AER 10.2 by Radcliffe Cardiology

Volume 10 • Issue 2 • Summer 2021

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The 2020 ESC Guidelines on the Diagnosis and Management of Atrial Fibrillation Agnieszka Kotalczyk, Gregory YH Lip and Hugh Calkins

Troubleshooting Programming of Conduction System Pacing Elise Bakelants and Haran Burri

The Subcutaneous ICD: A Review of the UNTOUCHED and PRAETORIAN Trials Ahmadreza Karimianpour, Leah John and Michael R Gold

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Conductive V3 heating V4

Oesophagus

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High-power, short duration radiofrequency ablation

Pre-shaped stylets of Ultralow Cryothermy Ablation System

Electrogram changes during loss of anodal capture

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Volume 10 • Issue 2 • Summer 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

Joseph G Akar

Stanford University Medical Center, CA, US

Editorial Board Yutao Guo

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

Chinese PLA General Hospital, Beijing, China

Charles Antzelevitch

Antwerp University and University Hospital, Antwerp, Belgium

Angelo Auricchio

University of Leipzig, Leipzig, Germany

Lankenau Institute for Medical Research, Pennsylvania, PA, US Fondazione Cardiocentro Ticino, Lugano, Italy

Hein Heidbuchel

Gerhard Hindricks Carsten W Israel

Andrea Natale

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

Mark O’Neill

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

Douglas Packer

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

Carina Blomström-Lundqvist

JW Goethe University, Frankfurt, Germany

Johannes Brachmann

Klinikum Coburg, II Med Klinik, Coburg, Germany

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

IRCCS Policlinico San Donato, Milan, Italy

Josep Brugada

Pierre Jaïs

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

Uppsala University, Uppsala, Sweden

Warren Jackman

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

University of Bordeaux, CHU Bordeaux, France

Pedro Brugada

Northshore University Hospital, New York, NY, US

University of Brussels, UZ-Brussel-VUB, Brussels, Belgium

Alfred Buxton

Beth Israel Deaconess Medical Center, Boston, MA, US

David J Callans

University of Pennsylvania, Philadelphia, PA, US

Roy John

Boyoung Joung

Yonsei University, Seoul, South Korea

Prapa Kanagaratnam

Imperial College Healthcare NHS Trust, London, UK

Josef Kautzner

A John Camm

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Shih-Ann Chen

Hospital Privado del Sur, Bahia Blanca, Argentina

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

KR Julian Chun

Roberto Keegan

Sabine Ernst

Richard Schilling

Barts Health NHS Trust, London, UK

Afzal Sohaib

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

William G Stevenson

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

Joseph E Marine

Royal Brompton & Harefield NHS Foundation Trust, London, UK

Frédéric Sacher

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

Francis E Marchlinski

Asklepios Klinik St Georg, Hamburg, Germany

Harry Crijns Sanjay Dixit

Edward Rowland

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

Vanderbilt School of Medicine, Nashville, TN, US

University of Pennsylvania Health System, Philadelphia, PA, US

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

Sunny S Po

Karl-Heinz Kuck

CardioVascular Center Bethanien, Frankfurt, Germany Maastricht University Medical Center, Maastricht, the Netherlands

Carlo Pappone

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

John M Miller

Indiana University School of Medicine, Indianapolis, IN, US

Fred Morady

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

Richard Sutton Marc A Vos

University Medical Center Utrecht, Utrecht, the Netherlands

Katja Zeppenfeld

Leiden University Medical Center, Leiden, the Netherlands

Douglas P Zipes

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

Volume 10 • Issue 2 • Summer 2021

Official journal of

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Volume 10 • Issue 2 • Summer 2021

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Contents

Foreword Maximising Opportunities Post Coronavirus Disease 2019: Time to Embrace a New Era of Atrial Fibrillation Research Pier D Lambiase https://doi.org/10.15420/aer.2021.29

Clinical Arrhythmias The 2020 ESC Guidelines on the Diagnosis and Management of Atrial Fibrillation Agnieszka Kotalczyk, Gregory YH Lip and Hugh Calkins https://doi.org/10.15420/aer.2021.07

Reconceptualising Atrial Fibrillation Using Renewal Theory: A Novel Approach to the Assessment of Atrial Fibrillation Dynamics Jing Xian Quah Dhani Dharmaprani Anandaroop Lahiri Kathryn Tiver and Anand N Ganesan https://doi.org/10.15420/aer.2020.42

Cardiac Pacing Troubleshooting Programming of Conduction System Pacing Elise Bakelants and Haran Burri https://doi.org/10.15420/aer.2021.16

Fusion Pacing with Biventricular, Left Ventricular-only and Multipoint Pacing in Cardiac Resynchronisation Therapy: Latest Evidence and Strategies for Use Peter H Waddingham Pier Lambiase Amal Muthumala, Edward Rowland and Anthony WC Chow https://doi.org/10.15420/aer.2020.49

Electrophysiology & Ablation The Cutting Edge of Atrial Fibrillation Ablation Maya S Verma, Maria Terricabras and Atul Verma https://doi.org/10.15420/aer.2020.40

The Subcutaneous ICD: A Review of the UNTOUCHED and PRAETORIAN Trials Ahmadreza Karimianpour, Leah John and Michael R Gold https://doi.org/10.15420/aer.2020.47

Drugs & Devices Clinical Utility of Body Surface Potential Mapping in CRT Patients Ksenia Sedova, Kirill Repin, Gleb Donin, Peter Van Dam and Josef Kautzner https://doi.org/10.15420/aer.2021.14

COVID-19 Remote Clinics and Investigations in Arrhythmia Services: What Have We Learnt During Coronavirus Disease 2019? Shohreh Honarbakhsh, Simon Sporton, Christopher Monkhouse, Martin Lowe, Mark J Earley and Ross J Hunter https://doi.org/10.15420/aer.2020.37

Letter to the Editor Comment on ‘Management of Cardiac Sarcoidosis in 2020’ Socrates Korovesis and Eleftherios Giazitzoglou https://doi.org/10.15420/aer.2021.19

Foreword

Maximising Opportunities Post Coronavirus Disease 2019: Time to Embrace a New Era of Atrial Fibrillation Research

Disclosure: PDL is supported by UCL/UCLH Biomedicine NIHR and Barts BRC and discloses research grants and speaker fees from Boston Scientific, Abbott and Medtronic. Citation: Arrhythmia & Electrophysiology Review 2021;10(2):63–4. DOI: https://doi.org/10.15420/aer.2021.29 Correspondence: Pier D Lambiase, Barts Heart Centre, West Smithfield, London EC1A 7BE, UK. E: p.lambiase@ucl.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

n this edition of Arrhythmia & Electrophysiology Review there is a strong emphasis on different aspects of AF care, including the use of remote monitoring accelerated by the coronavirus disease 2019 (COVID-19) pandemic, stroke risk and optimisation of therapy with ablation. Indeed, an elegant mechanistic paper highlights the random nature of AF proposing a novel concept of event analysis.1

However, a fundamental issue in current AF management still revolves around the lack of adequately powered multicentre trials that address key questions pertaining to making real differences to patient outcomes and quality of life. This is not surprising, as high quality randomised controlled trials are expensive along with being extremely difficult to design and execute. These challenges ultimately result in smaller scale technologydriven studies assessing the efficacy of new ablation technologies. Such approaches are manageable in terms of recruitment and have easily tractable outcomes, such as proof of pulmonary isolation on repeat electrophysiology study or reduction in overall AF burden. CABANA is the most ambitious AF trial to date. However, to trial purists it ultimately remains inconclusive as endpoints were changed during the study and the per assigned protocol analysis failed to show benefit of ablation over medical therapy for the combined composite endpoint.2 About halfway into the CABANA trial, the death/stroke/bleeding/cardiac arrest composite secondary endpoint was elevated to become the primary endpoint when it became clear that the initial enrolment target of 3,000 patients would not be achieved and the number of deaths would not be large enough to draw reliable conclusions. The original primary endpoint – all-cause mortality – became a secondary endpoint. The resulting patient treatment received data were positive but the trial suffers from the risk of bias, leading to on-going debate in the field.

CASTLE AF yielded highly positive results for the efficacy of AF ablation in heart failure, reducing mortality and hospitalisations, but this has not lead to a dramatic increase in clinical uptake.3,4 This is mainly because there remains considerable scepticism among physicians in the heart failure community since the majority of heart failure patients they see would not have been eligible for the trial, which focused on patients with implanted devices who failed anti-arrhythmic therapy. Even recruitment involved an 8:1 screening to enrolment ratio. Similarly, the RAFT-AF trial recently reported at the 2021 American College of Cardiology meeting failed to reach its primary endpoint of mortality and heart failure hospitalisation comparing ablation to rate control, mainly because it was underpowered to show a significant difference.5 This leaves the field at a crossroads in progressing ablation therapies for AF in a meaningful direction for patients and to convince health economists and governments regarding the utility of ablation – especially in persistent AF. This must ultimately be determined by patient selection and trial design with adequate sample sizes to detect meaningful differences in quality of life, hospitalisations and mortality. Furthermore, the concept of 30 seconds of AF representing a failure of therapy is a very high bar to reach and raises the question as to whether reduction in AF burden is a more realistic endpoint to evaluate.6 Until now the majority of AF research has focused on technological developments and novel mapping strategies to identify ‘rotors’ or other sites of organised activity with positive results that have not translated at scale. This is most likely because of a combination of initial positive reporting bias and very careful case selection in single-centre studies. In order to solve these challenges, wider clinical trial enrolment and follow-up requires the implementation of more electronic-data-driven strategies to collect outcomes at scale and draw meaningful conclusions for patients. In many ways, the pandemic has opened up the pathways to achieve this, with the necessary embracement of remote monitoring and electronic data collection now routinely employed in clinical care.7 With the availability of linked electronic health records in some countries, such as the UK through the NHS, one can track all hospital and medical encounters. Coupled with wearable devices, mobile phone apps, pacemakers/ICDs and loop recorders, one has the tools to truly track outcomes of interventions at scale and recruit real-world patients in interventional studies This revolution in the mindset of clinicians should provide the foundation for much smarter trial designs recruiting patients at scale and digital data capture with minimal human effort.

Maximising Opportunities Post COVID-19: A New Era of AF Research Indeed, this infrastructure provides the opportunity to undertake cluster randomisation studies at scale where patients can be allocated one treatment in one geographical/hospital group and an alternative in another, switching after 6 months to 1 year.8 This would enable recruitment of patients at scale and give statistically robust data. Such an approach has been employed in primary care to optimise AF management.9 Similarly, adaptive trial designs would mean that once one arm of a trial demonstrates futility, the arm could be changed accordingly whilst continuing to recruit new patients. This high throughput study design strategy was employed extremely effectively in the RECOVERY trial during the pandemic, discovering the utility of dexamethasone and proving the non-efficacy of chloroquine, lopinavir-ritonavir and colchicine.10 Such trial designs would lend themselves easily to specific drug or ablation strategies in AF. Therefore, the revolution in using remote data for clinical care and wearable technologies necessitated by the pandemic has given rise to new opportunities for data-driven research strategies and trial design. This should lead the way to execute clinical trials at scale with data collection integrated into usual care to provide a robust evidence base for AF treatment in the next decade. Pier D Lambiase Section Editor, Arrhythmia Risk Stratification, Arrhythmia & Electrophysiology Review Institute of Cardiovascular Science, University College London, London, UK; Barts Heart Centre, West Smithfield, London, UK 1. Quah JX, Dharmaprani D, Lahiri A, et al. Reconceptualising atrial fibrillation using renewal theory: a novel approach to the assessment of atrial fibrillation dynamics. Arrhythm Electrophysiol Rev 2021;10:78–85. https://doi.org/10.15420/aer.2020.42. 2. 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. 3. Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 2018;378:417–27. https://doi.org/10.1056/ NEJMoa1707855; PMID: 29385358. 4. Noseworthy PA, Van Houten HK, Gersh BJ, et al.

Generalizability of the CASTLE-AF trial: catheter ablation for patients with atrial fibrillation and heart failure in routine practice. Heart Rhythm 2020;17:1057–65. https://doi.org/10.1016/j.hrthm.2020.02.030; PMID: 32145348. 5. American College of Cardiology. RAFT-AF: Rhythm and rate control similar for death, HF progression in patients with AFib and HF. 17 May 2021. https://www.acc.org/ latest-in-cardiology/articles/2021/05/12/19/40/mon1045am-raft-af-acc-2021 (accessed 14 June 2021). 6. Wechselberger S, Kronborg M, Huo Y, et al. Continuous monitoring after atrial fibrillation ablation: the LINQ AF study. Europace 2018;20:f312–20. https://doi.org/10.1093/ europace/euy038; PMID: 29688326. 7. van den Dries CJ, van Doorn S, Rutten FH, et al. Integrated management of atrial fibrillation in primary

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

care: results of the ALL-IN cluster randomized trial. Eur Heart J 2020;41:2836–44. https://doi.org/10.1093/ eurheartj/ehaa055; PMID: 32112556. 8. Ajmera Y, Singhal S, Dwivedi SN, Dey AB. The changing perspective of clinical trial designs. Perspect Clin Res 2021;12:66–71. https://doi.org/10.4103/picr.PICR_138_20; PMID: 34012901. 9. Guo Y, Guo J, Shi X, et al. Mobile health technologysupported atrial fibrillation screening and integrated care: a report from the mAFA-II trial Long-term Extension Cohort. Eur J Intern Med 2020;82:105–11. https://doi. org/10.1016/j.ejim.2020.09.024; PMID: 33067121. 10. University of Oxford. RECOVERY. Azithromycin results. Oxford: University of Oxford, 14 December 2020. https:// www.recoverytrial.net/results/azithromycin-results (accessed 14 June 2021).

Clinical Arrhythmias

The 2020 ESC Guidelines on the Diagnosis and Management of Atrial Fibrillation Agnieszka Kotalczyk,1,2 Gregory YH Lip1,2,3 and Hugh Calkins4 1. Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, UK; 2. Department of Cardiology, Congenital Heart Diseases and Electrotherapy, Medical University of Silesia, Silesian Centre for Heart Diseases, Zabrze, Poland; 3. Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 4. Electrophysiology Laboratory and Arrhythmia Service, Johns Hopkins Hospital, Baltimore, MD, US

Keywords

AF, European Society of Cardiology, guidelines, management, screening, stroke prevention Disclosure: GYHL is a consultant and speaker for BMS-Pfizer, Boehringer Ingelheim and Daiichi Sankyo; no fees are received personally. GYHL and HC are section editors on the Arrhythmia & Electrophysiology Review editorial board. AK has no conflicts of interest to declare. Received: 10 February 2021 Accepted: 12 February 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(2):65–7. DOI: https://doi.org/10.15420/aer.2021.07 Correspondence: Gregory YH Lip, Liverpool Centre for Cardiovascular Science, Institute of Life Course & Medical Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby St, Liverpool L7 8TX, UK. E: gregory.lip@liverpool.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

AF has major clinical implications on patients’ quality of life, morbidity with ischaemic stroke and heart failure, and mortality when compared with the general population.1 AF is the most common sustained arrhythmia and it has been calculated that it will affect 17.9 million adults in the EU and the UK by 2060.2 The increasing prevalence of AF is driven mainly by the ageing population and the high burden of risk factors and comorbidities, which raises significant issues about the use of healthcare systems and economic costs.2–4

significant opportunities for the detection and diagnosis of AF and may be used for long-term AF screening, especially in high-risk cohorts.10 However, the diagnosis of clinical AF needs to be confirmed and documented by a conventional 12-lead ECG tracing or rhythm strip showing a typical AF pattern for ≥30 seconds. Nonetheless, a gap in data exists which raises the question of the management of patients with shorter AF duration (<30 seconds) or atrial high-rate episodes, without a ‘proper’ AF diagnosis.

The 2020 European Society of Cardiology (ESC) Clinical Practice Guidelines for AF summarise and evaluate the available evidence from 1,492 references to provide an overview of contemporary AF diagnosis, management and research.3 Given the complexity of AF and its poorly understood mechanisms, the management of AF patients requires a holistic, multidisciplinary approach, including individual assessment, patient preferences and active involvement in decision-making. The guidelines introduce a novel, simplified, holistic approach to care for patients with AF (Figure 1), incorporating screening, diagnosis and treatment for effective, integrated management.3 These AF guidelines should consider the clinical evaluation and the choice of the best treatment strategies for each individual patient with AF.3

A novel pathophysiology-based characterisation of AF patients to use in daily clinical practice has been proposed in the new guidelines, summed up as the 4S-AF scheme with the four Ss being: stroke risk, symptom severity, severity of AF burden and substrate for AF.11 This structured model was proposed to support daily decision-making regarding the use of oral anticoagulation (OAC), rate or rhythm control strategy (AF ablation or antiarrhythmic drug) and the treatment of concomitant comorbidities and risk factors. It may also provide prognostic information, improving further AF management and research.3,11

Characterisation of AF

Treatment of AF

The management of AF patients can be streamlined based on the AF Better Care (ABC) pathway:

To accompany the guidelines, the ESC published quality indicators (17 main and 17 secondary indicators from six domains of care) to help improve and allow comparisons of the overall quality of care among AF patients at various levels, by looking at data at patient, centre or international level.3,5

• A: Avoid stroke with anticoagulation; • B: Better symptom management with patient-centred, symptom-

directed decisions on rate or rhythm control; • C: Comorbidity and cardiovascular risk factor management, including lifestyle optimisation.12

Detection of AF

In recent years, substantial progress has been made in detecting AF, including asymptomatic AF. Increasing data on the identification and monitoring of AF are available for the use of wearable technology or implantable loop recorders to detect and record AF episodes.6–9 Novel tools and technologies for digital ECG analysis, in the form of wearables, machine learning and artificial intelligence, have brought potentially

In numerous studies, the use of a strategy that is compliant with the ABC pathway improved the outcomes for AF patients by reducing the rates of rehospitalisation, cardiovascular events and all-cause mortality.13,14 Longterm adherence and persistence with an app-based ABC pathway intervention has been demonstrated.15

2020 ESC Guidelines on the Diagnosis and Management of AF Figure 1: Management of Patients with AF Based on the 2020 ESC Guidelines3 AF screening • Opportunistic AF screening by taking the pulse of patients aged ≥65 years • New screening devices: smartphones, wristbands, watches • CIEDs interrogation for AHRE

Detect

Clinical AF lasting >30 s • Conventional 12-lead ECG tracing • Single-lead ECG tracing

Confirm

A: Avoid stroke • Optimal stroke prevention • Identify low-risk patients • Dynamic assessment of the risk of stroke and bleeding • Good quality anticoagulation (NOAC or VKA)

Treat: ABC pathway

4S-AF Scheme • Stroke risk • Symptom severity • Severity of AF burden • Substrate severity

Characterise

B: Better symptom control

C: Comorbidities and risk factors

• Decision based on patient's symptoms and preferences • Rate control strategy • Rhythm control strategy

• Hypertension, heart failure, diabetes, chronic kidney disease, sleep apnoea • Lifestyle changes: exercises, smoking cessation, reduction of obesity and alcohol intake

Treat: ABC pathway

AHRE = atrial high-rate episode; CIEDs = cardiac implantable electronic devices; ECG = electrocardiogram; NOAC = non-vitamin K antagonist; VKA = vitamin K antagonist.

A: Avoid Stroke with Anticoagulation

recently diagnosed.22,23 Indeed, improvements in existing ablation techniques and tools have increased the efficacy and safety of catheter AF ablation. One recent trial showed that an early rhythm control strategy (associated with an optimised structured package of care) reduced the composite endpoint of cardiovascular-related death, stroke or hospitalisation in patients with newly diagnosed AF.23

Effective stroke prevention with OAC is the cornerstone of the management of patients with AF and it reduces the risk of stroke and death.12 Treatment options include vitamin K antagonists (VKA) and nonVKA OACs (NOACs), whereby the NOACs are preferred.3,16,17 Maintaining a good quality of anticoagulation if VKAs are used and using label-adherent NOAC dosing is crucial. Of note, a subset of patients at high risk of stroke and bleeding have been under-represented or excluded from the randomised control trials on NOACs and special care in selecting an OAC is needed for these patients or left atrial appendage occlusion may be considered.18

C: Comorbidity and Cardiovascular Risk Management

Modifiable risk factors, such as weight loss, regular physical activity, smoking cessation, reducing alcohol and caffeine intake and diet modification, are often related to lifestyle choices. Subsequently, treatment of specific cardiovascular risks, such as hypertension, heart failure and coronary artery disease, and non-cardiovascular conditions, such as chronic kidney disease, diabetes and sleep apnoea, may reduce AF-related mortality and morbidity.3 Overall, strict control of risk factors, avoidance of AF triggers and treatment of underlying conditions complements stroke prevention and improves clinical outcomes by reducing AF burden or symptom severity.3

Optimal stroke assessment and prevention requires a regular reassessment of stroke and bleeding risk, which is influenced by ageing or comorbidities.19,20 Risk re-evaluation should be performed within 4 to 6 months after the first visit among AF patients with a low risk of stroke (CHA2DS2-VASc = 0 in men or 1 in women). Likewise, bleeding risk is highly dynamic and a high bleeding risk score (e.g. HAS-BLED ≥3) is not a reason for withholding OAC, but these patients should have proactive management of modifiable bleeding risk factors with scheduled early follow-up and review.3,19,21

The new ESC guidelines emphasise the relevance of a tailored, holistic treatment strategy, based on the individual risk assessment and patient preferences. Shared decision-making requires educating and empowering patients by encouraging active involvement in the therapeutic process using in-depth discussion with patients and an explanation of the benefits and risks of available treatment strategies. The choice of optimal management strategy still remains a challenge, especially among AF patients at the highest risk of stroke and bleeding and requires further research.

B: Better Symptom Control

Rate control allows AF to persist with well-controlled ventricular rates whereas rhythm control strategy involves the restoration of sinus rhythm using ablation, cardioversion or anti-arrhythmic drugs to mitigate AF symptoms and improve quality of life.3 Rhythm control may improve overall clinical outcomes compared with rate control in selected patient groups, for example those with heart failure or where AF has been

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

2020 ESC Guidelines on the Diagnosis and Management of AF 1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a global burden of disease 2010 study. Circulation 2014;129:837–47. https://doi. org/10.1161/CIRCULATIONAHA.113.005119; PMID: 24345399. 2. Krijthe BP, Kunst A, Benjamin EJ, et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur Heart J 2013;34:2746–51. https://doi.org/10.1093/eurheartj/eht280; PMID: 23900699. 3. 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– 98. https://doi.org/10.1093/eurheartj/ehaa612; PMID: 32860505. 4. Burdett P, Lip GYH. Atrial fibrillation in the United Kingdom: predicting costs of an emerging epidemic recognising and forecasting the cost drivers of atrial fibrillation-related costs. Eur Hear J Qual Care Clin Outcomes 2020. https://doi. org/10.1093/ehjqcco/qcaa093; PMID: 33346822; epub ahead of press. 5. Arbelo E, Aktaa S, Bollmann A, et al. Quality indicators for the care and outcomes of adults with atrial fibrillation. Europace 2020. https://doi.org/10.1093/europace/euaa253; PMID: 32860039; epub ahead of press. 6. Perez MV, Mahaffey KW, Hedlin H, et al. Large-scale assessment of a smartwatch to identify atrial fibrillation. N Engl J Med 2019;381:1909–17. https://doi.org/10.1056/ NEJMoa1901183; PMID: 31722151. 7. Turakhia MP, Desai M, Hedlin H, et al. Rationale and design of a large-scale, app-based study to identify cardiac arrhythmias using a smartwatch: the Apple Heart Study. Am Heart J 2019;207:66–75. https://doi.org/10.1016/j. ahj.2018.09.002; PMID: 30392584. 8. Guo Y, Wang H, Zhang H, et al. Mobile photoplethysmographic technology to detect atrial fibrillation. J Am Coll Cardiol 2019;74:2365–75. https://doi. org/10.1016/j.jacc.2019.08.019; PMID: 31487545.

9. Giada F, Gulizia M, Francese M, et al. Recurrent unexplained palpitations (RUP) study. Comparison of implantable loop recorder versus conventional diagnostic strategy. J Am Coll Cardiol 2007;49:1951–6. https://doi.org/10.1016/j. jacc.2007.02.036; PMID: 17498580. 10. Guo Y, Wang H, Zhang H, et al. Population-based screening or targeted screening based on initial clinical risk assessment for atrial fibrillation: a report from the Huawei Heart Study. J Clin Med 2020;9:1493. https://doi.org/10.3390/ jcm9051493; PMID: 32429241. 11. Potpara TS, Lip GYH, Blomstrom-Lundqvist C, et al. The 4S-AF scheme (stroke risk; symptoms; severity of burden; substrate): a novel approach to in-depth characterization (rather than classification) of atrial fibrillation. Thromb Haemost 2021;121:270–8. https://doi. org/10.1055/s-0040-1716408; PMID: 32838473. 12. Lip GYH. The ABC pathway: an integrated approach to improve AF management. Nat Rev Cardiol 2017;14:627–8. https://doi.org/10.1038/nrcardio.2017.153; PMID: 28960189. 13. Yoon M, Yang PS, Jang E, et al. Improved population-based clinical outcomes of patients with atrial fibrillation by compliance with the simple ABC (atrial fibrillation better care) pathway for integrated care management: a nationwide cohort study. Thromb Haemost 2019;19:1695– 703. https://doi.org/10.1055/s-0039-1693516; PMID: 31266082. 14. Guo Y, Lane DA, Wang L, et al. Mobile health technology to improve care for patients with atrial fibrillation. J Am Coll Cardiol 2020;75:1523–34. https://doi.org/10.1016/j. jacc.2020.01.052; PMID: 32241367. 15. Guo Y, Guo J, Shi X, et al. Mobile health technologysupported atrial fibrillation screening and integrated care: a report from the mAFA-II trial long-term extension cohort. Eur J Intern Med 2020;82:105–11. https://doi.org/10.1016/j. ejim.2020.09.024; PMID: 33067121. 16. Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel

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

report. Chest 2018;154:1121–201. https://doi.org/10.1016/j. chest.2018.07.040; PMID: 30144419. 17. Lip GYH, Freedman B, de Caterina R, Potpara TS. Stroke prevention in atrial fibrillation: past, present and future comparing the guidelines and practical decision-making. Thromb Haemost 2017;117:1230–9. https://doi.org/10.1160/ TH16-11-0876; PMID: 28597905. 18. Kotalczyk A, Mazurek M, Kalarus Z, et al. Stroke prevention strategies in high-risk patients with atrial fibrillation. Nat Rev Cardiol 2021;18:276–90. https://doi.org/10.1038/s41569-02000459-3; PMID: 33110242. 19. Chao TF, Lip GYH, Lin YJ, et al. Incident risk factors and major bleeding in patients with atrial fibrillation treated with oral anticoagulants: a comparison of baseline, follow-up and delta HAS-BLED scores with an approach focused on modifiable bleeding risk factors. Thromb Haemost 2018;118:768–77. https://doi.org/10.1055/s-0038-1636534; PMID: 29510426. 20. Chao TF, Lip GYH, Liu CJ, et al. Relationship of aging and incident comorbidities to stroke risk in patients with atrial fibrillation. J Am Coll Cardiol 2018;71:122–32. https://doi. org/10.1016/j.jacc.2017.10.085; PMID: 29325634. 21. Guo Y, Lane DA, Chen Y, Lip GYH. Regular bleeding risk assessment associated with reduction in bleeding outcomes: the mAFA-II randomized trial. Am J Med 2020;133:1195–202.e2. https://doi.org/10.1016/j. amjmed.2020.03.019; PMID: 32289310. 22. Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 2018;378:417–27. https://doi.org/10.1056/NEJMoa1707855; PMID: 29385358. 23. 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.

Clinical Arrhythmias

Impact of the Pattern of Atrial Fibrillation on Stroke Risk and Mortality Giovanni Luca Botto , Giovanni Tortora, Maria Carla Casale, Fabio Lorenzo Canevese and Francesco Angelo Maria Brasca Department of Cardiology – Electrophysiology, ASST Rhodense, Civile Hospital Rho and Salvini Hospital Garbagnate Milanese Hospital, Milan, Italy

Abstract

Thromboembolism is the most serious complication of AF, and oral anticoagulation is the mainstay therapy. Current guidelines place all AF types together in terms of anticoagulation with the major determinants being associated comorbidities translated into risk marker. Among patients in large clinical trials, those with non-paroxysmal AF appear to be at higher risk of stroke than those with paroxysmal AF. Higher complexity of the AF pattern is also associated with higher risk of mortality. Moreover, continuous monitoring of AF through cardiac implantable devices provided us with the concept of ‘AF burden’. Usually, the larger the AF burden, the higher the risk of stroke; however, the relationship is not well characterised with respect to the threshold value above which the risk increases. The picture is more complex than it appears: AF and underlying disorders must act synergically respecting the magnitude of its own characteristics, which are the amount of time a patient stays in AF and the severity of associated comorbidities.

Keywords

AF, AF type, stroke, thromboembolism, mortality, atrial high-rate episode, subclinical AF Disclosure: The authors have no conflicts of interest to declare. Received: 12 January 2021 Accepted: 15 March 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(2):68–76. DOI: https://doi.org/10.15420.aer.2021.01 Correspondence: Giovanni Luca Botto, ASST Rhodense, Ospedale Policlinico di Rho, UO Cardiologia – Elettrofisiologia, Corso Europa 250, 20017 Rho, Milan, Italy. E: gbotto@asst-rhodense.it 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.

variable follow-up, mainly depending upon age, underlying heart disease, and concurrent treatments.12

AF is the most common sustained arrhythmia encountered in clinical practice; the current estimated prevalence of AF in adults is 2–4%,1 and a steady increase is expected due to extended longevity in the general population and intensifying search for undiagnosed AF.2 It is estimated that the number of patients with AF will double over the next 40 years.3

Based on clinical presentation, available anamnestic data on AF duration, and spontaneous termination, different types of AF have been described, regardless of the presence/absence of symptoms (Table 1).9

AF is associated with substantial morbidity and mortality, thus posing significant burden to patients, the healthcare system, and the healthcare economy. One of the most serious complications of AF is thromboembolism, in particular stroke, which exists regardless of the presence or absence of symptoms.4,5 The risk of thromboembolism correlates with increases in CHADS2 and CHA2DS2-VASc scores.6–8

In the general population, permanent (PRM) AF is reported as the most frequent form of diagnosed AF.12 In the REALIZE-AF Registry, a contemporary, large-scale, international survey of patients with AF who had one or more episodes in the past year, 2,606 of 9,816 patients (26.5%) had paroxysmal (PRX), 2,341 (23.8%) had persistent (PRS) and 4,869 (49.6%) had PRM AF.13

The temporal pattern expressed as the type of AF, has shown conflicting results in consideration of its impact on the risk of thromboembolism and major outcome. Therefore, the current risk scoring systems do not include the pattern of AF and current practice guidelines make identical recommendations for anticoagulation in patients at moderate or high risk, regardless of the type of AF.9–11

The figure provided under the present classification is unfortunately incomplete in view of AF episodes that are often asymptomatic and because it depends on AF detection by ECG recording, which also depends on the variable intensity of ECG monitoring.

Device-detected Atrial Arrhythmias

The aim of the present paper is to critically review data from literature with the purpose of understanding the relationship between the temporal pattern of AF on the risk of thromboembolic events or mortality.

Unlike ambulatory ECG monitoring tools, cardiac implantable electronic devices (CIEDs) capable of detecting atrial signals provide full-time continuous monitoring of individual atrial arrhythmias that can be stored by the device through auto-triggered alerts. A full array of diagnostic information is available, including date and time of onset, duration, and atrial arrhythmia cycle length, as well as day-level AF. Because many ICDs implanted for the prevention of sudden death are single-ventricular-

Classification of Clinical AF

AF is a progressive disorder, and the transition from intermittent to continuous form of arrhythmia may occur in up to 25% of patients at

Pattern of AF and Major Outcomes Table 1: Patterns of AF and Relative Abbreviations AF Pattern

Definition

Comment

First diagnosed AF

AF that has not been diagnosed before, irrespective of the duration of the arrhythmia or the presence and severity of AF-related symptoms

The form diagnosed at the first clinical presentation of AF, irrespective of severity of symptoms, or the arrhythmia duration

Paroxysmal AF

Self-terminating, in most cases within 48 h. Some AF paroxysms may continue for up to 7 days. AF episodes that are cardioverted within 7 days should be considered paroxysmal

The classification extends the duration of the single AF episode up to 7 days, but the probability of spontaneous conversion to sinus rhythm is low after 48 h

Persistent AF

AF that lasts longer than 7 days, including episodes that are terminated The form of AF that persists beyond 7 days or requires active termination by cardioversion, either with drugs or by direct current cardioversion, for sinus rhythm restoration after 7 days or more

Long-standing persistent AF Continuous AF lasting for ≥1 year when it is decided to adopt a rhythm control strategy

A form of AF lasting for ≥12 months, when the adoption of a rhythm control strategy is required

Permanent AF

A form of AF for which cardioversion is not attempted since the arrhythmia is accepted by the patient and physician. Permanent AF represents a therapeutic attitude rather than an inherent pathophysiological attribute of AF, and the term should not be used in the context of a rhythm control strategy with antiarrhythmic drug therapy or AF ablation

AF that is accepted by the patient (and physician). Hence, rhythm control interventions are, by definition, not pursued in patients with permanent AF. Should a rhythm control strategy be adopted, the arrhythmia would be re-classified as ‘long-standing persistent AF’

Source: Kirchhof et al. 2016.9 Used with permission from Oxford University Press.

chamber devices, newer technologies have emerged to also allow for AF detection based on irregularity of R-R cycle length detected with conventional ventricular leads.14 Implantable loop recorders, which also mainly rely on R-R intervals for arrhythmia detection, have lower sensitivity and specificity for AF identification than CIEDs with an atrial lead.15

attributed to the arrhythmia have, in fact, a relatively low positive predictive value for AF.22 Subclinical AT/AF episodes are common in patients implanted with CIEDs: the reported incidence varies from 25% to 50% with the design of the study (retrospective/prospective), the underlying heart disease (SND, atrioventricular block, or heart failure [HF]), the presence/absence of history of clinically overt atrial arrhythmias, the definition of AHRE duration, type of device detecting the atrial arrhythmias, and the observation period.23–28

The definitions of device-detected atrial arrhythmias are shown in Table 2.16 Atrial high-rate episodes (AHRE) correspond to all atrial tachycardias (AT) above a predefined atrial rate threshold.17 Several technical issues are involved in the process of detecting and recording AHRE, including atrial sensitivity, and the programming of atrial rate and episode duration cutoffs, with some variability according to the device manufacturer, and the ability of storing AHRE electrograms.

In the ASSERT study, subclinical ATs with at least 6-minute duration were detected in approximately 25% of patients, during a follow-up of 2.5 years, and about 16% of those who had subclinical ATs developed a clinical AF.28 The capability of continuous monitoring of AF through CIEDs has led to the concept of ‘AF burden’, which is defined as the overall time spent in AF that an individual has in each day (daily AF burden) in a specific follow-up period, adopting it to describe the dynamic pattern of AF, not only in term of presence, but also in terms of duration of AF episodes.20,29–31

Caution is needed in interpreting device-detected AHREs and considering them as a surrogate for AF. False detection can occur because of myopotentials or other sources of electrical interference, far-field R wave over-sensing by the atrial lead or sustained runs of premature atrial complexes. Therefore, validation of the arrhythmia detected through device diagnostics is indicated by reviewing electrograms stored in the device’s memory to rule out artefacts and confirm the diagnosis of AT/AF.

The measurement of total AF burden includes asymptomatic as well as symptomatic episodes. This is important since the ratio of asymptomatic/ symptomatic episodes is about 12:1 in patients with symptomatic PRX AF, and the assessment of symptomatic burden alone would greatly underestimate the total burden.32 The advantage of using burden over other endpoints is that it is not subject to investigator bias. The sampling error introduced by relying on patient symptoms or episodic monitoring is eliminated. Unfortunately, literature on AF burden is sparse simply because continuous monitoring would be required to capture this information.

AF can be missed if episodes of AF are very brief or slow. Therefore, diagnostic accuracy becomes reliable when episodes ≥5–6 minutes in duration are considered, because, with this cutoff, the appropriateness in AF detection is 95%, minimising the risk of over-sensing.18 In a subanalysis of the ASSERT study, 17.3% of AHREs at >190 BPM that lasted ≥6 minutes were found to be false-positive for AF.19 Patients with CIEDs are at particularly high risk for AF, likely related to the high prevalence of underlying cardiac pathology, such as sinus node dysfunction (SND) and cardiomyopathies, which can predispose to AF.20

Risk of Stroke in Different AF Pattern and Type

The relationship between the AF pattern and the risk of stroke, regardless the CHADS2 and CHA2DS2-VASc scores, is currently a matter of huge discussion. The analysis of the relationship between AF pattern and outcomes is complicated by the evidence that the patient profile of PRX AF is different from the other types, because they are generally younger, with a lower prevalence of structural heart disease, and other comorbidities (HF, chronic kidney disease, chronic obstructive pulmonary

The diagnostic capabilities of CIEDs can detect AF episodes of sustained duration (>48 hours) much more frequently than conventional follow-up with ECG, and those episodes may be completely asymptomatic and unpredictable.21 Moreover, patients may experience both symptomatic and asymptomatic episodes of AF, of variable duration, and the symptoms

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Pattern of AF and Major Outcomes Table 2: Definition Related to Device-detected Atrial Arrhythmia and Relative Abbreviations Type of Arrhythmia

Definition

Atrial high-rate event

Atrial high-rate episodes are defined as atrial tachyarrhythmia episodes with rate >190 BPM detected by cardiac implantable electronic devices

Subclinical AF

Atrial high-rate episodes (>6 min and <24 h) with lack of correlated symptoms in patients with cardiac implantable electronic devices, detected with continuous ECG monitoring (intracardiac) and without prior diagnosis (ECG or Holter monitoring) of AF

Silent or asymptomatic AF

Documented AF in the absence of any symptoms or prior diagnosis often presenting with a complication related to AF (e.g. stroke, heart failure, etc.)

Source: Gorenek et al. 2017.16 Used with permission from Oxford University Press.

disease, peripheral vascular disease), as well as lower estimated thromboembolic and bleeding risks.33

In the RE-LY study, the stroke rates were lower in PRX versus PRS AF (1.32% versus 1.55%), but no formal adjusted comparisons were made, and patients with PRX AF tended to have lower CHADS2 scores.40

The above-considered factors, as well as the proportion of patients appropriately treated with antithrombotic therapy, may act as relevant confounders, thus making the assessment of the causal relationship problematic.

Older data on patients in the SPORTIF III and V trials (randomised to either VKA or ximelagatran) demonstrated an annual stroke/SE rate of 1.73% for PRS AF and 0.93% for PRX AF (HR 1.87; 95% CI [1.04–3.36]; p=0.037).41 However, in patients with two or more risk factors for stroke, the PRX AF pattern was not associated with significantly lower stroke risk, suggesting that at the higher level of the risk spectrum, clinical risk factors play a much important role than AF pattern.

Randomised Clinical Trials on Oral Antithrombotic Agents

Antiplatelet therapy plays no more role in preventing stroke in AF; however, a brief re-examination of studies involving antiplatelet therapy can shed some light on the relationship between AF pattern and stroke in patients who are not assuming oral anticoagulants (OAC).9 An analysis from the ACTIVE-A and AVERROES databases suggests that the pattern of AF is related to stroke risk in patients who were unsuitable for vitamin K antagonists (VKA). In a population of 6,563 aspirin-treated patients, the yearly ischaemic stroke rates were 2.1%, 3.0%, and 4.2% for PRX, PRS, and PRM AF, respectively, with an adjusted HR of 1.83 (p<0.001) PRM versus PRX AF and 1.44 (p=0.02) PRS versus PRX AF.34 Multivariable analysis identified age ≥75 years, sex, history of stroke or transient ischaemic attack (TIA), and AF pattern as independent predictors of stroke, with a PRM AF pattern being the second strongest predictor after prior stroke/TIA.

All those data have been collected in a large meta-analysis focusing on the efficacy and safety of OACs in 70,447 AF patients (78.7% non-PRX). Compared to PRS or PRM AF, the incidence of stroke/SE was lower in PRX AF patients (HR 0.79; 95% CI [0.71–0.88]; p<0.00001). Interestingly, annualised major bleeding rates were similar across AF types (HR 1.06; 95% CI [0.96–1.17]; p=0.22). The absence of an association with bleeding events supports the hypothesis that the association of non-PRX with thromboembolism might be a specific effect attributable to AF pattern.42 However, these studies suffer a major limitation of having included posthoc analyses of trials done for other purposes than to assess the pure role of AF type in predicting major outcomes.

Conversely, other randomised controlled trials (RCTs) have not confirmed the finding. The SPAF trial demonstrated similar annualised rate of ischaemic stroke in aspirin-treated patients with intermittent (3.2%) or sustained (3.3%) form of AF, and, similarly, the ACTIVE-W trial, demonstrated a comparable risk of ischaemic stroke or systemic embolism (SE) in patients treated with aspirin plus clopidogrel with PRX or sustained form of AF (HR 0.94; p=0.755).35,36 These studies might be comparatively underpowered in a population not treated with OAC, that might be potentially less representative of contemporary practice outcome.

The annualised rate of stroke or SE in major RCTs on antithrombotic therapy in different temporal pattern of AF is depicted in Figure 1.

Real-life Data from AF Registries and Population-based Studies

Data from AF registries and population-based studies are also heterogeneous, reflecting the complexity in risk adjustment between AF pattern and therapy, most of all, rate of OACs, which are confounders in evaluating the relationship between AF pattern and the risk of thromboembolism. It is well known that patient characteristics differ significantly by AF type. PRM AF carries a trend toward higher-risk features compared to non-PRM AF, as well as PRS AF compared to PRX AF, which makes any rigorous adjustment difficult for all population-based studies.13

Large RCTs on OACs have offered the opportunity to revisit the role of AF pattern in predicting thromboembolic events in the direct oral anticoagulant era. Some post-hoc analyses of RCTs on direct oral anticoagulants reported that the risk of stroke/SE is lower in patients with PRX AF compared with a non-PRX (mainly PRS) AF.

Some observational registries reported that patients with PRX AF have a risk of stroke/SEEs comparable to patients with non-PRX AF. In the prospective Euro Heart Survey that enrolled 5,333 AF patients, followed for 1 year, PRX AF had comparable risk for thromboembolic events as PRS and PRM AF (PRX 22/1170 – 1.9%; PRS 11/886 – 1.2%; PRM 19/1126 – 1.6%).43 Also, in the Loire Valley AF Project, the rates of stroke differed significantly by pattern of AF; however, clinical factors, not AF pattern, independently increased the risk of stroke in multivariate analyses.44 On the basis of this finding, the authors concluded that the choice for antithrombotic therapy should be based on clinical risk factors, not on AF pattern.

Post-hoc analyses of ROCKET-AF, ARISTOTLE and ENGAGE-AF have shown significantly lower stroke rates for patients with PRX AF at enrolment than for those with PRS AF, even after adjustment for baseline characteristics (ARISTOTLE: HR 0.70; 95% CI [0.51–0.93]; p=0.0159; ROCKET-AF: HR 0.79; 95% CI [0.63–1.0]; p=0.0481; and ENGAGE-AF: HR 0.79; 95% CI [0.66– 0.96]; p=0.0151).37–39

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Pattern of AF and Major Outcomes Figure 1: Rate per Patient/Year of Stroke or Systemic Embolism in Major Randomised Clinical Trials on Antithrombotic Therapy in Different Temporal Pattern of AF 4.5

<0.001 4.2

4 NS 3.5 3

Rate per patient/year

3.2

3.3

NS 3 0.048

2.4

2.5 2.1 2

0.015

2.18

0.037

0.04

1.73

1.55

1.5

1.73

1.52

1.32

1.95

1.49

0.98

0.93

1.83

0.003

0.5 0

ACTIVE-A AVERROES

SPAF

ACTIVE-W SPORTIF III-V non-OAC Paroxysmal Persistent

RE-LY

ROCKET-AF

ARISTOTLE

ENGAGE-AF

Permanent

SPAF trial, comparison between intermittent (paroxysmal and persistent) and permanent atrial fibrillation. ACTIVE-W trial and ARISTOTLE trials, comparison between paroxysmal and non-paroxysmal (persistent and permanent) AF. ACTIVE-W, presentation of results only related to the clopidogrel plus aspirin arm (non-anticoagulant arm). RE-LY, presentation of results only related to the lower dose (110 mg twice daily) arm. Source: Vanassche et al. 2015,34 Hart et al. 2000,35 Hohnloser et al. 2007,36 Steinberg et al. 2015,37 Al-Khatib et al. 2013,38 Link et al. 2017,39 Flaker et al. 201240 and Lip et al. 2008.41

The Chinese AF Registry, involving a total of 8,529 AF patients, concluded that AF type was not an independent predictor of thromboembolism. In non-anticoagulated patients, the PRS AF group demonstrated a higher risk of stroke/SE, compared to the PRX AF group, while no significant difference was found in anticoagulated subjects. On multivariate analysis in non-anticoagulated patients, age ≥75 years (p=0.046) and prior stroke/ TIA (p=0.018) but not AF type were significantly associated with the risk of stroke/SE.45

In this context of uncertainty, it may be interesting to consider the results of systematic reviews and meta-analysis of all the studies that have compared PRX and non-PRX AFs regarding the occurrence of thromboembolic events, although the heterogeneity of study design, type of treatment, and evaluation of outcomes in the various studies suggest caution in the interpretation. The incidence of thromboembolism and bleeding were analysed in a systematic review of indexed publications of RCTs, cohort studies, and case series reporting collected clinical outcomes stratified by AF type. Data from nearly 100,000 patients indicated that non-PRX AF is associated with a highly significant increase in thromboembolism with multivariable adjusted HR 1.38 (95% CI [1.19–1.61]); p<0.001, compared with PRX AF, while again rates of bleeding were similar, with adjusted HR 1.025 (95% CI [0.89–1.17]); p=0.715.49

The same result has provided by the analysis of 29,181 patients enrolled in the observational GARFIELD-AF, where a multivariable Cox regression was used to assess the risks of stroke/SE across patterns of AF, and whether this changed with anticoagulation on outcomes.46 Median CHA2DS2-VASc score was similar across AF patterns. During a 2-year follow-up, after adjustment, non-PRX AF patterns were associated with significantly higher rates of stroke/SE, than PRX AF in non-anticoagulated patients only. No difference remained in anticoagulated patients in nonPRX compared with PRX AF patterns.46 The latter two studies demonstrated that AF pattern is no longer prognostic for thromboembolic events when patients are treated with anticoagulants.

