suggesting weakness in the currently available data. Until randomised clinical trials can be performed, it is unlikely that guidelines will impart a higher level of recommendation for treatment of OSA in AF patients.

Lifestyle Modifications Reduce alcohol intake • Advantages: may promote weight loss and other beneficial health outcomes • Disadvantages: may require time-consuming and costly treatment Weight loss Diet and exercise • Advantages: non-invasive, may promote other beneficial health outcomes • Disadvantages: time-consuming, requires long-term maintenance Bariatric surgery • Advantages: rapid, effective • Disadvantages: invasive, possibility of complications, nutritional deficiencies

Numerous studies have evaluated the consequences of OSA in AF patients, as well as the impact of continuous positive airway pressure (CPAP) on outcomes (Table 4). The ORBIT-AF, a registry of outpatients in the US with AF, enrolled 10,132 patients, 18% of whom had cliniciandefined OSA.28 In adjusted analyses, patients with OSA had a higher risk of hospitalisation (HR 1.12; 95% CI [1.03–1.22]; p=0.0078), but no difference in the risk of death (HR 0.94; 95% CI [0.77–1.15]; p=0.54), the composite of cardiovascular death, MI and stroke/transient ischemic attack (HR 1.07; 95% CI [0.85–1.34]; p=0.57), major bleeding (HR 1.18; 95% CI [0.96–1.46]; p=0.11) or AF progression (HR 1.06; 95% CI [0.89–1.28]; p=0.51).28 However, patients with OSA on CPAP treatment were less likely to progress to more permanent forms of AF than patients without CPAP (HR 0.66; 95% CI [0.46–0.94]; p=0.021).28 A limitation of that study is that the results of sleep testing were not available and so the severity of underlying OSA was unknown.

Therapeutic Approaches Continuous positive pressure therapy • Advantages: gold standard, reduces snoring, multiple customisable options (CPAP, BiPAP, ASV) • Disadvantages: uncomfortable, cost (loss of insurance coverage if not used enough), loud (may disturb patient and/or bed partner) Implantable device therapy • Advantages: long-term treatment, effective for those who cannot tolerate PAP therapy, minimally invasive, easy to use • Disadvantages: possibility of complications ASV = adaptive servo ventilation; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; PAP = positive airway pressure.

possible to use overnight oximetry-derived ODI as a low-cost, accessible screening tool for SDB, especially as a method of excluding moderate– severe sleep apnoea.

The severity of OSA can influence the response to antiarrhythmic drug (AAD) therapy. One study evaluated 61 patients treated with an AAD for symptomatic AF who underwent overnight PSG.29 Twenty-four (40%) of those patients had severe OSA. Ultimately, 30 (49%) patients were rhythm controlled with an AAD, defined as a patient remaining on the same AAD therapy for ≥6 months with a ≥75% reduction in symptomatic AF burden.29 Non-responders to an AAD were more likely to have severe OSA than milder disease (52% versus 23%; p<0.05); those with severe OSA were less likely to respond to an AAD than participants with non-severe OSA (39% versus 70%; p=0.02).29

Regardless of the method chosen for diagnosis, additional limitations must be recognised. The severity of OSA is primarily determined by the AHI, which is the number of hypopnoeas and apnoeas per hour of sleep.

However, the detrimental effect of sleep apnoeas on the cardiovascular system may depend on the sleep stage in which the apnoeas occur, as well as whether they are associated with autonomic activation and cortisol arousals. For example, rapid eye movement (REM) sleep is associated with greater sympathetic activity, decreased vagal tone and cardiovascular instability. Consequently, obstructive respiratory events occurring during REM sleep could yield worse cardiovascular outcomes than events occurring in non-REM sleep.25 Furthermore, AHI scores do not fully address the absolute degree and duration of oxygen desaturation, and thus do not distinguish between patients with shorter, more mild episodes of OSA and those who have longer episodes with a greater degree of oxygen desaturation.25

This issue has also been examined in a population of AF patients undergoing electrical cardioversion. Linz et al. examined 72 patients with symptomatic persistent AF and an ESS score >10 who were undergoing cardioversion.30 Two minutes after cardioversion, which was performed under deep sedation, obstructive respiratory events (OREs) were determined visually and defined as cessation of air flow with maintained breathing efforts for at least 10 seconds. An ORE was observed in 40 (56%) patients; the incidence of premature atrial contractions (PACs) following cardioversion was significantly higher in patients with than without OREs (mean [± SD] 7 ± 2 versus 1 ± 1 /10 seconds, respectively; p<0.01). In addition, upon insertion of a nasopharyngeal tube, the occurrence of PACs was reduced by 79%.29 Moreover, of 20 patients who were found to have recurrent AF 1 week after cardioversion, 16 were in the ORE group and only

In addition to making sleep testing more readily accessible to patients, other issues with sleep testing must be addressed. The VARIOSA-AF Study used data from implanted pacemakers to demonstrate that there is dayto-day variability in the degree of SDB in AF patients.26 That observational cohort study evaluated 72 patients with a pacemaker capable of measuring a respiratory disturbance index (RDI), with an RDI ≥20/hour considered a marker of severe SDB. Individual patients showed a

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Sleep Apnoea and AF Table 4: Effect of Obstructive Sleep Apnoea on Outcomes in Patients with AF Source

Study Design

Patients Population with OSA (n)

Central Findings

ORBIT-AF 201526

Contemporary multicentre 1,841 registry of 10,132 patients with AF

Outpatients in US with AF

Prospective single-centre 61 registry

Patients with AF or atrial flutter Non-responders to antiarrhythmic drugs were more likely to have treated with ≥1 antiarrhythmic drug severe OSA than milder disease (52% versus 23%; p<0.05)

Linz et al. 201528

Prospective single-centre 72 study

Patients with persistent AF Patients were assessed for the presence of OREs following undergoing electrical cardioversion sedation Patients with OREs had a higher incidence of PACs after cardioversion; these could be abolished by insertion of a nasopharyngeal tube Patients with an ORE had a higher incidence of recurrent AF within the first week of cardioversion (p<0.01)

Caples et al. 201929

Single-centre randomized 25 trial

Patients with AF who underwent Patients with OSA were randomized to receive CPAP versus usual electrical cardioversion followed by care assessment of OSA Use of CPAP did not reduce the likelihood of patients having recurrent AF

Patel et al. 201030

Multicentre study

640

3000 consecutive patients undergoing pulmonary vein antral isolation

Patients with paroxysmal and persistent AF and OSA were: • more likely to have a non-pulmonary vein trigger • more likely to fail the ablation procedure Patients treated with CPAP therapy were more likely to maintain sinus rhythm than AF patients with OSA not using CPAP (79% versus 68%; p=0.003)

Fein et al. 201331

Prospectively collected single-centre database

62

Consecutive patients with AF undergoing ablation who had known moderate to severe OSA

Approximately half the patients were using CPAP 1 year after ablation, AF recurrence was reduced in patients on CPAP compared with patients not using CPAP (28.2% versus 63.3%; p=0.01)

Naruse et al. 201332

Prospectively collected single-centre database

116

Patients tested for OSA 1 week after undergoing AF ablation Patients with any degree aof OSA included

The presence of OSA was associated with a higher recurrence of AF during follow-up (HR 2.61; 95% CI [1.12–6.09]; p<0.05) In patients with OSA, the use of CPAP reduced the risk of AF (HR 0.41; 95% CI [0.22–0.76]; p<0.01)

Neilan et al. 201333

Prospectively collected single-centre database

142

Consecutive AF patients undergoing The presence of OSA (HR 2.79; CI [1.97–3.94]; p<0.0001) and a pre-ablation cardiac MRI untreated OSA (HR 1.61; CI [1.35–1.92]; p<0.0001) were associated with AF recurrence All patients were screened and tested for OSA

Patients with OSA had a higher risk of hospitalization (HR 1.12; 95% CI [1.03–1.22]; p=0.0078) Patients with OSA on CPAP treatment were less likely to progress to more permanent forms of AF than patients without CPAP (HR 0.66; 95% CI [0.46–0.94]; p=0.021)

Antiarrhythmics Monahan et al. 201227

After Cardioversion

After Ablation

CPAP = continuous positive airway pressure; OREs = obstructive respiratory events; OSA = obstructive sleep apnoea; PACs = premature atrial contractions.

four patients were among those without OREs (p<0.01).30 A small study randomised 25 patients diagnosed with OSA following cardioversion to receive CPAP therapy or usual care.31 In that study, the use of CPAP did not reduce the likelihood of patients having recurrent AF.

OSA treated with CPAP were more likely to maintain sinus rhythm (79% versus 68% in patients not using CPAP; p=0.003).32 However, compliance with CPAP was self-reported.

Subsequently, a number of prospectively collected single-centre database studies have been reported. Fein et al. assessed a database of 426 patients who underwent AF ablation; of these, 62 (15%) patients had PSGconfirmed moderate or severe OSA.33 CPAP use was present in 32 (52%) patients with OSA and resulted in a higher AF-free survival rate (71.9% versus 36.7%; p=0.01) and AF-free survival off an AAD or repeat ablation following pulmonary vein isolation (65.6% versus 33.3%; p=0.02). The AF recurrence rate in CPAP-treated patients was similar to that in patients without OSA (HR 0.7, p=0.46).33 Naruse et al. evaluated 153 patients who underwent a PSG 1 week after AF ablation.34 An AHI ≥5 was present in 116 (76%) patients. The presence of OSA was associated with a higher recurrence rate of AF during follow-up (HR 2.61; 95% CI [1.12–6.09]; p<0.05). CPAP was used in 82 (71%) patients with OSA and was associated

One of the major unanswered questions is the effect of OSA, and CPAP therapy, on outcomes after catheter ablation of AF. The largest study to date evaluated 3,000 patients enrolled in a multicentre database, 640 (21%) patients having at least moderate OSA.32 No information was provided on how OSA was assessed or when it was assessed relative to ablation. The ablation included pulmonary vein antral, posterior wall and superior vena cava isolation in patients with paroxysmal AF; in persistent AF patients, additional lesions were delivered on the left-side of the septum and defragmentation of both atria was performed. Finally, high-dose isoproterenol was infused to elicit non-pulmonary vein triggers. AF patients with OSA were more likely to have a non-pulmonary vein trigger and more likely to fail the ablation procedure. Patients with

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Sleep Apnoea and AF Figure 1: Lifecycle of Patients With AF

refers and manages patients by ensuring consistent follow-up and effective communication between clinicians and patients in a methodological manner.10

ECG diagnosis and monitoring

Stroke risk assessment and prevention

Rate and rhythm control

Risk factor modification (e.g. OSA)

At the Valley Health System, we created the Snyder Center for Comprehensive Atrial Fibrillation, which provides evidence-based, patient-centred and team-directed health care to our AF patients. Services outside of those provided by electrophysiologists include nutrition, weight loss management, fitness programs, evaluation and management of sleep apnoea and educational and behavioural-based patient seminars.

With respect to sleep apnoea, all AF patients are screened using the ESS and STOP-BANG questionnaires, which are formally incorporated into the patient’s electronic medical record. This approach has previously been recommended by Desteghe et al.37 At-risk patients are immediately scheduled for an HST; systems have been created to ensure interpretation and evaluation of the patient by a sleep specialist within 2 weeks of completion of the test. In the coming year, we aim to dispense the tests directly from our office at the time of the patient’s clinical evaluation to further streamline the process.

Patients with sleep apnoea who begin therapy are remotely monitored monthly by a research coordinator for compliance. Patients using therapy <70% of the time are flagged for the electrophysiologist; a patient coordinator initiates a conversation with the patient to understand the reason for non-compliance. If needed, some patients are asked to pursue alternative therapeutic options, such as implantable device therapy or even bariatric surgery. Finally, we prospectively monitor our patients for AF events to understand the relationship between sleep apnoea, treatment and AF events.

Shown are the four pillars of management that must be addressed in every AF patient.

OSA = obstructive sleep apnoea.

with a reduced risk of AF (HR 0.41; 95% CI [0.22–0.76]; p<0.01).34 Finally, Neilan et al. found OSA was present in 20% of 720 patients who underwent a cardiac MRI prior to AF ablation.35 The presence of OSA (HR 2.79; 95% CI [1.97–3.94]; p<0.0001) and untreated OSA (HR 1.61; 95% CI [1.35–1.92]; p<0.0001) were both associated with AF recurrence.

To summarise, a definitive understanding of this topic would require consideration of the following: • ensuring all patients with AF undergo an HST; • repeating the HST to understand the variability in the presence and severity of sleep apnoea; • determining what severity of sleep apnoea (any, only moderate or severe) warrants consideration of CPAP therapy; • determining whether CPAP must be started before an intervention (e.g. cardioversion, ablation) or can be started after the intervention; in either case, a randomised, multicentre assessment of CPAP therapy is warranted; • having an objective mechanism in place to assess compliance with CPAP; • incorporating a standardised ablation protocol; and • using an objective assessment of AF recurrence (e.g. implantable loop recorder).

In contrast to these studies, others have found that treatment of sleep apnoea does not affect outcomes. A meta-analysis of PAP therapy in patients with sleep apnoea included 10 randomised clinical trials (nine CPAP; one adaptive servo ventilation).36 Combined, the trials included 7,266 patients; of these, 356 (5%) patients experienced a major adverse cardiovascular event (MACE) and 613 (8%) died. The use of PAP did not reduce the risk of MACE, death due to a cardiovascular event or all-cause death. The same was true for acute coronary syndrome, stroke and heart failure. Furthermore, there was no association between PAP for different levels of apnoea severity, follow-up duration or adherence to therapy.36 This highlights the need for caution in misinterpreting the benefits of PAP therapy based solely on observational data.

Our Approach

The 2020 ESC AF guidelines emphasise the importance of a patientcentred, integrated care model in patients with AF. Such an approach provides patients with the tools needed for lifestyle modification, adherence to treatment protocols, education and psychosocial management. These tools are best provided via a multidisciplinary strategy that focuses on minimising the effects of comorbidities and risk factors on AF, reducing stroke risk and controlling rate and rhythm while adhering to patients’ preferences. These are the guiding principles for an AF centre of excellence. These centres recognise that successful AF treatment requires many strategies, which are often outside the expertise of any one clinician, and they use a team-based approach that

Conclusion

In the lifecycle of the AF patient, risk factor modification has become an important pillar of management (Figure 1). To that end, OSA has emerged as an important modifiable risk factor in AF patients. Nonetheless, major challenges remain to the effective interpretation of the existing literature.

Thus, a multicentre randomised clinical trial of CPAP therapy in AF patients is very much needed in order to inform clinical practice. Such a study is needed to determine the precise magnitude of benefit (especially as it relates to AF) and, importantly, to exclude the potential for harm.

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Sleep Apnoea and AF

Clinical Perspective

• The likelihood is that all patients with AF should be screened for OSA. • Although screening questionnaires are typically used, some form of sleep testing should be used.

• In the laboratory, polysomnography is the gold standard; however, home sleep testing is the most practical approach in clinical practice.

Various techniques are used, and each has its inherent advantages and disadvantages.

• Largely observational studies support the positive impact of CPAP therapy on outcomes after treatment in AF patients.

• There is a major need for randomised clinical trials to assess the impact of CPAP therapy on arrhythmia and other outcomes in AF patients.

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15. Chung F, Yegneswaran B, Liao P, et al. STOP questionnaire: a tool to screen patients for obstructive sleep apnea.

Anesthesiology 2008;108:812–21. https://doi.org/10.1097/ ALN.0b013e31816d83e4; PMID: 18431116.

16. Jafari B, Mohsenin V. Polysomnography. Clin Chest Med 2010;31:287–97. https://doi.org/10.1016/j.ccm.2010.02.005; PMID: 20488287.

17. Abrahamyan L, Sahakyan Y, Chung S, et al. Diagnostic accuracy of level IV portable sleep monitors versus polysomnography for obstructive sleep apnea: a systematic review and meta-analysis. Sleep Breath 2018;22:593–611. https://doi.org/10.1007/s11325-017-1615-1; PMID: 29318566.

18. Saraç S, Afsar GC. Effect of mean apnea–hypopnea duration in patients with obstructive sleep apnea on clinical polysomnography parameter. Sleep Breath 2020;24:77–81. https://doi.org/10.1007/s11325-019-01870-y; PMID: 31197639.

19. Malhotra RK, Kirsch DB, Kristo DA, et al. Polysomnography for obstructive sleep apnea should include arousal-based scoring: an American Academy of Sleep Medicine position statement. J Clin Sleep Med 2018;14:1245–7. https://doi. org/10.5664/jcsm.7234; PMID: 29991439.

20. CPAP For Obstructive Sleep Apnea. U.S. Centers for Medicare & Medicaid Services. 17 December 2020. https://www.cms.gov/Medicare/Coverage/Coverage-withEvidence-Development/CPAP (accessed 18 August 2021).

21. Tauman R, Berall M, Berry R, et al. Watch-PAT is useful in the diagnosis of sleep apnea in patients with atrial fibrillation.

Nat Sci Sleep 2020;12:1115–21. https://doi.org/10.2147/NSS. S278752; PMID: 33299372.

22. Ioachimescu OC, Dholakia SA, Venkateshiah SB, et al.

Improving performance of peripheral arterial tonometrybased testing for the diagnosis of sleep apnea. J Investig Med 2020;68:1370–8. https://doi.org/10.1136/jim-2020001448; PMID: 32900784.

23. Zou D, Grote L, Peker Y, et al. Validation a portable monitoring device for sleep apnea diagnosis in a population based cohort using synchronized home polysomnography.

Sleep 2006;29:367–74. https://doi.org/10.1093/ sleep/29.3.367; PMID: 16553023.

24. Linz D, Kadhim K, Brooks AG, et al. Diagnostic accuracy of overnight oximetry for the diagnosis of sleep-disordered breathing in atrial fibrillation patients. Int J Cardiol 2018;272:155–61. https://doi.org/10.1016/j.ijcard.2018.07.124; PMID: 30057161.

25. Linz D, Baumert M, Catcheside P, et al. Assessment and interpretation of sleep disordered breathing severity in cardiology: clinical implications and perspectives. Int J Cardiol 2018;271:281–8. https://doi.org/10.1016/j. ijcard.2018.04.076; PMID: 30049491.

26. Linz D, Brooks AG, Elliott AD, et al. Variability of sleep apnea severity and risk of atrial fibrillation: the VARIOSA-AF study.

JACC Clin Electrophysiol 2019;5:693–702. https://doi. org/10.1016/j.jacep.2019.03.005; PMID: 31221356.

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27. Heidenreich PA, Estes NAM, Fonarow GC, et al. 2020 update to the 2016 ACC/AHA clinical performance and quality measures for adults with atrial fibrillation or atrial flutter: a report of the American College of Cardiology/ American Heart Association Task Force on Performance Measures. J Am Coll Cardiol 2021;77:326–41. https://doi. org/10.1016/j.jacc.2020.08.037; PMID: 33303319.

28. Holmqvist F, Guan N, Zhu Z, et al. Impact of obstructive sleep apnea and continuous positive airway pressure therapy on outcomes in patients with atrial fibrillation – results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Am Heart J 2015;169:647–54. https://doi.org/10.1016/j.ahj.2014.12.024; PMID: 25965712.

29. Monahan K, Brewster J, Wang L, et al. Relation of the severity of obstructive sleep apnea in response to antiarrhythmic drugs in patients with atrial fibrillation or atrial flutter. Am J Cardiol 2012;110:369–72. https://doi.org/10.1016/j. amjcard.2012.03.037; PMID: 22516529.

30. Linz D, Hohl M, Ukena C, et al. Obstructive respiratory events and premature atrial contractions after cardioversion. Eur Respir J 2015;45:1332–40. https://doi. org/10.1183/09031936.00175714; PMID: 25745047.

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Clinical Arrhythmias

Residual Stroke Risk in Atrial Fibrillation Wern Yew Ding Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK

Abstract

AF contributes to increased stroke risk via various mechanisms, including deranged blood constituents, vessel wall abnormalities and abnormal blood flow. This excess risk is frequently managed with anticoagulation therapy, aimed at preventing thromboembolic complications. Yet, a significant proportion of patients with AF remain at high residual stroke risk despite receiving appropriate dose-adjusted anticoagulation. This article explores the residual stroke risk in AF and potential therapeutic options for these patients.

Keywords

AF, residual, stroke, risk factors, anticoagulated, management Disclosure: The author has no conflicts of interest to declare.

Received: 19 June 2021 Accepted: 22 July 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(3):147–53. DOI: https://doi.org/10.15420/aer.2021.34 Correspondence: Wern Yew Ding, Department of Cardiovascular and Metabolic Medicine, University of Liverpool, 6 West Derby Street, Liverpool L7 8TX, UK. E: dwyew@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.

AF is associated with excess stroke risk due to various mechanisms better explained with Virchow’s triad of deranged blood constituents, vessel wall abnormalities and abnormal blood flow.1 Hence, a vital aspect in the management of patients with AF includes the identification of non-lowrisk patients using risk stratification tools, such as the CHA2DS2-VASc score, to identify those who may derive a net benefit from anticoagulation therapy, aimed at preventing thromboembolic complications.2

range (TTR) as between 55% and 68%, remained suboptimal based on the recommendations of >70% according to current international guidelines.7–9 Given the importance of anticoagulation control, efforts were directed at achieving and maintaining a high TTR (>65–70%), especially in high-risk subgroups with AF, in order to improve clinical outcomes.10 However, the introduction of direct oral anticoagulants (DOACs) has changed the landscape of treatment in patients with AF such that TTR is a distant memory in those treated with these newer agents, although compliance continues to be an issue.11,12 Overall, DOACs have been shown to be more effective than warfarin for the prevention of stroke or systemic embolism, even in various high-risk AF subgroups, such as patients with concomitant heart failure, valvular heart disease and coronary artery disease.13–16 In addition, DOAC therapy may reduce stroke severity compared with warfarin.17

The benefit of anticoagulation in AF has long been established.3 In fact, a previous meta-analysis of warfarin treatment in patients with AF demonstrated significant reductions of stroke risk and all-cause mortality by 64% and 26%, respectively, compared with placebo or no treatment.4 Yet, a significant proportion of patients with AF remain at high residual stroke risk despite receiving appropriate dose-adjusted anticoagulation therapy, and some patients go on to suffer from anticoagulation-resistant stroke. This represents a clinical conundrum for physicians, particularly as contemporary guidelines in AF are silent in this regard, reflecting the limited evidence surrounding the topic.5–8 This review explores the residual stroke risk in AF and potential therapeutic options for high-risk patients.

Nonetheless, in landmark clinical trials evaluating the different DOAC agents against warfarin among patients with AF, the residual risk of stroke or systemic embolism despite anticoagulation treatment was between 1.11% and 2.40% per year (Table 1).18–21 Similar, if not higher, rates of between 1.73% and 2.78% were reported in real-world studies.22 This residual risk should not be underestimated because the threshold for consideration of oral anticoagulation in AF is approximately 0.9%, corresponding to a CHA2DS2-VASc score of 1, for the risk of thromboembolism. Therefore, there is a need for greater awareness among clinicians and better risk stratification of residual stroke in patients with AF.

Residual Stroke Risk in AF

To begin with, it is important to recognise that anticoagulation therapy reduces, but does not negate, the risk of stroke in AF. Recent estimates among patients with AF found that the annual incidence of stroke or systemic embolism with warfarin was 1.66%, an improvement compared with previous reports of 2.09%, which the authors attributed to better quality of anticoagulation control.9 There was a significant increase in the annual incidence of stroke or systemic embolism in patients with additional concomitant risk factors (CHADS2 score ≤1: 0.89% per year; CHADS2 score 2: 1.43% per year; CHADS2 score ≥3: 2.50% per year).9 Notably, the quality of anticoagulation control in that meta-analysis of eight randomised controlled trials, determined using time in therapeutic

There are several potential mechanisms of stroke despite anticoagulation, including small vessel disease, intracranial or extracranial atherosclerotic disease, cryptogenic stroke, arterial dissection and hypercoagulable states (e.g. inherited thrombophilia, antiphospholipid syndrome).

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Residual Stroke Risk in AF Table 1: Residual Thromboembolic Risk in Landmark Clinical Trials of AF Study

Year

No. Patients

Mean CHADS2 score

DOAC

Warfarin

RE-LY20

2008

18,113

2.1

1.11–1.53†

1.69

ROCKET AF

2011

14,264

3.5

2.10

2.40

ARISTOTLE19

2011

18,201

2.1

1.27

1.60

2013

21,105

2.8

1.18–1.61†

1.50

21

ENGAGE AF-TIMI 48

18

Residual thromboembolic Risk*

*Expressed as percentage per year or event rate per 100 patient-years. †Dose dependent. DOAC = direct oral anticoagulant.

Table 2: Studies on Risk Factors for Residual Stroke in AF Study

Year Study design

Prospective No. Follow-up Results or Patients Duration Retrospective

Szeto and Hui29

2010

Cohort study

Retrospective

Lip et al.33

2010

Albertsen et al.35

109

8 years

65.1% female, mean age 78 years, 83.5% had hypertension

Post hoc Retrospective analysis of RCT

7,329

1.5 years

Age ≥75 years (HR 1.77, 95% CI [1.32–2.38]), previous stroke or TIA (HR 2.24 [95% CI, 1.66–3.02]), coronary artery disease (HR 1.52, 95% CI [1.14–2.04]), smoking (HR 2.10, 95% CI [1.38–3.18]) and non-use of alcohol (HR 1.43, 95% CI [1.05–1.92]) were significant predictors of thromboembolism

2013

Meta-analysis of 6 RCTs

NA

58,883

NA

Age ≥75 years (RR 1.46, 95% CI [1.25–1.69]), female sex (RR 1.30, 95% CI [1.15–1.49]), previous stroke or TIA (RR 1.85, 95% CI [1.32–2.60]), VKA-naïve status (RR 1.18, 95% CI [1.03–1.35]), moderate renal failure (RR 1.54, 95% CI [1.30–1.81]), severe renal failure (RR 2.22, 95% CI [1.85–2.66]), previous aspirin use (RR 1.19, 95% CI [1.04–1.37]), Asian race (RR 1.70, 95% CI [1.42–2.03]) and CHADS2 score ≥3 (RR 1.64, 95% CI [1.18–2.27]) associated with higher stroke rates

Pancholy et al.37

2014

Meta-analysis of NA 6 RCTs

26,260

NA

Female AF patients on warfarin were at significantly greater risk of stroke or systemic embolism than their male counterparts (OR 1.28, 95% CI [1.11–1.47]), although this was not observed with DOAC therapy (OR 1.15, 95% CI [0.97–1.35])

Senoo et al.34

2015

Post hoc Retrospective analysis of RCT

4,556

11.6 months

Permanent AF (HR 1.66, 95% CI [1.08–2.55]), creatinine (HR 0.35, 95% CI [0.19–0.66]), prior cerebrovascular events (HR 1.97, 95% CI [1.31–2.96]) and previous coronary disease (HR 1.74, 95% CI [1.14–2.57]) were independently associated with a composite of stroke or systemic embolism and cardiovascular death

Paciaroni et al.30

2019

Case-control study

Prospective

713

NA

Off-label low dose of DOACs (OR 3.18, 95% CI [1.95–5.85]), atrial enlargement (OR 6.64, 95% CI [4.63–9.52]), hyperlipidaemia (OR 2.40, 95% CI [1.83–3.16]), CHA2DS2-VASc score (OR 1.72, 95% CI [1.58–1.88] for each 1-point increase) and non-paroxysmal AF (OR 2.22, 95% CI [1.64–3.03]) were associated with cerebrovascular ischaemic events

Maeda et al.38

2021

Cohort study

Retrospective

11,848

3 years

Older age (HR 2.02, 95% CI [1.49–2.73] for 65–74 versus <65 years), hypertension (HR 1.41, 95% CI [1.04–1.92]) hyperlipidaemia (HR 1.46, 95% CI [1.07–1.98]) and CHA2DS2 VASc score were significantly associated with increased risk of stroke or systemic embolism

DOAC = direct oral anticoagulant; NA = not available or not applicable; RCT = randomised control trial; RR = relative risk; TIA = transient ischaemic attack; VKA = vitamin K antagonist.

Medication errors have also been previously reported to be common among patients with AF.23 Furthermore, there are other causes of cardioembolic stroke besides AF, such as mitral stenosis, mechanical heart valves and left ventricular thrombus. An in-depth review of these factors has previously been published.24 Importantly, anticoagulation therapy has not been proven to be beneficial for stroke prevention in most of these conditions despite an excess risk of bleeding.

increased residual stroke risk in AF. However, there are currently no risk stratification tools that have been validated for the prediction of residual stroke risk in anticoagulated patients with AF. As a result, the identification of high-risk patients can be difficult, especially in the busy clinical environment.

Recently, a cohort study of patients who suffered from stroke despite DOAC therapy identified that most of these patients were older, female and hypertensive, with at least Stage 2 chronic kidney disease (estimated glomerular filtration rate <90 ml/min; Table 2).29 However, that study by Szeto and Hui was limited by its retrospective design and small sample size.29 A prospective case-control study showed that the use of off-label low-dose DOACs, atrial enlargement, hyperlipidaemia, a high CHA2DS2VASc score and non-paroxysmal AF were independently associated with an increased risk of stroke events among AF patients.30 Main contributors from the CHA2DS2-VASc score were increasing age, diabetes, congestive heart failure and prior stroke or transient ischaemic attack (TIA). Unlike in

Risk Factors for Residual Stroke Risk

AF is a multimorbid condition that is predisposed by the presence of risk factors such as advancing age, hypertension, diabetes, chronic kidney disease, heart failure and coronary artery disease.25,26 In addition, AF accelerates the progression of disease for many of these risk factors.26–28 Hence, AF rarely occurs in isolation, and concomitant diseases may influence the residual stroke risk either by their individual effects, synergism with AF or by reducing the effectiveness of anticoagulation therapy. Numerous risk factors have been shown to be associated with an

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Residual Stroke Risk in AF Figure 1: Risk Factors for Residual Stroke in Anticoagulated Patients with AF

Female sex

Age

Hyperlipidaemia Smoking Asian race

Previous stroke or TIA

Risk factors for residual stroke in AF

CAD

VKA-naïve status

Hypertension

Off-label low-dose DOAC

Non-paroxysmal AF

CHADS2 or CHA2DS2VASc score LA dilatation

Renal failure

Modifiable risk factors are shown in red. CAD = coronary artery disease; DOAC = direct oral anticoagulant; LA = left atrial; TIA =transient ischaemic attack; VKA = vitamin K antagonist. Created with BioRender.com.

the study of Szeto and Hui, female sex and hypertension were not found to be independent risk factors.29,30 Interestingly, Paciaroni et al. reported that approximately 30% of patients with cerebrovascular events had stroke due to causes other than cardioembolism; this reinforced the concept that ischaemic stroke in patients with AF is not exclusively cardiogenic in nature.30–32

untested within that study.35 In contrast, Pancholy et al. performed their meta-analysis using patients from both treatment groups (warfarin and DOAC) and demonstrated that female patients with AF who were treated with warfarin had a greater residual risk of stroke than their male counterparts, but no sex differences were observed with DOACs.37 Recently, a retrospective cohort study reported that the risk of ischaemic stroke or systemic embolism among patients with AF remained markedly higher than that of the general population even after anticoagulation therapy, as observed previously.38,39 Furthermore, approximately onethird of the residual risk was secondary to modifiable factors, including hypertension, diabetes and hyperlipidaemia.38 Overall, there appears to be an overlap between many of the risk factors for residual stroke risk in AF (Figure 1) and those that predispose to stroke events in nonanticoagulated AF patients.40 Nonetheless, the former remains poorly defined and further studies are needed to determine the extent and mechanisms by which these risk factors affect residual stroke risk in AF.

A post hoc analysis of the SPORTIF trials demonstrated that age ≥75 years, coronary artery disease, smoking and non-use of alcohol were significant predictors of thromboembolism.33 Using data of anticoagulated patients with AF from the AMADEUS clinical trial, Senoo et al. demonstrated worse outcomes of stroke or systemic embolism, and death among those with permanent AF, prior cerebrovascular events, coronary artery disease and impaired renal function.34 However, the results of that post hoc analysis should be interpreted with caution given the historical nature of the trial even though event outcomes were adjudicated.33 A meta-analysis of three randomised controlled trials focusing on warfarinised patients with AF found that age ≥75 years, female sex, prior stroke or TIA, vitamin K antagonist-naïve status, moderate or severe renal failure, previous aspirin use, Asian race and a CHADS2 score ≥3 were associated with higher stroke rates.35 Nonetheless, given the known importance of the quality of anticoagulation control and the fact that it could not be assessed within different subgroups of that meta-analysis, it was unclear whether the predictors identified were directly related to stroke risk or indirectly via their influence on anticoagulation control.36 In addition, the effects of these risk factors on DOAC therapy remained

Potential Treatment Options

Despite some awareness of residual stroke risk in AF, this issue presents a clinical problem to physicians because there is little evidence on effective management strategies for patients recognised to be at high risk. In this regard, several studies have explored the use of antiplatelet agents in addition to anticoagulation to further minimise stroke risk in AF. However, this approach should not be advocated for the management of residual stroke risk among the general AF population given the increased risk of harm and lack of demonstrable benefit.41,42

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Residual Stroke Risk in AF Table 3: Recent Studies on the Effects of Catheter AF Ablation on Stroke Risk Study

Year

Study Design

Prospective No. or Patients Retrospective

Follow-up Duration

Results of Catheter Ablation versus Non-ablation

Friberg et al.54

2016

PSM cohort study

Retrospective

4,992

4.4 years

Lower risk of ischaemic stroke (HR 0.69, 95% CI [0.51–0.93]); most prominent among patients with CHA2DS2-VASc score ≥2 (HR 0.39, 95% CI [0.19–0.78]) and all-cause death (HR 0.50, 95% CI [0.37–0.62])

Saliba et al.55

2017

PSM cohort study

Retrospective

4,741

4,237 person-years

Lower risk of ischaemic stroke (HR 0.62, 95% CI [0.47–0.82]), TIA (HR 0.47, 95% CI [0.20–0.78]) and all-cause death (HR 0.57, 95% CI [0.47–0.66])

Jarman et al.52

2017

PSM cohort study

Retrospective

9,982

2 years

Lower annual rates of stroke or TIA (0.64% versus 1.84%, p<0.0001)

Joza et al.

2018

PSM cohort study

Retrospective

3,667

3.6 years

No significant difference in the risk of stroke (HR 0.88, 95% CI [0.63–1.21]) or major bleeding (HR 0.88, 95% CI [0.73–1.06])

Srivatsa et al.53 2018

PSM cohort study

Retrospective

8,338

3.6 years

Lower risk of all-cause death (HR 0.59, 95% CI [0.45–0.77]), ischaemic stroke (HR 0.68, 95% CI [0.47–0.97]) and haemorrhagic stroke (HR 0.36, 95% CI [0.20–0.64])

Bunch et al.56

2018

PSM cohort study

Retrospective

971

5 years

No significant difference in the risk of stroke (HR 0.82, p=0.39) and all-cause death (HR 0.92, p=0.70), but with increased risk of heart failure (HR 3.08, p=0.001)

Noseworthy et al.89

2019

PSM cohort study

Retrospective

183,760

2.1–2.3 years

Lower risk of composite outcome including all-cause death, stroke, major bleeding and cardiac arrest (HR 0.75, 95% CI [0.70–0.81])

Yang et al.51

2020

Cohort study

Retrospective

27,955

43 months

Lower risk of composite outcome including all-cause death, heart failure admission and stroke/SE (HR 0.47, 95% CI [0.43–0.52]), all-cause death (HR 0.41, 95% CI [0.36–0.47]), heart failure admission (HR 0.43, 95% CI [0.37–0.50]) and ischaemic stroke/SE (HR 0.39, 95% CI [0.34–0.44])

Saglietto et al.58 2020

Meta-analysis of 9 studies

NA

241,372

3.5 years

Lower risk of all-cause death (HR 0.62, 95% CI [0.54–0.72]), stroke (HR 0.63, 95% CI [0.56–0.70]) and hospitalisation for heart failure (HR 0.64, 95% CI [0.51–0.80])

Liu et al.59

2020

Meta-analysis of 25 NA studies

104,687

6–144 months

Lower risk of thromboembolic events (RR 0.65, 95% CI [0.51–0.82])

Kim et al.57

2021

PSM cohort study

8,145

51 months

Lower risk of ischaemic stroke (HR 0.25, 95% CI [0.14–0.42]) and ICH (HR 0.20, 95% CI [0.05–0.84])

88

Retrospective

ICH = intracranial haemorrhage; NA = not available or not applicable; PSM = propensity score matched; SE = systemic embolism; TIA = transient ischaemic attack.

There is growing evidence to suggest that AF patients who have previously suffered a stroke despite anticoagulation are at increased risk of subsequent strokes compared to anticoagulation-naïve patients, highlighting the importance of managing the residual risk of ischaemic stroke in AF.43–45 There are several other strategies that have shown positive results for this purpose, including catheter AF ablation, left atrial appendage (LAA) occlusion and adherence to theAF Better Care (ABC) pathway. It is important to highlight that none of these approaches has been specifically proven for the management of residual stroke risk in AF.

have reported that catheter AF ablation was independently associated with a lower risk of ischaemic stroke, the effects of which were more pronounced among patients with higher CHA2DS2-VASc score (Table 3).51–55 In a study of patients with AF and prior stroke, Bunch et al. found that patients who underwent catheter AF ablation had lower rates of recurrent stroke over a 5-year period compared with those who were not ablated.56 Notably, the long-term rates of recurrent stroke were comparable between ablated AF patients and non-AF patients.56 Similar results were obtained in a nationwide study using the Korean National Health Insurance Service (NHIS) database.57

Catheter AF Ablation

Contemporary international guidelines recommend rhythm and/or rate control strategies for symptom management in patients with AF.6,8 This was on the basis of historical studies performed over a decade ago that failed to demonstrate any prognostic advantage of one over the other.46–48 Nonetheless, the results of these studies were confounded by the fact that there were high rates of anticoagulation discontinuation during follow-up among patients who were randomised to receive a rhythm control strategy. A post hoc analysis of the ATHENA trial suggests that a rhythm control approach in addition to usual care may reduce stroke events among patients with AF.49 Recent evidence demonstrates that early rhythm control, by any means, in AF was beneficial in reducing cardiovascular events (including stroke) compared with rate control.50

Recent meta-analyses reinforced that catheter AF ablation significantly reduces the risk of thromboembolism compared with medical therapy alone.58,59 Importantly, the vast majority of patients in these studies were anticoagulated, suggesting that catheter AF ablation may have a role as adjunctive therapy in the management of residual stroke risk in AF. A further advantage of this strategy is that it may be combined with LAA occlusion (discussed below) in a single procedure.60 Overall, although catheter AF ablation has shown promise, it is not currently indicated for the reduction of stroke risk in AF because it remains unclear whether this approach may interrupt the natural history of AF and/or cause a significant alteration in the subsequent stroke risk, despite the results from observational studies. This is supported by the lack of a temporal relationship between AF episodes and stroke complications, and an increased risk of thromboembolic events with traditional risk factors, even in the absence of AF.1,61,62 Moreover, the recent CABANA trial failed to demonstrate a significant benefit of catheter ablation over drug therapy

AF ablation is a means of rhythm control and an established treatment for patients with drug-refractory symptomatic AF. Although not used for the sole purpose of risk modification, several observational cohort studies

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Residual Stroke Risk in AF for the composite endpoint of all-cause death, disabling stroke, serious bleeding or cardiac arrest in the intention-to-treat analysis.63

Table 4: Management of Residual Stroke Risk in Anticoagulated Patients With AF

For patients who undergo catheter AF ablation, there is some debate as to whether anticoagulation therapy is necessary among those with successful maintenance of sinus rhythm after the initial prothrombotic phase postablation. In the landmark AFFIRM trial, patients randomised to the rhythm control arm exhibited a trend towards a greater risk of ischaemic stroke that largely occurred following discontinuation of anticoagulation therapy, indicating that the decision for anticoagulation should be guided by stroke risk factors rather than the perceived success of maintaining sinus rhythm.47 This observation may be due, in part, to undetected, asymptomatic recurrences that commonly occur in the postablation period, often found only with more aggressive monitoring strategies.64

Review and improve adherence to medications

Lately though, there is some evidence to suggest that the stroke risk in AF is significantly lowered by catheter ablation such that the risk-to-benefit ratio may favour the suspension of oral anticoagulation following a successful procedure.65 A meta-analysis of seven retrospective cohort studies demonstrated that the withdrawal of anticoagulation 3 months after successful radiofrequency catheter AF ablation was associated with a significant reduction in the risk of haemorrhage, and no difference in thromboembolic events at both short- and long-term follow-up.66 Nonetheless, this is a topic that warrants further investigation. Presently, the decision of whether to anticoagulate patients with successful catheter AF ablation should continue to be guided by individual stroke risk factors, as per contemporary international guidelines.7,8

Consider an integrated care approach with the ABC pathway

Optimise anticoagulation control (for VKA) Consider switching to DOAC (for VKA) Ensure appropriate dosage (for DOAC) Investigate thoroughly for other cardioembolic (e.g. MS, LV thrombus) and noncardiogenic aetiologies of stroke (e.g. large artery arteriosclerosis, small vessel disease, cryptogenic stroke, dissection, hypercoagulable states), using methods such as vascular imaging and brain MRI Review and optimise the management of other stroke risk factors Consider AF ablation Consider LAA occlusion ABC pathway = AF Better Care pathway; DOAC = direct oral anticoagulant; LAA = left atrial appendage; LV = left ventricular; MS = mitral stenosis; VKA = vitamin K antagonist.

who received LAA occlusion remained on anticoagulation therapy, proving the notion that there is a combined effect of LAA occlusion and anticoagulation for stroke prevention in AF. Overall, the use of LAA occlusion as add-on therapy to anticoagulation in AF for patients with high residual stroke risk remains to be proven, although it may offer some hope in desperate situations.76,77

AF Better Care Pathway

The ABC pathway was introduced as a means to facilitate an integrated management of patients with AF in a holistic manner.78 It was founded on three main principles: ‘A’, avoid stroke; ‘B’, better symptom management; and ‘C’, cardiovascular and comorbidity optimisation. Post hoc analysis of the AFFIRM trial showed that an integrated care approach based on the ABC pathway was associated with a significant decrease in the composite risk of stroke, major bleeding and cardiovascular death compared with non-ABC care.79 However, this finding was largely driven by a reduction in the risk of major bleeding and cardiovascular death, because stroke risk was not statistically different between the groups. Similarly, the risk of stroke was unchanged in AF patients with clinical management adherent to the ABC pathway from the ESC-EORP Atrial Fibrillation General LongTerm Registry.80

Left Atrial Appendage Occlusion

The LAA is an important structure in AF because the majority of cardioembolic stroke originates from here.67–69 Therefore, occlusion of this structure acts to isolate and prevent clot formation and subsequent embolisation. LAA occlusion may be performed using either a surgical or percutaneous approach. The latter is emerging as a viable treatment alternative to anticoagulation in AF, although more research is required to define its exact role.70 A meta-analysis of five randomised controlled trials of patients with AF or risk factors for AF comparing LAA occlusion to standard of care using anticoagulation therapy (in the era of warfarin) found that LAA occlusion was at least non-inferior for stroke prevention with a potential for reduction in mortality.71 The PRAGUE-17 randomised control trial demonstrated that among AF patients with a high risk of stroke (mean CHA2DS2-VASc score 4.7), LAA occlusion was non-inferior to DOAC therapy in preventing major AF-related cardiovascular, neurological and bleeding events.72 These results were reaffirmed in a real-world registry of AF patients with a very high stroke risk (CHA2DS2-VASc score ≥5) and ‘unacceptable’ risk of bleeding, where the residual annual ischaemic stroke risk was 2.8% after LAA occlusion.73 Furthermore, data from the Amplatzer Cardiac Plug registry suggest that LAA occlusion may be an effective treatment option for secondary stroke prevention in AF patients with anticoagulation-resistant stroke.74 Nonetheless, the retrospective nature of that small observational study should be acknowledged.

