AER 10.4

Arrhythmia & Electrophysiology Review Volume 10 • Issue 4 • Winter 2021

Volume 10 • Issue 4 • Winter 2021

www.AERjournal.com

Atrial Fibrosis, Ischaemic Stroke and Atrial Fibrillation Christian Mahnkopf, Younghoon Kwon and Nazem Akoum

Left Bundle Branch Pacing: A Perfect Compromise?

Alexandre Raymond-Paquin, Santosh K Padala and Kenneth A Ellenbogen

Successful Identification of and Discrimination Between Atrial and Ventricular Arrhythmia with the Aid of Pacing and Defibrillator Devices Rahul K. Mukherjee, Manav Sohal, Nesan Shanmugam, Simon Pearse and Fadi Jouhra

Inferior Extensions of the Atrioventricular Node Robert H Anderson, Jill PJM Hikspoors, Justin T Tretter, Yolanda Macías, Diane E Spicer, Wouter H Lamers, Damián Sánchez-Quintana and Eduardo Back Sternick

Measuring abnormalities: using ECG evidence to determine stroke evaluation.

The conduction system of the heart.

The atrioventricuar node.

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Volume 10 • Issue 4 • Winter 2021

Official journal of

Editor-in-Chief Demosthenes G Katritsis

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

Section Editor – Clinical Electrophysiology and Ablation Hugh Calkins

Section Editor – Arrhythmia Risk Stratification Pier D Lambiase

Johns Hopkins Medicine, Baltimore, MD, US

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

Section Editor – Implantable Devices Ken Ellenbogen

Section Editor – Atrial Fibrillation Gregory YH Lip

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

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

Section Editor – Arrhythmia Mechanisms/Basic Science Andrew Grace

Section Editor – Imaging in Electrophysiology Sanjiv M Narayan

Royal Papworth and Addenbrooke’s Hospitals, Cambridge, UK

Stanford University Medical Center, CA, US

Editorial Board Joseph G Akar

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

Robert Anderson

Eue-Keun Choi

Boyoung Joung

Seoul National University Hospital, Seoul, South Korea

Yonsei University, Seoul, South Korea

KR Julian Chun

Prapa Kanagaratnam

Newcastle University, Newcastle upon Tyne, UK

CardioVascular Center Bethanien, Frankfurt, Germany

Imperial College Healthcare NHS Trust, London, UK

Charles Antzelevitch

Harry Crijns

Josef Kautzner

Lankenau Institute for Medical Research, Pennsylvania, PA, US

Angelo Auricchio

Fondazione Cardiocentro Ticino, Lugano, Italy

Carina Blomström-Lundqvist Uppsala University, Uppsala, Sweden

Johannes Brachmann

Klinikum Coburg, II Med Klinik, Coburg, Germany

Josep Brugada

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

Maastricht University Medical Center, Maastricht, the Netherlands

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Luigi Di Biase

Roberto Keegan

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

Hospital Privado del Sur, Bahia Blanca, Argentina

Sanjay Dixit

Asklepios Klinik St Georg, Hamburg, Germany

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

Sabine Ernst

Alfred Buxton

Antwerp University and University Hospital, Antwerp, Belgium

David J Callans

University of Leipzig, Leipzig, Germany

A John Camm

JW Goethe University, Frankfurt, Germany

University of Pennsylvania, Philadelphia, PA, US St George’s University of London, London, UK

Tze-Fan Chao

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

Shih-Ann Chen

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

Joseph E Marine

Yutao Guo

Chinese PLA General Hospital, Beijing, China

Beth Israel Deaconess Medical Center, Boston, MA, US

Francis E Marchlinski

University of Pennsylvania Health System, Philadelphia, PA, US

Royal Brompton & Harefield NHS Foundation Trust, London, UK

Pedro Brugada

University of Brussels, UZ-BrusselVUB, Brussels, Belgium

Karl-Heinz Kuck

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

Hein Heidbuchel

John M Miller

Indiana University School of Medicine, Indianapolis, IN, US

Gerhard Hindricks

Fred Morady

Cardiovascular Center, University of Michigan, MI, US

Carsten W Israel

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

Edward Rowland

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

Frédéric Sacher

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

Richard Schilling

Barts Health NHS Trust, London, UK

Afzal Sohaib

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

Neil T Srinivasan

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

William G Stevenson

Vanderbilt School of Medicine, Nashville, TN, US

Richard Sutton

Andrea Natale

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

Mark O’Neill

University Medical Center Utrecht, Utrecht, the Netherlands

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

Warren Jackman

Sunny S Po

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

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

Marc A Vos

Katja Zeppenfeld

University of Bordeaux, CHU Bordeaux, France

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

Douglas Packer

Leiden University Medical Center, Leiden, the Netherlands

Roy John

Carlo Pappone

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

Pierre Jaïs

Northshore University Hospital, New York, NY, US

IRCCS Policlinico San Donato, Milan, Italy

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Douglas P Zipes

Volume 10 • Issue 4 • Winter 2021

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Volume 10 • Issue 4 • Winter 2021

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Contents

Foreword Artificial Intelligence, Superintelligence and Intelligence

223

Demosthenes G Katritsis https://doi.org/10.15420/aer.2021.61

Clinical Arrhythmias Atrial Fibrosis, Ischaemic Stroke and Atrial Fibrillation

225

Christian Mahnkopf, Younghoon Kwon and Nazem Akoum https://doi.org/10.15420/aer.2021.51

Is the Adenosine Test Obsolete in the Clinical Assessment of Syncope of Unknown Origin?

230

Melani Sotiriadou, Antonios P Antoniadis, Nikolaos Fragakis and Vassilios Vassilikos https://doi.org/10.15420/aer.2021.39

Contemporary Management of Persistent AF & VT Successful Identification of and Discrimination Between Atrial and Ventricular Arrhythmia with the Aid of Pacing and Defibrillator Devices

235

Rahul K. Mukherjee, Manav Sohal, Nesan Shanmugam, Simon Pearse and Fadi Jouhra https://doi.org/10.15420/aer.2021.54

Cardiac Pacing Left Bundle Branch Pacing: A Perfect Compromise?

241

Alexandre Raymond-Paquin, Santosh K Padala and Kenneth A Ellenbogen https://doi.org/10.15420/aer.2021.60

Cardiac Pacing in Cardioinhibitory Reflex Syncope: Clinical Use of Closed-loop Stimulation

244

Marco Tomaino, Vincenzo Russo, Daniele Giacopelli, Alessio Gargaro and Michele Brignole https://doi.org/10.15420/aer.2021.45

Electro-energetics of Biventricular, Septal and Conduction System Pacing

250

Frits W Prinzen, Joost Lumens, Jürgen Duchenn and Kevin Vernooy https://doi.org/10.15420/aer.2021.30

Electrophysiology & Ablation Impact of Catheter Ablation on Quality of Life and Healthcare Utilisation

258

Sanghamitra Mohanty and Andrea Natale https://doi.org/10.15420/aer.2021.50

262

Inferior Extensions of the Atrioventricular Node Robert H Anderson, Jill PJM Hikspoors, Justin T Tretter, Yolanda Macías, Diane E Spicer, Wouter H Lamers, Damián Sánchez-Quintana and Eduardo Back Sternick https://doi.org/10.15420/aer.2021.43

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Foreword

Artificial Intelligence, Superintelligence and Intelligence

Disclosure: The author has no conflicts of interest to declare.

Citation: Arrhythmia & Electrophysiology Review 2021;10(4):223–. DOI: https://doi.org/10.15420/aer.2021.61 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.

I

n October 2020, for a previous editorial in this journal, the term ‘artificial intelligence’ was searched in the National Library of Medicine via PubMed. At that time, the search yielded 110,855 publications.1 It is remarkable that performing that same search only a year later yields almost 28,500 further citations, with the total now – as of 2 October 2021 – being 139,304 publications. The potential impact of artificial intelligence (AI) has been realised by even its staunchest critics, and the possibility of a wonder thinking machine, ‘the Master Algorithm’ as computer scientist Pedro Domingo called it, is no longer just science fiction.2

Despite the recent explosion of interest in AI, the reality is that progress has been moving along for at least 180 years. The first published algorithm ever specifically tailored for implementation on a computer was published by Ada Lovelace – the disciple of Charles Babbage and daughter of the great philhellene Lord Byron – in 1843. Today, philosophers and futurists such as Nick Bostrom and Ray Kurzweil speak not of AI, but of superintelligence, far exceeding the capacity and might of the human brain.3 After all, Gary Kasparov did lose at chess to IBM’s Deep Blue.

For clinicians – in particular electrophysiologists and arrhythmia experts – the power of AI has become equally apparent. There is now emerging evidence that AI may support diagnostics in electrophysiology by automating common clinical tasks or aiding complex tasks using deep neural networks that are superior to currently implemented computerised algorithms.4 Soon, AI simulations of the circuit of monomorphic ventricular tachycardia may be used to guide catheter ablation, or even stereotactic radioablation for a vast number of patients.5 Combining data obtained from several diagnostic modalities using AI might elucidate pathophysiological mechanisms of new, rare, or idiopathic cardiac diseases, aid the early detection or targeted treatment of cardiovascular diseases or allow for screening of disorders currently not associated with the ECG.4 Is all this the future or just wishful thinking? Computer scientist and inventor Eric Larson has seriously challenged the notion of any supercomputer exceeding the human brain.6 This is not only a problem of Aristotelian deduction versus induction versus inference: it seems to be a matter of logistics too. Rebecca Goldin, writing for the Genetic Literacy Project in response to President Obama’s 2013 announcement of a broad new research initiative to understand the human brain, provides perspective:7 “The human brain is estimated to have approximately 86 billion neurons (8.6 x 1010), each neuron with possibly tens of thousands of synaptic connections; these little conversation sites are where neurons exchange information. In total, there are likely to be more than a hundred trillion neuronal synapses – so a computer recording a simple binary piece of information about synapses, such as whether it fired in a time window or not, would require 100 terabytes. The amount of storage needed to store even this very simple information every second over the course of one day for one person would more than 100,000 terabytes, or 100 petabytes. Supercomputers these days hold about 10 petabytes. And this quick calculation doesn’t account for the changes in connectivity and positioning of these synapses occurring over time. Counting how these connections change just after a good night’s sleep or a class in mathematics amounts to a whopping figure (and many more bytes than the estimated 1080 atoms in the universe). The wiring problem seems intractable in its magnitude.”

The evolution of quantum computers promises exponentially more computing power. Nevertheless, the fundamental problem remains: how can we imitate – let alone supersede – the human brain when we do not actually know how it works in all its complex, everchanging functions in the time domain? The concept of singularity, by connotation with the Big Bang and Stephen Hawking’s quest for the unified theory of physics, has always been appealing to the human intellect. Whether this motivation results in a future human-made super-intelligent machine and what the consequences of such an endeavour would be, remain to be seen. Ian McEwan’s most recent book reminds us of this dilemma.8 To understand the importance of human complexity, in its simplest form, is perhaps illustrated by the case of the residents of Scunthorpe in northeast England who, in the late 1990s, could not make an AOL account owing to the company’s profanity algorithm detecting a certain ‘inappropriate’ word within the city’s name! It is hard to teach an algorithm to contextualise like the human brain can.9 In contemporary medicine – and especially clinical electrophysiology and arrhythmia management – AI is promising, but in the context of continuous validation of its diagnostic and predictive accuracy. As stated in an elegant review in Arrhythmia & Electrophysiology Review, before © RADCLIFFE CARDIOLOGY 2021 Access at: www.AERjournal.com

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Foreword the implementation of AI algorithms in clinical practice, trust in the algorithms must be established.4 Perhaps one day machines and supercomputers will exceed human intelligence. Until then, electrophysiologists must rely on the best computer known today: their brain. This is what creates superintelligence after all.

Demosthenes G Katritsis Editor-in-Chief, Arrhythmia & Electrophysiology Review Hygeia Hospital, Athens, Greece Johns Hopkins School of Medicine, Baltimore, MD, US 1. Katritsis DG. In search of Homo Deus. Arrhythm Electrophysiol Rev 2020;9:112. https://doi.org/10.15420/ aer.2020.38; PMID: 33240505.

2. Pedro Domingo. The Master Algorithm: How the Quest for the Ultimate Learning Machine Will Remake Our World. New York: Basic Books, 2015.

3. Nick Bostrom. Superintelligence: Paths, Dangers, Strategies.

Oxford: Oxford University Press, 2014.

4. 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.

5. Prakosa A, Arevalo HJ, Deng D, et al. Personalized virtualheart technology for guiding the ablation of infarctrelated ventricular tachycardia. Nat Biomed Eng 2018;2:732–40. https://doi.org/10.1038/s41551-018-02822; PMID: 30847259.

6. Erik Larson. The Myth of Artificial Intelligence: Why Computers Can’t Think the Way We Do. Cambridge, MA: Belknap Press,

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

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2021.

7. Goldin R. Mind-boggling numbers: Genetic expression in the human brain. 2013. https://www.science20.com/ rebecca_goldin/mindboggling_numbers_genetic_ expression_human_brain-109345 (accessed 15 October 2021).

8. Ian McEwan. Machines Like Me. London: Jonathan Cape, 2019.

9. Wikipedia. Scunthorpe problem. https://en.wikipedia.org/ wiki/Scunthorpe_problem (accessed 15 October 2021).

Clinical Arrhythmias

Atrial Fibrosis, Ischaemic Stroke and Atrial Fibrillation Christian Mahnkopf,1 Younghoon Kwon2 and Nazem Akoum

2

1. Cardiology Department, Klinikim Coburg, Coburg, Germany; 2. Division of Cardiology, University of Washington, Seattle, WA, US

Abstract

Atrial fibrosis is an important component of the arrhythmic substrate in AF. Evidence suggests that atrial fibrosis also plays a role in increasing the risk of stroke in patients with the arrhythmia. Patients with embolic stroke of undetermined source (ESUS), who are suspected to have AF but are rarely shown to have it, frequently demonstrate evidence of atrial fibrosis; measured using late-gadolinium enhancement MRI, this manifests as atrial remodelling encompassing structural, functional and electrical properties. In this review, the authors discuss the available evidence linking atrial disease, including fibrosis, with the risk of ischaemic stroke in AF, as well as in the ESUS population, in whom it has been linked to recurrent stroke and new-onset AF. They also discuss the implications of this association on future research that may elucidate the mechanism of stroke and stroke prevention strategies in the AF and ESUS populations.

Keywords

Atrial fibrosis, embolic stroke of undetermined source, AF Disclosure: The authors have no conflicts of interest to declare.

Received: 17 August 2021 Accepted: 3 November 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(4):225–9. DOI: https://doi.org/10.15420/aer.2021.51 Correspondence: Nazem Akoum, Division of Cardiology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, US. E: nakoum@cardiology.washington.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.

Ischaemic stroke remains a leading cause of mortality and morbidity globally. The association between AF and stroke has long been established. Each year, AF-related cardio-embolic stroke accounts for up to one-quarter of ischaemic strokes in the US.1 The mechanisms behind cardio-embolic stroke in AF are not completely understood and are thought to involve blood stasis, hypercoagulability and tissue injury, similar to what is seen in other thrombotic phenomena in vascular beds, as previously described by Virchow.2

fibrosis is central to this relationship and is at the nexus between these two clinically important problems.

AF and Embolic Stroke: is AF necessary?

The classical mechanistic relationship between AF and stroke stipulates that AF, in the presence of cardiovascular risk factors, leads to stasis and hypercoagulability with subsequent thrombus formation and systemic embolisation. Patients with persistent and permanent patterns of AF, typically associated with a higher burden of arrhythmia, have a higher risk of stroke than patients with paroxysmal forms.6 A higher burden of AF has also been associated with a higher stroke risk in patients with paroxysmal AF.6

Atrial fibrosis plays a central role in creating a substrate for AF.3 Fibrosis results from myocyte loss and replacement with collagen in the extracellular space. This leads to increased heterogeneity in the atrial tissue which, coupled with atrial myocyte electrical remodelling, alters the anisotropy and conduction velocity of electrical wave propagation within the atrial myocardium, resulting in an increased probability of arrhythmia initiation and sustenance, in line with the concept of atrial myopathy presented by Goette et al.4,5

Suppression of AF with catheter ablation has been associated with a reduction in stroke risk in observational studies, and in a recent randomised trial of persistent and long-standing AF.7,8 Early rhythm control of patients within a year of diagnosis with AF has also been associated with stroke reduction.9

The relationship between atrial fibrosis and stroke is garnering more attention in view of supporting evidence from the AF patient population.

New research in patients with embolic stroke of undetermined source (ESUS) also suggests a relationship between atrial fibrosis and stroke independent of the presence of AF.

These findings support a causal association between AF and stroke. This is in contrast to other studies of patients with ICDs, such as pacemakers and implantable defibrillators, which have argued against causality because of the observed temporal dissociation of AF episodes with thrombo-embolic events.10

In this review, we discuss the available evidence linking atrial fibrosis to stroke in patients with and without known AF, as well as new evidence linking atrial fibrosis with new-onset AF and recurrent stroke in patients with ESUS. The evidence presented forms the foundation of a new paradigm in the relationship between atrial arrhythmia and stroke, where

Pacemakers and ICDs with atrial leads allowing for continuous atrial arrhythmia monitoring provide a high-fidelity rhythm recording of atrial arrhythmias including AF, and are a unique source of information for studying the temporal relationship between atrial arrhythmias and thromboembolic events, including stroke.

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Fibrosis in Arrhythmia and Stroke Several studies examining this temporal association have shown that there were no device-detected atrial arrhythmia episodes preceding thromboembolic events in a large majority of patients.11,12 In another study, oral anticoagulation with vitamin K antagonists was started and discontinued as device-detected episodes of arrhythmia failed to show benefits of this approach and also demonstrated a temporal dissociation between AF episodes and thromboembolic events.13 These findings suggest that, in this population of patients with ICDs, the presence of AF is not an essential component of the mechanism of thromboembolic events.

Against this background, an alternative explanation has been proposed.

This is based on the presence of underlying atrial disease manifesting with symptomatic bradycardia, hence requiring a ICD and, simultaneously, predisposing these patients to thrombo-emboli independent from atrial arrhythmic events.

Another stroke population where the association between atrial disease and stroke has been examined is ESUS, which is a subset of cryptogenic stroke. AF has long been suspected in these patients as a potential cause of cardiac thrombo-emboli. Long-term cardiac monitoring in patients with cryptogenic stroke has revealed that longer monitoring is associated with higher detection rates of AF.14 However, even using a relatively short duration of episodes (30 seconds), the rate of incident AF was about 30% after three years of monitoring using an implantable loop recorder in the CRYSTAL AF study.15 Another way of stating these findings is that 70% of these cryptogenic stroke patients did not have detectable arrhythmia.15 These findings also call into question the role of AF in thrombo-embolic stroke in this population. In the LOOP study, anticoagulation based on detected arrhythmias using implantable loop recorders in patients with stroke risk factors did not demonstrate a beneficial decrease in stroke rates, leading the investigators to conclude that not all AF is worth screening and anticoagulating for.16 Moreover, the role of clinical risk factors in modulating stroke risk in AF and ESUS populations is not clearly understood; research has demonstrated that the CHA2DS2-VASc aggregate score is more predictive of thrombo-embolic events in the absence than the presence of AF.17 An alternative mechanism has been gaining support with new evidence from various studies. In this new model, atrial fibrosis and associated atrial disease is the nexus between arrhythmia and thrombo-embolic phenomena. This new paradigm is supported by evidence of biomarker activation, atrial enlargement, contractile dysfunction and increased atrial fibrosis in patients with stroke, including ESUS, as well as AF.18,19 We discuss the available evidence in the paragraphs below.

Biomarkers of Fibrosis and Association with Stroke

Many biomarkers involved in the coagulation cascade and subsequent thrombolysis, including thrombin, fibrin and D-dimer, have been associated with cardioembolic stroke.20,21 Other biomarkers of cardiac dysfunction – including abnormal extracellular matrix homeostasis, which is linked to abnormal collagen turnover and subsequent fibrosis – have also been proposed.