This meta-analysis suggests that patients with PRX AF have a lower risk of stroke than those with non-PRX AF, but it remains unclear if AF pattern is an independent predictor of stroke or rather a reflection of a different patient profile in terms of risk factors and comorbidities.

Device-detected AF Duration and Risk of Stroke

Conversely, the observational Fushimi AF Registry found that PRX AF was associated with a significantly lower risk of stroke/SE than non-PRX forms even after adjusting for a series of potential confounders, including oral anticoagulation.47 The results were also reinforced by the evidence that the risk of stroke was lower in patients maintaining a PRX AF pattern than those with PRX AF at the baseline who progressed to a sustained AF during the 2-year follow-up.47 Moreover, a study in patients with previous stroke demonstrated a nearly two-fold increased risk of stroke with PRS AF compared to PRX AF, even after adjustment for age, sex, previous anticoagulation, and severity of the index event.48

The increased ability of CIEDs to detect silent AF through continuous monitoring for long periods of time has highlighted the potential opportunity to examine the AF burden, or threshold of AF burden, that is associated with a significant risk of stroke/SE to appropriately consider the benefit of anticoagulant prophylaxis in patients at risk, as evaluated through clinical score schemes. Studies have generally shown that higher AF burden is associated with a higher risk of stroke; however, thresholds have not been reproducibly

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Pattern of AF and Major Outcomes identified. Confounding the observation is that patients with higher AF burden also tend to have a higher prevalence of other conditions that increase risk of stroke.

previous TRENDS study) raised the short-term risk of stroke almost fivefold.51,54 Moreover, they found that majority of strokes occurred temporally dissociated from AF. Therefore, although a transient increase in risk based on AF onset was identified, the overall attributable risk was low.

Several studies in different populations with CIEDs have analysed the association of different AF burden thresholds with stroke/SE (Table 3).26,28,31,50–57 In these studies, with data collected from more than 35,000 patients, the participants were categorised according to the maximum duration of detected AHREs or by the maximum detected daily AF burden. The cutoff points of AF duration were generally arbitrarily pre-specified rather than empirically derived.

It is noteworthy that a device-detected AF burden of >5 minutes has been recently found to be significantly associated with silent ischaemic brain lesions (IBL) at CT scan. The study prospectively analysed 109 patients, mean aged 74±9 years with a mean CHA2DS2VASc scores of 3.9 ± 1.6. Seventy-five patients (69%) had no history of AF or stroke/TIA. CT scan showed silent IBLs in 28 (25.7%) patients. Multivariable analysis demonstrated that AHRE was an independent predictor for silent IBL in the overall population (HR 3.05; 95% CI [1.06–8.81]; p<0.05) but also in patients without prior history of AF or stroke/TIA (HR 9.76; 95% CI [1.76– 54.07]; p<0.05).59 This finding may be of some value for interpreting the risk of cognitive impairment in AF patients, since there is compelling evidence to support an association of greater cognitive decline and risk of dementia and AF independently of a history of stroke.60

In an ancillary analysis of the MOST trial of 316 patients with SND and dualchamber pacemakers, an AHRE (atrial rate >220 BPM) cutoff of 5 minutes was chosen to avoid false-positive results from overs-ensing.26 Presence of 5-minute AHREs was associated with increased risk of death or nonfatal stroke (HR 2.79; 95% CI [1.51–5.15]; p=0.0011) and of clinical AF (HR 5.93; 95% CI [2.88–12.2]; p=0.0001). This study was limited by its small size, retrospective design, and the fact that only AHREs that lasted >5 minutes were considered; thus, the prognostic significance of much longer episodes was not evaluated.

Mechanistic models have been proposed to explain the association of AF and dementia. Alterations of brain perfusion from embolic events, bleeding, and rhythm-related hypoperfusion underlie many of these models. Those observations have valuable relevance because potential therapeutic opportunities to reduce dementia risk, including early and effective use of OACs and strategies to improve brain perfusion through rhythm and rate control approaches.61,62 However, prospective trials are needed to evaluate these therapeutic opportunities.

The TRENDS study was a prospective, observational study of 2,846 patients with pacemakers or defibrillators and risk factors for stroke.51. The median value of AT/AF burden of 5.5 hours on any single day in a 30-day window was chosen as the cutoff between low/high-risk threshold. Compared with no AT/AF, the stroke risk was doubled in those with high AT/ AF burden (≥5.5 hours) but not in those with low AT/AF burden (<5.5 hours), suggesting that stroke risk is a quantitative function of AT/AF burden.51

Type and Burden of AF and Mortality

In the ASSERT study, subclinical episodes of AT (atrial rates ≥190 BPM lasting >6 minutes) were associated with an increased risk of ischaemic stroke/SE (HR 2.49) during a 2.5-year follow-up.28 The cutoff of 6 minutes was pre-specified. However, albeit important, data from ASSERT do not identify a specific threshold of AF duration or AF burden that may justify, from a risk–benefit perspective, the starting of prophylaxis with OACs.58 A further sub-analysis of the ASSERT study has given the answer, demonstrating that subclinical AT only increased the risk of stroke/SE for episodes >24 hours (adjusted HR 3.24; 95% CI [1.51–6.95]; p=0.003) and that risk of stroke in patients with subclinical AT between 6 minutes to 6 hours (adjusted HR 0.75; 95% CI [0.29–1.96]; p=0.562) and between 6 hours to 24 hours (adjusted HR 1.32; 95% CI [0.40–4.37]; p=0.646) was not significantly different from that of patients without subclinical AT.57

AF is associated with an increased risk of mortality.63–65 Importantly, higher AF burden is associated with higher risk of mortality. However, the role of AF type has shown conflicting results in term of its impact on the risk of death. In the meta-analysis by Zhang et al., solely based on RCTs in patients with moderate-to-high risk of stroke receiving anticoagulation, PRX AF showed significantly improved efficacy and a similar safety profile compared to PRS or PRM AF patients. Overall, the results included a reduction of allcause mortality in PRX compared to non-PRX AF patients (HR 0.72; 95% CI [0.66–0.79]; p<0.00001).42 The meta-analysis by Ganesan et al. has compared outcomes by type of AF, representing the largest aggregated AF patient dataset. Overall unadjusted all-cause mortality was higher in patients with non-PRX AF than in those with PRX AF (HR 1.46; 95% CI [1.26–1.70]; p<0.001); multivariable adjustment only partially attenuated this association (HR 1.22; 95% CI [1.09–1.37]; p<0.001).49 The mechanisms by which non-PRX patients experienced increased mortality include worsened HF or more severe stroke events, or perhaps a higher burden of underlying non-cardiovascular diseases.65,66

The SOS-AF project has collected the largest dataset of patients previously implanted with CIEDs, a pooled analysis of individual patient data from three prospective studies, with an overall population of 10,016 patients with median age of 70 years, without permanent AF.53 During a median follow-up of 24 months, 43% of patients experienced at least 1 day with ≥5 minutes of AF burden; and in a Cox regression analysis adjusted for CHADS2 score and use of OACs at baseline, the AF burden was an independent predictor of stroke, with a 1-hour threshold of AF burden associated with the highest HR for ischaemic stroke of 2.11 (95% CI [1.22– 3.64]; p=0.008) in a dichotomised analysis that compared various potential threshold cutoffs for AF burden.53

To further appreciate the complex picture of AF patients presenting with PRX on non-PRX AF, it is also interesting to consider an analysis of the predictors of outcome taking into account all-cause mortality instead of stroke. In the EORP-AF General Pilot Registry, patients with non-PRX AF had a worse outcome for all-cause mortality at 1 year than those with PRX AF; however, in the multivariable Cox model, non-PRX AF was not an independent predictor of death during follow-up being the adverse outcome maybe related to the worse clinical risk profile for age, underlying cardiac disease, comorbidities, and risk factors.33

In a case-crossover analysis involving 9,850 patients with CIEDs remotely monitored in the Veterans Administration Health Care System, it was found that AF burden of ≥5.5 hours in a given day (based on the

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Pattern of AF and Major Outcomes Table 3: Summary of Studies Regarding AF Detected by Cardiac Implantable Electronic Devices and Thromboembolic Risk Author

Trial

Patients Follow-up (n) Duration

Atrial Rate Cutoff

AF Burden Threshold

TE Event, HR TE Event Rate (Below (p-value) Versus Above AF Burden Threshold)

Glotzer et al. 200326

Ancillary MOST

312

27 months (median)

>220 BPM

5 min

6.7 (p=0.020)

3.2% overall (1.3% versus 5%)

Capucci et al. 2005

Italian AT500 Registry

725

22 months (median)

>174 BPM

24 h

3.1 (p=0.044)

1.2% annual rate

Bottoet al. 2009

Italian AT500 Registry

568

1 year (mean)

>174 BPM

CHADS2 + AF burden N/A

2.5% overall (0.8% versus 5%)

Glotzeret al. 200951

TRENDS

2,486

1.4 years (mean)

>175 BPM

5.5 h

2.2 (p=0.060)

1.2% overall (1.1% versus 2.4%)

Shanmugam et al. 201252 Home Monitor CRT

560

370 days (median)

>180 BPM

3.8 h

9.4 (p=0.006)

2.0% overall

Healey et al. 201228

ASSERT

2,580

2.5 years (mean)

>190 BPM

6 min

2.5 (p=0.007)

(0.69% versus 1.69%)

Boriani et al. 2014

SOS

10,016

2 years (median)

>175 BPM

2.11 (p=0.008)

0.39% per year overall

Turakhia et al. 201554

Veterans HCS

9,850

1–30 and 91–120 days before stroke

>175 BPM

5.5 h

4.2 VKA adjusted N/A

Witt et al. 201555

Danish National Registry 394

4.6 years (median)

Nominal setting 6 min

2.30 (p=0.028)

1.80% per year

Swiryn et al. 201656

RATE Registry

5,379

22.9 months

Nominal setting AT onset/offset on different EGM recordings

1.51 (p<0.05)

N/A

Van Gelder et al. 201757

ASSERT Substudy

2,455

2.5 years (mean)

>190 BPM

3.24 (p=0.003)

3.1 per year

24 h

AT = atrial tachycardia; EGM = electrogram; N/A = not available; TE = thromboembolic.

with higher risk of major events (including stoke and death, but not bleeding).42,49 These studies have included device-detected AF studies, which have the advantage of truly assessing total AF burden. The greater the AF burden, the higher the association with thromboembolism. However, further considerations are mandatory: non-device-assessed AF cannot provide assessment of AF burden, and, consequently, AF type/ pattern does not equate with AF burden. For example, frequent PRX-AF may result in more time in AF (greater AF burden) than occasional episodes of cardioverted PRS-AF. The latter could explain the discordant results among trials that simply looked at AF type versus outcome events.

The data are even less clear on how AHREs relate to mortality, with a suggestion that these low-burden events carry lower mortality risk, in part because studies have been smaller with less precision. In a study of 224 patients, 17% had AHREs of ≥5-minute duration within 6 months after pacemaker implantation; over a mean follow-up of 6.6 ± 2.0 years, the rate of all-cause mortality was 29%. In multivariate analysis adjusted for age, sex, and cardiovascular diseases, presence of AHREs was associated with a significant increase in cardiovascular mortality (HR 2.80; 95% CI [1.24–6.31]; p=0.030) and stroke mortality (HR 9.65; 95% CI [1.56– 59.9]; p=0.015), with a trend toward increased all-cause mortality (HR 1.79; 95% CI [0.98–3.26]; p=0.079). The subgroup of patients with AHREs of ≥5-minute but <24-hour duration also had a significantly increased cardiovascular mortality (HR 3.24; 95% CI [1.37–7.66]; p=0.007).67

Moreover, AF burden, beyond AF pattern, is not considered in the risk scoring systems, while some studies have demonstrated that this should be. Botto et al. assessed the interaction between AF and CHADS2 factors with respect to risk for stroke. Three groups: no AF, AF >5 minutes <24 hours, AF >24 hours. The rate of TE events increased linearly with the presence and duration of AF, so too as the CHADS2 score increased. Patients with a CHADS2 score of 0 were at low risk, even if they had longlasting AF, as were patients with a score of 1 if AFB was >5 minutes but <24 hours, and patients with a score of 2 if they had no AF. By contrast, patients with a CHADS2 score ≥3 demonstrated high risk, even without AF being recorded, as did patients with a score of 2 if they had AF >5 min.31 Thus, the mere presence/absence of AF is not enough of a consideration, especially in those with very-low or very-high risk score. That is: we cannot evaluate outcome events in AF without considering the state of the atria, that immediately refers to the concept of ‘atrial cardiomyopathy’ (ACMP).

By contrast, in one study of 394 patients implanted with cardiac resynchronisation therapy devices, and included in the Danish National Registry, although the 20% of patients with AHREs (compared with those without) had an increased risk of clinical AF (HR 2.35; 95% CI [1.47–3.74]; p<0.001) and thromboembolic events (HR 2.30; 95% CI [1.09–4.83]; p=0.028), the risk of mortality was not increased (HR 0.97; 95% CI [0.64–1.45]; p=0.87).55 Adjusting the analysis for pre-selected baseline risk factors (age at implantation, estimated glomerular filtration rate, left ventricular ejection fraction, QRS width, presence of coronary artery disease, and functional class) had no impact on this result (HR 1.08; 95% CI [0.71–1.65]; p=0.70). The story is much more complex than simply considering AF type/burden and the presence/absence of specific comorbidities (such as those used in risk marker scores). Moreover, comorbidities should also be considered in a qualitative-quantitative way rather than just as binomial (present/ absent) factors.68,69

A consensus document and detailed reviews have discussed aspects of the definition, histopathology, atrial-specific physiology, atrial pathology, impact on arrhythmia occurrence, imaging, mapping, and ablation of the ACMP.70–72 ACMP may be the cause and/or the consequence of AF, can vary with the number and severity of associated comorbidities as well as the amount of AF present over time (AF burden better than AF pattern with that regard) in a synergistic combination, and may finally results in thrombus formation. In patients with AF and stroke-risk comorbidities, the atria are not normal. Rather, in the atria there are endothelial, metabolic, anatomic,

Complex Relationship Between AF Type or Burden and Stroke: Magnitude Synergism and the Concept of Atrial Myopathy

According to the studies previously discussed it is possible to conclude that (even not consistently) more sustained patterns of AF are associated

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Pattern of AF and Major Outcomes Although increasing AF burden is generally associated with an increasing risk of stroke, the relationship is not well characterised with respect to the definition of threshold value above which the risk increases or the duration of any transient risk. Therefore, some caution is needed in interpreting AF burden–related ischaemic stroke risk derived from pivotal studies. In general, the higher the clinical risk as expressed by the CHA2DS2-VASc score, the lower the threshold of AF burden that should be considered for eventually initiating OACs. However, the latter is still matter of debate, since no intervention trial is in support of this reasonable choice, and newer specifically designed trials are ongoing.77,78

histopathologic, and contractile alterations. Those data suggest that the absolute rate of stroke should be expected higher with a greater AF as well as a greater degree on combined contributors. Therefore, magnitude synergism of contributing factors should be considered and our current risk scoring systems fail by missing this point. Certainly, the CHA2DS2-VASc score relates well to the number of contributory comorbidities, but only age is considered in any semiquantitative way. Yet, if one considers pathophysiologically how disease can contribute to thrombus formation in the left atrium, the process cannot simply be ‘all or nothing’. It is a clear limitation of the score systems.

Nevertheless, AF alone cannot be the sole factor that can explain the increased risk of thromboembolism. The total burden of AF and its effect on introducing fibrotic and mechanical abnormalities together with the magnitude of atrial pathophysiology consequent to any atrial-affecting disorder must interact synergistically to magnify the thromboembolic risk.49,73 Moreover, the synergism cannot be simply dichotomous (while the risk scores, unfortunately, are), it must have magnitude depending on the severity of the associated comorbidities and the total amount of AF.69,73,74

Therefore, the greater the atrial pathology created by the synergism of AF and underlying disease, the greater the risk. Here is the concept of ‘magnitude synergism’ that should be applied to understand the complex relationship between AF and outcomes.68,73 It is not enough to just note the presence of AF and its longest duration; rather, a quantitative description of the setting in which it occurs is also a necessity (quantitative and qualitative comorbidity).74 The KP-RHYTHM study clearly demonstrated this concept: AF burden, not just the presence of AF, is important in quantitating the risk for stroke since the highest tertile of AF burden was associated with a more than three-fold higher adjusted rate of thromboembolism compared with the combined lower 2 tertile.75

Even today, with the availability of sophisticated and advanced diagnostic tools, the primary approach to a patient with documented AF remains primarily clinical, based on the evaluation of underlying heart disease and associated comorbidities, the correction of precipitating risk factors, and the stratification for stroke risk. With that regard, current stroke risk scores are practical, but limited in their capacity to predict stroke risk accurately in individual patients. Stroke prediction might be improved by the addition of emerging risk factors, many of which are expressions of atrial fibrosis. The use of novel parameters, including biomarkers and imaging data, regardless of AF pattern or burden, might improve stroke risk prediction and inform optimal treatment for patients with AF.79–83

Conclusion

AF is associated with substantial mortality and morbidity, of which, the most serious is thromboembolism. The risk stratification for stroke is a crucial step in the clinical management of AF patients and is currently based on the evaluation of a series of clinical factors included in the CHADS2 and CHA2DS2-VASc scores.

Clinical Perspective

Current guidelines place all AF types together in term of anticoagulation with the major determinants being associated comorbidities translated into risk marker scores: Patients with a substantial clinical risk (CHA2DS2VASc scores ≥2) should receive OACs regardless of their AF pattern; therefore, PRX AF should not be an element to deny any anticoagulation in patients at risk.76 At the higher level of the risk spectrum, clinical risk factors play a much important role than AF pattern.41

• Current guidelines place all AF types together in terms of • •

Conversely, in deciding whether or not to offer anticoagulation to patients at lower risk (CHA2DS2-VASc scores =1), for whom the risk/benefit ratio of OACs is less clear, it might be useful to consider the type of AF (PRX versus non-PRX) since in studies among contemporary patients, the strongest evidence suggests that patients with PRX AF are at lower risk of stroke than those with non-PRX AF.34,37–39 However, it must be emphasised that these studies suffer a major limitation of having included post-hoc analyses of trials done for other purposes than to assess the pure role of AF type in predicting major outcomes.

• • •

The capability of continuous monitoring of AF through CIEDs has led to the concept of ‘AF burden’ defined as the overall time spent in AF that an individual has in each day in a specific follow-up period. The measurement of total AF burden includes asymptomatic as well as symptomatic episodes.

anticoagulation, with the major determinants being associated co-morbidities translated into risk marker scores. Patients with non-paroxysmal AF are at higher risk of stroke and death than those with paroxysmal AF. Continuous monitoring of AF through cardiac implantable devices has led to the concept of ‘AF burden’. Although increasing AF burden is generally associated with an increasing risk of stroke, the relationship is not well characterised with respect to the threshold value above which the risk increases. Underlying disorders alone cannot be the sole factors, nor can AF alone; those two factors must be considered within a more complex synergism. The synergistic risk must also have magnitude, depending on the amount of time a patient is in AF and the number and the severity of associated co-morbidities. The new knowledge will trigger further investigation into the pathological interplay between AF type or burden and underlying disorders, allowing us to better determine optimal risk assessment and therapy.

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Pattern of AF and Major Outcomes 1. Benjamin EJ, Muntner P, Alonso A, et al. American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics – 2019 update: a report from the American Heart Association. Circulation 2019;139:e56–528. https://doi.org/10.1161/ CIR.0000000000000659; PMID: 30700139. 2. Staerk L, Sherer JA, Ko D, et al. Atrial fibrillation: epidemiology, pathophysiology, and clinical outcomes. Circ Res 2017;120:1501–17. https://doi.org/10.1161/ CIRCRESAHA.117.309732; PMID: 28450367. 3. Krijthe BP, Kunst A, Benjamin EJ, et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur Heart J 2013;34:2746–51. https://doi.org/10.1093/eurheartj/eht280; PMID: 23900699. 4. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983–88. https://doi.org/10.1161/01.str.22.8.983; PMID: 1866765. 5. McManus DD, Rienstra M, Benjamin EJ. An update on the prognosis of patients with atrial fibrillation. Circulation 2012;126:e143–6. https://doi.org/10.1161/ CIRCULATIONAHA.112.129759; PMID: 22949543. 6. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864–70. https://doi.org/10.1001/ jama.285.22.2864; PMID: 11401607. 7. Lip GY, Tse HF, Lane DA. Atrial fibrillation. Lancet 2012;379:648–61. https://doi.org/10.1016/S01406736(11)61514-6; PMID: 22166900. 8. Lane DA, Lip GY. Use of the CHA2DS2-VASc and HAS-BLED scores to aid decision making for thromboprophylaxis in nonvalvular atrial fibrillation. Circulation 2012;126:860–5. https://doi.org/10.1161/CIRCULATIONAHA.111.060061; PMID: 22891166. 9. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. https://doi.org/10.1093/eurheartj/ehw210; PMID: 27567408. 10. 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 202;42:373–498. https://doi.org/10.1093/eurheartj/ehaa612; PMID: 32860505. 11. 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. Circulation 2019;140:e125–51. https://doi.org/10.1161/ CIR.0000000000000665; PMID: 30686041. 12. Zoni-Berisso M, Lercari F, Carazza T, et al. S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol 2014;6:213–20. https://doi.org/10.2147/CLEP.S47385; PMID: 24966695. 13. Chiang CE, MD, Naditch-Brûlé L, Murin J, et al. Distribution and risk profile of paroxysmal, persistent, and permanent atrial fibrillation in routine clinical practice. Insight From the Real-Life Global Survey Evaluating Patients with Atrial Fibrillation International Registry. Circ Arrhythm Electrophysiol 2012;5:632–9. https://doi.org/10.1161/CIRCEP.112.970749; PMID: 22787011. 14. Deshmukh A, Brown ML, Higgins E, et al. Performance of atrial fibrillation detection in a new single-chamber ICD. Pacing Clin Electrophysiol 2016;39:1031–7. https://doi. org/10.1111/pace.12918; PMID: 27433785. 15. Podd SJ, Sugihara C, Furniss SS, et al. Are implantable cardiac monitors the “gold standard” for atrial fibrillation detection? A prospective randomized trial comparing atrial fibrillation monitoring using implantable cardiac monitors and DDDRP permanent pacemakers in post atrial fibrillation ablation patients. Europace 2016;18:1000–5. https://doi. org/10.1093/europace/euv367; PMID: 26585596. 16. Gorenek B, Bax J, Boriani G, et al. Device-detected subclinical atrial tachyarrhythmias: definition, implications and management—an European Heart Rhythm Association (EHRA) consensus document, endorsed by Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS) and Sociedad Latinoamericana de Estimulacion Cardıacay Electrofisiologıa (SOLEACE). Europace 2017;19:1556–78. https://doi.org/10.1093/europace/eux163; PMID: 28934408. 17. Boriani G, Padeletti L. Management of atrial fibrillation in bradyarrhythmias. Nat Rev Cardiol 2015;12:337–49. https:// doi.org/10.1038/nrcardio.2015.30; PMID: 25781413. 18. Purerfellner H, Gillis AM, Holbrook R, et al. Accuracy of atrial tachyarrhythmia detection in implantable devices with arrhythmia therapies. Pacing Clin Electrophysiol 2004;27:983– 92. https://doi.org/10.1111/j.1540-8159.2004.00569.x; PMID: 15271020.

19. Kaufman ES, Israel CW, Nair GM, et al. for the ASSERT Steering Committee and Investigators. Positive predictive value of device-detected atrial high-rate episodes at different rates and durations: an analysis from ASSERT. Heart Rhythm 2012;9:1241–6. https://doi.org/10.1016/j. hrthm.2012.03.017; PMID: 22440154. 20. Gillis AM, Morck M. Atrial fibrillation after DDDR pacemaker implantation. J Cardiovasc Electrophysiol 2002;13:542–7. https://doi.org/10.1046/j.1540-8167.2002.00542.x; PMID: 12108493. 21. Israel CW, Grönefeld G, Ehrlich JR, et al. Long-term risk of recurrent atrial fibrillation as documented by an implantable monitoring device: implications for optimal patient care. J Am Coll Cardiol 2004;43:47–52. https://doi.org/10.1016/j. jacc.2003.08.027; PMID: 14715182. 22. Strickberger SA, Ip J, Saksena S, et al. Relationship between atrial tachyarrhythmias and symptoms, Heart Rhythm 2005;2:125–31. https://doi.org/10.1016/j.hrthm.2004.10.042; PMID: 15851283. 23. Chen-Scarabelli C, Scarabelli TM, Ellenbogen KA, et al. Device-detected atrial fibrillation. What to do with asymptomatic patients? J Am Coll Cardiol 2015;65:281–94. https://doi.org/10.1016/j.jacc.2014.10.045: PMID: 25614426. 24. Cheung JW, Keating RJ, Stein KM, et al. Newly detected atrial fibrillation following dual chamber pacemaker implantation. J Cardiovasc Electrophysiol 2006;17:1323–8. https://doi.org/10.1111/j.1540-8167.2006.00648.x; PMID: 17081212. 25. Healey JS, Martin JL, Duncan A, et al. Pacemaker-detected atrial fibrillation in patients with pacemakers: prevalence, predictors, and current use of oral anticoagulation. Can J Cardiol 2013;29:224–8. https://doi.org/10.1016/j. cjca.2012.08.019; PMID: 23142343. 26. Glotzer TV, Hellkamp AS, Zimmerman J, et al. Atrial high rate episodes detected by pacemaker diagnostics predict death and stroke: report of the Atrial Diagnostics Ancillary Study of the MOde Selection Trial (MOST). Circulation 2003;107:1614– 9. https://doi.org/10.1161/01.CIR.0000057981.70380.45; PMID: 12668495. 27. Ziegler PD, Glotzer TV, Daoud EG, et al. Detection of previously undiagnosed atrial fibrillation in patients with stroke risk factors and usefulness of continuous monitoring in primary stroke prevention. Am J Cardiol 2012;110:1309–14. https://doi.org/10.1016/j.amjcard.2012.06.034. 28. Healey JS, Connolly SJ, Gold MR, et al. ASSERT Investigators. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012;366:120–9. https://doi.org/10.1056/ NEJMoa1105575; PMID: 22236222. 29. Friedman PA, Dijkman B, Warman EN, et al. Atrial therapies reduce atrial arrhythmia burden in defibrillator patients. Circulation 2001;104:1023–8. https://doi.org/10.1161/ hc3401.095039; PMID: 11524396. 30. Israel CW, Hugl B, Unterberg C, et al. Pace-termination and pacing for prevention of atrial tachyarrhythmias: Results from a multicenter study with an implantable device for atrial therapy. J Cardiovasc Electrophysiol 2001;12:1121–8. https://doi.org/10.1046/j.1540-8167.2001.01121.x; PMID: 11699520. 31. Botto GL, Padeletti L, Santini M, et al. Presence and duration of atrial fibrillation detected by continuous monitoring: crucial implications for the risk of thromboembolic events. J Cardiovasc Electrophysiol 2009;20:241–8. https://doi. org/10.1111/j.1540-8167.2008.01320.x; PMID: 19175849. 32. Page RL, Wilkinson WE, Clair WK, et al. Asymptomatic arrhythmias in patients with symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia. Circulation 1994;89:224–7. https://doi.org/10.1161/01. cir.89.1.224; PMID: 8281651. 33. Boriani, C. Laroche, I Diemberger I, et al. ‘Real world’ management and outcomes of patients with paroxysmal versus non-paroxysmal atrial fibrillation in Europe: the EURObservational Research Programme–Atrial Fibrillation (EORP-AF) General Pilot Registry. Europace 2016; 18: 648–57. https://doi.org/10.1093/europace/euv390; PMID: 26826133. 34. Vanassche T, Lauw MN, Eikelboom JW, et al. Risk of ischaemic stroke according to pattern of atrial fibrillation: analysis of 6563 aspirin-treated patients in ACTIVE-A and AVERROES. Eur Heart J 2015;36:281–8. https://doi. org/10.1093/eurheartj/ehu307; PMID: 25187524. 35. Hart RG, Pearce LA, Rothbart RM, et al. for the Stroke Prevention in Atrial Fibrillation Investigators. Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. J Am Coll Cardiol 2000;35:183–7. https://doi.org/10.1016/s0735-1097(99)00489-1; PMID: 10636278. 36. Hohnloser SH, Pajitnev D, Pogue J, et al. Incidence of stroke in paroxysmal versus sustained atrial fibrillation in patients taking oral anticoagulation or combined antiplatelet

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

therapy: an ACTIVE W Substudy. J Am Coll Cardiol 2007;50:2156–61. https://doi.org/10.1016/j.jacc.2007.07.076; PMID: 18036454. 37. Steinberg BA, Hellkamp AS, Lokhnygina Y, et al. Higher risk of death and stroke in patients with persistent vs paroxysmal atrial fibrillation: results from the ROCKET-AF Trial. Eur Heart J 2015;36:288–96. https://doi.org/10.1093/ eurheartj/ehu359; PMID: 25209598. 38. Al-Khatib SM, Thomas L, Wallentin L, et al. Outcomes of apixaban vs. warfarin by type and duration of atrial fibrillation: results from the ARISTOTLE trial. Eur Heart J 2013;34:2464–71. https://doi.org/10.1093/eurheartj/eht135; PMID: 23594592. 39. Link MS, Giugliano RP, Ruff CT, et al. Stroke and mortality risk in patients with various patterns of atrial fibrillation: results from the ENGAGE AF-TIMI 48 Trial (effective anticoagulation with Factor Xa next generation in atrial fibrillation-thrombolysis in myocardial infarction 48). Circ Arrhythm Electrophysiol 2017;10:1–7. https://doi.org/10.1161/ CIRCEP.116.004267; PMID: 28077507. 40. Flaker G, Ezekowitz M, Yusuf S, et al. Efficacy and safety of dabigatran compared to warfarin in patients with paroxysmal, persistent, and permanent atrial fibrillation: results from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study. J Am Coll Cardiol 2012;59:854–855. https://doi.org/10.1016/j.jacc.2011.10.896; PMID: 22361407. 41. Lip GY, Frison L, Grind M. Stroke event rates in anticoagulated patients with paroxysmal atrial fibrillation. J Intern Med 2008;264:50–61. https://doi. org/10.1111/j.1365-2796.2007.01909.x; PMID: 18266660. 42. Zhang W, Xiong Y, Yu L, et al. Meta-analysis of stroke and bleeding risk in patients with various atrial fibrillation patterns receiving oral anticoagulation. Am J Cardiol 2019; 123: 922–8. https://doi.org/doi.org/10.1016/j. amjcard.2018.11.055; PMID: 30691678. 43. Nieuwlaat R, Prins MH, Le Heuzey JY, et al. Prognosis, disease progression, and treatment of atrial fibrillation patients during 1 year: follow-up of the Euro Heart Survey on atrial fibrillation. Eur Heart J 2008;29:1181–9. https://doi. org/10.1093/eurheartj/ehn139; PMID: 18397874. 44. Banerjee A, Taillandier S, Olesen JB, et al. Pattern of atrial fibrillation and risk of outcomes: the Loire Valley Atrial Fibrillation Project. Int J Cardiol 2013;167:2682–7. https://doi. org/10.1016/j.ijcard.2012.06.118; PMID: 22795403. 45. Wang Y, Ma CS, Du X, et al. Thromboembolic risks associated with paroxysmal and persistent atrial fibrillation in Asian patients: a report from the Chinese atrial fibrillation registry. BMC Cardiovasc Dis 2019; 19: 283–11. https://doi. org/10.1186/s12872-019-1260-7; PMID: 31810439. 46. Atar D, Berge E, Le Heuzey JY, et al. The association between pattern of atrial fibrillation, anticoagulation, and cardiovascular events. Europace 2020; 22: 195–204. https:// doi.org/10.1093/europace/euz292; PMID: 31747004. 47. Takabayashi K, Hamatani Y, Yamashita Y, et al. Incidence of stroke or systemic embolism in paroxysmal versus sustained atrial fibrillation: the Fushimi Atrial Fibrillation Registry. Stroke 2015;46:3354–61. https://doi.org/10.1161/ STROKEAHA.115.010947; PMID: 26514188. 48. Koga M, Yoshimura S, Hasegawa Y, et al. for the SAMURAI Study Investigators. Higher risk of ischemic events in secondary prevention for patients with persistent than those with paroxysmal atrial fibrillation. Stroke 2016;47:2582–8. https://doi.org/10.1161/STROKEAHA.116.013746; PMID: 27531346. 49. Ganesan AN, Chew DP, Hartshorne T, et al. The impact of atrial fibrillation type on the risk of thromboembolism, mortality, and bleeding: a systematic review and metaanalysis. Eur Heart J 2016;37:1591–1602. https://doi. org/10.1093/eurheartj/ehw007; PMID: 26888184. 50. Capucci A, Santini M, Padeletti L, et al. Italian AT500 Registry Investigators. Monitored atrial fibrillation duration predicts arterial embolic events in patients suffering from bradycardia and atrial fibrillation implanted with antitachycardia pacemakers. J Am Coll Cardiol 2005;46:1913– 20. https://doi.org/10.1016/j.jacc.2005.07.044; PMID: 16286180. 51. Glotzer TV, Daoud EG, Wyse DG, et al. The relationship between daily atrial tachyarrhythmia burden from implantable device diagnostics and stroke risk: the TRENDS study. Circ Arrhythm Electrophysiol 2009;2:474–80. https://doi. org/10.1161/CIRCEP.109.849638; PMID: 19843914. 52. Shanmugam N, Boerdlein A, Proff J, et al. Detection of atrial high-rate events by continuous home monitoring: clinical significance in the heart failure-cardiac resynchronization therapy population. Europace 2012;14:230–7. https://doi. org/10.1093/europace/eur293; PMID: 21933802. 53. Boriani G, Glotzer TV, Santini M, et al. Device-detected atrial fibrillation and risk for stroke: an analysis of >10,000

Pattern of AF and Major Outcomes patients from the SOS AF project (Stroke preventiOn Strategies based on Atrial Fibrillation information from implanted devices). Eur Heart J 2014;35:508–16. https:// doi.org/10.1093/ eurheartj/eht491; PMID: 24334432. 54. Turakhia MP, Ziegler PD, Schmitt SK, et al. Atrial fibrillation burden and short-term risk of stroke: case-crossover analysis of continuously recorded heart rhythm from cardiac electronic implanted devices. Circ Arrhythm Electrophysiol 2015;8:1040–7. https://doi.org/10.1161/CIRCEP.114.003057; PMID: 26175528. 55. Witt CT, Kronborg MB, Nohr EA, et al. Early detection of atrial high rate episodes predicts atrial fibrillation and thromboembolic events in patients with cardiac resynchronization therapy. Heart Rhythm 2015;12:2368–75. https://doi.org/10.1016/j. hrthm.2015.07.007; PMID: 26164377. 56. Swiryn S, Orlov MV, Benditt DG, et al. Clinical implications of brief device-detected atrial tachyarrhythmias in a cardiac rhythm management device population: results from the Registry of Atrial Tachycardia and Atrial Fibrillation Episodes. Circulation 2016;134:1130–40. https://doi.org/10.1161/ CIRCULATIONAHA.115.020252; PMID: 27754946. 57. Van Gelder IC, Healey JS, Crijns HJGM, et al. Duration of device-detected subclinical atrial fibrillation and occurrence of stroke in ASSERT. Eur Heart J 2017;38:1339–44. https://doi. org/10.1093/ eurheartj/ehx042; PMID: 28329139. 58. Lamas G. How much atrial fibrillation is too much atrial fibrillation? N Engl J Med 2012; 366:178–80. https://doi. org/10.1056/NEJMe1111948; PMID: 22236229. 59. Benezet-Mazuecos J, Rubio JM, Cortés M, et al. Silent ischaemic brain lesions related to atrial high rate episodes in patients with cardiac implantable electronic devices. Europace 2015;17:364–9. https://doi.org/10.1093/europace/ euu267; PMID: 25336664. epub ahead of print. 60. Kalantarian S, Stern TA, Mansour M, Ruskin JN. Cognitive impairment associated with atrial fibrillation: a metaanalysis. Ann Intern Med 2013;158:338–46. https://doi. org/10.7326/0003-4819-158-5-201303050-00007; PMID: 23460057. 61. Bunch TJ, Galenko O, Graves KG, et al. Atrial fibrillation and dementia: exploring the association, defining risks and improving outcomes. Arrhythm Electrophysiol Rev 2019;8:8–12. https://doi.org/10.15420/aer.2018.75.2; PMID: 30918661. 62. Bunch TJ. Atrial fibrillation and dementia. Circulation 2020;142:618–20. https://doi.org/10.1161/ CIRCULATIONAHA.120.045866; PMID: 32804567. 63. Benjamin EJ, Wolf PA, D’Agostino RB, et al. Impact of atrial

fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998;98:946–52. https://doi.org/10.1161/01. cir.98.10.946; PMID: 9737513. 64. Chen LY, Sotoodehnia N, Bůžková P, et al. Atrial fibrillation and the risk of sudden cardiac death: the Atherosclerosis Risk in Communities Study and Cardiovascular Health Study. JAMA Intern Med 2013;173:29–35. https://doi. org/10.1001/2013.jamainternmed.744; PMID: 23404043. 65. Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation 2003;107:2920–5. https://doi.org/10.1161/01. CIR.0000072767.89944.6E; PMID: 12771006. 66. Deguchi I, Fukuoka T, Hayashi T, et al. Clinical outcomes of persistent and paroxysmal atrial fibrillation in patients with stroke. J Stroke Cerebrovasc Dis 2014;23:2840–4. https://doi. org/10.1016/j.jstrokecerebrovasdis.2014.07.010; PMID: 25294056. 67. Gonzalez M, Keating RJ, Markowitz SM, et al. Newly detected atrial high rate episodes predict long-term mortality outcomes in patients with permanent pacemakers. Heart Rhythm 2014;11:2214–21. https://doi.org/10.1016/j. hrthm.2014.08.019; PMID: 25131667. 68. Reiffel JA. If it were only that simple. Eur Heart J 2016;37:1603–5. https://doi.org/doi.org/10.1016/j. amjcard.2019.04.004; PMID: 26984857. 69. Chen LY, Chung MK, Allen LA, et al. Atrial fibrillation burden: moving beyond atrial fibrillation as a binary entity: a scientific statement from the American Heart Association. Circulation 2018;137:e623-e644. https://doi.org/10.1161/ CIR.0000000000000568; PMID: 29661944. 70. Goette A, Kalman JM, Aguinaga L, et al. EHRA/HRS/APHRS/ SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication. Europace 2016;18:1455–90. https://doi.org/10.1093/europace/euw161; PMID: 27402624. epub ahead of print. 71. Guichard JB, Nattel S. Atrial cardiomyopathy: a useful notion in cardiac disease management or a passing fad? J Am Coll Cardiol 2017;70:756–65. https://doi.org/10.1016/j. jacc.2017.06.033; PMID: 28774383. 72. Rivner H, Mitrani RD, Goldberger JJ. Atrial Myopathy Underlying Atrial Fibrillation. Arrhythm Electrophysiol Rev 2020; 9:61–70. https://doi.org/10.15420/aer.2020.13; PMID: 32983526. 73. Reiffel JA. Optimum risk assessment for stroke in atrial fibrillation: should we hold the status quo or consider magnitude synergism and left atrial appendage anatomy. Arrhythm Electrophysiol Rev 2017;6:161–6. https://doi.

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

org/10.15420/aer.2017.33.1; PMID: 29326830. 74. Reiffel JA. Complexities in the atrial fibrillation-stroke relationship: improving comprehension of temporal discordance, magnitude synergism, and subclinical atrial fibrillation – three sources of consternation for physicians who care for patients with atrial fibrillation. J Atr Fibrillation 2018;11:2100–3. https://doi.org/10.4022/jafib.2100; PMID: 30505387. 75. Go AS, Reynolds K, Yang J, et al. Association of burden of atrial fibrillation with risk of ischemic stroke in adults with paroxysmal atrial fibrillation: the KP-RHYTHM Study. JAMA Cardiol 2018;3:601–8. https://doi.org/10.1001/ jamacardio.2018.1176; PMID: 29799942. 76. Boriani G, Pettorelli D. Atrial fibrillation burden and atrial fibrillation type: clinical significance and impact on the risk of stroke and decision making for long-term anticoagulation. Vasc Pharmacol 2016;83:26–35. https://doi.org/10.1016/j. vph.2016.03.006; PMID: 27196706. 77. Apixaban for the reduction of thrombo-embolism in patients with device-detected sub-clinical atrial fibrillation (ARTESiA). https://clinicaltrials.gov/ct2/show/NCT01938248 (accessed 15 March 2021). 78. Non-vitamin K Antagonist Oral Anticoagulants in patients with atrial high rate episodes (NOAH) https://clinicaltrials. gov/ct2/show/record/NCT02618577 (accessed 15 March 2021). 79. Hijazi Z, Lindbäck J, Alexander JH, et al. The ABC (age, biomarkers, clinical history) stroke risk score: a biomarkerbased risk score for predicting stroke in atrial fibrillation. Eur Heart J 2016;37:1582–90. https://doi.org/10.1093/eurheartj/ ehw054; PMID: 26920728. 80. Yaghi S, Moon YP, Mora-McLaughlin C, et al. Left atrial enlargement and stroke recurrence: the Northern Manhattan Stroke Study. Stroke 2015;46:1488–93. https:// doi.org/10.1161/STROKEAHA.115.008711; PMID: 25908460. 81. Saha SK, Anderson PL, Caracciolo G, et al. Global left atrial strain correlates with CHADS2 risk score in patients with atrial fibrillation. J Am Soc Echocardiogr 2011;24:506–12. https://doi.org/10.1016/j.echo.2011.02.012; PMID: 21477990. 82. Daccarett M, Badger TJ, Akoum N, et al. Association of left atrial fibrosis detected by delayed-enhancement magnetic resonance imaging and the risk of stroke in patients with atrial fibrillation. J Am Coll Cardiol 2011;57:831–8. https://doi. org/10.1016/j.jacc.2010.09.049; PMID: 21310320. 83. Calenda BW, Fuster V, Halperin JL, Granger GB. Stroke risk assessment in atrial fibrillation: risk factors and markers of atrial myopathy. Nat Rev Cardiol 2016;13:549–59. https://doi. org/10.1038/nrcardio.2016.106; PMID: 27383079.

Clinical Arrhythmias

Reconceptualising Atrial Fibrillation Using Renewal Theory: A Novel Approach to the Assessment of Atrial Fibrillation Dynamics Jing Xian Quah ,1,3 Dhani Dharmaprani ,1,2 Anandaroop Lahiri ,3 Kathryn Tiver

1,3

and Anand N Ganesan

1,3

1. College of Medicine and Public Health, Flinders University of South Australia, Adelaide, SA, Australia; 2. College of Science and Engineering, Flinders University of South Australia, Adelaide, SA, Australia; 3. Department of Cardiovascular Medicine, Flinders Medical Centre, Adelaide, SA, Australia

Abstract

Despite a century of research, the mechanisms of AF remain unresolved. A universal motif within AF research has been unstable re-entry, but this remains poorly characterised, with competing key conceptual paradigms of multiple wavelets and more driving rotors. Understanding the mechanisms of AF is clinically relevant, especially with regard to treatment and ablation of the more persistent forms of AF. Here, the authors outline the surprising but reproducible finding that unstable re-entrant circuits are born and destroyed at quasi-stationary rates, a finding based on a branch of mathematics known as renewal theory. Renewal theory may be a way to potentially unify the multiple wavelet and rotor theories. The renewal rate constants are potentially attractive because they are temporally stable parameters of a defined probability distribution (the exponential distribution) and can be estimated with precision and accuracy due to the principles of renewal theory. In this perspective review, this new representational architecture for AF is explained and placed into context, and the clinical and mechanistic implications are discussed.