In contrast, nationwide cohort studies of AF patients from the Korean NHIS database demonstrated a significant reduction in the rates of ischaemic stroke with implementation of the ABC pathway.81,82 In addition, the mAFA-II trial found that patients who were randomised to mobile health management based on the ABC pathway (versus usual care) had lower rates of ischaemic stroke.83 Overall, differences in the results of the aforementioned studies may be related to the methods in which the ABC pathway was evaluated and patients were deemed to be ABC adherent.

A recent meta-analysis of the ABC pathway in AF showed that this strategy was associated with a 45% reduction in the risk of ischaemic stroke, indicating the benefit of this approach in the management of residual stroke risk in AF.84

Management of Residual Stroke Risk

Importantly, none of the aforementioned studies showed that treatment with LAA occlusion was superior to anticoagulation for stroke prevention in AF. Recently, the LAAOS III trial reported that among patients with AF who had undergone cardiac surgery, the risk of ischaemic stroke or systemic embolism over a follow-up period of 3.8 years was lower with concomitant LAA occlusion than without it.75 The vast majority of patients

It is recommended that the management of patients with AF includes a holistic approach by combining patient education, lifestyle modification, psychosocial management and strategies that promote medication adherence.8 Hence, I propose that the management of residual stroke risk in AF should incorporate the implementation of an integrated,

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Residual Stroke Risk in AF multidisciplinary care strategy with clear communication between healthcare professionals and a structured approach (Table 4). In this regard, the importance of appropriate administration of dose-adjusted anticoagulation therapy in AF should not be overlooked because the use of off-label doses has been linked to poorer outcomes.85,86 The detection and management of modifiable risk factors associated with AF, such as hypertension, coronary artery disease, heart failure, diabetes, hyperthyroidism, obesity and valvular heart disease, must also be prioritised. An in-depth review of this has been published elsewhere.87 Moreover, other sources of stroke risk should be considered, because some may have a major effect on overall management strategies.24 Given the limited evidence in this area, the decision to pursue specific treatment options such as catheter AF ablation and LAA occlusion to minimise residual stroke risk in AF should be individualised.

explored topics. Future studies are needed to define risk factors of residual stroke in AF and determine the effects of specific treatments in this patient cohort.

Clinical Perspective

• A significant proportion of patients with AF remain at high

residual stroke risk despite receiving appropriate dose-adjusted anticoagulation therapy.

• Risk factors for residual stroke risk in AF may include age, female sex, Asian race, previous stroke or TIA, VKA-naïve status, non-paroxysmal AF, left atrial dilatation, smoking, hypertension, hyperlipidaemia, coronary artery disease, renal failure, CHADS2 or CHA2DS2-VASc score, and use of off-label low-dose DOAC. • The management of residual stroke risk should incorporate an integrated multidisciplinary care strategy, with clear communication between healthcare professionals and a structured approach.

Conclusion

Residual stroke risk among anticoagulated patients with AF represents a real challenge in the clinical environment. Presently, the identification and subsequent management of high-risk individuals are poorly 1. Ding WY, Gupta D, Lip GYH. Atrial fibrillation and the prothrombotic state: revisiting Virchow’s triad in 2020. Heart 2020;106:1463–8. https://doi.org/10.1136/ heartjnl-2020-316977; PMID: 32675218.

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6. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in collaboration with the Society of Thoracic Surgeons. J Am Coll Cardiol 2019;74:104–32. https://doi.org/10.1016/j.jacc.2019.01.011; PMID: 30703431.

7. Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report. Chest 2018;154:1121–01. https://doi.org/10.1016/j. chest.2018.07.040; PMID: 30144419.

8. 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.

9. Agarwal S, Hachamovitch R, Menon V. Current trialassociated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation: a metaanalysis. Arch Intern Med 2012;172:623–31. https://doi. org/10.1001/archinternmed.2012.121; PMID: 22450212.

10. Roldán V, Marín F. The importance of excellence in the quality of anticoagulation control whilst taking vitamin K antagonists. Thromb Haemost 2015;113:671–3. https://doi. org/10.1160/TH14-12-1087; PMID: 25673326.

11. Hwang J, Han S, Bae H-J, et al. NOAC adherence of patients with atrial fibrillation in the real world: dosing frequency matters? Thromb Haemost 2020;120:306–13. https://doi. org/10.1055/s-0039-1697954; PMID: 31659737.

12. Komen JJ, Heerdink ER, Klungel OH, et al. Long-term persistence and adherence with non-vitamin K oral anticoagulants in patients with atrial fibrillation and their associations with stroke risk. Eur Hear J Cardiovasc

Pharmacother 2021;7:f72–80. https://doi.org/10.1093/ehjcvp/ pvaa017; PMID: 32324233.

13. Xiong Q, Lau YC, Senoo K, et al. Non-vitamin K antagonist oral anticoagulants (NOACs) in patients with concomitant atrial fibrillation and heart failure: a systemic review and meta-analysis of randomized trials. Eur J Heart Fail 2015;17:1192–200. https://doi.org/10.1002/ejhf.343; PMID: 26335355.

14. He Q, Sze C-Y, Shum T-Y, et al. Comparing clinical outcomes of NOACs with warfarin on atrial fibrillation with valvular heart diseases: a meta-analysis. BMC Cardiovasc Disord 2019;19:113. https://doi.org/10.1186/s12872-019-1089-0; PMID: 31092194.

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Clinical Arrhythmias

The DAPA Trial in the Context of Previous Prophylactic ICD Landmark Trials Danielle Haanschoten

and Arif Elvan

Heart Centre, Department of Cardiology, Isala Hospital, Zwolle, the Netherlands

Abstract

In patients with ischaemic cardiomyopathy and severely reduced left ventricular ejection fraction (LVEF), an arrhythmogenic milieu is created by a complex interplay between myocardial scarring (assessed by cardiac MRI) and multiple other factors (ventricular ectopy, ischaemia and autonomic imbalance), favouring the occurrence of arrhythmic sudden cardiac death (SCD). Currently, a dynamic and robust model of dichotomised SCD risk assessment after primary percutaneous coronary intervention (PCI) is lacking, underlining the urgent need for further refinement of the widely accepted and guidelines-based criteria (ischaemic cardiomyopathy, LVEF ≤35%) for primary prevention. This review addresses the potential additional value of the recently published Defibrillator After Primary Angioplasty (DAPA) trial results. The DAPA trial conveys important messages and provides novel perspectives regarding left ventricular function post-primary PCI as an (early) risk marker for SCD and the impact of prophylactic ICD implantation on survival in this cohort. In the context of other previous primary prevention trials, DAPA was the first trial including only ST-elevation MI patients all treated with acute PCI.

Keywords

ICD therapy, MI, ventricular arrhythmia Disclosure: The authors have no conflicts of interest to declare.

Received: 2 June 2021 Accepted: 28 July 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(3):154–8. DOI: https://doi.org/10.15420/aer.2021.23 Correspondence: Arif Elvan, Isala Heart Center, Dr Van Heesweg 2, 8025 AB Zwolle, the Netherlands. E: a.elvan@isala.nl 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.

Philippe Coumel, one of the founding fathers of modern arrhythmology, stated in 1978: “There are always three main ingredients required for the emergence of a clinical arrhythmia: an arrhythmogenic substrate, a trigger and modulating factors such as imbalanced autonomic nervous tone and electrolyte disorders.”

medical considerations and patients’ personal preferences. Current guidelines recommend implantation of a prophylactic ICD in patients with functional New York Heart Association class I or II–III and left ventricular ejection fraction (LVEF) ≤30–35% at least 40 days post-MI and in US guidelines a condition of 90 days post-revascularisation.2,3 Real world registry data show that only a minority of patients selected for primary prevention ICD implantation based on current guidelines benefit from the ICD because of a low incidence of appropriate ICD therapy.4 An Israeli registry documented only 2.6% appropriate ICD therapy in patients with a prophylactic ICD (>70.0% ischaemic cardiomyopathy) after 2.5 years of follow-up.5 Furthermore, device and lead-related complications and inappropriate ICD shocks are important disadvantages of ICDs, which can have a significant negative impact on patients’ quality of life.6,7

The basic understanding of the mechanisms underlying ventricular arrhythmia (VA) is essentially unchanged. It is generally accepted that the occurrence of VA in ischaemic cardiomyopathy is an interplay between the presence of fibrotic scar tissue and transient electrical instability creating an arrhythmogenic milieu. An electrical unstable environment may be caused by an ischaemic event, autonomic imbalance, electrolyte disturbances, increased wall stress in heart failure patients or a combination of factors.1 The potentially lethal combination of these sudden cardiac death (SCD) risk factors is often unique to the individual and may change over time. The latter explains why there are still no optimal risk models available to identify patients with an increased risk of SCD. After all, one SCD that could have been prevented is one too many.

In this review, we highlight the gaps of knowledge in the available literature on primary prevention ICDs and the additional value of the Defibrillator After Primary Angioplasty (DAPA) trial results.8 We also discuss the potential role of contemporary advanced imaging modalities in risk stratification of patients for prophylactic ICD implantation.

Results of intensive research in the past 20 years have led to an increase in ICD implantations worldwide, of which primary prevention is the most common indication today. In general, the rationale behind secondary prevention ICD implantation is clear and there is no discussion regarding the indication for ICD eligibility in SCD survivors or patients with previous sustained VA. However, selecting patients for primary prevention ICD implantation is a far more complex matter and requires a meticulous decision-making process, with individual risk assessment and counselling.

The risks and benefits of ICD implantation need to be discussed based on

Primary Prevention ICD, Ageing Literature?

One of the most important cornerstones of today’s primary prevention ICD implantation guidelines for ischaemic cardiomyopathy is based on the results of MADIT II in 2002.9 Patients were included based on a history of remote MI (mean 6.7 years after index MI) and LVEF (<30%). Patients who underwent revascularisation within 3 months were excluded from the analysis. This complicates translation of MADIT II to today’s practice, as it is unknown whether outcomes are similar in ST-elevation MI (STEMI)

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154

DAPA in the Context of Previous Landmark Trials patients who are treated with primary PCI. The MADIT II population was a heterogeneous population from the perspective of Coumel’s triangle of factors involved in arrhythmic SCD. It is unknown whether two hypothetical post-MI patients with comparable LVEF <30% and either: a relatively small myocardial scar and suboptimal revascularised multivessel coronary disease or large MI after a successful revascularisation of a single vessel coronary artery disease, bear the same risks for VA/SCD.

The primary endpoint was all-cause mortality after 3 years. Additional survival assessment was performed in February 2019 for the primary endpoint. The trial prematurely ended after inclusion of 266 patients as a result of a slow inclusion rate (38% of the calculated sample size) with 131 patients randomised to the ICD arm and 135 patients to the control arm.

The greatest differences from former trials is that every patient underwent primary PCI (according to current standard of care) and echocardiographic LVEF evaluation was performed within 4 days of STEMI, in contrast to persistent low LVEF after remote MI such as in MADIT II, in which ICD implantation was performed approximately 6.7 years after index MI.

Of note, there is increasing evidence that infarct-related chronic total occlusions may contribute to an enhanced susceptibility for VA in both primary and secondary prevention.10 Moreover, new advances in late gadolinium enhancement (LGE) cardiac magnetic imaging (CMR) allows a detailed scar characterisation and has potentially promising value in the refinement of risk stratification and prediction of VA/SCD.11,12 The shortcomings of LVEF as a sole risk stratification factor for post-MI primary ICD indication are clear and it has been criticised numerous times, yet alternatives are still lacking.13–15

Although not confirmed by CMR-LGE imaging, low LVEF early after primary PCI in the DAPA trial may be regarded as a surrogate for a large scar caused by the acute MI (mainly anterior infarctions). Another important difference is that ICD implantation in the DAPA trial was postponed to at least 30 days post-MI (median of 50 days) to overcome the issue of mortality related to heart failure in the early healing phase, as this was the pitfall that caused the negative outcomes of IRIS and DINAMIT.23,24 Several issues related to the DAPA trial, of which premature termination is the most important factor, limit the ability to draw strong conclusions as justly expressed by Parkash et al.25 However, some interesting findings need to be recognised and may be used as a guide for future research.

A recent retrospective cohort analysis of four MADIT studies addressed the most important question in qualification of primary prevention ICD benefit: risk of life-threatening VA against competing risk of non-arrhythmic mortality as a result of pump failure.16 Patients with the greatest ICD benefit were considered to have an increased 3-year predicted risk of VA and a relatively low predicted 3-year risk for non-arrhythmic mortality, leading to a 74-days life gain in 3 years. A high VA score included established factors such as younger age, prior non-sustained ventricular tachycardia, faster baseline heart rate (increased sympathetic activity) and prior MI. While these factors may contribute to an improved risk stratification scheme, primary prevention trials (MUSTT, SCD-HeFT) using a variability of these criteria, had limited impact on the guidelines.17,18 The mixture of inclusion criteria, different primary outcomes (all-cause mortality or arrhythmic mortality) and patient populations (including non-ischaemic cardiomyopathy) potentially made interpretation of the available data even more complicated.19

DAPA data show a beneficial impact of early ICD implantation on all-cause mortality within the first 3 years after MI and this was sustained at 9 years of follow-up. In both groups, patients had similar follow-up visits. As such, we consider the potential bias of an improved heart failure treatment regime in the ICD group unlikely. It is reassuring that ICD implantation in low LVEF post-STEMI patients is associated with improved survival in this particular cohort of patients with STEMI treated with primary PCI, which is in line with the results of MADIT II. Nevertheless, it is important to realise that MADIT II focused on ICD benefit in patients with long-term low LVEF in general, while the scope of the DAPA trial is limited to patients in the current era with the widespread use of primary PCI. Different scopes of previous and future ICD trials are shown in Figure 1.

Furthermore, preventive measures to reduce the burden of coronary artery disease and heart failure have significantly improved over the past decades and their impact on the incidence of VA/SCD is not fully delineated yet. In conclusion, existing data in the area of primary ICD implantation seem to be outdated and are becoming more and more estranged from contemporary cardiology practice.20 However, repeating the previous clinical landmark trials, randomising patients with LVEF <30% to ICD implantation compared with optimal medical therapy, would now create an ethical dilemma. Despite promising results of novel heart failure drugs (for example, angiotensin receptor-neprilysin inhibitors), withholding an ICD from patients with LVEF <30% would be difficult to defend, especially in younger patients.21 Currently, researchers are challenged to develop novel risk stratification models based on observational and retrospective data in patients with severely reduced LVEF.22

A subanalysis of MADIT II revealed that in patients with recent revascularisation (less than 6 months previously), there was no benefit of ICD implantation.26 In contrast, the DAPA trial shows that appropriate ICD therapy occurred in five patients (1.9%) within the first 8 months after implantation. Primary PCI of the infarct-related artery reduces mortality by reducing infarct size and diminishing myocardial scarring-related arrhythmogenicity.27 However, several questions remain unanswered: Is arrhythmic SCD in the early healing phase after MI caused by a complex interaction between autonomic imbalance, triggering factors and scar inhomogeneity? Or does the extent of scar burden become more relevant over time after the early remodelling phase?

The following factors are important contributors to VA/SCD risk in the early phase after MI: success of revascularisation, severity of LV dysfunction, electrical instability and wall stress. Although we know the common denominator in the DAPA trial was a large infarction with severe LV dysfunction in the early phase after STEMI, the subgroup of patients with VA was too small to identify true triggers for VA. Another interesting finding of the DAPA trial is that follow-up data suggest the benefit of ICD may extend to patients whose LVEF had improved over time. LVEF increased ≥10.0% in 46.5% of the patients during follow-up. In a subgroup analysis of all patients with LVEF ≥35% (n=117) after 18 months of followup, there was a trend towards ICD benefit (HR 0.34; 95% CI [0.09–1.25]; p=0.100). Although these analyses are exploratory, similar results were

DAPA Trial and the Timing of Implantation

The latest randomised trial that compared ICD implantation with optimal medical therapy only in patients with LVEF <30% was the DAPA trial.8 This randomised, multicentre, controlled trial was conducted in high-risk primary PCI patients, defined as either:

• LVEF <30% (being the only criterion in 66.5% of the participants); • failure or suboptimal result of acute revascularisation (TIMI flow less than three in 20.3% of the participants); or

• a combination of factors, including primary VF and Killip class greater than −2.

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DAPA in the Context of Previous Landmark Trials Figure 1: DAPA Trial in the Context of Previous Prophylactic ICD Trials

significant heterogeneity between studies regarding type and dose of contrast agent administration, CMR sequence and assessment of border zones.37,38

Evidence-based ICD indication in ischaemic cardiomyopathy put into perspective: where do we go from here?

Also, timing of CMR after MI was not reported in most studies. As such, data regarding the importance of temporal dynamics of scar aging on VA risk are limited.35,39 The reason why young patients may benefit most from ICD may be the result of fewer competing risks of death.40 However, the impact of the dynamic nature of the scar healing process irrespective of patient age is not fully delineated yet.41,42 First presentation of VA/SCD may occur 10 years after the index MI, which younger patients are more likely to experience. Whether this is caused by a triggering factor (for example, acute ischaemia in progressed coronary disease), heart failure or a chronic myocardial scar, is unknown.

Coronary status

Electrophysiological markers

DAPA

• Ventricular ectopy burden • Programmed ventricular stimulation PRESERVE EF • ECG markers

MUSTT MADIT I

MADIT II SCD-HFT IRIS DINAMIT LV performance • LVEF ≤35–40% • Increased sympathetic activity • Wall/shear stress

• Primary PCI/complete revascularisation • Multivessel disease • Chronic total occlusion (innocent bystander?)

Other factors • Electrolytes balance • Neurohormonal influence • Genetic factors

Future research with CMR imaging at different time points after MI might provide more insights into the dynamic changes in the myocardial substrate. It was recently shown that the absence of conduction channels in the scar tissue and limited scar mass (<10 g) can identify patients at a very low risk of VAs in a primary prevention population with a negative predictive value of 97.2%.43 Implementation of advanced imaging in the standard follow-up of these patients may allow discrimination of low risk groups as a first step in refining primary prevention ICD indications, or perhaps even broaden ICD indications in patients with LVEF >35% and LGE presence, a population currently investigated in the CMR GUIDE trial.44

PROTECT ICD Substrate imaging • LGE-CMR (scar core/borderzone/channels)

CMR = cardiac MRI; LGE = late gadolinium enhancement; LV = left ventricular; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention.

Risk Stratification Beyond Left Ventricular Ejection Fraction and Substrate

found in a subanalysis of the SCD-HeFT.28 Furthermore, the VALIANT trial has shown that baseline LVEF <40% was strongly associated with the occurrence of SCD in hospital and after discharge and explained a limited amount of SCD risk during long-term follow-up (longer than 6 months).29

The results of the PRESERVE EF trial indicate that non-invasive risk factors,for example premature ventricular complexes, increased T wave alternans, reduced heart rate variability, etc., are important warning signals for the risk of VA in post-MI patients, even in preserved LVEF. The results also underline that programmed ventricular stimulation (PVS) may be useful to identify patients at risk for VA in selected cases, as was previously shown in randomised trials, for example MUSTT and MADIT.45–48 However, patients in the early post-MI period were largely excluded from the above mentioned randomised controlled trials. The PROTECT ICD trial, an international, multicentre randomised controlled trial uses a PVS protocol to discriminate patients with LVEF <40%, early post-MI who will potentially benefit most from an ICD.49 The combination of CMR imaging and PVS in early post-MI patients (2–40 days), has the potential to fill an important knowledge gap in the landscape of primary prevention ICD implantation indication.

To conclude, the DAPA trial has several limitations and lacks potentially important data regarding coronary revascularisation during follow-up and novel medical treatment strategies. Nevertheless, it is unique in its design compared with other primary prevention trials as patients all underwent primary PCI, an essential part of today’s treatment strategy in acute MI patients. Pharmacological and cardiac resynchronisation trials have shown that neurohormonal antagonists (for example angiotensin receptor–neprilysin inhibitors) and cardiac resynchronisation therapy (CRT) have a significant impact on heart failure hospitalisation and heart failure related death, but the effect on SCD is not well appreciated.30 As the journey of advancements in ICD therapy for primary prevention will continue, there is a clear need for future trials focusing on SCD risk assessment based on advanced substrate characterisation combined with contemporary coronary revascularisation and pharmacological therapy.

Conclusion

Robust and sophisticated SCD risk stratification in ischaemic cardiomyopathy patients in general, and STEMI patients treated with primary PCI in particular, remains a demanding challenge, as a combination of dynamic factors (e.g. heart failure, coronary revascularisation status and myocardial substrate characteristics) are involved in the susceptibility to SCD. Current guidelines need more nuance based on altered SCD risk levels as a result of contemporary pharmacological and nonpharmacological treatment strategies. The DAPA trial results suggest that the extent of LV dysfunction shortly after STEMI that is treated with primary PCI can be used to identify patients at enhanced risk for early mortality.

However, similarly to other characteristics, the ability to predict clinical events may be substantially less after a certain critical time window.

Advanced substrate imaging with LGE-CMR has the potential to embrace an important factor that may guide clinicians in providing tailored therapies to decrease disease burden and increase survival, but we are

The Value of Cardiac MRI

Although scar characterisation with LGE-CMR imaging is gaining interest, it still has several limitations. Solid data regarding the added value of substrate imaging for a more tailored and robust risk stratification of SCD in reduced LVEF patients are lacking.31 The occurrence of VA/SCD does not solely depend on the size or other characteristics of the substrate. The susceptibility for VA/SCD is based on a complex interplay of multiple factors.32,33 Furthermore, there is currently no consensus on which CMR method should be used to identify patients at risk for VA.34,35 Various observational studies indicated that the peri-infarct zone assessed by CMR is a strong predictor of all-cause mortality and arrhythmic outcomes in ischaemic cardiomyopathy in both severely depressed and moderately depressed LV function and even CRT patients.33,36 However, there is

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DAPA in the Context of Previous Landmark Trials not there yet. With respect to previous landmark primary prevention trials, updated randomised trials (including invasive and non-invasive tests) are

needed with the inclusion of a contemporary population, treated with novel treatment strategies.

Clinical Perspective

• Current guidelines for primary prevention ICD eligibility are mainly based on left ventricular ejection fraction (LVEF) ≤30–35%.

• The shortcomings of LVEF as a sole risk stratification factor for post-MI primary ICD indication are clear, yet alternatives are lacking.

• Despite limited power, the DAPA trial conveys important messages and provides novel perspectives regarding left ventricular function post-primary percutaneous coronary intervention as an early risk marker for sudden cardiac death.

• New randomised trials are needed that include a contemporary population, treated with novel treatment strategies.

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20. Silverstein JR, Katritsis DG, Josephson ME. Use and abuse of internal cardioverter defibrillators for primary prevention.

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21. Martens P, Nuyens D, Rivero-Ayerza M, et al. Sacubitril/ valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction. Clin Res Cardiol 2019;108:1074–82. https:// doi.org/10.1007/s00392-019-01440-y; PMID: 30788621.

22. Buxton AE, Waks JW, Shen C, Chen PS. Risk stratification for sudden cardiac death in North America – current perspectives. J Electrocardiol 2016;49:817–23. https://doi. org/10.1016/j.jelectrocard.2016.07.018; PMID: 27524476.

23. Steinbeck G, Andresen D, Seidl K, et al. Defibrillator implantation early after myocardial infarction. N Engl J Med 2009;361:1427–36. https://doi.org/10.1056/NEJMoa0901889; PMID: 19812399.

24. Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med 2004;351:2481–8. https:// doi.org/10.1056/NEJMoa041489; PMID: 15590950.

25. Parkash R, MacIntyree C, Dorian P. Predicting sudden cardiac death after myocardial infarction: a great unsolved challenge. Circ Arrhythm Electrophysiol 2021;14:e009422. https://doi.org/10.1161/CIRCEP.120.009422; PMID: 33464943.

26. Barsheshet A, Goldenberg I, Moss AJ, et al. Effect of elapsed time from coronary revascularization to implantation of a cardioverter defibrillator on long-term survival in the MADIT-II trial. J Cardiovasc Electrophysiol 2011;22:1237–42. https://doi. org/10.1111/j.1540-8167.2011.02096.x; PMID: 21615813.

27. Stone GW, Selker HP, Thiele H, et al. Relationship between infarct size and outcomes following primary PCI patientlevel analysis from 10 randomized trials. J Am Coll Cardiol 2016;67:1674–83. https://doi.org/10.1016/j.jacc.2016.01.069; PMID: 27056772.

28. Adabag S, Patton KK, Buxton AE, et al. Association of implantable cardioverter defibrillators with survival in patients with and without improved ejection fraction: secondary analysis of the sudden cardiac death in heart failure trial. JAMA Cardiol 2017;2:767–74. https://doi. org/10.1001/jamacardio.2017.1413; PMID: 28724134.

29. Piccini JP, Zhang M, Pieper K, et al. Predictors of sudden cardiac death change with time after myocardial infarction: Results from the VALIANT trial. Eur Heart J 2010;31:211–21.

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31. Gupta A. Substrate imaging to guide primary prevention implantable cardioverter-defibrillator in ischemic cardiomyopathy: fanciful or realistic aim? JACC Cardiovasc Imaging 2020;13:1767–70. https://doi.org/10.1016/j. jcmg.2020.05.013; PMID: 32653542.

32. Kwong RY, Chan AK, Brown KA, et al. Impact of unrecognized myocardial scar detected by cardiac magnetic resonance imaging on event-free survival in patients presenting with signs or symptoms of coronary artery disease. Circulation 2006;113:2733–43. https://doi.org/10.1161/ CIRCULATIONAHA.105.570648; PMID: 16754804.

33. Haghbayan H, Lougheed N, Deva DP, et al. Peri-infarct quantification by cardiac magnetic resonance to predict outcomes in ischemic cardiomyopathy: prognostic systematic review and meta-analysis. Circ Cardiovasc Imaging 2019;12:e009156. https://doi.org/10.1161/ CIRCIMAGING.119.009156; PMID: 31735067.

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Clinical Arrhythmias

Obesity and Atrial Fibrillation: Epidemiology, Pathogenesis and Effect of Weight Loss Ahmed M Al-Kaisey1,2 and Jonathan M Kalman1,2 1. Department of Cardiology, Royal Melbourne Hospital, Melbourne, Australia; 2. Department of Medicine, University of Melbourne, Melbourne, Australia

Abstract

The obesity epidemic continues its relentless advance and is paralleled by an increase in the incidence of AF. Several epidemiological studies have highlighted obesity as an independent risk factor for the development of AF. This relationship is likely multifactorial through a number of interacting mechanisms. Weight loss through lifestyle changes or surgery has been associated with reverse remodelling of the atrial substrate and subsequent reduction in AF, making it an essential pillar in the management of AF in obese patients. In this review, the epidemiological data that support the obesity–AF relationship, the current insights into the underlying pathophysiological mechanism, the impact of weight loss on reverse remodelling and AF reduction, and the strategies to achieve weight loss in patients with AF are discussed.

Keywords

AF, obesity, atrial substrate, epicardial atrial adipose tissue, reverse remodelling, weight loss, risk factor management Disclosure: JMK is supported by a practitioner fellowship from the NHMRC. He has received research support from Biosense Webster, Abbott and Medtronic, and has served on the advisory board of Biosense Webster. AMAK has no conflicts of interest to declare.

Received: 2 July 2021 Accepted: 9 August 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(3):159–64. DOI: https://doi.org/10.15420/aer.2021.36 Correspondence: Jonathan Kalman, Suite 1 Melbourne Heart Centre, Royal Melbourne Hospital, Royal Parade, Parkville, Melbourne, VIC 3050, Australia.

E: jon.kalman@mh.org.au 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 obesity epidemic continues its relentless advance, currently affecting 2 billion people.1 Obesity is associated with an increased burden of a spectrum of diseases, with the focus in this article being on AF. The health-related burden associated with obesity is estimated to have a substantial economic impact.2 In alignment with this epidemic, the prevalence of AF is increasing. In the US, a large observational study showed a significant increase in the incidence of new AF between 1980 and 2000, and estimated that the projected number of persons with AF in the US would exceed 10 million by 2050.3 Similar trends have been seen in Europe and Australia.4,5 The pathophysiological mechanisms that underline the AF–obesity relationship remain incompletely understood.

There are, however, consistent data that support weight management in improving AF outcomes. In this review, we discuss the AF–obesity relationship, the proposed underlying mechanisms, and the impact of weight loss on AF and its arrhythmogenic substrate.

To examine the impact of the obesity-associated traditional risk factors on the AF risk, a recent retrospective Korean study studied the AF risk among a cohort of metabolically healthy obese individuals (no diabetes, hypertension and dyslipidaemia) compared with metabolically unhealthy obese and non-obese individuals.8 Compared with non-obese individuals, the metabolically healthy obese cohort had a 20% increased AF risk, whereas metabolic unhealthiness increased the AF risk by 40%. In addition, elevated BMI has been shown to be associated with AF clinical phenotype progression from paroxysmal to persistent.10 In the Olmsted County study, where 3,248 patients with paroxysmal AF were followed up, 17% progressed to persistent AF. Obesity was independently associated with progression to persistent AF, even after adjusting for traditional risk factors, signalling its impact on the arrhythmogenic substrate of AF. However, while the aforementioned evidence supports the obesity–AF relationship, the mechanism underpinning the impact of obesity on the incidence of AF remains incompletely understood and is likely multifactorial (Figure 1). In the next section, we discuss the potential mechanisms that underpin the obesity–AF relationship, highlighting the recent insights from both animal and human studies.

The Obesity–AF Association

A number of observational cohort studies have highlighted obesity as an independent risk factor for the development of AF.6–11 In the Framingham Heart Study, 526 out of 5,282 participants developed AF over a mean follow-up of 13.7 years.11 Obesity was found to be an independent predictor for incident AF after adjusting for traditional risk factors. Similar findings were found in the Women’s Heart Study, where incident AF was confirmed in 2.4% of the cohort over a 12.9-year follow-up period.9 BMI was linearly associated with AF risk, with a 4.7% increase in risk with each kg/m2.

Pathophysiological Changes in Obesity and AF Haemodynamic Changes

Obesity leads to left atrial and ventricular remodelling through a number of haemodynamic mechanisms. Obesity is associated with an increase in both cardiac output and systolic blood pressure with little change in

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Obesity and AF Figure 1: Obesity, AF, Weight Loss and Reverse Remodelling

al. characterised the electroanatomic atrial remodelling and epicardial adipose tissue in a cohort of obese patients and compared it with a nonobese cohort.20 Obesity was associated with an increase in all measures of epicardial adipose tissue, with a predominant distribution adjacent to the posterior left atrium and the atrioventricular groove. Obese patients had reduced global conduction velocity, increased fractionation and increased low-voltage areas. Low-voltage areas were predominantly seen in the posterior and/or inferior LA, matching the location of epicardial adipose tissue (EAT) on cardiovascular MRI.

Obesity

Epicardial adipose tissue Vasocrine effect Paracrine effects

Systemic inflammation

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Associated comorbidities OSA HTN Heart failure Insulin resistance

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Role of Epicardial Adipose Tissue

The availability of cross-sectional imaging modalities such as cardiac computed tomography has enabled us to examine the relationship between the quantity and quality of the EAT and AF. This layer of adipose tissue is located between the visceral pericardial and the epicardial surface, and there is no fascial layer that separates the EAT and the myocardium. Epidemiological studies utilising non-invasive imaging with a focus on the abundance of EAT have consistently demonstrated an independent association between EAT volume and incident AF, even after adjusting for AF risk factors, including BMI and LA enlargement.21,22 Beyond predicting AF, this association appears to impact on the outcome of AF ablation.23 However, the underlying electrophysiological, cellular and molecular mechanisms that link epicardial adipose tissue with AF progression remain poorly defined, and a number of mechanistic theories have been proposed.

LA remodelling Mechanical dilatation Fibrosis Connexin lateralisation Conduction slowing Conduction heterogeneity Inducible and spontaneous AF

Weight loss diet, lifestyle, changes and bariatric surgery

Reverse remodelling and ↓ AF

LA = left atrium; LV = left ventricle; LVH = left ventricular hypertrophy; OSA = obstructive sleep apnoea; HTN = hypertension.

The proximity of the EAT layer to the myocardium means the EAT can exert important paracrine and vasocrine effects on neighbouring cardiomyocytes.24,25 In chronic inflammatory disorders, the epicardium becomes a site of deranged adipogenesis, leading to secretion of proinflammatory adipokines, such as interleukin-1β, interleukin-6, activin-A and tumour necrosis factor-alpha, which may play an important role in the development of atrial fibrosis.26 In an ovine model, Mahajan et al. demonstrated that sustained obesity resulted in global biatrial endocardial electrical and structural remodelling, and associated EAT infiltration in the posterior LA wall.27 A cohort of 10 sheep fed a calorie-dense diet to induce obesity were compared with 10 lean sheep, and all 20 sheep underwent invasive and non-invasive assessments of their atrial substrate. Compared with the lean sheep cohort, the obese sheep demonstrated both abnormal structural (increased LA volume and pressure) and electrical (reduced atrial conduction velocity, increased conduction heterogeneity, increased fractionated electrograms and decreased posterior LA voltage) remodelling. This was associated with more frequent, prolonged and greater cumulative duration of AF. Epicardial fat was seen to infiltrate the posterior LA in the obese group, and was associated with reduced endocardial voltage in this region.

the heart rate.12 This is related to both activation of the renin– angiotensin–aldosterone system and enhancement of the sympathetic nervous system.13 This increase in cardiac output will increase venous return to the heart, leading to enhanced atrial and ventricular wall stretch, and eventually dilatation.14 Moreover, obesity has a haemodynamic impact on the heart through the associated medical comorbidities, such as hypertension, sleep apnoea and insulin resistance. Hypertension increases left ventricular afterload, leading to further structural remodelling in the form of left ventricular hypertrophy, diastolic dysfunction and left atrial dilatation.15 Obesity-associated sleep-disordered breathing is associated with surges in symptomatic nervous system activity through intermittent episodes of hypoxia, which has been shown to be associated with a significant increase in the prevalence of both atrial and ventricular arrhythmia, even after adjusting for traditional risk factors.16

Left Atrial Remodelling and Left Atrial Substrate

Animal studies have consistently demonstrated the presence of an arrhythmogenic substrate in association with obesity. In an ovine model, progressive changes in electrical and structural atrial remodelling were seen in a cohort of 30 sheep being fed a high-calorie diet over an 8-month period.17 Increasing weight was associated with increasing left atrial (LA) volume, LA fibrosis and upregulation of inflammatory markers. The net effect was decreased conduction velocity and an increase in conduction heterogeneity, with an associated increase in both inducible and spontaneous AF. Other animal studies noted that a high-fat diet could increase AF duration due to slow atrial conduction and reduced pulmonary vein refractoriness. These changes could occur without necessarily being accompanied by development of obesity.18,19

Prior tissue culture studies have shown that epicardial adipose tissue is capable of releasing adipo-fibrokines, promoting atrial fibrosis and its associated electrical substrate.28,29 The critical role local EAT has on the atrial substrate was elegantly demonstrated in a recent study.30 In a cohort of patients undergoing cardiac surgery without AF, higher local epicardial adipose tissue volume on imaging correlated with slowed conduction, greater electrogram fractionation, increased fibrosis and lateralisation of cardiomyocyte connexin-40 (Figure 2). Moreover, atrial conduction heterogeneity was increased with more extensive myocardial adipose infiltration. Cardiomyocyte culture studies using multielectrode arrays showed that cardiac adipose tissue-secreted factors slowed conduction velocity and contained proteins with capacity to disrupt intermyocyte electromechanical integrity.

Similar abnormal substrate has been seen in human studies. A large observational longitudinal study found that obesity was a strong predictor of LA enlargement, after adjusting for age and sex.5 Moreover, Mahajan et

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Obesity and AF Figure 2: Right Atrial Conduction is Dependent on Anterior Right Atrial Adiposity

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A: Exemplar CT images of patients with low and high anterior RA EAT volumes. B: Exemplar isochronal (3-ms steps) maps at 600-ms pacing rate from patients with either low or high anterior RA EAT volumes. White star indicates the earliest plaque activation; the yellow star indicates latest plaque activation. C: Significant correlations existed between the RA EAT volume and plaque activation time, conduction velocity and number of complex points. D: In contrast, these electrophysiological parameters did not correlate with the biatrial adipose tissue volume. EAT = epicardial adipose tissue; RA = right atrial. Source: Nalliah et al. 2020.30 Reproduced with permission from Elsevier.

Recently, non-invasive assessment of the EAT activity on CT has gained significant interest. As inflammation increases, a significant change in the degree of epicardial fat attenuation values represented by Hounsfield units can be detected.31 This suggests that EAT attenuation may serve as a novel non-invasive radiographic sensor of inflammation. Adipose tissue activity on CT has been shown to be an independent predictor of high-risk coronary artery plaques and major adverse cardiovascular events.32 El Mahdiui et al. demonstrated that a higher attenuation of the EAT was associated with higher AF recurrent rates.33 In a cohort of 460 patients undergoing first AF catheter ablation for symptomatic AF, the total EAT and posterior LA adipose tissue was traced, and the attenuation value of the posterior LA adipose tissue was assessed. Following a mean followup of 18 months, 37% patients had AF recurrence, and patients with higher attenuation (>–96.4 Hounsfield units) were more likely to have AF recurrence than lower attenuation on both univariate and multivariate analyses. Similar findings were demonstrated in another study that

examined attenuation of the entire LA periatrial EAT.34 The ability of cardiac CT to provide both quantitative and qualitative assessments of the EAT provides a promising tool that may assist in individualising therapy for patients with AF.

Role of Inflammation

In addition to the local inflammatory role of EAT on the arrhythmogenic substrate of AF, obesity is associated with elevated systemic inflammatory markers, which have been linked to AF. Inflammation has been linked to various pathological processes, such as oxidative stress, apoptosis and fibrosis, which may promote AF substrate formation.35

Impact of Weight Loss on the Atrial Substrate and AF

Observational retrospective studies have suggested a role for weight loss in reducing AF.36 A number of prospective studies, both observational and

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Obesity and AF Figure 3: Reversal of Conduction Abnormalities and Inflammation with Weight Reduction A

Control

Obese

15% weight reduction

30% weight reduction

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A: Activation maps of the left atrium at 300 ms in the control, obese, 15% weight reduction and 30% weight reduction. The plaque was paced from the corner (red zone). The maps are drawn to the same scale, and 2-ms isochrones are superimposed. B: Haematoxylin–eosin-stained sections showing inflammatory infiltrate in the perivascular space in the left atrial posterior wall. Some of the inflammatory cells are marked by arrowheads. Scale bar: 100 µm. Source: Mahajan et al. 2021.42 Adapted with permission from Elsevier.

randomised, have confirmed the favourable effect of weight loss on AF.37–40 Abed et al. randomised 150 patients with AF to either weight management (intervention) or general lifestyle advice (control).37 At 1 year, the intervention group lost significantly more weight compared with controls, and had fewer AF episodes and symptoms, and less burden. In addition, the LA diameter and interventricular septum wall thickness was significantly reduced compared with the control arm.

(p<0.001). Moreover, increased weight loss was significantly associated with greater AF freedom: 45 (39%) in group 1, 69 (67%) in group 2 and 116 (86%) in group 3 (p<0.001). It is important to remember that the majority of the data on weight loss in AF used lifestyle changes to achieve weight loss, which without constant supervision is often unsustainable or unsuccessful.

As such, the impact of surgical weight loss through bariatric surgery on AF ablation outcomes was recently examined in an observational study by Donnellan et al.41 They reviewed a cohort of 51 morbidly obese patients (BMI >40 kg/m2) who had undergone bariatric surgery prior to AF ablation, and matched them to a cohort of 102 morbidly obese patients without prior bariatric surgery and 102 non obese patients. The three groups had similar LA dimensions on echocardiography at baseline. Bariatric surgery was associated with significant reductions in weight, systolic blood pressure and glycated haemoglobin. During follow-up, the bariatric surgery group had significantly fewer AF recurrences compared with the other two control groups.