Marìn et al. have demonstrated abnormal ratios of matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with AF, but a direct link to stroke is lacking.22 Similarly, pro-collagen type III N-terminal pro-peptide (PIIINP), C-telopeptide of type I collagen (ICTP),

fibroblast growth factor 23 (FGF-23) and galactin-3 (gal-3) have been studied as biomarkers of fibrosis in patients with AF and linked to arrhythmia recurrence after catheter ablation, but have not been studied in stroke in the setting of AF or other ischaemic strokes.23–25 Cardiac troponin and N-terminal-pro-B-type natriuretic peptide (BNP) have been linked to cardioembolic stroke, and ESUS in large cohort studies, including the MESA and the ARIC studies.26–29 BNP is a neurohormone that is primarily released from the ventricles in response to increased wall tension and stretch. It has diuretic (natriuretic) properties and attenuates the renin–angiotensin–aldosterone response, resulting in smooth muscle relaxation in blood vessels. It is synthesised as a prohormone (pro-BNP) and is later cleaved into a C-terminal and an N-terminal (NT)-proBNP fragments. Identifying elevated levels of NT-pro-BNP can be useful in the setting of ischaemic stroke, especially cryptogenic stroke, where they may indicate the presence of heart failure and AF, both important risk factors for cardiac embolism.30 It is important to note that, while these biomarkers suggest myocyte loss and subsequent atrial fibrosis, a direct link to thrombus formation is still lacking.

ECG Evidence of Fibrosis and Relationship with Stroke

The 12-lead ECG is a widely available tool that is commonly used in the setting of stroke to evaluate patients for the presence of AF. In patients in sinus rhythm, the ECG can be used to evaluate for evidence of left atrial remodelling. Of multiple P wave indices, the terminal portion in lead V1 has been studied in patients with ischaemic stroke and shown to correlate with this outcome.31 The P wave terminal force in V1 (PTFV1) is the product of P wave width and depth and can be calculated either manually or automatically on commercially available ECG signal processing software. Abnormal PTFV1 has been shown to be associated with incident ischaemic stroke in a number of studies.32 While PTFV1 appears to be a useful ECG marker for LA remodelling, its specific relationship with atrial fibrosis has not been studied. Moreover, the temporal stability of this index is not well studied.

Echocardiographic Assessment of Atrial Size and Function

Basic echocardiographic assessment of atrial structure includes atrial diameters and surface area in various views. Larger anterior–posterior atrial diameter in the parasternal long axis view and the left atrial area in the four-chamber view have been associated with stroke risk with or without AF.33,34 Similarly, larger atrial volume indexed to the body surface area has also been associated with ischaemic stroke.

More advanced echocardiographic measures, such as speckle tracking, can detect more subtle abnormalities in atrial function. Atrial reservoir dysfunction, a sign of reduced LA compliance, assessed using this approach has been associated with cryptogenic stroke.35 These atrial mechanical and contractile abnormalities measured using atrial strain and strain rate on echocardiography have also been associated with atrial fibrosis quantified using cardiac MRI.36

Cardiac MRI Assessment of Atrial Shape and Contractile Function

Feature tracking using cardiac MRI has been used to examine atrial relaxation and contraction. Atrial reservoir function and atrial emptying fraction were found to be associated with ischaemic stroke in the absence of prevalent or incident AF.37

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Fibrosis in Arrhythmia and Stroke Figure 1: Atrial Fibrosis With Embolic Stroke of Undetermined Source

Figure 2: Outcome by Degree of Fibrosis 1.00

40

p=0.113

p=0.280

Proportion with recurrent stroke or incident AF

Left atrial fibrosis (%)

60

p=0.001 p=0.034

20

0.75 Log-rank test p=0.040

0.50 0.25 0.00 0

0 No AF/ no prior stroke

No AF/ lacunar stroke

No AF/ ESUS

AF and prior stroke

AF/no prior stroke

10 20 Follow-up (months)

Number at risk Fibrosis <12% 21

16

7

5

32

22

10

7

Fibrosis ≥12%

Fibrosis <12% Box plot comparison of atrial fibrosis in patients with ESUS to various groups demonstrating a significantly higher burden of fibrosis compared to healthy controls and lacunar stroke, and similar fibrosis levels compared to AF patients with and without a prior history of stroke. ESUS = embolic stroke of undetermined source. Source: Kühnlein et al. 2021.47 Reproduced with permission from John Wiley & Sons.

30

Fibrosis ≥12%

Kaplan-Meier analysis of patients with embolic stroke of undetermined source follow-up for the combined endpoint of new onset AF or recurrent ischaemic stroke. Patients with atrial fibrosis greater than 12% are observed to have significantly higher rates of the combined endpoint.

Source: Kühnlein et al. 2021.47 Reproduced with permission from John Wiley & Sons.

Moreover, atrial shape deformation with increased atrial sphericity leading to abnormal blood-flow patterns in the left atrium and left atrial appendage have been proposed to have a role in thrombogenesis.38 These findings further support the concept of atrial disease or atrial myopathy as a contributor along the causative pathway of ischaemic stroke independent of AF.39

Cardiac MRI Fibrosis Quantification

MRI for the assessment of cardiac fibrosis is commonly used in the workup and assessment of various types of cardiomyopathies. Late-gadolinium enhancement MRI (LGE-MRI) is an established technique that leverages the washout kinetics of gadolinium, an extracellular contrast agent. The correlation of LGE-MRI-identified fibrosis with ventricular myocardial pathology has been established.40 Applying this imaging technique to the left atrium is more difficult owing to the thin atrial wall and the special resolution of this imaging modality.

Our previous research has correlated LGE-MRI fibrosis of the left atrium with an abundance of collagen on atrial biopsies and demonstrated a strong correlation with catheter ablation outcomes in AF.41,42 Fibrosis detected by LGE-MRI has been demonstrated to be significantly higher in patients with a prior history of stroke, as well as with new-onset major adverse cardiovascular events including ischaemic stroke.43,44 Atrial fibrosis was also found to be elevated in patients with left atrial appendage thrombi found on transoesophageal echocardiographic evaluation.45

recurrent stroke or incident AF.47 Those with atrial fibrosis ≥12% were found to have a 4.3-fold increase in the risk of the combined outcome of recurrent stroke or new-onset AF compared to those with fibrosis <12%, after an average follow-up period of 19 months (Figure 2). The potential implications of this study may be significant in patients with ESUS, as atrial fibrosis could be a patient selection tool for oral anticoagulation for secondary prevention. In addition, atrial fibrosis may be a therapeutic target to reduce the risk of stroke and new-onset AF. The NAVIGATE-ESUS and RESPECT-ESUS clinical trials randomized patients with ESUS to aspirin or oral anticoagulation therapy with rivaroxaban and dabigatran, respectively.48,49 Both studies showed no significant benefit in oral anticoagulation when using no atrial disease-specific selection strategy.

In a post-hoc analysis of the NAVIGATE-ESUS trial, patients with an increased atrial surface area were found to benefit from OAC, indicating that people with atrial disease may benefit from such therapy.50 Selecting patients based on suspected atrial disease for anticoagulation is being studied in the ARCADIA clinical trial, where patients with evidence of left atrial enlargement on echocardiography, PTFV1 or elevated plasma NT-pro-BNP will be randomised to receive either aspirin or oral anticoagulation with apixaban.51 Other trials using elevated LGE-MRI detected atrial fibrosis for selection for oral anticoagulation are also in preparation and will be launched soon.

Conclusion

In patients without known AF, atrial fibrosis has been demonstrated to be more pronounced in ESUS patients than in age- and sex-matched controls to a degree similar to that seen in AF, suggesting that atrial fibrosis may be in the causative pathway linking AF and stroke.46 In a larger study, atrial fibrosis was found to be significantly higher in patients with ESUS than in lacunar stroke patients and control subjects and comparable to that seen in patients with known AF (Figure 1).47

Atrial fibrosis is a multifactorial phenomenon with measurable abnormalities in biomarkers and cardiac imaging. While current evidence suggests there are links between atrial fibrosis and both atrial arrhythmia and thromboembolic disease, the mechanism by which fibrosis leads to thrombus formation and predisposition to embolisation including stroke is still not completely understood. It is also plausible, since fibrosis is associated with many cardiovascular risk factors, that it may be a marker of overall cardiovascular risk including stroke.

In a prospective study, patients with ESUS underwent LGE-MRI quantification of left atrial fibrosis and were followed prospectively for

In the presence of AF, fibrosis may play an important role in creating a state of electromechanical dysfunction that leads to stasis and localised contractile

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Fibrosis in Arrhythmia and Stroke dysfunction that may form a nidus for thrombus formation.52 Fibrosis may also be implicated in the pathogenesis of a hypercoagulable state.21 In the absence of AF, electromechanical dysfunction and altered blood flow

dynamics may also be at play. Research to understand these mechanisms is under way using computational modelling of arrhythmia and blood-flow dynamics in tissue fibrosis obtained through cardiac imaging.51

Clinical Perspective

• Embolic stroke of undetermined source (ESUS) is a clinical challenge for neurologists and cardiologists as the rate of AF detection is low and the risk of recurrent stroke is high.

• Evidence suggests a link between atrial fibrosis and ESUS independent of AF, which suggests that fibrosis is on the causal pathway for thrombo-embolisation.

• Atrial fibrosis-based strategies for risk stratification and secondary prevention of ischaemic stroke are needed.

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21. Ding WY, Gupta D, Lip GYH. Atrial fibrillation and the prothrombotic state: revisiting Virchow’s triad in 2020. Heart 2020;106:1463–8. https://doi.org/10.1136/ heartjnl-2020-316977; PMID: 32675218.

22. Marín F, Roldán V, Climent V, et al. Is thrombogenesis in atrial fibrillation related to matrix metalloproteinase-1 and its inhibitor, TIMP-1? Stroke 2003;34:1181–6. https://doi. org/10.1161/01.STR.0000065431.76788.D9; PMID: 12663879.

23. Begg GA, Karim R, Oesterlein T, et al. Intra-cardiac and peripheral levels of biochemical markers of fibrosis in patients undergoing catheter ablation for atrial fibrillation.

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24. Begg GA, Karim R, Oesterlein T, et al. Left atrial voltage, circulating biomarkers of fibrosis, and atrial fibrillation ablation. A prospective cohort study. PLoS One 2018;13:e0189936. https://doi.org/10.1371/journal. pone.0189936; PMID: 29293545.

25. Begg GA, Swoboda PP, Karim R, et al. Imaging, biomarker and invasive assessment of diffuse left ventricular myocardial fibrosis in atrial fibrillation. J Cardiovasc Magn Reson 2020;22:13. https://doi.org/10.1186/s12968-0200603-y; PMID: 32036784.

26. Cushman M, Judd SE, Howard VJ, et al. N-terminal pro-Btype natriuretic peptide and stroke risk: the reasons for geographic and racial differences in stroke cohort. Stroke 2014;45:1646–50. https://doi.org/10.1161/ STROKEAHA.114.004712; PMID: 24757103.

27. Hijazi Z, Oldgren J, Andersson U, et al. Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy.

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28. Folsom AR, Nambi V, Bell EJ, et al. Troponin T, N-terminal pro-B-type natriuretic peptide, and incidence of stroke: the Atherosclerosis Risk in Communities study. Stroke 2013;44:961–7. https://doi.org/10.1161/STROKEAHA.111.000173; PMID: 23471272.

29. Llombart V, Antolin-Fontes A, Bustamante A, et al. B-type natriuretic peptides help in cardioembolic stroke diagnosis: pooled data meta-analysis. Stroke 2015;46:1187–95. https:// doi.org/10.1161/STROKEAHA.114.008311; PMID: 25765726.

30. Fonseca AC, Brito D, Pinho e Melo T, et al. N-terminal probrain natriuretic peptide shows diagnostic accuracy for detecting atrial fibrillation in cryptogenic stroke patients. Int J Stroke 2014;9:419–25. https://doi.org/10.1111/ijs.12126; PMID: 23981586.

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35. Leong DP, Joyce E, Debonnaire P, et al. Left atrial dysfunction in the pathogenesis of cryptogenic stroke: novel insights from speckle-tracking echocardiography. J Am Soc Echocardiogr 2017;30:71–9.e1. https://doi.org/10.1016/j. echo.2016.09.013; PMID: 27843104.

36. Kuppahally SS, Akoum N, Burgon NS, et al. Left atrial strain and strain rate in patients with paroxysmal and persistent atrial fibrillation: relationship to left atrial structural remodeling detected by delayed-enhancement MRI. Circ Cardiovasc Imaging 2010;3:231–9. https://doi.org/10.1161/ CIRCIMAGING.109.865683; PMID: 20133512.

37. Habibi M, Zareian M, Ambale Venkatesh B, et al. Left atrial mechanical function and incident ischemic cerebrovascular events independent of AF: insights from the MESA study.

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Clinical Arrhythmias

Is the Adenosine Test Obsolete in the Clinical Assessment of Syncope of Unknown Origin?

Melani Sotiriadou , Antonios P Antoniadis , Nikolaos Fragakis

and Vassilios Vassilikos

Third Cardiology Department, Hippokration General Hospital, Aristotle University Medical School, Thessaloniki, Greece

Abstract

Syncope is a common clinical condition affecting 50% of the general population; however, its exact pathophysiology and underlying mechanisms remain elusive. The adenosine test (ADT) has been proposed as a complementary diagnostic test in the work-up of syncope of unknown origin aiming to further elucidate the underlying pathogenetic mechanism of spontaneous syncope. Although ADT has not been endorsed by the recent European Society of Cardiology guidelines on syncope management, the use of a quick, safe and non-invasive test which can contribute to an accurate diagnosis and rationalised therapy, may deserve further consideration. This review summarises the evidence on the role of ADT in the investigation and management of syncope of unknown origin and highlights future perspectives in this area.

The authors also analyse the current challenges and research targets on adenosine plasma levels and its receptors due to the involvement of the adenosine pathway in the ADT response.

Keywords

Neurally mediated syncope, head-up tilt table test, adenosine test, adenosine, adenosine receptors, syncope of unknown origin Disclosure: The authors have no conflicts of interest to declare.

Received: 5 July 2021 Accepted: 1 October 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(4):230–4. DOI: https://doi.org/10.15420/aer.2021.39 Correspondence: Nikolaos Fragakis, Associate Professor of Cardiology, Third Cardiology Department, Hippokration General Hospital, Aristotle University Medical School, Konstantinoupoleos 49, 546 42, Thessaloniki, Greece. E: fragakis.nikos@googlemail.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.

There is a large proportion of the population who are affected by syncope, and this underscores the importance of identifying patients with syncope who are at higher risk of adverse outcomes, both for their safety and the optimal use of healthcare resources. Many algorithms have been proposed for the risk stratification of syncopal patients and for identifying patients who would benefit from a more extensive diagnostic work-up.1 In the absence of structural heart disease or cardiac rhythm disturbances, neurally mediated syncope (NMS) appears to be the most likely diagnosis.

However, in one-third of cases, even after a detailed evaluation, the aetiology and mechanisms of syncope remain elusive and it is characterised as syncope of unknown origin (SUO).2 The adenosine (AD) test (ADT) has been proposed as a useful tool in investigating the pathogenesis of SUO. By exhibiting different responses to ADT, distinct subgroups may show a differential involvement of AD and its receptors in the pathophysiology of syncope helping to decide group-targeted therapeutic strategies.1,3 This article aims to present the evidence for the use of ADT to investigate unexplained syncope and to find out whether the outcome of the test could influence therapeutic strategies. We also present existing evidence on AD plasma (ADP) levels and its receptors due to the involvement of the adenosine pathway in the ADT response. A literature search was performed to identify relevant reviews and studies in this field. We used PubMed and searched for papers including the terms ADT, SUO, NMS, AD and AD receptors. We reviewed relevant reports and their reference lists, ranging from 1990 to 2021.

The Role of Adenosine in the Pathophysiology of Syncope

AD is a purine nucleoside molecule that consists of adenine and ribose. Its endogenous precursor is a nucleoside triphosphate called adenosine triphosphate (ATP). AD acts intracellularly and extracellularly and, together with its receptors, mediates a variety of adaptive responses in the cardiovascular system in normal or pathological conditions. AD seems to increase in cases of exaggerated metabolic demand in local tissue and, more specifically, in cases of low blood flow or hypoxia.4,5 AD and ATP exert their signalling effects by binding to two purine receptors on the cell membrane, called adenosine P1 receptors and ATP or P2 receptors. P1 receptors are G-protein receptors and are further classified into A1R, A2AR, A2BR and A3R. Two subtypes of P2 receptors have been identified: P2X, which are ion channels, and P2Y which bind to G proteins.

This interaction between AD or ATP and their receptors, makes up the so-called purinergic signalling, usually found in the pathogenetic mechanism of syncope.6–8 In the conduction system, ATP and AD exert a negative chronotropic and dromotropic effect, suppressing sinus node automaticity and prolonging conduction through the atrioventricular (AV) node.5 Also, AD causes a sympathetic withdrawal that may result in syncope in susceptible individuals. Two types of receptors seem to play a crucial role in syncope, the high-affinity A1R and the low-affinity A2R. A1R are mostly located in the sinoatrial node and the AV node and are mainly responsible for

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230

Adenosine Test in Syncope of Unknown Origin Methodology and Interpretation of Adenosine Test

Table 1: Subgroup Characteristics in Adenosinemediated Syncope and Neurally Mediated Syncope Group 1: AMS

Group 2: NMS

Patients

Older, female

Younger

ADP

Low

High

A2AR

Low

High

Action via

A1R

A2AR

ADT

Positive

Negative

HUTT

Negative

Positive

Therapy

Xanthine antagonists, theophylline, pacemaker

Training, fluid intake, midodrine, fludrocortisone etc.

The test is performed with the patient in a supine position under continuous ECG monitoring. A bolus dose of 0.15 mg/kg AD in a large antecubital or femoral vein is followed by rapid administration of 20 ml saline flush. Induction of cardiac asystole of ≥6 seconds or a high degree AV block of ≥ 10 seconds, is considered abnormal and the test is characterised as positive (Figure 1).5,11,13 ADT seems to be quite safe because any side-effects, such as facial flushing, headache or chest discomfort, are transient, lasting for up to one minute. Asthmatic patients deserve special consideration to avoid exacerbating the condition. AF can be occasionally induced, while an extremely rare, bradycardia-induced polymorphic tachycardia, mostly in patients with long QT, has been reported as a dangerous proarrhythmia that can occur after ATP or AD administration.14,15

ADP = adenosine plasma levels; ADT = adenosine test; AMS = adenosine-mediated syncope; AR: adenosine receptor; HUTT = head-up tilt table test; NMS = neurally mediated syncope.

The Current Status of the Adenosine Test

bradycardia-induced syncope. A2R – and more specifically A2AR – are located in high densities in vessels and are responsible for vasodilation during syncope.3,5

ADT has never gained wide clinical acceptance because it has been challenged by studies that doubted the clinical significance of asystole or a high-degree AV block occurring during the test, as being the predominant mechanism responsible for spontaneous syncope.2 Some of these studies that used an implantable loop recorder (ILR) in syncopal patients did not confirm the expected paroxysmal AV block at the time of syncope, even in cases of a previous positive ADT with long pauses.2,16–18 Moreover, the incidence of syncopal recurrences did not show any difference between patients with positive and negative ADT.16 Even in paced syncopal patients, no correlation of syncope recurrences with ADT positivity was noted.19

Several studies have investigated the role of AD as a modulator of syncope via A1R and A2R and how ADP levels and adenosine receptors’ expression might affect the outcome of the head-up tilt table test (HUTT) and ADT.3,5 Endogenous AD is comparable to isoproterenol – the synthetic compound used in the tilt-table test – and can trigger a vasovagal response during HUTT in susceptible patients.9 Deharo et al. supported the hypothesis that different purinergic profiles could differentiate HUTT and ADT outcomes.10,11 As for ADP levels, they were higher in patients with positive HUTT and lower in cases of positive ADT. The lowest levels were observed in positive ADT and negative HUTT and highest in cases of negative ADT and positive HUTT. Both positive or both negative tests related to intermediate ADP levels.10,11

According to the above findings, it was concluded that ADT does not provide predictive value for patients with SUO or when selecting patients that would benefit from pacemaker implantation.2,16,19 Following the above evidence, the recommendation to use ADT as a routine investigation for SUO was removed from the last European Society of Cardiology (ESC) guidelines for the investigation and management of syncope.13

Like many other cell surface receptors, the number of AD receptors undergoes up- or down-regulation according to the duration of exposure to low or raised concentrations of AD, respectively. For example, an increased expression and up-regulation of A2AR has been noted in patients with a positive HUTT.12 Such an adjustment seems to play a specific and critical role in the pathogenesis and manifestation of syncope – and in the outcomes of ADT.3–5,8

Adenosine Test as a Complementary Test to Headup Tilt Table Test in Syncope Diagnostic Work-up

HUTT is frequently used as part of the diagnostic algorithm for patients with syncope. According to the latest European Society of Cardiology guidelines for syncope, it possesses a class IIa indication for diagnostic purposes.13 The test should be considered:

In light of previous studies, ADP and AD receptor levels have been used to identify patients with syncope without structural heart disease in two distinct subgroups (Table 1):

• to confirm the diagnosis of NMS in patients in whom the diagnosis has been suspected but not confirmed by initial evaluation; and

• for the assessment of autonomic failure, delayed orthostatic

• Low-adenosine syncope: syncopal patients with low baseline ADP

hypotension and postural orthostatic tachycardia syndrome.20

and a low expression of A2AR. These patients usually exhibit a negative HUTT and a positive ADT although an overlap between the two tests has also been reported. Low ADP makes these patients susceptible to a sudden increase of spontaneously released AD, leading to syncope without prodromes due to a complete AV block or sinus arrest. A stimulation of the high-affinity A1R, which are free in cases of low ADP, have been predominantly implicated.3,10,11 • High-adenosine syncope: patients with high baseline ADP and a high expression of A2AR. These patients exhibit a positive HUTT and a negative ADT. Clinically, they manifest NMS with typical prodromes.