Keywords

AF, mechanistic, renewal theory Disclosure: The authors have no conflicts of interest to declare. Received: 1 November 2020 Accepted: 3 February 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(2):77–84. DOI: https://doi.org/10.15420/aer.2020.42 Correspondence: Anand Ganesan, College of Medicine and Public Health, Flinders University, Flinders Drive, Bedford Park, SA 5042, Australia. E: anand.ganesan@flinders.edu.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.

controversy of the field, as in the realm of quantum physics, has been between notions of randomness and determinism.11–15

Nearly a century ago, physicist Werner Heisenberg set the world of physics on fire with his declaration of the principle of Unbestimmtheit, or indeterminacy, at the centre of quantum mechanics.1 The core of Heisenberg’s Copenhagen doctrine was the idea that the statistical character of the new quantum theory established the final failure of causal determinism, because the new uncertainty principle established that although the precise momentum and velocity of subatomic particles could never be predicted from current behaviour, highly accurate probability distributions for potential particle behaviours could be precisely defined.2 Heisenberg’s argument against the notion of determinism in physics aroused a fierce response from, among others, Albert Einstein and Erwin Schrodinger that set in train a fierce debate about the relative role of causality and chance in modern physics.2

Traditionally, the rotor and multiple wavelet theories cast as two opposing theories of the mechanism of AF.3,16 In this paper, we review emerging evidence that, in AF, the rotor and multiple wavelet theories may, in fact, may intrinsically linked, with rotor formation and destruction able to be accurately modelled as a renewal processes.17 Renewal theory is a branch of probability theory that seeks to establish probability distributions for statistically independent events. Recently, we have reasoned that due to the disaggregated, turbulent nature of AF, the formation and destruction of re-entrant circuits could be modelled using renewal theory.17 Analogous to the way quantum mechanics seeks to predict accurate probability distributions for particle behaviour, we have used renewal theory to develop accurate probability distributions for the formation and destruction of re-entrant circuits in AF.17 We have shown that the renewal theory approach is robust in a variety of experimental conditions, and that the statistical signature of the renewal approach has been evident in all published data on phase singularity (PS) data published in the AF field.17

Analogous to this, the past five decades have seen an unceasing debate about the nature of the forces maintaining cardiac fibrillation.3–6 At the heart of this debate is the contest between those postulating fibrillation is maintained in a deterministic way, via the action of functional re-entrant drivers known as rotors, against the notion that fibrillation is sustained by more random forces, specifically multiple electrical wavelets stochastically wandering around the heart.7–10 Although other adjunctive mechanisms have been postulated to maintain fibrillation, including focal discharges and endocardial to epicardial dissociation, the core mechanistic

The renewal approach is quite different to existing approaches to deterministic modelling of AF because, at its heart, renewal theory does not seek to model particular rotor behaviours but, analogous to the quantum mechanical approach, seeks to understand the probability

AF Reconceptualised Using Renewal Theory could be triggered by pulmonary vein ectopy, the field has been revolutionised through the introduction of catheter ablation of AF. This approach has led to remarkable improvements in the efficacy of AF treatment.34–36

distributions. The power of this approach is that because of the disaggregated, uncorrelated nature of AF, the parameters of these distributions may be easier to accurately measure and model than developing precise models for each individual rotor and wavelet behaviours. Thus far, we have demonstrated it is possible to use the renewal approach in simulated, experimental and human AF.17,18

Despite this, pulmonary vein isolation (PVI) alone has only partially improved clinical outcomes in AF, with 50–60% of patients undergoing the procedure having at least some level of AF recurrence.37,38 In this context, there has been a push for new approaches to AF treatment that will improve clinical outcomes. Various strategies have been attempted, including ablation of complex electrograms, linear ablation and ablations of regions of high dominant frequency.39 All these strategies derived from observational evidence and were empirical rather than mechanistic, with none being consistently successful or reproducible at the present time.

In this review, we provide a brief overview of contemporary understanding of the AF mechanism, to place the renewal approach into context; provide a brief background on the key scientific ideas and applications of renewal theory; explain the derivation of the renewal rate constants, from starting premises in the context of AF; review current experimental data supporting the renewal approach, highlighting the consistency of evidence supporting the renewal paradigm that has accrued from multiple laboratories in the past 20 years; place the renewal theory approach into context by highlighting other scientific domains where similar ideas have been successful; and identify potential opportunities to use this conceptual paradigm in basic and clinical research into AF mechanisms.

In this context, the emergence of driver-based ablation has been an important development for the field.40 In 2012, Narayan et al. suggested not only the feasibility of using basket catheter mapping to identify rotors and focal activations driving AF, but also that these could be directly targeted via catheter ablation with improved patient clinical outcomes.41 However, other investigators have found that clinically mapped rotors are often temporally unstable and have not been able to achieve the same clinical benefit in the early focal impulse and rotor modulation (FIRM )studies, suggesting that current understanding of AF dynamics is incomplete and that new approaches to understanding fibrillatory dynamics are needed.42–44

Contemporary Understanding of the AF Mechanism

Although the origins of the rotor theory of fibrillation began with the detection of circular electrical waves in AF by Sir Thomas Lewis more than 100 years ago, it was the demonstration of spiral waves by Winfree in chemical media, and subsequently in cardiac fibrillation, that placed rotors at the centre of modern fibrillatory dynamics.19–24 Contemporary understanding of the mechanistic role of rotors in fibrillatory dynamics has been pioneered by the Jalife laboratory. In a series of studies, the Jalife group defined a critical role for rotors as the drivers of both VF and AF.7,8,25–28 Rotors, by leading to the synchronised rotational activation of regions within their domain, have been proposed as the deterministic drivers of AF.3 Rotors are organised regions of high activation frequency, with the aperiodic turbulence of AF believed to occur via the breakdown of these high-frequency domains due to wave break in surrounding areas with slower conduction.29,30

At the present time, the field of fibrillatory dynamics is, in some sense, in a state of flux. Mirroring the debate on randomness and determinism in quantum mechanics, many leading figures in the AF field advocate for a continuing search for critical drivers sustaining fibrillation as the key to improving treatment. However, alternative voices argue that fibrillation is maintained by the activity of more random wavelet dynamics and that modifying the atrial substrate is more important. Regardless, it is clear that, at the present time, fresh ideas are needed beyond PVI in the catheter ablation field, which can only be achieved by better understanding of the fibrillatory mechanism.40

However, support for the notions of rotors as drivers of fibrillation has not been universal. The pioneering computational studies of Moe and Abildskov postulated multiple wavelet theory as an alternative hypothesis to explain fibrillation.9,10,31 The key element of this theory was the premise that wave fragmentation and re-entry formation occurred via stochastic processes reliant on the inhomogeneous spatial distribution of tissue refractoriness. Support for the multiple wavelet theory in the experimental sense was led by Maurits Allesie, who failed to find evidence of rotors in human studies of AF.32 However, an important limitation of the multiple wavelet theory is that it was a descriptive rather than a statistical theory, and was thus unable to make testable quantitative predictions on the nature of fibrillatory behaviour, or provide links to the understanding of stochastic processes in comparable natural systems.33

Recently, we demonstrated a potential common link that could potentially reconcile these two competing notions of AF, with the reproducible finding that unstable re-entrant circuits are born and destroyed at quasistationary rates.17 This can be defined and predicted using a branch of mathematics known as renewal theory. In the next section we explain and place into context this new finding and discuss the clinical and mechanistic implications for the development of new approaches to AF ablation.

Renewal Theory: An Approach to Understanding the Probability Distributions of Statistically Independent Events

Renewal theory is a branch of probability theory that seeks to understand and model the probability distributions of statistically independent events. The mathematics of renewal theory are somewhat complex, but the key principles and power of renewal theory can be understood with the help of some relatively simple analogies.

Important adjunctive theories of AF have been the theory of focal discharges and endoepicardial breakthrough theories.11,13–15 These theories of AF have arisen due to the detection of spontaneous activations visible on the endo- and epicardial surfaces of the atrium in AF, postulating AF is sustained by repetitive focal activation or breakthrough of electrical activations between the myocardial surfaces.

A classic example of a renewal process is flipping a fair coin, whose outcome is a head or a tail. If a coil is flipped once, the outcome (head or tail) is uncertain, but each may occur with a probability of 50%. If the coin is flipped 10 times, we would anticipate that although the most likely outcome is five heads and five tails, other outcomes are possible. However, if we flipped the coin 1,000 or 10,000 times, we would expect

The mechanistic debate about fibrillatory mechanisms has had a profound effect on clinical practice in the past decade, particularly for the treatment of AF. After the watershed demonstration that paroxysmal AF episodes

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AF Reconceptualised Using Renewal Theory Figure 1: Properties of the Poisson Renewal Process Individual events in the series are independent

X1 1

Xn 7

5 4

0.6

Count N(t)

New event

h(t)

Interevent time

The cumulative hazard of events is a straight line (cumulative hazard)

The long-term average event rate (events per unit time) is constant C

Probability (%)

The probability distribution of interevent times is exponential

20 10

Time

500

1000

Time

Xn New event

500

1000

Time

that the probabilities for heads and tails would be much closer to 50% each and can be estimated with great accuracy. Other examples could be rolling a dice or spinning a roulette wheel. On any individual realisation of the system, the outcome is very difficult to predict. However, if each of these systems is observed over many rolls or spins, the outcome probabilities will converge and the underlying probability distributions can be identified with a high degree of accuracy.

N(t)

0.1 0

Arrival time

In the case of interformation event times, the probability distribution yields the rate constant λf , which, in effect, is the long-term average formation rate of PS. In the case of PS lifetimes, this probability distribution yields λd, which is the average rate of destruction of PS. From the above equation, λf is derived from fitting a distribution to interevent formation times and λd from fitting a distribution to PS lifetimes. The close correlation of λf and λd calculated from event time distributions to that derived directly from PS time series data has been demonstrated.17

The same kind of notion, namely that statistically independent events will eventually converge to predictable probability distributions, is the basis of renewal theory. In a renewal process, although the timing of individual events is statistically independent, the long-term rate of the event occurrence arises from a specific probability distribution.45 The simplest type of renewal process is a Poisson process, in which the underlying event rate is constant (Figure 1). A characteristic of this type of renewal process is that interevent times follow an exponential distribution. Mathematically, it can be shown that if the interevent times follow an exponential distribution, then the underlying data generating process is a Poisson renewal process.46

Renewal Processes in Nature

Renewal processes are a common motif in many other natural systems, ranging from radioactive decay to action potential firing in neurons and survival analysis.45,47,48 The Poisson process and exponential distribution are explained as inevitably arising in natural systems through the actions of multiple uncorrelated microscopic processes.45 The notion of statistically independent particle behaviour leading to predictable probability distributions, known as Stosszahlansatz, or the molecular chaos theory, underlies the kinetic theory of gases and is the basis of statistical mechanics.49

Rationale for a Renewal Theory Approach in AF

The most familiar example of a renewal process illustrating convergence to an exponential distribution is radioactive decay. If we take a lump of a radioactive isotope, the timings of individual atomic decays are statistically independent, due to probabilistic quantum tunnelling events, but the decay rate converges to a stable rate over time. This produces characteristic decay curves for individual radioisotopes, enabling the decay rate to be determined with great accuracy, which is the underlying principle used in the construction of atomic clocks.

The defining property that sets apart AF from other arrhythmias is disaggregated, disorganised and turbulent electrical wave propagation in terms of wave propagation in space and time.50,51 This breakdown in coherence has been conceptualised as a conservative, non-dissipative form of chaos.52–54 In our study, we reasoned that, given the highly disorganised nature of AF, the formation and destruction of re-entrant circuits in AF could reasonably be considered statistically independent events.17 Our suggested rationale for this proposition is that because of the disorganised nature of AF, where wave propagation is disaggregated, events in one part of the chamber are effectively statistically independent of events in other parts of the atrial chamber. This has recently been examined by consideration of the autocorrelation of PS interval series, which converge to zero in the case of non-zero interval lags.55

The key properties of a Poisson renewal process are summarised in Figure 1. Specifically: individual events in the series are independent (i.e. the occurrence of one has no bearing on the probability another event will occur); the probability distribution of interevent times is exponential; the long-term average event rate (events per unit time) is constant (constant hazard property); and the cumulative hazard of events is a straight line (cumulative hazard).

Mathematical Properties of the Poisson Renewal Processes

The renewal rate constants are readily calculated using a maximum likelihood-based approach by fitting to an exponential distribution using the following equation: f(t) = λe−λt t ≥ 0 …(1)

If the formation and destruction of re-entrant circuits was statistically independent, we reasoned, by analogy with other systems where statistical independence is a key property, that the formation and destruction rates of re-entrant circuits in AF should converge to a constant rate.17 This would be expected to yield, under the principles of renewal theory, an exponential distribution of interformation times and re-entrant circuit lifetimes.

where t is time and λ is the PS destruction or formation rate (referred to as λd and λf , respectively.17

An interesting point to consider is why re-entrant circuits are intrinsically vulnerable to a process of generation and destruction. A clue may be

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AF Reconceptualised Using Renewal Theory Figure 2: Evidence for Renewal Theory Approach in AF

λd = 4.6 %/ms 0

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Adapted from: Dharmaprani et al.17 Used with permission from Wolters Kluwer Health.

optical mapping.27 Chen et al. demonstrated that PS in this model had a mean lifespan of 19.5 ± 3.8 ms, and examination of the published histogram of the data from that paper showed the characteristic shape of an exponential distribution.27 Similar findings were observed in another study.56 In that study, rotor lifetimes were examined in epicardial mapped recordings from patients undergoing cardiac surgery, in both persistent and paroxysmal AF.56 Very similar findings have been observed in basket catheter recordings by Child et al.57 We have also identified the same pattern of PS lifetimes in VF from multiple distinguished laboratories.29,58–61 The convergence of renewal rates of PS formation and destruction conforms with models of spiral wave chaos showing quasi-stationary steady state numbers of PS.62

found in the description of a rotor PS by Winfree. In his seminal monograph on spiral wave dynamics, Winfree provides a critical explanation as to why generation of new PS occurs: “[Because] every phase of the cycle [is] simultaneously always present… [the] timing of a stimulus is then no longer critical, whenever it will find somewhere a strip of tissue in the critical phase”.22 By the same explanation, because all phases of the cycle are simultaneously always present, any PS is intrinsically vulnerable to annihilation by an incoming wavefront. In an arrhythmia with disaggregated and spatially separated PS-like AF, the annihilation of the PS is thus statistically inevitable and accounts for the destruction of PS. This provides an explanation for the exponential-type distribution of PS lifetimes that is universally observed in fibrillation.

A key question is why this exponential pattern of PS lifetimes repeatedly and reproducibly arises in both AF and VF. We reason that this is due to the disaggregated and turbulent nature of wave propagation that defines AF. In essence, because PS formation and destruction events are determined by local electrical activity in particular regions of the atrium, they become statistically independent of PS formation and destruction events at spatially separated regions of the atrium. Over time, this statistical independence yields a quasi-stationary rate of decay of formation and destruction times, which accounts for the reproducibility of the renewal paradigm.

Evidence for a Renewal Theory Approach in AF

Recently, we studied interevent times for PS formation events and PS lifetimes in several systems, including included human persistent AF (basket catheter mapping) and rat AF (optical mapping) (Figure 2).17 The key finding of our study was that in all systems studied, the distribution of PS inter-formation event times and PS formation times were consistent with exponential distributions.

Consistency of Our Renewal Findings with Prior Published Literature

Rationale for Focusing on Phase Singularities

The powerful consistency of the renewal pattern identified in our experimental observations has received insufficient emphasis in the published literature on PS dynamics. In our study, we performed a systematic review identifying key studies in the field that had shown very similar findings of an exponential distribution of PS lifetimes, but where this pattern had not been recognised by the investigators at the time (Figure 3).

The rationale for focusing on PS in AF is that these are located both at the heart of re-entrant circuits and at the free ends of wavelets during fibrillation. Gray et al. identified some key rules regarding PS based on principles of topology: phase lines cannot intersect; PS are joined by other isophasic lines to PS of opposite chirality or non-conducting boundaries; and PS form and terminate as oppositely rotating pairs.8 In our study, we reasoned that because PS are effectively subject to a quasi-stationary rate of decay, an exponential distribution should be observed in both PS overall and the subset of PS that are longer-lasting and have undergone one or multiple rotations.17 In fact, this is what we

The first study was from the group of Chen et al., using the classic cholinergic model of AF in the explanted sheep heart, mapped with

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AF Reconceptualised Using Renewal Theory Figure 3: Evidence of an Exponential Shape of Phase Singularity and Rotor Lifetimes in Two Models of AF 300 300

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The left panel shows phase singularity (PS) lifetimes from the classical cholinergic model of AF, mapped using optical mapping in the Jalife laboratory.24–28 The right panel shows rotor lifetimes mapped using epicardial electrogram recordings from human patients at cardiac surgery from the Schötten laboratory.52 In both examples, consistent with our data (Figure 2), an exponential distribution of PS lifetimes and rotors can be seen.17,18 This is consistent with the notion of quasi-stationary decay dynamics of unstable re-entrant circuits. PersAF = persistent AF. Source: Kuklik et al.56 and Chen et al.27 Used with permission from the IEEE and Oxford University Press.

deep mathematical structure to enable predictions about future behaviour. At present, in our current conceptualisation of renewal theory, we have not directly addressed the focal discharge or endoepicardial theories of AF because we have not had access to datasets in AF that were used to identify these potential mechanisms. However, we would hypothesise that renewal rate constants on the endoepicardial surfaces could potentially be correlated in individual atria; in relation to the focal discharge theory, under the renewal conceptualisation of AF, we would postulate that such focal discharges should converge to occur at temporally stable rates due to the fact they would not be expected to be correlated in space or time.

observed.17 We also noted that groups who have focused on PS arising only from re-entrant circuits that have undergone a complete rotation also find an exponential distribution of PS lifetimes. In effect, this would suggest that PS at the free ends of wavelets and those at the centre of rotors are effectively one class on a biological continuum, rather than being separate classes of re-entrant circuits.

Renewal Theory: A Conceptual Approach to Unify AF Mechanisms?

On the one hand, the characterisation of AF as a renewal process is intuitive and natural, given the essentially disaggregated nature of wave propagation in AF in space and time. An important concept is that renewal of PS provides a crucial link between the multiple wavelet and rotor theories of AF. An intriguing possibility that could be considered is that the renewal approach could link existing concepts of a multiplicity of AF mechanisms and suggests the possibility of a single unified AF mechanism.6

The consistent evidence supporting renewal theory would potentially suggest that the fundamental mechanism of AF is not one of AF as sustained by driving rotors, but that AF is, in fact, sustained by a repetitive cycle of PS annihilation and regeneration.17 In this respect, renewal theory fills in a key gap in the rotor theory of AF. There are two important ideas from renewal theory useful to from characterising PS formation and destruction. The first of these ideas is that the elementary renewal theorem, that limiting the mean average rate of events, is 1/μ:65

In Moe’s original conceptualisation of the multiple wavelet theory, although re-entry was recognised to occur in qualitative terms, it had no quantitative formulation.10,31 Moe’s simple computational model could not develop spiral waves, which are a defining property of re-entry in cardiac fibrillation.63 On the other hand, the rotor theory emphasises the role of re-entry as the driver of AF, with the chaotic turbulence of the arrhythmia explained as arising due to wave break at regions of slow conduction. Again, the classical rotor theory does not provide a quantitative architecture to measure the process by which this occurs.64

M(t) t

→

1 as t → ∞ µ

where t is time, M(t) is the number of events at time t, and μ is the inverse of the average rate. In the context of rotor formation and destruction, this means that the mean rotor formation (or destruction) rate should converge to a constant rate.

The key missing piece of the rotor theory of AF has been that it has not provided a mathematical framework to model how rotors are formed and destroyed to sustain the arrhythmia over time. Characterisation of PS formation and destruction as renewal processes provides a quantitative framework to model these processes. From a mechanistic point of view, this may be appealing on several levels because it provides a robust theoretical foundation in renewal theory. Renewal theory is a branch of probability theory to model events that occur randomly in time, with the basic assumption that the times between successive events are independent and identically distributed.65 Renewal theory provides a

The second ideas is the renewal theorem (i.e. that the expected number of events in a time interval is asymptotically proportional to the length of the interval; Blackwell’s theorem):65 h For h > 0,M(t,t +h) → µ as t → ∞ In the context of rotor destruction, this would mean that the number of rotors formed (or destroyed) in a time interval h is proportional to the length of h, where h represents the interval of time.

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AF Reconceptualised Using Renewal Theory Potential Applications of the Renewal Paradigm in Mechanistic Studies

First, these constants provide readily measurable clinical markers of global AF dynamics in ongoing fibrillation, directly related to the underlying AF mechanism. In this regard, they may potentially emerge as clinically reliable markers of AF persistence and progression. A more detailed understanding of the spatial distribution of the renewal rate constants in the atrium and their relationship to atrial microarchitecture could potentially inform novel approaches to AF ablation. The fact they arise consistently and reliably and are theoretically temporally stable could make them more reliable markers of AF dynamics than other measures, such as dominant frequency,72,73 entropy74,75 or quantitative electrogram complexity analyses, which can suffer from temporal instability.38,76 A key to utilisation would be the capacity to directly estimate these parameters from surface ECG data, which is the subject of ongoing research.71 To enable the development of these as reliable physiological markers, it would be ideal to be able to develop approaches to predict λf and λd from surface ECG data to enable longitudinal non-invasive measurement of rotor formation and destruction rates in individual patients.

A specific key area of future research is determining the relationship between AF renewal processes and AF persistence and termination. In the clinical context, the progression of AF from short-lasting episodes to a longer-lasting persistent pattern of AF is associated with poorer long-term outcomes, including higher rates of stroke and mortality.67 In computational models of AF, changes in substrate characteristics are associated with changes in the number of PS and PS lifetime.68 However, these processes have been described in mainly qualitative terms.69,70 It would be reasonable to hypothesise that changes in the rate constants of PS formation and destruction may be useful in predicting the persistence or termination of AF.18

In addition, the efficacy of other ablation methods beyond that of PVI particularly for patients with persistent AF have not been proven.77 Although additional lesion sets beyond PVI have been increasingly adopted for these patients, success rates for these adjunctive approaches for these patients remains uncertain.78 Moreover, if extra lesion sets beyond PVI are created, there are no current measures that could be undertaken during the procedure to monitor the clinical efficacy of the chosen method. The renewal paradigm may provide a useful explanation as to why potential approaches to map ‘drivers’ of AF have so far been inconsistent. The use of renewal rate constants as a marker of acute success during catheter ablation procedures could potentially overcome this limitation. Real-time modulation of intraprocedural λf and λd could be used to measure effectiveness of PVI, with or without a chosen nonpulmonary vein trigger approach for patients undergoing catheter ablation for AF. Studies are underway to define the spatial variation of the renewal rate constants in the atrium.71

The renewal process paradigm could be used in several contexts to quantify the dynamics of fibrillation. The renewal rate constants could provide a powerful means to quantify the relative effects of ion channel modulation via drugs, electrical and structural remodelling and the anatomical effects of variations in microarchitecture, as well as to quantify the effect of ablation on fibrillatory dynamics. Because the renewal rate constants are a consistent feature of the biology of fibrillation, identifying their determinants becomes important to understanding the AF mechanism. It is likely that varying extents of fibrosis and gap junction coupling, which contribute to differently perceived patterns of fibrillation, could manifest these changes by alterations in the renewal rate constants under these types of alterations in underlying determinants of AF physiology.66 Renewal theory may provide a useful way of quantifying the position on the spectrum of potential physiological fibrillatory dynamic patterns, as recently envisaged by Handa et al.66

A potential strength of renewal theory is that it may well be able to provide a way to accurately quantify differences in AF pathophysiology where AF is seen to arise from different mechanistic camps (e.g. hierarchical or nonhierarchical mechanisms). In our analyses thus far, we have found the renewal theory approach to apply universally in all systems and patients studied. It would be of great scientific interest to understand the differences in renewal rate constants in different forms of AF where the causes are perceived to be different.18 We are prospectively studying these issues in the RENEWAL AF study, which will prospectively recruit patients with different clinical classifications of AF, allowing for a comparison of renewal rate constants to clinical AF features.17,71

Conclusion

To date, AF mechanisms remain unresolved. The characteristic turbulent and random nature of AF has so far led to a lack of quantitative measure to analyse AF dynamics. Renewal theory provides a new mechanistic description of AF being sustained by a repetitive cycle of PS annihilation and regeneration, which, uniquely, also allows quantitative assessment of AF dynamics that is reproducible and consistent across different measuring modalities.

The renewal rate constants have several attractive properties. Because they have a defined distributional type, they can be accurately measured via repeated sampling. Under the central limit theorem, the maximum likelihood estimate for the renewal rate constant will rapidly be able to be estimated with repeated sampling of PS. Due to the short-lasting nature of PS, it is anticipated that it will take a relatively short period of time to gain a relatively accurate and precise estimate of the renewal rate constant. The renewal rate constants will be expected to have properties of temporal stability. Due to the quasi-ergodic nature in which the uncorrelated PS formation and destruction events occur, over time it is anticipated that renewal rate estimates will converge to quasi-stationary rates. This is analogous to the way the heads–tail, dice and roulette examples converge to accurate estimates once the system is sampled for sustained periods of time.

Clinical Perspective

• The mechanisms underlying AF maintenance remain unclear. • Renewal theory is a new quantitative framework to analyse

fibrillatory dynamics in AF and has the potential to reconcile these theories by providing governing equations for the formation and destruction of phase singularity. • Renewal theory could potentially be used to monitor AF progression in patients, guiding decisions for timing of AF ablation; and to allow individualisation of ablation strategies in patients with different AF phenotypes. • Spatial characterisation of the renewal rate constants throughout the atrial chamber might allow the development of strategies that could more reproducibly lead to the termination of AF and long-term maintenance of sinus rhythm.

Future Applications of Renewal Processes in Clinical Settings

The establishment of λf and λd as a universal rate constant of PS formation and destruction has several potential applications for clinical practice.

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AF Reconceptualised Using Renewal Theory 1. Heisenberg W. On the descriptive content of quantum theoretical kinematics and mechanics. Z Physik 1927;43:172– 98 [in German]. https://doi.org/10.1007/BF01397280. 2. Werner Heisenberg. The Information Philosopher. http:// www.informationphilosopher.com/solutions/scientists/ heisenberg (accessed 8 June 2021). 3. Jalife J. Deja vu in the theories of atrial fibrillation dynamics. Cardiovasc Res 2011;89:766–75. https://doi.org/10.1093/cvr/ cvq364; PMID: 21097807. 4. Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev 2011;91:265–325. https:// doi.org/10.1152/physrev.00031.2009; PMID: 21248168. 5. Roney CH, Wit AL, Peters NS. Challenges associated with interpreting mechanisms of AF. Arrhythm Electrophysiol Rev 2020;8:273–84. https://doi.org/10.15420/aer.2019.08; PMID: 32685158. 6. Ng FS, Handa BS, Li X, Peters NS. Toward mechanismdirected electrophenotype-based treatments for atrial fibrillation. Front Physiol 2020;11:987. https://doi.org/10.3389/ fphys.2020.00987; PMID: 33013435. 7. Gray RA, Jalife J, Panfilov AV, et al. Mechanisms of cardiac fibrillation. Science 1995;270:1222–3. https://doi.org/10.1126/ science.270.5239.1222; PMID: 7502055. 8. Gray RA, Pertsov AM, Jalife J. Spatial and temporal organization during cardiac fibrillation. Nature 1998;392:75– 8. https://doi.org/10.1038/32164; PMID: 9510249. 9. Moe GK. On the multiple wavelet hypothesis of atrial fibrillation. Arch Int Pharmacodyn Ther 1962;140:183–8. 10. Moe GK, Rheinboldt WC, Abildskov JA. A computer model of atrial fibrillation. Am Heart J 1964;67:200–20. https://doi. org/10.1016/0002-8703(64)90371-0; PMID: 14118488. 11. Lee S, Sahadevan J, Khrestian CM, et al. Simultaneous biatrial high-density (510–12 electrodes) epicardial mapping of persistent and long-standing persistent atrial fibrillation in patients: new insights into the mechanism of its maintenance. Circulation 2015;132:2108–17. https://doi.org/10.1161/CIRCULATIONAHA.115.017007; PMID: 26499963. 12. de Groot NM, Houben RP, Smeets JL, et al. Electropathological substrate of longstanding persistent atrial fibrillation in patients with structural heart disease: epicardial breakthrough. Circulation 2010;122:1674–82. https://doi.org/10.1161/CIRCULATIONAHA.109.910901; PMID: 20937979. 13. Lee S, Khrestian CM, Sahadevan J, Waldo AL. Reconsidering the multiple wavelet hypothesis of atrial fibrillation. Heart Rhythm 2020;17:1976–83. https://doi.org/10.1016/j. hrthm.2020.06.017; PMID: 32585192. 14. Eckstein J, Maesen B, Linz D, et al. Time course and mechanisms of endo-epicardial electrical dissociation during atrial fibrillation in the goat. Cardiovasc Res. 2011;89:816–24. https://doi.org/10.1093/cvr/cvq336; PMID: 20978006. 15. de Groot N, van der Does L, Yaksh A, et al. Direct proof of endo-epicardial asynchrony of the atrial wall during atrial fibrillation in humans. Circ Arrhythm Electrophysiol 2016;9:e003648. https://doi.org/10.1161/CIRCEP.115.003648; PMID: 27103089. 16. Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev 2011;91:265–325. https:// doi.org/10.1152/physrev.00031.2009; PMID: 21248168. 17. Dharmaprani D, Schopp M, Kuklik P, et al. Renewal theory as a universal quantitative framework to characterise phase singularity regeneration in mammalian cardiac fibrillation. Circ Arrhythm Electrophysiol 2019;12:e007569. https://doi. org/10.1161/circep.119.007569; PMID: 31813270. 18. Dharmaprani D, Jenkins E, Aguilar M, et al. M/M/infinity birth-death processes – A quantitative representational framework to summarize and explain phase singularity and wavelet dynamics in atrial fibrillation. Front Physiol 2021;11:1786. https://doi.org/10.3389/fphys.2020.616866; PMID: 33519522. 19. Lewis T. Observations of the movements of the heart by means of electrocardiograms. J R Soc Med 1912;5:189–92. https://doi.org/10.1177/003591571200500270. 20. Winfree AT. Spiral waves of chemical activity. Science 1972;175:634–6. https://doi.org/10.1126/ science.175.4022.634; PMID: 17808803. 21. Winfree AT. Stably rotating patterns of reaction and diffusion. In: Eyring H, Henderson D, eds. Theoretical Chemistry. Cambridge, MA: Academic Press, 1978;1–51. https://doi.org/10.1016/B978-0-12-681904-5.50007-3. 22. Winfree AT. When Time Breaks Down: The Three-Dimensional Dynamics of Electrochemical Waves and Cardiac Arrhythmias. Princeton, NJ: Princeton University Press, 1987. 23. Winfree AT. Excitable kinetics and excitable media. In: The Geometry of Biological Time. Interdisciplinary Applied

Mathematics, vol 12. New York: Springer, 2001;258–302. 24. Witkowski FX, Leon LJ, Penkoske PA, et al. Spatiotemporal evolution of ventricular fibrillation. Nature 1998;392:78–82. https://doi.org/10.1038/32170; PMID: 9510250. 25. Jalife J, Berenfeld O, Skanes A, Mandapati R. Mechanisms of atrial fibrillation: mother rotors or multiple daughter wavelets, or both? J Cardiovasc Electrophysiol 1998;9(8 Suppl):S2–12. PMID: 9727669. 26. Skanes AC, Mandapati R, Berenfeld O, et al. Spatiotemporal periodicity during atrial fibrillation in the isolated sheep heart. Circulation 1998;98:1236–48. https://doi.org/10.1161/01. CIR.98.12.1236; PMID: 9743516. 27. Chen J, Mandapati R, Berenfeld O, et al. Dynamics of wavelets and their role in atrial fibrillation in the isolated sheep heart. Cardiovasc Res 2000;48:220–32. https://doi. org/10.1016/S0008-6363(00)00177-2; PMID: 11054469. 28. Mandapati R, Skanes A, Chen J, et al. Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart. Circulation 2000;101:194–9. https://doi. org/10.1161/01.CIR.101.2.194; PMID: 10637208. 29. Chen J, Mandapati R, Berenfeld O, et al. High-frequency periodic sources underlie ventricular fibrillation in the isolated rabbit heart. Circ Res 2000;86:86–93. https://doi. org/10.1161/01.RES.86.1.86; PMID: 10625309. 30. Kalifa J, Tanaka K, Zaitsev AV, et al. Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation 2006;113:626–33. https://doi.org/10.1161/CIRCULATIONAHA.105.575340; PMID: 16461834. 31. Moe GK, Abildskov JA. Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge. Am Heart J 1959;58:59–70. https://doi.org/10.1016/0002-8703(59)902741; PMID: 13661062. 32. Allessie MA, Lammers W, Bonke FIM, et al. Experimental evaluation of Moe’s multiple wavelet hypothesis of atrial fibrillation. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology and Arrhythmias. Orlando, FL: Grune & Stratton; 1985;265–76. 33. Panfilov A, Pertsov A. Ventricular fibrillation: evolution of the multiple-wavelet hypothesis. Phil Trans R Soc Lond A 2001;359:1315–25. https://doi.org/10.1098/rsta.2001.0833. 34. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659–66. https:// doi.org/10.1056/NEJM199809033391003; PMID: 9725923. 35. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary. J Interv Card Electrophysiol 2017;50:1–55. https:// doi.org/10.1007/s10840-017-0277-z; PMID: 28914401. 36. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. https://doi.org/10.1093/eurheartj/ehw210; PMID: 27567408. 37. Ganesan AN, Shipp NJ, Sanders P, et al. Long-term outcomes of catheter ablation of atrial fibrillation: a systematic review and meta-analysis. J Am Heart Assoc 2013;2:e004549. https://doi.org/10.1161/JAHA.112.004549; PMID: 23537812. 38. 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. 39. Baumert M, Sanders P, Ganesan A. Quantitativeelectrogram-based methods for guiding catheter ablation in atrial fibrillation. Proc IEEE 2016;104:416–31. https://doi. org/10.1109/JPROC.2015.2505318. 40. Kistler PM, Chieng D. Persistent atrial fibrillation in the setting of pulmonary vein isolation – where to next? J Cardiovasc Electrophysiol 2020;31;1857–60. https://doi. org/10.1111/jce.14298; PMID: 31778259. 41. Narayan SM, Krummen DE, Shivkumar K, et al. Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol 2012;60:628–36. https://doi.org/10.1016/j. jacc.2012.05.022; PMID: 22818076. 42. Parameswaran R, Voskoboinik A, Gorelik A, et al. Clinical impact of rotor ablation in atrial fibrillation: a systematic review. Europace 2018;20:1099–106. https://doi.org/10.1093/ europace/eux370; PMID: 29340595. 43. Steinberg JS, Shah Y, Bhatt A, et al. Focal impulse and rotor modulation: acute procedural observations and extended clinical follow-up. Heart Rhythm 2017;14:192–7. https://doi. org/10.1016/j.hrthm.2016.11.008; PMID: 27826130. 44. Berntsen RF, Cheng A, Calkins H, Berger RD. Evaluation of spatiotemporal organization of persistent atrial fibrillation

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

with time- and frequency-domain measures in humans. Europace 2009;11:316–23. https://doi.org/10.1093/europace/ eun307; PMID: 19008240. 45. Kingman JFC. Stochastic models for random sets of points. In: Poisson Processes. Oxford: Oxford University Press, 1993. 46. Gallager RG. Discrete Stochastic Processes. Springer, 2012. 47. Song S, Lee JA, Kiselev I, et al. Mathematical modeling and analyses of interspike-intervals of spontaneous activity in afferent neurons of the zebrafish lateral line. Sci Rep 2018;8:14851. https://doi.org/10.1038/s41598-018-33064-z; PMID: 30291277. 48. Lee ET, Wang JW. Some well-known parametric survival distributions and their applications. In: Statistical Methods for Survival Data Analysis. Wiley, 2003:134–61. https://doi. org/10.1002/0471458546.ch6. 49. Ashley S. Core concept: ergodic theory plays a key role in multiple fields. Proc Natl Acad Sci USA 2015;112:1914. https:// doi.org/10.1073/pnas.1500429112; PMID: 25691699. 50. Botteron GW, Smith JM. Quantitative assessment of the spatial organization of atrial fibrillation in the intact human heart. Circulation 1996;93:513–8. https://doi.org/10.1161/01. CIR.93.3.513; PMID: 8565169. 51. Gerstenfeld EP, Sahakian AV, Swiryn S. Evidence for transient linking of atrial excitation during atrial fibrillation in humans. Circulation 1992;86:375–82. https://doi. org/10.1161/01.CIR.86.2.375; PMID: 1638706. 52. Qu Z, Weiss JN, Garfinkel A. From local to global spatiotemporal chaos in a cardiac tissue model. Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics 2000;61:727– 32. https://doi.org/10.1103/PhysRevE.61.727; PMID: 11046316. 53. Qu Z, Hu G, Garfinkel A, Weiss JN. Nonlinear and stochastic dynamics in the heart. Phys Rep 2014;543:61–162. https://doi. org/10.1016/j.physrep.2014.05.002; PMID: 25267872. 54. Garfinkel A, Chen PS, Walter DO, et al. Quasiperiodicity and chaos in cardiac fibrillation. J Clin Invest 1997;99:305–14. https://doi.org/10.1172/JCI119159; PMID: 9005999. 55. Dharmaprani D, Jenkins E, Aguilar M, et al. M/M/infinity birth–death processes – a quantitative representational framework to summarize and explain phase singularity and wavelet dynamics in atrial fibrillation. Front Physiol 2021;11:616866. https://doi.org/10.3389/fphys.2020.616866; PMID: 33519522. 56. Kuklik P, Zeemering S, van Hunnik A, et al. Identification of rotors during human atrial fibrillation using contact mapping and phase singularity detection: technical considerations. IEEE Trans Biomed Eng 2017;64:310–8. https://doi.org/10.1109/ TBME.2016.2554660; PMID: 27101596. 57. Child N, Clayton RH, Roney CR, et al. Unraveling the underlying arrhythmia mechanism in persistent atrial fibrillation: results from the STARLIGHT study. Circ Arrhythm Electrophysiol 2018;11:e005897. https://doi.org/10.1161/ CIRCEP.117.005897; PMID: 29858382. 58. Christoph J, Chebbok M, Richter C, et al. Electromechanical vortex filaments during cardiac fibrillation. Nature 2018;555:667. https://doi.org/10.1038/nature26001; PMID: 29466325. 59. Rogers JM. Combined phase singularity and wavefront analysis for optical maps of ventricular fibrillation. IEEE Trans Biomed Eng 2004;51:56–65. https://doi.org/10.1109/ TBME.2003.820341; PMID: 14723494. 60. Li X, Roney CH, Handa BS, et al. Standardised framework for quantitative analysis of fibrillation dynamics. Sci Rep 2019;9:16671. https://doi.org/10.1038/s41598-019-52976-y; PMID: 31723154. 61. Schlemmer A, Berg S, Lilienkamp T, et al. Spatiotemporal permutation entropy as a measure for complexity of cardiac arrhythmia. Front Phys 2018;6. https://doi.org/10.3389/ fphy.2018.00039. 62. Vidmar D, Rappel WJ. Extinction dynamics of spiral defect chaos. Phys Rev E 2019;99:012407. https://doi.org/10.1103/ PhysRevE.99.012407; PMID: 30780268. 63. Comtois P, Kneller J, Nattel S. Of circles and spirals: bridging the gap between the leading circle and spiral wave concepts of cardiac reentry. Europace 2005;7(Suppl 2):10– 20. https://doi.org/10.1016/j.eupc.2005.05.011; PMID: 16102499. 64. Jalife J, Berenfeld O, Mansour M. Mother rotors and fibrillatory conduction: a mechanism of atrial fibrillation. Cardiovasc Res 2002;54:204–16. https://doi.org/10.1016/ S0008-6363(02)00223-7; PMID:12062327. 65. Resnick SI. Adventures in Stochastic Processes. Springer Science & Business Media, 2013. 66. Handa BS, Li X, Baxan N, et al. Ventricular fibrillation mechanism and global fibrillatory organisation are determined by gap junction coupling and fibrosis pattern. Cardiovasc Res 2021;117:1078–90. https://doi.org/10.1093/cvr/ cvaa141; PMID: 32402067. 67. Ganesan AN, Chew DP, Hartshorne T, et al. The impact of atrial fibrillation type on the risk of thromboembolism,

AF Reconceptualised Using Renewal Theory mortality, and bleeding: a systematic review and metaanalysis. Eur Heart J 2016;37:1591–602. https://doi. org/10.1093/eurheartj/ehw007; PMID: 26888184. 68. Zou R, Kneller J, Leon LJ, Nattel S. Substrate size as a determinant of fibrillatory activity maintenance in a mathematical model of canine atrium. Am J Physiol Heart Circ Physiol 2005;289:H1002–12. https://doi.org/10.1152/ ajpheart.00252.2005; PMID: 15849234. 69. Kneller J, Kalifa J, Zou R, et al. Mechanisms of atrial fibrillation termination by pure sodium channel blockade in an ionically-realistic mathematical model. Circ Res 2005;96:e35–47. https://doi.org/10.1161/01. RES.0000160709.49633.2b; PMID: 15731458. 70. Biffi M, Boriani G, Bronzetti G, et al. Electrophysiological effects of flecainide and propafenone on atrial fibrillation cycle and relation with arrhythmia termination. Heart 1999;82:176–82. https://doi.org/10.1136/hrt.82.2.176; PMID: 10409531. 71. Quah J, Dharmaprani D, Lahiri A, et al. Prospective cross-

sectional study using Poisson renewal theory to study phase singularity formation and destruction rates in atrial fibrillation (RENEWAL-AF): study design. J Arrhythm 2020;36:660–7. https://doi.org/10.1002/joa3.12363; PMID: 32782637. 72. Habel N, Znojkiewicz P, Thompson N, et al. The temporal variability of dominant frequency and complex fractionated atrial electrograms constrains the validity of sequential mapping in human atrial fibrillation. Heart Rhythm 2010;7:586–93. https://doi.org/10.1016/j.hrthm.2010.01.010; PMID: 20156614. 73. Jarman JW, Wong T, Kojodjojo P, et al. Spatiotemporal behavior of high dominant frequency during paroxysmal and persistent atrial fibrillation in the human left atrium. Circ Arrhythm Electrophysiol 2012;5:650–8. https://doi.org/10.1161/ CIRCEP.111.967992; PMID: 22722660. 74. Dharmaprani D, McGavigan AD, Ganesan AN, et al. Temporal stability and specificity of high bipolar electrogram entropy regions in sustained atrial fibrillation. J Electrocardiol

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

75.

76.

77.

78.

2019;53:18–27. https://doi.org/10.1016/j. jelectrocard.2018.11.014; PMID: 30580097. Dharmaprani D, Dykes L, McGavigan AD, et al. Information theory and atrial fibrillation (AF): a review. Front Physiol 2018;9:957. https://doi.org/10.3389/fphys.2018.00957; PMID: 30050471. Lau DH, Maesen B, Zeemering S, et al. Stability of complex fractionated atrial electrograms: a systematic review. J Cardiovasc Electrophysiol 2012;23:980–7. https://doi. org/10.1111/j.1540-8167.2012.02335.x; PMID: 22554025. Brooks AG, Stiles MK, Laborderie J, et al. Outcomes of longstanding persistent atrial fibrillation ablation: a systematic review. Heart Rhythm 2010;7:835–46. https://doi.org/10.1016/j. hrthm.2010.01.017; PMID: 20206320. Ganesan AN, Shipp NJ, Brooks AG, et al. Long-term outcomes of catheter ablation of atrial fibrillation: a systematic review and meta-analysis. J Am Heart Assoc. 2013;2:e004549. https://doi.org/10.1161/JAHA.112.004549; PMID: 23537812.

Cardiac Pacing

Troubleshooting Programming of Conduction System Pacing Elise Bakelants

and Haran Burri

Department of Cardiology, University Hospital of Geneva, Geneva, Switzerland

Abstract

Conduction system pacing (CSP) comprises His bundle pacing and left bundle branch area pacing and is rapidly gaining widespread adoption. Effective CSP not only depends on successful system implantation but also on proper device programming. Current implantable impulse generators are not specifically designed for CSP. Either single chamber, dual chamber or CRT devices can be used for CSP depending on the underlying heart rhythm (sinus rhythm or permanent atrial arrhythmia) and the aim of pacing. Different programming issues may arise depending on the device configuration. This article aims to provide an update on practical considerations for His bundle and left bundle branch area pacing programming and follow-up.