In the LEGACY study, Pathak et al. demonstrated that patients who lost and maintained the loss of >10% of their bodyweight over 4 years had sixfold arrhythmia-free likelihood compared with those who lost <3% or gained weight. Moreover, weight fluctuation of >5% had an adverse effect on overall freedom from AF, suggesting the causal relationship between weight and AF.39 In addition, compared with baseline, patients who lost >10% of bodyweight had significantly decreased left atrial volume indexed for body surface area, interventricular septum thickness, left ventricular end diastolic diameter and E/E’, whereas patients who lost <3% had either an increased or unchanged difference from baseline. It is important to note that while this study targeted weight loss, it was associated with improvements in sleep apnoea, blood pressure and glycaemic control; making it difficult to ascertain the individual impact of each risk factor on both AF reduction and reverse remodelling.

The precise mechanism by which weight loss leads to AF reduction is not well defined. Recently, Mahajan et al. studied the impact of weight reduction on reverse remodelling of the atrial electrical and structural substrate.42 In a cohort of 30 sheep that had sustained obesity induced by a high-calorie diet over 18 months, the cohort was randomised into three groups: sustained obesity, and 15% and 30% weight loss. Sustained obesity was associated with adverse LA structural and electrical remodelling, whereas 30% weight loss was associated with a significant reversal of remodelling, translating into less AF inducibility (Figure 3).

A subanalysis of the same study cohort (REVERSE-AF trial) examined the association between weight loss and progression of AF.38 When patients were stratified according to the percentage of weight loss (group 1: <3%, group 2: 3–9% and group 3: >10%), 41% progressed from paroxysmal to persistent and 26% from persistent to paroxysmal or no AF in group 1. In group 2, 32% progressed from paroxysmal to persistent and 49% reversed from persistent to paroxysmal or no AF. In group 3, 3% progressed to persistent and 88% reversed from persistent to paroxysmal or no AF

Weight Management in Obese Patients with AF

The compelling body of evidence that supports weight reduction in the management of AF is clear. This has been reflected in scientific statements

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Obesity and AF from both the European Society of Cardiology and the American Heart Association.43,44 The 2020 European Society of Cardiology guidelines for management of AF proposed the Atrial fibrillation Better Care (ABC) holistic pathway (‘A’ anticoagulation; ‘B’ better symptom management; ‘C’ cardiovascular and comorbidity optimisation) as a simplified approach to care for AF patients across different health disciplines. Intense weight reduction, together with comprehensive management of interacting cardiovascular risk factors, is the cornerstone of the ‘C’ component of the ABC pathway.44

associated with achieving and maintaining weight reduction, bariatric surgery has the potential to achieve such results, and has been demonstrated to be associated with both a reduction in the incidence of AF among patients at risk and reversal of AF type among patients with known AF.47,48

Conclusion

Obesity and AF have emerged as major global epidemics. Their impact on the healthcare costs and burden on both patients and physicians is evident.

There is strong evidence that supports the obesity–AF relationship through multiple and interacting mechanisms, including diastolic dysfunction, local EAT inflammation and infiltration, and systemic inflammation. The current body of evidence strongly supports weight loss as an important pillar in the management of obese patients with AF. Weight reduction together with the management of other risk factors should be delivered using a comprehensive approach to obtain the best results.

However, successful and sustainable weight reduction remains a challenging task to achieve and a number of strategies have been proposed. These strategies stem from the concept of a chronic care model, which has been successful in the management of patients with various chronic illnesses, such as ischaemic heart disease and chronic heart failure. The integrated care approach in which the patient is the primary focus, together with multidisciplinary teams and community support, has been shown to be associated with a reduction in all-cause mortality and cardiovascular hospitalisations in a recent meta-analysis.45

Clinical Perspective • Obesity is an independent and important predictor of AF incidence and progression.

• Emerging data now support the impact of epicardial adipose

Sanders et al. showed that a dedicated risk factor management clinic focusing on all modifiable risk factors through both lifestyle and diet changes can deliver promising results.39,46 Such clinics have the potential to do this through identifying patient-specific modifiable risk factors, setting individual achievable targets, and working with patients to ensure ongoing motivation and adherence to their goals. Understanding the difficulties 1. Caballero B. Humans against obesity: who will win? Adv Nutr 2019;10(suppl_1):S4–9. https://doi.org/10.1093/advances/ nmy055; PMID: 30721956.

2. Wang YC, McPherson K, Marsh T, et al. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 2011;378:815–25. https://doi.org/10.1016/ S0140-6736(11)60814-3; PMID: 21872750.

3. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;114:119–25. https://doi. org/10.1161/CIRCULATIONAHA.105.595140; PMID: 16818816.

4. Ball J, Thompson DR, Ski CF, et al. Estimating the current and future prevalence of atrial fibrillation in the Australian adult population. Med J Aust 2015;202:32–5. https://doi. org/10.5694/mja14.00238; PMID: 25588442.

5. Stritzke J, Markus MR, Duderstadt S, et al. The aging process of the heart: obesity is the main risk factor for left atrial enlargement during aging the MONICA/KORA (monitoring of trends and determinations in cardiovascular disease/cooperative research in the region of Augsburg) study. J Am Coll Cardiol 2009;54:1982–9. https://doi. org/10.1016/j.jacc.2009.07.034; PMID: 19909880.

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8. Lee H, Choi EK, Lee SH, et al. Atrial fibrillation risk in metabolically healthy obesity: a nationwide populationbased study. Int J Cardiol 2017;240:221–7. https://doi. org/10.1016/j.ijcard.2017.03.103; PMID: 28385358.

9. Tedrow UB, Conen D, Ridker PM, et al. The long- and shortterm impact of elevated body mass index on the risk of new atrial fibrillation the WHS (Women’s Health Study). J Am Coll Cardiol 2010;55:2319–27. https://doi.org/10.1016/j. jacc.2010.02.029; PMID: 20488302.

10. Tsang TS, Barnes ME, Miyasaka Y, et al. Obesity as a risk factor for the progression of paroxysmal to permanent atrial fibrillation: a longitudinal cohort study of 21 years. Eur Heart J 2008;29:2227–33. https://doi.org/10.1093/eurheartj/ ehn324; PMID: 18611964.

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tissue on the arrhythmogenic substrate of AF patients, even without elevated BMI. • Weight loss through lifestyle changes or surgery is an important pillar in the management of AF in obese patients.

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19. Takahashi K, Sasano T, Sugiyama K, et al. High-fat diet increases vulnerability to atrial arrhythmia by conduction disturbance via miR-27b. J Mol Cell Cardiol 2016;90:38–46. doi: https://doi.org/10.1016/j.yjmcc.2015.11.034; PMID: 26654778.

20. Mahajan R, Nelson A, Pathak RK, et al. Electroanatomical remodeling of the atria in obesity: impact of adjacent epicardial fat. JACC Clin Electrophysiol 2018;4:1529–40. https://doi.org/10.1016/j.jacep.2018.08.014; PMID: 30573116.

21. Thanassoulis G, Massaro JM, O’Donnell CJ, et al. Pericardial fat is associated with prevalent atrial fibrillation: the Framingham Heart Study. Circ Arrhythm Electrophysiol 2010;3:345–50. https://doi.org/10.1161/CIRCEP.109.912055; PMID: 20558845.

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Heart 2017;103:1947–53. https://doi.org/10.1136/ heartjnl-2016-310952; PMID: 28490616.

46. Gallagher C, Fitzgerald JL, Stokes MB, et al. Risk factor management in atrial fibrillation: how to deliver a successful clinic. Curr Cardiovasc Risk Rep 2021;15:9. https://doi. org/10.1007/s12170-021-00671-x.

47. Donnellan E, Wazni OM, Elshazly M, et al. Impact of bariatric surgery on atrial fibrillation type. Circ Arrhythm Electrophysiol 2020;13:e007626. https://doi.org/10.1161/CIRCEP.119.007626; PMID: 31940441.

48. Höskuldsdóttir G, Sattar N, Miftaraj M, et al. Potential effects of bariatric surgery on the incidence of heart failure and atrial fibrillation in patients with type 2 diabetes mellitus and obesity and on mortality in patients with preexisting heart failure: a nationwide, matched, observational cohort study.

J Am Heart Assoc 2021;10:e019323. https://doi.org/10.1161/ JAHA.120.019323; PMID: 33754795.

Cardiac Pacing

Physiology and Practicality of Left Ventricular Septal Pacing Luuk Heckman ,1 Justin Luermans ,2,3 Floor Salden ,2 Antonius Martinus Wilhelmus van Stipdonk ,2 Masih Mafi-Rad,2 Frits Prinzen 1 and Kevin Vernooy 2,3 1. Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands; 2. Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre+ (MUMC+), the Netherlands; 3. Department of Cardiology, Radboud University Medical Centre (Radboudumc), Nijmegen, the Netherlands

Abstract

Left ventricular septal pacing (LVSP) and left bundle branch pacing (LBBP) have been introduced to maintain or correct interventricular and intraventricular (dys)synchrony. LVSP is hypothesised to produce a fairly physiological sequence of activation, since in the left ventricle (LV) the working myocardium is activated first at the LV endocardium in the low septal and anterior free-wall regions. Animal studies as well as patient studies have demonstrated that LV function is maintained during LVSP at levels comparable to sinus rhythm with normal conduction. Left ventricular activation is more synchronous during LBBP than LVSP, but LBBP produces a higher level of intraventricular dyssynchrony compared to LVSP. While LVSP is fairly straightforward to perform, targeting the left bundle branch area may be more challenging. Long-term effects of LVSP and LBBP are yet to be determined. This review focuses on the physiology and practicality of LVSP and provides a guide for permanent LVSP implantation.

Keywords

Left ventricular septal pacing, anti-bradycardia pacing, cardiac resynchronisation therapy Disclosure: FP has received research grants from Medtronic, Abbott, MicroPort CRM and Biotronik. KV has a consultancy agreement with Medtronic, Abbott and Philips.

JL has a consultancy agreement with Medtronic. All other authors have no conflicts of interest to declare.

Received: 21 May 2021 Accepted: 8 July 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(3):165–71. DOI: https://doi.org/10.15420/aer.2021.21 Correspondence: Kevin Vernooy, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center+, PO Box 5800, 6202 AZ Maastricht, the Netherlands. E: Kevin.Vernooy@mumc.nl 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 right ventricle (RV) apex has been the preferred site for ventricle lead placement since transvenous lead implantation for permanent pacing became available half a century ago.1 The RV apex is easily accessible for implantation and yields fixation that is stable in the long term and low capture thresholds. However, there are significant downsides to this approach. Pacing the RV apex results in a nonphysiological dyssynchronous ventricular activation, frequently reducing left ventricular (LV) function in the long run.2,3 This so-called pacinginduced cardiomyopathy is associated with an increased risk of AF, heart failure and cardiovascular death.4,5

A subsequent study evaluated the effects of different sequences of ventricular activation on cardiac function in a canine model of complete heart block. This study demonstrated that the haemodynamically more effective LV pacemaker sites resulted in higher cardiac outputs than any of the RV sites tested.7 The differences in cardiac performance between various ventricular pacemaker sites are best explained by varying degrees of dyssynchrony during ventricular contraction.

These findings were later confirmed in multiple animal studies, which showed that the abnormal electrical activation induced by ventricular pacing leads to a depression of systolic and diastolic LV function. The cause of this depression during abnormal electrical activation appears to be a combination of the non-physiological sequence of activation.3

In a search to prevent pacing-induced cardiomyopathy, alternative pacing sites that maintain interventricular and intraventricular synchrony have been studied intensively. Among the alternative pacing sites, biventricular pacing (BVP), His bundle pacing (HBP) and, more recently, LV septal pacing (LVSP) and left bundle branch pacing (LBBP) have been introduced. This review focuses on the physiology and practicality of LVSP.

The adverse effects of RV pacing in patients first became apparent in the MOST study, a randomised trial comparing DDDR with VVIR pacing in patients who requiring ventricular pacing because of bradycardia. In this study, in 1,339 patients with a narrow QRS and preserved left ventricular ejection fraction at baseline, it was shown that a high percentage of ventricular pacing was a strong predictor of heart failure (HF) hospitalisations and AF occurrence.5

Adverse Clinical Effects of Right Ventricular Pacing

The fact that the different ventricular activation sequences induced by artificial electrical stimulation (pacing) influence cardiac pump function was recognised by Wiggers et al. in 1925.6

Later, the DAVID trial demonstrated that, in patients with an ICD indication and reduced LV ejection fraction but without an indication for cardiac

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Left Ventricular Septal Pacing Figure 1: Ventricular Activation

In addition, it was demonstrated that the activation wavefront spreads much faster around the endocardium than towards the epicardium.9 In other words, endocardial conduction was found to be much faster than endocardium-to-epicardium spread of depolarisation.

Later, more detailed analysis of the spread of activation wavefronts and the distribution of stimulus potentials after epicardial stimulation and endocardial stimulation was performed.10–12 These studies confirmed earlier findings of preferential current flow and more rapid conduction velocity along the myocardial fibre orientation. Subsequent studies showed that myocardial fibres rotate between the epicardial and endocardial surfaces, while most of the endocardial surface contains a layer of Purkinje tissue electrically continuous with the myocardium.13,14 This is potentially one of the main reasons why endocardial spread of activation is faster than endocardium-to-epicardium spread.

5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100

Left Ventricular Endocardial Pacing

3D isochronic representation of the ventricular activation in a human isolated heart. The colour scheme indicates activation time in ms. Adapted from: Durrer et al. 1970.9 Used with permission from Wolters Kluwer Health.

The sequence of ventricular activation depends strongly on the pacing site. Back in 1988, a study on transmural activation showed there was a close correlation between fibre orientation and the spread of activation within the same plane for (sub)endocardial, midmyocardial and (sub) epicardial stimulation. In addition, conduction velocities were faster for endocardial than for midmyocardial and epicardial stimulation.15 Moreover, activation wavefront spread and conduction velocity during endocardial pacing were found to be similar to that during sinus rhythm.15

Figure 2: Electrical Activation Times BiV epicardial

LV epicardial

LBBB

0

40

80

Later, it was also shown that endocardial pacing increased the benefits of cardiac resynchronisation therapy (CRT) compared to epicardial pacing in a canine model of acute left bundle branch block (LBBB).16 Epicardial and endocardial mapping revealed that endocardial BVP reduced the total activation time more than epicardial BVP. Endocardial LV-only pacing resulted in fairly synchronous LV activation whereas, during epicardial LV pacing, large differences in electrical activation times occurred (Figure 2).

As a result, three possible mechanisms to explain the more rapid electric activation during endocardial pacing were proposed: a shorter path length of conduction; endocardial conduction is faster than epicardial conduction; and conduction is faster from the endocardium to the epicardium than vice versa.

120ms

BiV endocardial

LV endocardial

3D reconstruction of electrical activation times in the right and left ventricle, as measured with epicardial and endocardial electrodes. The left ventricular pacing site was the mid-lateral wall.

The colour bar indicates time scale in ms. Source: van Deursen et al. 2009.16 Reproduced with permission from Wolters Kluwer Health.

Preclinical Studies on Left Ventricular Septal Pacing

pacing, dual-chamber pacing (DDD-70) offered no clinical advantage over ventricular backup pacing (VVI-40). It was shown that dual-chamber pacing was even worse than ventricular back-up pacing, with an increased combined endpoint of death or hospitalisation for heart failure.8 Programming devices to dual-chamber pacing resulted in a ventricular pacing percentage of nearly 60%, while this was only 1% with ventricular back-up pacing.

In a study on ventricular activation and contraction patterns during ventricular pacing, it was demonstrated that, unlike pacing any site in the RV, pacing the left side of the IVS (LV septal pacing) resulted in findings similar to those seen in normal sinus rhythm: the IVS was activated from left to right, the LV pressure rise preceded the right ventricular pressure rise, and there was a normal IVS contraction pattern.17 A subsequent study found that cardiac function in terms of LV stroke volume and LV dP/dtmax was better during LVSP than RV pacing.18 The fact that LVSP maintained cardiac function at a level comparable to normal ventricular activation during sinus rhythm while QRS duration was prolonged confirmed the earlier hypothesis that LV function is dependent on the sequence of activation and not only on the duration of electrical activation. This was later confirmed in animal studies with extensive epicardial mapping and pace protocols. In these studies, multi-LV pacing considerably reduced LV activation time (compared to single-LV pacing), but the improvement in contractility by multi-LV pacing was limited to conditions where single-LV pacing provided only suboptimal improvement.19,20

Physiological Ventricular Activation Sequence

Under physiological circumstances, left ventricular (LV) activation is started from the left bundle branch from three endocardial areas (Figure 1): an area high on the anterior paraseptal wall just below the attachment of the mitral valve; a central area on the left surface of the interventricular septum (IVS); and the posterior paraseptal area at about one-third of the distance from apex to base. In the IVS, activation proceeds from left to right and in an apical-basal direction.9 Although these results were found in perfused isolated hearts, they were confirmed in canine hearts in situ.

The pattern of ventricular excitation, as judged from isochrone maps of sections of the hearts, did not change after isolation.9

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Left Ventricular Septal Pacing Figure 3: Systolic Shortening During Pacing and Normal Conduction End ejection

Apex Middle Base

Septal Anterior Lateral Posterior

0.1

Base

0 Apex

−0.1 Septal −0.2 −0.3

Posterior Right ventricle apex

Right ventricle septal

Left ventricle septal

Left ventricle apex

Normal condition

Typical example of left ventricle (LV) regional circumferential strain signals and bull’s eye plots of systolic shortening during pacing and normal conduction. LV septal pacing produces a more homogenous distribution of systolic shortening than RV pacing. Upper panels show the strain signals from 12 regions of the LV wall. Horizontal (time) axis starts at 15 ms after an R wave trigger. Vertical lines denote end ejection. Vertical (strain) axis ranges from +0.2 to −0.2, equivalent to 20% stretch and shortening, respectively. Lower panels show the distribution of systolic strain in the LV wall, as determined in the 160 regions (five short-axis slices, 32 regions per slice). Adapted from: Mills et al. 2009.23 Used with permission from Wolters Kluwer Health.

The activation sequence leading to the best LV pump function is that occurring during sinus rhythm with normal ventricular activation via the His-Purkinje system. Under these physiological circumstances, the electrical impulse exits the Purkinje system at sites on the LV endocardial surface of the septum. It was therefore hypothesised that pacing near LV exit sites of the Purkinje system would result in the most physiological activation and near-normal LV function. An LV pressure-volume analysis of the comparison between RV pacing and various sites within the LV showed, indeed, that LV function was maintained during LVSP when compared to normal ventricular activation, even though activation duration was longer (wide QRS).21 This finding again suggests that a good sequence of electrical activation is sufficient to allow for good LV function.

Besides the synchrony of ventricular contraction, temporal changes in haemodynamics and the efficiency of LVSP were studied. Shortly after onset of pacing as well as after 16 weeks, LV contractility and relaxation were comparable between LVSP and normal activation and LVSP maintained native interventricular dyssynchrony.23

Left Ventricular Septal Pacing in Patients

After preclinical studies demonstrated the long-term stability of the LVSP lead, the feasibility of permanently implanting an LV septal lead using the transvenous approach needed to beevaluated in patients.24 The acute haemodynamic effects of LVSP were also studied. In patients with structurally normal hearts with mainly a pacing indication because of sick sinus syndrome, it was demonstrated that LVSP maintained LVdP/dtmax to levels comparable to baseline atrial pacing.24 Importantly, the acute haemodynamic benefit of LVSP over RV apex and RV septal pacing was consistently observed in all patients. Right ventricular septal pacing (RVSP) resulted in a QRS duration of 165 ± 17 ms, while this was 144 ± 20 ms during LVSP. The large difference in QRS duration and haemodynamic effect between RVSP and LVSP, although these sites were only ~1 cm apart, has been related to a significant delay in transseptal conduction during RVSP, which causes considerably later LV mechanical activation and delayed contraction of the LV lateral wall, thereby inducing both inter- and intraventricular dyssynchrony.25

As a considerable part of the total dyssynchrony in LBBB hearts originate from the delay in conduction across the interventricular septum, a possible role for LVSP was also explored in cardiac resynchronisation therapy. In both ischaemic and non-ischaemic LBBB hearts, LVSP significantly increased LV function compared to baseline LBBB.22 After the acute beneficial haemodynamic effects of LVSP had been shown, the chronic effects of LVSP were studied in canine hearts after 4 months of pacing.23 Again, it was demonstrated that LVSP led to a rapid activation around the LV endocardium, resulting in a pattern that, of all tested pacing sites, most closely resembled the pattern during normal ventricular activation, although RV activation was somewhat delayed. MRI tagging measurements were performed to evaluate myocardial strains, work and indices of global mechanical discoordination (internal stretch fraction) and dyssynchrony (time to peak shortening). The contraction pattern was similar in normal ventricular activation and during LVSP. The pattern of regional time to peak shortening (earliest peak shortening was always observed in the lateral region and shortly thereafter observed in the other three quadrants) was identical for LVSP and normal activation. In addition, the myocardial oxygen consumption and perfusion were determined; LVSP did not significantly alter regional perfusion nor the distribution of regional myocardial work.23 Altogether, MRI tagging analysis showed that LVSP resulted in a homogenous distribution of systolic shortening in time, space and amplitude (Figure 3).

As a beneficial haemodynamic effect of LVSP was demonstrated in canine LBBB hearts, LVSP was studied as an alternative to CRT in patients. An acute haemodynamic pacing study comparing LVSP with BVP was performed in 12 patients with heart failure and an indication for CRT. The acute haemodynamic effect in these patients in terms of LVdP/dtmax was comparable between LVSP and BVP.22 More recently, a more extensive electrophysiological and haemodynamic study was performed in which the acute effects of LVSP were compared with BVP and HBP in patients receiving CRT.26 LVSP was performed using an electrophysiology catheter that was temporarily positioned, retrogradely through the aorta, on the left side of the interventricular septum. The study showed that QRS duration was reduced similarly by

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Left Ventricular Septal Pacing Figure 4: Haemodynamic and Electrophysiological Effects

*

*

*

Right

* *

Posterior Left

†

§

‡

* *

100

66

*

HBP SDAT = 27 ms

44

LVSP + RV

*

22

50

LV septal SDAT = 17 ms BL

BVP LVSP LVSP + RV

0

HBP LVSP

Subgroup (n=16)

†

30

88

BVP SDAT = 34 ms

150

Right 110

Baseline SDAT = 45 ms

50

0

C Anterior

Increase in LVdP/dtmax (%) Complared to Baseline (AAI)

150 100

0 200 QRS area (µVs)

B

Subgroup (n=16)

200

Activation time (ms)

QRS duration (ms)

A

*

*

*

*

LVSP

HBP

LVSP

*

20

10

0

BVP

LVSP + RV

A: Electrophysiological effects. QRS duration as time between QRS beginning and end (closed bars) and as time from pacing stimulus to QRS end (open bars) (upper panel) and QRS area (lower panel) during baseline (BL), conventional biventricular pacing (BVP), left ventricular septal pacing (LVSP) in combination with right ventricle (RV) pacing, and LVSP alone and in a subgroup (n=16) during (His bundle pacing (HBP) and LVSP. Results are presented as mean ± SD; *p<0.05 versus BL; †p<0.05 BVP versus LVSP; ‡p<0.05 LVSP + RV versus LVSP; §p< 0.05 HB versus LVSP. B: Isochronal maps.

Examples of isochronal maps with corresponding standard deviation of activation times (SDAT) during baseline (BL), conventional BVP, LVSP in combination with RV, and LVSP alone. C: Haemodynamic effects. Relative change in LVdP/dtmax compared with baseline (n = 27) during BVP, LVSP in combination with RV, and LVSP alone and in a subgroup (n = 16) during HBP and LVSP. Results are presented as mean ± SD. *p<0.05 versus BL; †p < 0.05 LVSP+RV versus LVSP. Adapted from: Salden et al. 2020.26 Used with permission from Wolters Kluwer Health, Inc.

Figure 5: Left Ventricular Septal Pacing

Benefits of LV septal pacing

RV

1. Compensation of slow transseptal conduction 2. Short path length of conduction 3. Fast endocardial conduction (fast-conducting endocardial, non-Purkinje fibres) 4. Faster endocardial-to-epicardial conduction than vice versa 5. Avoiding: • Phrenic nerve stimulation • Coronary sinus catheterisation • Posterolateral wall scar

LV

Left: Schematic transversal overview of ventricular activation during left ventricular septal pacing; red indicates early activation, blue indicates late activation. Right: Summary of benefits of left ventricular septal pacing. LV = left ventricle; RV = right ventricle.

LVSP and BVP, and was shortened even further by HBP. In contrast to BVP, LVSP and LBBP, HBP does not produce (additional) ventricular dyssynchrony and QRS duration is therefore shortest during HBP. Although the native His-Purkinje system is engaged in LBBP, QRS duration is similar in LVSP and LBBP. This is because both LVSP and LBBP, while restoring LV activation, induce delayed RV activation, of which the haemodynamic and long-term effects are unknown and need to be carefully evaluated in future studies.26 Interestingly, both QRS area and standard deviation of activation times SDAT – two measures of ventricular dyssynchrony – were significantly smaller during LVSP than BVP, and were comparable to HBP (Figure 4). Also, the increase in LV function (~18%) in these CRT patients, determined by invasive LV dP/dtmax measurements, was comparable for BVP and LVSP as well as HBP.26

LVSP has been demonstrated to have beneficial haemodynamic and electrophysiological effects in both animal and patient studies (Figure 5).

LVSP provides LV synchrony, based on: a shorter path length of conduction compared to epicardial pacing; a faster endocardial than epicardial conduction; and a faster conduction from endocardium to epicardium than vice versa. Furthermore, LVSP avoids the coronary sinus, phrenic nerve stimulation and posterolateral scar in CRT patients.

Practicality of Left Ventricular Septal Pacing

Initial animal studies investigating LVSP were performed using plunge electrodes, where the LV septal endocardium was reached by puncturing the RV free wall and subsequently the interventricular septum.21, 22 Later, clinical studies investigating the acute electrophysiological and haemodynamic effects of LVSP were performed using a steerable electrophysiology catheter advanced retrogradely through the aorta into the LV.22,26

Another interesting observation in the study was that no significant differences were found in the electrophysiological and haemodynamic effects of LVSP at the basal, mid- and apical LV septum levels.26 This finding supports the hypothesis that pacing the LV at the endocardium results in fast endocardial spread of activation, probably not necessarily through Purkinje fibres, providing a rather physiological LV activation.

To investigate electric activation and the mechanics, the haemodynamic performance and the efficiency of long-term LVSP, a customised pacing lead with an extended helix was used.23, 24 This Medtronic 09066 lead, a modified

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Left Ventricular Septal Pacing Figure 6: Implantation Procedure

3830 lead with longer, 4 mm screw, was introduced transvenously and, after being positioned against the RV septum using a preshaped guiding catheter (C315His, Medtronic), driven through the IVS until the LV endocardium was reached. After this type of investigational lead had been implanted in animal studies with stable lead measurements for more than 4 months, it was implanted in 10 patients with sinus node dysfunction, using the same transvenous approach, with the lead positioned deep into the IVS.24 In this first-in-human study of long-term LVSP, a 7 Fr preshaped guiding catheter (Model C315-S10, Medtronic) was used, since in HBP its specific shape allowing the catheter tip to be positioned perpendicularly against the IVS. Then, the implanter, using RAO and LAO views, positioned the tip of the lead to the middle of the IVS, guided by an RV angiogram. In the initial procedures, intracardiac echocardiography was used to verify the position of the lead tip on the IVS before screwing the lead into the IVS. Positioning the lead mid-ventricular in the IVS is different from the more recently applied left bundle branch pacing (LBBP), where the lead is placed closer to the anatomical level of the His bundle. Importantly, capture of the left conduction system was not studied nor pursued in this research. While rotating the lead, the implanter repeatedly assessed the IVS penetration depth by injecting small amounts of contrast medium through the guiding catheter against the IVS under fluoroscopy in LAO. In addition, pacing was repeatedly performed from the tip electrode while advancing the helix through the IVS to assess changes in paced QRS morphology that indicated that the left side of the IVS had been reached, i.e. a right bundle branch block-like QRS morphology. Pacing thresholds and impedances were measured to ensure that the helix did not protrude in the LV cavity. Images showing the implantation process are shown in Figure 6.

Practical Limitations of Left Ventricular Septal Pacing

Although the initial studies on long-term LVSP were performed with a modified version of the Medtronic 3830 lead (with an extended helix), it was recently shown that penetration of the septum was possible using the standard Medtronic 3830 lead, which is the most frequently used lead nowadays.27

The atrial lead is positioned in the right atrial (RA) appendage and a Certus PressureWire (Abbott) is positioned in the left ventricle (LV) for acute haemodynamic measurements (A). A right ventricular (RV) angiogram is performed in right anterior oblique (RAO; A) and left anterior oblique (LAO; B). The custom left ventricular septal (LVS) pacing lead is positioned perpendicularly against the interventricular septum (IVS) using a preshaped guiding catheter (C). The tip of the lead is positioned as close to the middle of the IVS as possible by using fluoroscopy in both RAO (C) and LAO (D) with reference to the corresponding RV angiogram (A and B). Intracardiac echocardiography ultrasound catheter is used to verify the position of the lead tip on the IVS achieved using fluoroscopy before screwing the lead into the IVS (E). The intracardiac echocardiogram shows the RV in a long-axis view that parallels the septum with the lead tip located at midlevel between the apex and base and the anterior and posterior border of the RV. F: A schematic representation of the intracardiac echocardiogram. After proper positioning of the LVS lead on the IVS, the lead is screwed through to the left side of the IVS. G: The tip of the lead resting perpendicular against the IVS (indicated by the dashed yellow line) before screwing the lead in. While rotating the lead, repeated hand injections of contrast medium through the guiding catheter against the IVS are used to assess the penetration depth (H and I). The part of the lead tip that protrudes into the IVS is not covered by contrast medium. Based on beforehand knowledge of the lead tip dimensions and the patient’s IVS wall thickness, this provides an estimation of penetration depth in the IVS. AO = indicates aorta; PA = pulmonary artery; TV = tricuspid valve. Adapted from: Mafi-Rad et al. 2016.24 Used with permission from Wolters Kluwer Health.

Despite the straightforward procedure, there are factors that possible complicate implantation. LVSP lead implantation failure is likely to result from difficulty in lead fixation, which is usually caused by septal hypertrophy and/or scar/fibrosis. In addition, tissue lodging into the helix induced by the drill effect and insufficient sheath support or reach is an issue.

Advances in dedicated implantation tools may overcome some of these practical issues. Structural evaluation of the heart, especially the interventricular septum thickness and the presence of septal scarring, can be beneficial. In the presence of septal hypertrophy or scar, reaching the far subendocardium, where the left bundle branch is situated, can be challenging. In these cases, LVSP can be of particular benefit since the more complicated targeting of the His-Purkinje system is not required. A recently published study investigating ventricular synchrony during transventricular pacing demonstrated that deep LVSP produces LV synchrony comparable to LBBP.28

maintain left ventricular synchrony.27 Multiple studies have demonstrated the safety and feasibility of LBBAP. However, reported left bundle branch capture rates differ, but are usually between 60% and 90%.28–30 Consequently, up to one-third of patients who are reported to have been treated with LBBP were in fact treated with LVSP.

Left Ventricular Septal Pacing Versus Left Bundle Branch Pacing

Unlike LVSP, LBBP and HBP engage the intrinsic His–Purkinje system and LBBP has been shown to maintain ventricular synchrony at levels comparable to HBP and even to intrinsic ventricular activation.31–35 Non-

Left bundle branch area pacing (LBBAP; LVSP and LBBP) has recently been introduced as alternative method of conduction system pacing to

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Left Ventricular Septal Pacing Figure 7: Left Ventricular Septal Pacing

septum and that the additional RV angiogram and intracardiac echocardiogram are not necessary, which facilitates the procedure.

Position lead against right ventricle septum

Advancement lead through septum

Reaching final lead position

• Perpendicular, using pre-shaped guiding • Tricuspid valve annulus is anatomical marker • Paced QRS morphology • I, II positive • III negative

• (Continuous) transseptal pacing • Ectopic ventricular (fixation) beats • Monitor pacing threshold and impedance

• Basal to mid- septal level • RBBB-like morphology • qR (lead Vl) • rsR (lead Vl) • Septal contrast angiography • V6 R-wave peak time <100 ms • Pacing threshold <1.5 V

The method as described by Huang et al. to perform permanent LBBP and evaluate left bundle branch capture is rather complex as it requires relatively advanced electrophysiological knowledge and electrophysiological equipment in the cath lab.38 The technique calls for simultaneously recording the 12-lead ECG and the intracardiac electrogram from the lead tip for the assessment of paced QRS morphology and measurement of intervals, while carefully advancing the lead transseptally.

In addition, the His bundle potential is searched for as reference point and the left bundle branch potential needs to be recorded. Furthermore, multiple repeated measurements are required to diagnose capture of the left bundle branch.39 In contrast, the LVSP implantation procedure is fairly straightforward to perform as the specialised His-Purkinje system is not targeted. As the exact septal position of the lead in LVSP is less critical compared to LBBP, there is no need for the recording of a His bundle or left bundle branch potential. After the lead has be positioned perpendicularly against the septum, the lead is fixated somewhere in the basal to mid-level of the septum. The tricuspid valve annulus, visible on standard fluoroscopy imaging, is used as an anatomical marker.

Flow chart for performing left ventricular septal pacing. RV = right ventricle. RBBB = right bundle branch block.

selective HBP, however, is claimed by some to be less beneficial. A possible explanation could be capture of only the right bundle branch, since published data suggest benefits to patients receiving selective or non-selective HBP, and ultra-high frequency ECG analysis has demonstrated that both types of His bundle capture preserve ventricular electrical synchrony.36 Capture of the right bundle branch without the left bundle branch results in delayed LV activation. In (especially selective) LBBP, there is delayed RV activation but this is likely to have fewer clinical implications (RBBB patients versus LBBB patients). In contrast, LVSP results in direct left-to-right septal activation and interventricular dyssynchrony is less with LVSP than with LBBP.37

The paced QRS morphology, visible on standard 12-lead ECG recording, is used to determine whether the initial position on the RV septum is valid.

Preferably, a QRS morphology with a positive QRS complex in leads I and II and a negative QRS complex in lead III are seen while pacing the RV septum. Advancement of the lead through the septum is guided by QRS morphology, especially in lead V1, either via continuous pacing or by evaluating ectopic ventricular beats occurring during lead rotations for deep intraseptal deployment (fixation beats).40–41

A recently published study comparing LBBAP with and without evidence of direct capture of the left conduction system showed that LV dyssynchrony is comparable between LVSP and LBBP.28 This study showed that, compared to RV pacing, QRS area and left ventricular activation time (now referred to as V6RWPT) decrease when the lead is advanced towards the LV subendocardium. A reasonably acceptable level of ventricular dyssynchrony is achieved when an R’ (right bundle branch block-like QRS morphology) becomes apparent in lead V1. The R’ in lead V1 indicates delayed RV activation and therefore suggests that the left part of the IVS is reached. A significantly lower QRS area during LBBP compared to LVSP was found, although the absolute difference was small.

The suitability of the final lead position can be determined from the standard 12-lead ECG, where preferably a paced ‘qR’ morphology in lead V1 is seen, indicating the lead is deployed deep within the left septum.

Besides the right bundle branch block-like QRS morphology induced by left-sided septal pacing, deep septal deployment can also be confirmed by septal contrast angiography. QRS duration during LVSP is comparable to BVP and LBBP, but prolonged compared to HBP.22,26,28,37 A flow chart for performing LVSP is shown in Figure 7.

Another recent study compared differences in ventricular depolarisation between LVSP and LBBP using ultra-high-frequency ECG (UHF-ECG).37 UHFECG analysis showed that, although during LBBP left ventricular lateral wall activation is faster compared to LVSP, LBBP results in greater interventricular dyssynchrony. Interventricular dyssynchrony is less in LVSP than in LBBP, since left-to-right transseptal depolarisation occurs immediately after pacing and left subendocardial Purkinje fibres are captured later, which results in a more balanced ventricular depolarisation.37

Conclusion

The severity of impairment of ventricular function induced by pacing depends largely on the site of pacing. The conventional and frequently used RV apex is a reliable and easy to reach position, but – in a subset of patients – using this site can increase cardiac morbidity and mortality.

Recently investigated techniques of pacing, such as LVSP and LBBP, seek to avoid pacing-induced cardiomyopathy leading to this. LVSP provides ventricular synchrony, based on compensation of slow transseptal conduction, short path length of conduction and fast endocardial conduction, and has been demonstrated to result in acute electrocardiographic and vectorcardiographic results comparable to BVP.

Developments in the Transseptal Approach

As with all new techniques, implantation of the ventricular lead via the transseptal approach is subject to development. In the initial patient study that demonstrated the feasibility of LVSP, total procedure time decreased from 237 minutes in the first patient to 83 minutes in the last. RV angiography and intracardiac echocardiography was performed to verify the position of the lead tip on the IVS before screwing the lead into the IVS.24 The experiences gained during this study taught us that, with the pre-shaped guiding catheters, leads were always directed towards the

LVSP can be a valuable alternative to LBBP, especially in patients where capture of the left bundle branch is impeded. The long-term clinical effects of LVSP and LBBP and the differences between them are still unknown and need to be investigated.

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Left Ventricular Septal Pacing

Clinical Perspective

• Left ventricular septal pacing(LVSP) and left bundle branch pacing (LBBP) have been introduced to maintain or correct (left) ventricular (dys) synchrony. While LBBP produces better intra left ventricular synchrony, LVSP provides better interventricular synchrony, based on compensation of slow transseptal conduction, short path length of conduction and fast endocardial conduction.

• LVSP has been demonstrated to result, in the short term, in electrocardiographic and haemodynamic results comparable to biventricular pacing.

• The LVSP procedure is more straightforward than that for LBBP. LVSP can be a valuable alternative to LBBP, in particular in patients where capture of the left bundle branch is impeded.

• The long-term clinical effects of LVSP and LBBP and the differences between them are still unknown and need to be investigated.

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2. Vassallo JA, Cassidy DM, Miller JM, et al. Left ventricular endocardial activation during right ventricular pacing: effect of underlying heart disease. J Am Coll Cardiol 1986;7:1228– 33. https://doi.org/10.1016/S0735-1097(86)80140-1; PMID: 3711479.

3. Prinzen FW, Peschar M. Relation between the pacing induced sequence of activation and left ventricular pump function in animals. Pacing Clin Electrophysiol 2002;25:484– 98. https://doi.org/10.1046/j.1460-9592.2002.00484.x; PMID: 11991375.

4. Nielsen JC, Kristensen L, Andersen HR, et al. A randomized comparison of atrial and dual-chamber pacing in 177 consecutive patients with sick sinus syndrome: echocardiographic and clinical outcome. J Am Coll Cardiol 2003;42:614–23. https://doi.org/10.1016/S07351097(03)00757-5; PMID: 12932590.

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8. Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial. JAMA 2002;288:3115–23. https:// doi.org/10.1001/jama.288.24.3115; PMID: 12495391.

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10. Baruffi S SS, Stilli D, Musso E, Taccardi B. The importance of fiber orientation in determining the features of cardiac electric field. In: Antaloczy Z, ed. Modern Electrocardiology.

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11. Roberts DE, Hersh LT and Scher AM. Influence of cardiac fiber orientation on wavefront voltage, conduction velocity, and tissue resistivity in the dog. Circ Res 1979;44:701–12. https://doi.org/10.1161/01.RES.44.5.701; PMID: 428066.

12. Myerburg RJ, Gelband H, Nilsson K, et al. The role of canine superficial ventricular muscle fibers in endocardial impulse distribution. Circ Res 1978;42:27–35. https://doi. org/10.1161/01.RES.42.1.27; PMID: 338194.

13. Streeter DD, Jr., Spotnitz HM, Patel DP, et al. Fiber orientation in the canine left ventricle during diastole and systole. Circ Res 1969;24:339–47. https://doi.org/10.1161/01.

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14. Spach MS, Huang SN, Ayers CR. Electrical and anatomic study of the Purkinje system of the canine heart. Am Heart J

1963;65:664–73. https://doi.org/10.1016/00028703(63)90129-7; PMID: 13978477; PMID: 13978477.

15. Frazier DW, Krassowska W, Chen PS, et al. Transmural activations and stimulus potentials in three-dimensional anisotropic canine myocardium. Circ Res 1988;63:135–46. https://doi.org/10.1161/01.RES.63.1.135; PMID: 3383372.

16. 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.

17. Little WC, Reeves RC, Arciniegas J, et al. Mechanism of abnormal interventricular septal motion during delayed left ventricular activation. Circulation 1982;65:1486–91. https:// doi.org/10.1161/01.CIR.65.7.1486; PMID: 7074805.

18. Prinzen FW, Van Oosterhout MF, Vanagt WY, et al.

Optimization of ventricular function by improving the activation sequence during ventricular pacing. Pacing Clin Electrophysiol 1998;21:2256–60. https://doi. org/10.1111/j.1540-8159.1998.tb01163.x; PMID: 9825329.

19. Ploux S, Strik M, van Hunnik A, et al. Acute electrical and hemodynamic effects of multisite left ventricular pacing for cardiac resynchronization therapy in the dyssynchronous canine heart. Heart Rhythm 2014;11:119–25. https://doi. org/10.1016/j.hrthm.2013.10.018; PMID: 24120876.

20. Heckman LIB, Anselme F, Ziglio F, et al. Evaluating multisite pacing strategies in cardiac resynchronization therapy in the preclinical setting. Heart Rhythm O2. 2020;1:111–9. https://doi. org/10.1016/j.hroo.2020.03.003; PMID: 34113865.