The high levels of spontaneously released AD are unable to affect the already saturated A1R. However, the effect of AD on A2AR causes vasodilation as a result of vagal stimulation and sympathetic inhibition leading eventually to syncope.3,10,11,13

HUTT could also be helpful in discriminating syncope from psychogenic syndromes or epileptic seizures while it might also have an educational role and be used to reassure the patient.13,20 According to recent guidelines, HUTT is not necessary when the clinical presentation of syncope is typical of NMS, implying that its major diagnostic value is for those cases categorised as SUO.13 However, HUTT is of limited value in syncope without prodromes as well as in atypical syncope with uncertain or absent triggers. This is because no reproduction of spontaneous syncope can be accomplished in patients with a history of syncope without prodromes since the patient cannot recall the event.

Also, a limitation of HUTT is that the provoked syncope could be entirely different from the clinical one. Therefore, additional diagnostic testing

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Adenosine Test in Syncope of Unknown Origin Figure 1: Positive Adenosine Test with Cardiac Asystole >6 Seconds and High-degree Atrioventricular Block 25 Seconds

that could provide further information about the syncope mechanism is warranted.11,13,20 ADT could have an additional role to HUTT in the diagnostic work-up of syncope. Although data from studies have failed to prove a consistent correlation between ADT and the rhythm disturbances occurring during spontaneous syncope, ADT can shed further light on the purinergic profile of syncopal patients and the results can have therapeutic implications.2,3 ADT could be used to complement HUTT in the following cases:

• Women over 40 years with a normal heart and a short history of SUO

without prodrome symptoms and sudden spells when upright, usually leading to injury. A positive ADT in this group of patients – especially in cases where there has been a negative HUTT – may reveal an adenosine sensitivity, which has implications for syncope management in this group, suggesting, for example, DDD pacing instead of conservative therapy.21–23 • HUTT-positive patients with a strong cardio-inhibitory response. This mostly applies to patients over 40 years where pacemaker implantation could be an option. Although the best strategy in these patients is ILR implantation to confirm asystole during syncope, ADT could also play a supplementary role, especially in cases where ILR implantation is not a feasible option. A positive ADT could predict probable long pauses during spontaneous syncope, therefore supporting a decision on pacemaker implantation.16,24 Taken together, the above pieces of evidence may be interpreted as follows:

• In cases with negative HUTT and negative ADT, the aetiology of

syncope remains undetermined and monitoring and investigations should continue as required, while the diagnosis of reflex syncope cannot be excluded.

• In cases of negative HUTT and positive ADT, especially in women >40 years without prodromes, efforts should be made to document paroxysmal AV block which may then justify permanent pacing or, depending on AD levels, administration of xanthine derivatives.

• In cases of positive HUTT advocating reflex syncope with a concomitant negative ADT, treatment should be tailored according to the severity and rate of recurrence of the episodes and also

depending on the clinical phenotype (low blood pressure, prodromal symptoms, dominant cardioinhibition) and age, as per the ESC guidelines.13 • In the subgroup of cases of positive HUTT and positive ADT, especially in cases of cardioinhibitory HUTT, an ILR implantation should be sought, but permanent pacing might be considered where this is not feasible.

Therapy Guided by the Adenosine Test

A major challenge regarding the ADT is the interpretation of a positive test result. It remains unclear whether a positive ADT indicates an underlying clinically significant cardioinhibitory NMS or unveils a mostly dormant conduction system disease that may spontaneously present with syncopal or presyncopal attacks.19 Some investigators support the concept of ADT unmasking idiopathic paroxysmal AV block, while other groups suggest that ADT can identify bradycardia-related pacing indications, such as sinus node disease and conduction system disease.11,21,25,26 There are also pilot studies supporting the role of ADT to identify those patients with NMS who may benefit from pacing therapy.27 According to the ISSUE-3 study, DDD pacing is effective in cardioinhibitory syncope with ILR-documented asystole during spontaneous syncope.24 This subgroup of patients – >40 years, mostly women, experiencing syncope without prodromes or with very short-lived prodromes, normal heart and normal ECG – may be more frequently characterised by a low-adenosine profile and a positive ADT.2,3,5,21 Therefore, ADT may possess a surrogate role in identifying this specific group of patients with asystolic syncope, especially when an ILR implantation is not feasible, and serve as a supplementary, easily performed and low-cost diagnostic test that can facilitate clinical decision-making. A proposed diagnostic algorithm incorporating ADT for patients with syncope of unknown origin is presented in Figure 2.

In patients with a low-adenosine profile of syncope who are quite susceptible to exogenous AD, few studies indicate that offering adenosine receptor antagonists, such as xanthine derivatives, would help prevent syncopal recurrences.28–30 Theophylline appeared quite promising in adenosine-mediated syncope, more specifically in preventing idiopathic AV block, delaying pacemaker implantation, or acting as a bridging

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Adenosine Test in Syncope of Unknown Origin Figure 2: Proposed Diagnostic Algorithm Incorporating Adenosine Test for Patients with Syncope of Unknown Origin Syncope of unknown origin (normal ECG, echocardiogram, Holter) Recurrent Severe presentation Prodromes absent or very short Age >40 years especially women

HUTT

Negative

Positive

Cardioinhibitory (asystolic response)

Vasodepressor or mixed response

ILR not feasible

ILR feasible

ADT

Asystole

Positive

Negative

DDD pacing may be an option

Continue monitoring and investigations as required

Patient education Pharmaceutical treatment where appropriate

DDD pacing

ADT = adenosine test; DDD pacing = dual chamber pacing; HUTT = head-up tilt table test; ILR = implantable loop recorder.

therapy to pacemaker implantation, especially in patients <40 years old who do not seem to benefit from a permanent pacemaker.3,11,20 It should be noted however that in the above studies, therapy with theophylline was guided by AD levels rather than by the results of ADT. Conversely, syncopal patients with typical NMS and negative ADT, do not seem to benefit from adenosine receptor antagonists or pacemaker implantation and other strategies are proposed that mainly centre on patient education.

Pharmaceutical therapies such as fludrocortisone or midodrine would be of partial benefit, along with autonomic educational skills, such as tilt training (Table 1).3,13,20,23,31

therapies. Undoubtedly, more research and further studies in large populations might shed light on neuro-hormonal and purinergic signalling in NMS and SUO and may endorse the ADT test along with the measurement of AD and its receptors as guiding tools for more accurate diagnosis and treatment of syncope.

Conclusion

ADT has a role in the diagnostic approach to SUO. Its correlation with ADP levels and A2AR could reveal particular subgroups of patients with syncope with different characteristics that would benefit from different therapeutic strategies. This can contribute to a more personalised approach to patients with syncope and allow the introduction of targeted 1. Quinn J, McDermott D, Stiell I, et al. Prospective validation of the San Francisco Syncope Rule to predict patients with serious outcomes. Ann Emerg Med 2006;47:448–54. https:// doi.org/10.1016/j.annemergmed.2005.11.019; PMID: 16631985.

2. Cheung JW, Stein KM, Markowitz SM, et al. Significance of adenosine-induced atrioventricular block in patients with unexplained syncope. Heart Rhythm 2004;1:664–8. https:// doi.org/10.1016/j.hrthm.2004.07.021; PMID: 15851237.

3. Brignole M, Groppelli A, Brambilla R, et al. Plasma adenosine and neurally mediated syncope: ready for clinical use. Europace 2020;22:847–53. https://doi.org/10.1093/ europace/euaa070; PMID: 32449908.

Clinical Perspective

• Syncope is a complex clinical condition.

• The adenosine test (ADT) and the head-up tilt table test could be used together for the diagnosis of syncope of unknown origin (SUO).

• Adenosine plasma (ADP) levels and adenosine receptors may reveal distinct subgroups of syncopal patients.

• ADT, ADP levels and adenosine receptors could serve in the investigation and management of SUO.

4. Fenouillet E, Mottola G, Kipson N, et al. Adenosine receptor profiling reveals an association between the presence of spare receptors and cardiovascular disorders. Int J Mol Sci 2019;20:5964. https://doi.org/10.3390/ijms20235964; PMID: 31783510.

5. Fragakis N, Antoniadis AP, Saviano M, et al. The use of adenosine and adenosine triphosphate testing in the diagnosis, risk stratification and management of patients with syncope: current evidence and future perspectives. Int J Cardiol 2015;183:267–73. https://doi.org/10.1016/j. ijcard.2015.01.089; PMID: 25725201.

6. Burnstock G. Purinergic signaling in the cardiovascular system. Circ Res 2017;120:207–28. https://doi.org/10.1161/

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CIRCRESAHA.116.309726; PMID: 28057794.

7. Burnstock G, Pelleg A. Cardiac purinergic signalling in health and disease. Purinergic Signal 2015;11:1–46. https://doi. org/10.1007/s11302-014-9436-1; PMID: 25527177.

8. Sheth S, Brito R, Mukherjea D, et al. Adenosine receptors: expression, function and regulation. Int J Mol Sci 2014;15:2024–52. https://doi.org/10.3390/ijms15022024; PMID: 24477263.

9. Saadjian AY, Levy S, Franceschi F, et al. Role of endogenous adenosine as a modulator of syncope induced during tilt testing. Circulation 2002;106:569–74. https://doi. org/10.1161/01.cir.0000023924.66889.4c; PMID: 12147538.

10. Deharo JC, Mechulan A, Giorgi R, et al. Adenosine plasma

Adenosine Test in Syncope of Unknown Origin

11.

12.

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14.

15.

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level and A2A adenosine receptor expression: correlation with laboratory tests in patients with neurally mediated syncope. Heart 2012;98:855–9. https://doi.org/10.1136/ heartjnl-2011-301411; PMID: 22581734.

Deharo JC, Guieu R, Mechulan A, et al. Syncope without prodromes in patients with normal heart and normal electrocardiogram: a distinct entity. J Am Coll Cardiol 2013;62:1075–80. https://doi.org/10.1016/j.jacc.2013.05.060; PMID: 23810895.

Carrega L, Saadjian AY, Mercier L, et al. Increased expression of adenosine A2A receptors in patients with spontaneous and head-up-tilt-induced syncope. Heart Rhythm 2007;4:870–6. https://doi.org/10.1016/j. hrthm.2007.03.002; PMID: 17599669.

Brignole M, Moya A, de Lange FJ, et al. 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J 2018;39:1883–948. https://doi.org/10.1093/eurheartj/ehy037; PMID: 29562304.

Wesley RC Jr, Turnquest P. Torsades de pointe after intravenous adenosine in the presence of prolonged QT syndrome. Am Heart J 1992;123:794–6. https://doi. org/10.1016/0002-8703(92)90525-z; PMID: 1539535.

Teodorovich N, Margolin E, Kogan Y, et al. Torsades de pointes after adenosine administration. J Electrocardiol 2016;49:171–3. https://doi.org/10.1016/j. jelectrocard.2015.12.013; PMID: 26850499.

Donateo P, Brignole M, Menozzi C, et al. Mechanism of syncope in patients with positive adenosine triphosphate tests. J Am Coll Cardiol 2003;41:93–8. https://doi.org/10.1016/ s0735-1097(02)02621-9; PMID: 12570950.

Brignole M, Sutton R, Menozzi C, et al. Lack of correlation between the responses to tilt testing and adenosine triphosphate test and the mechanism of spontaneous neurally mediated syncope. Eur Heart J 2006;27:2232–9.

https://doi.org/10.1093/eurheartj/ehl164; PMID: 16864606.

18. Deharo JC, Jego C, Lanteaume A, Djiane P. An implantable loop recorder study of highly symptomatic vasovagal patients: the heart rhythm observed during a spontaneous syncope is identical to the recurrent syncope but not correlated with the head-up tilt test or adenosine triphosphate test. J Am Coll Cardiol 2006;47:587–93. https:// doi.org/10.1016/j.jacc.2005.09.043; PMID: 16458141.

19. Flammang D, Church T, Waynberger M, et al. Can adenosine 5’-triphosphate be used to select treatment in severe vasovagal syndrome? Circulation 1997;96:1201–8. https://doi. org/10.1161/01.cir.96.4.1201; PMID: 9286950.

20. Sutton R, Fedorowski A, Olshansky B, et al. Tilt testing remains a valuable asset. Eur Heart J 2021;42:1654–60. https://doi.org/10.1093/eurheartj/ehab084; PMID: 33624801.

21. Brignole M, Deharo JC, De Roy L, et al. Syncope due to idiopathic paroxysmal atrioventricular block: long-term follow-up of a distinct form of atrioventricular block. J Am Coll Cardiol 2011;58:167–73. https://doi.org/10.1016/j. jacc.2010.12.045; PMID: 21570228.

22. Brignole M, Gaggioli G, Menozzi C, et al. Adenosine-induced atrioventricular block in patients with unexplained syncope: the diagnostic value of ATP testing. Circulation 1997;96:3921–7. https://doi.org/10.1161/01.cir.96.11.3921; PMID: 9403616.

23. Blanc JJ, Le Dauphin C. Syncope associated with documented paroxysmal atrioventricular block reproduced by adenosine 5’ triphosphate injection. Europace 2014;16:923–7. https://doi.org/10.1093/europace/eut322; PMID: 24128810.

24. Brignole M, Menozzi C, Moya A, et al. Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial. Circulation 2012;125:2566–71. https://doi.org/10.1161/

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25. Fragakis N, Iliadis I, Sidopoulos E, et al. The value of adenosine test in the diagnosis of sick sinus syndrome: susceptibility of sinus and atrioventricular node to adenosine in patients with sick sinus syndrome and unexplained syncope. Europace 2007;9:559–62. https://doi. org/10.1093/europace/eum099; PMID: 17640925.

26. Parry SW, Chadwick T, Gray JC, et al. The intravenous adenosine test: a new test for the identification of bradycardia pacing indications? A pilot study in subjects with bradycardia pacing indications, vasovagal syncope and controls. Q J Med 2009;102:461–8. https://doi.org/10.1093/ qjmed/hcp048; PMID: 19468041.

27. Flammang D, Church TR, De Roy L, et al. Treatment of unexplained syncope: a multicenter, randomized trial of cardiac pacing guided by adenosine 5’-triphosphate testing.

Circulation 2012;125:31–6. https://doi.org/10.1161/ CIRCULATIONAHA.111.022855; PMID: 22086879.

28. Brignole M, Guieu R, Tomaino M, et al. Mechanism of syncope without prodromes with normal heart and normal electrocardiogram. Heart Rhythm 2017;14:234–9. https://doi. org/10.1016/j.hrthm.2016.08.046; PMID: 27639455.

29. Brignole M, Iori M, Solari D, et al. Efficacy of theophylline in patients with syncope without prodromes with normal heart and normal ECG. Int J Cardiol 2019;289:70–3. https://doi. org/10.1016/j.ijcard.2019.03.043; PMID: 30928258.

30. Brignole M, Solari D, Iori M, et al. Efficacy of theophylline in patients affected by low adenosine syncope. Heart Rhythm 2016;13:1151–4. https://doi.org/10.1016/j.hrthm.2015.12.016; PMID: 26690065.

31. Sheldon R, Raj SR, Rose MS, et al. Fludrocortisone for the prevention of vasovagal syncope: a randomized, placebocontrolled trial. J Am Coll Cardiol 2016;68:1–9. https://doi. org/10.1016/j.jacc.2016.04.030; PMID: 27364043.

Contemporary Management of Persistent AF & VT

Successful Identification of and Discrimination Between Atrial and Ventricular Arrhythmia with the Aid of Pacing and Defibrillator Devices Rahul K. Mukherjee ,1,2 Manav Sohal,1 Nesan Shanmugam,1 Simon Pearse

3

and Fadi Jouhra1

1. Department of Cardiology, St George’s University Hospital NHS Foundation Trust, London, UK; 2. Division of Imaging Sciences and Biomedical Engineering, St Thomas’ Hospital, King’s College London, UK; 3. Department of Cardiology, Kingston Hospital, London, UK

Abstract

The presence of supraventricular tachycardia is the leading cause of inappropriate shock in ICD recipients, and it can be a significant cause of morbidity, psychological distress and worsened clinical outcome. Modern pacing and ICD systems offer a number of discriminators that are integrated into algorithms to differentiate sustained ventricular tachycardia from supraventricular tachycardia. These algorithms can be adapted and optimised for each individual patient to ensure that only those arrhythmias that need treatment through the use of an ICD, are actually treated. This review summarises the single- and dual-chamber discriminators that can be used in the detection and classification of tachyarrhythmias.

Keywords

Supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, discrimination algorithm Disclosure: RKM has received research support from Medtronic and honoraria from Daiichi Sankyo. SP has received research support from Boston Scientific and MicroPort. All other authors have no conflicts of interest to declare.

Received: 15 September 2021 Accepted: 25 October 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(4):235–40. DOI: https://doi.org/10.15420/aer.2021.54 Correspondence: Rahul Mukherjee, Department of Cardiology, St George’s University Hospital NHS Foundation Trust, Blackshaw Road, London SW17 0QT, UK. E: rahul.mukherjee@nhs.net Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Supraventricular tachycardias (SVTs) other than AF are common in the general population at an estimated incidence of 73 per 100,000 and prevalence of 140 per 100,000 people.1 Meanwhile, AF is the most common cardiac arrhythmia with a lifetime risk of around one in four in the Western world.2 Ventricular tachycardia (VT) is a life-threatening cardiac arrhythmia and a major cause of sudden cardiac death, the incidence of which is estimated to range from 50 to 100 per 100,000 in the general population.3 ICDs are the mainstay of therapy for ventricular tachyarrhythmias (e.g. VT or VF) and the prevention of sudden cardiac death. However, when shocks are delivered inappropriately (i.e. for rhythm disturbances other than VT or VF) they can be associated with significant morbidity, psychological distress and worse all-cause mortality.4 Although ICD shocks may increase heart failure-related hospitalisations and potentially cause direct myocardial damage, it remains unclear whether the presence of non-lethal SVTs or VTs, which themselves may be related to worsening cardiovascular morbidity and mortality, might explain this association, in part.5 Based on historical data, over a 5-year period, up to 18% of ICD recipients may receive an inappropriate shock while 80% of inappropriate shocks are caused by SVTs such as atrial flutter, sinus tachycardia, atrial tachycardia, atrioventricular re-entrant tachycardia (AVRT), AV nodal re-entrant tachycardia (AVNRT) and AF.6 With contemporary programming of ICDs with delayed high-rate detection and the use of SVT discriminators, the rates of inappropriate shock and therapy can be reduced to around 3–4%.7

Robust discrimination of SVT from VT or VF is therefore critical for optimal functionality of an ICD. This is achieved through the use of various detection algorithms developed by device manufacturers that aim to balance sensitivity (detection of potentially life-threatening VT/VF) with specificity (avoidance of inappropriate therapy). There are also benefits in utilising the diagnostic capabilities offered by the presence of atrial intracardiac electrograms (EGMs) within implanted devices. Devicedetected sub-clinical AF or atrial high-rate episodes (AHREs) are characterised by one or more runs of rapid atrial arrhythmia detected by a device without the presence of symptoms or clinical AF detected on routine monitoring with 12-lead ECG or ambulatory monitoring. The presence of AHREs has been associated with worsening heart failure, thromboembolism and more cardiovascular-related hospitalisations.8 There are studies currently underway to evaluate whether the initiation of oral anticoagulation in patients with AHRE can reduce the risk of stroke or cardiovascular death.9,10 In this article, we review the detection algorithms used by the major device manufacturers to classify cardiac rhythm and the discriminators that are used to help reduce inappropriate therapies.

Sensing, Therapy Zones and Detection Windows

The correct classification of cardiac rhythm and application of discrimination algorithms relies on accurate sensing and detection.