Keywords

Conduction system pacing, His bundle pacing, left bundle branch area pacing, programming, troubleshooting Disclosure: HB has received institutional fellowship support/research grants or consultancy/speaker fees from Abbott, Biotronik, Boston Scientific, Medtronic and Microport. EB has no conflicts to declare. Received: 7 April 2021 Accepted: 12 May 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(2):85–90. DOI: https://doi.org/10.15420/aer.2021.16 Correspondence: Haran Burri, Cardiac Pacing Unit, Cardiology Department, University Hospital of Geneva, Rue Gabrielle-Perret-Gentil 4, CH-1211 Geneva, Switzerland. E: haran.burri@hcuge.ch 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.

Conduction system pacing (CSP) is gaining widespread adoption as an alternative to right ventricular (RV) pacing and – in some instances – as an alternative to biventricular pacing for CRT.1 Whereas tools are evolving to facilitate implantation, there are currently no generators specifically designed to facilitate programming of CSP. Proper device programming is essential to ensure patient safety and obtain the greatest benefit from pacing therapy. Programming of His bundle pacing (HBP) has its challenges, which have been previously covered in depth.2 This review aims to provide an update on HBP programming and to outline the specificities of left bundle branch area pacing (LBBAP).

and far-field device electrogram).4 This could be time-sparing in the busy device clinic, but does not, as yet, replace the 12-lead ECG. Several ECG belts are commercially available that may streamline 12-lead ECG recordings.

General Considerations Device Labelling

Long-term results regarding lead revision for LBBAP remain to be published, but recent mid-term data show stable and high sensed R wave amplitudes and low capture thresholds.6 Pending more data on lead stability and long-term lead performance, patients implanted with an LBBAP lead are still followed-up on a 6-monthly basis at our institution, but this may change to a yearly basis in the future.

Follow-up Frequency

In general, follow-up of HBP is performed directly after implantation, after 1, 3 and 6 months, then continued on a 6-monthly basis. This may be more frequent than with standard pacing (usually seen yearly) due to loss of HBP in up to 17% of patients and necessity for lead revision in up to 11% of patients.5

As current implantable pulse generators are not specifically designed for CSP, it is important to indicate in the implanted device and on the patient’s device card that a CSP lead – either HBP or LBBAP – is present and which port it is connected to. This is particularly relevant when the lead is connected to the atrial port of the generator. This configuration may be confusing, as it may be mistakenly assumed during device interrogation that the atrial lead has dislodged into the ventricle.

Device Configuration

The port of the generator to which the CSP lead is connected to depends upon the baseline rhythm (sinus rhythm versus chronic atrial arrhythmia), presence of a ventricular backup lead, and indication for pacing therapy (anti-bradycardia pacing versus CRT).

Importance of the 12-lead ECG

When performing threshold tests, a 12-lead ECG is of utmost importance to recognise the various types of capture (selective versus non-selective conduction system capture, myocardial capture only or anodal capture). ECG analysis of HBP has been previously covered.3

Single-chamber devices are used with CSP in case of chronic atrial arrhythmias. Dual-chamber devices may be used either in sinus rhythm with an atrial and a CSP lead or – in case of chronic atrial arrhythmia – with a CSP lead connected to the atrial port and a backup right ventricular pacing lead (used in selected cases of HBP, and seldom with LBBAP) or in case of an ICD.

Recently, criteria have been proposed to differentiate between HBP morphologies and RV septal capture by careful analysis of the near-field

Troubleshooting Programming of Conduction System Pacing Table 1: Programming Recommendations for Conduction System Pacing Parameter

Recommendation HBP

Recommendation LBBAP

Pacing mode

Single-chamber device: VVI Dual-chamber or CRT device: • HBP lead in a ventricular port: DDD(R), DDI or managed ventricular pacing mode • HBP lead in atrial port (chronic AF) with backup ventricular lead: DDD(R), DDI(R) or DVI(R) if available

Single-chamber device: VVI Dual-chamber or CRT device: • LBBAP lead in a ventricular port: DDD(R), DDI or managed ventricular pacing mode. • LBBAP lead in atrial port (chronic AF) with backup ventricular or ICD lead: DDI(R) or DVI(R) if available

Pacing polarity

Unipolar (better visibility of the pacing spike to avoid confounding with Bipolar (lower current drain due to higher impedance; anodal intrinsic rhythm, lower capture thresholds) capture may narrow the QRS) Bipolar (lower durrent drain due to higher impedance) Unipolar if anodal capture is not desirable

Sensing vector

Bipolar (unipolar can be tried if low sensing amplitude or P wave/HB potential oversensing)

Sensitivity

HBP lead connected to atrial channel: set to the maximum value Usually, not an issue as R waves are of high amplitude (minimum sensitivity), as ventricular sensing is provided by the backup ventricular lead HBP lead connected to RV channel: adjust the level to ensure ventricular sensing, yet avoid oversensing of atrial or HB potentials

Output voltage

2 × threshold voltage Fixed safety margin, e. g. 1 V above the threshold, in non-dependent patients

2 × threshold voltage

Impulse duration

0.4 ms (1.0 ms if high capture threshold). 0.2–0.4 ms may be programmed according to chronaxie

0.4 ms (capture threshold is rarely an issue)

Automatic capture control algorithms

Deactivate, monitoring only (may be inaccurate or impossible to measure, especially if the HBP lead is connected to the atrial port)8, or activate only once the accuracy has been confirmed in the patient

Set to monitor or automatic once the accuracy has been confirmed in the patient

AV delay

HBP lead in ventricular port: Subtract HV interval (e.g. 40 ms) from desired AV interval HBP lead in atrial port with backup ventricular pacing: AV delay >His pace-RVS interval (e.g. 150 ms) HBP lead in atrial port with HOT-CRT: optimise AV interval based on QRS narrowing, or program empirically to 60% of the His pace – RV sense interval (usually 40–60 ms)8

LBBAP lead in ventricular port: Subtract LBB-V interval (e.g. 20 ms) from desired AV interval LBBAP lead in atrial port with backup ventricular pacing: AV delay >LBBAP–RVS interval (e.g. 150 ms) LBBAP lead in atrial port with LOT-CRT: optimise AV interval based on QRS narrowing

VV delay (CSP lead connected to LV port)

With backup RV pacing: program maximum LV channel pre-excitation (e.g 80 ms) In case fusion with RV pacing is desirable (e.g. in case of uncorrected RBBB): program LV channel pre-excitation 30–60 ms, optimised by surface ECG

With backup RV pacing (e.g. with ICD lead): program maximum LV channel pre-excitation (e.g 80 ms)

Ventricular safety pacing

Deactivate if the HBP lead is connected to the atrial port with an RV back-up lead, after having verified absence of crosstalk

Deactivate if the LBBAP lead is connected to the atrial port with an RV back-up lead (e.g. with an ICD or in case of LOT-CRT), after having verified absence of crosstalk

Automatic sensing control algorithms

Deactivate (P wave oversensing and HB sensing (may lead to asystole!) Can be left on

Sensing if CSP lead connected to LV port

Deactivate (Biotronik, Boston-Scientific)

Bipolar

Deactivate (Biotronik, Boston-Scientific)

AV and VV optimisation algorithms Deactivate

Deactivate

Ventricular triggered pacing (ventricular sense response, etc.)

Deactivate

AV = atrioventricular; CSP = conduction system pacing; HB = His bundle; HBP = His bundle pacing; HV = His-ventricle; HOT-CRT = His-optimised CRT; LBB = left bundle branch; LBBAP = left bundle branch area pacing; LOT-CRT = left bundle branch pacing optimised CRT; LV = left ventricular; RBBB = right bundle branch block; RV = right ventricular; VSP = ventricular safety pacing; VV = interventricular.

Programming Considerations

Biventricular devices may be used in the setting of sinus rhythm with an atrial lead, a CSP lead connected to the left ventricular (LV) port and an RV backup pacing or ICD lead. In patients with chronic atrial arrhythmias, the CSP lead is connected to the atrial port, with RV and LV leads to provide His-optimised CRT (HOT-CRT) or left bundle branch-optimised CRT (LOTCRT), whereby CSP is combined with the right and/or left ventricular pacing to optimise electrical synchrony.7,8

Pacing Mode

The programmed parameters will very much depend upon the device configuration and the indication for pacing therapy.

Patients with dual-chamber or biventricular devices are most often programmed to the DDD(R) mode. If intrinsic conduction is present and

Table 1 provides an overview of programming recommendations for CSP. CSP lead connected to a ventricular port: Patients with chronic atrial arrhythmias and a single-chamber device may be programmed to a VVI(R) mode.

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Troubleshooting Programming of Conduction System Pacing Figure 1: T Wave Oversensing in the AAI(R) Mode

Left panel: Real-time electrogram of a patient with heart failure (left ventricular ejection fraction 30%) and permanent AF implanted with a DDD-ICD (left bundle branch area pacing lead connected to the atrial port to provide antibradycardia pacing). The device was programmed AAI 85/min. There is oversensing of the T wave in the atrial channel, resulting in a lower pacing rate than programmed. This issue was resolved by reprogramming to a DDI(R) mode (right panel), resulting in the T wave falling in the post-ventricular atrial refractory period. A reduction in sensitivity of the atrial channel was also programmed.

desirable in patients in sinus rhythm, a pacing algorithm to avoid ventricular pacing (e.g. ‘managed ventricular pacing’, Medtronic) or DDI(R) mode may be programmed.

(i.e. capture from the CSP lead tip plus the RV lead ring), which can lead to transitions in QRS morphology during threshold testing and should not be mistaken as proof of conduction system capture.9

CSP lead connected to the atrial port: The DDI(R) mode may be programmed in most instances. This is particularly important in case of LBBAP due to sensing amplitudes that are often above the maximum programmable values (e.g. 4 mV) of the atrial channel. If the device is programmed in the DDD mode, a ventricular premature beat may be sensed in the atrial channel and undersensed in the ventricular channel (due to different orientations of these leads). This will trigger ventricular pacing which may be delivered during the vulnerable period. Another consideration is that devices function with ventricular-based timing when they are programmed in the DDI(R) mode. This will result in sensor-driven pacing rates that are above the programmed upper rate. For example, in a device with a programmed upper sensor-driven rate of 120 BPM (500 ms) and a paced atrioventricular interval of 180 ms, the VA interval will be 320 ms. If the AP–VS interval is 80 ms, the actual pacing rate will be 150 BPM (400 ms).2

In LBBAP, anodal capture (i.e. capture with the CSP lead ring) often occurs when pacing in a bipolar configuration, as both the tip and ring of the pacing electrode penetrate into the interventricular septum. Anodal capture will attenuate the right bundle branch pattern (i.e. smaller r wave in lead V1; Figure 2). Anodal capture should be carefully observed and documented when performing threshold tests, and is generally present at higher voltages (>2.0 V/0.4 ms). Other than providing backup pacing in case of lead tip perforation, or in some instances QRS narrowing, anodal capture does not provide any proven benefit and programmed pacing output should weigh clinical need for anodal capture against excessive battery drain. In case bipolar pacing is programmed with LBBAP, it is useful to check thresholds and impedances in the unipolar configuration to check for possible perforation of the lead tip during the first follow-ups. Strength-duration curves for His bundle (HB) capture follow a similar pattern compared to those of myocardial capture, although crossing of the curves has been reported.10,11 The chronaxie (point of minimal energy drain) is significantly lower in patients with selective His bundle pacing (S-HBP). Therefore, although a pulse width of 1 ms is often employed to reduce high amplitude threshold, a narrower pulse duration (0.2–0.4 ms) may save battery life in the case of short chronaxie (E = V2xPW/R).10 In general, the pacing amplitude should be at least twice the threshold amplitude, but in selected patients (who are non-dependent, have a backup ventricular lead or in whom S-HBP is desirable), a fixed safety margin (e.g. 1 V) may also be appropriate.

Lastly, the AAI(R) mode (e.g. in case the RV lead is only used for the ICD function) should be avoided, as there is a risk of T wave oversensing (Figure 1).

Pacing Polarity and Output

Unipolar pacing (usually not available in ICDs), other than for the left ventricular channel in some devices, results in a clear pacing spike on the surface ECG, which makes it easier to distinguish it from the intrinsic rhythm (as the QRS in HBP, and sometimes also LBBAP, may resemble that of intrinsic rhythm). Pacing thresholds are significantly lower than with bipolar stimulation, but lead impedance is about two-thirds of the bipolar lead impedance, which may negatively impact battery longevity (as E = V2 × PW/R).9

It has been described that HB and myocardial thresholds can vary considerably depending upon the pacing mode (DDD or VVI) which is programmed during the threshold test.11 Until the prevalence of this finding is determined, it is wise to perform threshold tests in the device’s permanently programmed mode.

When a CSP lead is connected to the LV-port of a CRT-device, an extended bipolar pacing configuration can be programmed (i.e. using the CSP lead tip as cathode and the RV ring or coil as anode), and can be useful in CRTDs, which may not have a unipolar pacing configuration of the LV channel. One should be aware that this configuration may lead to anodal capture

Capture management algorithms for HBP may yield erroneous values or may simply not function at all if the lead is connected to the atrial port of

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Troubleshooting Programming of Conduction System Pacing Figure 2: Anodal Capture with Left Bundle Branch Area Pacing 25.0 mm/sec

(1 mV)

2.00 V, 0.40 ms A b

A S

Lead I

V P

III

V P

EGM1

aVR aVL aVF

EGM2

V1 V2 V3 V4 EGM3

V5 V6

Cathodal and anodal capture with left bundle branch area pacing (LBBAP) in a bipolar pacing configuration (i.e. capture with both the lead tip and ring respectively). Left panel: loss of anodal capture with cathodal (tip) capture only (*) during decrementing pacing output with LBBAP. Right panel: Electrogram changes during loss of anodal capture (*). Note also the change in far-field electrogram morphology. Electrogram 1: atrial tip-ring. Electrogram 2: LBBAP tip-ring. Electrogram 3: far-field electrogram (impulse generator to LBBAP ring). All electrograms displayed at ±8mV.

atrial channel may be programmed to the highest value (e.g. 4 mV) to reduce oversensing issues.

the device. The algorithms should be programmed ‘off’ or ‘monitor’ and only activated if clinically required (e.g. in case of a high capture threshold) and if they have been shown to provide accurate measurements in a given patient.

Atrioventricular and Interventricular Delays

When the HB lead is connected to the RV port in patients in sinus rhythm with an atrial lead, the His-ventricle (HV) interval should be accounted for and subtracted from the desired AV delay. In case of selective HBP, one can measure the spike-QRS onset delay, or simply use a default value of 40 ms. For an LBBAP lead connected to the RV port, one can program the AV delay as usual, as the delay between the left bundle branch potential and QRS onset is negligible (<20 ms). Direct LBB capture may even not be present in a substantial proportion of these patients.

Of note, in Medtronic and Boston Scientific CRT devices, in case the output of an RV backup lead or ICD lead is programmed to a subthreshold value (to reduce current drain or to avoid RV capture), the LV capture management algorithm should be inactivated. This is because RV backup pacing is only delivered at the programmed amplitude during the threshold test and may result in transient asystole in case of complete atrioventricular (AV) block. Other manufacturers deliver biventricular backup pulses (Biotronik) or high-output RV backup pulses (5 V/≥0.5 ms for Abbott Cardiovascular) during LV threshold tests.

In patients in chronic atrial arrhythmia with a CSP lead connected to the atrial port with a backup pacing lead or ICD lead, a paced AV delay that is sufficiently long to avoid pacing from the ventricular channel should be programmed (e.g. 150 ms). Loss of capture from the CSP lead can be deduced by the percentage of pacing from the backup lead. The interval between HBP and RV sensing is on average about 80 ms, but may be as long as 150 ms in the setting of S-HBP without correction of right bundle branch block (RBBB).9 Excessively long AV intervals (>200 ms), as well as the AAI/DDD mode or AV hysteresis should be avoided, as these may result in HBP on the preceding T wave in case of intermittent loss of HB capture.

Sensing

With HBP, sensing amplitudes are lower than for traditional RV pacing (generally 2–4 mV but sometimes <1 mV) and major sensing issues may be encountered when an HBP lead is connected to the atrial or RV port (sensing is not available in the LV port, except for Biotronik and Boston Scientific devices, where it may be inactivated). Ventricular undersensing may occur due to low ventricular EGM amplitude. In addition, oversensing of atrial or HB potentials can lead to asystole in the case of total AV block (Figure 3). For HBP, programming a fixed sensitivity is preferred over activating automatic sensitivity, as low amplitude signals (such as atrial and HB potentials) may lure the device into programming low values, which may result in oversensing. Sensing is generally not an issue with LBBAP, as the R wave amplitudes are higher (similar to traditional RV pacing), and there are no atrial or HB potentials.

When a CSP lead is connected to the LV port, one can either program sequential pacing or CSP-only pacing via the LV channel. The RV lead serves for ventricular sensing and for backup pacing (or delivering therapy in case of an ICD). Sequential pacing can be programmed with CSP (LV channel) pre-excitation and the VV interval set to its maximum value (e.g. 80 ms) to minimise undesired RV fusion. Pacing by the RV lead will be delivered regardless of CSP capture (i.e. even if the CSP pace–ventricular sense delay

If the CSP lead is connected to the atrial port, the RV backup pacing or ICD lead ensures ventricular sensing. In these cases, the sensitivity of the

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Troubleshooting Programming of Conduction System Pacing Figure 3: Intermittent Oversensing by the His Bundle Pacing Lead A

25 mm/s

B A

A S V P

A S

A S V P

His

V P

A S V P

A S

V S

A S V P

V S

A S

A S V P

V P

Patient with complete atrioventricular block implanted with a dual chamber pacemaker with an atrial lead and a His bundle pacing lead (connected to the right ventricular port). Follow-up was performed due to recurrence of malaise. The rhythm strip (A) shows non-selective His bundle capture, with intermittent non-tracking of P waves (and an intrinsic junctional escape beat). The real-time electrogram (B) shows intermittent oversensing of the atrial potential by the His bundle pacing lead (*). The issue was corrected by reducing the programmed sensitivity.

Figure 4: Ventricular Safety Pacing VSP ON

VSP OFF

His bundle pacing lead connected to the atrial port of a dual-chamber pacemaker, with consistent His bundle capture and ventricular safety pacing (left panel), which was inactivated (right panel) after having checked for absence of crosstalk to avoid unnecessary battery drain. VSP = Ventricular safety pacing.

in most devices), but long blanking periods after ventricular sensing should be avoided as it can result in undersensing of rapid ventricular tachycardia (VT) or VF.

is shorter than the programmed VV interval) due to the interventricular refractory period.9 This results in pseudo-fusion, which is not harmful but results in unnecessary battery drain. Nevertheless, as in the setting of a CSP lead in the atrial port with a backup ventricular lead, this option ensures safety in the case of loss of capture by the CSP lead and makes it possible to program lower output safety margins. In order to avoid current drain resulting from unnecessary RV stimulation, pacing from the LV channel only may be programmed (with sensing from the RV lead). This should only be programmed only once stable thresholds with the CSP lead have been obtained. A potential issue might be R wave double counting if the delay between HB pace – RV sense is longer than the ventricular blanking period, e.g. in case of long HV delays or uncorrected RBBB.12 Ventricular blanking after ventricular pacing should therefore be programmed >200 ms (default

In case right and/or left ventricular pacing coupled to CSP is desirable, e.g. in case of HOT-CRT or LOT-CRT, the AV delay may be optimised using QRS duration. For HOT-CRT, when programming the AV delay, empiric values of 40–60 ms or 60% of the HBP-RV sensing interval may be used.8

Programming of Specific Device Features

Ventricular safety pacing (VSP): This is a very useful feature in standard configurations, but can result in unnecessary pacing when a CSP lead is plugged to the atrial port. As the interval between pacing from the atrial

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Troubleshooting Programming of Conduction System Pacing ventricular signals (V>A criterion). Only single-chamber discriminators (onset, stability and morphology) should be used.

(CSP) channel to RV sensing is very short (on average 85 ± 25 ms), the RV sensed event usually falls in the VSP window (which ranges from 64 ms in Abbott devices to 110 ms in Medtronic devices).4,9 This will result in RV pacing at the end of this window and hence pseudofusion and unnecessary battery drain (Figure 4). Before VSP is inactivated, the risk of AV crosstalk should be tested first by increasing the CSP output to its maximum value (unipolar if available) and setting the ventricular sensibility to its maximum (lowest) value, and the delay between the CSP spike and ventricular sensing analysed (and compared to during usual settings). Of note, VSP cannot be inactivated in Biotronik and Microport devices, and there is no VSP window for Boston Scientific devices.

Conclusion

Programming for CSP may be confusing and challenging, as no dedicated devices currently exist. Programming for HBP is generally more complex than with LBBAP because of more issues with sensing and more frequent use of ventricular backup leads. However, LBBAP leads may also be connected to the atrial or LV port of ICDs and thereby require specific programming settings. The introduction of automatic device settings for CSP is eagerly awaited. In the meantime, clinicians should recognise the possible pitfalls to ensure safe and effective CSP for their patients.

Automatic AV and VV optimisation algorithms for CRT: Algorithms that automatically optimise AV and interventricular delays should be inactivated, as they have not been designed for CSP.

Clinical Perspective

• Effective conduction system pacing not only depends on

Triggered ventricular pacing algorithms for CRT: These should in general be inactivated (nominally activated in most CRT-devices) as they result in pseudofusion and unnecessary battery drain.

successful device implantation but also on proper device programming. Current implantable impulse generators are not specifically designed for conduction system pacing. • Different pacing system configurations are used depending on the underlying heart rhythm (sinus rhythm or permanent atrial arrhythmia) and the aim of pacing. • Depending on the device configuration, different programming issues may arise.

ICD programming: In case the CSP lead is connected to the atrial port of an ICD, all dual-chamber discrimination algorithms should be inactivated. Otherwise, RV sensing by the His lead in the case of true VT will be classified as 1:1 junctional tachycardia, and all supraventricular tachycardias will be classified as VT if the CSP lead does not sense the 1. Arnold AD, Whinnett ZI, Vijayaraman P. His-Purkinje conduction system pacing: state of the art in 2020. Arrhythm Electrophysiol Rev 2020;9:136–45. https://doi.org/10.15420/ aer.2020.14; PMID: 33240509. 2. Burri H, Keene D, Whinnett Z, et al. Device programming for His bundle pacing. Circ Arrhythm Electrophysiol 2019;12:e006816. https://doi.org/10.1161/CIRCEP.118.006816; PMID: 30722682. 3. Burri H, Jastrzebski M, Vijayaraman P. Electrocardiographic analysis for His bundle pacing at implantation and follow-up. JACC Clin Electrophysiol 2020;6:883–900. https://doi. org/10.1016/j.jacep.2020.03.005; PMID: 32703577. 4. 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. 5. Teigeler T, Kolominsky J, Vo C, et al. Intermediate-term

performance and safety of His-bundle pacing leads: a single-center experience. Heart Rhythm 2021;18:743–9. https://doi.org/10.1016/j.hrthm.2020.12.031; PMID: 33418127. 6. 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. 7. Vijayaraman P, Herweg B, Ellenbogen KA, et al. Hisoptimized cardiac resynchronization therapy to maximize electrical resynchronization: a feasibility study. Circ Arrhythm Electrophysiol 2019;12:e006934. https://doi.org/10.1161/ CIRCEP.118.006934; PMID: 30681348. 8. Zweerink A, Zubarev S, Bakelants E, et al. His-optimized cardiac resynchronization therapy with ventricular fusion pacing for electrical resynchronization in heart failure. JACC Clin Electrophysiol 2021. https://doi.org/10.1016/j. jacep.2020.11.029; PMID: 33640346; epub ahead of press.

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9. Starr N, Dayal N, Domenichini G, et al. Electrical parameters with His-bundle pacing: considerations for automated programming. Heart Rhythm 2019;16:1817–24. https://doi. org/10.1016/j.hrthm.2019.07.035; PMID: 31377421. 10. Jastrzebski M, Moskal P, Bednarek A, et al. His bundle has a shorter chronaxie than does the adjacent ventricular myocardium: Implications for pacemaker programming. Heart Rhythm 2019;16:1808–16. https://doi.org/10.1016/j. hrthm.2019.06.001; PMID: 31181375. 11. Bakelants E, Zweerink A, Burri H. Crossing of strengthduration curves with His bundle pacing and impact of pacing mode on thresholds. HeartRhythm Case Rep 2021;7:123–6. https://doi.org/10.1016/j.hrcr.2020.11.015; PMID: 33665116. 12. Padala SK, Ellenbogen KA, Koneru JN. Intermittent loss of capture in a His bundle pacemaker: what is the cause? HeartRhythm Case Rep 2017;3:555–8. https://doi.org/10.1016/j. hrcr.2017.07.018; PMID: 29387549.

Cardiac Pacing

Fusion Pacing with Biventricular, Left Ventricular-only and Multipoint Pacing in Cardiac Resynchronisation Therapy: Latest Evidence and Strategies for Use Peter H Waddingham ,1,2 Pier Lambiase ,1,3 Amal Muthumala,1 Edward Rowland

and Anthony WC Chow1,2

1. St Bartholomew’s Hospital, Barts Health NHS Trust, London, UK; 2. William Harvey Research Institute, Queen Mary University of London, London, UK; 3. UCL Institute of Cardiovascular Science University College London, London, UK

Abstract

Despite advances in the field of cardiac resynchronisation therapy (CRT), response rates and durability of therapy remain relatively static. Optimising device timing intervals may be the most common modifiable factor influencing CRT efficacy after implantation. This review addresses the concept of fusion pacing as a method for improving patient outcomes with CRT. Fusion pacing describes the delivery of CRT pacing with a programming strategy to preserve intrinsic atrioventricular (AV) conduction and ventricular activation via the right bundle branch. Several methods have been assessed to achieve fusion pacing. QRS complex duration (QRSd) shortening with CRT is associated with improved clinical response. Dynamic algorithm-based optimisation targeting narrowest QRSd in patients with intact AV conduction has shown promise in people with heart failure with left bundle branch block. Individualised dynamic programming achieving fusion may achieve the greatest magnitude of electrical synchrony, measured by QRSd narrowing.

Keywords

Cardiac resynchronisation therapy, optimisation, MultiPoint pacing, fusion pacing, atrioventricular delay, left ventricular-only pacing Disclosure: PL is a section editor and ER is on the Arrhythmia & Electrophysiology Review editorial board, which did not affect the peer-review process. All other authors have no conflicts of interest to declare. Received: 10 December 2020 Accepted: 15 March 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(2):91–100. DOI: https://doi.org/10.15420/aer.2020.49 Correspondence: Peter H Waddingham, St Bartholomew’s Hospital, Barts Health NHS Trust, West Smithfield, London EC1A 7BE, UK. E: p.waddingham@doctors.org.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

location, suboptimal medical therapy or poor drug compliance, high scar burden and persistent mechanical dyssynchrony. Strategies for improving patient outcomes with CRT and approaches to non-response have been the subject of extensive research.13 Real world data suggest that suboptimal AV timing may be the most prevalent modifiable factor at follow-up.14

Cardiac resynchronisation therapy (CRT) is an established cornerstone of treatment for patients with heart failure (HF) and left ventricular (LV) conduction delay, most typically manifest as left bundle branch block (LBBB). International guidelines make a Class 1A recommendation for CRT device implantation in symptomatic patients with an LV ejection fraction (LVEF) of ≤35%, LBBB and QRS duration (QRSd) of ≥150 ms, despite optimal medical therapy; for the reduction of mortality and morbidity.1,2 The burden of HF remains high even with widespread implementation of CRT in developed countries.3,4

CRT programming optimisation is a contentious field due to the increasing complexity of modern devices, pacing algorithm and heterogeneity within the CRT patient cohort. This leads to uncertainty regarding traditional research methodology and the generalisability of RCTs for individualised programming. The physiological ‘sweet spot’ of CRT programming may vary widely for individuals and even across the disease course of the individual.

Clinical response rates to CRT have remained largely unchanged since early landmark randomised controlled trials (RCTs) first described their efficacy. Contemporary response rates from clinical trial and real world data demonstrate non-response rates of between 30–50%.5,6

This review aims to describe advances in programming strategies focused on the utility of the fusion of LV pacing with intrinsic conduction.

Landmark CRT trials demonstrating reductions in morbidity and mortality all involved some programming optimisation, with or without atrioventricular (AV) delay optimisation using echocardiography Doppler or algorithm-based optimisation methods.7–12 However, no unifying strategy for timing delay optimisation has been included in guidelines due to ongoing debate and conflicting evidence in the literature.

Fusion Pacing

Fusion pacing refers to the delivery of CRT pacing with a programming strategy to preserve intrinsic AV conduction via the right bundle branch (RBB). Fusion of the intrinsic activation wavefront with the LV pacing wavefront may be achieved by LV-only pacing or ‘triple fusion’ with the addition of RV pacing. Fusion optimisation methods may have arisen due to a desire to simplify complex echocardiographic optimisation techniques, previously considered to be the gold standard.15–17

Several common contributory factors have been associated with a lack of response to CRT. Implicated factors include suboptimal AV timing, arrhythmia limiting the percentage of biventricular (BiV) pacing, epicardial LV lead

Fusion Pacing for CRT Optimisation Intrinsic Conduction Characteristics

pacing stimulation to the QRS onset (S-QRS) <37 ms was associated with increased narrowing of paced QRSd in combination with QLV time >95 ms. This was an independent predictor of CRT response – left ventricular end systolic volume (LVESV) reduction >15% – in a study of 60 HF patients undergoing CRT implantation.29

The cardiac excitatory sequence was first mapped ex vivo in eight normal human hearts in 1970 using up to 870 electrodes per heart.18 This work demonstrated that the onset of LV activation is endocardial and trifascicular (anterior para-septal, central left interventricular septal and posterior para-septal) within the first 10 ms. The intricate LV conduction system causes activation to rapidly envelop the majority of the LV cavity within the first 20 ms at a conduction velocity approximating 2 m/s with the posterobasal or posterolateral regions activating last. Activation does not spread across the epicardial surface but from the endocardium to the epicardium.

Despite the value of QLV assessment for LV lead placement, its use when assessing CRT delivery may be limited. A recent retrospective study of 120 patients with HF, LBBB and QRSd >120 ms receiving CRT with quadripolar LV leads describes detailed assessments of intrinsic conduction and ventricular paced effects, measured via device EGMs.30 QLV times were typically similar from distal-proximal quadripolar lead electrodes however correlation was poor between QLV and LV pacing wavefront propagation (LV conduction time) as measured by LVpaced-RVsensed time from device EGMs; regardless of distal versus proximal electrode choice. LV pacing effects varied unpredictably based upon QRS morphology, QLV time and LV stimulation site. They should therefore be considered when individualising CRT programming including when implementing fusion pacing or altering timing (V-V delay) if RV pacing.

Adverse remodelling of the failing LV includes progressive dilatation and geometrical changes resulting in eccentric LV hypertrophy, increased wall tension and ultimately myocardial fibrosis. This process contributes to the loss of cardiac output and contractile reserve. The electrophysiological impact is typically manifest as intraventricular conduction delay and the development of bundle branch block due to a disease process affecting the LV conduction system. Unlike the RBB, a relatively delicate structure, the conduction system of the main LBB with its anterior and posterior fascicles, subdividing into the distal Purkinje network is less vulnerable to a focal insult.19 Therefore, a discrete lesion at or just distal to the bundle of His or extensive myocardial insult involving a significant proportion of the conduction system of both fascicles is required for LBBB to manifest. A spectrum of mechanisms and electrocardiographic characteristics are therefore evident in patients diagnosed with LBBB.20

QRS Duration as a Target for CRT

Several studies have shown that the magnitude of QRSd narrowing with CRT (intrinsic versus paced) is associated with improved clinical response.31–35 Takenaka et al. demonstrated that QRSd narrowing post CRT was an independent predictor by multivariate analysis of clinical response (LVESV reduction ≥15%).36 The positive association between the magnitude of QRSd narrowing with CRT and clinical response has also been demonstrated retrospectively in patients undergoing upgrade to CRT due to chronic RV pacing.37

An inverse correlation exists between the magnitude of conduction delay as measured by QRSd and the LV contractile function. Conversely, a positive correlation exists between the prevalence of LV systolic impairment and the presence of LBBB.21 The COMPANION trial showed an incremental increase in the benefit of CRT on mortality and hospitalisation with increasing intrinsic QRSd pre-CRT implantation, a finding supported by the RAFT study.10,22 A meta-analysis of six RCTs and 38 observational studies evaluated the association between baseline and follow-up QRSd with CRT implantation. The RCTs demonstrated that the benefits of CRT appeared restricted to those with a baseline QRSd ≥150 ms. Both broader baseline QRS and a greater magnitude of QRS narrowing were associated with CRT response in the observational studies.23 Additionally, an individual patient data meta-analysis including five RCTs (n=4,317) demonstrated that baseline QRSd was the only predictor by multivariate analysis of the magnitude of CRT effect on outcomes in patients with HF and LV systolic dysfunction in sinus rhythm.24

The relative change in QRS (QRS index) has also been studied.37,38 A QRS index of ≥10% was significantly associated with CRT response by multivariate analysis in a prospective multicentre study of 311 patients with HF of mixed aetiology.38 Reduction in QRS area as derived from 12-lead ECG by vectorcardiography has also been shown to have a strong association with acute haemodynamic, clinical and echocardiographic response to CRT with additional utility for patients without broad LBBB (<150 ms).39,40 Although single centre studies have disputed the relevance of QRSd narrowing with CRT and patients can respond to CRT without significant QRSd narrowing, accumulating evidence favours this with positive CRT response. Reducing the paced QRSd with device programming adjustment has therefore been investigated as an accessible target for CRT optimisation. The use of fusion of LV or BiV pacing with intrinsic conduction has consistently shown shorter paced QRSd and therefore may be an important strategy for improving CRT delivery.41–44

The MADIT-CRT trial and RAFT study confirmed the importance of QRS morphology and specifically the presence of LBBB to CRT response rates.22,25 Subsequently, varying definitions used for LBBB have been studied and implicated as a key factor in patient selection for CRT. Refined criteria proposed by Strauss et al. for defining complete LBBB as a substrate for CRT, which include sex differences (QRSd ≥140 ms for men and ≥130 ms for women), with mid-QRS notching or slurring in two or more contiguous leads, have been associated with an improved CRT response.26,27

Fusion Optimised Intervals

Table 1 summarises the key studies assessing fusion optimisation methods. The fusion optimised intervals (FOI) method was first described by Arbelo et al. in 2014, demonstrating greater QRSd narrowing with FOI versus nominal AV delay programming, associated with significant acute improvements in invasive haemodynamics (LV dP/dtmax).41 This method was corroborated in a single centre RCT by Trucco et al. in 2018, showing greater LV reverse remodelling which correlated with QRSd narrowing, by the use of FOI versus nominal programming.42 Ter Horst et al. used a similar methodology testing 20 percentile intervals of the RAsensed-RVsensed time measured from bipolar intracardiac EGMs.45 The cohort’s optimal timing for RV pacing was around the onset of the intrinsic far-field signal

The interval from the onset of the intrinsic QRS on the 12-lead surface ECG to the first large positive or negative peak of the LV electrogram (EGM) (the QLV time) has been investigated as a marker of delayed LV activation and CRT efficacy. QLV times of ≥95 ms have been associated with greater CRT response rates.16,28 With LV lead placement guided by QLV timing of ≥95 ms, the local electrical conduction characteristics have also been shown to be a factor in CRT efficacy. Measurement of the interval from LV

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Fusion Pacing for CRT Optimisation Table 1: Summary of Key Studies Demonstrating Efficacy of Fusion Optimisation Methods Study

Design

Patient Cohort

Fusion Methods

Findings

Arbelo et al. 201441

Single-centre acute study

n=76 with QRSd ≥120 ms, LBBB, sinus rhythm, PR <250 ms, LVEF ≤35%

FOI methods versus nominal AV interval programming using 12-lead ECG

FOI produced significantly increased acute invasive haemodynamics (dP/dtmax) and QRSd shortening versus nominal programming

Ter Horst et al. 201745

Post hoc analysis of single centre acute study

n=17 with de novo CRT indications, sinus rhythm, PQ interval 180 ± 24 ms, LBBB, QRS >120 ms, LVEF ≤35%

AV and VV interval optimisation using Greatest acute haemodynamic response (dP/dtmax) was 20, 40, 60 and 80% of the RA-RV sensed associated with triple wavefront fusion (RV and LV pacing, time, then 20 ms increments for VV intervals. intrinsic conduction) in 16 patients Fusion assessed by RV bipolar EGM and 12-lead ECG.

Birnie et al. 201758

Prospective, multicentre, double-blind 2:1 RCT

n=478 with de novo CRT indications, QRS >120 ms, LVEF ≤35%

aCRT versus echo optimisation of AV and VV intervals (aortic VTI)

Trucco et al. 201842

Single-centre n=180 with QRSd ≥120 ms, FOI versus nominal AV interval randomised controlled LBBB, sinus rhythm, PR programming using 12-lead ECG, study <250 ms, LVEF ≤35%, NYHA randomised 1:1 II–IV

FOI produced significantly greater LV reverse remodelling (>15% LVESV reduction) versus nominal programming (74% versus 53%, p=0.026) at 12 months, this correlated with QRSd narrowing. No significant difference in clinical response by 6-minute walk test or NYHA class (61% versus 53%, p=0.24)

Varma et al. 201843

Prospective, multicentre acute study

n=75 with QRSd ≥120 ms, LBBB, sinus rhythm, PR <300 ms, LVEF ≤35%

Post-CRT implant AV optimisation using SyncAV default offset (−50 ms), SyncAV custom offset in BiV and SyncAV default offset in LV-only pacing

Greatest QRSd narrowing was achieved with SyncAV and patient customised offset (default, custom offsets: 15.6%, 23.9% reduction versus intrinsic conduction, respectively p<0.001)

Thibault et al. 201944

Multicentre acute study

n=90 with QRSd ≥120 ms, LBBB, sinus rhythm, PR <300 ms, LVEF ≤35% with pre-existing CRT devices

BiV with nominal AV delays versus BiV + SyncAV default (−50 ms) + BiV + custom SyncAV offset

SyncAV improved QRSd narrowing incrementally with default and customised offset during BiV pacing

AlTurki et al. 202094

Prospective, single-centre cohort study

n=34 with chronic CRT (mean 17.8 ± 8.5 months post implant), sinus rhythm, PR <350 ms

SyncAV optimised to narrowest QRSd for Significant increase in LVEF at 6 months with 44% of 6 months, response assessed by echo patients converted to responders following SyncAV (LVEF ≥10% and a decrease in LVESV ≥15%) activation

O’Donnell et al. 202062

Multicentre acute study

n=103 with QRSd ≥150 ms, LBBB, sinus rhythm, PR <300 ms, LVEF ≤35%

Post-implant optimisation comparing nominal AV intervals with BiV and MPP, SyncAV with custom offset in BiV and MPP

aCRT cohort had significantly reduced incidence of AF versus echo-optimised CRT (8.7% versus 16.2%). Subgroups with the greatest treatment effect: prolonged baseline AV intervals and significant reverse remodelling of the LA

BiV+SyncAV reduced QRSd by 22% (p<0.001 versus intrinsic). MPP+SyncAV reduced QRSd by 25.6% (p<0.05 versus BiV+SyncAV). Baseline QRSd was the only independent predictor of QRSd narrowing. The narrowest QRSd was achieved by MPP using LV electrodes with widest anatomical separation and a patient specific SyncAV offset in 73%

aCRT = Adaptiv CRT; AV = atrioventricular; BiV = biventricular pacing, CRT = cardiac resynchronisation therapy; EGM = electrogram, FOI = fusion optimised intervals; LBBB = left bundle branch block; LV = left ventricular; LVEF = left ventricular ejection fraction; LVESV = left ventricular end systolic volume; MPP = multipoint pacing; QRSd = QRS duration; RA = right atrial; RV = right ventricular; RCT = randomised controlled trial; VV = interventricular; VTI = velocity time integral.

The FOI method

(98 ± 17% of RA-RV far-field interval) while preactivating the LV electrode at 50% of the RAsensed-RVsensed interval. VV interval adjustment ranged from 80 ms LV pre-excitation to 40 ms RV pre-excitation in 20 ms increments. The presence of fusion was established by the occurrence of an RV farfield signal prior to the RV pacing artefact during BiV pacing in the absence of a local sensing event. The timing of the far-field signal on RV EGM was verified with that recorded during intrinsic conduction, changes were also confirmed by 12-lead ECG.

FOI involves an ECG assessment of the fusion band: the range of AV intervals in which fusion of intrinsic conduction with LV pacing is present on the 12-lead ECG. The fusion band is established in both atrial sensed and paced modes, starting with the longest AV interval producing consistent LV capture. The AV interval is then sequentially shortened in 20 ms decrements until pure LV capture is identified. The interval with the narrowest QRSd is then chosen as the ‘fusion optimised AV interval’. RV pacing is then introduced and the VV offset altered with LV pre-excitation by 30 ms, simultaneous and RV pre-excitation by 30 ms to find the optimal VV interval. ECG assessments were performed acutely after CRT implantation with QRS measurements at a screen velocity of 300 mm/s although these correlated well with measurements at 50 mm/s. QRSd measurements involved three consecutive cycles, measuring the onset from the start of fast deflection not the pacing spike.

These studies used differing approaches to interventricular (VV) interval optimisation and debate persists among studies describing the useful range of VV intervals. Tamborero et al. described 88% (n=25) having optimal VV intervals of <30 ms, but Van Gelder et al. described mean VV intervals of 24 ms ± 33 ms, both optimised by LV dP/dtmax.46,47 Using dP/dtmax to select the optimal VV interval may lead to widely varying values depending on the substrate (ischaemic versus non-ischaemic) and the presence of AF.48 Van Gelder also showed a greater correlation between QRSd and haemodynamic response with QRSd measurement from the first fast deflection of the QRS not the pacing spike.46

Limitations

Detailed fusion optimisation methods may not fit with many clinical pathways for CRT implantation and optimisation. They involve optimisation

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Fusion Pacing for CRT Optimisation clinical response, including New York Heart Association (NYHA) class, 6-minute walk distance and quality of life score.16 This juxtaposed the positive outcomes from an acute optimisation study comparing echo versus dP/dtmax versus SmartDelay AV interval optimisation in 28 patients. The results showed that the algorithm accurately predicted both echocardiographic and invasive haemodynamically optimal AV intervals.16,56

of timing intervals at rest, typically supine. The impact of physiological factors including physical activity, and diurnal, postural or vagal variations in heart rate remain largely unknown. Whether the fusion band represents a broad enough interval to allow for these factors and the magnitude of inter and intra-patient variability is also unknown. Patient characteristics for benefit with fusion beyond that of sinus rhythm, intact AV conduction and LBBB are yet to be clearly identified. No unifying definition for intact AV conduction exists within the literature assessing fusion pacing although studies include resting PR intervals of <250–350 ms. This adds some uncertainty to the use of fusion optimisation for patients in sinus rhythm with prolonged PR or right atrium (RA)paced −right ventricle (RV)sensed intervals or those with intermittent AV block. It is also unknown whether patients with non-LBBB intraventricular conduction disturbances benefit from fusion optimisation or indeed whether fusion optimisation methods can be replicated in high degree AV block. Finally, these methods have only been tested in a single centre RCT involving 180 patients.

Sub-analysis of the SMART-AV trial has been performed comparing patients with nominal AV intervals versus SmartDelay optimised intervals.57 This study found that reverse remodelling with CRT, as assessed by changes in LVESV >15%, was strongly associated with the sensed RV-LV interval duration (the time between the peaks of the RV and LV EGMs) and that CRT response increased with RV-LV prolongation for both programming sub-groups. Patients with longer RV-LV intervals had greater benefit from AV interval optimisation versus nominal programming. Patients with the longest RV-LV durations (fourth quartile, ≥105ms) had 4.26 times greater odds of an LVESV response with AV optimisation versus nominal programming (p=0.01).