21. Peschar M, de Swart H, Michels KJ, et al. Left ventricular septal and apex pacing for optimal pump function in canine hearts. J Am Coll Cardiol 2003;41:1218–26. https:// doi.org/10.1016/S0735-1097(03)00091-3; PMID: 12679225.

22. 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.

23. Mills RW, Cornelussen RN, Mulligan LJ, et al. Left ventricular septal and left ventricular apical pacing chronically maintain cardiac contractile coordination, pump function and efficiency. Circ Arrhythm Electrophysiol 2009;2:571–9. https:// doi.org/10.1161/CIRCEP.109.882910; PMID: 19843926.

24. Mafi-Rad M, Luermans JG, Blaauw Y, et al. Feasibility and acute hemodynamic effect of left ventricular septal pacing by transvenous approach through the interventricular septum. Circ Arrhythm Electrophysiol 2016;9:e003344. https:// doi.org/10.1161/CIRCEP.115.003344; PMID: 26888445.

25. Strik M, van Deursen CJ, van Middendorp LB, et al.

Transseptal conduction as an important determinant for cardiac resynchronization therapy, as revealed by extensive electrical mapping in the dyssynchronous canine heart. Circ Arrhythm Electrophysiol 2013;6:682–9. https://doi.org/10.1161/ CIRCEP.111.000028; PMID: 23873141.

26. 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.

27. 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.

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28. Heckman LIB, Luermans J, Curila K, et al. Comparing ventricular synchrony in left bundle branch and left ventricular septal pacing in pacemaker patients. J Clin Med 2021;10. https://doi.org/10.3390/jcm10040822; PMID: 33671420.

29. Jastrzebski M, Kielbasa G, Curila K, et al. Physiology-based electrocardiographic criteria for left bundle branch capture.

Heart Rhythm 2021. https://doi.org/10.1016/j. hrthm.2021.02.021; PMID: 33677102.

30. Heckman LIB, Vijayaraman P, Luermans J, et al. Novel bradycardia pacing strategies. Heart 2020;106:1883–89. https://doi.org/10.1136/heartjnl-2020-316849; PMID: 33028670.

31. Li X, Li H, Ma W, et al. Permanent left bundle branch area pacing for atrioventricular block: feasibility, safety, and acute effect. Heart Rhythm 2019;16:1766–73. https://doi. org/10.1016/j.hrthm.2019.04.043; PMID: 31048065.

32. Cai B, Huang X, Li L, et al. Evaluation of cardiac synchrony in left bundle branch pacing: Insights from echocardiographic research. J Cardiovasc Electrophysiol 2020;31:560–9. https://doi.org/10.1111/jce.14342; PMID: 31919928.

33. Hou X, Qian Z, Wang Y, et al. Feasibility and cardiac synchrony of permanent left bundle branch pacing through the interventricular septum. Europace 2019;21:1694–702. https://doi.org/10.1093/europace/euz188; PMID: 31322651.

34. Chan JYS, Huang WJ and Yan B. Non-invasive electrocardiographic imaging of His-bundle and peri-left bundle pacing in left bundle branch block. Europace 2019;21:837. https://doi.org/10.1093/europace/euy293; PMID: 30590453.

35. Sharma PS, Vijayaraman P. Conduction system pacing for cardiac resynchronisation. Arrhythm Electrophysiol Rev 2021;10:51–8. https://doi.org/10.15420/aer.2020.45; PMID: 33936744.

36. Curila K, Prochazkova R, Jurak P, Jet al. Both selective and nonselective His bundle, but not myocardial, pacing preserve ventricular electrical synchrony assessed by ultra-high-frequency ECG. Heart Rhythm. 2020;17:607–14. https://doi.org/10.1016/j.hrthm.2019.11.016; PMID: 31805370.

37. Curila K, Jurak P, Jastrzebski M, et al. Left bundle branch pacing compared to left ventricular septal myocardial pacing increases interventricular dyssynchrony but accelerates left ventricular lateral wall depolarization. Heart Rhythm 2021;18:1281–9. https://doi.org/10.1016/j. hrthm.2021.04.025; PMID: 3393054.

38. Huang W, Chen X, Su L, et al. A beginner’s guide to permanent left bundle branch pacing. Heart Rhythm.

2019;16:1791–96. https://doi.org/10.1016/j.hrthm.2019.06.016; PMID: 31233818.

39. Wu S, Chen X, Wang S, et al. Evaluation of the criteria to distinguish left bundle branch pacing from left ventricular septal pacing. JACC Clin Electrophysiol 2021:S2405– 500X(21)00202–4. https://doi.org/10.1016/j. jacep.2021.02.018; PMID: 33933414; epub ahead of press.

40. Jastrzębski M, Moskal P. Reaching the left bundle branch pacing area within 36 heartbeats. Kardiol Pol 2021;79:587– 8. https://doi.org/10.33963/KP.15914; PMID: 34125940.

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Cardiac Pacing

ECG and Pacing Criteria for Differentiating Conduction System Pacing from Myocardial Pacing Marek Jastrzębski First Department of Cardiology, Interventional Electrocardiology and Hypertension, Jagiellonian University Medical College, Kraków, Poland

Abstract

During His-Purkinje conduction system (HPS) pacing, it is crucial to confirm capture of the His bundle or left bundle branch versus myocardialonly capture. For this, several methods and criteria for differentiation between non-selective (ns) capture – capture of the HPS and the adjacent myocardium – and myocardial-only capture were developed. HPS capture results in faster and more homogenous depolarisation of the left ventricle than right ventricular septal (RVS) myocardial-only capture. Specifically, the depolarisation of the left ventricle (LV) does not require slow cell-to-cell spread of activation from the right side to the left side of the interventricular septum but begins simultaneously with QRS onset as in native depolarisation. These phenomena greatly influence QRS complex morphology and form the basis of electrocardiographic differentiation between HPS and myocardial paced QRS. Moreover, the HPS and the working myocardium are different tissues within the heart muscle that vary not only in conduction velocities but also in refractoriness and capture thresholds. These last two differences can be exploited for the diagnosis of HPS capture using dynamic pacing manoeuvres, namely differential output pacing, programmed stimulation and burst pacing. This review summarises current knowledge of this subject.

Keywords

His bundle pacing, left bundle branch pacing, left bundle area pacing, deep septal pacing, conduction system pacing, ECG, capture criteria Disclosure: MJ has received honoraria from Medtronic but no financial support for this study.

Received: 2 June 2021 Accepted: 8 July 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(3):172–80. DOI: https://doi.org/10.15420/aer.2021.26 Correspondence: Marek Jastrzębski, First Department of Cardiology, Interventional Electrocardiology and Hypertension, Ul Jakubowskiego 2, 30-669 Kraków, Poland.

E: mcjastrz@cyf-kr.edu.pl 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.

His-Purkinje conduction system (HPS) pacing involves placing permanent pacing leads along the HPS with the goal of maintaining or restoring physiological, synchronous biventricular activation.1,2 The field of HPS pacing is still in the early development phase and we are far from understanding the complete electrocardiographic and electrophysiological characterisation of this pacing modality. Since the early studies in this field, confirmation of HPS capture has been considered an important aspect of this technique and new diagnostic approaches and criteria are still being developed.3 These methods and criteria focus on differentiation between non-selective (ns) capture – capture of the HPS and the adjacent myocardium – and myocardial-only capture. This review gives a summary of the current knowledge regarding this aspect of HPS pacing.

QRS Notching and Slurring During His Bundle and Left Bundle Branch Pacing

Standard ECG for Diagnosis of Conduction System Pacing

Occasionally, a QRS notch/slur can be seen despite confirmed HB capture.

This could be a marker of a non-corrected intra-Hisian or intra-left ventricular conduction disturbance. A non-corrected intra-Hisian conduction problem resulting in a long HV (His-ventricle) interval leads to an excessively large contribution by the direct septal depolarisation to the QRS morphology. Although from a formal point of view in such cases there is HB capture, the ventricular depolarisation is non-physiological and more akin to RVS than ns-HB capture. Therefore, from a clinical point of view, such capture cases could be seen as suboptimal capture or even equivalent to lack of HB capture.

The development of a mid-QRS notch/slur/plateau in left ventricular leads (I, V4-V6), which appears immediately with the loss of HB capture, provides a straightforward, specific morphological criterion (Figure 1).4 These morphological features likely have a similar aetiology to the QRS notch/slur seen during left bundle branch block (LBBB). Loss of HB capture and activation of the LV via the spread of the depolarisation wavefront through the working myocardium of the interventricular septum is parallel to the situation seen during LBBB. Similarly, the use of a QRS notch/slur to recognise loss of HB capture parallels the use of a QRS notch/slur to diagnose loss of conduction in the left bundle branch (LBBB criteria).5

HPS capture results in faster and more homogenous depolarisation of the left ventricle (LV) than right ventricular septal (RVS) myocardial-only capture. Specifically, depolarisation of the LV does not require slow cellto-cell spread of activation from the right side to the left side of the interventricular septum but starts at the same time as QRS onset, as in native depolarisation. These phenomena seriously influence QRS complex morphology and form the basis for electrocardiographic differentiation between HPS and myocardial paced QRS.

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Diagnosis of Conduction System Capture Versus Myocardial-only Capture Figure 1: QRS Morphology Changes from Non-selective His Bundle to Right Ventricular Septal Capture

Figure 2: QRS Transition from Non-selective Left Bundle Branch to Left Ventricular Septal Capture I II III

aVR aVL aVF

V1

V2 V3 V4

V5

V6

Map_b

Three examples of transition from non-selective left bundle branch (LBB) to left ventricular septal (LVS) capture. There is immediate prolongation of the V6RWPT while global QRS duration change is less impressive. Note the variable change in QRS morphology in V1: in the left panel, there is a significant decrease in the R wave amplitude; in the middle panel, the change is quite subtle (in both cases V1RWPT remains stable); and, in the right panel, QS appears. Additional changes of some diagnostic value: decrease/disappearance of the S wave in leads I and V6 and appearance of a pseudodelta in leads V3–V5.

septal depolarisation. Third, right ventricle (RV) depolarisation delay during LBB capture and HB capture with non-corrected RBBB significantly prolong the QRS duration. In contrast, the V6RWPT is affected by neither direct septal depolarisation nor RV depolarisation delay. This is because during ns-HB/ns-LBB capture, the lateral wall of the LV is activated purely via the left ventricular HPS.

With transition from non-selective His bundle capture to right ventricular septal capture, the QRS morphology changes in several leads. In lead I, the pointy peak changes into a slur/plateau, in leads V1 and V3 a notch appears and, in leads V4 and V5, a slur develops. The R wave peak time in lead V6 prolongs from 88 ms to 120 ms. Note that there is a notch in the transitional QRS (V2) already during non-selective His bundle capture; this is why transitional QRS complexes should not be included in the notch analysis. Source: Jastrzebski et al. 2019.4 Reproduced with permission from Oxford University Press.

None of ns-LBB, s-LBB or left ventricular septal (LVS) capture typically produces a QRS notch/slur in the left ventricular leads (I, aVL, V4-V6) (Figures 2 and 3). Therefore, this feature, although occasionally observed, is not useful for the diagnosis of loss of conduction system capture during LBB pacing.

The term RWPT rather than left ventricular activation time (LVAT) is preferred in this review even though LVAT is used more commonly in HPS pacing-related literature. The term RWPT is recommended by major cardiac societies for the description of the intrinsicoid deflection time and I see no reason to create an alternative term for this well-known, wellestablished ECG descriptor.6,7 The term RWPT is purely descriptive while LVAT implies a physiological correlation that is somewhat misleading. LV activation lasts until the end of the QRS, not until the R-wave peak; a popular derivative term, such as ‘time to LVAT’, seems grammatically illogical, while ‘peak LVAT’ raises questions on how to define peak activation. Moreover, the term LVAT is already used/defined in cardiac resynchronisation therapy patients for a different, more appropriate ECG metric by Sweeney et al.8 Perhaps the term LVAT should be reserved for examinations such as ECG imaging or endocardial mapping that can determine activation times more precisely.9

Time to V6 R-wave Peak During Conduction System Pacing

The V6R-wave peak time (V6RWPT) corresponds to the intrinsicoid deflection time in lead V6 that reflects the time it takes for the depolarisation wavefront to reach the epicardial surface of the lateral wall of the LV.6 Since the velocity of conduction in the HPS is much higher than in the working myocardium, it is logical that the V6RWPT would be shorter during HB capture than during RVS capture (Figure 1) and, similarly, shorter during LBB capture than during LVS capture (Figure 2). While this is true, there is a considerable overlap of activation time values, making any V6RWPT criterion based on a fixed cut-off value a trade-off between sensitivity and specificity (Figure 4).4 It may seem that the V6RWPT changes are similar in this regard the global QRS duration change and that it might be enough to assess the QRS duration for differentiation.

Binary Cut-off Criteria Based on V6RWPT

The easiest way to use the V6RWPT as a diagnostic tool is to follow an established, fixed cut-off criterion with known sensitivity and specificity to capture diagnosis. It is vital to ensure measurements are precise as differences of 5–10 ms are diagnostically important. This can be best achieved using digital calipers and a fast sweep speed of 100–200 mm/s; alternatively, a standard ECG at 25 mm/s can be used, albeit only when some method of enlargement is available (computer-based enlargement of a simple graphic file is sufficient).

However, assessing V6RWPT has several advantages over measuring QRS duration. First, the R-wave peak offers a distinct point for precise measurements; this is in contrast to the QRS offset, which often has a low amplitude and transitions smoothly into the ST-T complex. For this reason, QRS duration measurements have poor reproducibility and accuracy.

Second, during non-selective capture, the QRS duration is affected not only by HPS capture or non-capture but also by direct non-physiological

After analysis of a large cohort of patients with HB capture/loss of HB capture, my colleagues and I proposed the criterion of V6RWPT to be

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Diagnosis of Conduction System Capture Versus Myocardial-only Capture Figure 3: Transition from Non-selective to Selective Left Bundle Branch Capture

Figure 4: V6 R-wave Peak Time and QRS Duration ns-HB

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ns-LBB LVS

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Three examples of transition from non-selective to selective LBB capture. In each example, there is immediate increase in the V1RWPT, while the V6RWPT remains stable. The other diagnostic marker is the appearance of a broad, slurred or notched R wave in leads V1–V2. Other diagnostic features include: appearance/increase in amplitude of the S wave in I and V6 (left and middle panels), appearance of a tiny r in V1 (left panel), or appearance of a discrete potential on the endocardial channel (middle panel).

40

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Density plots for V6 R-wave peak time (V6RWPT) and QRS duration during non-selective His bundle capture (ns-HB) versus right ventricular septal (RVS) capture, and during non-selective left bundle branch capture (ns-LBB) versus left ventricular septal (LVS) capture. Note that the V6RWPT appropriately differentiates ns-HB from RVS capture, and ns-LBB from LVS capture (although overlap of values is considerable), while QRS duration is useless for differentiation as there is complete overlap of values during different LBB area capture types. Source: Jastrzebski et al.

2019.4 Adapted with permission from Oxford University Press and Jastrzebski et al. 2021.12 Adapted with permission from Elsevier.

≤100 ms (measured from the pacing stimulus) as 100% specific for HB capture.4 To better balance sensitivity and specificity, a criterion of V6RWPT ≤110 ms might be used. The V6RWPT criterion can be combined with the QRS notch/slur/plateau criterion in the form of a validated diagnostic two-step algorithm (Figure 5).4 Early in the development of the LBB pacing technique, experts proposed using the V6RWPT for the diagnosis of LBB capture, although without recommending a cut-off value.10 Various cut-off points (75–90 ms) have been used since then, as there were no validation studies, and the sensitivity and specificity of these arbitrary cut-offs were not known. Two recent validation studies support the use of V6RWPT <75 ms as a nearly 100% specific criterion; this offers quick and firm LBB capture diagnosis, albeit not in all patients as the sensitivity of this criterion is rather low (70–82%).11,12 In our cohort, V6RWPT <83 ms was identified, with receiver operating characteristics curve analysis having optimal overall diagnostic accuracy for LBB capture diagnosis with a sensitivity and specificity of 84.7% and 96.3%, respectively; this is the value we recommend for general use although, at the time of procedure, a more specific value of <75 ms might be preferred.

Figure 5: Diagnostic Algorithm QRS notch/slur/plateau in lead I or V4–V6

yes RVS

no yes V6RWPT >100 ms

RVS

no ns-HB Algorithm for the electrocardiographic diagnosis of loss of non-selective His bundle (ns-HB) capture.

RVS = right ventricular septal capture; V6RWPT = V6 R-wave peak time. Source: Jastrzebski et al.

2019.4 Adapted with permission from Oxford University Press.

For patients with a severely damaged LV conduction system, the above fixed cut-off V6RWPT criteria are even less sensitive; in such patients, it is not uncommon to see LBB capture with V6RWPT >90 ms (one of the reasons for the overlap in values illustrated in Figure 4). Although we have proposed a different cut-off for such patients (V6RWPT <101 ms as diagnostically optimal and V6RWPT <80 ms as 100% specific), it seems that this population requires the use of an individualised V6RWPT criterion for better diagnostic accuracy (see below).12

LV.12–14 Therefore, a ‘healthy’ native QRS might offer the best reference to determine if conduction system capture has been achieved. This principle is already implied in the fixed cut-off V6RWPT criteria discussed above. Note that the upper normal value for intrinsicoid deflection time in lead V6 is 50–60 ms (LBBB criteria). If the 40–50 ms of the normal HV interval is added to this interval, then we have the recommend cut-off value of 100–110 ms for HB capture diagnosis given above. Since the usual duration of the LBB potential to QRS interval is approximately 25 ms, then the above V6RWPT criteria of 75–83 ms for LBB capture also conform with known upper limits of normal physiological conduction (25 ms + 50–60 ms = 75–85 ms). However, given the substantial variability of normal activation times and because HPS pacing is often implemented in patients with diseased HPS, a more precise method of determining capture is to compare the obtained activation time during pacing with

Using Native QRS/V6RWPT as a Physiological Reference

Conduction system pacing is a physiological pacing method par excellence. The electrocardiographic hallmark of physiological pacing is the preservation or restoration of physiological activation times in the

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Diagnosis of Conduction System Capture Versus Myocardial-only Capture Figure 6: Native and Paced QRS Native

ns-LBB

LVS

Native

ns-LBB

s-LBB

Figure 7: Using the V6–V1 Criterion for the Diagnosis of Left Bundle Branch Capture

LVS

I Position 1

Position 2

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LBB lead V6RWPT = 80 ms

V6RWPT = 80 ms

V6RWPT = 92 ms

V6RWPT = 56 ms

V6RWPT = 56 ms

V6RWPT = 56 ms

V6

V6RWPT = 74 ms

Left panel: During non-selective capture of the left bundle branch (ns-LBBP), the interval from the stimulus to the R-wave peak in lead V6 (V6RWPT) equalled the interval from the LBB potential to the R-wave peak during native conduction. During loss of LBB capture, which resulted in left ventricular septal (LVS) myocardial-only capture, the V6RWPT was longer by 12 ms. Right panel: Four types of QRS complexes were obtained in the same patient. The R-wave peak time in lead V6 remained the same during the activation of the left bundle branch (LBB) via either intrinsic rhythm or pacing for both ns-LBB and selective (s-)LBB capture. However, the V6RWPT was evidently longer without LBB capture, i.e. during LVS capture. Source: Jastrzebski et al. 2021.12 Adapted with permission from Elsevier.

V6

Illustration of the practical application of the V6–V1 criterion for the diagnosis of left bundle branch (LBB) capture during the implantation procedure. In the first pacing position, lack of LBB potential and V6RWPT of 83 ms (i.e. over the used 75 ms cut-off) prompted the operator to look for a better position as he was not certain if LBB capture had been obtained. Unfortunately, all other subsequently obtained positions resulted in even longer V6RWPT of 100 ms and the procedure was concluded with only left ventricular septal (LVS) capture instead of LBB capture, which was most likely present already during the first lead position. This course of events would have been avoided if the V6–V1 interval value in the first pacing position was considered. The V6–V1 interval of 46 ms is 100% specific for obtaining LBB capture. In contrast to LBB capture, during LVS capture, the V6 and V1 peaks occur nearly simultaneously (V6–V1 interval of 16 ms); this is because the relative delay of right ventricular depolarisation is shorter.

the native V6RWPT in a particular patient; this serves as an individualised reference (Figure 6).

precise and elegant method is to temporarily restore conduction in the LBB via high-output HB pacing and then approximate the expected native V6RWPT during LBB capture.13

Initially, we applied the above reasoning for patients with LBB pacing, proposing the criteria presented below. If the paced V6RWPT does not exceed the native V6RWPT by more than 10 ms, then LBB capture should be diagnosed but, if it does exceed it, then LVS capture should be diagnosed.12 This approach resulted in a sensitivity of 95–98% and a specificity of 86–88% for the diagnosis of LBB capture, depending on the measurement method used (from LBB potential or from real QRS onset).

Note that, to compare native and paced QRS, two physiologically corresponding intervals must be used (Figure 6). If the paced QRS is measured from the pacing stimulus, then the corresponding native interval starts with the conduction system potential (as the pacing stimulus captures the conduction system exactly at the site where the potential is recorded). Therefore, the paced V6RWPT equals the time from the LBB potential to the V6R-wave peak. If the native QRS is measured from the QRS onset rather than from the LBB potential (which is often absent), then the corresponding measurement during pacing should not start from the pacing stimulus – and should omit the initial latency (usually 30 ms of the isoelectric line, partially obscured by the post-stimulus artefact) – but from the true onset of the QRS complex (all 12 leads; high augmentation and fast sweep speed have to be used for this measurement).

The second caveat is that if the interval from the potential to the QRS is short (<20 ms), indicating that this is not the main LBB potential but the Purkinje potential of LBB arborisation, so the interval from the potential to the R-wave peak does not correspond with the paced V6RWPT since, during pacing, the conduction pathway is partially retrograde.

Recently, we have also used the native left ventricular lateral wall activation time as the reference for the diagnosis of HB capture. Since, in contrast to LBB pacing, during HB pacing the HB potential is almost always recorded at the pacing site and during ns-HB pacing there is no initial latency, only the first method of comparison of conduction times is applicable (i.e. stimulus-V6RWPT = HBpotential-V6RWPT). We formulated the criterion that the interval from the stimulus to the V6RWPT (i.e. paced V6RWPT) should not exceed the corresponding interval during native conduction by more than 12 ms. This criterion offered unparalleled diagnostic accuracy (sensitivity of 100% and specificity of 99.1%).14 However, this method can be used only for patients with non-LBBB native QRS morphology and a normal HV interval duration (55–35 ms). When global QRS duration is used in a similar fashion (stimulus to QRS offset ≤ potential to QRS offset, as proposed by experts), the diagnostic accuracy is much lower (unless the method is limited to patients with narrow QRS), since QRS duration, in contrast to the V6RWPT, is influenced by direct septal myocardial capture.1,14–16

As with any diagnostic method, to use this correctly, the limitations and caveats must be known, two of which are especially important.

In patients with LBBB, the ‘healthy’ native V6RWPT cannot be obtained directly. Three possibilities were explored for such patients. First, the most simple method is to obtain the native V6RWPT from fortuitous beats with RBBB morphology (if, during the procedure, complete AV block develops due to the lead/sheath bump on the RBB, then conduction via LBB or escape rhythm originating in distal LBB often appears).12 Second, a more elaborate method is to calculate the approximate myocardial intraLV conduction time by subtracting the transseptal conduction time from the intrinsicoid deflection time measured in LBBB QRS; if the obtained paced V6RWPT is shorter, it indicates LBB capture.12 Third, the most

V6–V1 Interval Criterion

We recently developed a novel marker for LBB capture – the V6–V1 interval.17 This was based on observations that LVS capture results in simultaneous activation of the RV and LV and that in V1 and V6 R-wave peaks occur simultaneously, while during LBB capture RV activation is delayed in comparison to LV activation, hence the V6–V1 interval is longer. This criterion was intended to address some limitations of the V6RWPT criterion.

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Diagnosis of Conduction System Capture Versus Myocardial-only Capture Figure 8 : Programmed His Bundle Stimulation

Figure 9: An Extra-stimulus in a Patient with an ns-HB Capture I II III aVL aVF V1 V2 V4 V6

His

A single extra-stimulus at a coupling rate of 300 ms reveals the QRS morphology of right ventricular septal myocardial-only capture (QRS prolongation, appearance of a notch in V1, rounding of the R wave peak in I, and change of polarity in lead III). At an S2 coupling interval of 300 ms, the HB is nearly always already refractory while the RV myocardium is still not. Thus, in the majority of cases, a response diagnostic of His bundle capture during non-selective pacing can be obtained with the introduction of an extra-stimulus at a single coupling interval. Source: Jastrzebski et al. 2019.21 Reproduced with permission from Wolters Kluwer Health, Inc.

HB

HB RV

RV

In a patient with an ns-HB capture, an extra-stimulus was delivered at a coupling interval of 300 ms, first after a drive train (panel A) and then during native conduction (panel B). After a 600 ms drive train, the extra-stimulus resulted in only right ventricular septal myocardial capture. During native conduction, an extra-stimulus with an identical coupling interval resulted in selective HB capture. This can be explained by a different activation sequence. During native conduction, HB is activated 100 ms before the ventricular myocardium near the HB pacing lead, resulting in a coupling interval of 400 ms. Consequently, despite a longer refractory period (brown bar), the HB is excitable (blue bar), while the RV myocardium is not. During the 600 ms drive train of ns-HB pacing, both the HB and the local RV myocardium are depolarised at the same time, and the HB is not excitable due to the longer effective refractory period. Arrows mark the extent of the true coupling intervals for the HB and the RV. HB = His bundle; s-HB = selective HB; ns-HB = non-selective HB; His = endocardial signals from the screwed-in HB pacing lead; H = HB potential; RV = right ventricle. Source: Jastrzebski et al. 2019.21 Reproduced with permission from Wolters Kluwer Health, Inc.

Long V6RWPT might be caused not only by lack of LBB capture but also be due to initial latency, slower propagation via diseased HPS, substantial LV dilatation or, often, a combination of these factors. The V6–V1 interpeak interval is likely less influenced by these limitations. If there is substantial initial latency or slow conduction through the myocardium, it will affect the timing of the activation of the RV and LV to a similar degree. Consequently, the R-wave peak will be delayed in both V1 and V6, and the V6–V1 interpeak interval will not be affected much. In other words, the R-wave peak in V1 may provide a better reference time point than the pacing stimulus in assessing the timing of the R-wave peak in V6. A value of ≥33 ms was found to be diagnostically optimal to confirm LBB capture, while a value >40 ms was highly specific (recommended to use during the procedure).17

value of the ns-HB QRS in a large cohort was 140 ms.4 A diagnostically optimal differentiating cut-off for QRS duration seems to be around 150 ms, while values of <120–130 ms lack sensitivity but are 100% specific for ns-HB capture. The important caveat is that the analysed QRS should be a fully paced QRS and not a fused QRS as is often the case in patients with preserved native conduction during DDD pacing.

The V6–V1 is especially useful when the V6RWPT criterion is not diagnostic; using both criteria increase the diagnostic yield of ECG analysis. A clinical vignette illustrating the use of this new criterion is presented in Figure 7.

Global QRS Duration for Left Bundle Branch Capture Diagnosis

Global QRS Duration for His Bundle Capture Diagnosis

The typical ns-LBB-paced QRS has the terminal R/r wave in lead V1, which is a marker of partially non-corrected delay in RV activation. This delay considerably prolongs ns-LBB-paced QRS duration. While the LVS-paced QRS is relatively narrow, as during LVS capture, there is relatively fast activation of the LV from the left side of the septum, possible early engagement of the LV conduction system and a similar delay in RV and LV activation. Consequently, there is a nearly complete overlap of QRS duration values between ns-LBB and LVS pacing (Figure 4), eliminating QRS duration as a useful parameter for the diagnosis of LBB capture.

The global QRS duration – the QRS duration measured from the pacing stimulus to the QRS offset using all 12 standard ECG leads – should enable an intuitive and perfect diagnostic criterion. Unfortunately, as we have shown in earlier studies, there is a considerable overlap between the nsHB QRS and the RVS QRS, and an almost complete overlap between the ns-LBB and the LVS-paced QRS duration.4,12 In patients with a normal HV interval, the paced QRS duration during nsHB capture equals the sum of the HV interval and the baseline intrinsic QRS duration. Since the upper normal values of the HV interval and QRS are 55 ms and 110 ms, respectively, then an ns-HB-paced QRS, even in the absence of any intraventricular conduction disturbances, can be as wide as 165 ms. A similar duration is obtainable with RVS pacing. Non-corrected intraventricular conduction disturbances can further prolong the duration of an ns-HB-paced QRS. An average ns-HB QRS should be expected to be around 140 ms (HV of 45 ms + QRS of 95 ms) and, indeed, the median

Pacing Manoeuvres to Diagnose Conduction System Capture

The HPS and the working myocardium are two different tissues in the heart muscle that vary not only in their conduction velocities but also in their refractoriness and capture thresholds. The two differences can used in the diagnosis of HPS capture/loss of capture using dynamic pacing manoeuvres.

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Diagnosis of Conduction System Capture Versus Myocardial-only Capture Figure 10: Using Pacing Protocols to Change Refractory Periods

corrected conduction disturbance (such as LBBB or nonspecific intraventricular conduction delay), resulting in a long V6RWPT during nsHB capture. Such a situation, as well as the equal HB and RVS capture thresholds seen in 6–10% of cases, can be quite misleading and often requires other manoeuvres to determine HB capture (see below).

In patients with bundle branch blocks, it is possible to observe more QRS transitions because additional correction or loss of correction of LBBB or RBBB often occurs. These transitions are described in detail elsewhere, and are conceptually and clinically important.18 However, in essence, any transition is diagnostic of HB/RBB capture, since during RVS pacing the QRS morphology remains stable until complete loss of capture. One important caveat is that anodal capture should be ruled out; for this, it is enough to perform a threshold test in a unipolar mode.

LBB ERP MYO ERP

QRS Transition due to Differences in Capture Thresholds During LBB Pacing

For LBB pacing, output-dependent QRS transition is less useful than it is for HB pacing, as equal capture thresholds are predominant. In our series of >500 LBBP cases, output-dependent QRS transition was observed in only approximately 35% of cases during the procedure and less frequently during follow-up (estimated 18%). Moreover, transition in the acute phase is often a fleeting phenomenon (due to injury/recovery of both tissues) and should be assessed several times; often, it is possible to observe both types of transition on subsequent attempts and then no transition at all at the end of the procedure. Another method to increase diagnostic yield of this method is to use repeated testing at different intermediate lead depths in the septum or during continuous pacing during lead rotation.10,19 A more proximal pacing site and the presence of LBB potential increase the prevalence of output-dependent transition. This is probably why, in a study by Su et al., QRS transition (to s-LBB) was observed intraprocedurally more frequently (74% of cases) than in our laboratory although, similarly to our experience, this was less frequent at follow-up (reduced from 74% to 30%).20 Clearly, this method, although important, cannot serve as the mainstay diagnostic tool for LBB pacing as it could for HB pacing. Typical examples of QRS transition during ns-LBB pacing are illustrated in Figure 2.

LBB ERP MYO ERP

The presented tracings illustrate how tailored pacing protocols can be exploited to augment and reverse the differences in effective refractory periods (ERP) between the right ventricular septal (RVS) myocardium and the left bundle branch (LBB). In the upper panel, where S3 is preceded by a short–long sequence, the ERP of the LBB is prolonged and the ERP of the RVS is shortened.

Consequently, RVS capture QRS can be seen (S3); this is substantiated by the loss of r’ in V1 and by the retrograde LBB potential after the paced QRS. Conversely, in the lower panel, the S3 is preceded by a long–short sequence that prolongs the RVS ERP and abruptly shortens the LBB ERP. Consequently, in the lower panel, the S3 selectively captures the LBB, evidenced by the augmented and slurred R wave in V1, the lack of retrograde LBB potential, the presence of a latency interval after the pacing stimulus, and the appearance of a discrete deflection on the ventricular intracardiac electrogram. The application of tailored programmed stimulation protocols evoked impressive changes in ERPs in the current case. The short–long–short protocol resulted in a myocardial ERP of 250 ms, which was 150 ms shorter than the LBB ERP of 400 ms. Using the long–short–short protocol, this relationship was reversed: the LBB ERP (250 ms) was shorter than the myocardial ERP (290 ms) by 40 ms. Consequently, RVS capture QRS and selective LBB capture QRS were observed over a wide range of coupling intervals. Source: Jastrzebski et al.

2020.23 Reproduced with permission from Wiley.

QRS Transition due to Differences in Capture Thresholds During HB Pacing

Like with HB pacing, a non-selective (ns)-LBBP QRS can transition to either selective (s)-LBB capture QRS or left ventricular septal myocardial (LVS) capture QRS. Transition to LVS capture is marked by sudden V6RWPT prolongation, albeit this is much less prominent in comparison with loss of HB capture and occurs without simultaneous notch/slur development, hence it is easy to miss. This is because during LVS capture, despite the lack of direct depolarisation of the LBB, the activation wavefront does not need to cross the interventricular septum to reach the LV conduction system. Consequently, the V6RWPT prolongs only by the time it takes to reach the nearby Purkinje network/ myocardium interface. On average, the V6RWPT prolongs by 18 ms only.

Assuming that the myocardial cell-to-cell conduction velocity is 0.5 m/s, the HPS/myocardium interface is located on average only 9 mm from the LBB capture site. V6RWPT prolongation by 10 ms or more was found by us to be 100% sensitive albeit not 100% specific for loss of LBB capture, therefore we used a cut-off of 15 ms as this was 100% specific and still sensitive (97%).12 Recently, Wu et al. found that a cut-off value of 10 ms had similar diagnostic properties (specificity 100%; sensitivity not reported; n=30).11

During the implantation procedure and device follow-up, the most practical and conceptually straightforward method to determine HB capture is a simple threshold test performed in the unipolar pacing mode from the lead tip.3,15 When the pacing output slowly decreases, starting with 8–10 V at 0.5 ms, it is possible to observe a sudden change in QRS morphology in 90–95% of cases (Supplementary Material Figure 1S). When HB or RVS capture is lost, a transition to the RVS QRS or selective (s)-HB QRS, respectively, is observed. The type of transition (ns-HB to RVS or ns-HB to s-HB) depends on which tissue has the higher capture threshold.

It is of diagnostic importance to define when a change in QRS morphology can be considered a transition. Transition to s-HB is diagnosed by the appearance of a latency interval after the pacing stimulus and QRS morphology identical to the native supraventricular QRS, while transition to RVS is diagnosed by QRS prolongation, appearance of a notch/slur/ plateau in the left ventricular leads, and sudden prolongation in the V6RWPT by 20 ms or more.4 In patients with an undamaged distal conduction system, the V6RWPT on average prolongs by 33 ms with loss of HB capture; prolongation by less than 20 ms usually indicates non-

Apart from V6RWPT prolongation, another important transitional change occurs in the lead V1: the terminal R/r wave decreases in amplitude

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Diagnosis of Conduction System Capture Versus Myocardial-only Capture (although the V1RWPT usually remains stable) or disappears (QS complex in V1) (Figure 2). The type of V1 morphology during LVS capture probably depends on the depth of the pacing helix in the interventricular septum and hence balanced RV/LV activation (QS complex), preferential activation of the RV (broader QS complex), or preferential activation of the LV (Qr/QR complex) occurs.

likely to produce selective HB capture because of the local timing of the HB and septal depolarisation at the basal septum; there is more time for the HB to recover and less time for the myocardium to recover (Figure 9).

Alternatively, especially during follow-up, an asynchronous slow pacing mode (VOO) can be used to obtain both selective and myocardial response (Figure 2S).

Transition to s-LBB, in contrast to transition to LVS, does not result in V6RWPT prolongation but in V1RWPT prolongation and the spiky terminal R/r wave changing into a broader, slurred R/r wave.17 Often with s-LBB capture, a tiny r wave in leads V1–V2 appears together with an S wave in leads I and V6 (Figure 3).

Programmed LBB stimulation is much more rewarding than programmed HB stimulation because it can provide definitive diagnosis of LBB capture, which is so often lacking. Unfortunately, interpretation of responses and pacing protocols are less straightforward. To increase the diagnostic yield of this method, we prefer to use protocols tailored for obtaining selective LBB response and clear-cut myocardial response (Figure 10).23 This is because the standard S1 600 ms drive + S2 often results in a response that is difficult to interpret, owing to the overlap of the QRS morphology change resulting from the bona fide transition with the QRS morphology change resulting from QRS prolongation, due to the relative refractoriness of the myocardium. These two QRS morphology changes can be differentiated by rejecting the QRS change that occurs within the relative refractory period (30–40 ms before complete refractoriness), careful analysis of the change in V6RWPT and assessment of the V6–V1 interval (unpublished data).

Besides relying on the above QRS morphology changes as markers of output-dependent QRS transition, two ancillary methods can be employed to ensure that a bona fide transition does occur: appearance of a discrete endocardial potential on the endocardial channel (Figure 3); and appearance of a short latency interval (approximately 20 ms) before the QRS. Appearance of a latency interval is diagnostic of s-HB capture, although it might be missed during s-LBB capture, as it is shorter than during s-HB capture and often obscured by the post-pacing interval artefacts/oversaturation. Moreover, the diagnostic value of latency decreases during LBB pacing since, surprisingly, there is often also an isoelectric interval, which is especially obvious in the precordial leads during LVS capture (Figure 2).

To use tailored programmed pacing protocols, it must be realised that the refractory periods are not fixed but determined by the preceding cycles. Generally, short preceding cycles shorten the absolute refractory period. However, as showed by Denker et al., myocardial refractoriness demonstrates the cumulative effect of several preceding cycle lengths (i.e. mainly the basic drive cycle length or intrinsic rhythm), whereas conduction system refractoriness is predominantly influenced by the immediately preceding cycle length.24 This physiology can be easily exploited for HPS capture diagnosis (Figure 10). Myocardial response is facilitated by a fast drive that shortens myocardial refractoriness, followed by one long cycle that prolongs HPS refractoriness. In contrast, a selective response is facilitated by a slow drive that prolongs myocardial refractoriness, followed by one short cycle that shortens HPS refractoriness. If slow drive pacing cannot be accomplished due to faster intrinsic rhythm, then the best alternative to obtain selective LBB response is to try single and double extra-stimuli on intrinsic rhythm, as this is the slowest rhythm obtainable (Supplementary Material Figure 3S).

QRS Transition due to Differences in the Absolute Refractory Period

When the capture thresholds of the HPS and the adjacent myocardium are equal, the method of output-dependent QRS transition does not work.

This is frequently encountered with LBBP but also occasionally seen with distal HB/RBB pacing. To address this problem, we developed the technique of programmed HPS stimulation, which exploits differences in refractoriness between the HPS and the myocardium.21–23 This method was initially validated for HB capture diagnosis and then also for confirmation of LBB capture. It can be used during implantation, when a programmable external pacemaker/electrophysiological system is employed, or during follow-up using a non-invasive programmed stimulation function implemented in most pacemakers.

Depending on the type of QRS transition obtained – from non-selective to selective HPS or from non-selective to myocardial – we classified the responses to programmed stimulation as ‘selective response’ or ‘myocardial response’; selective response is unquestionably diagnostic of HPS capture, while myocardial response requires differentiation with QRS change due to the encroachment on the relative refractoriness of the myocardium. This is usually not problematic for HB pacing as RVS QRS is most often considerably different from ns-HB QRS (Figures 1 and 8; Supplementary Material Figure 1S), but it is an important limitation of programmed LBB stimulation since differences between LVS QRS and nsLBB QRS are often relatively subtle (Figures 2 and 6).

Alternative methods that can visualise refractoriness-dependent QRS morphology transition are burst and incremental pacing.25 If a selective response cannot be achieved with programmed stimulation, it can be obtained occasionally with burst and/or incremental pacing (Supplementary Material Figure 4S).26 In our practice, we routinely use incremental pacing up to the cycle length of 250 ms – this both ensures that capture is distal to the conduction block and provides additional information regarding capture diagnosis. For burst pacing, we start with a cycle length of 250 ms; if this is not diagnostic due to 2:1 capture, then the cycle length is increased with the goal to observe transition from 2:1 to 1:1 capture, as the sudden change of capture cycle length is most fruitful diagnostically. This method works well for HB pacing although it is limited when used for LBB capture diagnosis. One major limitation of burst pacing is that the predominant type of response is myocardial response, which is even more difficult to categorise for burst pacing than for programmed pacing. Moreover, burst pacing occasionally induces serious ventricular arrhythmias so has to be used with caution in individuals with a vulnerable substrate.

For programmed HB pacing, it is enough to perform an 8-beat drive (S1) with a 600 ms cycle + S2 starting from 400–450 ms and decreasing in 10 ms steps; this will provide a diagnostic response in nearly 100% of cases.

With progressively shorter coupling intervals, a sudden change in the QRS morphology of S2 occurs, usually around a coupling interval of 380–320 ms (Figure 8). To obtain a selective HB response, single or double extrastimuli on intrinsic rhythm or dedicated pacing protocols (see below) are recommended. An extra-stimulus delivered during intrinsic rhythm is more

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Diagnosis of Conduction System Capture Versus Myocardial-only Capture Miscellaneous Methods for His-Purkinje Conduction System Capture Diagnosis Device Electrograms and Ventriculoatrial Interval Analysis

22 ms) during anterograde native conduction should be similar as the interval from LBB potential to HB potential during retrograde conduction when LBB is captured during pacing.10,11 This criterion assumes that retrograde and anterograde conduction velocity does not differ much.

Also, left septal HPS potentials should precede the ventricular electrogram on the multielectrode catheter when LBB capture is achieved.