Sensing refers to the determination of the timing of cardiac depolarisation signals using filters, amplitude thresholds and blanking periods. Detection refers to the interpretation of that signal by the device, which involves classification of a sequence of sensed signals to determine the nature of

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SVT Discrimination Using CV Implantable Electronic Devices Table 1: Single-chamber and Dual-chamber Discriminators of SVT and VT Discriminator

Description

Disadvantages/Difficult Rhythms

Single-chamber Discriminators Stability

Enables discrimination of AF from VT based on R–R interval regularity

AF with rapid ventricular rates (>170 BPM) Rapid atrial flutter with regular R–R intervals VT with irregular R–R intervals

Onset

Sudden changes in ventricular rate are more likely in VT while sinus tachycardia expected to have gradual rate increase

Lack of specificity

Ventricular EGM Morphology

Analysis of QRS morphology in tachycardia to a reference QRS template Presence of rate-related aberrancy with SVTs in sinus rhythm to identify VT

Dual-chamber Discriminators Comparison of atrial versus ventricular rates

If ventricular rate > atrial rate, then VT is diagnosed

Atrial under-sensing or far-field R wave over-sensing is a potential source of error

AV association

AV dissociation is typically present in VT

Rhythms with 1:1 conduction are not effectively distinguished e.g. AVRT and VT with 1:1 retrograde conduction Rapid AF with apparent AV dissociation may be confused as VT

Chamber of onset

Determines whether a tachycardia initiates in the atrium with a short P–P interval or in the ventricle with a short R–R interval

Single episode of over-sensing could lead to erroneous classification

Atrial EGM morphology

Could help distinguish atrial arrhythmias or identify retrograde conduction

Far-field R waves could affect correct atrial sensing Changes from the reference atrial EGM morphology will affect correct classification

P–R relationship

A consistent 1:1 P–R relationship may indicate SVT

VT with 1:1 retrograde conduction AVRT

AV = atrioventricular; AVRT = atrioventricular re-entry tachycardia; EGM = electrogram; SVT = supraventricular tachycardia; VT = ventricular tachycardia.

the cardiac rhythm.11 Under-sensing occurs when there is a failure to detect a depolarisation, while over-sensing occurs when signals that are not part of local myocardial depolarisation are classified as such. Blanking periods can help to prevent over-sensing (e.g. a post-ventricular atrial blanking period [PVAB] that could prevent incorrect classification of AF or atrial tachycardia). Under-sensing, particularly of ventricular depolarisation, may be important in VF, in which the EGM amplitude may be below the sensing threshold, but this is rare in practice.6 Modern algorithms for delivery of ICD therapy involve a faster rate threshold and a longer duration of monitoring prior to therapy delivery, in order to prevent inappropriate or unnecessary shocks and allow some arrhythmia episodes to self-terminate.12 Tiered therapy ICD systems may have up to four VT detection zones that allow for zone-specific duration for detection and therapies. The slower zones (e.g. monitor-only zone) are classified as VT zones, while the fastest zone is conventionally classified as the VF zone. Therapies may be delivered in the VT zone if a programmed threshold is met. Additional algorithms such as a confirmation or redetection algorithm may enable inhibition of further therapy if the episode terminates spontaneously or through application of anti-tachycardia pacing (ATP) and/or shocks.

Single-chamber Discriminators

There are three main criteria used by single-chamber ICDs to differentiate SVT from VT: stability, onset and morphology. These are summarised in Table 1. The stability (R–R interval regularity) of a tachycardia allows discrimination between VT and AF. This is particularly effective when the ventricular rate is ≤170 BPM and in the absence of anti-arrhythmic drugs.

However, at faster cycle lengths the R–R intervals in AF may be more regular, although the use of anti-arrhythmic medications could cause regular monomorphic VT to have greater cycle length variability or cause rapid polymorphic VT to slow down into a detection zone from a therapy zone.13 In a cohort of patients with both ischaemic and non-ischaemic cardiomyopathy, programming of a stability value of 30 ms resulted in a sensitivity of 82.7%

and specificity of 91.4% for the detection of slow VT (<150 BPM), but for arrhythmia episodes >190 BPM this stability value gave a sensitivity of 78.2% and a specificity of 41.0% for detection of VT.14 There are variations in how different manufacturers calculate stability (e.g. Medtronic, 40–50 ms; St Jude/Abbott, 80 ms; Boston Scientific, 24–40 ms) and the specificity for the detection of VT can vary between 77% and 88%.15 The stability discriminator is generally used in conjunction with the other discriminators described here to achieve optimal diagnostic performance.16 An example of a device EGM of sustained VT with regular R–R intervals is shown in Figure 1.

The onset criterion enables differentiation of VT from sinus tachycardia.

VT tends to initiate with a sudden onset while in sinus tachycardia the rate usually increases gradually. A potential caveat is that exercise-induced VT may be preceded by sinus tachycardia and have a gradual onset, which may lead to erroneous classification using the onset criterion. Analysis of ventricular EGM morphology has also been used to successfully discriminate between SVT and VT. The EGM source used for discrimination can be programmed to different available vectors. For example, the Wavelet morphology discrimination algorithm (Medtronic) can be programmable to one of six available vectors with the right ventricular (RV) coil–can as the nominal and RV tip–RV ring, RV tip–RV coil, superior vena cava (SVC) coil–RV coil, RV ring–can and SVC coil–can available as alternatives. A template is collected to analyse the QRS in sinus rhythm. If the ventricular rate exceeds the programmed detection cut-off, the tachycardia EGM is matched to the template. The morphological similarity of each tachycardia EGM to the sinus EGM is calculated and a resultant percentage match score derived, which is based on the differences of corresponding coefficients of their wavelet transforms.17 Using this algorithm as a single discriminator, inappropriate therapies for SVT were reduced by 78% while the sensitivity for sustained VT was 98.6%.17 The MorphMatch algorithm is used in Biotronic ICDs and is based on a beat-to-beat analysis of the QRS peak amplitude, QRS area and four major QRS deflections. QRS morphology is analysed in a 250-ms window

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SVT Discrimination Using CV Implantable Electronic Devices around the peak of the QRS in the far-field EGM and the relative difference to a reference QRS is calculated for each beat. The reference QRS is continuously updated with normal beats and the mean variability of normal beats is calculated. The mean variability with the addition of a safety margin is used to program a threshold that can be used to declare a QRS complex as abnormal if the threshold is exceeded.18

Figure 1: Device Electrograms Demonstrating an Episode of Sustained Ventricular Tachycardia 1: I AutoGain (19.6 mm/mV) 4: A Sense Amp AutoGain (10.0 mm/mV) 2: Markers 5: V Sense Amp AutoGain (0.7 mm/mV) 3: II AutoGain (3.9 mm/mV) Sweep speed: 25 mm/s Lead I

Boston Scientific ICDs use the vector and timing correlation algorithm, which compares the EGM signals of a stored reference template of normal sinus rhythm to an ongoing arrhythmia. Conduction vector analysis is performed of the far-field shock EGM and the local bipolar rate EGM, and inhibition of therapy occurs if analysis of QRS morphology at eight points in each EGM matches the QRS in sinus rhythm.19

Marker channel

Lead II

Ventricular EGM

Contemporary devices manufactured by Abbott use the Far Field MD Morphology discrimination algorithm that applies the far-field vector (e.g.

RV tip–can) and near-field vector (e.g. RV tip–RV ring) for alignment and correlation of the far-field QRS complex with the template. The template may be updated every 8 hours. A percentage match score is assigned and a nominal setting usually programmed whereby at least three out of ten QRS complexes have to match the morphology of the template by at least 90%.20 Both patient-related or algorithm-related factors can lead to inappropriate detection of VT using the morphology criterion, with under-detection reported in up to 2% of VTs.13 Algorithm-related factors that may prevent the accurate detection of VT using the morphology criterion include misalignment of the sinus template EGM with the tachycardia EGM, shockinduced EGM changes, signal clipping caused by incorrect signal filtering leading to EGM truncation, or EGM distortions caused by myopotentials.13,15 A rate-related bundle branch block during SVT is an example of a patientrelated factor that could inhibit the performance of the morphology criterion for accurate detection. Errors due to alignment or truncation issues could be prevented through programming steps including appropriate EGM source selection and gain adjustment. Morphology discrimination is also not applied during re-detection after a shock, in order to prevent misclassification.15

Dual-chamber Discriminators

The addition of an atrial lead can increase the accuracy of rhythm identification given that additional parameters can be used in detection algorithms. These are also further summarised in Table 1. Broadly speaking, comparison of atrial and ventricular rates is a powerful discriminator because VT can be diagnosed if the ventricular rate exceeds the atrial rate (Figure 2). The AV association can also be used to distinguish VT from SVT given that VT is expected to demonstrate AV dissociation.

However, this criterion does not distinguish between SVT and VT with 1:1 ventriculo-atrial (VA) conduction. In these settings, a chamber of onset criterion can be applied in which atrial tachycardia would be expected to be initiated with a short P–P interval while VT may initiate with a short R–R interval. This discriminator, however, is therefore prone to error if there is a single episode of under- or over-sensing. The single-chamber discriminators (that is, stability, onset, morphology) can also be used in conjunction, as part of the dual-chamber device detection algorithms, to ensure robust rhythm identification.21 Medtronic devices use a hierarchical, rule-based algorithm (PR LogicTM) based on atrial and ventricular rate and regularity, P–R pattern and their associations. Pairs of R–R intervals and their associated P waves are used to determine ‘couple codes’ whereby the number and timing of P waves

23 s

24 s

25 s

26 s

27 s

28 s

29 s

30 s

Device electrograms (EGMs) demonstrating an episode of sustained ventricular tachycardia (VT; regular R–R intervals) with a cycle length ~330 ms induced during non-invasive programmed stimulation. The VT cycle length is regular with a superior axis while the beat-to-beat morphology appears consistent.

Figure 2: Episode of Non-sustained Ventricular Tachycardia Atrial EGM Ventricular EGM

Integrated EGM

Marker channel

Episode of non-sustained ventricular tachycardia (VT) with ventricular rate > atrial rate recorded on device electrograms (EGMs) and spontaneous termination. The first sensed ventricular activity following termination of tachycardia is labelled with a circle.

is associated with a letter of the PR Logic alphabet. Different sequences of couple codes are associated with the various SVTs and VTs.18 When the algorithm classifies a rhythm as SVT, the device will withhold detection and therapy. Boston Scientific dual-chamber devices use the Rhythm IDTM classification algorithm, which uses the comparison of atrial and ventricular rates in addition to the vector and timing correlation algorithm described earlier.19 Biotronik uses the SMARTTM algorithm for dual-chamber detection. The first criterion is to determine whether the atrial and ventricular rate are different from each other, followed by calculation of stability on a beat-by-beat basis.

The sudden onset criterion can then be applied to discriminate VT from slow-onset sinus tachycardia. Additional parameters for the algorithm include AV trend, whereby the strict order of AV intervals to identify consistent trends towards AV shortening or AV prolongation can be used to characterise AV dissociation. AV regularity and AV multiplicity (e.g. if the mean ventricular interval is a multiple of the mean atrial interval) can help establish whether atrial flutter (with 2:1, 3:1 conduction etc.) is present.18 Abbott dual-chamber devices uses a rate branch algorithm together with other discriminators such as chamber onset, AV association, AV interval delta, stability and morphology match to classify a rhythm as SVT or VT. Rate branch compares the mean atrial and ventricular intervals to identify any differences, and if no difference is found then sinus rhythm is

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SVT Discrimination Using CV Implantable Electronic Devices Figure 3: Device Electrograms Recorded in a Patient with a Sustained Atrial Tachyarrhythmia

Single-chamber ICD patients may also require fewer follow-up procedures for complications, such as lead displacement, perforation, pneumothorax and infection. In a randomised trial using optimal programming in primary prevention patients, the routine use of an atrial lead increased procedural expense while having little impact on the frequency of inappropriate shock or quality of life at 1 year.24

Atrial EGM Ventricular EGM

Rhythm Discrimination in the Subcutaneous ICD

Integrated EGM Marker channel

Atrial EGM Ventricular EGM

Integrated EGM

Marker channel

Device electrograms (EGMs) recorded in a patient with a sustained atrial tachycardia (AT) conducted at 235 ms resulting in an apparent inappropriate shock (arrow). Large far-field ventricular signals are seen on the atrial channel (bottom trace, circled). A dual tachycardia with simultaneous AF/AT with ventricular tachycardia has not been excluded.

assumed. AV interval delta sets the maximum difference between the second longest and second shortest AV interval in the QRS complexes found during the detection period. If there is a conflict between the AV association and AV interval delta algorithms, the diagnostic criteria can be programmed to resolve the scenario (e.g. an event can be adjudicated based on either discriminator classifying VT).20 There is some evidence that the addition of an atrial lead may have longterm benefits. The Dual Chamber and Atrial Tachyarrhythmias Adverse Events Study (DATAS) randomised patients with a conventional singlechamber ICD indication to a single-chamber ICD, dual-chamber ICD or a dual-chamber ICD programmed as a single-chamber ICD. The primary endpoint was a composite of all-cause mortality, invasive intervention, cardiovascular-related hospitalisation, inappropriate shock and sustained symptomatic AT lasting >48 hours. The primary endpoint was significantly lower in the dual-chamber ICD group (OR 0.31; 95% CI [0.14–0.67]; p=0.0028). There was also a reduced mortality in the dual-chamber ICD group.22 In patients with a dual-chamber ICD, improved rhythm interpretation could be facilitated at follow-up with the presence of an atrial lead, although a proportion of patients may require atrial pacing at a later date, which would necessitate a second procedure if only a singlechamber ICD had been implanted at the index procedure.22 Propensity-score matched analysis of registry data in primary prevention ICD recipients has also suggested that dual-chamber devices have a lower rate of inappropriate shock compared with single-chamber devices.23 In that analysis, independent predictors of inappropriate shock included a history of AF, chronic kidney disease and non-ischaemic cardiomyopathy, while PR Logic was the only discriminator that was related to a lower risk of inappropriate shock along with an SVT rate limit programmed to >200 BPM.23 The routine use of an additional atrial lead, however, comes at additional expense and procedural risk. In the US, the cost of a single-chamber ICD implant is approximately US$2,000 cheaper than a dual-chamber ICD.24

The placement of an extrathoracic subcutaneous ICD (S-ICD) avoids the need to enter the heart and vasculature and can be used to provide ICD therapy in patients for whom lead-related complications may be a concern and there is no pacing indication. An S-ICD uses three sensing vectors to record EGMs, which may closely resemble the surface ECG. The lead itself has two electrodes and the can serves as an electrode to result in three sense vectors. During the initial implantation, the sense vector with the optimal signal quality is selected and programmed. Rhythm discrimination is based on analysis of morphology of the S-ICD signal. During each detection, the waveform is compared with either a stored template obtained in normal sinus rhythm (static template) or with a previously detected waveform (dynamic template). These techniques can sometimes lead to the S-ICD being vulnerable to over-sensing (e.g. T wave oversensing). The S-ICD is programmed to contain a shock zone and a conditional shock zone. The decision regarding therapy is usually based on rate alone in the shock zone while the morphology discriminators are applied in the conditional shock zone.15,25 The performance of S-ICD systems has previously been evaluated in the Subcutaneous versus Transvenous Arrhythmia Recognition Testing (START) study, in which arrhythmias were induced in patients with both S-ICDs and transvenous ICDs and the sensitivity and specificity of SVT–VT discriminators evaluated. Both ICD systems reported excellent detection of VT/VF episodes, while the S-ICD had improved specificity in the accurate classification of SVTs. This may have been due to the use of a far-field EGM source for the S-ICD, which provides greater information on global cardiac activation, as well as to the increased number of analysis points for each ventricular complex in the S-ICD (i.e. a higher resolution analysis of the signal).26 New discrimination algorithms to reduce T wave over-sensing have also been implemented to reduce inappropriate shock using a correlation of existing complexes to previous complexes.27 Recently, the multi-centre PRAETORIAN trial reported that in patients without a pacing indication, an S-ICD was non-inferior to the transvenous ICD with respect to device-related complications and inappropriate shock, with no difference in appropriate shock between the two arms.28

Challenging Arrhythmias

Tachycardias that have a stable 1:1 AV relationship (e.g. AVNRT or VT with 1:1 retrograde conduction) may be difficult to differentiate using the stability and AV association criteria. In these circumstances, the chamber of onset criterion may be able to distinguish VT from an atrial tachycardia with rapid onset. Morphology may also be used for discrimination. AVNRTs typically have a 1:1 AV relationship with almost simultaneous atrial and ventricular depolarisation, with a VA interval <70 ms. The onset may be spontaneous and triggered by a premature atrial contraction and there may be a good match to the reference QRS morphology. AVNRT is a frequent cause of inappropriate ICD therapy given that the arrhythmia often conducts rapidly (>200 BPM), falling into the programmed VT or VF zones. Atrial activation may also occur in the PVAB period, which may lead to under-sensing of the atrial EGM and lead to incorrect classification of the rhythm as VT (given that tachycardia is classified as ventricular rate > atrial rate and therefore therapy will be delivered).29

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SVT Discrimination Using CV Implantable Electronic Devices The response of the tachycardia to unsuccessful ATP can also be helpful in the differential diagnosis. An atrial tachycardia may terminate with ATP if the atrial rate is accelerated and resets the tachycardia circuit, while ventricular overdrive pacing may also terminate AVNRT. This response is not helpful in differentiation because VT may also terminate with overdrive pacing. However, if the tachycardia is entrained during ATP, the postpacing response can help elucidate the mechanism, for example, in the case of a tachycardia with a 1:1 AV relationship that has not been successfully terminated by ATP and instead the atrial rate has been accelerated. Similar to a diagnostic electrophysiology study, an A-A-V response following cessation of pacing would rule in an atrial tachycardia, while a V-V-A response would be diagnostic of VT.15 A short post-pacing interval minus tachycardia cycle length (PPI − TCL <30 ms) during ventricular overdrive pacing would also favour VT or an AVRT over AVNRT, given that this suggests that the ICD lead is in close proximity to the circuit.29,30 Occasionally, VA block may be seen during ATP, without termination of the tachycardia, which would favour VT.31 However, this response does not definitively exclude AVNRT with retrograde block.

arrhythmias despite the presence of an ICD, which may have been due to inadequate recovery of myocardial output due to the underlying cardiovascular pathology, an acute myocardial ischaemic event or the presence of electromechanical dissociation.33

Conclusion

There are a number of single-chamber and dual-chamber discriminators that can help distinguish SVT from VT and ensure that ICD therapies are applied appropriately. These discriminators are integrated into different algorithms that are used by the various device manufacturers. The performance of these discriminators is reliant on accurate atrial and ventricular sensing. In patients without a pacing indication, an S-ICD may be an option and has shown similar rates of device-related complications and inappropriate shock as a transvenous ICD, while avoiding the complications related to lead insertion and long-term lead-related complications. Despite these capabilities, the presence of SVTs remains a leading cause of inappropriate therapy in ICD recipients.

The differentiation between AF and VF is usually made using the stability, AV association and morphology criteria. However, misclassification can occur if AF is particularly rapid and there is normalisation of the R–R intervals or if aberrancy with bundle branch block is present, which may make these discriminators unreliable. Inappropriate shock for AF or atrial flutter can be associated with an increased overall risk of mortality, particularly in younger patients (Figure 3).32 Despite the use of ICDs in the primary and secondary prevention of sudden cardiac death, all-cause mortality remains high in ICD recipients over the medium to long term. In a large retrospective analysis of cause of death in >2,700 ICD recipients, congestive cardiac failure accounted for 30% of all deaths while sudden death occurred in 20% over a mean follow-up of 5.4 years.33 Based on available post-mortem interrogations, >50% of sudden deaths in this cohort occurred due to ventricular 1. Go AS, Hlatky MA, Liu TI, et al. Contemporary burden and correlates of symptomatic paroxysmal supraventricular tachycardia. J Am Heart Assoc 2018;7:e008759. https://doi. org/10.1161/JAHA.118.008759; PMID: 29982228.

2. Kornej J, Borschel CS, Benjamin EJ, Schnabel RB. Epidemiology of atrial fibrillation in the 21st century. Circ Res 2020;127:4–20. https://doi.org/10.1161/ CIRCRESAHA.120.316340; PMID: 32716709.

3. Deo R, Albert C. Epidemiology and genetics of sudden cardiac death. Circulation 2012;125:620–37. https://doi. org/10.1161/CIRCULATIONAHA.111.023838; PMID: 22294707.

4. van Rees JB, Borleffs CJW, 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.

5. Tereshchenko LG, Faddis MN, Fetics BJ, et al. Transient local injury current in right ventricular electrogram after implantable cardioverter-defibrillator shock predicts heart failure progression. J Am Coll Cardiol 2009;54:822–8. https:// doi.org/10.1016/j.jacc.2009.06.004; PMID: 19695461.