Mechanism of Fusion Optimisation

It is likely that fusion optimisation directly affects CRT response by several factors. First, fusion optimisation alters the AV delays and, as previously mentioned, suboptimal AV timing is an important driver of reduced response. Second, there is a well-established close correlation between mechanical, contractile ventricular abnormalities and ventricular electrical conduction delay.49 Achieving fusion with intrinsic conduction may contribute to improved mechanics through the correction of electrical ventricular activation patterns, maximising cardiac output, improving LV filling and reducing mitral regurgitation.50,51 Specifically selecting AV intervals with the presence of fusion shortens QRSd, a simplified marker of LV activation time associated with improved CRT response and acute haemodynamics.52

Dynamic Electrogram Algorithms

Figure 1 displays a practical example of the use of a dynamic AV delay algorithm targeting fusion to achieve maximal QRS narrowing, in this case with an offset of -10 ms from the intrinsic AV delay. Table 2 summarises the available dynamic algorithms for managing AV interval timing in CRT. The AdaptivCRT (aCRT) algorithm was evaluated in a well-constructed prospective, multicentre, double-blind RCT.58 Subgroups with the greatest treatment effect were those with prolonged intrinsic AV intervals and significant reverse remodelling of the left atrium. Large retrospective registry datasets subsequently support these outcomes showing an association between aCRT, improved survival and reduced burden of AF.59,60 Recent analysis of this study shows that non-physiological AV programming is associated with an increased incidence of AF.61 The AdaptResponse trial (NCT02205359), a multicentre RCT has completed enrolment of 3,620 CRT-indicated patients with symptomatic HF, NYHA II–IV, LBBB (QRSd ≥140 ms in men; ≥130 ms in women, according to Strauss criteria) and PR interval ≤200 ms in sinus rhythm.62 This trial randomised patients 1:1 to aCRT on versus off (standard BiV CRT) and will report on a combined primary endpoint of all-cause mortality and intervention for decompensated HF at 2 years post-randomisation in late 2023 or early 2024.

Third, the contribution of the RV contractile function to LV contractility may be reduced by BiV pacing without fusion, conversely fusion of the LV pacing-derived wavefront with intrinsic RBB conduction may be required for maximum acute response.53,54 This is supported by an invasive electroanatomical contact mapping study which demonstrated an association between the presence of fusion of intrinsic activation following echoguided AV optimisation and a higher rate of LV and RV systolic function improvement at 6 months (n=8).55 Therefore the presence of intact conduction over the RBB leads to rapid RV activation and partial LV activation depending on the level and extent of conduction block present in LBBB.45 The potential benefits of fusion optimisation and mechanism of efficacy in selected patients are not fully explained and therefore require further study.

The SyncAV algorithm’s function is illustrated in Figure 2. Its use has been associated with improvements in electrical synchrony as measured by QRSd in patients with LBBB in sinus rhythm.43,44,63 These studies consistently demonstrated the potential for additional incremental QRSd narrowing achieved in patients with tailored SyncAV offsets during BiV pacing. Recently published data by O’Donnell et al. showed the effect may be further augmented with the addition of multipoint pacing (MPP).64 The impact of SyncAV programming on acute haemodynamic response has also been assessed non-invasively using aortic velocity time integral (VTI) and systolic blood pressure response, with augmentation of response seen using personalised SyncAV offsets.65,66

Electrogram Algorithm-based Programming Optimisation Static Electrogram Algorithms

Table 2 summarises algorithms aiming to target fusion which have been studied and largely implemented into routine device care. Preliminary studies often employed a static programming approach with optimisation techniques including infrequent or ‘one-off’ adjustments. These algorithms share some limitations with invasive haemodynamic and echocardiographic optimisation studies.

Hard outcome data from a well-designed RCT assessing the impact of SyncAV in CRT is awaited. The LV-only MPP with SyncAV study (NCT03567096) is currently recruiting patients with de novo CRT implants in sinus rhythm with LBBB randomised 1:1 to biventricular MPP or LV-only MPP using simultaneous V-V delays and widest anatomical LV electrode separation (≥30 mm). Response will be assessed by clinical composite

The SMART-AV trial randomised 980 patients 1:1:1 to the SmartDelay electrogram AV optimisation algorithm (Boston Scientific) versus echocardiographic AV optimisation versus nominal AV interval programming (120 ms). At 6 months there were no differences in the primary endpoint of LV reverse remodelling or secondary endpoints of

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Fusion Pacing for CRT Optimisation Table 2: Summary of Available Algorithms for CRT Optimisation Algorithm

Manufacturer

Static Versus Dynamic

Algorithm Function

Fusion Targeted?

Published Outcomes

Smartdelay

Boston Scientific

Static

EGM-based sensed and paced AV interval recommendation. Yes Uses intrinsic sensed or paced AV intervals and QRSd from a 12-lead ECG. A coefficient is introduced determined by LV lead location (anterior/free wall) and pacing mode (LV only or BiV). The outputs are restricted within a range of 50 ms to 70% of the intrinsic AV interval, to ensure consistent LV capture

SMART-AV trial – non-inferior versus echo AV delay optimisation versus fixed AV delay 120 ms16

AdaptivCRT

Medtronic

Dynamic

Yes EGM-based AV and VV interval adjustment. Paces LV only at >70% the intrinsic AV interval during normal AV conduction (RApaced/sensed to RVsensed – 40 ms is <220 ms) with HR <100 bpm. Paces BiV if AV interval >220 ms. Adjusts AV and VV intervals every min, paces after the end of the atrial EGM and >50 ms before RVsense calculated from intrinsic AV interval and P wave duration. P wave and QRS are measured every 16 hours

AdaptivCRT trial Reduced incidence of AF with aCRT versus nominal CRT programming58

SyncAV

Abbott

Dynamic

EGM-based adjustment of AV interval. Measures intrinsic AV interval every 256 beats and subtracts a custom offset (50 ms default, range 10–120 ms). Can be used in BiV, LV only and MPP including LV-only MPP; when intrinsic AV interval <350 ms

Yes

Improves QRSd narrowing incrementally versus nominal AV delays with default and custom offsets. May be augmented by SyncAV + MPP64

Autoadapt

Biotronik

Dynamic

EGM-based RA-RV/LV conduction time measurement and assessment of the presence of LBBB. The algorithm will reprogramme to LV-only pacing in normal AV conduction with LBBB

Yes

AV = atrioventricular; BiV = biventricular pacing; EGM = electrogram; LBBB = left bundle branch block; LV = left ventricular; MPP = multipoint pacing; NA = not applicable; RA = right atrial; RV = right ventricular; VV = interventricular.

Figure 1: An Example of Fusion AV Delay Optimisation Using Dynamic AV Algorithm (SyncAV) with a Customised Offset (−10 ms) Targeting Narrowest QRSd BiV nominal AV delay (140 ms) QRS duration 143 ms

Intrinsic rhythm QRS duration 153 ms

BiV SyncAV, custom effect (-10 ms) QRS duration 115 ms

I I

III

aVR

II III aVR aVL aVL

aVL

aVF aVF

aVF

V1 V1

V2 V2

V3 V3

V4 V4

V5 V5

V6 V6

0.1

0.2

0.3

0.4

Time [ms]

0.5

0.6

0.1

0.2

0.3

0.4

0.5

0.6

Time [ms]

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0.1

0.2

0.3

0.4

Time [ms]

0.5

0.6

Fusion Pacing for CRT Optimisation Figure 2: An Example of Device Intracardiac Electrograms with the SyncAV Dynamic AV Interval Algorithm

A sense AMP

Markers

V sense amp

LV distal tip 1 – Mid 2

Every 256 cycles the AV delay is set to the programmed value for three cycles (in this example 225 ms)

AV conduction occurs intrinsically and SyncAV CRT measures the conduction interval for these three cycles

SyncAV CRT adjusts the AV delay for the next 256 cycles using the equation below

AVdelay = (Intrinsic conduction time) – (SyncAV CRT Delta) Measurements of intrinsic conduction are performed in three consecutive cycles followed by implementation of the customisable delta (offset). In this case, the SyncAV CRT delta is 50 ms. Source: Reproduced with permission from Abbott.

regions of slow conduction through mapping significantly improved the acute haemodynamic response to CRT. This study also suggested that LV activation time is a more precise marker of resynchronisation than QRSd. Knowledge of the pattern of LV activation, location of conduction block and whether it is fixed or functional in response to LV pacing may allow better understanding of a poor response to CRT.

score (CCS) at 6 months following optimisation of SyncAV offset targeting the narrowest QRSd. This study will give further insights into the use of this dynamic device-based algorithm to achieve fusion pacing in the context of MPP. Additionally, the SyncAV post-market trial is a multicentre, open-label RCT actively recruiting to a target of 1,300 patients with symptomatic HF, LBBB (QRSd >120 ms) and intact AV conduction (PR interval <280 ms). Randomisation by 1:1 assignment to SyncAV on versus off (standard BiV fixed AV delays) with SyncAV offsets programmed to produce maximal QRSd narrowing. Optimisation will include assessment of LV only, RV ahead 30 ms and LV ahead 30 ms pacing; with repeat SyncAV optimisation at 3 and 6 months. The primary outcome measured will involve change in LVESV at 12 months assessed by echocardiography.

Non-invasive Mapping: Electrocardiographic Imaging in CRT

Electrocardiographic imaging (ECGi) is a non-invasive solution to invasive cardiac mapping, avoiding risks of arterial puncture and cardiac catheterisation. A vest applied to the torso with multiple electrodes (ranging from 50–300 depending on the manufacturer) records body surface EGMs via a specialised mapping system. Cross-sectional imaging using CT or MRI with the electrodes in situ acquires the 3D cardiac torso geometry necessary to compute epicardial potentials from body surface potentials using a mathematical inverse solution.69,70 This provides wholeheart imaging superior to conventional electrocardiography, allowing identification and quantification of global ventricular activation patterns and local events with high resolution (≤10 mm for earliest and latest sites), validated in vitro and in vivo.71, 72

The Role of Mapping in CRT Invasive Mapping

In vivo mapping of LBBB in 24 patients with HF using invasive contact and non-contact mapping was published by Auricchio et al. in 2004.67 This work demonstrated a U-shaped LV activation pattern due to a line of functional transmural conduction block. The location of conduction block was variable but present between the LV septum and lateral wall. Lambiase et al. performed the first invasive non-contact endocardial mapping study investigating the importance of LV lead position in 10 patients with recent CRT device implantation.68 The results demonstrated that endocardial pacing in regions of slow conduction produced delayed progression of the depolarisation wavefront. This affected the efficacy of resynchronisation of LV activation, resulting in persistence of dyssynchrony and lack of positive acute haemodynamic response. Thus, avoidance of

Non-invasive ECGi mapping has demonstrated heterogenous activation patterns among patients with HF and BBB, replicating invasive studies.73 ECGi has been used both to refine prediction of CRT response and as part of a multi-modality imaging assessment at the time of device implant to aid LV lead delivery.74

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Fusion Pacing for CRT Optimisation The impact of ECGi-guided programming optimisation for conventional BiV pacing, His-Bundle pacing and MPP is currently being evaluated.75–77 ECGi using the CardioInsight system (Medtronic) has suggested a reduction in global LV activation times through the use of MPP versus BiV pacing.76 ECGi has not yet been used to assess the impact or mechanism of fusion optimisation. Pre-implantation prediction of response to CRT using ventricular electrical uncoupling time (the difference between mean LV and RV activation times) >50 ms, achieved a 90% sensitivity and 82% specificity for predicting CRT response in 33 patients with mixed intraventricular conduction delay and QRSd >120 ms.78

Multipoint Pacing

Potential applications for ECGi involve pre-implantation prediction of response and procedural planning including guidance of LV lead delivery to LV segments of latest electrical activation away from zones of slow conduction. Post-implant mapping of the LV pacing wave front propagation (‘paced effects’) outside the catheter laboratory may provide valuable data to deliver individualised CRT programming including fusion optimisation as well as investigating non-response.

A systematic review and meta-analysis of 11 studies assessing MPP versus conventional BiV pacing demonstrated reduced HF hospitalisations, improved LVEF, improved CRT clinical response, decreased all-cause morbidity and cardiovascular mortality by sub-group analyses. This included variable study sizes and designs, limiting the applicability of this meta-analysis.88 Programming strategies varied across all included studies with regards to AV, VV intervals and LV pacing vectors, further limiting any conclusion regarding fusion pacing strategies with MPP.

MPP refers to CRT involving epicardial stimulation from more than one pole of a multipolar (typically quadripolar) LV lead. O’Donnell et al. have shown the incremental benefit to QRSd reduction of MPP versus BiV pacing when used in combination with SyncAV in patients with LBBB and PR interval of ≤300 ms. Several studies have demonstrated improvements in acute haemodynamic, echocardiographic, clinical response and QRSd reduction with MPP versus BiV however the true efficacy of MPP remains uncertain due a lack of prospective multicentre RCT trial data showing treatment benefit.87

LV-only Pacing

Any incremental benefits from MPP are likely to depend on factors including LV lead location, proximity to myocardial scar or regions of slow conduction, LV lead pacing thresholds, presence of phrenic nerve stimulation as well as appropriate AV and VV timing delay programming. Another study has suggested that AV intervals with optimal invasive haemodynamic response are similar in all electrodes of a quadripolar LV lead and that AV optimisation may only need to be performed in one electrode including for the use of MPP.89 This study indirectly assessed the impact of fusion with intrinsic conduction by 20% increments of the RApaced-RVsensed interval during AV optimisation and concluded that 50% of this interval was correlated with optimal haemodynamics by stroke work; assessment of change in QRSd or presence of fusion was not included.

LV-only pacing to fuse with the intrinsic activation (LVp), produces a double wave front of ventricular activation. This may avoid potentially adverse RV pacing-induced dyssynchrony. LVp is non-inferior to BiVp in patients with QRSd ≥120 ms and conventional indications for CRT in terms of exercise capacity, peak oxygen consumption, NYHA class, LVEF and acute haemodynamics measured invasively.79–84 The evidence for non-inferiority in patients with intact AV conduction and broad QRS includes high quality double blinded RCTs and a meta-analysis, leading to its use being endorsed by the European Society of Cardiology in CRT guidelines.84,85 Long-term clinical implications of LV-only pacing have been tested in the multi-centre double-blinded crossover GREATER-EARTH trial involving 211 patients with de novo CRT implantation randomised 1:1 to LV and BiV pacing for consecutive periods with 6 months crossover.79 The results showed non-inferiority of the primary outcome of exercise capacity and secondary outcome of reverse LV remodelling. After crossover >20% of the BiV pacing group became responders with LVp suggesting a role for LVp in non-responders to BiV pacing as an alternative therapy. A critique of this study design is that the AV delays were optimised to avoid fusion by programming AV intervals with complete LV capture and mean AV intervals of 101 ± 16 ms.

The use of MPP has been studied specifically for CRT non-responders in the MORE-CRT MPP study.90 Non-responders (<15% reduction in LVESV) were randomised 1:1 at 6 months follow-up post CRT implant to receive either MPP or continued conventional BiV pacing. MPP did not significantly increase the proportion of echocardiographic responders following a further 6-month period. Programming strategies were left to the physician’s discretion, however sub-group analysis showed that MPP programmed with a wide LV electrode anatomical separation (≥ 30 mm, MPP-AS) and shortest interventricular timing delays appeared to have the greatest incremental benefit in clinical response compared to other MPP programming (45.6% versus 26.2%, p=0.006).

LV univentricular/mono-ventricular pacing is a strategy involving the implant of a dual chamber pacemaker or CRT device with an LV epicardial lead and no RV lead. This is an option occasionally implemented in patients without HF but with anatomical constraints such as significant tricuspid valve pathology/replacement or congenital heart disease. It has also been explored for HF patients with CRT indications in developing countries with restricted resources where dual chamber pacemakers have been implanted with LV leads for patients with HF, LBBB and intact AV conduction.86 This non-randomised study included 30 patients receiving LV univentricular pacemakers and showed non-inferiority by clinical and echo criteria but significant cost savings at 6 months versus standard BiV pacing with fixed AV intervals. AV delay optimisation was performed using echo and 10 ms decrements from the resting PR interval prior to initiating rate adaptive AV delay algorithms.

The MPP IDE trial was a prospective, double-blinded, multicentre RCT with 469 participants using a complex design to assess MPP as a therapy for non-responders to CRT, defined at 3 months post-implant by CCS.91 After 3 months of BiV pacing, patients underwent echo assessment including Doppler of the transmitral flow (EA VTI) and only those with EA VTI during MPP ³BiV pacing were randomised 1:1 to receive continued BiV pacing versus MPP from 3–9 months. MPP programming was left to the physician’s discretion. The primary endpoint of non-inferiority and freedom from system-related complication was met with no significant difference between the responder rates of MPP and BiV pacing at 9 months. The incidence of incremental CRT response was, however, significantly higher in patients with MPP using the widest anatomical separation (≥30 mm) of LV electrodes (MPP-AS) at shortest interventricular delay (5 ms) versus MPP-other, 54% (28/52) versus 41% (61/147) (p=0.008).

Although this option exists, widespread implementation is likely to remain limited due to the lack of RV lead required to sense ventricular events, defibrillate and provide backup pacing if the LV lead fails.

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Fusion Pacing for CRT Optimisation morphology from continuous EGM analysis. Dynamic offsets could be applied with the ability to maintain fusion throughout the individual’s heart rate range.

Varma et al. have recently published further analysis of the MPP IDE study with patients dichotomised by median baseline left ventricular end diastolic volume index (LVEDVI) to height (LVEDVImedian).92 Patients with a higher than median LVEDVI had lower response rates to BiV at 3 months by CCS (65% versus 79%). MPP-AS programming produced greater CCS response rates versus BiV at 9 months (92% versus 65%, p=0.023). With LVEDV>Median, HF event rates increased between 3–9 months with BiV but stabilised with MPP-AS. This study concluded that patients programmed to MPP-AS after 3 months of BiV had a greater response and those with larger hearts (by LVEDVI) had lower response rates with BiV via a quadripolar lead.

Conclusion

Despite advances in CRT device technology and improved understanding of the complexity of HF with conduction delay, response rates and longevity of response remain relatively unchanged. This review specifically addresses the concept of fusion optimisation as a method for improving patient outcomes with CRT. LV-only pacing is an established alternative to BiV pacing and may be considered in a tiered fashion for BiV nonresponders with fusion optimisation maximising individual response. The addition of MPP-AS to fusion may produce the greatest electrical synchrony, however, definitive long-term outcome data are awaited and a well-constructed prospective RCT assessing clinical outcomes with this strategy would be of value.

The study is limited by its complex design and the selection criteria used for randomisation (positive EA VTI response to MPP) perhaps selecting patients more likely to respond. The study did not mandate programming for MPP therefore it is unclear whether AV intervals were programmed with any specific goal such as fusion.

Dynamic algorithm-based optimisation targeting narrowest QRSd for patients in sinus rhythm with intact AV conduction and LBBB shows promise as a strategy for improving CRT delivery. The aCRT algorithm has been shown to be clinically beneficial, particularly when RV-LV conduction times are prolonged. The SyncAV algorithm appears to incrementally improve electrical synchrony; however clinical outcome data are awaited. Both avoid the need for detailed electrocardiographic or invasive assessment. Gaps in the literature remain regarding the use of fusion optimisation in non-LBBB conduction delay, AV block, chronic AF and during MPP.

Given the growing data suggesting benefit with MPP (specifically MPPAS), the combination of fusion with intrinsic conduction and dual-site LV stimulation may achieve the most comprehensive electrical resynchronisation for selected patients. This strategy requires testing in a well-constructed prospective, randomised study.

Emerging Strategies and Future Directions

Although fusion optimisation of CRT using epicardial LV leads may provide additional benefit for patient outcomes, limitations remain in a significant minority of patients due to the epicardial location of the LV-pacing electrode. Several emerging strategies have sought to overcome these limitations through direct stimulation of the proximal conduction system with His-Bundle or LBB pacing and the distal conduction system with endocardial pacing. Physiological phenotyping by invasive electrophysiological testing has also shown potential by characterisation of the underlying pathophysiology. This may allow targeted and more complete electrical resynchronisation through conduction system (His bundle/LBB) pacing in selected patients.93 Additionally, non-invasive mapping (ECGi) is a powerful tool with the potential to improve assessment of non-responders and patient selection for CRT.

Clinical Perspective

• Suboptimal atrioventricular timing may be the most prevalent

modifiable factor influencing clinical response to cardiac resynchronisation therapy (CRT). • The magnitude of the QRS duration reduction with CRT is associated with improved outcomes. • Greater QRS narrowing may be achieved by fusion of left ventricular pacing with intrinsic conduction. • Fusion pacing appears to be effective in patients with intact atrioventricular conduction and broad left bundle branch block. The effect may be augmented by the addition of multipoint pacing.

With the emergence of artificial intelligence and machine learning into healthcare, advanced CRT devices could use feedback and learning loops to maintain pre-specified goals such as minimum QRSd and desired QRS 1. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891–5. https://doi.org/10.1002/ ejhf.592; PMID: 27207191. 2. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary. A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128:1810–52. https://doi. org/10.1161/CIR.0b013e31829e8807; PMID: 23741057. 3. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics – 2020 update: a report from the American Heart Association. Circulation 2020;141:e139–596. https://doi. org/10.1161/CIR.0000000000000757; PMID: 31992061. 4. Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics – 2019 update: a report from the American Heart Association. Circulation 2019;139:e56–528. https://doi. org/10.1161/CIR.0000000000000659; PMID: 30700139. 5. Birnie DH, Tang AS. The problem of non-response to cardiac resynchronization therapy. Curr Opin Cardiol 2006;21:20–6.

10.

https://doi.org/10.1097/01.hco.0000198983.93755.99; PMID: 16355025. Sieniewicz BJ, Gould J, Porter B, et al. Understanding nonresponse to cardiac resynchronisation therapy: common problems and potential solutions. Heart Fail Rev 2019;24:41– 54. https://doi.org/10.1007/s10741-018-9734-8; PMID: 30143910. Cleland JG, Daubert JC, Erdmann E, et al. The CARE-HF study (CArdiac REsynchronisation in Heart Failure study): rationale, design and end-points. Eur J Heart Fail 2001;3:481– 9. https://doi.org/10.1016/S1388-9842(01)00176-3; PMID: 11511435. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–49. https://doi. org/10.1056/NEJMoa050496; PMID: 15753115. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–53. https://doi.org/10.1056/NEJMoa013168; PMID: 12063368. Bristow MR, Saxon LA, Boehmer J, et al. Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140–50. https://doi.org/10.1056/NEJMoa032423;

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

PMID: 15152059. 11. Linde C, Abraham WT, Gold MR, et al. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol 2008;52:1834–43. https://doi.org/10.1016/j.jacc.2008.08.027; PMID: 19038680. 12. Moss AJ, Hall WJ, Cannom DS, et al. Cardiacresynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1329–38. https://doi. org/10.1056/NEJMoa0906431; PMID: 19723701. 13. Thomas G, Kim J, Lerman BB. Improving cardiac resynchronisation therapy. Arrhythm Electrophysiol Rev 2019;8:220–7. https://doi.org/10.15420/aer.2018.62.3; PMID: 31463060. 14. Mullens W, Grimm RA, Verga T, et al. Insights from a cardiac resynchronization optimization clinic as part of a heart failure disease management program. J Am Coll Cardiol 2009;53:765–73. https://doi.org/10.1016/j.jacc.2008.11.024; PMID: 19245967. 15. Barold SS, Ilercil A, Herweg B. Echocardiographic optimization of the atrioventricular and interventricular intervals during cardiac resynchronization. Europace

Fusion Pacing for CRT Optimisation 2008;10(Suppl 3):iii88–95. https://doi.org/10.1093/europace/ eun220; PMID: 18955406. 16. Ellenbogen KA, Gold MR, Meyer TE, et al. Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial: a randomized trial comparing empirical, echocardiography-guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy. Circulation 2010;122:2660–8. https://doi.org/10.1161/CIRCULATIONAHA.110.992552; PMID: 21098426. 17. Chung ES, Leon AR, Tavazzi L, et al. Results of the predictors of response to CRT (PROSPECT) trial. Circulation 2008;117:2608–16. https://doi.org/10.1161/ CIRCULATIONAHA.107.743120; PMID: 18458170. 18. Durrer D, van Dam RT, Freud GE, et al. Total excitation of the isolated human heart. Circulation 1970;41:899–912. https:// doi.org/10.1161/01.CIR.41.6.899; PMID: 5482907. 19. Neeland IJ, Kontos MC, de Lemos JA. Evolving considerations in the management of patients with left bundle branch block and suspected myocardial infarction. J Am Coll Cardiol 2012;60:96–105. https://doi.org/10.1016/j. jacc.2012.02.054; PMID: 22766335. 20. Lambiase PD. Defining left bundle branch block – is this a roadblock to CRT delivery? Int J Cardiol 2019;286:78–80. https://doi.org/10.1016/j.ijcard.2019.03.028; PMID: 30928259. 21. Kashani A, Barold SS. Significance of QRS complex duration in patients with heart failure. J Am Coll Cardiol 2005;46:2183–92. https://doi.org/10.1016/j.jacc.2005.01.071; PMID: 16360044. 22. Birnie DH, Ha A, Higginson L, et al. Impact of QRS morphology and duration on outcomes after cardiac resynchronization therapy: results from the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT). Circ Heart Fail 2013;6:1190–8. https://doi. org/10.1161/CIRCHEARTFAILURE.113.000380; PMID: 23995437. 23. Bryant AR, Wilton SB, Lai MP, Exner DV. Association between QRS duration and outcome with cardiac resynchronization therapy: a systematic review and meta-analysis. J Electrocardiol 2013;46:147–55. https://doi.org/10.1016/j. jelectrocard.2012.12.003; PMID: 23394690. 24. Cleland JG, Abraham WT, Linde C, et al. An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure. Eur Heart J 2013;34:3547–56. https://doi.org/10.1093/eurheartj/ eht290; PMID: 23900696. 25. Zareba W, Klein H, Cygankiewicz I, et al. Effectiveness of cardiac resynchronization therapy by QRS morphology in the Multicenter Automatic Defibrillator Implantation TrialCardiac Resynchronization Therapy (MADIT-CRT). Circulation 2011;123:1061–72. https://doi.org/10.1161/ CIRCULATIONAHA.110.960898; PMID: 21357819. 26. Strauss DG, Selvester RH, Wagner GS. Defining left bundle branch block in the era of cardiac resynchronization therapy. Am J Cardiol 2011;107:927–34. https://doi. org/10.1016/j.amjcard.2010.11.010; PMID: 21376930. 27. Caputo ML, van Stipdonk A, Illner A, et al. The definition of left bundle branch block influences the response to cardiac resynchronization therapy. Int J Cardiol 2018;269:165–9. https://doi.org/10.1016/j.ijcard.2018.07.060; PMID: 30025653. 28. Bilchick KC, Kuruvilla S, Hamirani YS, et al. Impact of mechanical activation, scar, and electrical timing on cardiac resynchronization therapy response and clinical outcomes. J Am Coll Cardiol 2014;63:1657–66. https://doi.org/10.1016/j. jacc.2014.02.533; PMID: 24583155. 29. Yagishita D, Shoda M, Yagishita Y, et al. Time interval from left ventricular stimulation to QRS onset is a novel predictor of nonresponse to cardiac resynchronization therapy. Heart Rhythm 2019;16:395–402. https://doi.org/10.1016/j. hrthm.2018.08.035; PMID: 30193853. 30. Wisnoskey BJ, Varma N. Left ventricular paced activation in cardiac resynchronization therapy patients with left bundle branch block and relationship to its electrical substrate. Heart Rhythm 2020;1:85–95. https://doi.org/10.1016/j. hroo.2020.04.002. 31. Hsing JM, Selzman KA, Leclercq C, et al. Paced left ventricular QRS width and ECG parameters predict outcomes after cardiac resynchronization therapy: PROSPECT-ECG substudy. Circ Arrhythm Electrophysiol 2011;4:851–7. https://doi.org/10.1161/CIRCEP.111.962605; PMID: 21956038. 32. Bonakdar HR, Jorat MV, Fazelifar AF, et al. Prediction of response to cardiac resynchronization therapy using simple electrocardiographic and echocardiographic tools. Europace 2009;11:1330–7. https://doi.org/10.1093/europace/eup258; PMID: 19797149. 33. Iler MA, Hu T, Ayyagari S, et al. Prognostic value of

electrocardiographic measurements before and after cardiac resynchronization device implantation in patients with heart failure due to ischemic or nonischemic cardiomyopathy. Am J Cardiol 2008;101:359–63. https://doi. org/10.1016/j.amjcard.2007.08.043; PMID: 18237600. 34. Lecoq G, Leclercq C, Leray E, et al. Clinical and electrocardiographic predictors of a positive response to cardiac resynchronization therapy in advanced heart failure. Eur Heart J 2005;26:1094–100. https://doi.org/10.1093/ eurheartj/ehi146; PMID: 15728648. 35. Molhoek SG, VAN Erven L, Bootsma M, et al. QRS duration and shortening to predict clinical response to cardiac resynchronization therapy in patients with end-stage heart failure. Pacing Clin Electrophysiol 2004;27:308–13. https://doi. org/10.1111/j.1540-8159.2004.00433.x; PMID: 15009855. 36. Takenaka M, Inden Y, Yanagisawa S, et al. Myocardial viability as shown by left ventricular lead pacing threshold and improved dyssynchrony by QRS narrowing predicts the response to cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2019;30:311–9. https://doi.org/10.1111/jce.13806; PMID: 30516312. 37. Rickard J, Cheng A, Spragg D, et al. QRS narrowing is associated with reverse remodeling in patients with chronic right ventricular pacing upgraded to cardiac resynchronization therapy. Heart Rhythm 2013;10:55–60. https://doi.org/10.1016/j.hrthm.2012.09.018; PMID: 23000040. 38. Coppola G, Ciaramitaro G, Stabile G, et al. Magnitude of QRS duration reduction after biventricular pacing identifies responders to cardiac resynchronization therapy. Int J Cardiol 2016;221:450–5. https://doi.org/10.1016/j.ijcard.2016.06.203; PMID: 27414720. 39. van Stipdonk AMW, Ter Horst I, Kloosterman M, et al. QRS area is a strong determinant of outcome in cardiac resynchronization therapy. Circ Arrhythm Electrophysiol 2018;11:e006497. https://doi.org/10.1161/CIRCEP.118.006497; PMID: 30541356. 40. Engels EB, Vis A, van Rees BD, et al. Improved acute haemodynamic response to cardiac resynchronization therapy using multipoint pacing cannot solely be explained by better resynchronization. J Electrocardiol 2018;51:S6–6. https://doi.org/10.1016/j.jelectrocard.2018.07.011; PMID: 30055846. 41. Arbelo E, Tolosana JM, Trucco E, et al. Fusion-optimized intervals (FOI): a new method to achieve the narrowest QRS for optimization of the AV and VV intervals in patients undergoing cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2014;25:283–92. https://doi.org/10.1111/ jce.12322; PMID: 24237881. 42. Trucco E, Tolosana JM, Arbelo E, et al. Improvement of reverse remodeling using electrocardiogram fusionoptimized intervals in cardiac resynchronization therapy: a randomized study. JACC Clin Electrophysiol 2018;4:181–9. https://doi.org/10.1016/j.jacep.2017.11.020; PMID: 29749935. 43. Varma N, O’Donnell D, Bassiouny M, et al. Programming cardiac resynchronization therapy for electrical synchrony: reaching beyond left bundle branch block and left ventricular activation delay. J Am Heart Assoc 2018;7:e007489. https://doi.org/10.1161/JAHA.117.007489; PMID: 29432133. 44. Thibault B, Ritter P, Bode K, et al. Dynamic programming of atrioventricular delay improves electrical synchrony in a multicenter cardiac resynchronization therapy study. Heart Rhythm 2019;16:1047–56. https://doi.org/10.1016/j. hrthm.2019.01.020; PMID: 30682433. 45. Ter Horst IAH, Bogaard MD, Tuinenburg AE, et al. The concept of triple wavefront fusion during biventricular pacing: Using the EGM to produce the best acute hemodynamic improvement in CRT. Pacing Clin Electrophysiol 2017;40:873–82. https://doi.org/10.1111/pace.13118; PMID: 28543106. 46. Tamborero D, Mont L, Sitges M, et al. Optimization of the interventricular delay in cardiac resynchronization therapy using the QRS width. Am J Cardiol 2009;104:1407–12. https://doi.org/10.1016/j.amjcard.2009.07.006; PMID: 19892059. 47. van Gelder BM, Meijer A, Bracke FA. The optimized V-V interval determined by interventricular conduction times versus invasive measurement by LVdP/dtMAX. J Cardiovasc Electrophysiol 2008;19:939–44. https://doi. org/10.1111/j.1540-8167.2008.01160.x; PMID: 18399968. 48. van Gelder BM, Bracke FA, Meijer A, et al. Effect of optimizing the VV interval on left ventricular contractility in cardiac resynchronization therapy. Am J Cardiol 2004;93:1500–3. https://doi.org/10.1016/j. amjcard.2004.02.061; PMID: 15194020. 49. Xiao HB, Roy C, Gibson DG. Nature of ventricular activation in patients with dilated cardiomyopathy: evidence for bilateral bundle branch block. Br Heart J 1994;72:167–74.

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

https://doi.org/10.1136/hrt.72.2.167; PMID: 7917691. 50. Auricchio A, Stellbrink C, Block M, et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. Circulation 1999;99:2993–3001. https://doi.org/10.1161/01. CIR.99.23.2993; PMID: 10368116. 51. Butter C, Auricchio A, Stellbrink C, et al. Effect of resynchronization therapy stimulation site on the systolic function of heart failure patients. Circulation 2001;104:3026– 9. https://doi.org/10.1161/hc5001.102229; PMID: 11748094. 52. Köbe J, Dechering DG, Rath B, et al. Prospective evaluation of electrocardiographic parameters in cardiac resynchronization therapy: detecting nonresponders by left ventricular pacing. Heart Rhythm 2012;9:499–504. https:// doi.org/10.1016/j.hrthm.2011.11.009; PMID: 22079557. 53. Lumens J, Ploux S, Strik M, et al. Comparative electromechanical and hemodynamic effects of left ventricular and biventricular pacing in dyssynchronous heart failure: electrical resynchronization versus left-right ventricular interaction. J Am Coll Cardiol 2013;62:2395–403. https://doi.org/10.1016/j.jacc.2013.08.715; PMID: 24013057. 54. Verbeek XA, Auricchio A, Yu Y, et al. Tailoring cardiac resynchronization therapy using interventricular asynchrony. Validation of a simple model. Am J Physiol Heart Circ Physiol 2006;290:h968–77. https://doi.org/10.1152/ ajpheart.00641.2005; PMID: 16172160. 55. Vatasescu R, Berruezo A, Mont L, et al. Midterm ‘superresponse’ to cardiac resynchronization therapy by biventricular pacing with fusion: insights from electroanatomical mapping. Europace 2009;11:1675–82. https://doi. org/10.1093/europace/eup333; PMID: 19880850. 56. Gold MR, Niazi I, Giudici M, et al. A prospective comparison of AV delay programming methods for hemodynamic optimization during cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2007;18:490–6. https://doi. org/10.1111/j.1540-8167.2007.00770.x; PMID: 17313533. 57. Gold MR, Yu Y, Singh JP, et al. Effect of interventricular electrical delay on atrioventricular optimization for cardiac resynchronization therapy. Circ Arrhythm Electrophysiol 2018;11:e006055. https://doi.org/10.1161/CIRCEP.117.006055; PMID: 30354310. 58. Birnie D, Hudnall H, Lemke B, et al. Continuous optimization of cardiac resynchronization therapy reduces atrial fibrillation in heart failure patients: results of the Adaptive Cardiac Resynchronization Therapy Trial. Heart Rhythm 2017;14:1820–5. https://doi.org/10.1016/j.hrthm.2017.08.017; PMID: 28893549. 59. Singh JP, Cha YM, Lunati M, et al. Real-world behavior of CRT pacing using the AdaptivCRT algorithm on patient outcomes: effect on mortality and atrial fibrillation incidence. J Cardiovasc Electrophysiol 2020;31:825–33. https://doi.org/10.1111/jce.14376; PMID: 32009263. 60. Hsu JC, Birnie D, Stadler RW, et al. Adaptive cardiac resynchronization therapy is associated with decreased risk of incident atrial fibrillation compared to standard biventricular pacing: a real-world analysis of 37,450 patients followed by remote monitoring. Heart Rhythm 2019;16:983–9. https://doi.org/10.1016/j.hrthm.2019.05.012; PMID: 31102750. 61. Gasparini M, Birnie D, Lemke B, et al. Adaptive cardiac resynchronization therapy reduces atrial fibrillation incidence in heart failure patients with prolonged av conduction: the Adaptive CRT randomized trial. Circ Arrhythm Electrophysiol 2019;12:e007260. https://doi.org/10.1161/ CIRCEP.119.007260; PMID: 30991823. 62. Wilkoff BL, Birnie D, Gold MR, et al. Differences in clinical characteristics and reported quality of life of men and women undergoing cardiac resynchronization therapy. ESC Heart Fail 2020;7:2972–82. https://doi.org/10.1002/ ehf2.12914; PMID: 32790108. 63. AlTurki A, Lima PY, Garcia D, et al. Cardiac resynchronization therapy reprogramming to improve electrical synchrony in patients with existing devices. J Electrocardiol 2019;56:94–9. https://doi.org/10.1016/j.jelectrocard.2019.07.008; PMID: 31349133. 64. O’Donnell D, Wisnoskey B, Badie N, et al. Electrical synchronization achieved by multipoint pacing combined with dynamic atrioventricular delay. J Interv Card Electrophysiol 2020. https://doi.org/10.1007/s10840-02000842-7; PMID: 32740689. epub ahead of press. 65. Wang J, Liang Y, Chen H, et al. Patient-tailored SyncAV algorithm: A novel strategy to improve synchrony and acute hemodynamic response in heart failure patients treated by cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2020;31:512–20. https://doi.org/10.1111/jce.14315; PMID: 31828904. 66. Ferchaud V, Garcia R, Bidegain N, et al. Non-invasive hemodynamic determination of patient-specific optimal pacing mode in cardiac resynchronization therapy. J Interv Card Electrophysiol 2020. https://doi.org/10.1007/s10840-020-

Fusion Pacing for CRT Optimisation 00908-6; PMID: 33128179. epub ahead of press. 67. Auricchio A, Fantoni C, Regoli F, et al. Characterization of left ventricular activation in patients with heart failure and left bundle-branch block. Circulation 2004;109:1133–9. https://doi.org/10.1161/01.CIR.0000118502.91105.F6; PMID: 14993135. 68. Lambiase PD, Rinaldi A, Hauck J, et al. Non-contact left ventricular endocardial mapping in cardiac resynchronisation therapy. Heart 2004;90:44–51. https://doi. org/10.1136/heart.90.1.44; PMID: 14676240. 69. Rudy Y, Messinger-Rapport BJ. The inverse problem in electrocardiography: solutions in terms of epicardial potentials. Crit Rev Biomed Eng 1988;16:215–68. PMID: 3064971. 70. van Oosterom A. The inverse problem of bioelectricity: an evaluation. Med Biol Eng Comput 2012;50:891–902. https:// doi.org/10.1007/s11517-012-0941-5; PMID: 22843426. 71. Bear LR, Huntjens PR, Walton RD, et al. Cardiac electrical dyssynchrony is accurately detected by noninvasive electrocardiographic imaging. Heart Rhythm 2018;15:1058– 69. https://doi.org/10.1016/j.hrthm.2018.02.024; PMID: 29477975. 72. Cluitmans MJM, Bonizzi P, Karel JMH, et al. In vivo validation of electrocardiographic imaging. JACC Clin Electrophysiol 2017;3:232–42. https://doi.org/10.1016/j.jacep.2016.11.012; PMID: 29759517. 73. Varma N, Jia P, Rudy Y. Electrocardiographic imaging of patients with heart failure with left bundle branch block and response to cardiac resynchronization therapy. J Electrocardiol 2007;40:S174–8. https://doi.org/10.1016/j. jelectrocard.2007.06.017; PMID: 17993318. 74. Nguyên UC, Cluitmans MJM, Strik M, et al. Integration of cardiac magnetic resonance imaging, electrocardiographic imaging, and coronary venous computed tomography angiography for guidance of left ventricular lead positioning. Europace 2019;21:626–35. https://doi.org/10.1093/europace/ euy292; PMID: 30590434. 75. Arnold AD, Shun-Shin MJ, Keene D, et al. His resynchronization versus biventricular pacing in patients with heart failure and left bundle branch block. J Am Coll Cardiol 2018;72:3112–22. https://doi.org/10.1016/j. jacc.2018.09.073; PMID: 30545450. 76. Sieniewicz BJ, Jackson T, Claridge S, et al. Optimization of CRT programming using non-invasive electrocardiographic imaging to assess the acute electrical effects of multipoint pacing. J Arrhythm 2019;35:267–75. https://doi.org/10.1002/ joa3.12153; PMID: 31007792. 77. Pereira H, Jackson TA, Claridge S, et al. Comparison of echocardiographic and electrocardiographic mapping for

cardiac resynchronisation therapy optimisation. Cardiol Res Pract 2019;2019:4351693. https://doi. org/10.1155/2019/4351693; PMID: 30918721. 78. Ploux S, Lumens J, Whinnett Z, et al. Noninvasive electrocardiographic mapping to improve patient selection for cardiac resynchronization therapy: beyond QRS duration and left bundle branch block morphology. J Am Coll Cardiol 2013;61:2435–43. https://doi.org/10.1016/j.jacc.2013.01.093; PMID: 23602768. 79. Thibault B, Ducharme A, Harel F, et al. Left ventricular versus simultaneous biventricular pacing in patients with heart failure and a QRS complex ≥120 milliseconds. Circulation 2011;124:2874–81. https://doi.org/10.1161/ CIRCULATIONAHA.111.032904; PMID: 22104549. 80. van Gelder BM, Bracke FA, Meijer A, et al. Morphology of the RV electrogram during LV pacing is related to the hemodynamic effect in cardiac resynchronization therapy. Pacing Clin Electrophysiol 2007;30:1381–7. https://doi. org/10.1111/j.1540-8159.2007.00875.x; PMID: 17976103. 81. Lee KL, Burnes JE, Mullen TJ, et al. Avoidance of right ventricular pacing in cardiac resynchronization therapy improves right ventricular hemodynamics in heart failure patients. J Cardiovasc Electrophysiol 2007;18:497–504. https:// doi.org/10.1111/j.1540-8167.2007.00788.x; PMID: 17428272. 82. Liang Y, Pan W, Su Y, Ge J. Meta-analysis of randomized controlled trials comparing isolated left ventricular and biventricular pacing in patients with chronic heart failure. Am J Cardiol 2011;108:1160–5. https://doi.org/10.1016/j. amjcard.2011.06.018; PMID: 21813108. 83. Gasparini M, Bocchiardo M, Lunati M, et al. Comparison of 1-year effects of left ventricular and biventricular pacing in patients with heart failure who have ventricular arrhythmias and left bundle-branch block: the Bi vs Left Ventricular Pacing: an International Pilot Evaluation on Heart Failure Patients with Ventricular Arrhythmias (BELIEVE) multicenter prospective randomized pilot study. Am Heart J 2006;152:155.e1–7. https://doi.org/10.1016/j.ahj.2006.04.004; PMID: 16824846. 84. Boriani G, Kranig W, Donal E, et al. A randomized doubleblind comparison of biventricular versus left ventricular stimulation for cardiac resynchronization therapy: the Biventricular versus Left Univentricular Pacing with ICD Back-up in Heart Failure Patients (B-LEFT HF) trial. Am Heart J 2010;159:1052–8.e1. https://doi.org/10.1016/j. ahj.2010.03.008; PMID: 20569719. 85. Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of

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

100

Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J 2013;34:2281–329. https://doi.org/10.1093/eurheartj/eht150; PMID: 23801822. 86. Zhao L, Pu L, Hua B, et al. Left univentricular pacing by rateadaptive atrioventricular delay in treatment of chronic heart failure. Med Sci Monit 2017;23:3971–80. https://doi. org/10.12659/MSM.904348; PMID: 28814710. 87. Thibault B, Mondésert B, Cadrin-Tourigny J, et al. Benefits of multisite/multipoint pacing to improve cardiac resynchronization therapy response. Card Electrophysiol Clin 2019;11:99–114. https://doi.org/10.1016/j.ccep.2018.11.016; PMID: 30717857. 88. Hu F, Zheng L, Ding L, et al. Clinical outcome of left ventricular multipoint pacing versus conventional biventricular pacing in cardiac resynchronization therapy: a systematic review and meta-analysis. Heart Fail Rev 2018;23:927–34. https://doi.org/10.1007/s10741-018-9737-5; PMID: 30209643. 89. van Everdingen WM, Zweerink A, Salden OAE, et al. Atrioventricular optimization in cardiac resynchronization therapy with quadripolar leads: should we optimize every pacing configuration including multi-point pacing? Europace 2019;21:e11–9. https://doi.org/10.1093/europace/euy138; PMID: 30052906. 90. Leclercq C, Burri H, Curnis A, et al. Cardiac resynchronization therapy non-responder to responder conversion rate in the MORE response to cardiac resynchronization therapy with MultiPoint Pacing (MORE-CRT MPP) study: results from Phase I. Eur Heart J 2019;40:2979–87. https://doi.org/10.1093/ eurheartj/ehz109; PMID: 30859220. 91. Niazi I, Baker J, Corbisiero R, et al. Safety and efficacy of multipoint pacing in cardiac resynchronization therapy: the multipoint pacing trial. JACC Clin Electrophysiol 2017;3:1510–8. https://doi.org/10.1016/j.jacep.2017.06.022; PMID: 29759832. 92. Varma N, Baker J 2nd, Tomassoni G, et al. Left ventricular enlargement, CRT response and impact of MultiPoint pacing. Circ Arrhythm Electrophysiol 2020;13:e008680. https:// doi.org/10.1161/CIRCEP.120.008680; PMID: 33028082. 93. 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. 94. AlTurki A, Lima PY, Bernier ML, et al. Optimization of chronic cardiac resynchronization therapy using fusion pacing algorithm improves echocardiographic response. CJC Open 2020;2:62–70. https://doi.org/10.1016/j.cjco.2019.12.005; PMID: 32190827.