Saini et al. reported the use of device electrograms (EGM) analysis for differentiation of various forms of capture during HB pacing.27 They analysed far-field EGM QRS duration, near-field EGM time-to-peak and near-field EGM polarity and found that the device EGM transitions correlated well with QRS morphology transition on a 12-lead ECG. The near-field EGM time-to-peak is a device-based equivalent of the presence or absence of discrete local potential on the endocardial channel during implantation and the far-field EGM QRS duration is the equivalent of surface ECG global QRS duration.

Far-field EGM QRS duration was shorter during ns-HB capture than during RVS capture (103 versus 145 ms), and transition to RVS capture was always accompanied by prolongation of the far-field EGM QRS duration by at least 40 ms. EGM data can be supported with marker channel data as it provides reliable information regarding sudden increase in ventriculo-atrial (VA) interval that indicates loss of HB capture (mean delta VA = 70 ms).27,28 This last method is limited to patients without atrial fibrillation and with preserved retrograde conduction but it can also be used to analyse regular surface ECG, occasionally providing the strongest evidence for loss of conduction system capture (Supplementary Material Figure 5S).

During myocardial-only capture, the situation is different: left septal HPS potentials do not precede the QRS but are buried within it, while the HB potential is absent on the HB lead. Using retrograde HB potential for LBB capture diagnosis requires a diagnostic catheter or a separate lead implanted in the HB region (which can be later used for atrial pacing). This method is limited to patients with preserved conduction in the proximal HPS and requires extra time for HB lead positioning.

Another caveat is that retrograde conduction during HPS capture does not give 100% certainty that anterograde conduction from the capture site is also present. Practicalities of the invasive left septal potential mapping constitute a serious limitation of this technique for routine implantation.

Conclusion

At the current state of knowledge, no single method for differentiation between HPS and myocardial-only capture can be recommended as straightforward and 100% accurate. Nevertheless, an accurate diagnosis can be reached in the vast majority of cases using the methods and criteria developed over the last couple of years (Tables 1 and 2).

Automated Methods and Artificial Intelligence

Analysis of conduction system pacing ECG may pose a considerable challenge to an inexperienced interpreter and automated interpretation by standard ECG machines and pacemaker analysers would be welcome.

Arnold et al. applied machine learning to diagnose loss of HB capture.29 Although the overall accuracy of 75% during differentiation of various forms of HB area capture was disappointing, this is a promising method.

Perhaps simply including V6RWPT and V1RWPT in automated ECG interpretation reports would be helpful.

Clinical Perspective • The goal of His-Purkinje conduction system (HPS) pacing is

Conduction System Potential Mapping

•

Activation mapping of the conduction system enables the determination of HPS capture with high accuracy, making this technique an excellent research tool.

• •

Wu et al. studied 30 patients using His bundle potential mapping and multielectrode catheter mapping of the left septal HPS to determine LBB capture.11 Multielectrode left septal mapping can also be used to determine the correction of the LBBB during HB pacing.30,31 Upadhyay et al. observed presystolic recruitment of latent Purkinje potentials in patients with complete conduction block in the left bundle during His corrective pacing.30,31

•

When such extensive HPS mapping is performed, diagnosis of LBB capture can be based on simple observations (Supplementary Material

maintaining or restoring physiological, synchronous biventricular activation of the heart.

HPS pacing is a promising technique with potential for application in both bradyarrhythmia and heart failure patients.

During HPS pacing, it is crucial to confirm capture of the His bundle or left bundle branch versus myocardial-only capture.

HPS capture results in faster and more homogenous depolarisation of the left ventricle than ventricular myocardialonly capture. This influences QRS complex morphology and form the basis for electrocardiographic differentiation between HPS and myocardial paced QRS. The HPS and working myocardium differ in their capture thresholds and refractoriness. These differences can be exploited for the diagnosis of HPS capture using dynamic pacing manoeuvres such as differential output pacing and programmed stimulation.

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17. Jastrzębski M. The V6–V1 interpeak interval: a novel criterion for the diagnosis of left bundle branch capture.

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18. Burri H, Jastrzębski M, Vijayaraman P. Electrocardiographic analysis for His bundle pacing at implantation and followup. JACC Clin Electrophysiol 2020;6:883–900. https://doi. org/10.1016/j.jacep.2020.03.005; PMID: 32703577.

19. Jastrzębski M, Moskal P. Reaching the left bundle branch pacing area within 36 heartbeats. Kardiol Pol 2021;79:587– 8. https://doi.org/10.33963/KP.15914; PMID: 34125940.

20. Su L, Wang S, Wu S, et al. Long-term safety and feasibility of left bundle branch pacing in a large single-center study.

Circ Arrhythm Electrophysiol 2021;14:e009261. https://doi. org/10.1161/CIRCEP.120.009261; PMID: 33426907.

21. Jastrzębski M, Moskal P, Bednarek A, et al. Programmed His bundle pacing. Circ Arrhythm Electrophysiol 2019;12:e007052. https://doi.org/10.1161/CIRCEP.118.007052; PMID: 30707037.

22. Jastrzębski M, Moskal P, Bednarek A et al. Programmed deep septal stimulation: a novel maneuver for the diagnosis of left bundle branch capture during permanent pacing. J Cardiovasc Electrophysiol 2020;31:485–93. https:// doi.org/10.1111/jce.14352; PMID: 31930753.

23. Jastrzębski M. Permanent left bundle branch pacing: what is the mechanism of divergent responses during programmed stimulation? J Cardiovasc Electrophysiol 2020;31:1222–5. https://doi.org/10.1111/jce.14449; PMID: 32187413.

24. Denker S, Lehmann MH, Mahmud R, et al. Divergence between refractoriness of His-Purkinje system and ventricular muscle with abrupt changes in cycle length.

Circulation 1983;68:1212–21. https://doi.org/10.1161/01.

CIR.68.6.1212; PMID: 6640874.

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25. Liang Y, Yu H, Wang N et al. Cycle length criteria for Hisbundle capture are capable of determining pacing types misclassified by output criteria. Heart Rhythm 2019;16:1629– 35. https://doi.org/10.1016/j.hrthm.2019.04.032; PMID: 31096063.

26. Jastrzębski M. Programmed HB pacing and decremental HB pacing are complementary techniques. 2019. https:// twitter.com/Marek_Jastrz_EP/ status/1108810446214254592?s=20 (accessed 6 August 2021).

27. Saini A, Serafini NJ, Campbell S et al. Novel method for assessment of his bundle pacing morphology using near field and far field device electrograms. Circ Arrhythm Electrophysiol 2019;12:e006878. https://doi.org/10.1161/ CIRCEP.118.006878; PMID: 30707036.

28. Hirao K, Otomo K, Wang X et al. Para-Hisian pacing. A new method for differentiating retrograde conduction over an accessory AV pathway from conduction over the AV node.

Circulation 1996;94:1027–35. https://doi.org/10.1161/01. cir.94.5.1027; PMID: 8790042.

29. Arnold AD, Howard JP, Gopi AA et al. Discriminating electrocardiographic responses to His-bundle pacing using machine learning. Cardiovasc Digit Health J 2020;1:11–20. https://doi.org/10.1016/j.cvdhj.2020.07.001; PMID: 32954375.

30. Upadhyay GA, Cherian T, Shatz DY et al. Intracardiac delineation of septal conduction in left bundle branch block patterns: mechanistic evidence of left intra-hisian block circumvented by His pacing. Circulation 2019;139:1876–88 https://doi.org/10.1161/CIRCULATIONAHA.118.038648; PMID: 30704273.

31. Tung R, Upadhyay GA. Defining left bundle branch block patterns in cardiac resynchronisation therapy: a return to his bundle recordings. Arrhythm Electrophysiol Rev 2020;9:28–33. https://doi.org/10.15420/aer.2019.12; PMID: 32637117.

Cardiac Pacing

The Atrioventricular Conduction Axis and its Implications for Permanent Pacing José-Ángel Cabrera ,1 Robert H Anderson ,2 Andreu Porta-Sánchez ,1,3 Yolanda Macías ,4 Óscar Cano ,5 Diane E Spicer 6 and Damián Sánchez-Quintana 7 1. Unidad de Arritmias, Departamento de Cardiología, Hospital Universitario Quirón-Salud Madrid and Complejo Hospitalario Ruber Juan Bravo, Universidad Europea de Madrid, Spain; 2. Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK; 3. Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; 4. Department of Medical and Surgical Therapeutics, Faculty of Veterinary, University of Extremadura, Cáceres, Spain; 5. Unidad de Arritmias, Servicio de Cardiología, Hospital Universitari i Politècnic La Fe, Centro de Investigaciones Biomédicas en RED en Enfermedades Cardiovasculares (CIBERCV), Valencia, Spain; 6. Congenital Heart Centre, University of Florida, Gainesville, Florida, US; 7. Departamento de Anatomía Humana y Biología Celular, Facultad de Medicina, Universidad de Extremadura, Badajoz, Spain

Abstract

Extensive knowledge of the anatomy of the atrioventricular conduction axis, and its branches, is key to the success of permanent physiological pacing, either by capturing the His bundle, the left bundle branch or the adjacent septal regions. The inter-individual variability of the axis plays an important role in underscoring the technical difficulties known to exist in achieving a stable position of the stimulating leads. In this review, the key anatomical features of the location of the axis relative to the triangle of Koch, the aortic root, the inferior pyramidal space and the inferoseptal recess are summarised. In keeping with the increasing number of implants aimed at targeting the environs of the left bundle branch, an extensive review of the known variability in the pattern of ramification of the left bundle branch from the axis is included. This permits the authors to summarise in a pragmatic fashion the most relevant aspects to be taken into account when seeking to successfully deploy a permanent pacing lead.

Keywords

His bundle, penetrating atrioventricular bundle, left bundle branch, inferoseptal recess, inferior pyramidal space, conduction axis pacing, His pacing Disclosure: RHA is on the Arrhythmia & Electrophysiology Review editorial board; this did not influence peer review. All other authors have no conflicts of interest to declare.

Received: 17 June 2021 Accepted: 4 August 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(3):181–9. DOI: https://doi.org/10.15420/aer.2021.32 Correspondence: José-Ángel Cabrera, Departamento de Cardiología, Hospital Universitario Quirón-Salud Madrid and Complejo Hospitalario Ruber Juan Bravo, Universidad Europea de Madrid, CIBER Enfermedades Cardiovasculares (CIBERCV), 1 Diego de Velázquez, Pozuelo de Alarcón, Madrid, Spain.

E: jose.cabrera@quironsalud.es 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.

Direct pacing of the atrioventricular conduction axis, usually known as the His–Purkinje system, is currently considered the most physiological of the methods available for restoring intrinsic atrioventricular conduction.

Pacing the His bundle, the left bundle branch or the region surrounding it can restore physiological activation of the ventricles, thus restoring electrical synchrony caused by bundle branch block. Such pacing can also improve clinical outcomes in patients with heart failure.1–8 Pacing of this type corrects the situation either by delivering an impulse beyond the site of block or by penetrating beyond the area of block, and, hence, directly recruiting the fascicles of the left bundle branch. There is an emerging role for such pacing to achieve cardiac resynchronisation in addition to conventional biventricular pacing, particularly in patients with more proximal diseases of the conduction system.3–8 Recognition of these possibilities has underscored the current resurgence of interest in the topic of the anatomical relationships of the atrioventricular conduction axis, and their implications for pacing.9–15

myocardial connection between the atrial and ventricular myocardial compartments.16 The concept of corrective pacing is based on the notion that the abnormalities in conduction are due to proximal focal lesions producing either intra- or infra-Hisian lesions. The consequence of such lesions is complete atrioventricular dissociation, severe slowing of conduction or asynchronous conduction along pre-destined, longitudinally dissociated pathways, as elegantly demonstrated by Narula in 1977.17 Successful pacing with early capture of the conduction system or biventricular pacing results in simultaneous physiological activation of both ventricles. This prevents the untoward effects of non-physiological chronic right ventricular apical pacing.11 The procedure, however, has some limitations. These include the narrow target zone of the conduction axis, which varies greatly between individual patients, along with the dense nature of the fibrous tissue that surrounds the penetrating bundle.

These anatomical features explain, in part, the technical challenges of the procedure, along with the frequent occurrence of high and unstable pacing thresholds subsequent to implantation.4–6 They also account for the delayed rise in thresholds, abnormal sensing and permanent acute or

Of course, the His bundle is but a part of the overall axis of specialised conduction tissue that, in the normal heart, provides the solitary

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Permanent Pacing of the Conduction Axis Figure 1: Human Atrioventricular Axis A

B Aortic root

Membranous septum Non-branching AV bundle Left bundle branch

Right bundle branch Penetrating AV bundle Right atrium

Compact AV node Hinge of septal leaflet Septal isthmus

Tendon of Todaro Coronary sinus

Triangle of Koch

A: Gross dissection of the human atrioventricular (AV) conduction axis relative to the triangle of Koch, which is represented by a dashed red line, revealing the location of the compact AV node and penetrating bundle. The right bundle branch can be seen on the right side of the interventricular septum. B: Schematic drawing representing the arrangement of the AV conduction axis at the level of the Koch triangle. The AV conduction axis is made up of the compact node, the penetrating AV bundle, the non-branching AV bundle, the branching AV bundle, and the right and left bundle branches. The triangle of Koch is delimited by the hinge line of the septal tricuspid leaflet, the tendon of Todaro and the mouth of the coronary sinus forming its base. The fibrous membranous septum forms the apex of the triangle. The hinge of the septal leaflet of the tricuspid valve provides the dividing line between the AV (yellow star) and interventricular (pink star) components of membranous septum.

CSO = coronary sinus orifice; OF = oval fossa; RVA = right ventricular apex; RVOT = right ventricular outflow tract; STV = septal tricuspid valve. Sources: A: Cabrera et al. 2020.9 B: Cabrera et al. 2020.15 Both adapted with permission from Elsevier.

Figure 2: Triangle of Koch, Inferoseptal Recess and Inferior Pyramidal Space

unacceptable need for repositioning of the leads in one-tenth of patients.18 Because of these inherent limitations associated with attempts at pacing the His bundle, which is either the penetrating or non-branching components of the axis, direct pacing of the left bundle branch has recently emerged as an alternative option.1,5 Such pacing, by means of intraseptal lead fixation deep into the left side of the muscular ventricular septum, can bypass distal pathological lesions involving the left bundle branch and its surrounding regions.7 The procedure is aimed at direct capture of the fascicles of the left bundle branch, thus preserving or restoring physiological activation of the left ventricle. The narrow QRS duration achieved is likely due to the dense arborisation of the left bundle branch, which permits rapid conduction and simultaneous capture of the greater part of the left ventricle.11 The procedure is associated with technically easier implantation of the lead, a shorter learning curve and higher rates of success of implantation. It produces stable and reliable lead parameters.

It is axiomatic that precise knowledge of the anatomy and histology of the atrioventricular conduction axis is critical for those seeking to achieve such direct pacing. With this in mind, we have reviewed our recent investigations of the anatomical variations involving the axis, features necessary for a proper understanding of pacing of the conduction system in the human heart.

A: Left ventriculography in RAO to visualise the LV and AO (note the fluoroscopic relationship between the region of the inferoseptal recess, the inferior pyramidal space and triangle of Koch (white dotted line). B: This heart has been sectioned along the inferior pyramidal space and roof of the inferoseptal recess, and shows the alignment of the aortic root relative to the hinge of the aortic leaflet of the mitral valve. C: RAA in RAO projection to show the fluoroscopic limits of the triangle of Koch. D: This image shows the right atrial aspect of the triangle of Koch, as viewed in an attitudinally appropriate fashion with the transilluminated membranous septum forming the apex of the triangle. AO = aorta; CS = coronary sinus; LV = left ventricle; RAA = right atrial angiograms; RAO = right anterior oblique projection; RV = rght ventricle; SCV = superior caval vein; STV = septal leaflet of the tricuspid valve. Source: C: Cabrera et al. 2020.9 Adapted with permission from Elsevier.

The Area of the His Bundle: Anatomical Considerations

In 1893, Wilhelm His Jr was the first to report the location of the solitary strand of specialised myocardium providing electrical connection between the atria and ventricles, but he was unaware of its atrial and ventricular extensions.11,19 It was not until 1906 that Tawara clarified the

chronic damage to the atrioventricular conduction axis itself. Taken together, as demonstrated during mid-term follow-up, they produce an

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Permanent Pacing of the Conduction Axis Figure 3: Inferior Pyramidal Space

A: Fluoroscopic limits of the inferior pyramidal space (red circle) in left anterior oblique projection (LAO) showing the nodal artery (AVNa) towards the His bundle (black circle). B: Basal view in simulated LAO projection showing the course of the RCA and nodal arteries macroscopically, both painted in red, across the inferior pyramidal space. Note the nodal artery crossing the adipose tissue along the right side of the space. At the base of the triangle of Koch, the artery runs inferior to the mouth of the coronary sinus and follows a course close to the tricuspid–mitral continuity towards the His bundle.

C: Note the fibro-adipose tissue filling the pyramidal space (white asterisk). The red circle in B and C shows the vertex of the pyramidal space. AO = aorta; MV = mitral valve; PA = pulmonary artery; RCA = right coronary artery; RVA = right ventricular apex; TV = tricuspid valve.

Figure 4: Atrio and Interventricular Membranous Septum

situation.16 He showed that the transition from atrial to the ventricular components occurred as the conduction axis entered the insulating tissues of the atrioventricular junctions. He described, for the first time, the extent of the solitary pathway of specialised myocardium, demonstrating the histologically distinct cells that conducted impulses from the atrial chambers to the apical ventricular myocardium.11,16 It is now well recognised that the atrial components of the conduction axis are located within the atrial wall of the triangle depicted by Koch. The area is part of the septal vestibule of the tricuspid valve. It forms the atrial wall of the inferior pyramidal space. It contains not only the atrioventricular node, but also its rightward inferior extension and overlies the septal inputs. The paraseptal area is an overlap of the atrial and ventricular musculatures, with a superior extension of the inferior atrioventricular groove separating its muscular walls. The triangle is limited cranially by the fibrous part of the septal components, usually known as the membranous septum. The mouth of the coronary sinus, and the septal isthmus, form the base of the triangle (Figures 1 and 2).20–25 The atrial wall of the triangle is separated from the underlying crest of the muscular ventricular septum by the fibro-adipose tissue that fills the inferior pyramidal space.

A: Gross dissection from the right atrial cavity, the membranous septum forms the apex of the triangle of Koch (transillumination). The hinge of the STV provides the dividing line between the atrioventricular and interventricular components of the membranous septum. B and C: Gross dissections of the compact AV node and penetrating AV bundle relative to the apex of the triangle of Koch. The hinge line of the septal leaflet of the tricuspid valve represented by a dashed red line (panel inferior, transillumination) provides the dividing line between the AV MS and IV MS. Note that the compact node becomes the penetrating AV bundle as the axis itself enters the AV component of the membranous septum (transillumination), thus becoming encircled by the fibrous tissue of the central fibrous body. AV = atrioventricular; AV MS = atrioventricular component of membranous septum; CSO = coronary sinus orifice; IV MS = interventricular component of membranous septum; OF = oval fossa; RVOT = right ventricular outflow tract; STV = septal leaflet of the tricuspid valve; TC = terminal crest. Source: A: Cabrera et al. 2020.15 Adapted with permission from Elsevier.

When considered in attitudinally appropriate fashion, the pyramidal space is the superior continuation of the inferior atrioventricular groove (Figures 2 and 3). It is bounded on the atrial side by the diverging vestibules of the mitral and tricuspid valves. Its ventricular boundary is formed by the crest of the muscular ventricular septum. At its apex is found the inferior margin of the membranous septum, which is typically an atrioventricular partition as this level. It is often overlaid by a layer of atrial vestibular myocardium, which then separates the apex of the pyramidal space from an inferoseptal recess within the left ventricle (Figure 2). The tissues occupying the pyramidal space are themselves thickened at its apex, forming a fibrous insulating plate on the crest of the ventricular septum. The atrioventricular node becomes the penetrating bundle by passing through the fibrous tissues of the atrioventricular junctions, specifically through an area of fibrous continuity between the leaflets of the mitral and tricuspid valves (Figure 4).

interposes between the aortic leaflet of the mitral valve and the septal surface of the left ventricle. It is roofed by an area of mitral-to-tricuspid valvar continuity that supports the base of the atrial septum. The conduction axis usually penetrates through this fibrous tissue, which then forms the rightward wall of the recess. The variation in the depth of the inferoseptal recess is itself reflected in the extent of observed off-setting of the leaflets of the mitral and tricuspid valves (Figure 2). This feature, in turn, influences the location of the node, and its transition to the His bundle within the apex of the triangle of Koch.9,21

In the majority of individuals, the apex of the pyramidal space is itself adjacent to the inferoseptal recess of the left ventricle. This latter space

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Permanent Pacing of the Conduction Axis Figure 5: Atrioventricular Node

The left panel shows features of the septal surface of the right atrium, with the location by transillumination of the oval fossa and apex of the triangle of Koch. The white lines A, B, C and D (close to apex) show the levels of the histological sections cutting at right angles to the hinge of the septal leaflet of the tricuspid valve and stained with Masson trichrome technique. Level A shows the extensions from the atrioventricular node that occupy the inner layers of the tricuspid and mitral vestibules. Level B, taken at a superior level within the floor of the triangle of Koch, shows how the cardiomyocytes derived from the deeper left side of the atrial septum provide the greatest inferior input to the compact AV node. Level C shows that the compact node takes a sloping shape as it approaches the AV component of the membranous septum, and at this level, its major myocardial connections are with the central part of the atrial septum. Level D shows that the central connections remain dominant, and provide the final last input to the node before it becomes insulated by the tongue of fibrous tissue that is continuous with the hinge of the septal leaflet of the tricuspid valve. Once insulated by this fibrous tongue, the conduction axis is usually known as the His bundle. AV = atrioventricular; CSO = coronary sinus orifice; OF = oval fossa; MV = mitral valve; STV = septal leaflet of the tricuspid valve; TV = tricuspid valve.

Table 1: Dimensions and Distance to the Right Atrial Endocardium of the Penetrating His Bundle

specimens, with the transition found inferiorly within the triangle of Koch in the remaining two-fifths of hearts.

Penetrating His Bundle

Consequently, we observed that the axis penetrated on the atrial side of the hinge-line in just over half of the hearts, whereas in the remainder, the transition was either at the hinge-line or on its ventricular aspect. This is in keeping with our findings regarding the location of the largest His bundle deflection relative to the septal leaflet and the angiographic vertex of the triangle of Koch (Figure 6).9,26 This is significant for those seeking to find the optimal site for direct pacing, since the conduction axis is generally mapped along the tricuspid vestibule in the triangle of Koch. It is intuitive to suggest that the point of transition will prove to be the optimal site for direct engagement of the so-called His bundle.

Length

2.68 ± 0.74 mm (1.4–4.7)

Width

3.7 ± 1.4 mm (2.5–5.6)

Thickness

1.4 ± 0.5 mm (0.5–2.2)

Distance endocardium

0.81 ± 0.46 mm (0.3–2.5)

Data are expressed as mean ± SD (range). Source: Cabrera et al. 2020.9 Adapted with permission from Elsevier.

It is the combination of knowledge of these anatomical features, and the site of recording of the His bundle electrograms, that will determine the optimal positioning of the pacing lead.

When assessed relative to the right-sided chambers, the site of penetration was found in an atrial location within the triangle in just over half of hearts, whereas penetration coincided with the hinge point of the septal leaflet of the tricuspid valve, adjacent to its zone of apposition with the anterosuperior leaflet in one-third of hearts. In the remaining onesixth of hearts, the site of penetration was within the ventricular component of the membranous septum. In over nine-tenths of hearts having an inferior site of penetration, the axis penetrated at the atrial side, but was centrally located within the triangle. In contrast, in those hearts with a superior site of penetration, penetration occurred within the atrial tissues in only one-third of the cases. It was at the level of the hinge of the septal leaflet, or in its ventricular aspect, in the remaining two-thirds (Figure 6).9

Anatomy Relevant to Direct Pacing of the Penetrating or Non-branching Atrioventricular Bundle

When searching for the optimal site for pacing of the penetrating component of the conduction axis, electrophysiologists should map both the atrial and ventricular aspects of the tricuspid valvar vestibule. In our anatomical studies, we have encountered marked inter-individual differences, with significant variations in the site of transition from the atrioventricular node to the non-branching component of the axis relative to both the hinge of the septal leaflet of the tricuspid valve and the atrioventricular septal structures. As we have emphasised, we followed the precedent of Tawara when taking the site of penetration into the insulating tissues provided by the continuity between the leaflets of the mitral and tricuspid valves as representing the transition from the node to the penetrating component of the axis (Figure 5).9,16 This penetration into the insulating fibrous tissues occurred superiorly in almost three-fifths of

The adjacency of the conduction axis to the right-sided endocardial surface, and the atrial myocardial overlay, is itself a further important consideration for direct pacing of the conduction axis. Typical values for

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Permanent Pacing of the Conduction Axis Figure 6: Variable Location of the Atrioventricular Node and the Penetrating Bundle

the length, width and thickness of the penetrating His bundle, and its distance from the right atrial endocardium, are shown in Table 1.9 Selective pacing results in exclusive capture of the non-branching component of the conduction axis, without myocardial capture. Non-selective pacing occurs when the adjacent atrioventricular and ventricular septal myocardium is captured alongside capture of the axis itself. When the conduction axis is not captured, but the pacing stimulus produces ventricular activation, then only the local myocardium is captured.7 The covering between the axis and endocardium provided by a layer of overlying right atrial myocardium was greater in hearts with an inferior transition from the node to penetrating bundle than in those hearts with a superiorly located transition. The latter arrangement was associated with a thicker surrounding connective component and less overlying atrial vestibular myocardium (Figure 6).

This latter point is obviously of significance in terms of sensing and threshold for those hoping to achieve direct pacing of the conduction axis. When the distal sensing electrode of the lead sits on the atrial side, it could oversense the atrial potential, with concomitant undersensing of the ventricular signal. As a consequence, the position of the lead may have an important impact on pacing parameters. Capture is known more often to be selective when the pacing lead tip is placed on the atrial side of the site of insulation. Positioning it as distally as possible can significantly help increase the sensing values.

Investigators had recently explored the relationship between the location of the tip of the pacing lead and the hinge of the septal leaflet of the tricuspid valve using cross-sectional echocardiography. Tang et al., for example, showed that the site of implantation of the leads has a significant effect on sensing values.27 They found that, on average, the distance from the tip of the leads targeting the axis to the attachment of the septal leaflet of the tricuspid valve was 3.16 ± 1.54 mm with an atrial location, but was 6.12 ± 2.21 when the lead was located at the ventricular aspect of the hinge. A ventricular location of the lead was linked to higher sensing values, but the achievement of selective pacing was greater when pacing was performed at the atrial side. In contrast, when the lead is deployed in the ventricular position, there is a greater chance of non-selective pacing, capturing both the conduction axis and the surrounding right ventricular myocardium. This latter result might prove to be safer. Other have suggested, however, that pacing on the atrial side can reduce any deleterious impact on the tricuspid valve, which is considered an advantage of direct compared with conventional pacing.13

The images show gross dissections of the human AV conduction axis relative to the triangle of Koch, revealing the variable position of the atrioventricular node and the penetrating bundle relative to the tendon of Todaro and the hinge line of the septal leaflet of the tricuspid valve, which is represented by the discontinuous blue line. The compact AV node shows an inferior location (A1) and there is a superior location of the conduction axis (B1). A2 and B2: Histological sections showing the variable location of the penetrating bundle with respect to the location of the septal leaflet of the tricuspid valve. A2: The penetrating His bundle is distant from the insertion of the septal leaflet and it is separated from the right-sided endocardium by a layer of atrial cardiomyocytes overlying the atrial component of the membranous septum (red star). B2: The site of penetration of the His bundle is at the level of insertion of the septal leaflet and is within the atrioventricular component of the membranous septum (blue star). A3 and B3: Right angiography in RAO displays the tricuspid valve annulus and the relationship between the site of recording of the largest His bundle potential (His) and the landmarks of the triangle of Koch. B3: The His bundle was recorded superiorly at the vertex of the triangle at the ventricular aspect of the hinge of the tricuspid valve. A3: The arrangement with an inferior and atrial location of the recording.

AV = atrioventricular; CSO = coronary sinus orifice; OF = oval fossa; RAA = right atrial angiograms; RAO = right anterior oblique projection; SCV = superior caval vein; TV = tricuspid valve. Adapted from: Source: Cabrera et al. 2020.9 Adapted with permission from Elsevier.

The process of implantation for direct pacing of the conduction axis can often be challenging. In clinical practice, it is technically difficult to determine whether the pacing lead has crossed the hinge of the tricuspid valve during the implantation procedure. This is because standard fluoroscopy cannot determine the precise location of the site of penetration of the conduction axis.26,28,29 The standard procedure for implantation involves seeking a His bundle potential when using fluoroscopy in the right anterior oblique view. There is no clear anatomical marker for the site of penetration of the conduction axis when using this approach. The view does provide anterior and posterior orientations, and helps to localise the plane of the tricuspid valve. It is the view obtained in the left anterior oblique orientation, however, that identifies the septal contact of the catheter. In the right anterior oblique view, the translucent area that indicates the atrioventricular groove can be useful when seeking to approximate the location of the coronary sinus to the hinge of the leaflets of the tricuspid valve.12

In some instances, the location of a prosthetic aortic valve can be used as an anatomical landmark for localising the conduction axis, thus improving implantation on the ventricular side (Figure 7).30 In particular, for individuals in whom self-expandable valves have been inserted by catheter, it seems reasonable when seeking to pace the fascicles of the left bundle branch to avoid placing the pacing lead in contact with the struts of the prosthesis. This should ensure no early damage to the lead, and avoid sensing issues due to noise detection. Clinical evidence to support this recommendation, however, is currently lacking. We have previously shown that right atrial angiography may help to identify the variable sites of recording of the conduction axis in relation to the limits of the triangle of Koch and the septal hinge of the tricuspid valve.26,29 The atrial and ventricular location of the His catheter in relation to the hinge of the valvar leaflets can readily be identified by this technique. Other authors have used injection of contrast into the right ventricle to provide

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Permanent Pacing of the Conduction Axis Figure 7: Area of His and the Left Bundle Branch Pacing

A: Simulated (gross human specimen) right anterior oblique view of the right heart showing the limits of the triangle of Koch. The white point marks the area of the His bundle. B1 and B2: Fluoroscopic views in right anterior oblique projection demonstrating the HB and the LBB pacing lead distal to the aortic prosthetic valves (TAVR). C: LBB pacing lead 17 mm below and apical to the HB pacing lead position, as seen from the ventricular aspect in right anterior oblique fluoroscopic view. Dashed lines in A and C indicate the schematics of the left bundle branch and its branches on the left side of the interventricular septum. CSO = coronary sinus orifice; HB = His bundle; LBB = left bundle branch; OF = oval fossa; RAA = right atrial appendage; RVOT = right ventricular outflow tract; STV = septal leaflet of the tricuspid valve; TAVR = transcatheter aortic valve replacement; TC = terminal crest.

for good delineation of all these structures.31 This approach may be of great help. It identifies the potential atrial as opposed ventricular sites of the conduction axis. Those using this approach found that capture was more often selective when the pacing lead tip was placed on the atrial side of the site of penetration. Such visualisation shortens the procedural and fluoroscopic times for implantation. Others have used tomographic reconstruction in a subgroup of patients undergoing successful His bundle pacing. The location of the tip of the lead was, in almost four-fifths of cases, on the ventricular aspect. An atrial position was most commonly linked to selective capture, although this was linked to increased atrial oversensing.32 Knowledge of the anatomical location of the site of penetration, therefore, can help guide optimal placement of the lead. It is linked to different physiological pacing characteristics (Supplementary Material Video 1).27,31

The arrangement of the fibrous membranous septum itself is also known to be variable.19,22,24,25 In many instances, the atrioventricular component, as we have discussed, is overlaid by a layer of atrial myocardium, which often includes the atrioventricular node itself. The conduction axis itself, having penetrated to enter the subaortic outflow tract beneath the circumference of the aortic root, usually gives off the right bundle branch at the level of the interleaflet fibrous triangle between the non-coronary and right coronary aortic sinuses. The right bundle branch is a thin cordlike structure. It typically takes a short course embedded within the muscular ventricular septum before emerging in the subendocardium of the right ventricle at the base of the medial papillary muscle, also known as the muscle of Lancisi.11 Some may identify this muscle as being ‘septal’, but this is potentially confusing, since multiple small muscles tether the septal leaflet of the tricuspid valve. The right bundle then courses towards the moderator band and anterolateral papillary muscle, arborising to supply the right ventricular myocardium.

The Ventricular Components of the Conduction Axis

The conduction axis, having penetrated by passing through the fibrous tongue, producing continuity between the hinges of the leaflets of the mitral and tricuspid valves, continues as the non-branching component. In over three-quarters of individuals, this part runs for less than 3 mm along the crest of the muscular ventricular septum before giving rise to the fascicles of the left bundle branch. This part of the axis is embedded within the fibrous tissues forming the right wall of the inferoseptal recess.

Variations in the location of this non-branching component relative to the crest of the muscular ventricular septum were assessed in detail by Kawashima and Sasaki.33 They identified three distinct patterns. In just over half of their specimens, the bundle ran along the lower border of the membranous part of the ventricular septum, usually covered with a thin layer of ventricular myocardium. In one-third, the bundle was separated from the membranous septum, being further covered by a thick myocardial layer. In the remaining one-fifth, the bundle was directly subendocardial, lacking any myocardial covering.

The inter-individual variations in the location of the components of the conduction axis are of particular importance not only for identification of the site for optimal pacing of the penetrating bundle, but also for recognition of the origin of the ramifications of the left bundle branch. It is for this reason that identification of the site of penetration is itself of importance, even if direct pacing of the left bundle branch is the objective of the pacing procedure (Figure 7).

Pacing the Left Bundle Branch and its Surrounding Regions

Direct implantation of the pacing lead in one of the fascicles of the left bundle branch has recently emerged as a further strategy for patients with infra-Hisian block.1,2,5 Unlike direct pacing of the penetrating bundle, where the target zone for effective pacing is very small, the fascicles of the left bundle, despite presenting large inter-individual variations, are widely distributed. Indeed, the presence of the branching as an extensive

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Permanent Pacing of the Conduction Axis Figure 8: Subaortic Outflow Tract and the Crest of the Muscular Septum

Figure 9: Left Bundle Branch

The left panel shows by transillumination the level of the crest of the muscular ventricular septum and membranous septum relative to the basal ring of the aortic root. The right panel is a histological section that shows the extension of the crest of the muscular septum relative to the hinge of the noncoronary leaflet of the aortic valve, which could be used as a potential indicator of the proximity of the left bundle branch to the basal ring.

A: Histological section (stained with Masson’s trichrome) through the division of the bundle of His, and its right and left branches at the level of the interventricular component of the membranous septum, being attached inferiorly to the crest of the muscular interventricular septum. Note the relationship of the left branch (subendocardial) with the nadir of the non-coronary leaflet of the aortic valve and the right branch is running intramyocardially from the endocardium of the right ventricle. B: The left posterior oblique view shows the transilluminated membranous septum located inferior to the interleaflet triangle between the right and non-coronary sinus of the aortic valve. Note that we have highlighted in dark colour the limits of the endocardial position of the LBB of His and its three fascicles. C: Histological sections stained with Masson’s trichrome of the left bundle branch 10 mm distal from its origin. The thickness of the muscle fibres of the left branch is very variable, small in the left panel and abundant in the right panel; the endocardium has smooth muscle cells in its thickness; and surrounding the left branch there is connective tissue or adipose tissue of variable thickness. HB = His bundle; LBB = left bundle branch; RBB = right bundle branch; TV = tricuspid valve. Source: A and C: Cabrera et al. 2020.15 Adapted with with permission from Elsevier.

subendocardial network may facilitate the implantation of a lead via the intraseptal approach.

In 2017, Huang et al. reported direct pacing of the left bundle branch.1 This was achieved by transseptal implantation of a lead, usually resulting in capture with low pacing thresholds. Using the location of the His recording as a reference, the initial site for implantation was up to 15 mm below the hinge of the leaflets of the tricuspid valve, as seen from the ventricular aspect, and apical to the position of the His potential in the 30° right anterior oblique fluoroscopic view. This emphasises that knowledge of the location of the site of penetration of the axis is also of critical importance in seeking to identify the optimal position to deploy the pacing lead.

of ramification. Its origin from the axis is broad in some individuals, and narrow in others. This can range in size from less than 1 mm to over 1 cm.

As it courses down the surface of the ventricular septum towards the left ventricle, the bundle widens rapidly in some hearts, and gradually in others.34–36

Using this technique, it is necessary to penetrate deep into the muscular ventricular septum, so as to implant the lead on either the trunk or the ramifications of the left bundle branch. Such pacing also demonstrates selective, as opposed to non-selective, capture of the left bundle, or left ventricular septal pacing without direct capture of the conduction system.7 It may be very difficult, nonetheless, to differentiate the exact electrophysiological location of the pacing lead and the tissue captured.

Technically speaking, furthermore, deep intramural pacing is not identical to direct capture of a fascicle of the left branch. Although little evidence exists due to obvious limitations of the lead deployment, we speculate that fascicular capture will be indicated when the initial deflection of the paced QRS is narrower than achieved using deep intramural pacing. Such differentiation, although theoretically interesting, may not always be possible in the clinical situation.

The fashion of subdivision of the left bundle continues to be debated amongst electrophysiologists. It is surprising in this regard, however, that some researchers still consider the left bundle branch in the human heart to be bifascicular.37 We are unaware of any study that endorses this investigation. Since the pioneering work of Tawara himself, it has been evident that the bundle ramifies in a trifascicular fashion.16 The stimulation data produced by Durrer et al. showed three distinct endocardial areas to be synchronously excited within the left ventricle.38 It is reasonable to presume these areas to correspond to the terminations of the three fascicles of the left bundle branch, which have been identified in the human heart by almost all anatomists. Although some have described the branching as ‘unpredictable’, our own investigations confirm that the left bundle ramifies with a thin and elongated superior radiation, a wider inferior radiation and a third radiation that covers the middle of the septum. The superior fascicle is often a thin and long structure that extends towards the superolateral papillary muscle. The inferior fascicle is usually thicker, broader and shorter. It extends towards the base of the inferoseptal papillary muscle. The septal branch emerges from the axis between the inferior and superior fascicles (Figure 9).35,39

It is the rule for the component of the axis giving rise to the left bundle branch to be sandwiched between the inferior border of the membranous septum, and the crest of the muscular ventricular septum. Indeed, in many instances, the axis itself, as it gives off the fascicles of the left bundle branch, is embedded within the base of the membranous septum (Figure 8). The origin of the most cranial fascicle of the left branch typically marks the end of the branching portion of the axis. Not always, however, is the axis carried on the crest of the muscular septum. It was quite some time ago that, in addition to variation relative to the septal crest, Massing and James described the variation in terms of take-off of the right bundle branch.34 The most impressive feature of the left bundle branch, in contrast to the right branch, is the marked variability found in its patterns

The ideal target for direct pacing is the base of the bundle close to its origin at the septal crest. Penetration of the septal area at this level of the conduction axis should then permit excitation of the left bundle in a

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Permanent Pacing of the Conduction Axis Figure 10: Angiographic Anatomy for Left Bundle Branch Pacing

of both the procedure and the time required for fluoroscopy is significantly shortened with less need to reposition the lead.42,43 During fixation of the lead, the characteristic findings of capture should be assessed using different pacing outputs. The thickness of the fascicles themselves vary, ranging from one to 25 cell layers of specialised conducting tissue, surrounded by equally varying amounts of subendocardial collagen and smooth muscle. The presence of a so-called ‘injury current’ may suggest that the tip of the lead is in close contact with the left-sided conduction system, with possible penetration into the fibrous insulating sheath and the risk of septal perforation (Figure 9).44 The large variability in the diameter, length, location, ramifications, and insulation of the bundles and their fascicles is probably the explanation behind an important degree of variability of the captured morphology when deploying the lead in anatomically small portions of septal myocardium.

Conclusion

We have reviewed, based on our own experience, the anatomical relationships and normal variability of the atrioventricular conduction axis.

In particular, we have emphasised the location of the axis as it enters the subaortic outflow tract, pointing to the variability in the ramifications of the left bundle branch. These anatomical variations are of importance for the interventional electrophysiologist when seeking the optimal locations for direct pacing of either the penetrating bundle or the left bundle branch. We hope our descriptions will be prove of value for those physicians seeking to achieve permanent pacing of the atrioventricular conduction in the safest and most effective fashion.

A1 and A2: Right atrial angiography in RAO and LAO projections to visualise the anatomical relationships of the LBB pacing lead with the hinging of the tricuspid valve and the vertex of the triangle of Koch (white circle). Also note the location of the LAA and PFO occluder. B1 and B2: Prosthetic valves might also act as a fluoroscopic marker of the LBB area. LAA = left atrial appendage; LAO = left anterior oblique; LBB = eft bundle branch; PFO = persistent foramen ovale; RAA = right atrial appendage; RAO = right anterior oblique; RV = right ventricle; RVOT = right ventricular outflow tract.

selective fashion. Taking account of the complexity and variability of branching, however, it is likely that the intraseptal lead may often times reach the septal branch, or even the wider inferior fascicle. It is common for the proximal portion of the branch not to be reached because of technical or anatomical difficulties. Despite this, capture of the inferior fascicle will still very often be possible. In a recent study using the 30° right anterior oblique ventricular fluoroscopic image, it was found that acceptable initial fixation points are concentrated in, or near, the area of the basal lower one-third of the ventricle. This fan-shaped area is consistent with the known anatomical location of the ramification of the inferior fascicle.40

Clinical Perspective

• There is marked inter-individual variability in the location of the penetrating atrioventricular bundle within the triangle of Koch.

• The location of site of penetration of the conduction axis is of

critical importance in seeking to identify the optimal position to deploy the pacing lead if the operator is aiming to capture the fascicles of the left bundle branch from the right side via the intraseptal approach.