6. Daubert JP, Zareba W, Cannom DS, et al. Inappropriate implantable cardioverter-defibrillator shocks in MADIT-II: frequency, mechanisms, predictors and survival impact. J Am Coll Cardiol 2008;51:1357–65. https://doi.org/10.1016/j. jacc.2007.09.073; PMID: 18387436.

7. Cheng A, Auricchio A, Schloss EJ, et al. SVT discrimination algorithms significantly reduce the rate of inappropriate therapy in the setting of modern-day delayed high-rate detection programming. J Cardiovasc Electrophysiol 2019;30:2877–84. https://doi.org/10.1111/jce.14250; PMID: 31646695.

8. Hindricks G, Varma N, Kacet S, et al. Daily remote monitoring of implantable cardioverter-defibrillators: insights from the pooled patient-level data from three randomised controlled trials (IN-TIME, ECOST, TRUST). Eur Heart J

9.

10.

11.

12.

13.

14.

15.

Clinical Perspective

• The majority of inappropriate shocks in patients with an ICD are

caused by supraventricular tachycardias such as AF, atrial flutter, atrial tachycardia, atrioventricular (AV) re-entry tachycardia and AV nodal re-entry tachycardia (AVNRT).

• Modern pacing and defibrillator systems have a number of algorithms to enable reliable discrimination of supraventricular tachycardia from ventricular tachycardia, in order to limit therapies to those rhythms that definitively require them.

• It can be challenging to discriminate between tachycardias with a stable 1:1 AV relationship, for example ventricular tachycardia with 1:1 retrograde conduction or rapid AVNRT with a cycle length <300 ms, the latter of which may be a frequent cause for inappropriate ICD therapy.

2017;38:1749–55. https://doi.org/10.1093/eurheartj/ehx015; PMID: 29688304.

Kirchhof P, Blank BF, Calvert M, et al. Probing oral anticoagulation in patients with atrial high rate episodes: rationale and design of the non-vitamin K antagonist oral anticoagulants in patients with atrial high rate episodes (NOAH-AFNET 6) trial. Am Heart J 2017;190:12–18. https://doi. org/10.1016/j.ahj.2017.04.015; PMID: 28760205.

Lopes RD, Alings M, Connolly SJ, et al. Rationale and design of the apixaban for the reduction of thromboembolism in patients with device-detected sub-clinical atrial fibrillation (ARTESiA) trial. Am Heart J 2017;189:137–45. https://doi. org/10.1016/j.ahj.2017.04.008; PMID: 28625370.

Kossaify A. Sensing and detection functions in implantable cardioverter defibrillators: the good, the bad and the ugly.

Acta Cardiol Sin 2020;36:308–17. https://10.6515/ ACS.202007_36(4).20191201A; PMID: 32675922.

Auricchio A, Schloss EJ, Kurita T, et al. Low inappropriate shock rates in patients with single and dual/triple chamber implantable cardioverter-defibrillators using a novel suite of detection algorithms: PainFree SST trial primary results.

Heart Rhythm 2015;12:926–36. https://doi.org/10.1016/j. hrthm.2015.01.017; PMID: 25637563.

Swerdlow C. Supraventricular tachycardia–ventricular tachycardia discrimination algorithms in implantable cardioverter defibrillators: state of the art review. J Cardiovasc Electrophysiol 2001;12:606–12. https://doi. org/10.1046/j.1540-8167.2001.00606.x; PMID: 11386525.

Kettering K, Dornberger V, Lang R, et al. Enhanced detection criteria in implantable cardioverter defibrillators: sensitivity and specificity of the stability algorithm at different heart rates. Pacing Clin Electrophysiol 2001;24:1325– 33. https://doi.org/10.1046/j.1460-9592.2001.01325.x; PMID: 11584454.

Madhavan M, Friedman PA. Optimal programming of implantable cardiac-defibrillators. Circulation 2013;128:659–

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72. https://doi.org/10.1161/CIRCULATIONAHA.112.000542; PMID: 23918187.

16. Boriani G, Occhetta E, Pistis G, et al. Combined use of morphology discrimination, sudden onset and stability as discriminating algorithms in single chamber cardioverter defibrillators. Pacing Clin Electrophysiol 2002;25:1357–66. https://doi.org/10.1046/j.1460-9592.2002.01357.x; PMID: 12380773.

17. Klein GJ, Gillberg JM, Tang A, et al. Improving SVT discrimination in single-chamber ICDs: a new electrogram morphology-based algorithm. J Cardiovasc Electrophysiol 2006;17:1310–19. https://doi. org/10.1111/j.1540-8167.2006.00643.x; PMID: 17096661.

18. Bruggemann T, Dahlke D, Chebbo A, Neumann I. Tachycardia detection in modern implantable cardioverter-defibrillators.

Herzschrittmacherther Elektrophysiol 2016;27:171–85. https://doi. org/10.1007/s00399-016-0449-z; PMID: 27576695.

19. Zanker N, Schuster D, Gilkerson J, Stein K. Tachycardia detection in ICDs by Boston Scientific. Herzschrittmacherther Elektrophysiol 2016;27:186–92. https://doi.org/10.1007/ s00399-016-0454-2; PMID: 27605235.

20. Zdarek J, Israel CW. Detection and discrimination of tachycardia in ICDs manufactured by St Jude Medical.

Herzschrittmacherther Elektrophysiol 2016;27:226–39. https://doi.org/10.1007/s00399-016-0455-1; PMID: 27605236.

21. Glikson M, Swerdlow CD, Gurevitz OT, et al. Optimal combination of discriminators for differentiating ventricular from supraventricular tachycardia by dual-chamber defibrillators. J Cardiovasc Electrophysiol 2005;16:732–9. https://doi.org/10.1046/j.1540-8167.2005.40643.x; PMID: 16050831.

22. Almendral J, Arribas F, Wolpert C, et al. Dual-chamber defibrillators reduce clinically significant adverse events compared with single-chamber devices: results from the DATAS trial. Europace 2008;10:528–35. https://doi. org/10.1093/europace/eun072; PMID: 18390985.

SVT Discrimination Using CV Implantable Electronic Devices 23. Briongos-Figuero S, Sanchez A, Perez ML, et al. Singlebrand dual-chamber discriminators to prevent inappropriate shocks in patients implanted with prophylactic implantable cardioverter defibrillators: a propensity-weighted comparison of single and dual chamber devices. J Interv Card Electrophysiol 2019;54:267–75. https://doi.org/10.1007/ s10840-018-0494-0; PMID: 30523511.

24. Friedman PA, Bradley D, Koestler C, et al. A prospective randomised trial of single or dual-chamber implantable cardioverter-defibrillators to minimise inappropriate shock risk in primary sudden cardiac death prevention. Europace 2014;16:1460–68. https://doi.org/10.1093/europace/euu022; PMID: 24928948.

25. Brisben A. How the S-ICD (subcutaneous implantable cardiac defibrillator) senses cardiac signals to minimise cardiac over-sensing and maximise rhythm discrimination. J Electrocardiol 2018;51:S38–S43. https://doi.org/10.1016/j. jelectrocard.2018.08.022; PMID: 30220546.

26. 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.

27. 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.

28. Enriquez A, Ellenbogen KA, Boles U, Baranchuk A. Atrioventricular nodal re-entrant tachycardia in implantable cardioverter defibrillators: diagnosis and troubleshooting. J Cardiovasc Electrophysiol 2015;26:1282–8. https://doi. org/10.1111/jce.12772; PMID: 26249214.

29. Knops RE, Olde Nordkamp LRA, Delnoy PPHM, et al.

Subcutaneous or transvenous defibrillator therapy. N Engl J Med 2020;383:526–36. https://doi.org/10.1056/ NEJMoa1915932; PMID: 32757521.

30. Bennett MT, Leader N, Sapp J, et al. Differentiating

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ventricular from supraventricular arrhythmias using the postpacing interval after failed antitachycardia pacing. Circ Arrhythm Electrophysiol 2018;11:e005921. https://doi. org/10.1161/CIRCEP.117.005921; PMID: 29618476.

31. Arenal A, Ortiz M, Peinado R, et al. Differentiation of ventricular and supraventricular tachycardias based on the analysis of the first postpacing interval after sequential antitachycardia pacing in implantable cardioverter-defibrillator patients. Heart Rhythm 2007;4:316–22. https://doi. org/10.1016/j.hrthm.2006.10.032; PMID: 17341396.

32. Chang PM, Powell BD, Jones PW, et al. Implantable cardioverter defibrillator programming characteristics, shocked rhythms and survival among patients under thirty years of age. J Cardiovasc Electrophysiol 2016;27:1183–90. https://doi.org/10.1111/jce.13038; PMID: 27334356.

33. Nagele H, Groene E, Stierle D, Nagele MP. Analysis of causes of death in patients with implanted defibrillators. Clin Res Cardiol 2021;110:895–904. https://doi.org/10.1007/ s00392-021-01825-y; PMID: 33687520.

Cardiac Pacing

Left Bundle Branch Pacing: A Perfect Compromise?

Alexandre Raymond-Paquin ,1,2 Santosh K Padala

1

and Kenneth A Ellenbogen

1

1. Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, US; 2. Montreal Heart Institute, Department of Medicine, Université de Montréal, Quebec, Montreal, Canada

Keywords

Conduction system pacing, His bundle pacing, left bundle branch area pacing, left bundle branch pacing Disclosure: KE is a section editor on the Arrhythmia & Electrophysiology Review editorial board; this did not influence peer review. All other authors have no conflicts of interest to declare.

Received: 3 October 2021 Accepted: 13 October 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(4):241–3. DOI: https://doi.org/10.15420/aer.2021.60 Correspondence: Alexandre Raymond-Paquin, Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Gateway Building, 3rd floor, 3–216, 1200 East Marshall St, Richmond, VA, US. E: alexandre.raymond.p@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.

Pacing from the RV septum or the RV outflow tract have been explored, but results remain conflicted and no clear clinical benefit has been observed.5

Historically, pacing from the right ventricular (RV) apex has been the favoured approach to treat patients with bradyarrhythmia. RV apical pacing has generally been considered as a reliable technique that is well tolerated, safe and effective. However, this paradigm has been seriously challenged because of the detrimental consequences of long-term RV apical pacing. The need for a better pacing solution has paved the way to the quest of conduction system pacing (CSP).

Cardiac resynchronisation therapy (CRT), achieved with biventricular (BIV) pacing, has unequivocally demonstrated its superiority over RVA pacing for patients with heart failure (HF), severe LV systolic dysfunction (ejection fraction (EF) <35%) and significant intraventricular conduction delay.6 Nevertheless, despite refinement of patient selection, device and lead technology, approximately 30% of these patients do not show improvement with CRT.

RV Apical Pacing

Evidence is overwhelming regarding the deleterious physiological and clinical effects of RV apical (RVA) pacing. Pacing from the RV apex induces abnormal electrical activation and mechanical contraction of the ventricles with interventricular and intraventricular dyssynchrony.

BIV pacing is beneficial in patients with symptomatic HF, mild LV systolic dysfunction (EF<50%) and a high expected pacing burden (>40%).6 The benefit of BIV pacing in these two populations may be only a lesser evil compared to RVA pacing. BIV CRT is achieved using the fusion of two nonphysiological wavefronts between RV endocardial depolarisation (RV lead) and epicardial LV depolarisation (coronary sinus lead) to improve ventricular synchronisation. It does not re-establish normal physiology and will always remain a source of significant ventricular electromechanical dyssynchrony.

Long-term RVA pacing may result in left ventricular (LV) remodelling, micro-architectural alterations and myocardial perfusion abnormalities.

These adverse effects have been related to reduced LV function and perturbed cardiac haemodynamics.1 Clinically, RVA pacing is associated with increased risks of atrial fibrillation, pacing-induced cardiomyopathy, hospitalisation for heart failure and mortality.2,3 Importantly, these deleterious effects do not occur equally in all patients.

RVA pacing-induced cardiomyopathy can manifest in different ways over a wide clinical spectrum, from asymptomatic subclinical LV remodelling to worsening pre-existing cardiomyopathy or de novo congestive heart failure with LV dysfunction. No clear model to predict individual susceptibility has been validated.

Conduction System Pacing

CSP is the ideal approach to preserve normal ventricular electromechanical synchrony and haemodynamic physiology. Therefore, it has the potential to avoid the deleterious effects of RVA pacing.

Moreover, CSP can normalise bundle branch block (BBB). The longitudinal dissociation of the His bundle fibres theory most probably accounts for this phenomenon.7 BBB is typically in the proximal His region, and pacing distal to the site of the block results in recruitment of the conduction system. Another explanation is virtual electrode effect wherein pacing at a higher output proximal to the block may overcome the block by capturing distal conduction fibres.

Alternatives

Several alternatives have been put forward to circumvent the adverse effects of RVA pacing.

Algorithms to minimise RV pacing have been developed to promote intrinsic atrioventricular (AV) conduction. Although efficient at reducing the ventricular pacing burden, these algorithms have failed to improve clinical outcomes and, at times, can be proarrhythmic.4

CSP has been shown to provide superior CRT compared to BIV pacing.8

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Left Bundle Branch Pacing: A Perfect Compromise?

His-bundle Pacing

His-bundle pacing (HBP) is, unquestionably, the ultimate physiologic pacing approach to provide complete ventricular synchrony. Accordingly, HBP has been shown to be better at preventing pacing-induced cardiomyopathy and heart failure hospitalisations than RVA pacing.9 HBP has also been shown to reverse pacing-induced cardiomyopathy in patients with chronic RVA pacing and be beneficial for patients with CRT indications. It significantly reduces QRS duration when baseline BBB is present and improves LVEF and clinical status in patients with heart failure.10,11 However, despite decent overall success rates and favourable clinical outcomes, the initial excitement has led to significant scepticism owing to several inherent limitations. The His bundle is a small, cylindrical structure with significant anatomical variations relative to the triangle of Koch and the septal tricuspid leaflet.12 Therefore, HBP requires a longer learning curve and success rates vary according to the experience of the centre. The overall success rate is approximately 85% but decreases significantly in the presence of advanced AV conduction disease.13,14 The low R wave amplitude may result in atrial or His oversensing and ventricular undersensing.

Long-term success is also undermined by several factors. As the His bundle is encased by the central fibrous body, higher pacing output is required in 25–30% of cases at follow-up.

The high capture threshold, either at implantation or during follow-up, is unpredictable and of major concern. First, it can cause loss of His bundle capture, resulting in myocardial septal pacing in 9–17% of patients. Second, unacceptably high thresholds lead to an increased number of lead revisions in up to 11% of patients. Finally, when a lead revision is not deemed necessary, the higher output required can lead to premature battery depletion and increased frequency of generator change procedures.15,16

Left Bundle Branch Area Pacing

Left bundle branch area pacing (LBBAP) has emerged as an enticing solution to the limitations of HBP. This is largely explained by favourable anatomical and histological characteristics.

The left bundle branch (LBB) is surrounded by dense myocardial tissue and offers a larger target zone for pacing owing to its thick, band-like structure. Moreover, the LBB can be recruited from the main trunk, the posterior fascicle or the septal fascicle.12 Therefore, LBBAP is technically easier with a relatively shorter learning curve.

Enlarged right cavities and interventricular septum fibrosis are two technical hurdles occasionally encountered during implantation.

Procedural success rates are high, even in the presence of intraventricular conduction disease.17–20 LBBAP provides stable and reliable lead parameters with longer battery life at short and intermediate follow-up.17,18 The need for a back-up RV lead is abolished, and device programming is simplified.21 Importantly, complication rates remain low with LBBAP. Increased threshold at followup is unusual and lead revision is hardly ever necessary.

Septal perforation rarely occurs but remains a concern. It is usually observed intraoperatively and is not associated with major adverse events when the lead is appropriately repositioned.17,18 Long-term followup on lead performance and issues related to transvenous lead extraction are questions that remain to be answered in the future.

Pacing from the LBB does not result in complete right bundle branch block but rather in right bundle branch conduction delay with a relatively narrow QRS, suggesting mild interventricular dyssynchrony. Limited studies suggest that inter-ventricular dyssynchrony might have fewer deleterious effects than intraventricular dyssynchrony.22,23 Therefore, whether RV activation delay during LBBAP is of clinical importance remains to be determined and will require further study.

Of note, bipolar pacing with anodal capture of the RV septum might be a potential avenue to attenuate interventricular synchrony. Adequate AV delay programming allowing fusion with native right bundle branch conduction is another option.

LBBAP preserves intraventricular LV mechanical synchrony comparable to that from HBP or native conduction.24,25 In patients with heart failure and LBBB, LBBAP improves intra- and interventricular synchrony and is associated with a similar QRS duration reduction and LVEF improvement to HBP.26–27 LBBAP is promising as a future alternative to standard BIV CRT. It achieves CRT with high success rates, significant QRS duration reduction, LVEF increase and clinical status improvement.20 LBB pacing (LBBP) is defined as capturing the LBB either selectively or non-selectively (with LV septal capture). LV septal pacing (LVSP) occurs when only septal myocardium is captured without engaging the LBB. LBBAP encompasses both entities. LVSP activates both ventricles with delay, resulting in relative interventricular synchrony; it does not provide intraventricular synchrony, however.28 Criteria defining LBBP have been described, although differentiating nonselective LBBP from LV septal pacing can be challenging at times.29 We believe that effort should be made to ensure LBB capture when physiological CSP is sought. New criteria have been published recently and should help to refine our definition of LBBP.30

Have We Reached a Perfect Compromise?

HBP has been described more than 20 years ago, yet the quest for ideal CSP remains unachieved. Although appealing, HBP comes with numerous problems that are probably irreconcilable. Without significant change, HBP is condemned to remain limited to a handful of highly experienced implanters and centres.

As evidenced by the astonishing number of publications over the past years, LBBAP has gained significant interest and our knowledge is rapidly evolving. It is now established that LBBAP is feasible, effective, safe and provides reliable long-term lead parameters. Moreover, descriptive studies suggest advantageous surrogate and clinical outcomes.17,18,20 LBBAP has the ‘disadvantage’ of selectively engaging the LBB and delaying RV activation. This concession might in fact be the best thing that could have happened to CSP. By pacing downstream in the conduction system, away from the anatomically and histologically hostile His bundle region, LBBAP circumvents HBP’s greatest limitations. The price to pay seems reasonable. LBBAP-induced RV activation delay appears to be marginal, especially with adequate device programming. We acknowledge that the clinical impact of this remains to be clarified, although no deleterious signal has been identified so far. This ‘disadvantage’ is at the heart of LBBAP’s success, and we believe it might be the key to finally consolidate CSP into routine clinical practice, making LBBAP a perfect compromise.

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Left Bundle Branch Pacing: A Perfect Compromise?

1. Tops LF, Schalij MJ, Bax JJ. The effects of right ventricular apical pacing on ventricular function and dyssynchrony implications for therapy. J Am Coll Cardiol 2009;54:764–76. https://doi.org/10.1016/j.jacc.2009.06.006; PMID: 19695453.

2. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003;107:2932–7. https://doi. org/10.1161/01.CIR.0000072769.17295.B1; PMID: 12782566.

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

4. Shurrab M, Healey JS, Haj-Yahia S, et al. Reduction in unnecessary ventricular pacing fails to affect hard clinical outcomes in patients with preserved left ventricular function: a meta-analysis. Europace 2017;19:282–8. https:// doi.org/10.1093/europace/euw221; PMID: 28175255.

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

6. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/ AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019;74:e51– 156. https://doi.org/10.1016/j.hrthm.2018.10.037; PMID: 30412778.

7. Upadhyay GA, Cherian T, Shatz DY, et al. Intracardiac delineation of septal conduction in left bundle-branch block patterns. Circulation 2019;139:1876–88. https://doi.org/10.1161/ CIRCULATIONAHA.118.038648; PMID: 30704273.

8. 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.

9. Abdelrahman M, Subzposh FA, Beer D, et al. Clinical outcomes of His bundle pacing compared to right ventricular pacing. J Am Coll Cardiol 2018;71:2319–30. https:// doi.org/10.1016/j.jacc.2018.02.048; PMID: 29535066.

10. Huang W, Su L, Wu S, et al. Long-term outcomes of His

bundle pacing in patients with heart failure with left bundle branch block. Heart 2019;105:137–43. https://doi.org/10.1136/ heartjnl-2018-313415; PMID: 30093543.

11. Sharma PS, Dandamudi G, Herweg B, et al. Permanent Hisbundle pacing as an alternative to biventricular pacing for cardiac resynchronization therapy: a multicenter experience.