Electrophysiology & Ablation

The Cutting Edge of Atrial Fibrillation Ablation Maya S Verma , Maria Terricabras

and Atul Verma

Southlake Regional Health Centre, University of Toronto, Newmarket, Ontario, Canada

Abstract

This article describes the advances in catheter ablation for AF that have allowed the creation of more durable and efficient lesions. It describes advances in high-power, short-duration radiofrequency ablation, radiofrequency balloon devices, ultra-low cryoablation and irreversible electroporation. It also considers the way these devices may change the way catheter ablation is performed for AF.

Keywords

AF, ablation, novel technologies Disclosure: AV has received research grants and honoraria from Bayer, Biosense, Biotronik, Boston Scientific, Medtronic, Thermedical. The other authors have no conflicts of interest to declare. Received: 28 October 2020 Accepted: 7 January 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(2):101–7. DOI: https://doi.org/10.15420/aer.2020.40 Correspondence: Atul Verma, Suite 602, 581 Davis Drive, Newmarket, Ontario L3Y 2P6, Canada. E: atul.verma@utoronto.ca Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

and the tissue, creating superficial lesions. Conductive heating is time dependent and it extends deeper in the tissue creating transmural lesions (Figure 1).13 Standard power and duration RF ablation with open saline irrigation results in a small region of resistive heating and deeper conductive heating which can produce transmural lesions in thin atrial tissue, but can limit the surface area of lesions and potentially cause collateral injury to the oesophagus, phrenic nerve and other adjacent structures.14 HPSD ablation uses power of 50 W or higher for a shorter period of time, typically 5–15 seconds. This causes a larger zone of resistive heating, while conductive heating is limited resulting in shallower and broader lesions. This modality may increase the efficiency of ablation while potentially reducing the opportunity for collateral damage. Furthermore, shorter duration deliveries may improve catheter stability and reduce oedema formation and smaller lesions.15,16

AF is one of the most widespread and sustained cardiac arrhythmias and it affects more than 30 million people worldwide.1 While prevalence in developed nations tends to be small (1–4%), it is steadily increasing and it is well known that AF is associated with an increased risk of all-cause mortality, heart failure, thromboembolism and dementia.2–5 Catheter ablation is an alternative treatment option that is more effective than antiarrhythmic medications. Pulmonary vein isolation (PVI), which involves electrically isolating the pulmonary veins (PV) from the left atrium, remains the cornerstone of AF ablation.6 However, despite numerous advances in mapping and ablation technologies over the past few years, its efficacy for maintaining sinus rhythm, especially in persistent and long-standing cases is still <70%.7 One of the main limitations of the current technologies is their ability to achieve chronic durable lesions. PV reconnection rates still range from 15–50% depending on the energy and the catheter used for the procedure.8–10 Other concerns include the efficiency of ablation procedures as pointby-point radiofrequency (RF) encirclement of the PVs is very timeconsuming. Similarly, safety is an ongoing concern with phrenic nerve and oesophageal injury occurring in up to 5–10% and 0.1–0.5% of patients, respectively.11,12

The new trend of HPSD ablation using conventional RF ablation catheters has been proved to be efficient by reducing the total RF delivery time and total procedure time with a similar or even better safety profile compared with conventional RF ablation.17 With the exception of thicker areas such as the mitral or tricuspid annulus, HPSD seems to create durable lesions and therefore, improve PVI durability.18 However, oesophageal injuries are still seen post procedure when RF ablation is guided by time or ablation index.19,20 Kaneshiro et al. reported that oesophageal thermal injury was seen in 37% of the patients using HPSD, although these lesions were limited to the shallow layer of the oesophageal wall.21 Other groups have suggested that using higher power (60 W) for a shorter period could be associated with a lower risk of complications.22

In this review, we describe the new and developing ablative technologies which may improve the efficacy, safety and efficiency of ablation for persistent AF. These techniques include high-power, short-duration (HPSD) RF delivery, single-shot RF balloons, advances in cryoablation, and electroporation.

High-power, Short-duration Radiofrequency Ablation

The concept of HPSD using contemporary available catheters has two main limitations. The first problem is the use of high flow irrigation (15–30 cc/min) in combination with high power. Cold saline irrigation cools the tissue surface during ablation creating lower quality lesions by reducing the area of resistive heating which is important in the thin atrial tissue.

Lesion formation using contemporary RF ablation catheters has two simultaneous phases: resistive heating and conductive heating. Resistive heating is caused by the direct contact between the tip of the catheter

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The Cutting Edge of AF Ablation Figure 1: High-power, Short-duration Radiofrequency Compared with Standard Radiofrequency Ablation

Resistive heating

The conventional width separating electrodes is 8 mm but the small distal tip electrodes are separated by a 1.1 mm distance. Short spacing between high-resolution electrodes (HREs) at the catheter tip allows for highly localised signals to be recorded at the ablation centre.23 Many studies support the improved safety profile and effectiveness of the DiamondTemp catheter. Clinically, the TRAC-AF pilot study (NCT02821351) demonstrated that the catheter could achieve 100% acute procedural success in all subjects, but in a shorter period and with less RF delivery compared with historical controls.24 The FASTR-AF trial (NCT036266499) also showed procedural safety and effectiveness with the DiamondTemp catheter. Freedom from AF at 12 months was 74.3% while total RF time was only 19.8 ± 8.6 minutes. No steam pops occurred and there was no evidence of char formation on the tip of the catheter.25 The DIAMOND-AF study (NCT03334630), to be published soon, showed that there was no difference in success between the diamond-tipped catheter and traditional contact force sensing (CFS) catheters in 1-year follow-up for patients with paroxysmal AF. The success rate at 1 year for the diamond tip group was 71% compared with 72% for CFS. The study also showed that procedural time and RF delivery and saline volume were all reduced. The DIAMONDAF II study (NCT03643224) will compare results between the diamond-tip catheter system and traditional RF in patients with persistent AF.

Resistive heating

Conductive heating

Oesophagus

Standard ablation

High-power, short-duration ablation

Longer applications using conventional parameters (20–30 W for 20–40 seconds) result in more conductive heating that reaches deep structures (left). The presumed advantage of higher powers with shorter durations (≥50 W for 5–12 seconds) is the larger endocardial lesion as a result of the high energy applied from the tip of the catheter to the myocardium (resistive heating) but less conduction of heat to deeper structures (right). Higher irrigation used in conventional ablation also translates into deeper lesions (left). Conversely, lower irrigation only creates superficial and non-transmural lesions (right).

Irrigation also enhances the depth of the lesion, increasing the risk of collateral damage in the atrium.

QDOT Micro Catheter

The QDOT Micro Catheter (Biosense Webster) is another emerging system also designed to achieve better monitoring of tissue temperature. It has six thermally isolated thermocouples embedded in the tip and side of the catheter rather than proximally. The tip is made of traditional platinumiridium composite. There are two delivery modes: very high power for very short durations (QMODE+) and more standard delivery mode (QMODE). In QMODE+, the catheter delivers 90 W for 4 seconds, while in QMODE, powers of 40 to 50 W are typically used for 5–15 seconds. The irrigation rate varies between 5–15 ml depending on the tip temperature and power output. This optimised system ensures the tip remains within the allowed temperature to avoid overheating and tissue damage to contiguous areas.13

The second limitation is the concept of time- or ablation index-guided ablation when using this approach. High-flow irrigation does not allow precise temperature feedback from the tip of the catheter. The quality of the lesion and the possible collateral damage is directly related to the temperature achieved at the level of the tissue, not so much to the power delivered. There are two novel catheters – the diamond-tipped catheter and the micro catheter – used to perform HPSD that introduce the concept of temperature-controlled ablation from the tip of the catheter to limit power delivery, reduce open irrigation to allow for better assessment of the tip temperature and reduce the total duration of RF delivery.

Diamond-tipped Catheter Technology

A novel diamond-tipped catheter ablation system merges development in catheter structure, temperature sensing technology, high-resolution ECG and diamond cooling. The catheter is 7.5 Fr with a 4.1 mm tip. A network of chemical vapour deposit industrial diamonds is designed to act as heat shunting material at the catheter tip. The structure allows for high thermal diffusivity as thermal energy undergoes quick conduction through the shunting network. This heat and cool transfer is 200–400 times faster using a chemical vapour deposit diamond network compared to conventional platinum-iridium structures.23

Preclinical data demonstrated that broader, shallower lesions could be obtained. Compared to standard ablation, the use of HPSD resulted in 100% contiguous and transmural lines, whereas standard ablation showed gaps in 25% and non-transmural lesions in 29%. Ablation at 90 W was identified as having no steam pops or char formation. Clinical data from the QDOT FAST study showed shorter procedure and fluoroscopy times of 105.2 ± 24.7 minutes and 6.6 ± 8.2 minutes respectively.26 Acute success was achieved in 94.2% of the patients at 3 months post ablation and no major side effects including death, stroke, oesophageal fistula or PV stenosis were reported.

Irreversible tissue damage occurs when tissue temperature exceeds 50°C. Overshooting this temperature point is a common safety challenge in catheter ablation. The DiamondTemp catheter (Medtronic) protects against temperature-derived tissue damage as the system starts by running in temperature control mode where the temperature is sampled every 20 ms by each sensor. The system continuously monitors and records the highest temperature while the power is automatically adjusted. The catheter includes six thermocouples for temperature sensing, which are thermally isolated from the RF electrode. Since these structures are located on the catheter tip, they provide accurate tissue-tip temperature measurements. The low irrigation rate of 8 cc/min allows for better real-time temperature measurement. The maximum power delivery is 50 W and lesions in the atrium are typically applied for 5–10 seconds.

Overall, optimising HPSD techniques is a continuous work in progress as the optimal power to be used has yet to be determined. Although HPSD boasts shorter procedure times and less fluid load than for patients undergoing conventional RF, procedural complications may be difficult to assess in real time when lesions are delivered between 3–4 seconds. For instance, oesophageal temperature rises are latent after the first RF delivery and procedural complications may be difficult to mitigate if the RF application is too fast. As time goes on, an optimal RF power output with optimal duration will hopefully be determined for different tissue types. Although many advances in HPSD seem promising for the field of electrophysiology, it is crucial that the proper technologies are employed.

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The Cutting Edge of AF Ablation Temperature control is one of the keystones for HPSD ablation. Without temperature control, power delivery cannot be actively titrated by the generator to optimise the lesion and avoid complications like steam pops, perforation or char formation. For example, Kottmaier et al. presented findings where they applied 70 W of energy for 7 seconds at the anterior left atrium and 5 seconds at posterior left atrium using a standard, highirrigation catheter without any temperature control. Despite some early promising results, the findings should be interpreted with caution. For example, the group found three participants with pericardial effusion with HSPD, as opposed to two in the standard ablation group. This rate of effusion is much higher than reported in other traditional technologies.27 Without temperature control to limit power delivery, HPSD lesions can result in steam pops and micro-perforations.

Figure 2: Ultra-low Cryoablation System

Single-shot Radiofrequency Balloons

Illustration of the ultra-low cryoablation system (intelligent Continuous Lesion Ablation System – iCLAS, Adagio). A: Cryoablation catheter with a proximal ablation portion and a distal diagnostic portion used to confirm isolation of the pulmonary vein or other structure. B: Different pre-shaped stylets that can be advanced into the ablation catheter, allowing it to take different shapes depending on the specific location or vein size. C: Oesophageal warming balloon with saline at 38°C.

A Cryoablation section

Diagnostic section

Point-by-point ablations are time-consuming and require high technical experience on the part of physicians. However, balloon-based ablation allows for quick, easy isolation of the PVs in a single shot. The two most prominent developments in RF balloon ablation are the HELIOSTAR RF balloon (Biosense Webster) and the LUMINIZE RF balloon (Boston Scientific).

LUMINIZE RF Balloon

The LUMINIZE RF balloon is 28 mm in diameter and is compliant with 12 equatorial and six forward-facing irrigated electrodes. Microelectrodes are also printed along splines of the catheter which can map ECGs. The catheter has built-in cameras with LED lighting for visualisation and no additional diagnostic catheters are needed. An over-the-wire technique and steerable sheath is used to navigate the balloon in the left atrium. The catheter delivers RF energy in either a bipolar or unipolar fashion. Specifically, the equatorial electrodes deliver bipolar RF at 6–10 W for 60 seconds with an irrigation rate of 30 ml/min. The forward-facing electrodes can deliver bipolar or unipolar energy and can be used for non-PV ablation. LUMINIZE uses electrode impedance readings to determine contact. The built-in camera allows for real-time visualisation of the electrodes on the tissue to confirm contact and energy delivery.30

HELIOSTAR RF Balloon

The HELIOSTAR is a 13.5 Fr RF balloon with a 3 Fr circular mapping catheter, a 13.5 Fr steerable sheath and a dedicated multichannel generator. The balloon is 28 mm in diameter with 10 irrigated, flexible, gold-plated electrodes on the distal end of the catheter. Integrated thermistors monitor tissue temperature throughout the procedure. The multi-electrode RF balloon is manipulated over a guidewire using a deflectable sheath. The RF balloon is sited at the antra of each of the PVs, inflated, and irrigated at a rate of 35 ml/min. Ablation is delivered in the unipolar mode at 15 W and is temperature-controlled to a target of 60°C for 60 seconds. Electrodes of the RF balloon that are adjacent to the posterior wall can be identified and RF can be stopped at these electrodes after 20 seconds of ablation. The ablation electrodes are gold-plated and are bonded to the surface of the balloon. The electrodes are teardrop in shape and measure 14.4 mm in length with a width of 1.1 mm distally to 4.4 mm proximally. This technology uses a magnet-based visualisation system (CARTO3, Biosense Webster) to map and navigate the balloon around the veins and left atrium.28

The two-phase AF-FICIENT 1 study examined acute and procedural success and safety for LUMINIZE in a cohort of 100 patients with paroxysmal AF. The first phase of the study investigated the original design of the device, while phase 2 investigated changes which enhanced manoeuvrability with added dedicated pacing and sensing electrodes. Overall, the study demonstrated a high rate of acute PV isolation (99.4% in phase 2) with no device-related serious adverse events. The median time the balloon spent in the left atrium went from 91 minutes in phase 1 to 29 minutes in phase 2, which brought the total procedure time down to a median of 71 minutes.31 Although the preliminary results with LUMINIZE RF balloon seemed promising, the future of this device is now unclear.

The RADIANCE trial evaluated the 1-year outcome and safety of the HELIOSTAR balloon. The results demonstrated acute PV isolation in 100% of the 39 patients enrolled. The mean duration of ablation lesion delivery was 5.9 (4.5–7.6) minutes, which is short compared to cryoablation. Isolation was achieved after just one delivery in 79.6% of PVs. Acute PV reconnection was seen in 4.6% (7/150) of PVs. Freedom from documented atrial arrhythmia at 12 months was 86.4% (32/37) or 75.7% from antiarrhythmic medications. The larger, ongoing investigational device exemption (IDE) trial STELLAR (NCT03683030) will give further results.

Ultra-low Temperature Cryoablation

Unlike RF ablation, cryoablation methods withdraw heat for ablation. The cryoballoon was the first balloon platform for PVI isolation.2 The cryoballoon uses a single-shot delivery method to ablate in an efficient manner.2 Traditional cryotherapy uses pressurised nitric oxide to absorb heat from surrounding tissues, achieving temperatures as low as −80°C. Ice crystal formation causes cell death and ice crystal expansion during melting causes further cell destruction.32

The clearest advantage of RF balloons for PV isolation lies in their efficiency. Compared to the cryoballoon, where applications are 2–3 minutes each and an additional ‘bonus’ lesion is often required, RF balloons can achieve isolation within one minute in the majority of veins with a single application. However, the long-term safety of such powerful devices remains to be seen. In RADIANCE, for example, asymptomatic cerebral lesions were seen in 30% of patients, which is on the higher end of accepted ablation technologies. Gastroscopy revealed asymptomatic oesophageal erythema in 5 of 39 patients (13%) which is also higher than reported for other ablation technologies.29

Recently, a system using ultra-low cryoablation was developed using the intelligent continuous lesion ablation system (iCLAS; Adagio Medical). The system uses an 8.5 Fr catheter which is very malleable. Pre-shaped nitinol stylets can then be advanced into the catheter to allow it to take a circular, linear or curved shape suited for specific locations in the left and right

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The Cutting Edge of AF Ablation Figure 3: Lattice-tipped Radiofrequency and Pulsed Field Ablation Catheter

Lattice-tipped, spherical ablation catheter with combined temperature-controlled radiofrequency and pulsed field ablation capabilities (Sphere-9 catheter, Affera). It has an expandable spheroid-shaped lattice tip capable of making large, point-by-point lesions (A and B). The tip is flexible allowing it to conform to tissue (C). Source: Anter et al. 2020.46 Reproduced with permission from Elsevier.

delivered in several trains, each consisting of several pulses, in a repetitive series. The width of each pulse is typically measured in nanoseconds or milliseconds, so one delivery of a train of pulses can be delivered in a fraction of a second. This contributes to one of the chief benefits of IRE as an energy source: ultra-rapid and efficient energy delivery.36,37

atria. Some stylets have a double circular design such that the inner circle records signals within the PV while the outer circle ablates around the PV. Other curves are designed for single shot cavotricuspid isthmus ablation. The device uses highly purified liquid nitrogen to cool the tissue to −190°C. Lesions are administered for 30–60 seconds followed by a repeat application. The profound cooling helps to create more transmural lesions compared to traditional cryoablation.33 To protect against oesophageal injury, a warmed saline filled balloon is placed in the oesophagus to keep the temperature at 38°C during ablation over the oesophageal regions (Figure 2).

The other advantage of IRE is that cardiac tissue seems to be more susceptible to cell death than other tissues. This may be due to tissue selectivity. It may also be due to the limited regeneration capability of cardiac tissue in comparison to oesophageal tissue, and the insulating effect of multiple tissue layers. For example, nerves are surrounded by a myelin sheath which may make them more resistant to IRE. If IRE is delivered in the left atrium, the outer layer of the myocardium, the pericardial layer and adipose tissue may all insulate the oesophagus. Therefore, IRE’s principal advantage will be enabling ablation in the left atrium while minimising, if not eliminating, the possibility of damage to the phrenic nerve or oesophagus.38–40

In the CRYO-CURE 2 study (NCT02839304), results from 48 patients were reported (35 for both safety and efficacy and 13 for safety only). Two patients had persisting phrenic nerve palsy, but no other safety events were reported. Five patients with paroxysmal AF and 17 with persistent AF were followed up for 6 months and the success rate was 100%. Success rates dropped to about 78% at 12 months.34 A larger IDE trial for persistent AF is starting which will provide more safety and efficacy data. The efficiency of the procedure is also good with a mean procedure time of 116 minutes. Ongoing developments include combining cryoablation with novel pulsed field ablation.

Since lesions are created by a field of energy and not by selected regions of heat or cold, the lesions seem to be more contiguous than traditional ablation. IRE is also more forgiving when it comes to contact with the tissue since the field can reach the tissue even if the catheter has suboptimal contact force. Some contact, however, is still required. What is unclear, however, is whether PFA will be any more effective than thermal ablation. Current systems are optimised for tissue depths of 3–7 mm which is fine for left atrial tissue but may not be sufficient for ventricular tissue. However, if the same efficacy can be achieved with more safety and efficiency, then IRE will still be a game changer.

Electroporation

Electroporation is a non-thermal ablation technique using electric fields to produce nanoholes in the cell membranes of targeted cardiac tissue cells by exposing them to a high-voltage field. If sufficient voltage is applied, the effects of electroporation are irreversible leading to cellular apoptosis and replacement fibrosis. These changes probably occur over days to weeks but this is not well known. Irreversible electroporation (IRE) is also referred to as pulsed field ablation (PFA).35 There are multiple ways that IRE can be delivered. Pulses can use alternating current or direct current and delivery may be unipolar (from the catheter tip to a return electrode on the skin of the patient) or bipolar (between adjacent electrodes). It may also be delivered using a monophasic or biphasic waveform. Most systems to date use bipolar, biphasic pulse delivery. The rationale is that bipolar, biphasic delivery can reduce the recruitment of skeletal muscle and the voltage delivered, avoiding twitching or movement of the patient as we might observe during a cardioversion. The disadvantage is that bipolar delivery of higher voltages results in some minor electrode heating. Typically, IRE is

Microbubble formation has been noted with IRE, with some forms of delivery being more prone to this than others. While it is assumed that such microbubbles are due to fluid electrolysis and have a very short halflife, it is unclear what risk, if any, they pose. Early cerebral MRI data has suggested that they do not create any acute, asymptomatic cerebral lesions. Further data will be forthcoming. In this section, we will summarise the IRE systems closest to market release. However, there are multiple companies developing newer IRE systems all the time, so this section is not meant to be comprehensive.

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The Cutting Edge of AF Ablation Figure 4: Spherical, Multipolar Combination Mapping and Ablation Catheter

A multipolar, spherical combined mapping and ablation system (Globe, Kardium). A: Fluoroscopic image of the Kardium Globe catheter inside the left atrium. B: Illustration of the catheter outside of the left superior pulmonary vein. C: Map of the left atrium performed with the Globe catheter using an integrated mapping system (Globe Positioning System). The large size of the catheter allows for ‘single-shot’ mapping and energy application.

Medtronic Pulsed Field Ablation System

oesophageal lesions or enhancement, no silent ischaemia in postprocedure MRIs in 13 patients and phrenic nerve assessment showed no paresis or palsy after 3 months. There was also no PV stenosis or narrowing. The system underwent several iterations in pulse delivery from monophasic pulses (which required general anaesthesia and paralytics) to different biphasic deliveries which improved lesion durability from 18% to 100% at 3 months.42 A more recent study showed that the system can also create posterior wall lesions in addition to PVI with 100% posterior wall durability at 3 months.43 Pre-clinical data has shown that the delivery of IRE does not cause oesophageal lesion and also seems to avoid any PV or superior vena cava stenosis.44,45

The Medtronic pulse direct system consists of a circular catheter with nine gold electrodes with bipolar and biphasic delivery. Alternating current’s electric fields can be adjusted via different energy profiles. Typically, four applications are made at each catheter position and each application takes a fraction of a second. Pre-clinical data has shown that the oesophagus and phrenic nerve are quite resistant to any damage from this system. PV stenosis is also very unlikely to occur despite delivery deep inside the veins. Animal data at 1 and 3 months also suggest that the lesions created are durable and contiguous and capable of 3–7 mm tissue depth. Human studies have just begun. The PULSED AF pilot study has demonstrated 100% PV isolation with no serious adverse events, including no change in oesophageal temperature or phrenic nerve injury. Patients did require heavy sedation or general anaesthesia for pain management but no skeletal muscle twitching or paralytics were required.41

New Lattice Catheter – Combination Irreversible Electroporation and Pulsed Field Ablation

The novel Sphere-9 catheter (Affera) has an expandable spheroid-shaped lattice tip with a 10-fold larger effective area compared to the conventional 3.5 mm electrode. It can deliver higher energy with a lower risk of tissue overheating. The entire lattice framework emits RF energy to deliver a uniform current cloud, and its temperature-controlled mode modulates the current output to avoid overheating (Figure 3).

Farapulse Irreversible Electroporation System

The Farapulse system includes a 20-electrode catheter arranged in a flower-like configuration with five ‘petals’. The catheter can also resemble a basket. It delivers DC bipolar and biphasic trains.36,42 This system was the first used in a human trial. The IMPULSE (NCT03700385) and PEFCAT (NCT03714178) trials were prospective feasibility trials investigating the use of the Farapulse PFA system for the treatment of paroxysmal AF and cavotricuspid isthmus-dependent atrial flutter and all the participants in both groups achieved acute PV isolation. Primary safety endpoints were achieved with no adverse events other than cardiac perforation or tamponade in one patient in the IMPULSE cohort. There were no

In the first-in-human study of this device, PVI was achieved in 64 of 65 patients (98.5%) using the lattice alone and mitral block was achieved in 100% of patients.46 Roof line and cavotricuspid isthmus ablation were achieved in 95.8% and 100% of patients, respectively. The device boasts a high safety profile with no complications after a 3-month follow-up.46 Despite epicardial cooling, the large surface area of the device enables lesions suitable for varied tissue thickness. Furthermore, the lower

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The Cutting Edge of AF Ablation current density allows homogenous heating with reduced risks of hot spots and steam pops, or damage due to passive conductive heating. Using high resolution mapping and ablation in one, physicians can define the anatomy of the individual patient as they go, with included voltage and activation mapping. All these integrated advantages of the lattice-tip catheters will advance catheter ablation beyond conventional PVI methods.47

Despite successes in these trials, certain questions remain for clinical practice. How do we increase the depth of lesions to affect deeper ventricular tissue without creating thermal damage or altering tissue selectivity? Initial pre-clinical studies have shown that ventricular ablation is feasible but probably lacks the depth needed for broad application. Physicians also need to better understand the exact mechanisms of myocardial sensitivity and cell death to guarantee positive safety outcomes.

The device has demonstrated its capability to deliver PFA.48 The first-inhuman trial showed 100% acute procedural efficacy with a left atrial ablation time less than 25 minutes and no evidence of oesophageal injury in the patients receiving PFA alone. There were no cases of phrenic nerve injury or PV stenosis. There were 6% of patients with fluid-attenuated inversion recovery (FLAIR) positive lesions on cerebral MRI and 10% with positive diffusion weighted MRI, but the activated clotting time appeared to be sub-therapeutic in all of these cases and patients were not necessarily receiving PFA alone.

Conclusion

The optimal ablation strategy is still unknown and it is unlikely that a perfect ablation strategy will ever exist. Comparative clinical trials will dictate which factors physicians should consider when deciding which strategy is most effective, efficient and safe. HPSD, single-shot RF balloons, cryoablation, electroporation and lattice catheters are among few of the many new emerging technologies which could revolutionise the field of electrophysiology.

There are other devices that are exploring the combination of thermal and PFA energy. The Adagio system described above is looking at combination cryoablation and PFA delivered together to improve tissue contact, minimise any heating or microbubble formation, and potentially create deeper lesions. The novel Kardium Globe catheter (Kardium) offers global multielectrode contact mapping and ablation and combines the benefits of single-tip catheters with the simplicity of balloon catheters. The catheter structure includes 16 flat ribs with 122 gold-plated electrodes, which individually measure tissue contact pressure, temperature, current and intracardiac ECGs, and apply RF accordingly in a temperaturecontrolled, non-irrigated fashion. In the GLOBAL AF study, 60 patients with symptomatic AF underwent PVI using Globe and 72% were free from AF and atrial tachycardia at 12 months without antiarrhythmic drugs. The Globe catheter seems well suited for PFA and may be used as another combination device (Figure 4).49 1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a global burden of disease 2010 study. Circulation 2014;129:837–47. https://doi. org/10.1161/CIRCULATIONAHA.113.005119; PMID: 24345399. 2. January CT, Wann LS, Alpert JS, et al. 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 Practice Guidelines and the Heart Rhythm Society. Circulation 2019;140:e125–51. https://doi.org/10.1161/ CIR.0000000000000665; PMID: 30686041. 3. Stewart S, Hart CL, Hole DJ, McMurray JJV. A populationbased study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am J Med 2002;113:359–64. https://doi.org/10.1016/S00029343(02)01236-6; PMID: 12401529. 4. Benjamin EJ, Wolf PA, D’Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998;98:946–52. https://doi.org/10.1161/01. CIR.98.10.946; PMID: 9737513. 5. Marijon E, Le Heuzey JY, Connolly S, et al. Causes of death and influencing factors in patients with atrial fibrillation: a competing-risk analysis from the randomized evaluation of long-term anticoagulant therapy study. Circulation 2013;128:2192–201. https://doi.org/10.1161/ CIRCULATIONAHA.112.000491; PMID: 24016454. 6. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017;14:e275–444. https://doi.org/10.1016/j. hrthm.2017.05.012; PMID: 28506916. 7. Clarnette JA, Brooks AG, Mahajan R, et al. Outcomes of persistent and long-standing persistent atrial fibrillation ablation: a systematic review and meta-analysis. Europace 2018;20:f366–76. https://doi.org/10.1093/europace/eux297; PMID: 29267853. 8. De Potter T, Van Herendael H, Balasubramaniam R, et al.

10.

11.

12.

13.

14.

15.

Clinical Perspective

• Higher-power, shorter-duration lesions with temperature control

and lower irrigation can produce lesions with more resistive and less conductive heating which can increase lesion width without extending lesion depth. • Single-shot radiofrequency balloon devices can produce rapid pulmonary vein isolation and safety will be determined from larger clinical trials. • Ultra-low cryoablation attempts to address the issue of lesion transmurality and requires oesophageal warming. • Electroporation, either in isolation or combined with other energy sources, may offer much better efficiency and improved safety.

Safety and long-term effectiveness of paroxysmal atrial fibrillation ablation with a contact force-sensing catheter: real-world experience from a prospective, multicentre observational cohort registry. Europace 2018;20:f410–8. https://doi.org/10.1093/europace/eux290; PMID: 29315382. Aryana A, Singh SM, Mugnai G, et al. Pulmonary vein reconnection following catheter ablation of atrial fibrillation using the second-generation cryoballoon versus openirrigated radiofrequency: results of a multicenter analysis. J Interv Card Electrophysiol 2016;47:341–8. https://doi. org/10.1007/s10840-016-0172-z; PMID: 27475949. Kautzner J, Neužil P, Lambert H, et al. EFFICAS II: Optimization of catheter contact force improves outcome of pulmonary vein isolation for paroxysmal atrial fibrillation. Europace 2015;17:1229–35. https://doi.org/10.1093/europace/ euv057; PMID: 26041872. Mansour M, Lakkireddy D, Packer D, et al. Safety of catheter ablation of atrial fibrillation using fiber optic-based contact force sensing. Heart Rhythm 2017;14:1631–6. https://doi. org/10.1016/j.hrthm.2017.07.023; PMID: 28734985. Deshmukh A, Patel NJ, Pant S, et al. In-hospital complications associated with catheter ablation of atrial fibrillation in the United States between 2000 and 2010: analysis of 93,801 procedures. Circulation 2013;128:2104–12 https://doi.org/10.1161/CIRCULATIONAHA.113.003862; PMID: 24061087. Leshem E, Zilberman I, Tschabrunn CM, et al. High-power and short-duration ablation for pulmonary vein isolation: biophysical characterization. JACC Clin Electrophysiol 2018;4:467–79. https://doi.org/10.1016/j.jacep.2017.11.018; PMID: 30067486. Nath S, DiMarco JP, Haines DE. Basic aspects of radiofrequency catheter ablation. J Cardiovasc Electrophysiol 1994;5:863–76. https://doi.org/10.1111/j.1540-8167.1994. tb01125.x; PMID: 7874332. Shin DG, Ahn J, Han SJ, Lim HE. Efficacy of high-power and short-duration ablation in patients with atrial fibrillation: a

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prospective randomized controlled trial. Europace 2020;22:1495–501. https://doi.org/10.1093/europace/ euaa144; PMID: 32810203. 16. Chen S, Schmidt B, Bordignon S, et al. Ablation indexguided 50 W ablation for pulmonary vein isolation in patients with atrial fibrillation: Procedural data, lesion analysis, and initial results from the FAFA AI High Power Study. J Cardiovasc Electrophysiol 2019;30:2724–31. https:// doi.org/10.1111/jce.14219; PMID: 31588620. 17. Winkle RA, Mohanty S, Patrawala RA, et al. Low complication rates using high power (45–50 W) for short duration for atrial fibrillation ablations. Heart Rhythm 2019;16:165–9. https://doi.org/10.1016/j.hrthm.2018.11.031; PMID: 30712645. 18. Yavin HD, Leshem E, Shapira-Daniels A, et al. Impact of high-power short-duration radiofrequency ablation on longterm lesion durability for atrial fibrillation ablation. JACC Clin Electrophysiol 2020;6:973–85. https://doi.org/10.1016/j. jacep.2020.04.023; PMID: 32819533. 19. Chen S, Schmidt B, Seeger A, et al. Catheter ablation of atrial fibrillation using ablation index-guided high power (50 W) for pulmonary vein isolation with or without esophageal temperature probe (the AI-HP ESO II). Heart Rhythm 2020;17:1833–40. https://doi.org/10.1016/j. hrthm.2020.05.029; PMID: 32470628. 20. Chen S, Chun KRJ, Tohoku S, et al. Esophageal endoscopy after catheter ablation of atrial fibrillation using ablationindex guided high-power: Frankfurt AI-HP ESO-I. JACC Clin Electrophysiol 2020;6:1253–61. https://doi.org/10.1016/j. jacep.2020.05.022; PMID: 33092751. 21. Kaneshiro T, Kamioka M, Hijioka N, et al. Characteristics of esophageal injury in ablation of atrial fibrillation using a high-power short-duration setting. Circ Arrhythm Electrophysiol 2020;13:e008602. https://doi.org/10.1161/ CIRCEP.120.008602; PMID: 32915644. 22. Castrejón-Castrejón S, Martínez Cossiani M, Ortega Molina M, et al. Feasibility and safety of pulmonary vein isolation by

The Cutting Edge of AF Ablation high-power short-duration radiofrequency application: short-term results of the POWER-FAST PILOT study. J Interv Card Electrophysiol 2020;57:57–65. https://doi.org/10.1007/ s10840-019-00645-5; PMID: 31713704. 23. Iwasawa J, Koruth JS, Petru J, et al. Temperature-controlled radiofrequency ablation for pulmonary vein isolation in patients with atrial fibrillation. J Am Coll Cardiol 2017;70:542– 53. https://doi.org/10.1016/j.jacc.2017.06.008; PMID: 28750697. 24. Starek Z, Lehar F, Jez J, et al. TRAC-AF trial: first-in-man multicenter prospective clinical experience using a novel diamond tip temperature controlled irrigated ablation system: safety results and initial effectiveness performance. Europace 2018;20:i61. https://doi.org/10.1093/europace/ euy015.168. 25. Neuzil P. First-in-man FASTR-AF Study: novel temperaturecontrolled fast ablation system to rapidly create lesions for the treatment of persistent and paroxysmal atrial fibrillation. Presented at Heart Rhythm Society 2019 Scientific Sessions, San Diego, CA, US, 8–11 May 2019. 26. Reddy VY, Grimaldi M, De Potter T, et al. Pulmonary vein isolation with very high power, short duration, temperaturecontrolled lesions: the QDOT-FAST trial. JACC Clin Electrophysiol 2019;5:778–86. https://doi.org/10.1016/j. jacep.2019.04.009; PMID: 31320006. 27. Kottmaier M, Popa M, Bourier F, et al. Safety and outcome of very high-power short-duration ablation using 70 W for pulmonary vein isolation in patients with paroxysmal atrial fibrillation. Europace 2020;22:388–93. https://doi. org/10.1093/europace/euz342; PMID: 31872249. 28. Gianni C, Chen Q, Della Rocca D, et al. Radiofrequency balloon devices for atrial fibrillation ablation. Card Electrophysiol Clin 2019;11:487–93. https://doi.org/10.1016/j. ccep.2019.05.009; PMID: 31400873. 29. Reddy VY, Schilling R, Grimaldi M, et al. Pulmonary vein isolation with a novel multielectrode radiofrequency balloon catheter that allows directionally tailored energy delivery: short-term outcomes from a multicenter first-in-human study (RADIANCE). Circ Arrhythm Electrophysiol 2019;12:e007541. https://doi.org/10.1161/CIRCEP.119.007541; PMID: 31826648. 30. Dhillon GS, Honarbakhsh S, Di Monaco A, et al. Use of a multi-electrode radiofrequency balloon catheter to achieve pulmonary vein isolation in patients with paroxysmal atrial

fibrillation: 12-month outcomes of the RADIANCE study. J Cardiovasc Electrophysiol 2020;31:1259–69. https://doi.org/10.1111/jce.14476; PMID: 32250514. 31. Al-Ahmad A, Aidietis A, Daly M, et al. Assessment of the safety and performance of a novel RF balloon catheter system to isolate pulmonary veins: results of the multicenter AF-FICIENT 1 Trial. Presented at European Heart Rhythm Association Congress, Lisbon, Portugal, 17 March 2019. 32. Khairy P, Dubuc M. Transcatheter cryoablation part i: preclinical experience. Pacing Clin Electrophysiol 2007;31:112– 20. https://doi.org/10.1111/j.1540-8159.2007.00934.x; PMID: 18181919. 33. De Potter T, Boersma L, Babkina A, et al. Novel linear cryoablation catheter to treat atrial fibrillation. Presented at Heart Rhythm Society Scientific Sessions, Boston, MA, US, 9–12 May 2018. 34. De Potter T. Investigation of the Adagio cryoablation system in patients with atrial fibrillation (CryoCure2). Presented at 24th Annual International AF Symposium, Boston, MA, US, 24–26 January 2019. 35. Wittkampf FHM, van Es R, Neven K. Electroporation and its relevance for cardiac catheter ablation. JACC Clin Electrophysiol 2018;4:977–86. https://doi.org/10.1016/j. jacep.2018.06.005; PMID: 30139498. 36. Reddy VY, Koruth J, Jais P, et al. Ablation of atrial fibrillation with pulsed electric fields: an ultra-rapid, tissue-selective modality for cardiac ablation. JACC Clin Electrophysiol 2018;4:987–95. https://doi.org/10.1016/j.jacep.2018.04.005; PMID: 30139499. 37. Wittkampf FH, van Driel VJ, van Wessel H, et al. Feasibility of electroporation for the creation of pulmonary vein ostial lesions. J Cardiovasc Electrophysiol 2011;22:302–9. https://doi. org/10.1111/j.1540-8167.2010.01863.x; PMID: 20653809. 38. Wojtaszczyk A, Caluori G, Pešl M, et al. Irreversible electroporation ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2018;29:643–51. https://doi.org/10.1111/ jce.13454; PMID: 29399927. 39. Sugrue A, Maor E, Ivorra A, et al. Irreversible electroporation for the treatment of cardiac arrhythmias. Expert Rev Cardiovasc Ther 2018;16:349–60. https://doi.org/10.1080/1477 9072.2018.1459185; PMID: 29595355. 40. Maor E, Sugrue A, Witt C, et al. Pulsed electric fields for cardiac ablation and beyond: a state-of-the-art review. Heart

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Rhythm 2019;16:1112–20. https://doi.org/10.1016/j. hrthm.2019.01.012; PMID: 30641148. 41. Verma A, Boersma LV, Hummel JD, et al. PULSED AF: first human experience and acute procedural outcomes using a novel pulsed field ablation system. Presented at Heart Rhythm Society, 8 May 2020. 42. Reddy VY, Neuzil P, Koruth JS, et al. Pulsed field ablation for pulmonary vein isolation in atrial fibrillation. J Am Coll Cardiol 2019;74:315–26. https://doi.org/10.1016/j.jacc.2019.04.021; PMID: 31085321. 43. Reddy VY, Anic A, Koruth J, et al. Pulsed field ablation in patients with persistent atrial fibrillation. J Am Coll Cardiol 2020;76:1068–80. https://doi.org/10.1016/j.jacc.2020.07.007; PMID: 32854842. 44. Koruth JS, Kuroki K, Kawamura I, et al. Pulsed field ablation versus radiofrequency ablation: esophageal injury in a novel porcine model. Circ Arrhythmia Electrophysiol 2020;13:e008303. https://doi.org/10.1161/CIRCEP.119.008303; PMID: 31977250. 45. Koruth J, Kuroki K, Iwasawa J, et al. Preclinical evaluation of pulsed field ablation: electrophysiological and histological assessment of thoracic vein isolation. Circ Arrhythmia Electrophysiol 2019;12:1–9. https://doi.org/10.1161/ CIRCEP.119.007781; PMID: 31826647. 46. Anter E, Neužil P, Rackauskas G, et al. A lattice-tip temperature-controlled radiofrequency ablation catheter for wide thermal lesions: first-in-human experience with atrial fibrillation. JACC Clin Electrophysiol 2020;6:507–19. https:// doi.org/10.1016/j.jacep.2019.12.015; PMID: 32439034. 47. Reddy VY, Neužil P, Peichl P, et al. A lattice-tip temperaturecontrolled radiofrequency ablation catheter: durability of pulmonary vein isolation and linear lesion block. JACC Clin Electrophysiol 2020;6:623–35. https://doi.org/10.1016/j. jacep.2020.01.002; PMID: 32553211. 48. Reddy VY, Anter E, Rackauskas G, et al. Point-by-point pulsed field ablation (+/- radiofrequency ablation) to treat atrial fibrillation: a first in human trial. Presented at Heart Rhythm Society, 8 May 2020. 49. Kottkamp H, Hindricks G, Pönisch C, et al. Global multielectrode contact-mapping plus ablation with a single catheter in patients with atrial fibrillation: GLOBAL AF study. J Cardiovasc Electrophysiol 2019;30:2248–55. https://doi. org/10.1111/jce.14172; PMID: 31512340.

Electrophysiology and Ablation

The Subcutaneous ICD: A Review of the UNTOUCHED and PRAETORIAN Trials Ahmadreza Karimianpour , Leah John

and Michael R Gold

Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, SC, US

Abstract

The ICD is an important part of the treatment and prevention of sudden cardiac death in many high-risk populations. Traditional transvenous ICDs (TV-ICDs) are associated with certain short- and long- term risks. The subcutaneous ICD (S-ICD) was developed in order to avoid these risks and complications. However, this system is associated with its own set of limitations and complications. First, patient selection is important, as S-ICDs do not provide pacing therapy currently. Second, pre-procedural screening is important to minimise T wave and myopotential oversensing. Finally, until recently, the S-ICD was primarily used in younger patients with fewer co-morbidities and less structural heart disease, limiting the general applicability of the device. S-ICDs achieve excellent rates of arrhythmia conversion and have demonstrated noninferiority to TV-ICDs in terms of complication rates in real-world studies. The objective of this review is to discuss the latest literature, including the UNTOUCHED and PRAETORIAN trials, and to address the risk of inappropriate shocks.

Keywords

Subcutaneous ICD, inappropriate shocks, sudden cardiac death, defibrillators, clinical trials Disclosure: MRG is a consultant and receives clinical trial support from Boston Scientific. All other authors have no conflicts of interest to declare. Received: 6 December 2020 Accepted: 17 February 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(2):108–12. DOI: https://doi.org/10.15420/aer.2020.47 Correspondence: Michael R Gold, Division of Cardiology, Department of Medicine, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29407, US. E: goldmr@musc.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.

The prevention of sudden cardiac death is one of the main goals of cardiac device therapy.1–3 ICDs are effective in sensing and treating deadly ventricular arrhythmias through complex iteratively developed rhythm identification algorithms.4,5 For decades, the only available implantable options proven to be effective have been transvenous ICDs (TV-ICDs) and surgical implantation of patches and epicardial leads on the heart. However, the short- and long-term risks involved with implantation are significant. The subcutaneous ICD (S-ICD) has been developed as an alternative to these transvenous devices.6 S-ICDs avoid many of the shortterm risks associated with de novo implantation, such as pneumothorax or cardiac perforation, and long-term risks, such as systemic infection.6–8

are T wave oversensing and myopotentials.12–14 Misclassification of supraventricular arrhythmias is infrequent with S-ICDs. These different aetiologies of IAS largely offset each other.15 Nonetheless – regardless of the type of implantable device – IASs are painful, hazardous and can result in psychological sequalae.11,16–18 TV-ICD sensing was developed as a beat-by-beat counter to classify arrhythmias rapidly and deliver therapy.11 S-ICD algorithms sense somewhat differently and intended to be a rhythm detector.12 This device has a more detailed morphology matching process and a much longer time to classify the rhythm.19,20 The algorithm is comprised of three phases. Phase 1 is the sensed event detection phase, which filters signals and adjusts sensitivity based on preceding QRS complexes before certifying an elevated heart rate to reduce R wave double counting and T wave oversensing. Phase 2 classifies sensed events as certified QRS complexes or as suspected oversensing events and calculates the heart rate. This includes advanced waveform algorithms that use frequency and slew-rate analysis to reject myopotentials and electromagnetic interference. Phase 3 is the decision phase during which ventricular arrhythmias are discriminated from supraventricular tachycardias.21–23

For more than a decade, S-ICDs have been studied in multicentre clinical trials and have proven to be effective.7,8 Moreover, recent data suggest that S-ICDs may even be superior to TV-ICDs in some respects.9,10 Nevertheless, S-ICDs present a unique set of potential complications and risks – as well as the risks that are common to both types of ICDs.8,9 Complications and risks unique to S-ICDs are discussed in further detail in the following sections. However, the main objective of this review is to discuss the most recent literature and contemporary populations studied with this device, with a focus on the risk of inappropriate shocks (IAS) – an issue mutual to both S-ICDs and TV-ICDs.