• Fixation points for pacing of the left bundle branch region should be concentrated in, or near, the area of the basal lower one-third of the ventricle.

• Visualisation of the site of hinging of the leaflets of the tricuspid valve, using contrast injected into the right atrium or right ventricle, may permit anatomically well-defined placement of pacing leads.

It remains challenging, but nonetheless very important, to find an acceptable initial fixation site for the pacing lead.41 Visualisation of the site of hinging of the leaflets of the tricuspid value using contrast injected into the right atrium or right ventricle may permit well-defined placement (Figure 10 and Supplementary Material Video 1). It follows that the duration 1. 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.

2. Liu P, Wang Q, Sun H, et al. Left bundle branch pacing: Current knowledge and future prospects. Front Cardiovasc Med 2021;8 630399. https://doi.org/10.3389/ fcvm.2021.630399; PMID: 33834042.

3. 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.

4. 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.

5. Zhang S, Zhou X, Gold MR. Left bundle branch pacing: JACC review topic of the week. J Am Coll Cardiol 2019;74:3039–49. https://doi.org/10.1016/j.jacc.2019.10.039; PMID: 31865972.

6. 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.

7. Arnold AD, Whinnett ZI, Vijayaraman P. His-Purkinje conduction system pacing: state of the art in 2020.

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9. 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

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Vijayaraman P, Panikkath R. Intracardiac echocardiographyguided left bundle branch pacing in a patient with tricuspid

Permanent Pacing of the Conduction Axis valve replacement. J Cardiovasc Electrophysiol 2019;30:2525– 7. https://doi.org/10.1111/jce.14205; PMID: 31578805.

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15. Cabrera J-Á, Porta-Sánchez A, Tung R, et al. Tracking down the anatomy of the left bundle branch to optimize left bundle branch pacing. JACC Case Rep 2020;2:750–5. https:// doi.org/10.1016/j.jaccas.2020.04.004; PMID: 34317341.

16. Tawara S. Das Reizleitungssystem des Säugetierherzens: eine anatomisch-histologische Studie über das Atrioventrikularbündel und die Purkinjeschen Fäden. Fischer; 1906.

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19. His W. Das Herz. In: Anatomie menschlicher embryonen.

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24. Sánchez-Quintana D, Ho SY, Cabrera JA, et al. Topographic anatomy of the inferior pyramidal space: relevance to

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28. Farre J, Anderson RH, Cabrera JA, et al. Cardiac anatomy for the interventional arrhythmologist: I. Terminology and fluoroscopic projections. Pacing Clin Electrophysiol 2010;33:497–507. https://doi.org/10.1111/j.1540-8159.2009.

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Electrophysiology & Ablation

Diagnosis and Management of Complex Reentrant Arrhythmias Involving the His-Purkinje System Raphael K Sung ,1 Penelope A Boyden,2 Satoshi Higuchi

3

and Melvin Scheinman

3

1. National Jewish Health, Denver, CO, US; 2. Department of Pharmacology, Columbia University, New York, NY, US; 3. University of California San Francisco, San Francisco, CA, US

Abstract

The His-Purkinje system is a network of bundles and fibres comprised of specialised cells that allow for coordinated, synchronous activation of the ventricles. Although the histology and physiology of the His-Purkinje system have been studied for more than a century, its role in ventricular arrhythmias has recently been discovered with the ongoing elucidation of the mechanisms leading to both benign and life-threatening arrhythmias. Studies of Purkinje-cell electrophysiology show multiple mechanisms responsible for ventricular arrhythmias, including enhanced automaticity, triggered activity and reentry. The variation in functional properties of Purkinje cells in different areas of the His-Purkinje system underlie the propensity for reentry within Purkinje fibres in structurally normal and abnormal hearts. Catheter ablation is an effective therapy in nearly all forms of reentrant arrhythmias involving Purkinje tissue. However, identifying those at risk of developing fascicular arrhythmias is not yet possible. Future research is needed to understand the precise molecular and functional changes resulting in these arrhythmias.

Keywords

His-Purkinje system, fascicular tachycardia, ventricular tachycardia, ventricular fibrillation, interfascicular reentry, bundle branch reentrant ventricular tachycardia Disclosure: The authors have no conflicts of interest to declare.

Received: 27 May 2021 Accepted: 13 July 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(3):190–7. DOI: https://doi.org/10.15420/aer.2021.22 Correspondence: Raphael Sung, 1400 Jackson St, Denver, CO 80206, US. E: sungr@njhealth.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The His-Purkinje system (HPS) is a complex network of specialised conduction tissue. Jan Purkinje was the first to describe the fibres in 1845, followed by Wilhelm His Jr who made the observation in 1893 that these specialised muscle fibres connected the atria and ventricles and thus severing the ‘His bundle’ resulted in atrioventricular dissociation.1–3 However, it was not until 1906 that Sunao Tawara discovered the right and left bundle branches and accurately determined their role in conduction of excitatory impulses across the ventricular myocardium.4

simultaneous activation sites.7,8 In addition to the two activation sites represented by LAF and LPF breakout, a third area is activated along the basal third of the mid-left ventricular septum and represents the endocardial breakout from the septal fascicle.

Further branching of the conduction system from the LAF, LPF and LSF forms a dense, complex network of Purkinje fibres that result from both bifurcation as well as merging of two separate fibres. This network is described as a ‘fractal pattern’ rather than a ‘hierarchical tree structure’.9 This is clearly evident from Tawara’s original depiction which showed the complex network of branching articulations and reconnections, resulting in an interconnected web of conduction fibres.5 All of these key anatomical descriptions are critical to understanding the reentrant substrate in the various forms of fascicular-based ventricular tachycardias.

The left trifascicular system originating from the left bundle was first described in Tawara’s macroscopic delineation of the left ventricular conduction system.4 He described a middle or septal fascicle running in between the commonly recognised left anterior fascicle (LAF) and left posterior fascicle (LPF).5 Demoulin and Kulbertus further refined the anatomical variation of the left-sided trifascicular conduction system by reconstructing transverse histological sections from 20 human hearts. These studies revealed that the left septal fascicle (LSF) emerges in four distinct patterns:

• • • •

Ventricular arrhythmias dependent on the specialised conduction tissue of the HPS occur in both structurally normal and abnormal hearts. Studies show fascicular-dependent ventricular tachycardias account for about 15% of idiopathic ventricular tachycardias from the left ventricle in structurally normal hearts.10–12 The incidence of ventricular tachycardia (VT) originating from the HPS in structurally abnormal hearts is more difficult to quantify.

In one study, about 11% of monomorphic VT post MI were dependent on the fascicular system, while 37% of all inducible sustained monomorphic VT in patients with idiopathic dilated cardiomyopathy were due to bundle branch reentrant tachycardia (BBRVT).13,14

direct extension from the left bundle; extension from the LAF; extension from the LPF; and contribution from LAF and LPF.6

The functional nature of this septal fascicle has been demonstrated through endocardial activation mapping showing three distinct,

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Reentrant Arrhythmias of the His-Purkinje System Electrical Conduction in Purkinje Fibres

Figure 1: Longitudinal and Cross-sections of Purkinje Fibres

In normal human hearts, PF bundles provide the major route for rapid conduction at approximately 3–4 m/s of the impulse from the AV node tissues to the ventricular muscle. This is in contrast to much slower conduction in cardiac muscle (0.2–0.6 m/s).22 In 1972, Myerburg et al. reported on conduction of premature impulses in the ‘normal’ myocardium.23 They noted that the PF action potential duration (APD) increased progressively along the left bundle and reached a maximum value at an area they called ‘the gate’ situated at the intersection of the PF and papillary muscle.24 From this area onto the apex, the subendocardial PF APD shortened. In the mouse heart, conduction velocity (CV) in the midseptal region is reduced compared to proximal CV; the geometry of the bundle branches appears to be responsible for the reduced midseptal CV (Figure 1).25 This heterogeneity of APDs in the PF network prevents retrograde activation of PF from premature stimuli arising from the myocardium, serving as a functional ‘gate’.

In this review, we discuss the development of the conduction system and the abnormal physiology underpinning the mechanism of reentrant arrhythmias from the HPS. We also review the clinical manifestations and successful management strategies for these arrhythmias.

When the described ‘normal’ PF APD heterogeneity is disturbed, the gate protection may be lost and reentry could occur. For example, cardiac ion channels in PCs are robustly remodelled during ischaemia and following MI, resulting in PF/PC APDs that are longer than their non-infarcted counterparts.26,27 In this remodelled substrate, premature impulses may conduct, but slowly and inhomogenously, blocking in several areas between the apex to the base to set up conditions for reentry. Similar findings would be expected to occur in the subendocardium of the left ventricle of failing hearts, where remodelling of the PC and associated prolongation of APDs are seen to be similar to that of post-infarcted PCs.27

Anatomy of the Purkinje Fibres and Purkinje Cells

Reentrant Arrhythmias in the His-Purkinje System

Dark structures represent strands of Purkinje cells that are well connected end to end as well as side by side. White areas denote fibrous tissue. Source: Romero et al. 2016.15 Reproduced from PLoS under a Creative Commons (CC BY 4.0) licence.

In the 1970s, the isolated Purkinje fibre (PF) was used to study cardiac electrophysiology because it was easy to visualise and isolate it from the heart to be studied in vitro. Free running Purkinje strands appear to have unique end-to-end connections in the longitudinal direction.15 This anatomy is important to note when discussing bundle branch physiology.

In adult rabbits, some Purkinje cells (PCs) within a strand have end-to-end connections but also make contact transversally. A bundle of longitudinally oriented cell strands is also tightly surrounded by a connective tissue sheath.15 At the single cell level, a PC has defined gap junctions with a few (1–2 per cell) side-to-side connections of connexin (Cx) 40 and Cx43.16 In some cases, PF bundles are separated by collagen within a larger bundle.15 PCs within these bundles travel longitudinally, but others connect transversely. Thus, internal bundles within a sheathed strand can communicate using a physical network. This microanatomical arrangement is consistent with a set of separated strands running parallel to each other after arising from different sources.

Reentrant arrhythmias are self-sustaining rhythm abnormalities that are distinct from disorders of impulse generation such as automaticity and triggered activity. Reentry occurs in the presence of anatomical or functional obstacles, allowing for the formation of circus movement that is similar to a closed loop circuit. First described by Mines in 1914, reentrant excitation requires three criteria:

• An area of unidirectional block of the propagating impulse in a potential pathway.

• Slowed conduction of the propagating wavefront allowing for

sufficient time for substrate recovery and propagation of reentry (tissue size greater than arrhythmia wavelength, defined by action potential duration x conduction velocity).28 • Interruption of the reentrant circuit at any point along its path terminates the circus movement.

Thus, reentry is supported by the combination of reduced APD, reduced CV, or an increase in tissue size. In patients with structural heart disease (SHD), such as ischaemia, infarct and cardiomyopathy, the effects of electrical remodelling and scar formation leading to the conditions for reentry is intuitively easy to understand. This includes a wide spectrum of reentrant mechanisms, including BBRVT, interfascicular VT, and intrafascicular-mediated macro- and micro-reentrant VT.29–33 However, with an increasing recognition of the role the HPS plays in arrhythmogenesis, there is a growing body of literature showing similar reentrant mechanisms in structurally normal hearts.12,34–36

Further, a 3D confocal analysis of PF networks shows that there are two types of Purkinje-ventricular connections.15 One is called a 2D interface and the other is a funnel interface. At a micro level, the tissues of a Purkinje strand could give rise to a reentrant rhythm if there were one or more areas of slowed conduction, such as reduced excitability. On the macro scale, conduction in such Purkinje strands has been observed by others and discussed by Professor Cranefield.17–19 Several reports have described an ‘asynchrony of conduction within strands of Purkinje fibres’.

This was thought to be due to longitudinal dissociation of the conducting impulse.20,21 Some arrhythmogenic consequences of longitudinal dissociation during premature stimulation protocols were shown by Myerburg et al. while Scherlag et al. showed that acute ischaemic injury to a His-Purkinje bundle in vitro induced conduction delays as well as a split in the His-Purkinje bundle potentials.18,21

Bundle Branch Reentrant Ventricular Tachycardia

BBRVT is a macro-reentry circuit using the left and right bundle branches and myocardium connecting the two bundles. Typical BBRVT displays a left bundle branch block (LBBB) QRS morphology, resulting from anterograde

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Reentrant Arrhythmias of the His-Purkinje System Figure 2: Eccentric His-Right Bundle Activation Sequence During Bundle Branch Reentry Ventricular Tachycardia and Left Septal Fascicle Mediated Interfascicular Tachycardia

conduction down the right bundle (RB), transseptal conduction across the interventricular septum and retrograde conduction up the left bundle (LB).

Atypical BBRVT uses the same circuit in the reverse direction, exhibiting a right bundle branch block (RBBB) QRS pattern due to anterograde conduction down the LB and retrograde conduction up the RB.

AV node

BBRVT was initially described in patients with SHD and conduction system disease with prolonged HV interval, particularly in patients with dilated cardiomyopathy of both ischaemic and non-ischaemic cardiomyopathy patients.30,31 HPS disease (and the associated conduction delays along the fascicles and bundles) serves as the substrate for BBRVT, allowing sufficient time for recovery of refractoriness and sustained reentry. There has been increasing recognition of BBRVT occurring without SHD and in younger patients with normal biventricular size and function.37 In a series of six cases, all patients exhibited prolonged HV at baseline (with a mean 69.2 ms), with ECG evidence of conduction system disease apparent in four of the patients. Genetic testing identified mutations in the sodium voltage-gated channel alpha subunit protein coding gene (SCN5A) or lamin A/C protein coding gene (LMNA) in three of the six patients, resulting in isolated conduction system disease. Despite the normal biventricular structure and function, these patients presented with syncope and cardiac arrest, highlighting the malignant potential of BBRVT and the viable role in cases of unexplained sudden cardiac death.

AV node

His p

His p

His

His d

His

His d

RB p

LAF

RB d

LAF

RB p RB d

LPF

RB

RB

LSF LPF

LSF-mediated interfascicular tachycardia

BBRVT

Both tachycardias show early activation in the mid-Hisian area with parallel spread to proximal recording sites. The left bundle branch enters the His bundle at an angle allowing for an eccentric activation of the His bundle. Black arrows show activation sequence on a multipolar catheter.

AV = atrioventricular; BBRVT = bundle branch reentrant tachycardia; LAF = left anterior fascicle; LPF = left posterior fascicle; LSF = left septal fascicle; RB = right branch.

Figure 3: Schematic Representation of the Intraventricular Activation Sequence

BBRVT should be considered in all cases of monomorphic VT, particularly if the surface ECG shows classic LBBB or RBBB QRS morphology during VT. At a minimum, His recordings should be obtained during sinus rhythm and tachycardia. Prolonged HV interval during sinus rhythm should alert the clinician to the possibility of BBRVT. During tachycardia, His activation is eccentric if both the His bundle and RB electrograms are encompassed by multiple electrode recordings (Figure 2), with HV intervals sometimes being the same but usually longer than intervals during sinus rhythm. His signals (H) preceding ventricular activation (V), with changes in H-H interval driving changes in V-V intervals strongly imply BBRVT, but do not exclude other fascicular mechanisms of VT, including interfascicular reentry.30,31 Confirmation of BBRVT must be made by verifying bundle-tobundle reentry by:

A

Sinus rhythm

B

C

Common ILVT

Upper septal ILVT His

RBB LPF (P2)

LVS

LPF (P2)

P1

LBB

P1

LAF P1

LVS LPF (P2)

RAO

• entrainment mapping of the RV apical region (in circuit) and RV base

A: During sinus rhythm, the impulse propagates anterograde down the left posterior fascicle giving rise to P2 then the activation goes from P2 to P1 at the point of fusion; therefore, P1 is buried in the local ventricular activation. B: During common ILVT, P1 and P2 are activated in the reverse direction. VT activation propagates antegradely from the basal to the apical site down P1, with retrograde conduction up P2. C: During upper septal ILVT, both the left anterior fascicle and left posterior fascicle are the antegrade limbs of the reentrant circuit, whereas the retrograde activation occurs via the abnormal Purkinje fibre at the middle septum. All the hypothetical circuits are demonstrated in the RAO position. P1 refers to a specialised Purkinje tissue with decremental property and verapamil sensitivity. The red undulating line represents a zone of slow conduction.

The dotted lines indicate the unsolved parts in the circuit. ILVT = idiopathic left ventricular tachycardia; LBB = left bundle branch; RAO = right anterior oblique; VT = ventricular tachycardia Source: Talib et al. 2015.12 Reproduced with permission from Elsevier.

(out of circuit) affirming the RV apex as part of the macroreentrant circuit; or • comprehensive recording of LB, RB and fascicular potentials, allowing identification of the retrograde (evident by retrograde conduction pattern and preceding His signals) and anterograde limbs exhibiting an anterograde conduction pattern and inscribed between His and V signals) limbs.

Ablation is a highly effective treatment for BBRVT and is the preferred approach for managing this disease.30,31,38,39 The RB is the ablation target in both typical and atypical BBRVT. Care should be taken to avoid mechanical injury to the RB during mapping given the proximity to the endocardium and propensity for temporary conduction block from local endocardial pressure. Ablation should be performed along the proximal portion of the RB, ensuring there is an adequate distance from the His bundle/AV node to avoid complete heart block. Following ablation, a repeat electrophysiology study should be performed to confirm lack of inducibility, particularly with long-short extrastimuli. Although ablation results in curative therapy, due to the advanced conduction system disease and SHD in most of these patients, implantation of an ICD may be needed.40–42

Intrafascicular Reentrant Tachycardia

Intrafascicular tachycardia is synonymous with idiopathic left ventricular tachycardia (ILVT). Using the nomenclature from Nogami, the anterograde limb of tachycardia is termed P1 (which may be the septal fascicle), comprised of slowly conducting, abnormal PFs giving rise to diastolic potentials during tachycardia. The retrograde limb is termed P2, comprised of normal Purkinje/ fascicular tissue giving rise to the presystolic Purkinje potentials (PP).35 Entrainment studies have confirmed reentry as the mechanism for ILVT.43 ILVT may be induced with both atrial and ventricular pacing.44,45 During sinus rhythm, anterograde conduction down P1 and P2 is present, but due

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Reentrant Arrhythmias of the His-Purkinje System Figure 4: Intracardiac Recordings from Octapolar Electrode Catheter in a Patient with Idiopathic Left Ventricular Tachycardia A: Ventricular tachycardia I II

B: Sinus rhythm I 1

1 1

II

aVF 1

aVF 1 V1

1

V1

1

1

HBE2-3 0.1

HBE2-3 0.1 335

RVO3-4 2.5

RVO3-4 2.5

-84 LV7-8

0.25

LV6-7

0.25

LV5-6

0.5

0.5

LV4-5

0.5

LV3-4

1

LV3-4

1

LV1-2

1

LV1-2

1

LV7-8

0.25

LV6-7

0.25

LV5-6

0.5

LV4-5

P2 P1

H

P2

-28

100 ms

A: During VT a diastolic potential (P1) and a presystolic Purkinje potential (P2) were recorded. While P1 was recorded earlier from the proximal than the distal electrodes, P2 was recorded earlier from the distal than the proximal electrodes. B: During sinus rhythm recording at the same site demonstrated the P2, which was recorded before the onset of QRS complex.

Source: Nogami et al. 2000.35 Reproduced with permission from Elsevier.

to the slow conduction of P1, collision from the retrograde wavefront occurs from the distal connection of P1 with P2 (Figure 3). During ILVT reentry, anterograde conduction uses P1 with retrograde conduction over P2 (Figures 3 and 4). Previous studies have shown verapamil selectively affects P1 conduction without affecting P2.43 The typical VT morphology is RBBB with left axis deviation (LAD), due to involvement of the LPF and its associated myocardial exit.35 However, ILVT with RBBB and RAD QRS morphology may also be observed, resulting from tachycardia involving LAF and subsequent local myocardial exit.44

Recently, three cases of reverse-type left posterior fascicular VT (LPFVT) were described in a series of 242 patients with ILVT, with ECG characteristics of rSr’ morphology in V1, early precordial transition and inferior axis.49 Two of the three patients had concomitant common-type LPFVT. In all three cases, the electrophysiology study demonstrated the following:

• The left superior middle septum was the site of the earliest ventricular activation.

• Fragmented P1 signals were buried within the local ventricular

Analogous fascicular-mediated reentrant VT has been observed in a case series of four patients with either acute or remote MI with SHD, with successful ablation targeting diastolic Purkinje potentials (Purkinje-QRS interval of 58 ± 26 ms).46 It is unclear whether VT in these cases resulted from electrical remodelling due to ischaemia/infarct or whether it represents the same substrate as patients with ILVT coincidentally occurring in patients with acute/chronic infarct.

electrogram.

• The P1 activation sequence demonstrated ‘retrograde’ conduction with apical to basal wavefront.

• P1 signals were linked to the subsequent LV septal signal.

Based on their findings, Phanthawimol et al. suggest P1 activates in a retrograde fashion opposite to anterograde conduction in common type LPFVT with myocardial exit in the intraseptum resulting in simultaneous exit in both RV and LV anterior septum that results in the rSr’ pattern in V1 (Supplementary Material Figure 1).

Originally, the reentrant circuit was thought to be contained within the Purkinje system, isolated from the surrounding myocardium.35 However, cases of verapamil-sensitive idiopathic LV tachycardia with RBBB superior axis VT have been reported, demonstrating participation of the LV septum in the circuit, sometimes without participation of the LPF in the tachycardia circuit.47,48 This shows that in some cases of ILVT, the LAF or LPF may act as a bystander, with myocardium serving as P2 or the retrograde limb of the reentrant circuit.

Oral verapamil may be effective in ILVT, particularly in patients with mild to moderate symptoms, but it is much less effective in patients with severe symptoms from VT.50 In a series of 37 patients, those with severe symptoms of ILVT ultimately required some form of non-pharmacological therapy, mostly with catheter ablation.50 Ablation is considered safe and

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Reentrant Arrhythmias of the His-Purkinje System Figure 5: Fascicular Arrhythmias Triggered by a Premature Atrial Complex

appropriate, particularly in patients with severe symptoms or those who cannot tolerate anti-arrhythmic medications.

Several studies have shown high rates of acute ablation efficacy using various approaches, with long-term success rates varying from 70– 90%.35,48,51–58 We previously detailed the published approaches for successful ablation of ILVT and refer the reader there for detailed discussion.59 Some key approaches for ILVT ablation include the following:

A

I

C

II III aVR

LAF

RB LPF

LSF

aVL aVF

• Targeting the site of the earliest Purkinje potential during VT. • Targeting the site of mid-diastolic Purkinje potential during VT. • Ablation at or near VT exit sites or areas of earliest endocardial

V1 V2

RB

V3

activation (especially in presence of PPs).

• Targeting sites of double potentials (presence of both P1 and P2) during VT. • Empiric ablation perpendicular to the long axis of LV, particularly along sites of PP along the presumed, involved fascicle (when VT is not inducible).

• Targeting retrograde PPs observed during sinus rhythm (when VT is not inducible).35,48,51–56

LAF

LPF LSF

V4 V5 V6

B

I aVF V1 LAF d LAF p HRA d HRA p LPF p

Given the complexity and variation in HPS and Purkinje network, it is not surprising that there are likely variations in the anatomical structure and underlying VT circuit among various ILVT cases. In the studies mentioned above, each study required more than one technique to achieve successful ablation in a series of patients, highlighting the importance of understanding ILVT mechanism and having the flexibility to adjust the ablation strategy based on clinical findings rather than using a standard method.

RB

LAF

LPF LSF

LPF d I aVF V1 HRA d HRA p LAF p

LAF d

In patients with inducible and sustained ILVT, we recommend careful mapping of both endocardial and Purkinje activation signals on two separate maps, paying close attention to the subtle timing differences in Purkinje signals. Care should be taken to avoid mechanical injury during mapping which may render VT non-inducible. In addition to activation mapping, entrainment mapping should be performed to confirm the location of circuit, with careful assessment of myocardial versus Purkinje pacing capture and signal return (recognising that some ILVT may involve myocardium in the tachycardia circuit).

A: Spontaneous initiation of VF preceded by a PAC (arrow). The PAC is immediately followed by aberrant ventricular conduction and several beats of pleiomorphic VT. B: Intracardiac electrograms at time of the initiation of stereotypic pleiomorphic ventricular beats with programmed atrial extra-stimulus. Upper panel: single atrial extra-stimulus results in an incomplete LBB block pattern followed by eccentric activation of the LPF. The local potential at LAF (d) exhibits the earliest potential in the LAF. Note that the earliest potentials in both the LAF and LPF were nearly simultaneous (dotted line). Lower panel: single atrial extra-stimulus results in an eccentric activation pattern of the LAF. C: Proposed schema of a PAC resulting in anterograde block in the septal fascicle and relative delay in the LAF and LPF resulting in incomplete LBBB pattern (top panel). This is followed by retrograde activation of the septal fascicle (middle panel) and eccentric activation of the LAF and LPF leading to initiation of several beats of organised fascicular reentry (bottom panel) followed by multiple micro-reentrant circuits that degenerate into VF. Dotted lines represent slow conduction. d,p = distal, proximal electrode pairs of the relevant catheter; HRA = high right atrium; LAF = left anterior fascicle; LBB = left bundle branch; LBBB = left bundle branch block; PAC = premature atrial complex Source: Sanchez et al. 2021.63 Reproduced with permission from Elsevier.

In general, we recommend targeting P1 for ablation, highlighted by relatively slow, anterograde, mid-diastolic potentials. The junction of P1 and P2 may be targeted, but may require more extensive ablation, particularly when the LPF is involved. One should always be aware of the proximity to His and left bundles when ablating along the basal septum to avoid LBBB or complete heart block. In cases where VT is non-inducible, empiric ablation may be performed following previously described approaches.55,56 The anatomical approach consists of an ablation line perpendicular to the long axis of the LV at the midway point along the mid- to mid-inferior apical septum (targeting PPs).56 An alternative strategy includes mapping of the left-sided HPS and endocardial sinus breakout point, followed by a linear lesion perpendicular to the course of the LPF, 1 cm above the sinus breakout point. Although these studies evaluated patients with common ILVT involving the LPF (RBBB, LAD VT), one may consider an analogous approach in patients with ILVT involving the LAF who present with RBBB and RAD VT where VT cannot be induced.

interfascicular reentrant VT uses two of three left-sided fascicles and the intervening myocardium to create the reentrant circuit. This form of reentry using the fascicular system is most commonly observed in SHD, likely the result of electrical remodelling that results in slowed conduction necessary to sustain reentry.29,30,32,33,60 These cases usually involve the LAF and LPF acting as the anterograde or retrograde limbs of the VT circuit. Depending on the direction of the circuit, VT QRS morphology will show RBBB with LAD versus RAD, representing LPF versus LAF acting as the anterograde limb, respectively. VT morphology is the same as VT morphology seen in ILVT due to endocardial activation via fascicular exit.

Rare cases of interfascicular reentry have been observed in structurally normal hearts, exclusively using the septal fascicle as the retrograde limb, termed upper septal-dependent ILVT.12,36,61 These arrhythmias typically have narrow complex QRS morphology often with incomplete RBBB,

Interfascicular Reentrant Ventricular Tachycardia

Interfascicular reentrant VT represents another form of macro-reentry using the HPS. Unlike BBRVT which uses both left and right bundles,

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Reentrant Arrhythmias of the His-Purkinje System which may often be mistaken for supraventricular tachycardia. During electrophysiology study, this form of ILVT may be distinguished from supraventricular tachycardia by a shorter HV interval compared to HV interval in sinus rhythm and eccentric His activation and AV dissociation.

Upper septal ILVT may sometimes manifest following successful ablation of common ILVT with ablation at or near the LPF.36,62

difficult unless pacing results in selective Purkinje capture only without local myocardial capture.

• Ideal sites of ablation including concealed entrainment with post-pacing interval equal to tachycardia cycle length, stimulus to QRS interval during entrainment equal to Purkinje to QRS interval (P-QRS) during tachycardia, and P-QRS of 50 ms or longer.

• Although upper septal ablation has been performed near the LB without proximal HPS injury, ablation should be performed more distally when possible to avoid injury to the His/left bundles.36,64,65

The septal fascicle, located along the upper septum (between the LAF and LPF, often just distal to the left bundle), manifests P1 signals, but in retrograde activation during VT (Figure 3). This retrograde wavefront enters the main HPS, resulting in anterograde activation of the LPF and LAF, as well as eccentric activation of the His bundle (accounting for the shortened HV time compared to sinus rhythm; Figure 2) and anterograde conduction down the RB. The variability in QRS morphology is explained by the relative conduction times down the three bundles (RB, LPF, LAF). If myocardial exit is simultaneous along all three bundles, this would manifest with narrow QRS and normal axis. If there is an exit delay along the RB, LPF or LAF, the VT QRS would exhibit (incomplete) RBBB, LAD or RAD, respectively, or in various combinations of the above. Therefore, arrhythmias resulting from involvement of the septal fascicle are suspected when multiform fascicular tachycardia or alternate narrow and fascicular form are present at the same rates.36,63

Purkinje–Myocardial Reentry

Bogun et al. showed that nine of 81 consecutive patients with previous MI and monomorphic VT demonstrated reentry using the Purkinje system, with all cases demonstrating QRS duration <145 ms.13 Although this macroreentrant circuit mostly involved the myocardium looping around the area of MI scar, the Purkinje fibre was involved in the VT circuit and served as the target for successful ablation. Specifically, seven of the nine patients had successful ablation targeting the exit site from the Purkinje fibres following verification of PPs and concealed entrainment at that site. In two other cases, successful ablation was performed along the myocardium at the VT common pathway site. In these cases, electrical remodelling of the surviving PFs near regions of scarring resulted in enough conduction delay to allow reentry.

More recently, Sanchez et al. demonstrated a unique case of fascicular arrhythmias triggered by a premature atrial complex (PAC) and reproducibly degenerated into VF.63 All episodes were initiated by a PAC, which resulted in incomplete LBBB followed by multiform fascicular beats and then VF (Figure 5A). Following the PAC, there is LB delay with anterograde activation of the LAF and LPF, followed by eccentric activation of LAF and LPF preceding the fascicular beats (Figure 5B). These findings are best explained by PAC blocking anterogradely in the septal fascicle, with delayed conduction into the LAF and LPF producing LBB conduction delay (Figure 5C upper panel). This is followed by retrograde activation of the septal fascicle (Figure 5C middle panel), with eccentric and simultaneous activation of both the LAF and LPF (Figure 5C bottom panel) which results in several beats of fascicular reentry and VF. Tachycardia was eliminated with ablation of the septal fascicle.

Clues for fascicular involvement in post-infarct VT include narrow QRS during VT and the presence of PPs preceding ventricular activation.

Confirmation of fascicular involvement include changes in PP driving changes in VV during tachycardia cycle length changes and concealed entrainment from PP sites.

Conclusion

An increasing body of evidence has illustrated the various reentrant VT circuits involving the fascicular tissue in both structurally normal and abnormal heart, with overlap between the two. Despite the heterogeneity of location of the reentrant mechanism, the overall principles underlying each reentrant VT form are similar. A methodical approach to fascicular VT by incorporating our understanding of HPS anatomy and application of standard electrophysiological principles will help guide successful ablation.

These arrhythmias are sensitive to verapamil therapy, and catheter ablation is effective with low rates of major complications.36,62,64,65 Consider the following points when deciding on ablation:

Clinical Perspective

• Search for retrogradely conducting P1 signals along the left upper to

• The His-Purkinje system is a complex network of conduction

mid-ventricular septum; • Activation mapping should be performed along the HPS in the diastolic period, tagging sites with PPs and identifying the earliest diastolic potential.

• Earliest endocardial activation is remote from the critical limb of tachycardia and ablation at these sites will not be successful. The same is true for ablation along any fascicles/bundles that are conducting signals anterogradely.

• Entrainment mapping may help identify a successful ablation site by identifying whether the P1 signal is part of the reentrant circuit. It is important to ensure capture of the P1 signal during attempted entrainment and measuring post-pacing interval to the Purkinje signal rather than myocardial signals. Concealed entrainment may be

fibres located throughout the ventricles, composed of specialised conduction cells called Purkinje cells.

• Reentry is one of several mechanisms that result in ventricular arrhythmias involving the His-Purkinje system. Enhanced automaticity and triggered activity are others.

• Reentrant arrhythmias of the His-Purkinje system consist of bundle-to-bundle reentry, interfascicular reentry, intrafascicular reentry and macro-reentry involving the myocardium. These reentrant arrhythmias may occur in both structurally normal and abnormal hearts.

• Catheter ablation is an effective tool in the treatment of reentrant arrhythmias in the His-Purkinje system.

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29. Berger RD, Orias D, Kasper EK, et al. Catheter ablation of coexistent bundle branch and interfascicular reentrant ventricular tachycardias. J Cardiovasc Electrophysiol 1996;7:341–7. https://doi.org/10.1111/j.1540-8167.1996. tb00535.x; PMID: 8777482.

30. Blanck Z, Dhala A, Deshpande S, et al. Bundle branch reentrant ventricular tachycardia: cumulative experience in 48 patients. J Cardiovasc Electrophysiol 1993;4:253–62. https://doi.org/10.1111/j.1540-8167.1993.tb01228.x; PMID: 8269297.

31. Caceres J, Jazayeri M, McKinnie J, et al. Sustained bundle branch reentry as a mechanism of clinical tachycardia.

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32. Crijns HJ, Smeets JL, Rodriguez LM, et al. Cure of interfascicular reentrant ventricular tachycardia by ablation of the anterior fascicle of the left bundle branch. J Cardiovasc Electrophysiol 1995;6:486–92. https://doi. org/10.1111/j.1540-8167.1995.tb00421.x; PMID: 7551317.

33. Simons GR, Sorrentino RA, Zimerman LI, et al. Bundle branch reentry tachycardia and possible sustained interfascicular reentry tachycardia with a shared unusual induction pattern. J Cardiovasc Electrophysiol 1996;7:44–50. https://doi.org/10.1111/j.1540-8167.1996.tb00459.x; PMID: 8718983.

34. Belhassen B, Rotmensch HH, Laniado S. Response of recurrent sustained ventricular tachycardia to verapamil. Br Heart J 1981;46:679–82. https://doi.org/10.1136/hrt.46.6.679; PMID: 7317238.

35. Nogami A, Naito S, Tada H, et al. Demonstration of diastolic and presystolic Purkinje potentials as critical potentials in a macroreentry circuit of verapamil-sensitive idiopathic left ventricular tachycardia. J Am Coll Cardiol 2000;36:811–23. https://doi.org/10.1016/s0735-1097(00)00780-4; PMID: 10987604.

36. Sung RK, Kim AM, Tseng ZH, et al. Diagnosis and ablation of multiform fascicular tachycardia. J Cardiovasc Electrophysiol 2013;24:297–304. https://doi.org/10.1111/ jce.12020; PMID: 23110306.

37. Roberts JD, Gollob MH, Young C, et al. Bundle branch re-entrant ventricular tachycardia: novel genetic mechanisms in a life-threatening arrhythmia. JACC Clin Electrophysiol 2017;3:276–88. https://doi.org/10.1016/j. jacep.2016.09.019; PMID: 29759522.

38. Blanck Z, Jazayeri M, Dhala A, et al. Bundle branch reentry: a mechanism of ventricular tachycardia in the absence of myocardial or valvular dysfunction. J Am Coll Cardiol 1993;22:1718–22. https://doi.org/10.1016/07351097(93)90602-w; PMID: 8227845.

39. Cohen TJ, Chien WW, Lurie KG, et al. Radiofrequency catheter ablation for treatment of bundle branch reentrant ventricular tachycardia: results and long-term follow-up. J Am Coll Cardiol 1991;18:1767–73. https://doi.org/10.1016/07351097(91)90519-f; PMID: 1960328.

40. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter–defibrillator for congestive heart failure. New Engl J Med 2005;352:225–37. https://doi. org/10.1056/nejmoa043399; PMID: 15659722.

41. Bristow MR, Saxon LA, Boehmer J, et al. Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. New Engl J Med 2004;350:2140–50. https://doi.org/10.1056/ nejmoa032423; PMID: 15152059.

42. Wilber DJ, Zareba W, Hall WJ, et al. Time dependence of mortality risk and defibrillator benefit after myocardial infarction. Circulation 2004;109:1082–4. https://doi. org/10.1161/01.cir.0000121328.12536.07; PMID: 14993128.

43. Okumura K, Matsuyama K, Miyagi H, et al. Entrainment of idiopathic ventricular tachycardia of left ventricular origin

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with evidence for reentry with an area of slow conduction and effect of verapamil. Am J Cardiol 1988;62:727–32. https://doi.org/10.1016/0002-9149(88)91211-8; PMID: 3421173.

44. Ohe T, Shimomura K, Aihara N, et al. Idiopathic sustained left ventricular tachycardia: clinical and electrophysiologic characteristics. Circulation 1988;77:560–8. https://doi. org/10.1161/01.cir.77.3.560; PMID: 3342487.

45. Zipes DP, Foster PR, Troup PJ, et al. Atrial induction of ventricular tachycardia: reentry versus triggered automaticity. Am J Cardiol 1979;44:1–8. https://doi. org/10.1016/0002-9149(79)90242-x; PMID: 453035.

46. Hayashi M, Kobayashi Y, Iwasaki YK, et al. Novel mechanism of postinfarction ventricular tachycardia originating in surviving left posterior Purkinje fibers. Heart Rhythm 2006;3:908–18. https://doi.org/10.1016/j. hrthm.2006.04.019; PMID: 16876739.

47. Morishima I, Nogami A, Tsuboi H, et al. Negative participation of the left posterior fascicle in the reentry circuit of verapamil-sensitive idiopathic left ventricular tachycardia. J Cardiovasc Electrophysiol 2012;23:556–9. https://doi.org/10.1111/j.1540-8167.2011.02251.x; PMID: 22235753.

48. Ouyang F, Cappato R, Ernst S, et al. Electroanatomic substrate of idiopathic left ventricular tachycardia: unidirectional block and macroreentry within the Purkinje network. Circulation 2002;105:462–9. https://doi.org/10.1161/ hc0402.102663; PMID: 11815429.

49. Phanthawimol W, Nogami A, Haruna T, et al. Reverse-type left posterior fascicular ventricular tachycardia: a new electrocardiographic entity. JACC Clin Electrophysiol 2021;7:843–54. https://doi.org/10.1016/j.jacep.2020.11.022; PMID: 33640356.

50. Ohe T, Aihara N, Kamakura S, et al. Long-term outcome of verapamil-sensitive sustained left ventricular tachycardia in patients without structural heart disease. J Am Coll Cardiol 1995;25:54–8. https://doi.org/10.1016/0735-1097(94)00324-j; PMID: 7798526.

51. Nakagawa H, Beckman KJ, McClelland JH, et al.

Radiofrequency catheter ablation of idiopathic left ventricular tachycardia guided by a Purkinje potential.

Circulation 1993;88:2607–17. https://doi.org/10.1161/01. cir.88.6.2607; PMID: 8252671.

52. Tsuchiya T, Okumura K, Honda T, et al. Significance of late diastolic potential preceding Purkinje potential in verapamil-sensitive idiopathic left ventricular tachycardia.

Circulation 1999;99:2408–13. https://doi.org/10.1161/01. cir.99.18.2408; PMID: 10318662.

53. Nogami A, Naito S, Tada H, et al. Verapamil-sensitive left anterior fascicular ventricular tachycardia: results of radiofrequency ablation in six patients. J Cardiovasc Electrophysiol 1998;9:1269–78. https://doi. org/10.1111/j.1540-8167.1998.tb00102.x; PMID: 9869526.

54. Kottkamp H, Chen X, Hindricks G, et al. Idiopathic left ventricular tachycardia: new insights into electrophysiological characteristics and radiofrequency catheter ablation. Pacing Clin Electrophysiol 1995;18:1285–97. https://doi.org/10.1111/j.1540-8159.1995.tb06970.x; PMID: 7659584.

55. Chen M, Yang B, Zou J, et al. Non-contact mapping and linear ablation of the left posterior fascicle during sinus rhythm in the treatment of idiopathic left ventricular tachycardia. Europace 2005;7:138–44. https://doi. org/10.1016/j.eupc.2004.12.011; PMID: 15763527.

56. Lin D, Hsia HH, Gerstenfeld EP, et al. Idiopathic fascicular left ventricular tachycardia: linear ablation lesion strategy for noninducible or nonsustained tachycardia. Heart Rhythm 2005;2:934–9. https://doi.org/10.1016/j.hrthm.2005.06.009; PMID: 16171747.

57. Liu Y, Fang Z, Yang B, et al. Catheter ablation of fascicular ventricular tachycardia: long-term clinical outcomes and mechanisms of recurrence. Circ Arrhythm Electrophysiol 2015;8:1443–51. https://doi.org/10.1161/CIRCEP.115.003080; PMID: 26386017.

58. Collins KK, Schaffer MS, Liberman L, et al. Fascicular and nonfascicular left ventricular tachycardias in the young: an international multicenter study. J Cardiovasc Electrophysiol 2013;24:640–8. https://doi.org/10.1111/jce.12105; PMID: 23437865.

59. Sung R, Scheinman M. Spectrum of fascicular arrhythmias.

Card Electrophysiol Clin 2016;8:567–80. https://doi. org/10.1016/j.ccep.2016.04.006; PMID: 27521090.

60. Reithmann C, Hahnefeld A, Ulbrich M, et al. Different forms of ventricular tachycardia involving the left anterior fascicle in nonischemic cardiomyopathy: critical sites of the reentrant circuit in low-voltage areas. J Cardiovasc Electrophysiol 2009;20:841–9. https://doi. org/10.1111/j.1540-8167.2009.01467.x; PMID: 19490268.