Heart Rhythm 2018;15:413–20. https://doi.org/10.1016/j. hrthm.2017.10.014; PMID: 29031929.

12. Padala SK, Cabrera JA, Ellenbogen KA. Anatomy of the cardiac conduction system. Pacing Clin Electrophysiol 2021;44:15–25. https://doi.org/10.1111/pace.14107; PMID: 33118629.

13. Vijayaraman P, Naperkowski A, Ellenbogen KA, Dandamudi G. Electrophysiologic insights into site of atrioventricular block: lessons from permanent his bundle pacing. JACC Clin Electrophysiol 2015;1:571–81. https://doi.org/10.1016/j. jacep.2015.09.012; PMID: 29759411.

14. Zanon F, Ellenbogen KA, Dandamudi G, et al. Permanent His-bundle pacing: a systematic literature review and metaanalysis. Europace 2018;20:1819–26. https://doi.org/10.1093/ europace/euy058; PMID: 29701822.

15. 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.

16. Zanon F, Abdelrahman M, Marcantoni L, et al. Long term performance and safety of His bundle pacing: a multicenter experience. J Cardiovasc Electrophysiol 2019;30:1594–601. https://doi.org/10.1111/jce.14063; PMID: 31310410.

17. Padala SK, Master VM, Terricabras M, et al. Initial experience, safety, and feasibility of left bundle branch area pacing: a multicenter prospective study. JACC Clin Electrophysiol 2020;6:1773–82. https://doi.org/10.1016/j. jacep.2020.07.004; PMID: 33357573.

18. 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.

19. Jiang Z, Chang Q, Wu Y, et al. Typical BBB morphology and implantation depth of 3830 electrode predict QRS correction by left bundle branch area pacing. Pacing Clin Electrophysiol 2020;43:110–7. https://doi.org/10.1111/ pace.13849; PMID: 31773756.

20. Vijayaraman P, Ponnusamy S, Cano O, et al. Left bundle branch area pacing for cardiac resynchronization therapy: results from the international LBBAP collaborative study group. JACC Clin Electrophysiol 2021;7:135–47. https://doi.

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org/10.1016/j.jacep.2020.08.015; PMID: 33602393.

21. Bakelants E, Burri H. Troubleshooting programming of conduction system pacing. Arrhythm Electrophysiol Rev 2021;10:85–90. https://doi.org/10.15420/aer.2021.16; PMID: 34401180.

22. Bader H, Garrigue S, Lafitte S, et al. Intra-left ventricular electromechanical asynchrony. A new independent predictor of severe cardiac events in heart failure patients.

J Am Coll Cardiol 2004;43:248–56. https://doi.org/10.1016/j. jacc.2003.08.038; PMID: 14736445.

23. Fauchier L, Marie O, Casset-Senon D, et al. Interventricular and intraventricular dyssynchrony in idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2002;40:2022–30. https:// doi.org/10.1016/S0735-1097(02)02569-X; PMID: 12475464.

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

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

26. Zhang W, Huang J, Qi Y, et al. Cardiac resynchronization therapy by left bundle branch area pacing in patients with heart failure and left bundle branch block. Heart Rhythm 2019;16:1783–90. https://doi.org/10.1016/j. hrthm.2019.09.006; PMID: 31513945.

27. Wu S, Su L, Vijayaraman P, et al. Left bundle branch pacing for cardiac resynchronization therapy: nonrandomized on-treatment comparison with his bundle pacing and biventricular pacing. Can J Cardiol 2021;37:319–28. https:// doi.org/10.1016/j.cjca.2020.04.037; PMID: 32387225.

28. Curila K, Jurak P, Jastrzebski M, et al. Left bundle branch pacing compared to left ventricular septal myocardial pacing increases interventricular dyssynchrony but accelerates left ventricular lateral wall depolarization. Heart Rhythm 2021;18:1281–9. https://doi.org/10.1016/j. hrthm.2021.04.025; PMID: 33930549.

29. 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.

30. Jastrzebski M, Burri H, Kielbasa G, et al. The V6-V1 interpeak interval: a novel criterion for the diagnosis of left bundle branch capture. Europace 2021. https://doi. org/10.1093/europace/euab164; PMID: 34255038; epub ahead of press.

Cardiac Pacing

Cardiac Pacing in Cardioinhibitory Reflex Syncope: Clinical Use of Closed-loop Stimulation Marco Tomaino,1 Vincenzo Russo ,2 Daniele Giacopelli ,3 Alessio Gargaro

3

and Michele Brignole

4,5

1. Ospedale Generale Regionale, Bolzano, Italy; 2. Department of Cardiology, University of Campania ‘Luigi Vanvitelli’, Ospedale Monaldi, Naples, Italy; 3. Research Clinical Unit, Biotronik Italy, Vimodrone, Italy; 4. IRCCS Istituto Auxologico Italiano, Faint and Fall Programme, Ospedale San Luca, Milano, Italy; 5. Arrhythmology Centre and Syncope Unit, Department of Cardiology, Ospedali del Tigullio, Lavagna, Italy

Abstract

Cardiac pacing has been studied extensively in patients with reflex syncope over the past two decades. The heterogeneity of the forms and clinical manifestations of reflex syncope explain the controversial results of older randomised clinical trials. New evidence from recent trials has changed medical practice, now leading to clear indications for pacing in patients with asystolic syncope documented during carotid sinus massage, implantable cardiac monitoring or tilt testing. Given that recent trials in reflex syncope have been performed using the closed-loop stimulation algorithm, the authors will briefly discuss this pacing mode, review hypotheses about the mechanisms underlying its activation during syncope and provide practical instructions for programming and troubleshooting.

Keywords

Reflex syncope, cardiac pacing, head-up tilt test, cardioinhibitory syncope, vasodepressor syncope, closed-loop stimulation, BIOSync CLS study Disclosure: The authors have no conflicts of interest to declare.

Acknowledgement: MT and VR contributed equally.

Received: 31 July 2021 Accepted: 5 October 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(4):244–9. DOI: https://doi.org/10.15420/aer.2021.45 Correspondence: Michele Brignole, IRCCS Istituto Auxologico Italiano, Ospedale San Luca, Piazzale Brescia 20, 20149 Milano, Italy. E: mbrignole@outlook.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.

The role of cardiac pacing in patients with reflex syncope has been discussed controversially in the last two decades.1–3 Recent multicentre randomised clinical trials, however, have demonstrated the benefit of dual-chamber pacing, leading the European Society of Cardiology (ESC) to provide strong recommendations on patient selection and the diagnostic pathway in their 2021 guidelines on cardiac pacing, to obtain the maximum benefit from pacing in such a benign but disabling condition.4–7 Today, the role of cardiac pacing is finally established and can change medical practice significantly.

There is a growing interest among electrophysiologists in dual-chamber pacing using the closed-loop stimulation (CLS) algorithm.8–10 Although a few small, controlled studies and retrospective analyses suggested a benefit of CLS in reflex syncope compared with conventional dualchamber pacing, the real effect of CLS on reflex syncope has not yet been fully confirmed, and a large randomised trial is needed to demonstrate any added benefit of CLS over conventional dual-chamber pacing and other syncope algorithms.11,12 The aim of this article is to review the most recent literature, to describe the CLS algorithm, to report plausible evidence-based hypotheses of CLS activation during reflex syncope, and to provide practical advice on the use and programming of the CLS algorithm based on our experience.

Pacing in Reflex Syncope: Which Patients?

Reflex syncope is a very common condition, associated with parasympathetic hyperactivity elicited by central, orthostatic, somatic, and visceral triggers. In most cases clinical presentation is characterised by clear triggers and prodromes. In rarer cases, triggers are uncertain and prodromes are fleeting or completely absent (atypical forms).13 The underlying physiological mechanism basically involves two components: vasodilation and cardioinhibition. Vasodilation generally occurs in all reflex syncope and is complicated by cardioinhibition in some.14,15 Concomitant vasodilation, even in patents with cardioinhibitory forms, still represents a controversial point.

According to the current 2018 ESC guidelines for the diagnosis and management of syncope, the therapeutic approach to reflex syncope should be mainly driven by the patient’s age and the severity of syncope episodes.13 Patients who may benefit most from cardiac pacing are ≥40 years old, have severe clinical presentation of reflex syncope, and show ECG evidence of cardioinhibition during carotid sinus massage, head-up tilt test (HUTT), or implantable cardiac monitoring (ICM). The 2021 ESC guidelines on cardiac pacing have now ranked these conditions as a class I indication for cardiac pacing with level of evidence A.7 The age cutoff of 40 years is related to the inclusion criteria of previous randomised trials. Severe reflex syncope forms are characterised by significant impairment of quality of life, traumas due to syncope episodes, and

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Cardiac Pacing in Reflex Syncope high‑risk professional life because of recurrent or unpredictable episodes with no or very short prodromes.

In this highly selected patient group, cardiac pacing plays an important role in improving quality of life, reducing syncope burden, and/or prolonging prodromes, which may be important for improvement of symptom management. It is worth underlining that pacemaker therapy will not completely eliminate recurrence of syncope in the long term due to a possible accompanying vasodilation.

Evidence from Randomised Clinical Trials

In 2012, the ISSUE-3 trial first showed the efficacy of dual-chamber pacing with the rate drop response function versus no pacing in reducing syncope recurrences in ≥40-year-old patients with severe asystolic reflex syncope documented on ICM (≥3-second syncope or ≥6-second asymptomatic pauses).4 The rate drop response function operates on top of a dual-chamber mode, initiating high-frequency pacing (110–120 BPM) for a programmable time interval, in response to sudden drops in spontaneous heart rate. The absolute and relative syncope risk reductions were 32% and 64%, respectively.

Nevertheless, 25% of patients in the pacing group had a recurrence after 2 years.

In 2015, these results were corroborated by the SUP-2 study, an Italian prospective multicentre observational study investigating the role of dual-chamber pacing with the rate drop response feature in patients affected by severe, unpredictable reflex syncope.16 Following a standardised diagnostic algorithm, ≥40-year-old patients who had an asystolic event documented on carotid sinus massage, HUTT or ICM (in this specific order) underwent pacemaker implantation, while the others continued long-term ICM. The 137 patients with a pacemaker had a significantly lower actuarial syncope recurrence rate at 3 years (20%) than 142 patients without pacemaker (43%), regardless of the index diagnostic test. In agreement with previous data, cardiac pacing reduced syncope burden and improved quality of life. However, transient loss of consciousness was not totally abolished due to concomitant vasodilation. Interestingly, in the subgroup of 81 patients who underwent HUTT and eventually received pacemaker based on any index diagnostic test, the probability of syncope recurrence was only 5% after a negative HUTT and 24% after a positive HUTT (asystolic or non-asystolic). A similarly low rate after negative HUTT had also been observed in the ISSUE-3 sub-study.17 These findings shed light on the role of the HUTT in the diagnosis of reflex syncope: if an asystole is documented on long-term heart rate monitoring, a negative response to HUTT is predictive of a pure cardioinhibitory component at the origin of reflex syncope. Conversely, a positive response to HUTT cannot exclude vasodilation, regardless of whether symptoms elicited by the test are associated with an asystole.

Therefore, the last piece of missing information was whether a positive cardioinhibitory response to HUTT is sufficient to select patients who may benefit from cardiac pacing (before starting long-term heart rate monitoring). This was the objective of the recently concluded multicentre randomised placebo-controlled BIOSync CLS trial.6 This patient- and outcome assessor-blind trial verified the efficacy of dual-chamber pacing with CLS in ≥40-year-old patients with ≥2 syncope episodes in the past year, selected based on an asystolic positive response to HUTT. The CLS function was previously tested in reflex syncope with promising results and was therefore selected as the pacing mode in BIOSync CLS.11,12,18 The study had a sequential design with early stopping rules

and was based on a rigorous methodology to ensure the blinded adjudication of study endpoints. The 127 enrolled patients underwent pacemaker implantation and were subsequently randomised to dualchamber pacing mode with CLS (Pacing ON group; n=63) or no pacing with only sensing functions (Pacing OFF group; n=64). The primary endpoint was the time to first post-randomisation syncope. The study was terminated early at the second planned interim analysis due to superiority in the Pacing ON group. The estimated syncope recurrence rate was 19% (Pacing ON) versus 53% (Pacing OFF) at 1 year, and 22% (Pacing ON) versus 68% (Pacing OFF) at 2 years. Dual-chamber pacing with CLS was therefore associated with a 77% reduction in syncope recurrence rate in patients selected for asystolic positive response to HUTT. Of note, almost seven of every ten patients in the Pacing OFF group had at least one recurrence in 2 years. The findings of the BIOSync CLS trial support the inclusion of HUTT as a useful method to select candidates for cardiac pacing. According to a large consortium of experts, accumulated evidence is now sufficient to confirm the central role of the HUTT in the diagnostic route of reflex syncope.19

Mechanisms of Closed-loop Stimulation in Reflex Syncope

The CLS algorithm measures intracardiac impedance curves of the right ventricle during the systolic phase of each cardiac cycle by injecting subthreshold high-frequency unipolar current pulses from the ventricular lead tip.8,9 Given that the density of electric field lines is greatest around the electrode tip, most of the induced voltage drop at each subthreshold pulse and, in turn, the main contribution to impedance, occurs in an approximately 5 cm3 volume (≈1 cm radius) surrounding the electrode, which includes a varying amount of blood and myocardial tissue.

Therefore, local changes in the small volume surrounding the electrode (rather than changes in the entire intraventricular volume) are the main drivers of impedance variations. During contraction, blood ejection causes tighter electrode contact with myocardial tissue (involving a larger proportion of tissue relative to blood volume), leading to a progressive impedance increase towards late systole.

Although the operating principle of CLS is sufficiently clear in chronotropic incompetence, the CLS activation during a reflex syncope remains a matter of investigation. Until detailed physiological studies become available, it is possible only to speculate on the results of the studies presented here.

Figure 1 illustrates a possible activation scheme. When reading the scheme from right to left, pacing rate is increased by CLS activation, which is triggered by a detected variation of the shape of rising impedance curves during systole. Changes in right ventricular impedance are strictly correlated to right ventricular dP/dtmax, which is a surrogate of right ventricular contraction speed.10 Contraction speed in turn is influenced by two factors:

• Heart rate: high heart rate causes an intrinsic increase of conduction

speed per se, which is reflected by an increase in intracardiac impedance. This is a physiological phenomenon known as positive force–frequency relationship (FFR). Up to 40% of cardiac output is regulated through the positive FFR principle under normal conditions.20 FFR is influenced by β-adrenergic regulation, which operates during exercise, and other conditions affecting the speed of myocardial contraction. In fact, CLS has been shown to react to active standing, handgrip, cold pressor test, mental stress and dobutamine infusion.9,10,21–23

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Cardiac Pacing in Reflex Syncope Figure 1: Heart Rate Regulation Mechanism Triggers Emotional β-adrenergic

Elevated heart rate (FFR)

Contraction speed

RV systolic impedance

CLS sensor

Elevated pacing rate

Myocardial contractility

Physical

Shows factors triggering CLS and pacing rate adaptation. CLS = closed-loop stimulation; FFR = force–frequency relationship; RV = right ventricular.

Table 1: Head-up Tilt Tests Performed in the BIOSync CLS Study6 Age (Years)

Sex

CLS Pacing Onset

SBP at Pacing Onset (mmHg)

Max. Intrinsic Heart Rate Before Pacing (BPM)

Pacing Rate at Onset (BPM)

Lowest SBP (mmHg)

Response to HUTT

47

F

Yes

80

100

100

80

Negative

68

M

Yes

105

100

100

105

Negative

63

F

Yes

110

n.a.

n.a.

110

Negative

43

M

Yes

126

96

88

69

Presyncope

58

F

Yes

85

120

100

40

Syncope

69

M

Yes

100

79

75

80

Syncope

61

M

Yes

80

107

94

50

Syncope

83

F

Yes

70

120

120

70

Syncope

71

M

Yes

80

91

91

60

Syncope

74

F

Yes

130

n.a.

n.a.

70

Syncope

48

M

Yes

113

n.a.

n.a.

26

Syncope

56

F

Yes

160

n.a.

n.a.

77

Syncope

67

F

Yes

85

n.a.

n.a.

53

Syncope

45

F

Yes

144

n.a.

n.a.

67

Syncope

40

M

No

–

–

–

48

Syncope

57

F

No

–

–

–

95

Negative

61

M

No

–

–

–

115

Negative

CLS = closed-loop stimulation; HUTT = head-up tilt test; n.a. = not available; SBP = blood pressure.

• Myocardial contractility: at given preload and afterload conditions,

contraction speed also correlates with myocardial contractility, which is regulated by the Frank–Starling mechanism and by humoral and neural sympathetic innervation. Left ventricular myocardial contractility and sympathetic cardiac tone of the autonomic nervous system indirectly affect contraction speed and intracardiac impedance measured by the CLS algorithm at the right ventricle.

In patients with chronotropic incompetence, cardiac output is mainly regulated via increased myocardial contractility in response to physical triggers (this regulating factor clearly prevails). But it is not completely clear what initiates CLS pacing in patients with impending reflex syncope.

We speculate that a heart rate increase and the related positive FFR is dominant in the early (pre-syncope) phase of the reflex (phase 2 of the vasovagal reaction), when the progressive increase in heart rate counteracts vasodilation and pressure drop, starting on average 8 minutes

before loss of consciousness, as observed during orthostatic stresses.14,15 Heart rate increases as a consequence of baroreceptor activation and neuroendocrine response to counteract vasodilation.13–15 Contractility is unlikely to come into play at this stage, given that stroke volume has been shown to initially decrease, and the Frank–Starling principle cannot be invoked.14 It is therefore likely that vasodilation ultimately triggers early onset of CLS pacing, as proposed by Sutton et al.3 This hypothesis needs to be confirmed in a future study that would compare stroke volume trends during phase 2 with and without CLS. Also, impedance curves detected by the device would greatly add to the understanding and possible optimisation of CLS.

Closed-loop Stimulation During Tilt-induced Reflex Syncope

The aforementioned speculations are supported by acute HUTT studies.

In a cross-over study, CLS was able to increase pacing rate starting from

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Cardiac Pacing in Reflex Syncope Figure 2: Continuous Recording of Heart Rate and Blood Pressure During a Head-up Tilt Test

120 HR (BPM)

80

Trend 30 min

CLS pacing ON 120

BP (mmHg) 60

III (mV)

ECG

CLS pacing ON

100 BPM

(mV)

Event 30 s

BP non-corrected (mmHg) 160 BP

120 80 40 0

CLS pacing emerged at ~100 BPM, when intrinsic heart rate reached the peak and the vasovagal reaction began. BP = blood pressure; CLS = closed-loop stimulation; HR = heart rate.

8 minutes before syncope and to avoid the heart rate drop that precedes syncope by maintaining a constant heart rate at approximately 90 BPM.24 Consequently, the onset of syncope was significantly delayed by 4 minutes and the blood pressure drop was reduced by 22 mmHg. Overall, syncope was induced in 30% of patients in dual-chamber pacing with CLS as compared with 77% in dual-chamber pacing without CLS. The objective is to avoid vagally induced bradycardia. Given that stroke volume and heart rate contribute similarly to the determination of blood pressure at the time of impending syncope, a heart rate increase achieved early through CLS (during phase 2 before syncope) could sustain cardiac output even when the blood pressure begins to fall due to the vasodilation reflex.14 In the BIOSync CLS trial, 17 patients repeated the HUTT after CLS activation (Table 1).6 In 14 of the 17 patients, there was a pacing response. At the time of pacing onset, systolic blood pressure was 105 ± 27 mmHg. Continuous heart rate monitoring data during the test were available in eight patients.

At the beginning of phase 2 (cardioinhibitory), the intrinsic heart rate was 102 ± 14 BPM (range, 79–120 BPM) and then decreased progressively. CLS pacing began when the intrinsic heart rate fell to 96 ± 13 BPM. These cases show that CLS pacing is appropriately activated during an orthostatic stress-

induced vasovagal response, confirming the study rationale and data from Palmisano et al.24 According to the protocol, the patients remained in an upright position until syncope occurred (n=11) or until the test was completed (n=3). The number of positive responses should not be misleading here, because HUTT is well known to be an unreliable test for demonstrating the effectiveness of pacing therapy in a clinical setting.25,26 Figure 2 shows a case of activation of CLS pacing in a patient with reflex syncope during HUTT. The heart rate increased spontaneously to sustain cardiac output despite the falling blood pressure (phase 2). At the zenith of the heart rate trend, when blood pressure has approximately reached its nadir, CLS pacing emerged at approximately 100 BPM, first as atrial pacing only and then as sequential atrial and ventricular pacing.