Except for the initial generation of ICDs, TV-ICDs have the pacing capabilities to terminate ventricular tachycardia without a shock. This made the programming of multiple zones important.11,24 S-ICDs only deliver full energy shocks but have two programmable zones: a conditional zone, where the discrimination algorithms are active; and a shock zone, which delivers therapy based solely on rate.20 Initially, many implanters did not activate the conditional zone for programming as the same therapy is

Inappropriate Shocks

The rate of IAS in TV-ICDs with contemporary programming is typically less than 5% annually.4,5,11 Common causes of IAS in people with TV-ICDs are misdiagnosed AF or abnormal sensing in the setting of lead malfunction.9,11 In contrast, with S-ICDs the most common causes of IAS

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S-ICD Recent Trials Table 1: Baseline Characteristics of Four Large S-ICD Trials EFFORTLESS 201728

S-ICD PAS 2017, 202029,30

PRAETORIAN 20209 UNTOUCHED 202110

Region

US and EU

North America and EU

Patients (n)

985

1,637

426 (S-ICD only)

1,116

Age (years), mean ± standard deviation

48 ± 17

53 ± 15

63 (median)

56 ± 12

Male

72%

69%

79%

74%

Ejection fraction, mean ± SD

43 ± 18%

32 ± 15%

30% (median)

26 ± 6%

Primary prevention

65%

77%

81%

100%

Heart failure (NYHA Class II)

27%

74%

65%

88%

Hypertension

28%

62%

54%

71%

Diabetes

11%

34%

26%

33%

15.9%

16%

27%

13%

NYHA = New York Heart Association; S-ICD = subcutaneous ICD.

programming was approximately 98% at hospital discharge and 96% throughout the study. IAS due to cardiac oversensing occurred in 2.7% of patients, with the most common cause being T wave oversensing (1.6%). Non-cardiac oversensing (including myopotentials) occurred in 1.4% of patients. Remarkably, there were no cases of supraventricular tachycardia misdiagnosis or discrimination errors. Overall, at 18 months, the IAS-free rate was 95.9%. Moreover, the complication-free rate was 95.8% at 30 days, which satisfied the performance goal of 93.8%. Despite a cohort with greater left ventricular dysfunction and heart failure, the UNTOUCHED trial outcomes demonstrated the lowest ever IAS rate compared to prior S-ICD trials and the MADIT-RIT trial.10

delivered in both zones. However, the importance of the conditional zone for discrimination became clear in analyses of prospective clinical trials, so it is now standard.25 Advances have been made in the programming and algorithms of both types of devices to reduce IAS rates. Ironically, this was because TV-ICDs were classifying rhythms and delivering therapies too quickly. Clinical trials showed that prolonging detection in TV-ICDs reduced IAS.4,11 In contrast, the duration of detection is not programmable in the S-ICD. However, improvements in the SMART Pass technology reduced IAS rates by 50% in real-world studies.26,27

Table 1 shows a comparison of baseline characteristics between four major multicentre S-ICD trials. In the UNTOUCHED trial, regression analysis revealed that predictors of IAS were history of AF and twoincision implant technique.10 It is postulated that distal lead migration may result in detection of myopotentials resulting in IAS. However, in a direct comparison of three- versus two-incision technique, there were no differences in first shock efficacy during conversion testing, shock impedance, complication-free survival at 5 years, or IAS rate at 5 years.31

Previous cohorts that studied outcomes in S-ICD, such as the EFFORTLESS registry and S-ICD IDE studies, enrolled patients that were younger and with fewer comorbidities and demonstrated higher IAS rates.7,28 The Food and Drug Administration mandated a post-marketing registry of the S-ICD (Post-Approval Study) to include more typical ICD patients.29 Early results from this planned 5-year registry showed that the device performed well despite a sicker cohort of patients.30

UNTOUCHED

PRAETORIAN

The Understanding Outcomes with the S-ICD in Primary Prevention Patients with Low Ejection Fraction (UNTOUCHED) was designed as a multinational, prospective trial to investigate limitations of S-ICDs in a higher risk population of patients.10 The trial spanned almost 3 years across North America and Europe, enrolling more than 1,100 patients with left ventricular ejection fractions ≤35% due to both ischaemic and non-ischaemic aetiologies. Patients who had indications for pacing or cardiac resynchronisation therapy, history of sustained ventricular arrhythmias, New York Heart Association classification IV and life expectancy shorter than 18 months were excluded from the study. Patients underwent standard pre-implant screening and devices were programmed based on MADIT-RIT TV-ICD programming to optimise detection and appropriate arrhythmia therapy.11 The primary endpoint for the study was the IAS-free rate at 18 months, which was compared to a performance goal of 91.6% (MADIT RIT arms B [higher rate] and C [longer duration to therapy], which is the standard for contemporary programming of TV-ICDs). An important feature of the study design was the use of prescriptive programming requiring a conditional zone at 200 BPM and shock zone at 250 BPM.10

The long-anticipated Prospective Randomized Comparison of Subcutaneous and Transvenous Implantable Cardioverter Defibrillator Therapy (PRAETORIAN) was a head-to-head trial comparing S-ICDs to TVICDs in terms of device-related complications and IASs.9 The study spanned almost seven years and included 876 patients across Europe and the US. The majority of patients were men and had ischaemic cardiomyopathy with a median left ventricular ejection fraction of 30%. Over an almost 50-month follow-up period, the incidence of IAS in a subgroup analysis was slightly higher in the S-ICD group, though not statistically significant, and were mostly due to cardiac oversensing. Notably, appropriate ICD shocks were more frequent in the S-ICD group, as the system is incapable of delivering anti-tachycardia pacing. In the TV-ICD group, the rate of anti-tachycardia pacing was higher, and successfully terminated 55% of all treated ventricular arrhythmias.9 The primary endpoint of the PRAETORIAN trial was a composite of IASs and device-related complications. The S-ICD group had a nonsignificant trend towards more shocks while the TV-ICD group had a trend towards more device-related complications and significantly more lead-related complications.9 It is noteworthy that the majority of patients in this trial had older second-generation devices in which SMART Pass filter is not available

Approximately 87% of patients had more than one passing vector in the supine and upright position at screening, and adherence to prescribed

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S-ICD Recent Trials Figure 1: Rates of Inappropriate Shocks in Major Trials

or not activated automatically. In the UNTOUCHED study, a majority of patients had more contemporary third-generation devices with SMART Pass filter activated, and therefore the IAS rate was lower in this study than in either arm of the PRAETORIAN trial.10 Figure 1 provides a comparison of annual IAS rate between five S-ICD trials and three TV-ICD trials.

Annual IAS rate (%)

Efficacy

The S-ICD delivers all shocks at 80 J and has the ability to reverse vector polarity similar to TV-ICDs for unsuccessful defibrillation. Although average defibrillation thresholds of S-ICDs are threefold higher than those of TV-ICDs, 80 J shocks provide a large safety margin.20 Failure of conversion with the first shock is predicted by patient height and BMI.30 In an analysis of the S-ICD IDE population, lower BMI and shock impedance were associated with higher conversion success rates while white race was associated with lower conversion success rates.32 Various trials have reported an 83–90% success rate for first shock in TV-ICDs and 97.3– 99.6% overall shock efficacy.1,32–35 S-ICDs were initially reported to have 100% sensitivity for detection of induced VF and 98% shock efficacy.6 However, a more recent multicentre study of 137 patients undergoing conversion testing at time of implantation revealed undersensing with >18 seconds time-to-therapy in 14% of patients and absence of therapy related to noise oversensing in 6% of patients.36 This finding has not been confirmed in much larger multicentre registries and time to therapy >20 seconds is well recognised in a minority of patients during testing.9,10,29,30 Whether conversion testing is still needed routinely at implantation is unclear given the extremely high success rate of such procedures in prospective studies.10,29,30

TV-ICD trials

S-ICD trials

12 10 8 6 4 2

09 02 D, 2

AE TO R

IA N

TV -IC

T, 2

01 65

01 74 AD ITM

io n

), 2

1 10 02 D, 2 g

de te ct

III (lo n

UN TO

ET O PR A

AD VA NC E

RI AN

S-

PA S, D

IC D, 20 20 9

20 20

01 7 28 ,2 ES S S-

RT L O EF F

SIC D

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,2 01 37

Comparison of the annual rate of IAS amongst the major S-ICD and TV-ICD trials demonstrates improvement over time. IAS rates in the latest S-ICD trials are comparable to those in TV-ICD trials. IAS = inappropriate shock; S-ICD = subcutaneous ICD; TV-ICD = transvenous ICD.

Early trials of S-ICDs demonstrated higher complications rates, partly attributable to the learning curve of implantation. In a Dutch cohort of 118 patients, 16 experienced complications with higher frequency in the initial 15 implantations.12 The S-ICD IDE study reported a 180-day complicationfree rate of 92.1%.7 The EFFORTLESS Registry study reported complicationfree rates of 97% and 94% at 30 and 260 days, respectively.28 Importantly, in-hospital complication rates are 0.9%, similar to TV-ICDs.43 Most notably, S-ICD infections are uniformly not associated with bacteraemia or systemic involvement as they are with TV-ICDs.44

Finally, chronic conversion testing performed ≥150 days after implantation revealed a 96% success rate with 65 J shock and 100% with 80 J shock. In the same study where 119 spontaneous ventricular arrhythmia episodes were observed in 21 patients, the S-ICDs demonstrated a 92.1% first shock success rate with 100% overall conversion rate.7 In fact, the START trial had already demonstrated equivalent S-ICD efficacy in detection and discrimination of ventricular arrhythmias.20

In the PRAETORIAN trial, the incidences of composite primary end point (IAS and device-related complications) between the two systems were nearly equivalent. Device-related complications occurred in 31 patients with S-ICD and 44 with TV-ICDs. The incidence of complications within the first 30 days and lead-related complications were lower in the S-ICD group. Importantly, rate of pocket haematoma was slightly higher in the S-ICD group. These similar rates of complications and IAS between S-ICDs and TV-ICDs demonstrate the noninferiority of S-ICDs in select patients without pacing indications.9 In the UNTOUCHED trial, complication rates remained low despite a higher risk population of patients in the study.10

Complications

Complications associated with TV-ICD implantation include vascular or brachial plexus injury, cardiac perforation and tamponade, pneumothorax or haemothorax, lead dislodgement or malfunction and infection and haematoma formation.37 According to a systematic review of real-world reported data from the National Cardiovascular Data Registry, TV-ICD implantation carries a 3.08% risk of complication. However, a pooled complication rate from randomised clinical trials reveals a rate of 9.1%, suggesting underestimation of long-term complications due to variable reporting.38 S-ICDs were designed, in part, as a way to circumvent many of the risks associated with TV-ICDs. Unique approaches to S-ICD implantation are needed such as the need for deep sedation or regional anaesthesia, although general anaesthesia is not obligatory.39 Moreover, anticoagulation is a risk factor for haematoma formation in these devices.40

As of December 2020, there have been 27 reported cases of electrode body fractures (Model 3501) distal to the proximal sense ring, resulting in a cumulative occurrence rate of 0.2% at 41 months and potential for lifethreatening harm of 1 in 25,000 (0.004%) at 10 years.45 However, this needs to be placed in perspective of TV-ICD lead survival rates of 85% and 60% at 5 and 8 years, respectively.46 Additionally, there is an advisory on the elevated likelihood of a low voltage capacitor (in models A209 and A219) causing accelerated battery depletion.47 The battery longevity of the S-ICD is significantly less than that of single chamber TV-ICDs.48 More long-term observation is needed to better define the magnitude and consequences of these issues along with shared decision-making regarding the optimal device to implant.

Finally, the intermuscular technique was adopted to reduce pocket complications and infections. Although there is a learning curve associated with successful intermuscular implantation (between the latissimus dorsi and serratus anterior muscles), this technique has been shown to reduce pocket infections, haematoma formation, and demonstrate lower shock impedance and defibrillation threshold by allowing more posterior device position with less adipose tissue separating the pulse generator and the rib cage.41 In fact, combining two-incision and intermuscular technique resulted in the lowest risk PRAETORIAN scores.42

Finally, modular cardiac rhythm management systems are in development to address the deficit of anti-tachycardia pacing in S-ICDs. One such system is the EMPOWER leadless pacemaker that can be implanted at a later date if anti-tachycardia pacing is desired or indicated. This system communicates

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S-ICD Recent Trials treat ventricular arrhythmias.20,25,26,36 Lastly, the implementation of specific analgesic protocols and telephone follow-up for early device-related pain enables successful same-day discharges after outpatient implantation of S-ICDs which is an area of attention in the modern era of high-value healthcare.52

with the S-ICD system as one unit, broadening the applicability of totally extra-vascular cardiac rhythm management systems.49 The other concept is an ICD with an extravascular yet substernal lead that has shown promising results for successful pacing and defibrillation.50

Conclusion

The ICD is a cornerstone in treatment for the prevention of sudden cardiac death.2 Traditional TV-ICDs are associated with certain short-term risks such as pneumothorax, vascular and valvular injury, cardiac perforation and infection. Long-term risks include lead malfunction and systemic infection resulting in endocarditis.37,38,46 The S-ICD system was developed in order to further mitigate the potential for complications especially in higher risk patients.6 Recent S-ICD studies show favourable outcomes of this device even in patients with similar co-morbidities to typical TV-ICD cohorts.

S-ICDs have been studied in large randomised clinical trials and have proven to be effective and achieve excellent arrhythmia conversion.7,20 Despite a cohort with higher left ventricular dysfunction and heart failure, as shown in Table 1, the UNTOUCHED trial outcomes demonstrated the lowest ever IAS rate compared to prior S-ICD trials and the MADIT-RIT trial as depicted in Figure 1. Finally, the PRAETORIAN trial demonstrated noninferiority of S-ICDs to TV-ICDs in terms of device-related complications and IAS.9,10

Clinical Perspective

Despite the very encouraging results from recent S-ICD trials, there are limitations and complications. First, patient selection is important, as S-ICDs do not provide pacing-therapy currently.6,7 Second, pre-procedural screening is important to determine appropriate sensing of the cardiac electrical complex to reduce the risk of undersensing or T wave oversensing.6–10,32,36 The importance of electrocardiographic screening for appropriate sensing in multiple postures has been a requirement for this device as part of labelling and has been employed in all major trials of the S-ICD. More recently, an automated screening tool was developed to facilitate this process.51 Third, IAS occur, although iterative improvements in SMART Pass filtering and contemporary programming have reduced IAS significantly while maintaining the ability to successfully diagnose and 1. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37. https://doi. org/10.1056/NEJMoa043399; PMID: 15659722. 2. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2018;138:e210–71. https://doi. org/10.1016/j.hrthm.2017.10.035; PMID: 29097320. 3. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 1996;335:1933–40. https://doi.org/10.1056/ NEJM199612263352601; PMID: 8960472. 4. Gasparini M, Lunati MG, Proclemer A, et al. Long detection programming in single-chamber defibrillators reduces unnecessary therapies and mortality: the ADVANCE III trial. JACC Clin Electrophysiol 2017;3:1275–82. https://doi. org/10.1016/j.jacep.2017.05.001; PMID: 29759624. 5. Kutyifa V, Daubert JP, Schuger C, et al. Novel ICD programming and inappropriate ICD therapy in CRT-D versus ICD patients: a MADIT-RIT sub-study. Circ Arrhythm Electrophysiol 2016;9:e001965. https://doi.org/10.1161/ CIRCEP.114.001965; PMID: 26743237. 6. Bardy GH, Smith WM, Hood MA, et al. An entirely subcutaneous implantable cardioverter-defibrillator. N Engl J Med 2010;363:36–44. https://doi.org/10.1056/ NEJMoa0909545; PMID: 20463331. 7. Weiss R, Knight BP, Gold MR, et al. Safety and efficacy of a totally subcutaneous implantable-cardioverter defibrillator. Circulation 2013;128:944–53. https://doi.org/10.1161/ CIRCULATIONAHA.113.003042; PMID: 23979626. 8. Burke MC, Gold MR, Knight BP, et al. Safety and efficacy of the totally subcutaneous implantable defibrillator: 2-year results from a pooled analysis of the IDE study and EFFORTLESS registry. J Am Coll Cardiol 2015;65:1605–15. https://doi.org/10.1016/j.jacc.2015.02.047; PMID: 25908064. 9. Knops RE, Olde Nordkamp LRA, Delnoy PPHM, et al. Subcutaneous or transvenous defibrillator therapy (PRAETORIAN trial). N Engl J Med 2020;383:526–36. https:// doi.org/10.1056/NEJMoa1915932; PMID: 32757521. 10. Gold MR, Lambiase PD, El-Chami MF, et al. Primary results

11.

12.

13.

14.

15.

16.

17.

18.

19.

• Subcutaneous ICD technology has evolved to meet clinical

standards and noninferiority in terms of device-related complications when compared to transvenous ICDs, as shown in the PRAETORIAN trial. • The UNTOUCHED trial demonstrated that inappropriate shock rates of subcutaneous ICDs in a sicker cohort of patients are similar, if not lower, compared with transvenous ICDs. • Appropriate patient selection and screening alongside contemporary device programming are paramount to the success of subcutaneous ICDs.

from the Understanding Outcomes with the S-ICD in Primary Prevention Patients with Low Ejection Fraction (UNTOUCHED) trial. Circulation 2021;143:7–17. https://doi. org/10.1161/CIRCULATIONAHA.120.048728; PMID: 33073614. Moss AJ, Schuger C, Beck CA, et al. Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med 2012;367:2275–83. https://doi. org/10.1056/NEJMoa1211107; PMID: 23131066. Olde Nordkamp LRA, Dabiri Abkenari L, Boersma LV, et al. The entirely subcutaneous implantable cardioverterdefibrillator: initial clinical experience in a large Dutch cohort. J Am Coll Cardiol 2012;60:1933–9. https://doi. org/10.1056/j.jacc.2012.06.053; PMID: 23062537. Jarman JW, Lascelles K, Wong T, et al. Clinical experience of entirely subcutaneous implantable cardioverter-defibrillators in children and adults: cause for caution. Eur Heart J 2012;33:1351–9. https://doi.org/10.1093/eurheartj/ehs017; PMID: 22408031. Jarman JW, Todd DM. United Kingdom national experience of entirely subcutaneous implantable cardioverterdefibillator technology: important lessons to learn. Europace 2013;15:1158–65. https://doi.org/10.1093/europace/eut016; PMID: 23449924. Basu-Ray I, Liu J, Jia X, et al. Subcutaneous versus transvenous implantable defibrillator therapy: a metaanalysis of case-control studies. JACC Clin Electrophysiol 2017;3:1475–83. https://doi.org/10.1016/j.jacep.2017.07.017; PMID: 29759827. Van Rees JB, Borleffs CJ, de Bie MK, et al. Inappropriate implantable cardioverter-defibrillator shocks: incidence, predictors, and impact on mortality. J Am Coll Cardiol 2011;57:556–62. https://doi.org/10.1016/j.jacc.2010.06.059; PMID: 21272746. Humphreys NK, Lowe R, Rance J, Bennett PD. Living with an implantable cardioverter defibrillator: the patients’ experience. Heart Lung 2016;45:34–40. https://doi. org/10.1016/j.hrtlng.2015.10.001; PMID: 26581117. Kajanova A, Bulava A, Eisenberger M. Factors influencing psychological status and quality of life in patients with implantable cardioverter-defibrillators. Neuro Endocrinol Lett 2014;35:54–8. PMID: 25433355. Knops RE, Brouwer TF, Barr CS, et al., on behalf of the IDE and EFFORTLESS investigators. The learning curve associated with the introduction of the subcutaneous implantable defibrillator. Europace 2016;18:1010–5. https://

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

111

doi.org/10.1093/europace/euv299; PMID: 26324840. 20. Gold MR, Theuns DA, Knight BP, et al. Head-to-head comparison of arrhythmia discrimination performance of subcutaneous and transvenous ICD arrhythmia detection algorithms: the START study. J Cardiovasc Electrophysiol 2012;23:359–66. https://doi.org/10.1111/j.1540-8167.2011. 02199.x; PMID: 22035049. 21. Allavatum V, Palreddy S, Sanghera R, Warren JA. Accurate cardiac event detection in an implantable cardiac stimulus device. US Patent 8,565,878 B2 issued 22 October 2013. 22. Warren JA, Allavatum V, Sanghera R, Palreddy S. Method and devices for identifying overdetection of cardiac signals. US Patent 8,437,838 B2 issued 7 May 7 2013. 23. Allavatum V, Palreddy S, Sanghera R, Warren JA. Methods and devices for accurately classifying cardiac activity. US Patent 8,626,280 B2 issued 7 January 2014. 24. Arias MA, Puchol A, Castellanos E, Rodriguez-Padial L. Antitachycardia pacing for ventricular tachycardia: good even after being bad. Europace 2007;9:1062–3. https://doi. org/10.1093/europace/eum163; PMID: 17666444. 25. Gold MR, Weiss R, Theuns DAMJ, et al. Use of a discrimination algorithm to reduce inappropriate shocks with a subcutaneous implantable cardioverter-defibrillator. Heart Rhythm 2014;11:1352–8. https://doi.org/10.1016/j. hrthm.2014.04.012; PMID: 24732366. 26. Brisben AJ, Burke MC, Knight BP, et al. A new algorithm to reduce inappropriate therapy in the S-ICD system. J Cardiovasc Electrophysiol 2015;26:417–23. https://doi. org/10.1111/jce.12612; PMID: 25581303. 27. Theuns DAMJ, Brouwer TF, Jones PW, et al. Prospective blinded evaluation of a novel sensing methodology designed to reduce inappropriate shocks by the subcutaneous implantable cardioverter-defibrillator. Heart Rhythm 2018;15:1515–22. https://doi.org/10.1016/j. hrthm.2018.05.011; PMID: 29758404. 28. Boersma L, Barr C, Knops R, et al. Implant and midterm outcomes of the subcutaneous implantable cardioverterdefibrillator registry: the EFFORTLESS study. J Am Coll Cardiol 2017;70:830–41. https://doi.org/10.1016/j.jacc.2017.06.040; PMID: 28797351. 29. Gold MR, Aasbo JD, El-Chami MF, et al. Subcutaneous implantable cardioverter-defibrillator post-approval study: clinical characteristics and perioperative results. Heart Rhythm 2017;14:1456–63. https://doi.org/10.1016/j. hrthm.2017.05.016; PMID: 28502872.

S-ICD Recent Trials 30. Burke MC, Aasbo JD, El-Chami MF, et al. 1-year prospective evaluation of clinical outcomes and shocks: the subcutaneous ICD post approval study. JACC Clin Electrophysiol 2020;6:1537– 50. https://doi.org/10.1016.j.jacep.2020.05.036; PMID: 33213814. 31. van der Stuijt W, Baalman SWE, Brouwer TF, et al. Long-term follow-up of the two-incision implantation technique for subcutaneous implantable cardioverter-defibrillator. Pacing Clin Electrophysiol 2020;43:1476–80. https://doi.org/10.1111/ pace.14022; PMID: 32720398. 32. Amin AK, Gold MR, Burke MC, et al. Factors associated with high-voltage impedance and subcutaneous implantable defibrillator ventricular fibrillation conversion success. Circ Arrhythm Electrophysiol 2019;12:e006665. https://doi. org/10.1161/CIRCEP.118.006665; PMID: 30917689. 33. Blatt JA, Poole JE, Johnson GW, et al. No benefit from defibrillation threshold testing in the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial). J Am Coll Cardiol 2008;52:551–6. https://doi.org/10.1016/j.jacc.2008.04.051; PMID: 18687249. 34. Saxon LA, Hayes DL, Gilliam FR, et al. Long-term outcomes after ICD and CRT implantation and influence of remote device follow-up: the ALTITUDE survival study. Circulation 2010;122:2359–67. https://doi.org/10.1161/ CIRCULATIONAHA.110.960633; PMID: 21098452. 35. Gold MR, Higgins S, Klein R, et al. Efficacy and temporal stability of reduced safety margins for ventricular defibrillation: primary results from the Low Energy Safety Study (LESS). Circulation 2002;105:2043–8. https://doi. org/10.1161/01.cir.0000015508.59749.f5; PMID: 11980683. 36. le Polain de Waroux JB, Ploux S, Mondoly P, et al. Defibrillation testing is mandatory in patients with subcutaneous implantable cardioverter-defibrillator to confirm appropriate ventricular fibrillation detection. Heart Rhythm 2018;15:642–50. https://doi.org/10.1016/j. hrthm.2018.02.013; PMID: 29709229. 37. van Rees JB, de Bie MK, Thijssen J, et al. Implantationrelated complications of implantable cardioverter-

defibrillators and cardiac resynchronization therapy devices: a systematic review of randomized clinical trials. J Am Coll Cardiol 2011;58:995–1000. https://doi.org/10.1016/j. jacc.2011.06.007; PMID: 21867832. 38. Ezzat VA, Lee V, Ahsan S, et al. A systematic review of ICD complications in randomized controlled trials versus registries: is our ‘real-world’ data an underestimation? Open Heart 2015;2:e000198. https://doi.org/10.1136/ openhrt-2014-000198; PMID: 25745566. 39. Essandoh MK, Mark GE, Aasbo JD, et al. Anesthesia for subcutaneous implantable cardioverter-defibrillator implantation: perspectives from the clinical experience of a U.S. panel of physicians. Pacing Clin Electrophysiol 2018;41:807– 16. https://doi.org/10.1111/pace.13364; PMID: 29754394. 40. Afzal MR, Mehta D, Evenson C, et al. Perioperative management of oral anticoagulation in patients undergoing implantation of subcutaneous implantable cardioverterdefibrillator. Heart Rhythm 2018;15:520–3. https://doi. org/10.1016/j.hrthm.2017.11.010; PMID: 29146276. 41. Migliore F, Mattesi G, De Franceschi P, et al. Multicentre experience with the second-generation subcutaneous implantable cardioverter-defibrillator and the intermuscular two-incision implantation technique. J Cardiovasc Electrophysiol 2019;30:854–64. https://doi.org/10.1111/ jce.13894; PMID: 30827041. 42. Francia P, Biffi M, Adduci C, et al. Implantation technique and optimal subcutaneous defibrillator chest position: a PRAETORIAN score-based study. Europace 2020;22:1822–9. https://doi.org/10.1093/europace/euaa231; PMID: 33118017. 43. Friedman DJ, Parzynski CS, Varosy PD, et al. Trends and in-hospital outcomes associated with adoption of the subcutaneous implantable cardioverter-defibrillator in the United States. JAMA Cardiol 2016;1:900–11. https://doi. org/10.1001/jamacardio.2016.2782; PMID: 27603935. 44. Lewis GF, Gold MR. Safety and efficacy of the subcutaneous implantable defibrillator. J Am Coll Cardiol 2016;67:445–54. https://doi.org/10.1016/j.jacc.2015.11.026; PMID: 26821634. 45. Boston Scientific. Important medical device advisory. Boston

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

112

Scientific, December 2020. https://www.bostonscientific. com/content/dam/bostonscientific/quality/dlt/reg-code228/2020Dec_BSC_EmblemElectrode3501_PhysLtr_Final. pdf (accessed 22 March 2021). 46. Kleemann T, Becker T, Doenges K, et al. Annual rate of transvenous defibrillation lead defects in implantable cardioverter-defibrillators over a period of >10 years. Circulation 2007;115:2474–80. https://doi.org/10.1161/ CIRCULATIONAHA.106.663807; PMID: 17470696. 47. Boston Scientific. Important medical device advisory. Boston Scientific, December 2020. https://www.bostonscientific. com/content/dam/bostonscientific/quality/dlt/reg-code228/2020Dec_BSC_EmblemPBD_PhysLtr_US_Final.pdf (accessed 22 March 2021). 48. Hussam A, Lupo P, Cappato R. The entirely subcutaneous defibrillator – a new generation and future expectations. Arrhythm Electrophysiol Rev 2015;4:116–21. https://doi. org/10.15420/aer.2015.04.02.116; PMID: 26835112. 49. Tjong FVY, Koop BE. The modular cardiac rhythm management system: the EMPOWER leadless pacemaker and the EMBLEM subcutaneous ICD. Herzschrittmacherther Elektrophysiol 2018;29:355–61. https://doi.org/10.1007/ s00399-018-0602-y; PMID: 30382341. 50. Crozier I, Haqqani H, Kotschet E, et al. First-in-human chronic implant experience of the substernal extravascular implantable cardioverter-defibrillator. JACC Clin Electrophysiol 2020;6:1525–36. https://doi.org/10.1016/j.jacep.2020. 05.029; PMID: 33213813. 51. Bögeholz N, Pauls P, Guner F, et al. Direct comparison of the novel automated screening tool (AST) versus the manual screening tool (MST) in patients with already implanted subcutaneous ICD. Int J Cardiol 2018;265:90–6. https://doi. org/10.1016/j.ijcard.2018.02.030; PMID: 29885706. 52. Okabe T, Miller A, Koppert T, et al. Feasibility and safety of same day subcutaneous defibrillator implantation and send home (DASH) strategy. J Interv Card Electrophysiol 2020;57:311–8. https://doi.org/10.1007/s10840-019-00673-1; PMID: 31813098.

Drugs and Devices

Clinical Utility of Body Surface Potential Mapping in CRT Patients Ksenia Sedova ,1 Kirill Repin ,1 Gleb Donin ,1 Peter Van Dam

and Josef Kautzner

1. Department of Biomedical Technology, Faculty of Biomedical Engineering, Czech Technical University in Prague, Kladno, Czech Republic; 2. Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands; 3. Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Abstract

This paper reviews the current status of the knowledge on body surface potential mapping (BSPM) and ECG imaging (ECGI) methods for patient selection, left ventricular (LV) lead positioning, and optimisation of CRT programming, to indicate the major trends and future perspectives for the application of these methods in CRT patients. A systematic literature review using PubMed, Scopus, and Web of Science was conducted to evaluate the available clinical evidence regarding the usage of BSPM and ECGI methods in CRT patients. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement was used as a basis for this review. BSPM and ECGI methods applied in CRT patients were assessed, and quantitative parameters of ventricular depolarisation delivered from BSPM and ECGI were extracted and summarised. BSPM and ECGI methods can be used in CRT in several ways, namely in predicting CRT outcome, in individualised optimisation of CRT device programming, and the guiding of LV electrode placement, however, further prospective or randomised trials are necessary to verify the utility of BSPM for routine clinical practice.

Keywords

Body surface potential mapping, ECG imaging, heart failure, CRT Funding: This study was supported by the research grant NV18-02-00080 from the grant agency AZV (Ministry of Health of the Czech Republic). Disclosure: JK has received personal fees from Bayer, Biosense Webster, Boehringer Ingelheim, Daiichi Sankyo, Medtronic, Merck Sharp & Dohme, Merit Medical and St Jude Medical (Abbott) for participation in scientific advisory boards; and speaker honoraria from Bayer, Biosense Webster, Biotronik, BMS, Boehringer Ingelheim, Boston Scientific, Daiichi Sankyo, Medtronic, Merck, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, ProMed sro and St Jude Medical (Abbott). PVD is the owner of Peacs BV and ECG Excellence BV. All other authors have no conflicts of interest to declare. Received: 21 March 2021 Accepted: 12 May 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(2):113–9. DOI: https://doi.org/10.15420/aer.2021.14 Correspondence: Ksenia Sedova, Department of Biomedical Technology, Faculty of Biomedical Engineering, Czech Technical University in Prague, Sitna sq. 3105, 27201 Kladno, Czech Republic. E: ksenia.sedova@fbmi.cvut.cz 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.

methods for patient selection, left ventricular (LV) lead positioning, and optimisation of CRT programming, to determine the major trends and future perspectives for the application of these methods in CRT patients.

Heart failure (HF) is a common condition with significant morbidity and mortality. One of the therapeutic options for advanced management of patients with HF with reduced or preserved left ventricular ejection fraction (HFrEF or HfpEF, respectively) is CRT. In a selected population of candidates, it improves symptoms, quality of life, and prognosis. However, not all patients respond favourably to CRT, which indicates that there are unsolved issues in accurate patient selection and the proper delivery of CRT.1 Several characteristics predict improvement in morbidity and mortality, and the extent of reverse remodelling is one of the most important mechanisms of action of CRT. Of the clinical parameters, QRS duration is always used as an outcome parameter in all available trials, but consensus has not been reached regarding the optimal ECG-based criteria for patient selection for a CRT device.

Given that the body surface potential mapping (BSPM) and ECGI methods are used mostly in the research field rather than in clinical settings, no standardised terminology concerning the specification of approaches exists. For this review, the methods related to the analysis and interpretation of body surface multi-lead ECG are referred to as BSPM. Techniques involved in the reconstruction of myocardial electrical potentials using body surface ECGs are termed ECGI.

Methods

A systematic literature review was carried out to evaluate the available clinical evidence regarding non-invasive cardiac mapping methods for patient selection, lead placement, and optimisation of CRT programming. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement was used as a basis for this review.6

The strategy for CRT device optimisation also remains challenging. The available methods include echocardiography, ECG QRS-based assessment, invasive haemodynamic measurements, and/or non-invasive cardiac mapping.2 Among others, ECG imaging (ECGI) may be a comprehensive tool for measuring ventricular electrical dyssynchrony.3–5 However, the results are fragmentary and have not been summarised. This paper reviews the current knowledge on non-invasive ECG mapping

In this review, we included randomised controlled trials and observational studies, such as cohort studies or case–control studies. Conference

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Body Surface Potential Mapping in CRT Patients

Records identified through database searching PubMed (n=144) Scopus (n=187) Web of Science (n=89)

Included

Eligibility

Screening

Identification

Figure 1: PRISMA Flow Diagram

original studies met the inclusion criteria. The procedure for selecting publications is shown in the PRISMA diagram (Figure 1). Table 1 summarises the 23 selected original studies in the population, intervention, control and outcomes (PICO) format.3,5,7–27 They include both BSPM (n=8) and ECGI methods (n=15). The median number of body surface leads used for ECGI was higher than for BSPM techniques (252 [IQR 192– 252] versus 64 [IQR 53–87], respectively, p<0.0001). Non-invasive cardiac mapping approaches were applied in patients with CRT in several scenarios: the prediction of CRT response and patient selection; the selection of optimal LV pacing site; and the optimisation of CRT programming. Quantitative parameters of ventricular depolarisation are listed in Table 2. BSPM characteristics of depolarisation were mostly based on the detection of activation time, defined as the minimum of the first derivative of potential with respect to time during the QRS complex in unipolar body surface ECG leads. Parameters of ventricular activation obtained from reconstructed epicardial electrical potentials using ECGI techniques included local characteristics of ventricular depolarisation such as LV activation time, the interventricular difference in activation time, and intraventricular activation time distribution (Figure 2).

Additional records identified through other sources (n=0)

Records identified (n=420)

Duplicates removed (n=190)

Records screened (n=230)

Records excluded (n=156)

Full-text articles assessed for eligibility (n=74)

Full-text articles excluded, with reasons (n=42)

Studies included in qualitative synthesis (n=23 primary studies, n=9 review papers)

Duplicate data, n=3 In silico study, n=4 Wrong population, n=7 Wrong publication type, n=8 Wrong intervention, n=20

Patient Selection for CRT

Current European Society of Cardiology guidelines approve CRT as an indication for patients with symptomatic HFrEF and intraventricular conduction abnormality, especially QRS duration >150 ms and left bundle branch block (LBBB) morphology. In contrast, patients with QRS duration <120–130 ms are not indicated for CRT, due to a low success rate and possible worsening of HF.21,28

abstracts, letters and case reports were excluded. To cover all available evidence, we did not use any publication date restrictions. The search was conducted using MEDLINE (through PubMed), Web of Science and Scopus databases. No limits were applied to language and foreign papers were translated. The reference lists of all included publications were checked to identify additional relevant studies. We also examined any relevant retraction statements and errata for the included studies.

Assessment of electrical dyssynchrony is important for the accurate identification of appropriate CRT candidates. Although QRS duration is used as an indirect measure of dyssynchrony, some studies noted a weak correlation between QRS duration and mechanical dyssynchrony.29,30 BSPM and ECGI approaches have been applied in clinical studies to develop reliable parameters of ventricular activation for assessment of the CRT effects (Table 2).

The search terms included ‘CRT’, ‘BSPM’, ‘ECGI’, ‘electrocardiographic mapping (ECM)’, ‘congestive HF’, ‘HFrEF’, and various combinations of these terms. The full search strategies are given in the Supplementary Material.

BSPM-based Selection Criteria

BSPM-derived activation time (AT) is the duration between the QRS complex onset and the steepest negative slope of the QRS complex.3 This can then be visualised as body surface isochronal maps of ATs. The isochronal maps of ATs have been obtained using BSPM with 53 ECG leads to assess the changes in electrical dyssynchrony in patients with CRT. Quantitative metrics of dyssynchrony such as the standard deviation of activation times (SDAT) and average left thorax activation time (LTAT) have been suggested. Patients with native SDAT ≥35 ms and QRS duration ≥120 ms had significant reverse LV remodelling (improvement in left ventricular ejection fraction [LVEF] and decrease in end-systolic volume), thus both parameters have been suggested as predictors of CRT response.3 The longest activation time (ATmax) detected in any of 123 unipolar chest leads, served as a reliable dyssynchrony marker to predict CRT outcome.14 The right ventricular to left ventricular (RV–LV) activation gradient was identified through measures of QRS durations in 87-lead BSPM. It was suggested that an RV–LV activation gradient <20 ms during biventricular pacing could identify patients with improved functional class after CRT.23

The selected review publications were used to identify other publications not covered by our search. From the original studies included in the qualitative analysis, we extracted the following characteristics for each included study: participants (number of participants, target population); BSPM type (ECGI or simple BSPM); and BSPM parameters (definition and findings). Duplicate articles were identified and excluded. Title and abstract screening for eligibility was performed by two reviewers independently. The full text of citations judged as potentially eligible was retrieved and screened in a blinded manner. The disagreement between the reviewers was then resolved by discussion or, if required, with the help of a third independent reviewer.

Results Search Results

In our pilot study, an analysis of ventricular depolarisation was performed during different pacing configurations in selected patients using the QRS integral maps produced from a 96-lead mapping system (unpublished data). A 46-year-old patient with a history of post-myocarditis

The literature search was performed on 21 January 2020. In total, 420 publications were identified in the main sources (PubMed, Scopus, and Web of Science). After the title and abstract screening, 156 records were excluded. The full text of 74 records was assessed for eligibility, and 23

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Body Surface Potential Mapping in CRT Patients Table 1: Summary of Included Original Studies Objective

Population

Intervention, No. of Leads

69 ± 11 years; 68% men; EF 26 ± 7%; QRSd 159 ± 23 ms; MI 50%; LBBB 62%

BSPM, 53

Berger et al. 2005

61 ± 8 years; 76% men; EF 21 ± 5%; QRSd 150 ± 24 ms; MI 44%; LBBB 100%

BSPM, 64

Lumens et al. 201315

66 ± 12 years; 71% men; EF 27 ± 3%; QRSd 164 ± 22 ms; MI 33%

ECGI, 252

Pastore et al. 2006

61 ± 9 years; 71% men; EF 28 ± 8%; QRSd 180 ± 19 ms; MI 11%; LBBB 100%

BSPM, 87

Pereira et al. 2018

68 ± 13 years; 79% men; MI 63%; LBBB 74%

ECGI, 252

Pereira et al. 201919

69 ± 12 years; 81% men; EF 27 ± 10%; QRSd 162 ± 21 ms; MI 62%; LBBB 71%

ECGI, 252

Samesima et al. 2013

61 ± 10 years; 60% men; EF 28 ± 9%; QRSd 182 ± 24 ms; MI 20%

BSPM, 87

Sieniewicz et al. 201926

61 ± 13 years; 80% men; EF 28 ± 9%; QRSd 168 ± 8 ms; MI 80%; LBBB 80%

ECGI, 252

67 ± 10 years; 53% men; EF 26 ± 7%; QRSd 158 ± 21 ms (BiV pacing); MI 38%; LBBB 100%

ECGI, 252

51 ± 18 years; 44% men; EF 22 ± 5%; QRSd 138 ± 27 ms; MI 0%;

ECGI, NA

Johnson et al. 2017

65 ± 14 years; 75% men; EF 27 ± 7%; QRSd 165 ± 26 ms; MI 40%; LBBB 58%

BSPM, 53

Nguyen et al. 201916

71 ± 8 years; 81% men; EF 24 ± 8%; QRSd 142 ± 21 ms; MI 69%; LBBB 38%

ECGI, 184

Rudy 2006

72 ± 11 years; 75% men

ECGI, 220 - 250

Varma 201427

54 ± 15 years; 33% men; EF 18 ± 3%; QRSd 146 ± 7 ms; MI 33%; LBBB 66%

ECGI, >200

Dawoud et al. 201610

63 ± 10 years; 75% men; EF 20 ± 5%; QRSd 149 ± 9 ms; MI 37%; LBBB 100%

ECGI, 120

Gage et al. 2017

70 ± 11 years; 67% men; EF 27 ± 7%; QRSd 152 ± 26 ms; MI 48%; LBBB 55%

BSPM, 53

Jia et al. 200612

72 ± 11 years; 75% men; EF 19 ± 7%; QRSd 155 ± 22 ms; MI 75%; LBBB 75%;

ECGI, NA

Kittnar et al. 2018

62 ± 6 years; 57% men; EF 25 ± 8%; QRSd 170 ± 12 ms; LBBB 52%;

BSPM, NA

Ploux et al. 2013

65 ± 9 years; 85% men; EF 27 ± 4%; QRSd 152 ± 22 ms; MI 42%; LBBB 55%

ECGI, 252

Ploux et al. 201521

65 years (median); 80% men; EF 28%(median); QRSd 146 ms (median); MI 46%; LBBB 43%

ECGI, 252

Samesima et al. 2007

60 ± 11 years; 62% men; EF 31 ± 8%; QRSd 185 ± 35 ms; MI 18%; LBBB 100%

BSPM, 87

Shannon et al. 200825

64 ± 12 years; 71% men; MI 56%

ECGI, 80

Strik et al. 2018

67 ± 10 years; 78% men; EF 29 ± 5%; MI 48%; LBBB 51%

ECGI, 252

CRT optimisation Bank et al. 20188 9

LV lead positioning Arnold et al. 20187 Ghosh et al. 2011

11 13

Patient selection 3

Data given as mean ± SD if not otherwise specified. BSPM = body surface potential mapping; ECGI = ECG imaging; EF = ejection fraction; LBBB = left bundle branch block; NA = not available; QRSd = QRS duration.

cardiomyopathy, LBBB (QRS 172 ms) and progressive LV dysfunction (LVEF 30%) underwent permanent CRT defibrillator (CRT-D) implantation in 2019, leading to reverse remodelling 6 months after CRT-D implantation (improvement of LVEF to 45%). The distribution of positive and negative time integrals correlated with the acute haemodynamic response to the different pacing configurations. Obtained time integral maps of the QRS complex reflected the improvement in LVEF during LV pacing compared with atrial pacing (Figure 3).