61. Nishiuchi S, Nogami A, Naito S. A case with occurrence of antidromic tachycardia after ablation of idiopathic left

Reentrant Arrhythmias of the His-Purkinje System fascicular tachycardia: mechanism of left upper septal ventricular tachycardia. J Cardiovasc Electrophysiol 2013;24:825–7. https://doi.org/10.1111/jce.12072; PMID: 23350939.

62. Talib AK, Nogami A, Morishima I, et al. Non-reentrant fascicular tachycardia: clinical and electrophysiological characteristics of a distinct type of idiopathic ventricular tachycardia. Circ Arrhythm Electrophysiol 2016;9:27729344.

https://doi.org/10.1161/CIRCEP.116.004177; PMID: 27729344.

63. Sanchez JM, Higuchi S, Walters TE, et al. The role of the left septal fascicle in fascicular arrhythmias: clinical presentation and laboratory evaluation. JACC Clin Electrophysiol 2021;7:858–70. https://doi.org/10.1016/j. jacep.2020.12.012; PMID: 33640350.

64. Shimoike E, Ueda N, Maruyama T, et al. Radiofrequency catheter ablation of upper septal idiopathic left ventricular

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tachycardia exhibiting left bundle branch block morphology. J Cardiovasc Electrophysiol 2000;11:203–7. https://doi.org/10.1111/j.1540-8167.2000.tb00321.x; PMID: 10709716.

65. Nogami A. Idiopathic left ventricular tachycardia: assessment and treatment. Card Electrophysiol Rev 2002;6:448–57. https://doi.org/10.1023/a:1021100828459; PMID: 12438827.

Electrophysiology and Ablation

Hybrid Convergent Procedure for the Treatment of Persistent and Long-standing Persistent Atrial Fibrillation David B DeLurgio ,1 Jaswinder S Gill ,2 Syed Ahsan,3 Riyaz A Kaba ,4 Kristen M Plasseraud

5

and Michael E Halkos

1

1. Emory St Joseph’s Hospital, Atlanta, GA, US; 2. Guy’s and St Thomas’ NHS Trust, London, UK; 3. St. Bartholomew’s Hospital, London, UK; 4. St George’s University Hospitals NHS Foundation Trust, London, UK; 5. AtriCure, Mason, OH, US

Abstract

Recent advances have been made in AF treatment, including the role of early rhythm control and landmark clinical trials using ablation therapy.

However, some treatment gaps remain, including the creation of durable lesions outside the pulmonary veins and effective treatment of longstanding persistent AF. A novel epicardial-endocardial ablation approach – the hybrid convergent procedure – was developed to combine surgical and catheter ablation techniques into a collaborative, multidisciplinary approach to managing AF. In this review, the authors discuss recently published data on hybrid convergent ablation, including results of the CONVERGE clinical trial, in the context of current challenges to treatment of persistent and long-standing persistent AF. The review also aims to provide perspective on outstanding questions and future directions in this area.

Keywords

Hybrid ablation, hybrid convergent, persistent atrial fibrillation, long-standing persistent atrial fibrillation, epicardial, endocardial Disclosure: DBD is a consultant and on speakers bureaux for AtriCure and Boston Scientific, and is a consultant to Medtronic. JSG holds research funding from Abbott (St Jude Medical) and speaker honoraria from AtriCure. SA is on speakers bureaux for AtriCure, Biosense Webster and Boston Scientific. RAK is a consultant for AtriCure and Biotronik and on speakers bureaux for Daiichi Sankyo and Bayer. KMP is an employee with stock ownership at AtriCure. MEH has consulted and is a member of the advisory board for Medtronic and has received compensation for services from AtriCure.

Received: 31 May 2021 Accepted: 8 August 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(3):198–204. DOI: https://doi.org/10.15420/aer.2021.24 Correspondence: David B DeLurgio, Emory University, St Joseph’s Hospital, 5671 Peachtree Dunwoody Rd, Fl 3, Ste 300, Atlanta, GA 30342, US. E: ddelurg@emory.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.

Treatment Gaps in Advanced AF

of endocardial radiofrequency (RF) or cryoballoon ablation for paroxysmal AF.6–8 These findings are complemented by long-term outcomes in catheter ablation registries.9 However, non-randomised clinical trial data exist for catheter ablation of persistent and long-standing persistent AF. Two recent contemporary endocardial ablation trials, STOP PERSISTENT AF and PRECEPT, were non-randomised and included patients with less than 6 months or 12 months of persistent AF.10,11 Ablation was primarily focused on PVI, although 56% of patients in the PRECEPT trial had additional linear and/or complex fractionated atrial electrogram (CFAE) ablation.11 Treatment gaps for persistent and long-standing persistent AF include the role of systematic non-PVI ablation in improving clinical outcomes in persistent AF and an effective treatment strategy for longstanding persistent AF. In this review, we explore both topics in context of hybrid epicardial-endocardial ablation and specifically recent results of the prospective, randomised, multi-centre CONVERGE clinical trial.

AF is a global health problem, affecting between 2% and 4% of adults worldwide and is increasing.1 Based on the Global Burden of Disease, Injuries and Risk Factors Study, an estimated 59.7 million people globally had prevalent AF or atrial flutter (AFL) in 2019 and approximately 300,000 deaths were attributed to AF/AFL.2 Three primary concerns with unmanaged AF are an increased risk of stroke, progressive or worsening heart failure and increased mortality. Other less acute but nonetheless important implications of AF include impaired patient quality-of-life, increased healthcare resource use and potential for cognitive decline. It is estimated that the AF-related cost to the healthcare system in the US is $6 billion per year for AF alone and up to $26 billion including other cardiovascular and non-cardiovascular costs.3 Anti-arrhythmic drugs (AADs) and ablation are key treatment strategies for treating AF, and recent evidence has suggested that early rhythm control with these strategies is more beneficial than traditional care focused on rate control.4 The prioritisation and success of ablative treatment strategies can be influenced by the type of AF. Paroxysmal AF accounts for approximately 30% of AF cases, whereas non-paroxysmal AF – including persistent and long-standing persistent AF – account for the majority at approximately 70%.5 Treatment of paroxysmal AF is based on pulmonary vein isolation (PVI), which is considered the cornerstone of AF treatment. Randomised clinical trial data support favourable effectiveness

Role for Posterior Wall Ablation and Current Challenges

AF is initiated by a focal arrhythmogenic trigger. Seminal work by Haissaguerre et al. first demonstrated ectopic beats within the pulmonary veins (PVs) in AF, thereby establishing the PVs as the main target for AF ablation strategies.12 To this day, PVI is still considered the cornerstone of AF treatment and it is certainly mandatory for any ablation strategy to treat AF. However, it is also recognised that non-PV triggers of AF are

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Hybrid Convergent Procedure for Persistent AF present, even in paroxysmal AF or groups of unselected AF.13,14 Regions of AF triggers include the left atrial posterior wall, the left atrial appendage (LAA), coronary sinus, superior vena cava, crista terminalis, and ligament of Marshall. Given the diminished success rates of PVI-only strategies as AF progresses, it is reasonable to assume that contribution of non-PV triggers is increased in persistent and long-standing persistent AF relative to paroxysmal AF.

wall, lack of routine verification of posterior wall isolation and inherent limitations of endocardial ablation to overcome complex atrial substrate that is present in persistent and long-standing persistent AF.

Hybrid Convergent Approach

Hybrid epicardial-endocardial ablation is an ablation strategy aimed at isolating the PVs and left atrial posterior wall using a heart team collaboration between cardiothoracic surgery and electrophysiology and combined techniques from both disciplines. Epicardial ablation is performed first, via a minimally invasive surgical approach, which is then followed by endocardial mapping and ablation to complete PVI as well as to address any identified gaps or arrhythmogenic areas. There are currently two predominant hybrid ablation approaches. A thoracoscopic hybrid ablation technique uses bipolar RF clamps and pens for epicardial ablation followed by endocardial catheter ablation.34 Randomised clinical trial results from the HARTCAP-AF trial were recently reported, showing significantly improved arrhythmia-free survival without AADs at 12 months with thoracoscopic hybrid ablation compared to endocardial ablation.35 Other randomised clinical trials comparing thoracoscopic hybrid ablation and endocardial ablation are on-going.

The posterior wall of the left atrium has been a major focus of extra-PV ablation. The posterior wall shares embryological origin with the PVs, as the left atrium incorporates parts of the embryological common PV after its second bifurcation.15,16 Therefore, the intrinsic propensity of PV cardiomyocytes for arrhythmogenicity are shared with those of the posterior wall.14 In addition to the presence of triggers, the posterior wall also acts as anatomical substrate for AF thus it can initiate and potentiate AF as the disease continues and progresses. Like the unique electrophysiological properties of its cardiomyocytes, the posterior wall also has inherent anatomical features that become substrate for AF. These include the heterogeneous orientation of myocardial fibres, tissue thickness variation, presence of epicardial fat and density of autonomic innervation and ganglionated plexi.17 Additionally, the posterior wall is subject to electroanatomical changes that occur with continuous AF, including development of fibrosis and infiltration of fat into the myocardial tissue, which can contribute to abnormal conduction.18 Myocytes in the posterior wall tend to have shorter action potential duration than the rest of the atrium and this enhances the tendency to arrhythmogenesis.

The other epicardial-endocardial approach to ablation and main focus of this review is the hybrid convergent procedure. In this technique, access to the pericardial space is achieved through a subxiphoid incision (Figure 1). Detailed technical aspects of the procedure and best practices have been described elsewhere and are reviewed briefly here.24,36,37 Using endoscopic visualisation, an irrigated, unipolar RF catheter is used to make parallel rows of ablation lines across the left atrial posterior wall between the PVs. The catheter is designed such that the electrodes face the epicardium during ablation so that energy is applied towards the heart, in contrast with endocardial energy application that is applied from the inside of the heart towards the outside. The superior epicardial ablation margin is naturally limited by the pericardial reflections, which are not dissected, and the inferior margin is created such that the area between the inferior PVs and the coronary sinus is not ablated to avoid creating left AFL. Following surgical closure, endocardial mapping and ablation are performed to complete the lesion set so that both the PVs and posterior wall are electrically isolated at the end of the procedure (Figure 2). Both the epicardial and endocardial procedures can be performed on the same day, and even in the same room if set up as a hybrid room. Alternatively, the procedures can be staged at least one month apart. The pre- and post-procedure workflows and coordination of the surgical-electrophysiological heart team require considerable attention particularly when setting up a new programme, but represent a unique opportunity for multidisciplinary arrhythmia management.24 The electrophysiologist plays a key role in coordinating collaboration with surgical, administrative, and nursing colleagues in this process.

Isolation of the posterior wall including PVI has remained a constant through iterations of the Cox-Maze procedure. Voeller et al. showed improved freedom from atrial arrhythmias off AADs with the inclusion of both a roof and floor line connecting PVI lines (i.e. box lesion) to isolate the entire posterior wall compared to only a roof line connecting PVI lines.19 Several strategies have been described to isolate the posterior wall with endocardial catheters, including a single-ring encompassing the PVs and posterior wall, a box lesion and debulking the entire posterior wall.20 There are several potential impediments to successful posterior wall isolation using endocardial ablation only. The durability of endocardial posterior wall isolation after a single procedure is suboptimal with a recent meta-analysis reporting a 63% rate of posterior wall reconnection.21–23 Technological, anatomical and functional factors may contribute to this issue.24 There are still limitations to catheter-based technology to make continuous linear lesions without the potential for pro-arrhythmic gaps. Endocardial ablation of the posterior wall carries some risk of collateral damage with the close proximity of the oesophagus to the posterior left atrium, as well as the phrenic nerve and lungs.

Mitigation strategies may reduce the potential for thermal injury but also may reduce the likelihood of successful, durable posterior wall isolation.

In addition, endocardial-epicardial dissociation – asynchrony in the activation patterns of the endocardial and epicardial surfaces – may increase as AF progresses to persistent and long-standing persistent form.25–27 Endocardial-only or epicardial-only ablation may not be sufficient to overcome this observed dissociation.

A previous meta-analysis comparing hybrid ablation studies with epicardial-only surgical ablation reported similar clinical success rates between the methods, but higher complications with hybrid ablation.38 This meta-analysis combined six studies that used hybrid thoracoscopic ablation and three studies that used hybrid convergent ablation. The majority of the convergent procedures were performed between 2009 and 2013 using earlier device technology and lesion sets. With gained experience, the hybrid convergent procedure has evolved over time since its original development in 2009, with many of these changes focused on reducing the risk of complications.39 The lesion set has evolved from an extra-cardiac Maze lesion set to a posterior wall box to finally a contiguous set of parallel lesions across the posterior wall (Figure 3).40 Other changes

Meta-analyses have concluded that overall there may be a benefit of posterior wall isolation in addition to PVI in persistent and long-standing persistent AF.23,28 However, outcomes with endocardial posterior wall ablation are variable across studies, particularly in randomised clinical trials comparing endocardial PVI to endocardial PVI with posterior wall ablation.21,29–33 The mixed outcomes that have been reported are likely a product of the various endocardial strategies to address the posterior

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Hybrid Convergent Procedure for Persistent AF to the procedure include new generations of the unipolar RF device and pericardial access approach from transdiaphragmatic to subxiphoid.

Additionally, peri-procedural medication strategies have evolved such that many institutions use an uninterrupted anticoagulation strategy prior to the epicardial procedure to mitigate risk of thromboembolic events and prophylactically prescribe anti-inflammatory drugs to prevent delayed inflammatory pericardial effusions.36 As previously mentioned, thermal injury to surrounding tissues including the oesophagus is a concern with any posterior wall ablation. As identified in the meta-analysis by Pearman et al., atrio-oesophageal fistulas were reported with early convergent procedure experience.38 Several procedural steps are now recommended to avoid thermal injury to nontarget tissue during epicardial ablation. The unipolar RF device has electrodes that are exposed on one surface only; this surface is oriented towards, and in direct contact with, the heart. Although the other surface abuts the pericardium, this surface is unexposed and well-insulated, providing very good protection against collateral thermal injury to the pericardium and adjacent non-cardiac structures such as the oesophagus.

The device also has an internal perfusion system for cooling. The device instructions for use and best practices recommend use of oesophageal temperature monitoring to avoid increases >0.5°C or absolute temperature >38°C during ablation.36 Room temperature saline irrigation through the cannula also helps reduce heating within the pericardial space. It is also recommended to not proceed with ablation if overlapping anatomical structures cannot be separated and thermally isolated.

Figure 1: Surgical Approach to Epicardial Ablation A Subxiphoid incision

B Cannula insertion

C Endoscopic view through cannula

D Unipolar device inserted in cannula

A: A subxiphoid incision is made to obtain pericardial access; B: A pericardioscopic cannula is inserted into the subxiphoid incision; C: An endoscope is used for visualisation through the cannula; D: The unipolar radiofrequency device (EPi-Sense, AtriCure) is inserted into the cannula such that the electrodes face the epicardium.

Figure 2: Left Atrial Posterior Wall and Pulmonary Vein Isolation After Hybrid Convergent Ablation A

Post-epicardial ablation

B Post-epicardial-endocardial ablation

The CONVERGE Clinical Trial

The epicardial-endocardial hybrid convergent procedure was compared to endocardial catheter ablation in a prospective, multicentre, randomised clinical trial, Convergence of Epicardial and Endocardial RF Ablation of the Treatment of Symptomatic Persistent AF (CONVERGE; NCT01984346).41,42 The aim of the CONVERGE trial was to evaluate the safety of the Hybrid Convergent procedure and compare its effectiveness with endocardial catheter ablation for the treatment of persistent and long-standing persistent AF. A total of 153 patients with persistent or long-standing persistent AF were randomised 2:1 to either the Hybrid Convergent procedure or endocardial catheter ablation. Forty-two percent of patients in the study had long-standing persistent AF, which was a unique aspect of CONVERGE among contemporary ablation studies to include a substantial proportion of long-standing persistent AF patients. The Hybrid Convergent arm lesion set included epicardial ablation with a unipolar RF catheter focused on the posterior wall and PVs followed by endocardial catheter ablation to complete PVI and address remaining gaps. The catheter ablation arm lesion set was made using an irrigated RF catheter to isolate the PVs and create atrial roof and cavotriscupid isthmus lines.

Additional CFAEs were left to operator decision and ultimately 26% of patients in the catheter ablation arm received CFAEs.42 This was considered the optimal endocardial lesion set at the time of study design for persistent AF ablation. Unlike the Hybrid Convergent arm, posterior wall isolation was not performed in the endocardial catheter ablation arm.

This was due to several aforementioned factors, which are also reflected in guideline recommendations: inconsistent effectiveness outcomes reported for endocardial posterior wall ablation, concerns for thermal injury or perforation, and substantial reconnection rates that calls into question lesion durability.21–23,29 The primary safety events in the Hybrid Convergent arm included eight major adverse events (7.8%) within 30 days of the procedure, which was less than the pre-specified primary safety goal.42 Four of the events were

Endocardial mapping post-epicardial ablation (A) and post-epicardial-endocardial ablation (B).

The left atrial posterior wall is shown on the right in each panel.

Figure 3: Contemporary CONVERGE Lesion Set Convergent (2012–present)

Aorta

Standardised comprehensive posterior homogenisation

PA

Pericardial reflections SVC

RA

LA Epicardial lesions of convergent procedure Endocardial lesions of convergent procedure

IVC

Epicardial ablation (blue) is focused on contiguous parallel rows of lesions to ablate the posterior wall between the pulmonary veins, limited by the pericardial reflections at the superior margin and with a margin at the inferior aspect to avoid the region of the coronary sinus. Endocardial ablation (red) is focused on completing pulmonary vein isolation. IVC = inferior vena cava; LA = left atrium; PA = pulmonary artery; RA = right atrium; SVC = superior vena cava. Source: Wats et al. 2020.40 Reproduced with permission from Atricure.

delayed inflammatory pericardial effusions that resolved without sequalae after planned intervention for pericardial effusion drainage. The primary effectiveness endpoint – freedom from AF/AFL/atrial tachycardia (AT)

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Hybrid Convergent Procedure for Persistent AF Table 1. Summary of Randomised Or Matched Studies Comparing Hybrid Convergent Procedure Versus Endocardial Ablation Study

Study Design

Patient Population

Effectiveness Endpoint

Hybrid Convergent

Endocardial Ablation

p-value

CONVERGE, 202042

Randomised clinical trial

Persistent and long-standing persistent AF

12-month freedom from AF/AFL/AT absent new/increased dose previously failed AADs

67.7%

50%

0.036

12-month freedom from AF/AFL/AT off AADs

53.5%

32%

0.013

12-month freedom from AF/AFL/AT irrespective of AADs

76.8%

60%

0.033

Kress et al.

201743

Propensity-score matching

Persistent and long-standing persistent AF

16-month AF-free survival

72%

51%

0.01

Maclean et al. 202044

Propensity-score matching

Long-standing persistent AF

AF-free at 12 months on AADs

60.5%

25.6%

0.002

AF-free at 12 months off AADs

37.2%

13.9%

0.025

AAD = anti-arrhythmic drugs; AFL = atrial flutter; AT = atrial tachycardia.

absent new AADS or increased dose of previously failed AADs – was achieved in 67.7% of patients in the Hybrid Convergent arm compared to 50% in the catheter ablation group (p=0.036). The success rate was also significantly higher in the Hybrid Convergent arm off all AADs (53.5% versus 32.0%; p=0.013) and irrespective of AADs (76.8% versus 60.0%; p=0.033). In effect, the CONVERGE trial met its primary and safety endpoints, showing improved effectiveness with hybrid ablation compared to endocardial catheter ablation.

al. performed hybrid ablation in the same setting with most patients receiving endocardial cryoballoon. Despite these differences, overall these non-randomised findings are consistent with improved clinical success of hybrid convergent ablation compared to endocardial catheter ablation. A limitation of these studies is that the endocardial approach in the control groups was not strictly defined.

Arrhythmia Burden

By definition, a 30-second atrial arrhythmia recurrence during follow-up resulted in a failure of the primary effectiveness endpoint of CONVERGE and other recent contemporary ablation trials.10,11,42 The 30-second atrial arrhythmia recurrence definition is controversial for its stringency, being outside the limit of detection of many continuous monitoring methods, and the potential to overlook meaningful improvements in symptoms and quality-of-life for patients – particularly those with advanced AF.45 For this reason, AF burden – often defined as the proportion of time a patient is in AF – has been proposed as an appropriate outcome endpoint for persistent and long-standing persistent AF.46 Assessment of AF burden may help shift the overly simplistic perception of AF as a binary disease.47 The CONVERGE trial assessed the reduction of AF burden at 12 months (with 24-hour Holter) and 18 months (with 7-day Holter) following the Hybrid Convergent and catheter ablation procedures. At 12 months, 80% of patients in the Hybrid Convergent arm achieved ≥90% AF burden reduction compared to baseline versus 56.8% of patients in the catheter ablation group (p=0.007).

At 18 months, ≥90% AF burden reduction was seen in 74% of patients in the Hybrid Convergent arm compared to 55% in the catheter ablation group (p=0.0395). These results attest to the durability of the Hybrid Convergent procedure compared to endocardial ablation.

Other Studies Comparing Hybrid Ablation to Endocardial Ablation

CONVERGE is the only randomised study of hybrid convergent ablation compared to endocardial ablation in persistent and long-standing persistent AF. However, other retrospective analyses that compared hybrid convergent ablation to endocardial catheter ablation have been published (Table 1). Contemporary published experience with similar approach to convergent ablation is consistent with that of CONVERGE, where improved rhythm outcomes were observed with the hybrid convergent procedure compared to endocardial ablation. Kress et al. reported outcomes of patients who received hybrid convergent ablation (using a previous generation unipolar RF catheter for epicardial ablation) compared to endocardial ablation, using propensity-score matching to balance the two groups of 40 patients each.43 Significantly improved rates of arrhythmia recurrence (36.5% versus 57.9%; p=0.013) and freedom from AF (72% versus 51%; p=0.01) at 16 months were achieved in the hybrid convergent group compared to endocardial ablation group, respectively.

In a more recent study, Maclean et al. compared outcomes of 43 patients with exclusively long-standing persistent AF who received hybrid convergent procedure with 43 propensity-matched patients who received endocardial catheter ablation during the same time period between 2013 and 2018.44 At 12 months, AF-free survival was 60.5% with hybrid convergent ablation versus 25.6% (p=0.002) after a single-procedure. Off AADs, 12-month AF-free survival rates were significantly higher in the hybrid convergent group at 37.2% compared to 13.9% (p=0.025) in the endocardial ablation group. The study by Kress et al. did not find a significant difference in procedural complications between groups before matching, while Maclean et al. found a higher overall complication rate in the hybrid convergent group compared to catheter ablation.43,44 Other differences in the studies were that Maclean et al. performed staged hybrid procedures and used exclusively endocardial RF, whereas Kress et

Other studies have also reported on the potential benefit of hybrid epicardial-endocardial ablation on AF burden (Table 2). We evaluated a subgroup of 93 patients at our institution who had continuous monitoring following the convergent procedure.48 These patients had a mean duration of 5.1 years since AF diagnosis with 88% having persistent or long-standing persistent AF. At one year after the post-blanking period, 94% of these patients were free from arrhythmia burden >5%. For those who did have arrhythmia recurrence, their mean burden was <5% with only three patients having higher residual burden. Makati et al. reported residual AF burden in patients with continuous monitoring after the hybrid convergent procedure using cryoballoon for endocardial ablation.49 Of patients with 12–24 months of follow-up post-procedure, 88% had AF

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Hybrid Convergent Procedure for Persistent AF Table 2: AF Burden: Summary of Published Results Larson et al. 202048

Makati et al. 202049

Gersak et al. 201650

Patients with continuous monitoring (n)

92

84

76

Persistent/long-standing persistent AF

88%

100%

95%

Follow-up time

12 months

12–24 months

12 months, 24 months

Residual AF burden

Mean 2.8%

Mean 8.5%

Median 0.1% (12 months), 0.4% (24 months)

≤10% AF burden ≤5% AF burden

82% (12 months), 73% (24 months) 94%

88%

≤3% AF burden

75% (12 months), 70% (24 months)

≤1% AF burden

80%

≤0.5% AF burden

69% (12 months), 66% (24 months) 62% (12 months), 62% (24 months)

burden of ≤5% and mean residual AF burden was 8.5%. Based on implantable loop recorders, Gersak et al. reported 82% and 73% of patients had ≤10% AF burden at 12 and 24 months after the hybrid convergent, respectively.50 Taken together, these studies show that a consistent, substantial proportion of patients have relatively low residual AF burden, which seems to be durable at least 1 year after the hybrid convergent procedure. For patients with advanced AF, consideration of residual arrhythmia burden and change from baseline is important in addition to conventional freedom from arrhythmia recurrence endpoints.

Long-standing Persistent AF

As mentioned above, CONVERGE included 42% long-standing persistent AF patients. This population of AF patients has historically been difficult to treat, evidenced by poor long-term results with endocardial catheter ablation.51 In addition to CONVERGE, other studies have focused on the long-standing persistent AF subgroup. Makati et al. demonstrated favourable outcomes of 70% freedom from atrial arrhythmias at a mean 16.8 months follow-up in a subgroup of 109 patients with long-standing persistent AF.49 Residual AF burden was 7.5% in 57 patients with longstanding persistent AF between 12 and 24 months of follow-up (mean 19.5 months). In 43 patients with long-standing persistent AF, Maclean et al. reported 57.1% of patients with long-standing persistent AF were free from all arrhythmias at a mean 30.5 months from the hybrid convergent procedure, taking into account redo procedures.44

should not be overlooked or undervalued, particularly in advanced AF treatment. There are several quality-of-life assessment tools, some of which are general, such as the Short Form 36 health survey and others that are specific to AF, such as the Atrial Fibrillation Effect on Quality of Life questionnaire and the Atrial Fibrillation Severity Scale.58–60 In a single centre retrospective analysis, Tonks et al. reported the majority of patients at their centre who underwent the convergent procedure reported reduced AF episode severity and frequency after the procedure, which resulted in significant improvements in quality of life.56 The CONVERGE clinical trial included quality-of-life assessments at baseline and follow-up as secondary endpoints and these outcomes will be a focus of future analyses.41

Conclusion

Cumulative evidence on hybrid convergent procedures, including retrospective analyses and the CONVERGE randomised clinical trial, have shown that the hybrid convergent procedure achieves favourable clinical outcomes in patients with persistent and long-standing persistent AF. These clinical outcomes are improved when compared to similar patients treated with endocardial ablation alone. The impact of hybrid convergent ablation on quality-of-life and additive benefit of LAA exclusion have been preliminarily assessed and are of interest for future studies.

Future Perspective

Another well-recognised site of non-PV triggers that may be important in persistent forms of AF is the LAA.52,53 The BELIEF trial showed an improvement in recurrence-free survival in patients with long-standing persistent AF who received empirical LAA electrical isolation in addition to extensive endocardial ablation compared to those who received extensive endocardial ablation alone.52 This suggests that electrical isolation of the LAA may have a beneficial effect on rhythm outcomes. One caveat of catheter-based electrical isolation is the potential to create LAA contractile dysfunction, which raises concern of potential thrombus formation in the LAA and potential need for continued anticoagulation.52 Epicardial LAA exclusion with a clip device offers electrical isolation as well as mechanical exclusion of the LAA.54 To this end, some investigators have reported the technical approach and outcomes of patients who received both convergent procedure and LAA clip exclusion.37,55–57 Future comparison studies are warranted to evaluate the potential benefit of LAA exclusion in conjunction with hybrid convergent ablation.

While reducing or eliminating atrial arrhythmia recurrence are often the primary endpoints of AF clinical trials, quality-of-life is an endpoint that

Clinical Perspective

• There is a treatment gap for patients with advanced AF, particularly long-standing persistent AF.

• The left atrial posterior wall is a potential target for ablation in

drug-refractory persistent and long-standing persistent AF because it is a site of AF triggers and substrate as AF progresses.

• The hybrid convergent procedure was developed as a minimally invasive approach to effectively isolate the posterior wall and pulmonary veins using combined epicardial and endocardial ablation.

• The prospective, randomised clinical trial, CONVERGE, demonstrated superior effectiveness of hybrid convergent ablation to endocardial ablation in persistent and long-standing persistent AF, and favourable clinical outcomes with hybrid convergent procedures have also been reported in retrospective studies.

• The success of this hybrid approach hinges on the collaboration between electrophysiology and cardiothoracic surgery.

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31. Lee JM, Shim J, Park J, et al. The electrical isolation of the left atrial posterior wall in catheter ablation of persistent atrial fibrillation. JACC Clin Electrophysiol 2019;5:1253–61. https://doi.org/10.1016/j.jacep.2019.08.021; PMID: 31753429.

32. Lim TW, Koay CH, See VA, et al. Single-ring posterior left atrial (box) isolation results in a different mode of recurrence compared with wide antral pulmonary vein isolation on long-term follow-up: longer atrial fibrillation-free survival time but similar survival time free of any atrial arrhythmia. Circ Arrhythm Electrophysiol 2012;5:968–77. https://doi.org/10.1161/CIRCEP.111.970293; PMID: 22972873.

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Electrophysiology and Ablation

Impact of Catheter Ablation on Stroke, Cognitive Decline and Dementia Tyson S Burnham , Monte L Scott , Benjamin A Steinberg , Daniel L Varela , Brian Zenger

and T Jared Bunch

Department of Medicine, School of Medicine, University of Utah, Salt Lake City, Utah, US

Abstract

AF has been consistently associated with multiple forms of dementia, including idiopathic dementia. Outcomes after catheter ablation for AF are favourable and patients experience a better quality of life, arrhythmia-free survival, and lower rates of hospitalisation compared to patients treated with antiarrhythmic drugs. Catheter ablation is consistently associated with lower rates of stroke compared to AF management without ablation in large national and healthcare system databases. Multiple observational trials have shown that catheter ablation is also associated with a lower risk of cognitive decline, dementia and improved cognitive testing that can be explained through a variety of pathways. Long-term, adequately powered, randomised trials are required to define the role of catheter ablation in the management of AF as a means to lower the risk of cognitive decline, stroke and dementia.

Keywords

AF, stroke, dementia, anticoagulants, catheter ablation Disclosure: BAS reports research support from the National Heart, Lung, and Blood Institute of the National Institutes of Health (#K23HL143156), AltaThera, Abbott, Boston Scientific and Janssen; and consulting to Janssen, AltaThera and Merit Medical. BZ reports research support from the National Heart, Lung, and Blood Institute of the National Institutes of Health (#F30HL149327). TJB reports research grants from Boehringer Ingelheim, Boston Scientific and Altathera. All other authors have no conflicts of interest to declare.

Received: 19 July 2021 Accepted: 19 August 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(3):205–10. DOI: https://doi.org/10.15420/aer.2021.42 Correspondence: T Jared Bunch, University of Utah School of Medicine, Department of Internal Medicine, Division of Cardiovascular Medicine, 30 North 1900 East, Room 4A100, Salt Lake City, UT 84132, US. E: jared.bunch@hsc.utah.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.

AF is the most common sustained arrhythmia, both clinically and worldwide, with a lifetime incidence estimated at ~20%.1,2 The total number of cases of AF in the US is expected to exceed 2.5 million by the year 2030 and 7.5 million by 2050.3,4 Furthermore, AF carries significant morbidity and is one of the leading causes for hospitalisation in the US, with annual AF admissions exceeding 450,000 cases per year since 2010.3,4 In developed countries, common neurological diseases – including dementia – are increasingly prevalent and account for a significant burden on society.5 Population longevity and ageing are leading contributors to this trend.6 These adverse associations are compounded in patients with AF, which drives morbidity and mortality in patients with neurological diseases.7 Recent studies have begun to explore the concept of cerebrovascular reserve and risk of idiopathic dementia, such as Alzheimer’s disease.8 This concept of microvascular disease as a chronic cause of cerebral vascular hypoperfusion begins to link the brain more broadly to vascular health. Similarly, AF is also a manifestation of both macro- and micro-vessel disease that result in elevated filling pressures, left atrial enlargement and atrial arrhythmias.

As a consequence of patients living longer following AF diagnosis, the detrimental impact of this arrhythmia and its treatments can be seen in long-term end organ dysfunction, including cerebral pathology. AF has a clinical association with a broad spectrum of central nervous system pathology, including clinical and subclinical strokes, clinical and subclinical bleeds, repetitive microbleeds, cerebral hypotension/hypoperfusion,

atrophy and volume loss, grey matter changes and amyloid plaques.9 It is critical to identify the underlying mechanisms of these associations and continue to explore focused treatment approaches for AF and its comorbidities that may benefit cerebral function chronically.

AF and Dementia

The association between AF and dementia is multifactorial and can present both in the acute setting following a stroke and in the chronic setting due to progressive cognitive impairment or multiple repeated injuries. Acutely, AF can precipitate stroke in the setting of the arrhythmia and conversion to normal sinus rhythm. This has been traditionally the most feared complication of AF, as these strokes are associated with significant morbidity and mortality.10,11 However, it is not uncommon in clinical practice for patients to describe cognitive dysfunction or ‘brain fog’ as a symptom of AF. These symptoms tend to reverse or improve with restoration of sinus rhythm. One of the limitations of historic research in AF has been the general application of symptoms to all patients with AF. Elderly patients at risk for cognitive decline and dementia may not report concerns of dyspnoea or palpitations when climbing stairs, but instead report difficulty in concentrating or processing when in AF. In a study from the Utah My Evaluation programme, younger patients were much more likely to correctly identify their AF and associate them with traditional cardiac symptoms.12 We have also recently found that symptoms of middle- and late-onset depression in patients with AF may be an early sign of dementia and also contribute to disease mismanagement that can increase dementia risk.13

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Impact of Catheter Ablation on Stroke, Cognitive Decline and Dementia Multiple possible mechanistic pathways have been proposed to explain this spectrum of acute and chronic brain injury manifestations, such as micro- and macro-embolic events, micro- and macro-haemorrhagic events, haemodynamic changes related to perfusion and/or pulsatility, atrioventricular asynchrony causing arterial hypotension and capillary hypertension, poor cerebrovascular reserve, and extra- and intra-cranial vascular disease that impacts adaptation, among others.9,14–18 One pathway of particular interest involves embolic and haemorrhagic states that are associated with AF. Classically, AF has been associated with micro and macro-embolic events felt to originate from left atrial thrombus formation in the setting of AF. The timing and development of these ischaemic events and the underlying mechanisms remain controversial; in part due to the lack of consistent temporal association between arrhythmia onset and stroke events.19–21 Nonetheless, the mainstay of AF treatment remains chronic anticoagulation to lower the risk of ischaemic stroke, although this therapy also can cause micro and macro-haemorrhagic events. These thrombotic and haemorrhagic events do not always present acutely or in a clinical manner, but instead they may lead to progressive cognitive impairment (subclinical and clinical), cerebral dysfunction and volume loss over time.9 In this pathway, the timing, use, agent selection and efficacy of anticoagulation are critical.

Brain ischaemic injury, whether clinical or subclinical, does not account for all the increased risk of cognitive decline and dementia in patients with AF.22 Nor can it account for the abrupt cognitive symptoms many experience with AF onset. An alternative pathway relates to the haemodynamics during AF when compared to haemodynamic measurements in normal sinus rhythm and may explain the abrupt onset of cognitive decline that seems immediately reversible with reversion to sinus rhythm. A study performed by Saglietto et al. showed that haemodynamic stability and hypoperfusion episodes are often described in AF.18 This vascular dysfunction reflects varied R-R intervals and atrioventricular asynchrony causing repetitive hypoperfusion at the arteriolar level and hypertension at the capillary level.

This vascular dysfunction reflects varied R-R intervals and atrioventricular asynchrony leading to repetitive hypoperfusion at the arteriolar level and hypertension at the capillary level. Cerebral perfusion imaging of patients with AF identify perfusion deficits globally compared to sinus rhythm, but in particular the inferotemporal regions that are critical in memory and recall.18 Cerebral hypoperfusion has been shown to be associated with the presence and severity of white matter lesions and as these lesions increase or progress cognitive dysfunction risk increases.23 As the risk factors for vascular disease increase, vascular disease is diagnosed, or systemic health worsens, both men and women with AF have increased risk of dementia.24 Patients with carotid arterial disease have an increased risk of stroke and dementia and have been reported to be the most likely to benefit with an aggressive rhythm control approach to lower these risks compared to those patients without carotid arterial disease.25

Restoring Sinus Rhythm to Lower Stroke Risk in Patients with AF

If AF is associated with stroke risk, then it seems plausible that treatment of the abnormal rhythm would lower stroke rates. However, randomised controlled trials of rhythm versus rate control (AFFIRM and AF-CHF) failed to show a reduction in stroke risk in those treated with antiarrhythmic drug therapy.26,27 The lack of benefit was explained in part by

discontinuation of anticoagulation, which occurred more often in the rhythm control group, as well as lack of efficacy of antiarrhythmic drug therapy. The latter explanation was supported by a subanalysis of the AFFIRM trial that found that patients who maintained sinus rhythm had lower stroke rates compared to those who did not.28 Recently, the EAST-AFNET 4 trial, published in 2020, randomised 2,789 patients within 1 year of AF diagnosis to either early rhythm control or standard treatments prioritizing rate control. Differing from historical studies, this study demonstrated a lower risk of adverse cardiovascular outcomes in the early rhythm control arm, including stroke.29 Compared to AFFIRM, EAST-AFNET 4 only included patients with recently diagnosed AF (<12 months) and a high adherence to anticoagulation in both arms of >90% throughout the study follow-up duration.

Similarly, the ATHENA trial randomised 4,628 participants to receive either the antiarrhythmic drug dronedarone or a placebo.30 This study demonstrated reduced cardiovascular hospitalisations and deaths in AF patients who were successfully rhythm controlled. The ATHENA trial included patients that were relatively healthy – or earlier in the AF disease history – with a mean CHADS2 score of 2. In a subanalysis of this study, dronedarone reduced the risk of stroke from 1.8% per year to 1.2% per year (HR 0.66; p=0.027).31 Taken together, these studies strongly support the use of medical rhythm control, on a background of strong adjunctive medical therapy (e.g. anticoagulation and blood pressure control) to improve neurological outcomes among patients with AF.

Catheter Ablation of AF to Lower Stroke Risk

Large population-based observational trials have found that AF ablation is associated with lower long-term stroke rates and mortality compared to medical therapy for AF alone. In a study of the Intermountain Healthcare registry, 4,212 consecutive patients who underwent their first AF ablation and had at least 3 years of follow-up and compared them 1:4 to 16,848 age- and sex- matched controls with AF (no ablation) and 16,848 age- and sex- matched controls without AF.32 In patients with AF with no ablation, there was a significant increased risk of stroke/cerebrovascular accident at 1- and 3-year follow-up (OR 2.12; p<0.0001 and OR 1.90; p<0.0001, respectively) compared to those patients with AF who underwent an ablation. In patients with AF who underwent an ablation there were no significant differences at 1- and 3-year follow-up (OR 0.94; p=0.68 and OR 0.86; p=0.21, respectively) compared to patients without AF. In those AF ablation patients in this registry without any observed recurrence of AF, the stroke rates were very low at 1.0% at 1 year and 1.7% at 3 years in a population with an average age of 65 years in which 6% had a prior stroke, 45% had hypertension, 21% had diabetes and 24% had heart failure. In this study, anticoagulation use was strongly advocated over the first year after ablation, but information regarding long-term use was not available.

Using the same database, outcomes were assessed in high-risk patients with AF for recurrent stroke that had a prior history of stroke. The 5-year risk of stroke (HR 2.26; p<0.0001) and death (HR 2.43; p<0.0001) were higher in the AF with no ablation group compared to those that were ablated. AF ablation patients compared to no AF patients experienced similar 5-year risks of stroke (HR 0.82; p=0.39) and death (HR 0.92; p=0.70) despite higher heart failure risk (HR 3.08; p=0.001).33 Other large observational studies have demonstrated similar findings. In a study of 361,913 patients with a diagnosis of AF in the Swedish Patient

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Impact of Catheter Ablation on Stroke, Cognitive Decline and Dementia Figure 1: Potential Mechanisms Leading to Decreased Risks of Stroke, Dementia and Cognitive Decline After Catheter Ablation

Ablation patients • More likely to be adherent to medications and risk factor treatments/modifications • Feel better → more active • More follow-up appointments

• Procedure ↑ the likelihood of maintenance of sinus rhythm compared to antiarrhythmic drugs • With arrhythmia recurrences: – Lower burden compared to medications – Lower risk of progression from paroxysmal to persistent/longstanding persistent AF – Less adverse atrial remodelling

↓Ischaemic injury Observational studies – risk of stroke is similar to patients without AF

May reduce need for long-term anticoagulation (low risk, low–moderate risk, ?moderate risk)

↑Cerebral perfusion

Sinus rhythm minimises periods of arteriolar hypotension/capillary hypertension

Extra- or intra-cranial vascular disease that ↓compensation may augment risk of organ dysfunction in AF

registry, catheter ablation was associated with lower risk of stroke (HR 0.69) and mortality (HR 0.50) compared to patients with AF that did not receive an ablation.34 In an institutional propensity-score-matched study of 3,953 (83.4% patients with a CHA2DS2-VASc score of ≥2), a reduction in stroke/transient ischaemic attack rate was observed in the ablation group compared to a non-ablated group (HR 0.61) and remained so after adjustment for the baseline CHA2DS2-VASc score.35 In a multicentre registry of 1,273 patients, freedom from AF was associated with strokefree survival (HR 0.30). Also, the rates of stroke and death were significantly lower in this registry cohort (0.5%/patient-year each) compared with AF patient treated medically in the Euro Heart Survey (2.8% and 5.3%, respectively; p<0.0001).36

risk-related comorbidities and understanding their severity is dynamic and should ideally be tailored in each setting to lower risk of cognitive decline.

For example, using common lab measurements of health, such as the complete blood count and basic metabolic profile, an augmented intelligence tool can stratify risk of dementia in both men and women in addition to that assigned historically by the CHA2DS2-VASc scoring system into low, medium and high risk.24 Consideration of this tool used here as an example, and others that may emerge, is important as we explore therapeutics which may alter risk – something that cannot be accomplished with static or regression scores, such as CHA2DS2-VASc.