Device Programming and Troubleshooting

Due to a lack of evidence for what happens in timing and evolution of a syncope attack, it is not possible to make conclusive recommendations for CLS programming. In Table 2 we report the details of the CLS programming used in the BIOSync CLS study, which was shown to be effective in preventing many, but not all, syncope recurrences.6 Therefore, further individual optimisation may be necessary.

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Cardiac Pacing in Reflex Syncope Basic and maximum CLS pacing rates are the main parameters that define the maximum range of pacing rate modulation. Basic and maximum rates of 50 and 120 BPM, respectively, should meet most needs, even beyond reflex syncope, although personalisation may occasionally be required.

The parameter ‘CLS response’ regulates the amplitude of the CLS reaction to detected changes in the impedance curves: a higher response leads to a faster increase in pacing rate and vice versa.

Table 2: Recommended Programming of Closedloop Stimulation in Cardioinhibitory Reflex Syncope Programmable parameter

Value

Mode

DDD-CLS

Basic rate day/night

50 BPM/OFF

Maximum CLS rate

120 BPM

In the BIOSync CLS study, the setting ‘medium’ did not require any adjustments. The parameter ‘CLS resting rate control’ limits the pacing rate increase when no physical activity is detected by an accelerometer sensor. Due to the special application in reflex syncope and the considerations described here, this limiter was disabled during the study. Although this setting was expected to increase the probability of patient-reported palpitations caused by inappropriately high pacing rates, this adverse event was reported only by one of 63 patients and was resolved by reducing the maximum CLS rate from 120 to 100 BPM. Reducing the CLS response from medium to lower levels would have been an equally valid option to test. Conversely, an increase of the CLS response to a higher level may be worth considering in the case of syncope recurrence.

CLS response

Medium

CLS resting rate control

OFF

Atrioventricular delay

Low; 180–140 ms

Atrioventricular hysteresis mode

IRSplus

Atrial overdrive pacing

OFF

PMT protection

ON

High atrial rate limit

200 BPM

Finally, the remaining, non-CLS-specific parameters listed in Table 2 are included to describe study settings and may be optimised on an individual basis.

High ventricular rate limit

180 BPM

High ventricular rate counter

8 events

Case Report from the BIOSync CLS Trial

A 48-year-old woman with a smoking habit and no other cardiovascular risk factors was referred to an investigational site for recurrent, unpredictable transient loss of consciousness associated with sweating and dizziness.6 Episodes were not responsive to initial nonpharmacological treatments, including education, lifestyle modification, and psychological counselling. ECG was normal; orthostatic hypotension test and carotid sinus massage were negative. Also, transthoracic echocardiography showed normal ejection fraction and mild mitral regurgitation. HUTT was performed according to the Italian protocol with continuous ECG monitoring and beat-to-beat blood pressure measurements.27 Baseline blood pressure and heart rate were 115/75 mmHg and 80 BPM, respectively. After the 20-minute drug-free passive orthostatic phase, 300 µg sublingual nitroglycerin was given when blood pressure was 125/70 mmHg, and heart rate was 92 BPM. Three minutes later, the patient started complaining of sweating, dizziness, and blurred vision. Blood pressure was 100/60 mmHg and heart rate was 120 BPM. Syncope followed shortly thereafter. A 10-second complete asystole without ventricular escape beats was documented.

The HUTT was interrupted, and the patient completely recovered consciousness in a few seconds.

Because of the burden of reported unpredictable syncope episodes and because asystole was the dominant feature of the HUTT-induced syncope, the patient was eligible for enrolment in the BIOSync CLS trial. At 1-year follow-up after pacemaker implantation, the patient did not experience new syncope episodes; the device interrogation showed atrial and ventricular pacing percentages of 40% and 1%, respectively (Figure 3).

The atrial pacing rate observed in this case is consistent with the average value in the active group of the BioSync study: comparison of long-term heart rate profiles showed that the CLS algorithm modulated the pacing rates over a wide frequency range, reproducing a heart rate distribution similar in each rate bin to the distribution seen in the control group, despite the average overall pacing rate of 43%.28

IEGM recordings High atrial rate

AT

High ventricular rate

ON

Patient triggering

OFF

Rates for statistics

AT = atrial tachyarrhythmia; CLS = closed-loop stimulation; DDD = dual-chamber sensing and pacing; IEGM = intracardiac electrogram; IRS = intrinsic rhythm support (a specific function favouring intrinsic atrioventricular contraction); PMT = pacemaker-mediated tachycardia. Source: Brignole et al.6

Figure 3: Heart Rate Sensed/Paced Atrial and Ventricular Events 40% 20%

0% <40

130

230

>380 BPM

60% 40% 0%

40% 1%

As–Vs As–Vp Ap–Vs Ap–Vp As

0% PVC

1% Ap

Vp

Ap

Pacemaker-reported long-term distribution of heart rate sensed/paced atrial and ventricular events in a patient with positive cardioinhibitory response to head-up tilt test, enrolled in the BIOSync CLS trial and randomised to the active-pacing study group. Ap = atrial paced event; As = atrial sensed event; PVC = premature ventricular contraction; Vp = ventricular paced event; Vs = ventricular sensed event.

Clinical Implications

According to the 2021 ESC guidelines on cardiac pacing, dual-chamber pacemaker therapy is now a class I indication with level of evidence A, in patients with severe, unpredictable, recurrent syncope and an asystole either documented on ICM or induced by carotid sinus massage or HUTT.7 By comparison, in the previous guidelines (2013) cardiac pacing in asystolic HUTT was recommended only with the weakest level of evidence (class IIb).13 The significant increase in the recommendation class was triggered by the latest evidence from the Closed Loop

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Cardiac Pacing in Reflex Syncope Stimulation for Neuromediated Syncope (SPAIN) and the BIOSync CLS trials.5,6 Both trials compared dual-chamber CLS pacing with sham or disabled pacing. Therefore, the reported benefit of pacemaker therapy is related to the specific pacing mode used in these trials. However, it is not possible to separate the contribution of CLS to the prevention of syncope until the mechanisms of action are clarified and the outcomes

are confirmed by a direct comparison of CLS with standard dualchamber pacing.

Finally, the evidence provided by the BIOSync CLS trial has confirmed the role of the HUTT as an essential step in the decision-making process for pacing in reflex syncope.6

Clinical Perspective

• Recent randomised trials have assessed the benefit of dual-chamber pacing in patients older than 40 years with reflex syncope and asystolic syncope induced by tilt testing.

• Among the available pacing algorithms, the design of closed-loop stimulation is likely to activate pacing early at an adequate rate before a

drop in blood pressure, as has been observed during tilt testing. Whether early activation is reproduced in spontaneous clinical episodes is not proven, but it is supported by the positive results from the BIOSync CLS trial.

• Closed-loop stimulation programmability enables a consistent troubleshooting approach. A limited number of patients may still experience syncope recurrence despite pacing. These patients need to be investigated more closely to assess whether relapses should be ascribed to dominant vasodilation or if the pacing mode needs to be optimised.

1. Brignole M, Tomaino M, Gargaro A. Vasovagal syncope with asystole: the role of cardiac pacing. Clin Auton Res 2017;27:245–51. https://doi.org/10.1007/s10286-017-0441-7; PMID: 28669088.

2. de Jong JSY, Jardine DL, Lenders JWM, Wieling W. Pacing in vasovagal syncope: a physiological paradox? Heart Rhythm 2020;17:813–20. https://doi.org/10.1016/j.hrthm.2019.09.022; PMID: 31561028.

3. Sutton R, de Jong JSY, Stewart JM, et al. Pacing in vasovagal syncope: physiology, pacemaker sensors, and recent clinical trials – precise patient selection and measurable benefit. Heart Rhythm 2020;17:821–8. https://doi. org/10.1016/j.hrthm.2020.01.029; PMID: 32036025.

4. Brignole M, Menozzi C, Moya A, et al. Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial. Circulation 2012;125:2566–71. https://doi.org/10.1161/ CIRCULATIONAHA.111.082313; PMID: 22565936.

5. Baron-Esquivias G, Morillo CA, Moya-Mitjans, et al. Dualchamber pacing with closed loop stimulation in recurrent reflex vasovagal syncope: the SPAIN study. J Am Coll Cardiol 2017;70:1720–8. https://doi.org/10.1016/j.jacc.2017.08.026; PMID: 28958328.

6. Brignole M, Russo V, Arabia F, et al. Cardiac pacing in severe recurrent reflex syncope and tilt-induced asystole.

Eur Heart J 2021;42:508–16. https://doi.org/10.1093/eurheartj/ ehaa936; PMID: 33279955.

7. Glikson M, Nielsen JC, Kronborg MB, et al. 2021 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: developed by the Task Force on Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology (ESC) with the special contribution of the European Heart Rhythm Association (EHRA). Eur Heart J 2021;42:3427–520. https://doi.org/10.1093/eurheartj/ ehab364; PMID: 34455430.

8. Schaldach M, Hutten H. Intracardiac impedance to determine sympathetic activity in rate responsive pacing.

Pacing Clin Electrophysiol 1992;15:1778–86. https://doi. org/10.1111/j.1540-8159.1992.tb02968.x; PMID: 1279547.

9. Schaldach M, Ebner E, Hutten H, et al. Right ventricular conductance to establish closed-loop pacing. Eur Heart J 1992;13(Suppl E):104–12. https://doi.org/10.1093/eurheartj/13. suppl_e.104; PMID: 1478202.

10. Osswald S, Cron T, Grädel C, et al. Closed-loop stimulation using intracardiac impedance as a sensor principle: correlation of right ventricular dP/dtmax and intracardiac impedance during dobutamine stress test. Pacing Clin Electrophysiol 2000;23:1502–8. https://doi. org/10.1046/j.1460-9592.2000.01502.x; PMID: 11060870.

11. Palmisano P, Zaccaria M, Luzzi G, et al. Closed-loop cardiac pacing vs. conventional dual-chamber pacing with specialized sensing and pacing algorithms for syncope prevention in patients with refractory vasovagal syncope: results of a long-term follow-up. Europace 2012;14:1038– 43. https://doi.org/10.1093/europace/eur419; PMID: 22247273.

12. Russo V, Rago A, Papa AA, et al. The effect of dual-chamber closed-loop stimulation on syncope recurrence in healthy patients with tilt-induced vasovagal cardioinhibitory syncope: a prospective, randomised, single-blind, crossover study. Heart 2013;99:1609–13. https://doi.org/10.1136/ heartjnl-2013-303878; PMID: 23723446.

13. Brignole M, Moya A, de Lange FJ, et al. 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J 2018;39:1883–948. https://doi.org/10.1093/eurheartj/ehy037; PMID: 29562304.

14. van Dijk JG, Ghariq M, Kerkhof FI, et al. Novel methods for quantification of vasodepression and cardioinhibition during tilt-induced vasovagal syncope. Circ Res 2020;127:126–38. https://doi.org/10.1161/CIRCRESAHA.120.316662; PMID: 32460687.

15. Jardine DL, Wieling W, Brignole M, et al. The pathophysiology of the vasovagal response. Heart Rhythm 2018;15:921–9. https://doi.org/10.1016/j.hrthm.2017.12.013; PMID: 29246828.

16. Brignole M, Arabia F, Ammirati F, et al. Standardized algorithm for cardiac pacing in older patients affected by severe unpredictable reflex syncope: 3-year insights from the Syncope Unit Project 2 (SUP-2) study. Europace 2016;18:1427–33. https://doi.org/10.1093/europace/euv343; PMID: 26612880.

17. Brignole M, Donateo P, Tomaino M, et al. Benefit of pacemaker therapy in patients with presumed neurally mediated syncope and documented asystole is greater when tilt test is negative: an analysis from the Third International Study on Syncope of Uncertain Etiology (ISSUE-3). Circ Arrhythm Electrophysiol 2014;7:10–6. https://doi. org/10.1161/CIRCEP.113.001103; PMID: 24336948.

18. Russo V, Rago A, De Rosa M, et al. Does cardiac pacing reduce syncopal recurrences in cardioinhibitory vasovagal syncope patients selected with head-up tilt test? Analysis of a 5-year follow-up database. Int J Cardiol 2018;270:149–53. https://doi.org/10.1016/j.ijcard.2018.06.063; PMID: 29980368.

19. Sutton R, Fedorowski A, Olshansky B, et al. Tilt testing remains a valuable asset. Eur Heart J 2021;42:1654– 60. https://doi.org/10.1093/eurheartj/ehab084; PMID: 33624801.

20. Bondke H, Borges AC, Petersen S, et al. Non-invasive

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assessment of myocardial contractility from force-frequency relationship in patients with implanted pacemakers: first results. Europace 2010;12:968–71. https://doi.org/10.1093/ europace/euq096; PMID: 20382968.

21. Binggeli C, Duru F, Corti R, et al. Autonomic nervous systemcontrolled cardiac pacing: a comparison between intracardiac impedance signal and muscle sympathetic nerve activity. Pacing Clin Electrophysiol 2000;23:1632–7. https://doi.org/10.1046/j.1460-9592.2000.01632.x; PMID: 11138300.

22. Santini M, Ricci R, Pignalberi C, et al. Effect of autonomic stressors on rate control in pacemakers using ventricular impedance signal. Pacing Clin Electrophysiol 2004;27:24–32. https://doi.org/10.1111/j.1540-8159.2004.00381.x; PMID: 14720151.

23. Proietti R, Manzoni G, Di Biase L, et al. Closed loop stimulation is effective in improving heart rate and blood pressure response to mental stress: report of a singlechamber pacemaker study in patients with chronotropic incompetent atrial fibrillation. Pacing Clin Electrophysiol 2012;35:990–8. https://doi.org/10.1111/j.1540-8159.2012.

03445.x; PMID: 22680238.

24. Palmisano P, Dell’Era G, Russo V, et al. Effects of closedloop stimulation vs. DDD pacing on haemodynamic variations and occurrence of syncope induced by head-up tilt test in older patients with refractory cardioinhibitory vasovagal syncope: the Tilt test-Induced REsponse in Closed-loop Stimulation multicentre, prospective, single blind, randomized study. Europace 2018;20:859–66. https:// doi.org/10.1093/europace/eux015; PMID: 28407148.

25. Sra JS, Jazayeri MR, Avitall B, et al. Comparison of cardiac pacing with drug therapy in the treatment of neurocardiogenic (vasovagal) syncope with bradycardia or asystole. N Engl J Med 1993;328:1085–90. https://doi. org/10.1056/NEJM199304153281504; PMID: 8455666.

26. Petersen ME, Price D, Williams T, et al. Short AV interval VDD pacing does not prevent tilt induced vasovagal syncope in patients with cardioinhibitory vasovagal syndrome. Pacing Clin Electrophysiol 1994;17:882–91. https:// doi.org/10.1111/j.1540-8159.1994.tb01429.x; PMID: 7517523.

27. Bartoletti A, Alboni P, Ammirati F, et al. ‘The Italian Protocol’: a simplified head-up tilt testing potentiated with oral nitroglycerin to assess patients with unexplained syncope.

Europace 2000;2:339–42. https://doi.org/10.1053/ eupc.2000.0125; PMID: 11194602.

28. Russo V, Anguera I, de Lange FJ, et al. Heart rate distribution in paced and non-paced patients with severe recurrent reflex syncope and tilt-induced asystole: findings from the BIOSync CLS study. Int J Cardiol 2021;335:52–4. https://doi.org/10.1016/j.ijcard.2021.04.032; PMID: 33887343.

Cardiac Pacing

Electro-energetics of Biventricular, Septal and Conduction System Pacing Frits W Prinzen ,1 Joost Lumens ,2 Jürgen Duchenn

3

and Kevin Vernooy

4,5

1. Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands; 2. Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands; 3. Department of Cardiovascular Sciences, KU Leuven, Belgium; 4. Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center+ (MUMC+), the Netherlands; 5. Department of Cardiology, Radboud University Medical Centre (Radboudumc), Nijmegen, the Netherlands

Abstract

Abnormal electrical activation of the ventricles creates abnormalities in cardiac mechanics. Local contraction patterns, as reflected by strain, are not only out of phase, but also show opposing length changes in early and late activated regions. Consequently, the efficiency of cardiac pump function (the amount of stroke work generated by a unit of oxygen consumed), is approximately 30% lower in dyssynchronous than in synchronous hearts. Maintaining good cardiac efficiency appears important for long-term outcomes. Biventricular, left ventricular septal, His bundle and left bundle branch pacing may minimise the amount of pacing-induced dyssynchrony and efficiency loss when compared to conventional right ventricular pacing. An extensive animal study indicates maintenance of mechanical synchrony and efficiency during left ventricular septal pacing and data from a few clinical studies support the idea that this is also the case for left bundle branch pacing and His bundle pacing. This review discusses electro-mechanics and mechano-energetics under the various paced conditions and provides suggestions for future research.

Keywords

Myocardial work, efficiency, biventricular pacing, septal pacing, conduction system pacing Disclosure: FWP has research grants from Medtronic, Abbott, MicroPort CRM and Biotronik. KV has research grants from Medtronic, Abbott and Biotronik, and a consultancy agreement with Medtronic. JL has received research grants from Medtronic. JD has no conflicts of interest to declare.

Received: 10 June 2021 Accepted: 27 October 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(4):250–7. DOI: https://doi.org/10.15420/aer.2021.30 Correspondence: Frits W Prinzen, Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands. E: frits.prinzen@maastrichtuniversity.nl Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Over the last few decades there has been increasing interest in local and global cardiac electro-mechanics. This is largely because of the recognition of the adverse effects of conventional right ventricular pacing (RVP) and beneficial effects of cardiac resynchronisation therapy (CRT) and novel pacing modalities, such as left bundle branch pacing (LBBP), His bundle pacing (HBP) and left ventricular septal (LVSP).1–5 While CRT is usually considered to consist of biventricular pacing (BiVP), it was already known in the 1970s that HBP could normalise the QRS complex of left bundle branch block (LBBB) patients.6 Such an effect can only be understood if the conduction block in LBBB is proximal, which was demonstrated elegantly by Upadhyay et al.7 More recently, LBBP was introduced as an easier way to capture the left bundle branch in LBBB patients,8 while LVSP (septal pacing without capturing the conduction system) also appeared to also provide excellent cardiac pump function.9,10 For proper understanding of the effect of ventricular dyssynchrony and its prevention or correction by a pacing therapy, insights into cardiac mechanics and energetics are imperative. After all, mechanical coordination between all muscle fibres determines total pump function as well as the amount of energy required for the contraction. Fortunately, information on cardiac mechanics is rapidly increasing because of the development of dedicated non-invasive imaging techniques for assessment of regional myocardial deformation (strain). Also, modern

modalities like PET allow us to obtain information on regional myocardial metabolism. While in many studies the sole emphasis is on improving pump function, it may also be important to pay attention to the metabolic economy of the heart. After all, clinical studies have shown the potentially harmful effects of longer-lasting increases in myocardial energy expenditure through inotropic drug therapy.11 In this review we will address cardiac electro-mechanics and mechanoenergetics during dyssynchronous and (re)synchronised activation. For this purpose, we review information from studies in animal experimental models and patients.

Electro-mechanical Coupling and Myocardial Efficiency

The sequence of electrical activation in the normal heart – as well as in the paced heart – is elaborated on in a related article in this volume.12 Like in any muscle, contraction of cardiac muscle cells is evoked by an action potential. The action potential triggers calcium influx that subsequently initiates calcium-induced calcium release. The time between the upslope of the action potential and binding of calcium to the myofibrils is approximately 30 ms. On a global basis this delay can be observed as the delay between the R wave of the ECG and the onset of left ventricular (LV) pressure rise. Because of this excitation–contraction coupling, it is not

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Electro-energetics of Biventricular, Septal and Conduction System Pacing Figure 1: Electrical Activation and Contraction in Left Bundle Branch Block and Biventricular Pacing LBBB

BiVP 120 ms

100

80

60

40

20 0

A

MVC 5

AVO

AVC

B

MVO

5

MVC AVO

AVC

0

0

–5

18

18

16

16 –5

14

14

12 10 –10

12 10

11.75 –10

8 4 SYSTOLE

2 0

15.1

8

6 –15

MVO

6 4

3.25

–15

1.25

SYSTOLE

2 0

0.6 1.05

Upper panels: 3D representation of ventricular electrical activation in a canine heart with LBBB before (left) and during BiVP (right). Lower panels: strain patterns from a patient with LBBB before (left) and during BiVP (right). Thick tracings are septal strain; thin tracings are left ventricular free wall strain. Contribution of each of the following strains to total shortening is depicted in the coloured bars.