Given that VEU represents the impairment of ventricular depolarisation only with regard to time, an activation delay vector (ADV) adds an additional parameter: a direction in space. This parameter represents a comprehensive electrical substrate, such that patients may have a similar direction of activation delay but a great difference in its magnitude. This parameter might be used to determine right-to-left activation delay and identify responders.5 Electrical synchrony of ventricles was assessed using isochronal activation maps obtained with the ECGI technique. The interventricular synchrony index, Esyn (the difference between activation times in the RV and LV), for estimation of electrical synchrony, however, did not always correlate with clinical improvement.12 In that case, a non-invasive ECGI approach for reconstruction of epicardial ventricular activation was then applied, in combination with cardiac magnetic resonance used for mechanical imaging of dyssynchrony in the LV. Electromechanical dissociation has been suggested as a marker of reduced response to CRT.10

ECGI-based Selection Criteria

In patients with LBBB and non-specific intraventricular conduction disturbance (NICD), an ECGI-derived index of electrical dyssynchrony, ventricular electric uncoupling (VEU), defined as the difference between the mean epicardial LV and RV activation times, served as a significant predictor of response to CRT. It was concluded that in consecutive CRT candidates with QRS duration ≥120 ms, VEU is a more reliable predictor of clinical CRT response than QRS duration or the presence of LBBB.20 Supporting data were obtained in the study in which VEU was calculated at baseline and during biventricular pacing to assess the resynchronising effect in relation to the underlying electrical substrate. Responders had higher baseline VEU and more intensive reduction of VEU in response to biventricular pacing than did non-responders.21

Spatiotemporal myocardial activation maps were constructed using the ECGI method in patients with wide QRS complex before CRT. The different patterns of myocardial activation described suggested an association between electrophysiological pattern and the effect of CRT.25

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Body Surface Potential Mapping in CRT Patients Table 2: Parameters of Ventricular Activation Derived from Body Surface Potential Mapping or ECG Imaging Reference

ECGI-based LV Lead Placement

In patients with a quadripolar LV lead, ECGI visualisation of endocardial and epicardial activation was applied to identify the optimal area for pacing, that is, the site with the shortest total activation duration of both ventricles.27,31 ECGI isochronal maps of epicardial ventricular depolarisation also enabled the guidance of LV lead placement for improved clinical outcome.22 Another study integrated ECGI with CT angiography and cardiac magnetic resonance to develop the ‘CRT roadmap’, which provides data on scar localisation, epicardial activation sequence, and coronary venous anatomy. This CRT roadmap was suggested to be a reliable tool to guide LV lead placement.16

Parameters

BSPM Bank et al. 20188

SDAT SDAT, LTAT

Gage et al. 20173 Johnson et al. 2017

SDAT, LTAT

ATmax, ATmin

Kittnar et al. 2018

Pastore et al. 200617

mAS, mLV, mRV 23

Samesima et al. 2007

Global VAT, regional VAT, RV–LV VAT difference

Samesima et al. 201324

Global VAT, regional VAT, RV–LV VAT difference

In some cases, LV lead placement is suboptimal due to unfavourable anatomy of the coronary venous system, and the response to CRT may be inferior.32 Recently, His bundle pacing (HBP) has emerged as an alternative to CRT. With the help of ECGI, it was established that HBP reduced LV activation time and LV dyssynchrony index (LVDI) more than twofold compared with biventricular pacing.7,11 The His-SYNC (His Bundle Pacing versus Coronary Sinus Pacing for Cardiac Resynchronisation Therapy) pilot trial was an investigator-initiated, prospective, randomised controlled study that demonstrated that there were no significant improvements in ECG or echocardiographic parameters compared with biventricular pacing-CRT.33

ECGI Arnold et al. 20187

LVAT, LVAT-95, LVDI

Ghosh et al. 2011

Esyn

Jia et al. 200612 15

ATLV, ATTOT

Pereira et al. 2018

TVaT, VaT10–90

Pereira et al. 201919

TVaT, VaT10–90

Ploux et al. 2013

LVTAT, RVTAT, VEU

Ploux et al. 201521

LVTAT, TAT, VEU

Lumens et al.2013

Rudy 2006

Sieniewicz et al. 2019

VVsync, VVTAT, LVTAT, LVdisp

Strik et al. 2018

ADV

Varma 2014

Optimisation of CRT Programming

Esyn

LV pacing and biventricular pacing have a similar, positive effect on the haemodynamic function of patients with HF, while RV pacing alone is highly ineffective.12,17,22,34

LVTAT

BSPM-based CRT Optimisation

ADV = activation delay vector; ATLV = left ventricular activation time; ATmax = maximum activation time; ATmin = minimum activation time; ATTOT = total ventricular activation time; BSPM = body surface potential mapping; ECGI = ECG imaging; ED = electrical dyssynchrony; Esyn = electrical synchrony index; LTAT = average left thorax activation time; LVAT = left ventricular activation time; LVAT-95 = left ventricular activation time spanning 95% of activations; LVDI = left ventricular dyssynchrony index; LVdisp = global left ventricular dispersion of activation; LVTAT = left ventricular total activation time; mAS = anterior septal area mean activation time; mLV = left ventricle mean activation time; mRV = right ventricle mean activation time; RVTAT = right ventricular total activation time; SDAT = standard deviation of activation times; TAT = total activation time; TVaT = total ventricular activation time; VAT = ventricular activation time; VaT10–90 = ventricular activation time10–90 (delay between the 10th and 90th percentiles of ventricular activation time); VEU = ventricular electrical uncoupling; VVsync = global right/left ventricular electrical synchrony.

BSPM parameters such as SDAT can be useful for both LV pacing and biventricular pacing programming.8 CRT programmed at baseline settings can reduce dyssynchrony by up to 20%. This improvement is greater in the LBBB group of patients with wide QRS, and is lacking in the non-LBBB group. However, individualised and optimised settings based on BSPM parameters, such as SDAT, can further improve ventricular activation time by 46%, compared with standard pacing settings.3 SDAT reduction ≥10% was a significant predictor of improved ejection fraction and LV end-systolic volume response. With CRT optimisation, it is possible to achieve twofold improvement in electrical synchrony, regardless of patient baseline characteristics.8 Another BSPM approach based on measurement of QRS duration in 87 body surface unipolar leads showed that regional activation time in the RV increased in biventricular pacing, but it was compensated for by an even greater decrease in activation time in the LV, therefore the effect of CRT could be optimised by decreasing the inter-regional RV–LV gradients.23,24 In addition, BSPM parameters of ventricular repolarisation dispersion such as Tpeak–Tend interval, Tpeak–Tend integral, and T wave amplitude were reduced compared with sinus rhythm under biventricular pacing, whereas RV or LV pacing resulted in increased dispersion of repolarisation.9

In summary, the most promising predictors of response to CRT appear to be SDAT and LTAT, parameters that can be derived from BSPM, without the need for 3D imaging. These parameters are easy to obtain and analyse.

LV Lead Placement

The degree of cardiac resynchronisation response is influenced by many factors, of which the position of the LV lead on the heart is an important one. Many strategies have been used to optimise LV lead placement. Some of them use QLV interval, that is, the time between Q onset on the ECG and local depolarisation at the LV electrode, as measured during implantation, to determine the site of the latest activation. Other strategies involve echocardiography or MRI to evaluate the proximity of the lead to the site of maximal mechanical dyssynchrony.

ECGI-based CRT Optimisation

Using ECGI techniques to reconstruct epicardial isochronal maps, it has been shown that, despite the positive haemodynamic response during LV pacing, only biventricular pacing has resulted in reduced electrical dyssynchrony, represented by decreased total RV and LV activation time.15 The individual configuration of LV quadripolar leads guided by the parameters total ventricular activation time (TVaT) and the time for the bulk of ventricular activation (VaT10–90), which were obtained from ECGI,

BSPM-based LV Lead Placement

More recently, BSPM has been suggested as another alternative for LV lead positioning.2,13 The pacing site with the greatest decrease in SDAT and LTAT has been shown to have a strong correlation with the acute haemodynamic response measured invasively.13

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Body Surface Potential Mapping in CRT Patients Figure 2: Schematic Presentation of BSPM and ECGI Approaches to Determine Electrical Synchrony in Heart Ventricles Body surface potential map

ECG

ECG-derived AT

BSPM parameters: SDAT, LTAT

● ●

VAT

●

ATmax, ATmin

●

mLV, mRV

QRS

Inverse ECG problem solvers CT/MRI model

Potential inverse AT AT

ECGI parameters:

●

LVAT, LVAT-95, LVDI

●

TVaT, VAT10–90

●

LVTAT, RVTAT, TAT, VEU

●

ED, Esyn

Reconstructed local ATs

Body surface electrodes are applied to the patient’s torso for simultaneous recording of 52–252 unipolar ECG leads using a multichannel ECG recording system. For the body surface potential mapping (BSPM) approach, each ECG signal is processed to determine specific signal features, for example duration and amplitude of the Q, R, and S waves, and ECG-derived activation time (AT, (dV/dt)min during the QRS complex). Based on these quantitative parameters the ventricular electrical dyssynchrony is estimated. For ECG imaging (ECGI) methods, thoracic CT or MRI is used to provide the patientspecific anatomical model of cardiac geometry and torso-electrode positions. Body surface ECGs and CT or MRI model data are combined in the inverse procedure to obtain non-invasive ECGI epicardial electrograms (blue lines) and isochronal activation sequences (colour-coded reconstructed myocardial ATs on the heart surface). ATmax = maximum activation time; ATmin = minimum activation time; ED = electrical dyssynchrony; Esyn = electrical synchrony index; LTAT = average left thorax activation time; LVAT = left ventricular activation time; LVAT-95 = left ventricular activation time spanning 95% of activations; LVDI = left ventricular dyssynchrony index; LVTAT = left ventricular total activation time; mLV = left ventricle mean activation time; mRV = right ventricle mean activation time; RVTAT = right ventricular total activation time; SDAT = SD of activation times; TAT = total activation time; TVaT = total ventricular activation time; VAT = ventricular activation time; VaT10–90 = ventricular activation time10–90 (delay between the 10th and 90th percentiles of ventricular activation time); VEU = ventricular electrical uncoupling.

significantly increased the resynchronisation effect in both ischaemic and non-ischaemic patients.18 The aforementioned parameters, TVaT and VaT10–90, were also used to identify the optimal atrioventricular delay (AVD) and interventricular pacing interval (VVD). The minimum TVaT and VaT10–90 values were associated with the most improved ventricular haemodynamics, suggesting that ECG mapping approaches are effective for programming optimisation.19 The potential of ECGI activation maps for detection of the best configuration of multi-polar pacing was demonstrated in a pilot study with five patients.26

BSPM could be useful for the selection of HFrEF patients with a borderline QRS width on standard ECG. Most of the evidence suggests that SDAT ≥35 ms from BSPM with 53 leads can predict reverse LV remodelling after CRT, as can the greater change of SDAT (∆SDAT) from baseline to postimplant values. ECGI can further improve patient selection with the use of parameters such as ADV or VEU. BSPM has been advocated as an alternative guide for the positioning of the LV lead during the implant procedure. It is based on the presumption that choosing the pacing site with the greatest reduction in SDAT will correspond to an improvement in haemodynamics as evaluated using invasive measurement of acute haemodynamic response. However, there is no comparison between these BSPM-derived parameters and the simple strategy, such as the selection of the pacing site based on the identification of the late local activation in sinus rhythm. In our opinion, BSPM has a large potential for individualising the optimisation of CRT device programming. This conclusion is based on studies showing that the optimised SDAT parameter is predictive of reverse remodelling, regardless of the baseline characteristics of the CRT candidates.

Discussion

One of the therapeutic options for advanced management of HFrEF patients during the last 30 years has been CRT. To increase the efficiency of CRT, different approaches have been applied, such as clinical and experimental approaches, and computer simulation. The experimental porcine model of LBBB to induce electrical and mechanical dyssynchrony was suggested for the study of the mechanisms of CRT effect in a treatment of HF.35 Preclinical studies, including both animal experimental models and patient-specific computational models of the heart, demonstrate a high potential for prediction and optimisation of CRT treatment. Nevertheless, clinical studies are required to validate the efficacy of these models in the target HF population, as well as the applicability of these models to the ECGI methods discussed in this work.36

As an alternative to BSPM, a novel approach based on ultra-highfrequency ECG was recently suggested to improve patient selection for CRT treatment. Jurak et al. demonstrated that an ultra-high-frequency 14lead ECG technique could improve the application of CRT based on new

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Body Surface Potential Mapping in CRT Patients Figure 3: QRS Integral Maps of a Patient with Heart failure Under Atrial Pacing (Top) and Left Ventricular Pacing (Bottom) Interval: 0, 186 ms

Map type: Qo,J Min,Max,Step: −86.08, +134.47

17.00 mV.ms

+136 +102 +68 +34 +0 −34 −68 −102 −136 Interval: 0, 193 ms

Map type: Qo,J

Min,Max,Step: −177.37, +90.99

23.00 mV.ms

+184 +138 +92 +46 +0 −46 −92 −138 −184 Distribution of 96 torso electrodes in the QRS time integral maps. The left and right sides of each map correspond to the anterior and posterior torso aspects, respectively. Maximum and minimum are marked by plus and minus signs, respectively.

number of required ECG leads, preferably to the standard 12-lead ECG configuration. Recent developments in the anatomical localisation of premature ventricular contractions from a 12-lead ECG using ECGI technology show that the potential of the ECGI technology has not been fully explored.43

ECG indices of ventricular depolarisation.37 This technique may prove to be a valuable addition to the discussed BSPM and ECGI methods. Artificial intelligence techniques have recently been proposed as a promising tool in cardiac electrophysiology to increase the diagnostic accuracy and treatment capabilities of medical technologies such as surface ECG, intracardiac mapping and cardiac implantable electronic devices.38,39 A machine learning model with nine variables demonstrated improved CRT response prediction compared with guidelines.40 Kalscheur et al. developed a random forest model that predicted all-cause mortality and HF hospitalisation in patients receiving CRT implantation, based on pre-implant characteristics.41 Hu et al. successfully applied machine learning techniques with natural language processing to identify a subgroup of patients who were unlikely to benefit from CRT.42 Machine learning models that relied on pre-implantation clinical, echocardiographic, and ECG characteristics produced understandably better predictions of CRT benefit than those that relied on ECG parameters.41,42 This integration approach based on analysis of many clinical parameters may provide a new opportunity for personalised management of patients with HF. The combination of ECGI-derived parameters and machine learning models may provide a pathophysiological interpretation of related clinical features and CRT response.

Conclusion

BSPM and ECGI can be used in CRT in several ways. There is a potential for improvement of patient selection for CRT, optimisation of CRT programming and LV lead placement. The most promising parameter (and also the easiest to obtain) is SDAT derived from BSPM. Further prospective or randomised trials are necessary to identify the utility of BSPM for routine clinical practice.

Clinical Perspective

• For clinical use, the standard deviation of activation times

appears to be the most promising parameter for individualised optimisation of CRT device programming without the need for imaging studies. • Further prospective or randomised trials are necessary to verify the utility of body surface potential mapping for routine clinical practice. • ECG imaging approaches can provide detailed information on the depolarisation process in ventricles with heart failure, which is crucial for understanding the relationship between electromechanical status and CRT effect.

An advantage of ECGI methods relates to the ability to obtain important information on CRT effect through an electrical solution to a mechanical problem. A solid understanding of the electromechanical structure of the heart is required. Future ECGI developments should therefore aim to increase the modelling capabilities used in ECG technology to reduce the 1. Thomas G, Kim J, Lerman BB. Improving cardiac resynchronisation therapy. Arrhythm Electrophysiol Rev 2019;8:220–7. https://doi.org/10.15420/aer.2018.62.3; PMID: 31463060. 2. Pujol-Lopez M, San Antonio R, Mont L, et al. Electrocardiographic optimization techniques in resynchronization therapy. Europace 2019;21:1286–96. https://doi.org/10.1093/europace/euz126; PMID: 31038177.

3. Gage RM, Curtin AE, Burns KV, et al. Changes in electrical dyssynchrony by body surface mapping predict left ventricular remodeling in cardiac resynchronization therapy patients. Heart Rhythm 2017;14:392–9. https://doi. org/10.1016/j.hrthm.2016.11.019; PMID: 27867072. 4. Bear LR, Huntjens PR, Walton RD, et al. Cardiac electrical dyssynchrony is accurately detected by noninvasive electrocardiographic imaging. Heart Rhythm 2018;15:1058–

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

118

69. https://doi.org/10.1016/j.hrthm.2018.02.024; PMID: 29477975. 5. Strik M, Ploux S, Huntjens PR, et al. Response to cardiac resynchronization therapy is determined by intrinsic electrical substrate rather than by its modification. Int J Cardiol 2018;270:143–8. https://doi.org/10.1016/j. ijcard.2018.06.005; PMID: 29895424. 6. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred

Body Surface Potential Mapping in CRT Patients

10.

11.

12.

13.

14.

15.

16.

17.

reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e1000097. https:// doi.org/10.1371/journal.pmed.1000097; PMID: 19621072. Arnold AD, Shun-Shin MJ, Keene D, et al. His resynchronization versus biventricular pacing in patients with heart failure and left bundle branch block. J Am Coll Cardiol 2018;72:3112–22. https://doi.org/10.1016/j. jacc.2018.09.073; PMID: 30545450. Bank AJ, Gage RM, Curtin AE, et al. Body surface activation mapping of electrical dyssynchrony in cardiac resynchronization therapy patients: potential for optimization. J Electrocardiol 2018;51:534–41. https://doi. org/10.1016/j.jelectrocard.2017.12.004; PMID: 29273234. Berger T, Hanser F, Hintringer F, et al. Effects of cardiac resynchronization therapy on ventricular repolarization in patients with congestive heart failure. J Cardiovasc Electrophysiol 2005;16:611–17. https://doi.org/10.1046/ j.1540-8167.2005.40496.x; PMID: 15946359. Dawoud F, Spragg DD, Berger RD, et al. Non-invasive electromechanical activation imaging as a tool to study left ventricular dyssynchronous patients: implication for CRT therapy. J Electrocardiol 2016;49:375–82. https://doi. org/10.1016/j.jelectrocard.2016.02.011; PMID: 26968312. Ghosh S, Silva JNA, Canham RM, et al. Electrophysiologic substrate and intraventricular left ventricular dyssynchrony in nonischemic heart failure patients undergoing cardiac resynchronization therapy. Heart Rhythm 2011;8:692–9. https://doi.org/10.1016/j.hrthm.2011.01.017; PMID: 21232630. Jia P, Ramanathan C, Ghanem RN, et al. Electrocardiographic imaging of cardiac resynchronization therapy in heart failure: observation of variable electrophysiologic responses. Heart Rhythm 2006;3:296– 310. https://doi.org/10.1016/j.hrthm.2005.11.025; PMID: 16500302. Johnson WB, Vatterott PJ, Peterson MA, et al. Body surface mapping using an ECG belt to characterize electrical heterogeneity for different left ventricular pacing sites during cardiac resynchronization: relationship with acute hemodynamic improvement. Heart Rhythm 2017;14:385–91. https://doi.org/10.1016/j.hrthm.2016.11.017; PMID: 27871987. Kittnar O, Riedlbauchova L, Adla T, et al. Outcome of resynchronization therapy on superficial and endocardial electrophysiological findings. Physiol Res 2018;67:601–10. https://doi.org/10.33549/physiolres.934056; PMID: 30607967. Lumens J, Ploux S, Strik M, et al. Comparative electromechanical and hemodynamic effects of left ventricular and biventricular pacing in dyssynchronous heart failure: electrical resynchronization versus left-right ventricular interaction. J Am Coll Cardiol 2013;62:2395–403. https://doi.org/10.1016/j.jacc.2013.08.715; PMID: 24013057. Nguyen UC, Cluitmans MJM, Strik M, et al. Integration of cardiac magnetic resonance imaging, electrocardiographic imaging, and coronary venous computed tomography angiography for guidance of left ventricular lead positioning. Europace 2019;21:626–35. https://doi.org/10.1093/europace/ euy292; PMID: 30590434. Pastore CA, Tobias N, Samesima N, et al. Body surface potential mapping investigating the ventricular activation patterns in the cardiac resynchronization of patients with left bundle-branch block and heart failure. J Electrocardiol 2006;39:93–102. https://doi.org/10.1016/j. jelectrocard.2005.07.004; PMID: 16387060.

18. Pereira H, Jackson TA, Sieniewicz B, et al. Non-invasive electrophysiological assessment of the optimal configuration of quadripolar lead vectors on ventricular activation times. J Electrocardiol 2018;51:714–19. https://doi. org/10.1016/j.jelectrocard.2018.05.006; PMID: 29997019. 19. Pereira H, Jackson TA, Claridge S, et al. Comparison of echocardiographic and electrocardiographic mapping for cardiac resynchronisation therapy optimisation. Cardiol Res Pract 2019;2019:4351693. https://doi.org/10.1155/ 2019/4351693; PMID: 30918721. 20. Ploux S, Lumens J, Whinnett Z, et al. Noninvasive electrocardiographic mapping to improve patient selection for cardiac resynchronization therapy: beyond QRS duration and left bundle branch block morphology. J Am Coll Cardiol 2013;61:2435–43. https://doi.org/10.1016/j.jacc.2013.01.093; PMID: 23602768. 21. Ploux S, Eschalier R, Whinnett ZI, et al. Electrical dyssynchrony induced by biventricular pacing: implications for patient selection and therapy improvement. Heart Rhythm 2015;12:782–91. https://doi.org/10.1016/j.hrthm.2014.12.031; PMID: 2554681. 22. Rudy Y. Noninvasive electrocardiographic imaging of cardiac resynchronization therapy in patients with heart failure. J Electrocardiol 2006;39:28–30. https://doi. org/10.1016/j.jelectrocard.2006.03.012; PMID: 16950331. 23. Samesima N, Douglas R, Tobias N, et al. Twenty-millisecond interventricular difference as assessed by body surface potential mapping identifies patients with clinical improvement after implantation of cardiac resynchronization device. Anadolu Kardiyol Derg 2007;7(Suppl 1):213–5. PMID: 17584728. 24. Samesima N, Pastore CA, Douglas RA, et al. Improved relationship between left and right ventricular electrical activation after cardiac resynchronization therapy in heart failure patients can be quantified by body surface potential mapping. Clinics 2013;68:986–91. https://doi.org/10.6061/ clinics/2013(07)16; PMID: 23917664. 25. Shannon J, Navarro CO, McEntee T, et al. An early phase of slow myocardial activation may be necessary in order to benefit from cardiac resynchronization therapy. J Electrocardiol 2008;41:531–5. https://doi.org/10.1016/j. jelectrocard.2008.07.028; PMID: 18817924. 26. Sieniewicz BJ, Jackson T, Claridge S, et al. Optimization of CRT programming using non-invasive electrocardiographic imaging to assess the acute electrical effects of multipoint pacing. J Arrhythm 2019;35:267–75. https://doi.org/10.1002/ joa3.12153; PMID: 31007792. 27. Varma N. Variegated left ventricular electrical activation in response to a novel quadripolar electrode: visualization by non-invasive electrocardiographic imaging. J Electrocardiol 2014;47:66–74. https://doi.org/10.1016/j. jelectrocard.2013.09.001; PMID: 24099886. 28. Sorgente A, Cappato R. A critical reappraisal of the current clinical indications to cardiac resynchronisation therapy. Arrhythm Electrophysiol Rev 2013;2:91–4. https://doi. org/10.15420/aer.2013.2.2.91; PMID: 26835046. 29. Auger D, Bleeker GB, Bertini M, et al. Effect of cardiac resynchronization therapy in patients without left intraventricular dyssynchrony. Eur Heart J 2012;33:913–20. https://doi.org/10.1093/eurheartj/ehr468; PMID: 22279110. 30. Bleeker GB, Schalij MJ, Molhoek SG, et al. Relationship between QRS duration and left ventricular dyssynchrony in patients with end-stage heart failure. J Cardiovasc

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

119

Electrophysiol 2004;15:544–9. https://doi.org/10.1046/ j.1540-8167.2004.03604.x; PMID: 15149423. 31. Seger M, Hanser F, Dichtl W, et al. Non-invasive imaging of cardiac electrophysiology in a cardiac resynchronization therapy defibrillator patient with a quadripolar left ventricular lead. Europace 2014;16:743–9. https://doi. org/10.1093/europace/euu045; PMID: 24798964. 32. Lambiase PD, Rinaldi A, Hauck J, et al. Non-contact left ventricular endocardial mapping in cardiac resynchronisation therapy. Heart 2004;90:44–51. http://dx. doi.org/10.1136/heart.90.1.44; PMID: 14676240. 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. 33. Vatasescu R, Berruezo A, Mont L, et al. Midterm ‘superresponse’ to cardiac resynchronization therapy by biventricular pacing with fusion: insights from electroanatomical mapping. Europace 2009;11:1675–82. https://doi. org/10.1093/europace/eup333; PMID: 19880850. 34. Rigol M, Solanes N, Fernandez-Armenta J, et al. Development of a swine model of left bundle branch block for experimental studies of cardiac resynchronization therapy. J Cardiovasc Trans Res 2013;6:616–22. https://doi. org/10.1007/s12265-013-9464-1; PMID: 23636845. 35. Lee AWC, Costa CM, Strocchi M, et al. Computational modeling for cardiac resynchronization therapy. J Cardiovasc Trans Res 2018;11:92–108. https://doi.org/10.1007/s12265-0179779-4; PMID: 29327314. 36. Jurak P, Curila K, Leinveber P, et al. Novel ultra-highfrequency electrocardiogram tool for the description of the ventricular depolarization pattern before and during cardiac resynchronization. J Cardiovasc Electrophysiol 2020;31:300–7. https://doi.org/10.1111/jce.14299; PMID: 31788894. 37. Muthalaly RG, Evans RM. Applications of machine learning in cardiac electrophysiology. Arrhythm Electrophysiol Rev 2020;9:71–7. https://doi.org/10.15420/aer.2019.19; PMID: 32983527. 38. van de Leur RR, Boonstra MJ, Bagheri A, et al. Big data and artificial intelligence: opportunities and threats in electrophysiology. Arrhythm Electrophysiol Rev 2020;9:146–54. https://doi.org/10.15420/aer.2020.26; PMID: 33240510. 39. Feeny AK, Rickard J, Patel D, et al. Machine learning prediction of response to cardiac resynchronization therapy: improvement versus current guidelines. Circ Arrhythm Electrophysiol 2019;12:e007316. https://doi.org/10.1161/ CIRCEP.119.007316; PMID: 31216884. 40. Kalscheur MM, Kipp RT, Tattersall MC, et al. Machine learning algorithm predicts cardiac resynchronization therapy outcomes. Circ Arrhythm Electrophysiol 2018;11:e005499. https://doi.org/10.1161/circep.117.005499; PMID: 29326129. 41. Hu S-Y, Santus E, Forsyth AW, et al. Can machine learning improve patient selection for cardiac resynchronization therapy? PLoS One 2019;14:e0222397. https://doi.org/10.1371/ journal.pone.0222397; PMID: 31581234. 42. Misra S, van Dam PM, Chrispin J, et al. Initial validation of a novel ECGI system for localization of premature ventricular contractions and ventricular tachycardia in structurally normal and abnormal hearts. J Electrocardiol 2018;51:801–8. https://doi.org/10.1016/j.jelectrocard.2018.05.018; PMID: 30177316.

COVID-19

Remote Clinics and Investigations in Arrhythmia Services: What Have We Learnt During Coronavirus Disease 2019? Shohreh Honarbakhsh, Simon Sporton, Christopher Monkhouse, Martin Lowe, Mark J Earley and Ross J Hunter Department of Arrhythmia Management, Barts Heart Centre, Barts Health NHS Trust, London, UK

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has had a dramatic impact on the way that medical care is delivered. To minimise hospital attendance by both patients and staff, remote clinics, meetings and investigations have been used. Technologies including hand-held ECG monitoring using smartphones, patch ECG monitoring and sending out conventional Holter monitors have aided remote investigations. Platforms such as Google Meet and Zoom have allowed remote multidisciplinary meetings to be delivered effectively. The use of phone consultations has allowed outpatient care to continue despite the pandemic. The COVID-19 pandemic has resulted in a radical, and probably permanent, change in the way that outpatient care is delivered. Previous experience in remote review and the available technologies for monitoring have allowed the majority of outpatient care to be conducted without obviously compromising quality or safety.

Keywords

Arrhythmias, atrial fibrillation, coronavirus, COVID-19, electrocardiogram, monitoring, remote clinics Disclosures: RJH has received research grants, educational grants and speaker fees from Biosense Webster and Medtronic. SH and RJH are shareholders in Rhythm AI. CM has received speaker fees from Abbott, BIOTRONIK, Boston Scientific and Medtronic. All other authors have no conflicts of interest to declare. Received: 8 November 2020 Accepted: 15 February 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(2):120–4. DOI: https://doi.org/10.15420/aer.2020.37 Correspondence: Ross J Hunter, Barts Heart Centre, Barts Health NHS Trust, West Smithfield, London EC1A 7BE, UK. Email: ross.hunter@bartshealth.nhs.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Our previous experience using this approach in the research setting has lent itself well to use in the COVID-19 pandemic. However, even though this approach has helped us ensure patients can obtain these investigations without having to visit the hospital, we have found that a minority of Holter monitors need to be repeated as a result of poor-quality recordings. The use of enhanced instructions and guidance to patients on fitting of Holter monitors could potentially help to minimise this, and our research team has found that a phone call to talk patients through this process can be helpful.

The coronavirus disease 2019 (COVID-19) pandemic has had a dramatic impact on the way that medical care is delivered. An overarching principle of the response to the pandemic has been to minimise hospital attendance by both patients and staff. Our hospital provides secondary and tertiary cardiac arrhythmia services to patients from across the UK. Before the pandemic, we had a well-established remote monitoring service for device patients and had successfully introduced remote follow-up of patients after catheter ablation procedures. The pandemic has meant that virtually every aspect of outpatient care delivered by our service now takes place remotely, with some significant benefits and some limitations and disadvantages. We describe our experience.

Holter monitoring is a useful diagnostic tool, but it can be difficult to capture an episode of symptoms using this, particularly if symptoms are infrequent. With this in mind, several hand-held monitoring devices that use smartphones have been developed – for example, AliveCor KardiaMobile or Apple Smart Watch – allowing patients to obtain an ECG trace at the time of their symptoms without being reliant on a monitor that is time dependent. These devices also have the advantage of allowing the patient to share the ECG traces with physicians via email. As a result, a clinical diagnosis can effectively be made through remote investigations. For example, the AliveCor KardiaMobile (Figure 1) has been shown to effectively identify AF and can do so in a larger proportion of patients compared with standard care, as shown in a randomised controlled trial.1,2

Remote Investigations

The management of many arrhythmia patients is reliant on obtaining ECGs, both at baseline and during episodes of symptoms. If an abnormality is found, a large proportion of these patients will have a discussion regarding an invasive procedure to diagnose and/or treat their underlying arrhythmia. Holter monitoring remains a useful investigation for some patients. Where Holter monitoring was still required during the COVID-19 pandemic, these monitors were posted to patients with clear instructions provided regarding fitting and use of the Holter monitors, with patients often called by phone and talked through the process of attaching the monitor. Once the patient had completed the recording, the monitors were then mailed back to the hospital for analysis using a recorded delivery postal system.

Even though these devices have clear advantages, not all patients are able to use them effectively, particularly older patients and those who do not have access to a smartphone or watch. In addition, for certain

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Remote Clinics and Investigations in Arrhythmia Services Figure 1: ECG Traces from AliveCore KardiaMobile Device Patient: Recorded: Heart rate: Duration:

Thursday 11 June 2020 at 1.29.19 pm 122 BPM 30 seconds

Notes: Instant analysis: Tachycardia *Instant analysis is done on lead I Enhanced filter, Mains frequency: 50Hz, Scale: 25 mm/s, 10 mm/mV

ECG traces from two leads obtained from an AliveCor KardiaMobile device. This patient had the version of the device that allowed a six-lead ECG recording. ECG traces from lead I and II are displayed. The traces demonstrate sinus rhythm, which corresponded to the patient’s symptoms of palpitations. The patient was reassured that no arrhythmia was present and her symptoms were benign.

conditions, more detailed monitoring is required when investigating syncopal episodes. In these patients, alternative remote monitoring systems are available, such as the Carnation Ambulatory Monitor patch (BardyDx), consisting of a patch positioned over the sternum that allows ECG recording for 14 days. The patient can then transfer the data from the device onto a computer and share these with their clinician. These cardiac patches are also provided by other companies, such as the Zio XT patch by iRhythm Technologies (Figure 2), which has been compared to Holter monitoring and shown to be as good at detecting clinically significant arrhythmias.3 The main advantage of all of these devices is that the data can be readily shared between patient and clinician, providing a platform where remote investigations can be acted on promptly.

Virtual Meetings

There are other devices available with the predominant focus on detection of AF. One of these devices is the FibriCheck app, which works through a smartphone app. This detects irregularities in heart rhythm that can be indicative of AF using validated photoplethysmography (Figure 3).4 FibriCheck was made available for free during the COVID-19 pandemic. The purpose of these devices is to detect episodes of AF, whether capturing episodes of symptoms, or screening patients without symptoms. Similarly to the other devices discussed, the findings from these devices can be readily sent to the clinician.

Remote Clinic Follow-up

Multidisciplinary team meetings are an increasingly important part of medical decision-making. Virtual meeting platforms, such as Google Meet, Zoom Video Communications, Microsoft Teams and StarLeaf, are well suited to this purpose and are now used widely in the NHS. Experience gained during the pandemic has demonstrated benefits that will have a lasting impact on the way we practise. The ability to join meetings without the need to be physically present in the hospital provides the foundation for a more national and international forum to bring together key opinions on management of patients with complex problems. These meetings also provide fantastic educational opportunities and, indeed, clinical teaching sessions have evolved in the same way. It is likely that these platforms will be more readily used after the pandemic, in view of the benefits they bring. Remote clinic follow-up has been in place for several months at our centre, whereby all patients discharged after elective procedures are reviewed remotely via a phone consultation with arrhythmia nurse specialists, unless there is a clinical need for physician review in person. Approximately 250 patients are currently under remote follow-up at our centre. Remote clinic follow-up has several advantages; the time, expense and infection risk of a hospital visit are avoided. This is especially advantageous for those living far away, which can be a large proportion of patients in tertiary and quaternary centres. Remote follow-up also preserves outpatient facilities for patients needing physician-delivered care. This not only ensures shorter waiting times for patients to see physicians, but also allows longer follow-up for patients seen remotely as a result of the availability of this additional resource.

These devices have provided a leap forwards in terms of remote investigations, particularly for infrequent symptoms that are difficult to capture by conventional Holter monitoring, but this has relied largely on patients purchasing their own devices. Some patients are less willing or able to meet this cost. State-funded healthcare in the UK will not reimburse patients for monitoring equipment or reimburse hospitals for providing this to patients. Private medical insurers have begun to do so. However, the economics of this arrangement in the private and state sectors is not yet resolved.

These clinics have taught us that patients can obtain effective postprocedural care without needing hospital visits. As symptoms are fundamental in determining the management of most arrhythmia conditions, phone consultations have been an effective way to obtain a

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Remote Clinics and Investigations in Arrhythmia Services Figure 2: ECG Trace from Zio XT Patch 3.3–10.4 seconds of ventricular asystole due to complete heart block (22–37 BPM), possible high-grade AV block (22–35 BPM) 30/07/20

15:57:03

Summary

Events

Associated with patient-triggered event Patient events

Pauses

AVB

SVT

VEs

Additional strips

An ECG trace obtained from the Zio XT patch, which demonstrates complete heart block and an episode of ventricular standstill. This corresponded to the patient’s symptoms of presyncope and syncope and was recorded by the device as a patient-triggered event. The app also provides a summary of the findings of the whole recording. The traces, together with the summary of findings, are sent to the referring clinician. AV = Atrioventricular; AVB = atrioventricular block; SVT = supraventricular tachycardia; VEs = eentricular ectopic beats; VT = ventricular tachycardia.

Even though remote outpatient clinics have several advantages, particularly in the current climate, it is important to recognise some of the limitations of remote follow-up. A lot of available technologies and use of our existing experience with remote monitoring allowed us to effectively achieve remote monitoring during the pandemic, but several measures had to be taken to make this feasible. Firstly, all patients were contacted by secretaries prior to their clinic appointment and informed that their appointments were via phone rather than face-to-face. This rescheduling process required additional administration time. The running of these clinics required some adjustment. However, the time dedicated to faceto-face consultations was quickly directed towards phone consultations, which required limited adjustment to our services. The same time slots were used for phone appointments as for face-to-face clinics, so the volume of appointments offered was unaffected.

patient history without being reliant on face-to-face consultations. Several apps have been launched to allow remote follow-up appointments. OrtusiHealth is one such app that can be used by patients and clinicians to manage their outpatient care. This app in particular allows patients to get reminders for appointments, access their clinic letters, communicate with their clinician and give consent for procedures via a smartphone. The physician can use the app via a web portal. Such apps are already facilitating remote follow-up appointments at our centre and will no doubt continue to evolve. Digital health technologies are expanding and are being used more widely during the COVID-19 pandemic.5 Their use in the remote management of arrhythmia patients in the context of the pandemic is supported by the Heart Rhythm Society clinical guidelines.6 Mobile health system technologies available on mobile phones can also be helpful for remote patient management and are widely used worldwide, particularly in the US.7,8 Mobile technologies for outpatient platforms are not as widely used at our centre. However, their use is likely to be incorporated into the on-going remote management of arrhythmia patients.

Care was taken to verify patient identification with phone calls. Where possible patient communication was kept within working hours to minimise intrusion. Patient preferences for communication, including text messages, WhatsApp and email, were considered, while highlighting to patients where gaps in data security might exist and where they may jeopardise their privacy. From a patient’s perspective, these appointments can make it difficult for relatives and next of kin to participate. They also limit clinical examination of the patient, which plays a particularly important role in those with underlying heart failure. The lack of face-to-face consultation can also affect the rapport and the doctor–patient relationship. Going forwards, using additional resources

Remote monitoring has also been implemented in patients with COVID-19 using an automated text-messaging system.5 The Covid Watch combined automated twice-daily text message check-ins with a team of telemedicine clinicians available to respond 24/7 to escalations in patients’ needs. This is an alternative remote monitoring approach that could potentially also be expanded into areas of arrhythmia management.

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Remote Clinics and Investigations in Arrhythmia Services Figure 3: FibriCheck App

The FibriCheck app available for smartphones. The app uses the camera on the phone to run the photoplethysmography technology and get a pulse reading. The user is required to hold their finger gently at the camera for 60 seconds, as shown (A). Once the recording has been completed, a summary of the findings is provided, which includes the regularity and the rate of the pulse (B). These findings can then be used to generate a report that provides the patient with recommendations about whether there is a concern regarding their findings and whether they should seek medical attention. The patient can share these reports with their clinician via email (C).

monitoring, which hospitals have absorbed in the short term. Again, the economics of this approach are not fully resolved yet and device companies may adjust costs of home monitoring to facilitate the massive explosion in demand.

such as virtual meeting platforms and being even more reliant on community services could potentially help to minimise the impact of some of these limitations. As in many UK centres, our pacemaker and device clinic follow-up has been moved, where possible, to a remote format. Dedicated administration time was required for the physiologists to arrange the remote clinic appointments and for patients to obtain a home monitor. All device checks since March have become remote monitoring downloads at 4–6 weeks post-implant rather than an in-person check.

Further to this, remote device clinic follow-up does have limitations. For example, these appointments do not allow any alterations to the device parameters and functionalities. Concerns related to cybersecurity and liability are partly responsible for the lack of advancement in this area.10 With the changes in remote management these advances might follow.

Likewise, a large portion of subsequent follow-up for pacemakers, implantable loop recorders, ICDs and CRT devices has been moved to remote follow-up. Many centres were already using home monitoring devices for complex devices such as ICDs and CRT devices, but extending this to simple pacemakers has been a massive expansion. Remote monitoring of simple pacemakers has not been shown to be inferior to in-office follow-up, although only one manufacturer’s model has been assessed to date.9 At St Bartholomew’s Hospital, the number of patients with pacemakers on remote monitoring has increased 15-fold because of the COVID-19 pandemic. The total number of patients now on remote monitoring is around 6,500 patients. Some 1,500 of these patients are on remote monitoring because of the COVID-19 pandemic; around a 20% increase. As a result of the COVID-19 pandemic, the remote workload now consists of around 90–100 patients per day during the week and around 40 patients during the weekend. Although there may be a long-term saving with this approach, there is an up-front cost associated with remote

Remote device clinic follow-up also does not enable physical wound reviews and so reviews of wound pictures at 4–6 weeks follow-up postprocedure was implemented to mitigate this. However, this is not practical for a large portion of the population, particularly older patients and those who do not have access to digital imaging or email technologies. As a result of the sudden nature of the transition to remote follow-up, not all patients’ parameters have been programmed for this follow-up schedule and some patients did not have remote follow-up enabled on their device. This requires them to return to the hospital to be set up for remote follow-up. Remote monitoring does have the advantage of daily alert transmissions for arrhythmia and device function issues, which can be dealt with quickly. However, if these device alert settings are not personally tailored the burden of unnecessary transmissions can be drastically increased. With the introduction of the LINQ II (Medtronic) and

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Remote Clinics and Investigations in Arrhythmia Services highlighted some of the benefits and limitations of remote care for arrhythmia patients. It is expected that technology will evolve to address these limitations and that new funding models will be developed, reflecting the radically altered landscape.

Lux-Dx ICM (Boston Scientific) loop recorder, remote programming will help reduce this burden. Finally, in the UK, the remote reimbursement tariff is significantly lower than for a face-to-face appointment, providing no financial incentive for services to continue to adapt to this model in the long term. The main incentive is to reduce the risk to patients and staff of contracting COVID-19 but, the longer-term motivation will be to have a better, more efficient and flexible service.

Clinical Perspective • The coronavirus disease 2019 pandemic has resulted in a

Conclusion

radical, and probably permanent, change in the way we deliver outpatient care. • Our previous experience with remote monitoring and available technologies for monitoring have allowed us to conduct the majority of outpatient care without obviously compromising quality or safety.

The COVID-19 pandemic has resulted in a radical, and probably permanent, change in the way that we deliver outpatient care. Our previous experience in remote review and the available technologies for monitoring have allowed us to conduct the majority of outpatient care without obviously compromising quality or safety, although the precipitous nature of change has meant that this assertion is largely untested. We have 1. Lau JK, Lowres N, Neubeck, et al. iPhone ECG application for community screening to detect silent atrial fibrillation: a novel technology to prevent stroke. Int J Cardiol 2013;165:193–4. https://doi.org/10.1016/j.ijcard.2013.01.220; PMID: 23465249. 2. Halcox JPJ, Wareham K, Cardew A, et al. Assessment of remote heart rhythm sampling using the AliveCor heart monitor to screen for atrial fibrillation: the REHEARSE-AF study. Circulation 2017;136:1784–94. https://doi.org/10.1161/ CIRCULATIONAHA.117.030583; PMID: 28851729. 3. Bolourchi M, Silver ES, Muwanga D, et al. Comparison of Holter with Zio patch electrocardiography monitoring in children. Am J Cardiol 2020;125:767–71. https://doi. org/10.1016/j.amjcard.2019.11.028; PMID: 31948666. 4. Proesmans T, Mortelmans C, Van Haelst R, et al. Mobile phone-based use of the photoplethysmography technique

to detect atrial fibrillation in primary care: diagnostic accuracy study of the FibriCheck app. JMIR Mhealth Uhealth 2019;7:e12284. https://doi.org/10.2196/12284; PMID: 30916656. 5. Webster P. Virtual health care in the era of COVID-19. Lancet 2020;395:1180–1. https://doi.org/10.1016/S01406736(20)30818-7; PMID: 32278374. 6. Lakkireddy DR, Chung MK, Gopinathannair R, et al. Guidance for cardiac electrophysiology during the COVID19 pandemic from the Heart Rhythm Society COVID-19 Task Force; Electrophysiology Section of the American College of Cardiology; and the Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology, American Heart Association. Heart Rhythm 2020;17:e233–41. https://doi.org/10.1016/j. hrthm.2020.03.028; PMID: 32247013.

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7. Park YT. Emerging new era of mobile health technologies. Healthc Inform Res 2016;22:253–4. https://doi.org/10.4258/ hir.2016.22.4.253; PMID: 27895955. 8. Lee JH. Future of the smartphone for patients and healthcare providers. Healthc Inform Res 2016;22:1–2. https://doi.org/10.4258/hir.2016.22.1.1; PMID: 26893944. 9. Watanabe E, Yamazaki F, Goto T, et al. Remote management of pacemaker patients with biennial in-clinic evaluation: continuous home monitoring in the Japanese at-home study: a randomized clinical trial. Circ Arrhythm Electrophysiol 2020;13:e007734. https://doi.org/10.1161/CIRCEP.119.007734. PMID: 32342703. 10. Alexander B, Baranchuk A. Remote device reprogramming: has its time come? Circ Arrhythm Electrophysiol 2020;13:e008949. https://doi.org/10.1161/CIRCEP.120.008949; PMID: 32910697.

Letter to the Editor

Comment on ‘Management of Cardiac Sarcoidosis in 2020’ Socrates Korovesis and Eleftherios Giazitzoglou Hygeia Hospital, Athens, Greece

Disclosure: The authors have no conflicts of interest to declare. Received: 22 April 2021 Accepted: 22 April 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(2):125. DOI: https://doi.org/10.15420/aer.2021.19 Correspondence: Socrates Korovesis, Department of Cardiology, Hygeia Hospital, 15123 Athens, Greece. E: skorovessis64@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

We read with great interest the profound and instructive review by Gilotra et al. on cardiac sarcoidosis.1 However, we were surprised to see no comment on the raised possibility that steroids might precipitate electrical instability.2 Ventricular tachyarrhythmias and electric storm have been

reported to frequently occur in the first 12 months after initiation of corticosteroid therapy.3 This is an issue of clinical importance and it would have been useful to include this in the review along with a commentary from the authors.

1. Gilotra N, Okada D, Sharma A, Chrispin J. Management of cardiac sarcoidosis in 2020. Arryth Electrophysiol Rev 2020;9:182–8. https://doi.org/10.15420/aer.2020.09; PMID: 33437485. 2. Okada DR, Smith J, Derakhshan A, et al. Ventricular arrhythmias in cardiac sarcoidosis. Circulation 2018;138:1253–64. https://doi.org/10.1161/CIRCULATIONAHA.118.034687; PMID: 30354431. 3. Segawa M, Fukuda K, Nakano M, et al. Time course and factors correlating with ventricular tachyarrhythmias after introduction of steroid therapy in cardiac sarcoidosis. Circ Arrhythm Electrophysiol 2016;9:e003353. https://doi.org/10.1161/CIRCEP.115.003353; PMID: 27301264.

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Maximising Opportunities Post Coronavirus Disease 2019: Time to Embrace a New Era of Atrial Fibrillation Research