These studies strongly suggest interventional approaches to rhythm control (e.g. catheter ablation) are associated with improved neurological outcomes compared with medical therapy, despite a short-term increased risk of stroke associated with such procedures.

Catheter ablation is a more efficacious and durable approach to AF compared to antiarrhythmic drugs.41 Recent trial evidence supports its use early in the disease course of AF to improve long-term outcomes and lower risk of arrhythmic recurrences and AF burden.42,43 Catheter ablation, in comparison to antiarrhythmic medications, is a more effective modality and may reduce the risk of brain dysfunction/cognitive impairment in the following studies described below. There are several mechanistic pathways in which ablation may improve or preserve brain health (Figure 1).

Restoring Sinus Rhythm to Lower Risk of Cognitive Decline and Dementia in Patients with AF

Several studies have examined the impact of rhythm versus rate control on metrics of brain perfusion and/or cognition.37–40 In a study of 44 patients with AF who underwent cardioversion, restoration of sinus rhythm improved brain perfusion and cerebral blood flow.40 In another study that examined the role of rhythm and cerebral perfusion, perfusion was less in patients in AF compared to sinus rhythm, but also worse in those with persistent AF compared to paroxysmal.39 In a retrospective analysis of 272 patients that compared a rhythm control strategy versus rate control with anticoagulation, a rhythm-control strategy was associated with a lower risk of cognitive impairment as measured by cognitive performance testing.38 Personalised medicine for patients with AF may identify risk of cognitive decline and dementia beyond traditional risk scores, which provide relatively poor predictive accuracy.24 This idea of more personalised treatment plans for AF in the setting of cognitive function is explained by the multiple variabilities between patients, including drug–drug interactions, ageing, genetics and medicine adherence. Controlling these

Catheter Ablation of AF To Lower Risk of Cognitive Impairment/Dementia

Multiple large-volume epidemiological studies have shown benefit on brain function with AF ablation. Using the Korean National Health Insurance database, a 2020 nationwide cohort study identified 194,928 adults with AF treated with either catheter ablation or pharmacotherapy either using antiarrhythmic or rate-control drugs. They selected 9,119 patients undergoing ablation and 17,978 patients managed with medical therapy to follow for a median course of 52 months. When compared to the medical therapy group, those patients treated with catheter ablation showed lower risks and overall incidence of dementia (8.1 versus 5.6 per 1,000 person/years).44 This benefit persisted with censoring for prevalent and incident stroke.

In the previously described population-based study of 4,212 AF patients treated with ablation matched 1:4:4 with patients with a history of AF who did not receive a catheter ablation and population without AF, long-term general and Alzheimer’s dementia rates were similar in the patients with

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Impact of Catheter Ablation on Stroke, Cognitive Decline and Dementia Table 1: Observational Data Evaluating the Influence of Catheter Ablation and Risk of Cognitive Decline and Dementia Study

Population

Results

Conclusions

Kim at al. 2020

194,928 adults with AF 9,119 managed with ablation 17,978 managed with medical therapy

Lower incidence and overall risk of dementia in patients treated with ablation (HR 0.73; 95% CI [0.58–0.93])

Ablation was associated with decreased dementia risk

Hsieh et al. 202053

787 AF patients treated with ablation 787 AF patients not treated with ablation 770 patients without AF

AF patients treated with ablation had lower incidence of dementia (HR 0.44) and lower rates of AF-related hospitalisation (HR 0.72) than AF patients not treated with ablation

Catheter ablation reduced the risk of dementia and hospitalisation in AF patients compared to AF patients not treated with ablation

Bunch et al. 201132

4,212 AF patients receiving first ablation 16,848 AF patients not treated with ablation 16,848 patients without AF

5-year risk of stroke (HR 2.26; p<0.0001) higher in the AF without ablation group compared those with ablation. No significant difference in 5-year risk of CVA for AF with ablation and no-AF (HR 0.82; p=0.39). Alzheimer’s dementia occurred in 0.2% of the AF ablation patients compared to 0.9% of the AF without ablation patients and 0.5% of the no AF patients (p<0.0001). Other forms of dementia occurred in 0.4% of the AF ablation patients compared to 1.9% of the AF without ablation patients and 0.7% of the no AF patients (p<0.0001)

Risk of stroke, dementia, and Alzheimer’s disease in patients with AF after catheter ablation were similar to patients without AF and better than patients with AF not treated with ablation

Jin et al. 201944

308 AF patients treated with ablation 50 AF patients with similar indications but managed medically

Montreal Cognitive Assessment score significantly improved 1 year after radiofrequency catheter ablation in both the overall ablation group (from 24.9 ± 2.9 to 26.4 ± 2.5; p<0.001) and the propensity-matched ablation group (from 25.4 ± 2.4 to 26.5 ± 2.3; p<0.001), but not in the control group (from 25.4 ± 2.5 to 24.8 ± 2.5; p=0.012)

Catheter ablation of AF, at least, does not deteriorate cognitive function, but rather improves the performance on 1-year follow-up neurocognitive tests

Piccini et al. 202054

518 patients who underwent AF ablation

Median changes in the SF-12 physical (3 [25th, 75th percentile: −1, 8] versus 1 [−5, 8]; p=0.026) and mental scores (2 [−3, 9] versus 0 [−4, 5]; p=0.004), EQ-5D (0 [0,2] versus 0 [−0.1, 0.1]; p=0.027) and Karnofsky functional status scores (10 [0–10] versus 0 [0–10]; p=0.001) were more favourable in patients without recurrent AT/AF, which was used as a surrogate for successful ablation

Patients without recurrent AT/AF appear to have greater improvement in functional status but similar QoL as those with recurrent AT/AF after AF ablation

44

AT = atrial tachycardia; CVA = cerebrovascular accident; QoL = quality of life.

AF who underwent ablation and those patients without AF, both of which were better than patients with AF not treated with ablation.32 Data from the large Swedish health database further support these outcomes after ablation. Friberg et al. identified 5,176 ablations performed across 4,728 patients over a 7-year period.34 When compared with AF patients managed without catheter ablation, those receiving ablation had lower incidents of stroke, transient ischaemic attack and death.

Other large trials have largely supported these findings (Table 1), including those that have included more specific cognitive testing. Of these trials, one used serial cognitive testing in 308 patients who underwent ablation compared to 50 patients with AF who did not.45 In this trial, the Montreal Cognitive Assessment (MOCA) score improved in patients who underwent ablation and this improvement was seen when comparing different age groups and AF severity subtypes. Of particular interest, the area of most improvement in the MOCA was in memory/recall, a critical finding when considering the observational studies that report dementia rates are reduced in patients that undergo an ablation.

It should be noted that there is controversy about the mechanisms of ablation impacting dementia risk and if there is true benefit.46,47 This controversy originates from several factors, including selection bias whereby healthier patients are referred for ablation, improved clinical management of comorbidities in patients who receive AF ablation and the recognition that ablated patients receive more frequent follow-up. This possibility is supported in part by a discrepancy in data regarding a

reduction in stroke after ablation between randomised control trials and observational trials.46 In randomised control trials outcomes are similar in regard to stroke compared to discrete differences in observational trials in which ablation patients experience much lower stroke rates. Some of this reflects a randomised trial design in which patients must be selected for the trial and meet an often relatively narrow inclusion criterion. Next, a recent study of 30 patients with AF did not find a preferential benefit in cognitive function in patients with a low AF burden compared to a high burden.47 Given the data we have presented, it would seem that patients who experience a lower AF burden should also have improved cognition.

However, these outcomes were from a relatively short follow-up period of 6 months, a low number of patients were enrolled in study (30 patients total) and the AF burden used for comparison has unclear clinical significance (<0.5% versus >0.5%). Consequently, we view this study as hypothesis-generating and look towards larger studies with longer followup periods to define the role of AF burden on cognitive function. Similarly, the role of catheter ablation as a means to improve long-term brain health and cognitive in patients with AF requires prospective long-term study and any preferential benefit over alternative therapies in a randomised controlled analysis.

Catheter Ablation of AF as a Risk Factor for Cognitive Impairment/Dementia

There are important potential risk factors that may increase risk of brain injury after ablation, many of which reflect ablation approach and subsequent management (Figure 2). Ablation is a destructive therapy that can decrease atrial compliance and function. Atrial functional impairment

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Impact of Catheter Ablation on Stroke, Cognitive Decline and Dementia Figure 2: Potential Mechanisms Leading to Increased Risks of Stroke, Dementia and Cognitive Decline After Catheter Ablation

Procedure-dependent • Excessive scar procedure (ablation or intrinsic) • Atrial noncompliance

• Atrial appendage isolation (intentional and accidental)

Procedure-independent • Long-term adherence to anticoagulation or stroke prevention treatments • Treatment and adherence to treatments of risk factors (sleep apnoea, hypertension, vascular disease, etc.)

• Physical and social activity

• Peri- or post-procedural embolism • Iatrogenic atrial septal defect

can persist years after even a successful ablation.48 Ablation is known to increase the risk of peri-procedural cranial embolic events from clots (e.g., denuded endothelium), char, air, etc. Although left atrial appendage isolation improves arrhythmia free survival, patients remain at an increased risk of stroke that may not be lowered completely with anticoagulation.49,50 An alternative, left atrial appendage occlusion, has been advocated to be used in concert with appendage isolation procedures.51 A challenge with this approach is that these occlusion devices have never lowered embolic/ ischaemic stroke rates compared to warfarin and require long-term study against direct oral anticoagulation.52 Additionally, there remains significant intermediate-term risk for device-related thrombus. Aggressive ablation approaches can cause right and left atrial dyssynchrony and as a consequence haemodynamic function and at times also result in severe bradycardia. Finally, rarely patients can have a persistent septal defect that raises risk of paradoxical embolus. Each of these potential risk factors for augmented risk of cognitive decline and stroke much be considered in all patients and also prompt the need to carefully consider ablation approaches and long-term patient management.

• Atrial dyssynchrony • Sinus node dysfunction/bradycardia

national databases and across broad differences in healthcare utilisations and resources.

Recent observational data, including studies with specific cognitive testing, show that catheter ablation is also associated with a lower risk of cognitive decline and dementia that can be explained through a variety of pathways. Long-term, adequately powered randomised trials are required to define the role of catheter ablation in the management of AF to lower risk of cognitive decline, stroke and dementia.

Conclusion

Outcomes after catheter ablation for AF are favourable and patients experience a better quality of life, arrhythmia-free survival and lower rates of hospitalisation compared to patients treated with antiarrhythmic drugs.

When a patient is managed comprehensively for their AF and its associated comorbidities early in the disease state, then stroke rates also are reduced. In community settings, catheter ablation is consistently associated with lower rates of stroke compared to AF management without ablation in studies derived from large healthcare systems,

Clinical Perspective

• AF has been consistently associated with multiple forms of dementia, including idiopathic dementia.

• Outcomes after catheter ablation for AF are favourable and

patients experience a better quality of life, arrhythmia-free survival and lower rates of hospitalisation compared to patients treated with antiarrhythmic drugs.

• Catheter ablation is consistently associated with lower rates of stroke compared to AF management without ablation in large national and healthcare system databases.

• Multiple observational trials have shown that catheter ablation is also associated with a lower risk of cognitive decline, dementia and improved cognitive testing that can be explained through a variety of pathways.

• Long-term, adequately powered randomised trials are required to define the role of catheter ablation in the management of AF as a means to reduce risk of cognitive decline, stroke and dementia.

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27. Talajic M, Khairy P, Levesque S, et al. Maintenance of sinus rhythm and survival in patients with heart failure and atrial fibrillation. J Am Coll Cardiol 2010;55:1796–802. https://doi. org/10.1016/j.jacc.2010.01.023; PMID: 20413028.

28. Corley SD, Epstein AE, DiMarco JP, et al. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation 2004;109:1509–13. https://doi. org/10.1161/01.CIR.0000121736.16643.11; PMID: 15007003.

29. 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.

30. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation.

N Engl J Med 2009;360:668–78. https://doi.org/10.1056/ NEJMoa0803778; PMID: 19213680.

31. Connolly SJ, Crijns HJ, Torp-Pedersen C, et al. Analysis of stroke in ATHENA: a placebo-controlled, double-blind, parallel-arm trial to assess the efficacy of dronedarone 400 mg BID for the prevention of cardiovascular hospitalization or death from any cause in patients with atrial fibrillation/ atrial flutter. Circulation 2009;120:1174–80. https://doi. org/10.1161/CIRCULATIONAHA.109.875252; PMID: 19752319.

32. Bunch TJ, Crandall BG, Weiss JP, et al. Patients treated with catheter ablation for atrial fibrillation have long-term rates of death, stroke, and dementia similar to patients without atrial fibrillation. J Cardiovasc Electrophysiol 2011;22:839–45. https://doi.org/10.1111/j.1540-8167.2011.02035.x; PMID: 21410581.

33. Bunch TJ, May HT, Bair TL, et al. 5-year impact of catheter ablation for atrial fibrillation in patients with a prior history of stroke. J Cardiovasc Electrophysiol 2017;29:221–6. https:// doi.org/10.1111/jce.13390; PMID: 29131434.

34. Friberg L, Tabrizi F, Englund A. Catheter ablation for atrial fibrillation is associated with lower incidence of stroke and death: data from Swedish health registries. Eur Heart J 2016;37:2478–87. https://doi.org/10.1093/eurheartj/ehw087; PMID: 26984861.

35. Saliba W, Schliamser JE, Lavi I, et al. Catheter ablation of atrial fibrillation is associated with reduced risk of stroke and mortality: a propensity score-matched analysis. Heart Rhythm 2017;14:635–42. https://doi.org/10.1016/j. hrthm.2017.02.001; PMID: 28189823.

36. Hunter RJ, McCready J, Diab I, et al. Maintenance of sinus rhythm with an ablation strategy in patients with atrial fibrillation is associated with a lower risk of stroke and death. Heart 2012;98:48–53. https://doi.org/10.1136/ heartjnl-2011-300720; PMID: 21930724.

37. Gallinoro E, D’Elia S, Prozzo D, et al. Cognitive function and

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atrial fibrillation: from the strength of relationship to the dark side of prevention. Is there a contribution from sinus rhythm restoration and maintenance? Medicina (Kaunas) 2019;55:587. https://doi.org/10.3390/medicina55090587; PMID: 31540311.

38. Damanti S, Pasina L, Cortesi L, et al. Atrial fibrillation: possible influences of rate and rhythm control strategy on cognitive performance. J Am Geriatr Soc 2018;66:2178–82. https://doi.org/10.1111/jgs.15568; PMID: 30281781.

39. Gardarsdottir M, Sigurdsson S, Aspelund T, et al. Atrial fibrillation is associated with decreased total cerebral blood flow and brain perfusion. Europace 2018;20:1252–8. https:// doi.org/10.1093/europace/eux220; PMID: 29016776.

40. Gardarsdottir M, Sigurdsson S, Aspelund T, et al. Improved brain perfusion after electrical cardioversion of atrial fibrillation. Europace 2020;22:530–7. https://doi.org/10.1093/ europace/euz336; PMID: 31860069.

41. Packer DL, Mark DB, Robb RA, et al. Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA 2019;321:1261–74. https://doi.org/10.1001/jama.2019.0693; PMID: 30874766.

42. 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.

43. 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.

44. Kim D, Yang PS, Sung JH, et al. Less dementia after catheter ablation for atrial fibrillation: a nationwide cohort study. Eur Heart J 2020;41:4483–93. https://doi.org/10.1093/eurheartj/ ehaa726; PMID: 33022705.

45. Jin MN, Kim TH, Kang KW, et al. Atrial fibrillation catheter ablation improves 1-year follow-up cognitive function, especially in patients with impaired cognitive function. Circ Arrhythm Electrophysiol 2019;12:e007197. https://doi. org/10.1161/CIRCEP.119.007197.

46. Siontis KC, Ioannidis JPA, Katritsis GD, et al. radiofrequency ablation versus antiarrhythmic drug therapy for atrial fibrillation: meta-analysis of quality of life, morbidity, and mortality. JACC Clin Electrophysiol 2016;2:170–80. https://doi. org/10.1016/j.jacep.2015.10.003; PMID: 29766867.

47. Herm J, Schirdewan A, Koch L, et al. Impact of atrial fibrillation burden on cognitive function after left atrial ablation – results of the MACPAF study. J Clin Neurosci 2020;73:168–72. https://doi.org/10.1016/j.jocn.2019.12.030; PMID: 31992513.

48. Cochet H, Scherr D, Zellerhoff S, et al. Atrial structure and function 5 years after successful ablation for persistent atrial fibrillation: an MRI study. J Cardiovasc Electrophysiol 2014;25:671–9. https://doi.org/10.1111/jce.12449; PMID: 24798070.

49. Di Biase L, Burkhardt JD, Mohanty P, et al. Left atrial appendage: an underrecognized trigger site of atrial fibrillation. Circulation 2010;122:109–18. https://doi. org/10.1161/CIRCULATIONAHA.109.928903; PMID: 20606120.

50. Kim YG, Shim J, Oh SK, Lee KN, Choi JI, Kim YH. Electrical isolation of the left atrial appendage increases the risk of ischemic stroke and transient ischemic attack regardless of postisolation flow velocity. Heart Rhythm 2018;15:1746–53. https://doi.org/10.1016/j.hrthm.2018.09.012; PMID: 30502771.

51. Fink T, Vogler J, Heeger CH, et al. Impact of left atrial appendage closure on LAA thrombus formation and thromboembolism after LAA isolation. JACC Clin Electrophysiol 2020;6:1687–97. https://doi.org/10.1016/j.jacep.2020.07.003; PMID: 33334448.

52. Reddy VY, Doshi SK, Kar S, et al. 5-Year outcomes after left atrial appendage closure: from the PREVAIL and PROTECT AF Trials. J Am Coll Cardiol 2017;70:2964–75. https://doi. org/10.1016/j.jacc.2017.10.021; PMID: 29103847.

53. Hsieh YC, Chen YY, Chien KL, et al. Catheter ablation of atrial fibrillation reduces the risk of dementia and hospitalization during a very long-term follow-up. Int J Cardiol 2020;304:75–81. https://doi.org/10.1016/j. ijcard.2019.12.016; PMID: 31884008.

54. Piccini JP, Todd DM, Massaro T, et al. Changes in quality of life, cognition and functional status following catheter ablation of atrial fibrillation. Heart 2020;106:1919–26. https:// doi.org/10.1136/heartjnl-2020-316612; PMID: 33046527.

Electrophysiology and Ablation

The Use of Electrocardiographic Imaging in Localising the Origin of Arrhythmias During Catheter Ablation of Ventricular Tachycardia Adam J Graham1 and Richard J Schilling

2

1. Barts Heart Centre, St Bartholomew’s Hospital, London, UK; 2. Barts Health NHS Trust, London, UK

Abstract

Non-invasive electrocardiographic imaging (ECGI) is a novel clinical tool for mapping ventricular arrhythmia. Using multiple body surface electrodes to collect unipolar electrograms and conventional medical imaging of the heart, an epicardial shell can be created to display calculated electrograms. This calculation is achieved by solving the inverse problem and allows activation times to be calculated from a single beat. The technology was initially pioneered in the US using an experimental torso-shaped tank. Accuracy from studies in humans has varied. Early data was promising, with more recent work suggesting only moderate accuracy when reproducing cardiac activation. Despite these limitations, the system has been successfully used in pioneering work with non-invasive cardiac radioablation to treat ventricular arrhythmia. This suggests that the resolution may be sufficient for treatment of large target areas. Although untested in a well conducted clinical study it is likely that it would not be accurate enough to guide more discreet radiofrequency ablation.

Keywords

Ventricular tachycardia, electrocardiographic imaging, ablation, mapping Disclosure: RJS receives research grants and advisory fees from Biosense, Abbott, Medtronic and Boston Scientific and is on the Arrhythmia & Electrophysiology Review editorial board; this did not influence peer review. AJG is the holder of an educational grant from Abbot.

Received: 8 June 2021 Accepted: 9 August 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(3):211–7. DOI: https://doi.org/10.15420/aer.2021.27 Correspondence: Richard J Schilling, Cardiology Department, Barts Heart Centre, Barts Health NHS Trust, West Smithfield, London EC1A 7BE, UK. E: richard.schilling@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.

Catheter ablation of ventricular tachycardia (VT) has for many years used the 12-lead ECG as an adjunct to contact mapping to localise the site of origin (SoO) of the arrhythmia. Its widespread use is due to the majority of induced VTs not being haemodynamically tolerated during ablation procedures.1 However, the resolution it offers in delineating the SoO is limited and cannot be used to solely guide ablation. Contact mapping offers accurate localisation and delineation of arrhythmia mechanisms, but is limited by the time taken to collect and process electrograms.2 This has resulted in various ECG algorithms designed to improve the resolution of the ECG and help electrophysiologists localise the SoO.3–5 Despite these attempts, the technology is limited as body surface measurements reflect activation from the whole heart and attempts to localise the exit site of re-entrant circuits in the heart are confounded.6 Furthermore, in interpreting the ECG, correction is not made for the anatomical orientation of the heart within the thorax. This position and orientation is wide ranging in patients with structurally abnormal hearts.7 Therefore in this context it can be used as an adjunct but not as the sole guide to ablation.5

Expedient mapping of ventricular arrhythmia is feasible, as is the capability to non-invasively guide therapy and produce personalised models of cardiac electrical activation.

A solution to the inverse problem of electrocardiography is needed if this is to be achieved. The inverse solution is a mathematical formula that predicts the electrical source based on the recorded electrical signals some distance from it. In the case of body surface mapping used in ECGI, the epicardial activation is the former and the electrical cardiac recordings from the skin the latter. The accuracy of this calculation depends on having a complete recording of the ECG on the skin surface by using multiple electrodes over the whole torso, accurate measurements of the distances from the recording site to the source using imaging, such as CT, which allows such a calculation, and a uniform or at least predictable medium between the two. This final factor is the greatest weakness of body surface mapping because although standardised models of the tissues in the thorax can be built, there is clearly a big individual variation in fat, muscle and lung distribution between the heart and the skin which adds error to the inverse solution calculation.9

Electrocardiographic imaging (ECGI) is an imaging modality developed to address the shortcomings of existing technology, in particular the 12-lead ECG. Body surface unipolar electrograms are used to calculate and display electrograms on a digitised model of the epicardial surface of the heart.6 With reconstruction of the ventricular activation and repolarisation sequences in various cardiac rhythms, it is possible to use a single beat.8

There are a variety of systems that use body surface mapping to map ventricular activation and in this review the term ECGI is used as an umbrella term for technologies that are in principle using similar mathematical constructs to produce ventricular maps.

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ECGI Mapping of Ventricular Tachycardia Figure 1: The Tank–Torso Set-up A

geometry. This capability is of particular interest in the arena of VT ablation given the lack of haemodynamic tolerance in most cases.19

B

Electrocardiographic Imaging Mapping of Ventricular Activation

The first human application of ECGI was a qualitative study in four subjects, assessing sinus rhythm, right bundle branch block (RBBB) and right/left ventricle (RV/LV) pacing. In sinus rhythm, epicardial breakthrough occurred at the RV free wall. Breakthrough in the antero-septal LV consistent with the left anterior fascicle activation was also seen. This activation pattern contrasted to RBBB which was predictably delayed in the RV, with similar LV activation via the left anterior fascicle, as seen in the normal control. Pacing was performed from the RV and LV with earliest activation on ECGI located to within 7–11 mm. The authors also studied repolarisation, finding as expected that repolarisation was static and unaffected by activation time in areas of normal conduction.8 These findings were backed up by another study assessing activation and repolarisation under physiological conditions. Volunteers with normal hearts were studied and the earliest epicardial breakthrough was at the RV apex as expected. Repolarisation was again determined by local properties and independent of activation.20

A: Rods are depicted protruding inwards from the body surface to the epicardial surface of the heart. B: Photograph of the set up with container for the heart seen in the centre with electrode-containing rods seen protruding inwards towards it.

Electrocardiographic Imaging – Initial Validation

Research and development of the technology has been conducted using mainly canine and porcine hearts. The most prominent research was performed by the Rudy research group in the US. Their work resulted in the creation of the most readily available commercial system (CardioInsight™, Medtronic). Reconstruction of ventricular activation using a tank-torso model has been shown to be accurate and capable of differentiating between endocardial and epicardial activation (Figure 1).10,11 Further studies demonstrated the capacity to detect scar and re-entrant circuits.12,13 More contemporary research using the tank torso showed a correlation of 0.68 between actual and reconstructed electrograms during sinus rhythm, right bundle branch block (RBBB) and pacing from different sites. Endocardial sites of activation were elucidated with an accuracy of 9.1 ±0.6 mm. Importantly, this study highlighted blocking artefacts which appear as lines on ECGI maps.14

Ghanem et al. studied the accuracy of ECGI in localising areas of early activation during ventricular pacing using an electrode sock placed on the epicardial surface of the heart during cardiac surgery as a comparator.

Pacing sites were <10 mm away from the ECGI predicted site.21 This pacing data can be compared to another study, exclusively assessing accuracy regarding pacing sites. Accuracy for RV pacing was 7.7 mm and 7.9 mm for LV pacing. The patients all had pacemakers implanted and distances from LV and RV pacing sites to earliest activation on ECGI where analysed.22 Electrograms reconstructed during sinus rhythm in the Ghanem et al. study showed good correlation – mean cross correlation (CC) was 0.89 for RV and 0.67 for LV. Similarly, the T-wave morphology was faithfully reconstructed with CC 0.77 for the LV with worse accuracy for the RV at 0.55. This discrepancy was postulated to be on account of different filling pressures in the RV, which alludes to one of the main confounding factors for this study and those that have succeeded it.

Epicardial sock data and ECGI data were collected at different times. This non-simultaneous data collection has the potential to add significant error. For ECGI’s purported ability to map VT, low amplitude details on the electrograms are seen to be lost on the reconstruction in ECGI, meaning there is likely to be insufficient resolution to map diastolic pathways during VT.21

The tank-torso studies were proceeded by assessment in the ex vivo setting. Using epicardial sock electrodes in the open chest of a dog, good correlation was found between measured and reconstructed electrograms during VT.15 Components of re-entrant VT circuits could be seen, including lines of block. Good correlation was also found in a recent study with a similar set up, with a correlation for activation time of 0.82. Additionally, this study showed that the use of a spatiotemporal algorithm to calculate the earliest site of activation had the potential to improve accuracy.16 Other algorithms have been used to improve the resolution of ECGI with varied results.17 A full commentary on the development of the technology is beyond the scope of this review and the most relevant studies are summarised in Table 1.

Sapp et al. performed the first validation of ECGI using a contact mapping system to collect data from the epicardial surface using a 120-lead system.

Data was collected from VT ablation procedures requiring epicardial access. They showed that the location of epicardial pacing sites was heavily influenced by scarring. Pacing from areas of scar reduced accuracy to 43 mm from a mean for all sites of 13.6 mm. Repolarisation was not assessed but activation time was reconstructed with no quantitative analysis. Activation maps were qualitatively similar, but showed variation including abrupt changes in activation times giving the appearance of lines of block and rapid activation over large areas of myocardium (Figure 3).23 These latter two features have been seen in other studies and have important implications for ECGI’s use in ventricular arrhythmia.8,21,20 Large areas activating simultaneously would affect the accuracy of using the system to locate exit sites for VT. Blocking could falsely allocate areas as zones of slow conduction, hindering the capability to risk stratify patients for arrhythmia or locate VT circuits.

Electrocardiographic Imaging Clinical Set-up in Humans

The workflow for the system is illustrated in Figure 2. Most commonly, a vest consisting of multiple electrodes is attached to the patient’s torso before an imaging scan. This scan can be a cardiac MRI or more frequently a CT scan. In the case of the commercially available system (CardioInsight™, Medtronic) a CT scan is the preferred modality. This is used to create 3D geometry of the heart’s epicardial surface and to localise the body surface electrodes on the torso. Each of these electrodes is radio-opaque and therefore visible, allowing their geometric position in relation to the epicardial surface to be calculated. This data is then used to display reconstructed electrograms using the inverse method.18 One beat of a cardiac rhythm is necessary to produce an activation map on the

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ECGI Mapping of Ventricular Tachycardia Table 1: Compilation of Results Validating Electrocardiographic Imaging Against Contact Data Study

n

EGM Correlation

AT Correlation

RT Correlation

Localisation accuracy (cm)

Type

1

>0.9

NA

NA

<1.0

Torso-tank

Burnes et al. 2001

1

0.9

NA

NA

8.69

Torso-tank

Ghanem et al. 200521

3

0.72 ± 0.25

NA

NA

NA

Human

Cluitman et al. 2017

4

0.71 ± 0.5

0.82

0.73

1.0 (0.7–1.7)

Dog

17

Bear et al. 2018

5

0.69–0.72

0.72–0.78

NA

1.6 (0.9–2.9)

Pig

Bear et al. 201814

8

NA

0.68 ± 0.25

NA

NA

Torso-tank

Bear et al. 2019

3

NA

0.79 ± 0.11

NA

NA

Torso-tank

Oster et al. 199737 12

16

38

AT = activation time; Correlation = median or mean correlation; EGM = electrogram; RT = repolarisation time

Figure 2: The Electrocardiographic Imaging Procedure

Heart-torso geometry Epicardial surface

CT scan

CT images Potentials (mV) ECGI software

Electrodes strips

Electrograms (mV) 250 ECGs

Isochrones (ms) Body surface potentials

Geometric data collected using CT. Algorithms from ECGI software use the geometric and electric data to create maps of electrograms, potentials, repolarisation and activation on the epicardium.

250 electrodes record the body surface electric data. Source: Rudy et al. 2015.36 Reproduced with permission from Elsevier.

A quantitative comparison of ECGI and contact mapping was provided

by Duchateau et al. whose large study of 55 patients demonstrated poor correlation (CC = 0.03) between invasive and non-invasive mapping. Wide inter-patient variability (-0.68–0.82) was found suggesting significant heterogeneity and agreement between maps was poorest in areas of scarred myocardium. As mentioned above, artificial lines of block were present in the majority of ECGI maps providing further evidence of potential limitations to the system’s clinical usefulness.24

pacing sites with an accuracy of 13.2 mm. This value was negatively affected when pacing was from within scar, which was purported to be due to far field capture or activation of surviving myocardial bundles within the scar.25 The large differences in correlation between the findings of these similar studies is difficult to fully account for. The Duchateau et al. study collected contact mapping in a non-simultaneous manner which although it could confound the results, is unlikely to solely account for the heterogeneity. There is evidence that small variations in the alignment of cardiac geometries from two different systems, which is necessary for quantitative comparison, can lead to large variations in correlation. Additionally, most of the data was collected in sinus rhythm thereby using the heart’s intrinsic conduction system and reducing total time for ventricular activation. With ECGI having been shown to be more reliable with a slower ventricular conduction, this could also have contributed to the findings.25

A more recent study, again employing quantitative analysis to compare ECGI to ground truth data collected using contact mapping on the epicardium, found more favourable results. Eight patients were studied with geometries aligned using fiducial anatomical points. The correlation between ground truth contact mapping data and ECGI was 0.71 for the morphology of the unipolar electrograms and 0.66 for activation times.

Results were similar to those in earlier studies for localisation of epicardial

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ECGI Mapping of Ventricular Tachycardia Figure 3: Contact Electroanatomic Mapping of Epicardial Activation msec

Case 3

msec 180

250

160 140

200

120 150

100 80

100

60

Superior

50

Inferior

Superior

40

Inferior

Contact Electroanatomic Epicardial Activation Maps

Inverse Solution Epicardial Isochronal Maps

msec

220

msec

200

130

180

120

Case 4

160

110

140

100

120

90

100

80

80 60

70

40

60

20

Superior

50

Inferior

Superior

Inferior

Isochronal maps (left) and reconstructed ECGI maps (right). Top and bottom rows are from two different patients and from data during right ventricular endocardial pacing. Qualitatively, activation patterns are similar between ECGI and measured data. Lines of block can be seen in the ECGI map that are absent from the measured data. Source: Sapp et al. 2012.23 Reproduced with permission from Wolters Kluwer.

sites of earliest origin on ECGI were qualitatively similar to those of the contact maps. RV sites were correctly reconstructed in 10 out of 11 locations and in the LV in 11 of 12. Discrepancy in these cases was purported to be due to a prior accessory pathway ablation in the rightsided case and due to a large LV aneurysm in the left. The latter circuit was said to have had multiple potential exit sites. Five patients had epicardial exit sites for VT and a pure Q wave was seen on ECGI. For the remainder (excluding RV outflow tract because of its thin wall) 88% had an rS morphology, denoting a mid-myocardial or endocardial origin.

Electrocardiographic Imaging Mapping of Ventricular Arrhythmia

The mapping of VT with contact electroanatomic mapping (EAM) involves invasive procedures associated with a high risk of complications and long procedures. As we know, it is the potential for expedient localisation of VT that makes ECGI a potentially efficacious clinical tool. VT results in a large electrical signal, has a high signal-to-noise ratio and has reduced involvement of the conduction system. Despite this, initial validation of the system suggests that it does not possess sufficient resolution to solely guide ablation.

While this work is important in analysing ECGI’s potential for use in ventricular arrhythmia, it is subject to several limitations. VT was induced and recorded outside of the setting of VT ablation resulting in nonsimultaneous data collection adding an array of confounding variables.

Furthermore, as discussed earlier, the most reliable means of localising a VT site of origin is with entrainment which was not performed in this study.

There was also no mention of measures taken to ensure the VTs recorded preoperatively corresponded to those mapped during ablation procedures. This could have been achieved using a simple 12-lead ECG but was not explicitly stated in the study’s methodology.

The first application of ECGI in humans assessing its reliability in localising VT was performed in a patient with a structurally normal heart. Earliest activation was tracked to the LV apex on both ECG and EAM.26 Another study assessed purely outflow tract (left and right) ventricular arrhythmias and compared ECGI to conventional 12-lead ECG in 24 patients.

Localisation using ECGI was superior with correct localisation of arrhythmia in 96% of patients and the ability to discern between septal and free-wall origin in 100%, and 12-lead performance was significantly worse with 50–88% and 37–58%, respectively.27 These results are perhaps unsurprising given known limitations, with pace mapping leading to errors of up to 2 cm in localisation.28

A more recent study assessed a body surface ECGI system in four patients during VT ablation. ECGI was seen to faithfully recreate the activation sequences of VT when compared to contact mapping data.23 Although this study addressed the limitations posed from non-simultaneous recordings, no quantitative assessment of sites of earliest activation were performed. This was due to a lack of data points from activation mapping and entrainment. A subsequent study which used an inverse method to reconstruct electrograms on the epicardial and endocardial surfaces showed that mapping during VT was qualitatively accurate, but no quantitative comparisons were made.30

Wang et al. studied 25 patients undergoing mapping of VT, with four patients having ECGI performed intraoperatively.29 The remainder had ECGI performed preoperatively. VTs were localised using contact activation mapping strategies, which were subsequently compared to those of ECGI (Figure 4). The majority of the VTs mapped were found to be focal, with ECGI localising arrhythmia to the correct ventricle in all cases.

No quantitative analysis was performed examining location accuracy, but

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ECGI Mapping of Ventricular Tachycardia Figure 4: Electrocardiographic Imaging of Re-entrant Ventricular Tachycardia from Inferobasal Scar RAO

Left lateral

LAO

A SC RA

LAO inferior

LA

LA

RA

LA

B VT

B

V2

B

A

B

RA

LA

AO LAD

RA

AO LAD

RA

LA Scar

C SPECT

LA

RA

NavX

Scar

I

ms 165 150 135 120 105 90 75 60 45

II III aVR aVL aVF V1 V2

ms 166 154 142 130 118 106 94 82 70

V3 V4 V5 V6 I aVF V1 50ms

ABL d ABL HIS

400ms

200ms

0ms

–200ms

–400ms

CS RVa d

A: Sinus rhythm ECGI maps displayed in four views (electrogram seen in blue and labelled A). Arrows are indicative of activation wavefront direction. B: Activation maps during VT (electrogram seen in red and labelled B). Left lateral and LAO views contain white arrows showing a clockwise loop in activation. Propagation into the RV is shown by pink arrows. C: Image on the left shows SPECT images with scar in the inferobasal LV region in blue. Image on the right shows the invasive endocardial map of VT activation with early activation in red and late in blue. The 12-lead surface ECG and intracardiac signals during VT are on the far right. The earliest electrogram is seen on the ablation catheter, which was in the inferobasal LV, 50 ms before onset of the surface QRS. LAO: left anterior oblique; LV = left ventricle; RV = right ventricle; VT = ventricular tachycardia Source: Wang et al. 2011.29 Reproduced with permission from American Association for the Advancement of Science.

Clinical Outcome Studies

A quantitative analysis of the accuracy in mapping VT was performed by Graham et al. VT SoO was localised using validated techniques such as entrainment and pacemapping during catheter ablation procedures.

Haemodynamically stable VT was mapped using entrainment or areas where ablation terminated the rhythm. Unstable VT was mapped using pacemapping. These regions were then marked on the EAM for comparison with ECGI areas of earliest activation. Distances between the SoO of VT and the earliest sites of activation on ECGI was 22.6 mm.

Comparison was also made between ECGI and standard 12 lead, using a validated method for allocating SoO based on 12-lead results which showed ECGI to be significantly more accurate (p<0.05).31 The results of this study, while offering the best available quantitative data on ECGI resolution during VT in humans, is subject to potential errors including far field capture during pacemapping, exit sites being remote from the point of entrainment and error introduced with alignment of geometries.

In a prospective randomised controlled trial of premature ventricular contractions (PVC) ablation, conventional ablation using a 12-lead ECG was compared to an ECGI-guided approach in 21 patients. Clinical parameters for assessment included time to ablation, acute success (termination of PVCs), 3-month success, fluoroscopy time and procedure time. ECGI resulted in more accurate localisation of arrhythmia with 95.2% of arrhythmias correctly located. The 12-lead ECG predicted the correct chamber in 76.2% of cases and identified arrhythmia origin in 38.1%. The time-to-ablation metric was reduced in the ECGI arm but the fluoroscopy times were significantly higher. No difference was seen in outcome at 3 months.32 The increased accuracy of ECGI could result in fewer vascular complications by avoiding unnecessary transeptal puncture as well as improving clinical workflows. However, lack of effect on clinical outcome data could hinder widespread use of the system.

Regarding the mapping of PVCs the capacity of the system to map the entire ventricular activation sequence using one beat of arrhythmia could be used to target infrequent PVCs that are difficult to map in the electrophyiology lab. The body surface electrodes could be worn before a procedure, enabling mapping to be conducted on the ward or even provoked during exercise. This could be of particular use in VF that is triggered ectopically and the system may offer useful insight into the

This latter study demonstrates that the resolution of the system is inadequate to be the sole guide for ablation. The significantly increased resolution offered when compared to the 12-lead ECG is promising, but data demonstrating its clinical efficacy would be needed before the system was put into wider use. Given that VT clinical outcome studies are notoriously difficult to conduct, this may not be forthcoming.

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ECGI Mapping of Ventricular Tachycardia substrate of VF itself. It has been demonstrated that ECGI drivers found during the mapping of VF co-localised to abnormal areas of depolarisation denoted by contact mapping. The targeting of these areas with ablation was an effective treatment for patients with recurrent VF.33

More recent data has suggested that when localising SoO for ventricular tachycardia (VT) it has reasonable accuracy and outperforms the 12-lead ECG. This accuracy is not currently sufficient to solely guide ablation although this could be improved with further research into the algorithms used to reconstruct the electrograms. Further work is also needed to understand the aetiology and impact of artefactual block lines that could hinder clinical application.

The use of ECGI in the clinical context has been extended to its use as an adjunct to non-invasive ablation of VT. VT was targeted non-invasively using single-fraction stereotactic body radiation therapy (SBRT) delivering 25 Gy to the area targeted. Areas were chosen based on non-invasive imaging of anatomy including ECGI. Using this novel technique on five patients, VT burden at 3 months was found to be reduced by 99.9%.34 This study was followed by the prospective Encore VT trial enrolling 19 patients (17 for VT, two for PVC). The median number of VT episodes reduced from 119 to three (p<0.001). Shocks from an implantable cardioverter defibrillator and anti-tachycardia pacing decreased along with a 94% reduction in VT episodes or PVC burden. Survival at 6 months was 89% and 72% at 12 months. There was a significant decrease in the use of antiarrhythmic agents.35 Caution does need to be exercised in interpreting these results.

At 90 days, 10.5% of patients had developed a serious adverse event related to the procedure. The study demonstrates the potential benefit that using ECGI could have for patient outcomes. However, data beyond that collected from a single centre is needed.

Positive clinical outcomes have been demonstrated in non-invasive radiation-based ablation of VT suggesting that the resolution it offers is sufficient when larger areas of myocardium are targeted, although lack of data prohibits any inferences regarding outcomes on guidance of RF ablation. If direct integration with contact mapping systems, where the calculated electrograms could be visualised on the contact mapping geometry, were feasible it could become a useful tool to expedite catheter ablation of VT. This latter point would be especially salient if further progress is made on the resolution of mapping.

Clinical Perspective

• Recent data from human studies comparing electrocardiographic

imaging to electroanatomic mapping suggests the system has moderate accuracy in mapping cardiac activation times.

• This accuracy is sufficient to localise VT for defining large target areas for non-invasive ablation using stereotactic body radiation therapy with excellent outcomes in clinical trials.

• The capacity of the system to map activation times using a single beat may prove useful in haemodynamically non-tolerated VT, but resolution is insufficient to be the sole guide for ablation.

Conclusion

The use of ECGI in the mapping of ventricular arrhythmia is a nascent field, with potential for use in SBRT and ablation of VF. The accuracy of the system’s capacity to reconstruct the ventricular activation sequence during sinus rhythm and pacing has varied across studies with methodological differences perhaps accounting for some of the variability.

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