On the basis of the slope of the deformation curve systolic deformation at each wall is divided into shortening (systolic total shortening; red), stretching preceded by shortening (SRS; blue), or early stretching not preceded by shortening (SPS; green). Systolic stretch index is calculated as SRS + SPS. AVC = aortic valve closure; AVO = aortic valve opening; BiVP = biventricular pacing; LBBB = left bundle branch block; MVC = mitral valve closure; MVO = mitral valve opening; SPS = systolic pre-stretch; SRS = systolic rebound stretch. Source: Upper panel: Strik et al. 2013.55 Adapted with permission from Wolters Kluwer. Lower panel: De Boeck et al. 2009.33 Adapted with permission from John Wiley & Sons.

referred to as systolic rebound stretch (SRS; blue in Figure 1).16–18 An index combining SRS and SPS is the systolic stretch index (SSI) where SSI = SRS + SPS).

surprising that dyssynchronous electrical activation also leads to dyssynchronous contraction. In various studies in normal canine hearts, the onset of segment shortening proved to be closely related to the timing of electrical activation.13–15 Accordingly, regions with earliest electrical activation (red in left upper panel of Figure 1) also start to contract first (thick tracing in lower left panel of Figure 1).

The functional meaning of these strain differences can be better appreciated when plotting strain as a function of pressure or stress. The area of the pressure-strain or stress-strain loops reflects external mechanical work of a particular segment. Figure 2 (right panel) shows that pressure-strain loops have a figure-of-eight shape in the early-activated septum of a LBBB heart and are enlarged in the late-activated lateral wall.

In cases where significant septal rebound stretch is seen, loops in earlyactivated regions run in a clockwise direction, indicating that work is being performed on that segment rather than that it generates work.

Russell et al. have called this behaviour ‘wasted work’.19 During considerable dyssynchrony, such as during RVP and LBBB, external work is close to zero, and often even negative in early activated regions and double the normal values in late activated regions.18,20

However, this figure also depicts that shortening patterns are not just shifted in time, but also have a completely different morphology, indicating discoordination of contraction. These complicated regional differences in contraction pattern are most likely related to the local differences in myocardial fibre length during the early systolic phase, i.e. regional differences in effective preload. The discoordination is characterised by early systolic shortening in early-activated regions and coincident systolic pre-stretch (SPS; green in Figure 1) in late-activated regions. Later in systole, late-activated regions show pronounced shortening, while early-activated regions may be even stretched,

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Electro-energetics of Biventricular, Septal and Conduction System Pacing Figure 2. Calculation of Regional Pressure-work Loops

Non-invasive LVP (mmHg)

LVP (mmHg)

Septum

150

150 100 50

5

100 Clockwise loop ~ negative work!

50

0 −10

Lateral wall

−5

Non-invasive LVP (mmHg)

Strain (%)

5

Lateral wall

150 −5 Septum −10

−15

0 Strain (%)

0

100 Supra-normal work!

50

0

SYSTOLE

−20

−15

−10

−5

0

5

Strain (%) Synchronisation of the left ventricular pressure curve (upper left) and septum and lateral wall strain curves (lower left) of the LBBB patient presented in Figure 1 and pressure-strain loops constructed from such data (right panels). LBBB = left bundle branch block; LVP = left ventricular pressure. Source: Left panel: De Boeck et al. 2009.33 Adapted with permission from John Wiley & Sons. Right panel: Russell et al. 2012.2 Adapted with permission from Oxford University Press.

While originally myocardial pressure-strain loops required invasive LV pressure measurements, Russell et al. developed a non-invasive method to assess LV pressure.21 It was shown that peak systolic arterial pressure (measured using the arm-cuff method) in combination with timing of opening and closure of the cardiac valves (using echoDoppler), provided a reliable systolic part of the LV pressure curve that can be used to plot strain against and thus non-invasively determine regional myocardial work.

On the other hand, Duchenne et al. modified the invasive technique so that actual stress-strain loops could be determined. To this end, they used the dynamic curvature and thickness of the local wall segment and applied the LaPlace law.22 In later studies, the authors used non-invasive LV pressure data to construct stress-strain loops without the need for intra-arterial access.23 With this approach, stress-strain loops can also be safely determined in a clinical setting. An interesting observation by these authors is that by using the stress-strain approach they showed in an animal model of ventricular dyssynchrony that the distribution of local work became inhomogeneous acutely after inducing dyssynchrony, but almost normalised after 8 weeks of dyssynchrony. This relative normalisation of local mechanical work was mirrored by normalisation of the distribution of glucose uptake, measured using fluorodeoxyglucosePET scan. In contrast, pressure-strain loops demonstrated less homogenisation in work, and a weaker correlation to glucose uptake.22 Because stress-strain loops correct LV pressure for the effect of the asymmetric remodelling and curvature induced by dyssynchrony – whereas pressure-strain loops do not – it is likely that they better represent the true work performed by the myocardium. Indeed, the septum of a remodelled, dyssynchronous LV is typically thin, and as a result, experiences relatively higher wall stress. In contrast, the typically

thickened lateral wall thereby experiences relatively lower wall stress.

The effect of the regional wall stress on the calculation of myocardial work is demonstrated in Figure 3.

Because local myocardial perfusion adapts itself to the oxygen demand (autoregulation), it is not surprising that during dyssynchronous activation myocardial blood flow, oxygen consumption and glucose uptake also differ between regions.16,17,24–28 Compared with sinus rhythm, myocardial blood flow and oxygen consumption are 30% lower in early-activated regions and 30% higher in late-activated regions.16,17,20,26 Furthermore, compared to a LV with normal conduction, dyssynchronous hearts show on average significantly higher glucose consumption for the same amount of performed regional myocardial work, supporting the notion that dyssynchrony leads to less efficient work.22 The discoordination in contraction also impacts overall myocardial efficiency, the amount of oxygen needed for a unit output of the cardiac pump. In anaesthetised open-chest and conscious dogs RV apex pacing decreased mechanical output, whereas myocardial oxygen consumption was unchanged or even increased compared to atrial pacing.29,30 Consequently, efficiency decreased by 20–30% in these studies.

A similar number has been reported by Mills et al., who determined mechanical energy using potential energy and stroke work from pressure volume relations and oxygen consumption by direct measurements.31 These investigators found that while in the normal heartbeat ~22% of all oxygen consumed is used for pump action, during RVP this amount drops to ~14%, so a ~30% reduction in efficiency (Figure 3). The figure also depicts that this reduction in efficiency by RV apex pacing is almost completely abrogated when applying LVSP (see below).31

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Electro-energetics of Biventricular, Septal and Conduction System Pacing Figure 3. Conceptual and Practical Difference between Pressure–Strain and Stress–Strain Analysis Stress–strain loop analysis

140

80 60

Lateral

40

Stress (mmHg)

100

−5 −10 −15

20 0

160

0

120 Strain (%)

Stress (mmHg)

5

Septum

140

0

0.2

0.4

0.6

−20

0.8

Stress–strain loop area (mmHg × %)

160

120 100 80 60 40 20

0

0.2

Time (s)

0.4

0.6

0 −20 −15

0.8

Time (s)

−10

−5

0

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900 800 700 600 500 400 300 200 100 0

Septum

Lateral

Septum

Lateral

Strain (%)

Pressure–strain loop analysis

100 80

LV

60 40 20 0

0.2

0.4 Time (s)

0.6

0.8

0.04 0.03 0.02 0.01 0

0

0.2

0.4

0.6

160 140 120 100 80 60 40 20 0

0.8

Time (s)

Pressure–strain loop area (mmHg × %)

0.05

120

0

Pressure (mmHg) strain (%)

0.06

140 Curvature (mm−1)

Pressure (mmHg) strain (%)

160

−20 −15

−10

−5

0

5

900 800 700 600 500 400 300 200 100 0

Strain (%)

Stress–strain and pressure–strain loop analysis of an animal model of ventricular dyssynchrony. Note the higher stress for the septal wall (red), and lower stress for the lateral wall (blue), compared to the left ventricular pressure trace (green), which assumes uniform wall stress (first column). Source: Mills et al. 2009.31 Reproduced with permission from Wolters Kluwer.

Electro-mechanics During Biventricular Pacing

With the main messages of the previous paragraph in mind we now discuss to what extent BiVP, LVSP and conduction system pacing prevent or reverse dyssynchronous activation, depending on whether pacing is performed in a heart with narrow or wide QRS complex, respectively.

Because BiVP has been performed for more than two decades, it is not surprising that considerably more information is available on this pacing mode than on LVSP, HBP or LBBP. The primary application of BiVP is CRT and there is extensive literature on the change in strain patterns in hearts after starting biventricular pacing.

When looking at gross level (difference between septum and LV lateral wall), BiVP clearly creates a more uniform strain pattern compared to RVP or LBBB (Figure 1, right panels). This has been demonstrated in animals (Duchenne using speckle tracking and Vernooy using MRI tagging) and in humans.20,22,32 DeBoeck et al. demonstrated that BiVP does not change the total amount of systolic deformation, but that it redistributes shortening from the LV lateral wall to the septum and decreases systolic stretch (mainly SRS in the septum, right panel Figure 1).33 These investigators also demonstrated that SRS was a more sensitive marker of the mechanical substrate for CRT response than the time interval between peak shortening in the various segments.33,34 More recent studies corroborated these findings by showing that the sum of postero-lateral systolic prestretch and septal rebound stretch, called SSI, is strongly associated with clinical outcome after CRT.35,36 Because SRS is tightly related to negative or very low external work, it is not surprising that also the normalisation of myocardial work distribution after CRT is related to the benefit of CRT.23 A prospective randomised trial was performed in 200 patients to evaluate the clinical usefulness of

myocardial work to select patients who benefit from CRT.37 The investigators showed that the difference between myocardial work performed by septum and LV lateral wall at baseline predicted CRT response (defined as LV end-systolic volume reduction >15% after 6 months) with an area under the curve (AUC) of 0.77 (95% CI [0.70–0.84]).

The predictive value was further increased by adding information on septal scar as obtained by magnetic resonance late enhancement in a subpopulation of patients (AUC 0.88; 95% CI [0.81–0.95]). Importantly, predictive value was as good in patients with QRS duration 120–150 as in the entire cohort. Equally important was the observation that work difference alone and combined with septal viability predicted long-term survival without heart transplantation with HR of 0.36 (95% CI [0.18–0.74]) and 0.21 (95% CI [0.072–0.61]), respectively.

What may make SRS, SSI and myocardial work good predictive measures is that they all are dependent on the contralateral septum-lateral wall interaction. Importantly, this mechanical behaviour of contralateral stretching and shortening is not only indicative for an electrical activation delay, it also strongly indicates good contractile function of the myocardium. Therefore, large SRS, SSI and septum-lateral wall work difference are all indicative of the combination of gross electrical septumlateral wall dyssynchrony and good overall myocardial viability and contractile function.

Because abnormal systolic strains in dyssynchronous hearts are closely related to local energetics (see above), it is reconfirming that upon resynchronisation the distribution of blood flow, oxygen consumption and glucose uptake, as studied by PET, becomes more uniform.24,27,38,39 The finding that this recovery of blood flow occurs within 2 weeks after onset of CRT and disappears within 15 min after stopping CRT, indicates

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Electro-energetics of Biventricular, Septal and Conduction System Pacing that the perfusion inhomogeneities in the LBBB hearts importantly relate to the abnormal distribution of workload (for example evidenced by the inhomogeneities in strain between septum and later wall).24,39 In addition, Knaapen et al. demonstrated that CRT also increases septal blood flow during adenosine infusion.39 This increase in septal flow was immediately abrogated upon stopping CRT, suggesting that CRT alleviates impediment of perfusion by the abnormal contraction pattern.39 Furthermore, an increase in hyperaemic flow was found to be associated with a decrease in eccentricity of LV hypertrophy, an index of wall stress.

The more uniform distribution of cardiac contraction during CRT also leads to a higher efficiency of the entire LV chamber. Nelson et al. showed that resynchronisation increases the maximum rate of rise of LV pressure while myocardial oxygen consumption even slightly decreased.

In these patients a similar increase in the rate of rise of LV pressure, evoked by dobutamine infusion, significantly increased myocardial oxygen consumption.40 Kyriacou et al. showed that BiVP at optimal atrioventricular-delay increases both LV external work and oxygen consumption, but the increase in cardiac work was ~80% greater than the increase in oxygen consumption, signifying an improvement in cardiac mechano-energetics.41 Therefore, restoration of coordination of contraction by CRT improves cardiac function through a mechanism different from that by inotropic stimulation. The observation that CRT improves ventricular efficiency is important for two reasons. First of all, there is evidence that, in general, failing hearts have a reduced ratio between work performed and oxygen consumed (mechanical efficiency).42 Also, these hearts often have compromised energy metabolism, as evidenced by a reduced ratio of phosphocreatine to total adenosine triphosphate.43 So, any relief of the compromised energy metabolism can be expected to have a relevant benefit.

Very few therapies in heart failure improve cardiac efficiency. While inotropic drugs increase myocardial oxygen consumption in parallel with contractility, vasodilators decrease both parameters. The effect of phosphodiesterase III inhibitors depends on the vasodilative and inotropic effects as well.44

What is Known About Left Ventricular Septal, His Bundle and Left Bundle Branch Pacing ?

Until now there are no patient studies comparing the strain patterns or electro-mechanics during BiVP, LVSP, HBP and LBBP. The most detailed information on this topic has been obtained in animal studies on LVSP in comparison with normal conduction and RVP.31 In this study, MRI tagging was used to determine strain patterns. While during RVP circumferential strain, external work and blood flow were significantly lower in the septum and elevated in the LV free wall, such differences were not observed during LVSP and during normal conduction (Figure 4). These differences coincided with lower values of internal stretch fraction (a measure of mechanical discoordination) and peak shortening delay. Both at 1 hour and 16 weeks of pacing, myocardial efficiency (ratio of external work and oxygen consumption) was 30–40% decreased during RVP compared to normal conduction, whereas there was no decrease in efficiency during LVSP (Figure 5). Moreover, at the end of the 16-week experimental protocol, myocardial efficiency was compared between RVP, BiVP LVSP in the acute setting. Here efficiency was significantly higher during LVSP than during RVP, whereas there was no significant difference between LVSP and BiVP.

Figure 4. Cardiac Efficiency During Various Modes of Pacing MVO2

Stroke work

PVA

ATP Basal metabolism

Ca2+ handling

Dyssynchrony

Total non-mechanical consumption

Potential energy Heat

Normal RV apex

*

*

LV septum 100

90

40 30 20 % of oxygen consumed

10

0

Upper panel: steps in the energy transfer from oxygen uptake by the myocardium (MVO2) to stroke work and the various sources of dissipation of energy into heat. A box with ‘dyssynchrony’ is added to this scheme, based on the observation of ‘wasted work’ as discussed in the text. Lower panel: horizontal bars indicating the total amount of oxygen consumed and the contribution of external work (red) and potential work (green). ATP = adenosine triphosphate; LV = left ventricular; RV = right ventricular; PVA = pressure–volume area. Data source: Duchenne et al. 2019.22

Zanon et al. investigated the distribution of myocardial blood flow during RVP and HBP in patients with standard pacemaker indication. They observed a significantly better perfusion score during HBP than during RVP, which was also shown by a more uniform distribution of blood flow.45 As myocardial blood flow and work are closely related, as discussed above, these data seem to corroborate the idea that HBP maintains a more uniform distribution of myocardial work. In a similar patient cohort Tang et al. investigated regional LV function during selective HBP and RVP.46 These investigators found that during RVP the maximal time difference in peak strain between all segments increased from ~100 to ~180 ms, whereas during selective HBP this increase was less pronounced (~135 ms). While the latter data show that selective HBP did lead to some degree of desynchronisation, this is significantly less than during RVP. In the CRT application HBP has shown to provide a haemodynamic improvement that is at least as large as that of BiVP.10,47 In HBP (and also LBBP) the exact position of the pacing lead is important.

When the lead is positioned exactly in the conduction system (‘selective’ HBP) low-voltage stimulation suffices to achieve a narrow QRS complex.

However, higher voltages are needed in less optimal positions (nonselective HBP).48 Bednarek et al. investigated mechanical dyssynchrony using speckle tracking echocardiography in patients during selective and non-selective HBP.49 Speckle tracking images showed premature contraction in the basal septal segment only during non-selective HBP, but this was confined to the basal septum and basal inferior segment.

Moreover, this delay was only ~50 ms, as compared ~30 ms during selective HBP, but much smaller than values over 100 ms, known to occur during RVP. This small degree of dyssynchrony also explains the lack of significant differences in LV global longitudinal strain, as measure of global LV function.

The only article so far to report speckle tracking measurements during LBBP compared LBBP to RVP and found shorter maximal time differences in peak strain during LBBP (66 ms) than during RVP (149 ms).50

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Electro-energetics of Biventricular, Septal and Conduction System Pacing Figure 5. Distribution of Regional Work and Perfusion During Various Modes of Pacing

Regional work (% of mean)

250 200

*

150

*

100 50

*

0

RV apex

* RV septal

LV septal

LV apex

Normal conditions

Regional perfusion (% of baseline)

140 120 100

†

80 60

†

†

†

†

40 20 0

RV apex

RV septal Septal

LV septal Anterior

Lateral

LV apex Posterior

Regional distribution of regional myocardial work (upper) and perfusion (microsphere technique, lower) as measured in canine hearts after 16 weeks of ventricular pacing at the sites mentioned.

Mechanical work and perfusion are expressed as percentage of the mean of each subject’s BL value. Values are mean ± SD. *Significant compared with the corresponding region in the normal conduction group and †with the corresponding region’s BL value. BL = baseline; LV = left ventricular; RV = right ventricular. Data source: Mills et al. 2009.31

Together these studies indicate that the degree of dyssynchrony (as assessed by time-to-peak shortening, strain patterns or internal stretch fraction) during conduction system pacing is moderate and close to physiological while significantly smaller than during RVP. These results also make a uniform distribution of myocardial work likely, but this needs to be confirmed by future studies, involving measurement of regional work, as described above.

Furthermore, while the above-mentioned publications relate to the use of LVSP and conduction system pacing in patients with bradycardia indication, normal LV ejection fraction and a narrow QRS complex, there is no data on the effect of these pacing modes on myocardial strains and work in patients with CRT indication. Theoretically the effect of conduction system pacing would depend on the function of the Purkinje system, especially in case of LBBP. Upadhyay et al. recently showed convincingly that in patients with LBBB who were referred for device implantation or substrate mapping the site of complete conduction block was in the His bundle in 72% and in the proximal bundle in 28%. HBP corrected wide QRS in 54% of all patients with LBBB pattern and 85% of those with complete conduction block.7 Moreover, LVSP and LBBP may at least partly take advantage of the rapid conducting endocardial muscle fibres. Indeed, several studies showed the benefit of HBP, LBBP and LVSP as alternative to CRT, as evidenced by reduction in QRS width, acute haemodynamic effect and long-term outcome.10,51,52 Therefore, more studies on the electro-mechanical and mechano-energetic consequences of LVSP, LBBP and HBP are needed to fully understand the benefits of these pacing strategies when applied with the purpose of resynchronisation.

Atrioventricular Delay in Resynchronisation

Beside resynchronising ventricular activation, any kind of CRT can also improve atrioventricular coupling. In many LBBB patients not only is intraventricular conduction delayed, but also atrioventricular conduction, as shown by a prolonged PR-delay. A combined clinical-computational modelling study indicated that up to two-thirds of the haemodynamic benefit of CRT may be caused by improving atrioventricular coupling and thereby preload.53 A patient study showed that CRT increased cardiac pump function more than proportionally compared to myocardial oxygen consumption, indicating that the combination of ventricular and atrioventricular resynchronisation can make the heart more efficient and yet increase pump function.41 While this study was performed using conventional BiV pacing, it is likely that a similar effect occurs during the more novel resynchronisation modes. Moreover, a recent study showed that BiV pacing in patients who are not CRT candidates but have a prolonged PR-interval improves ventricular stroke work, because of improved filling, further underlining the considerable effect of filling on cardiac pump function.54 In that study it was also suggested that HBP, LBBP and LVSP could be used for this purpose.

Conclusion

CRT has several beneficial effects on mechano-energetics of the heart: it alleviates impediment of the abnormal contraction on blood flow and increases myocardial efficiency. These two factors act together to increase the range of cardiac work that can be delivered by the patients’ heart, an effect that can explain the increased exercise tolerance and quality of life reported in several CRT trials. The positive effects of BiVP on mechano-energetics are established, but further confirmation is needed for LVSP, LBBP and HBP.

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Clinical Perspective

• The efficiency of cardiac pump function (the amount of stroke work generated by a unit of oxygen consumed), appears to be an important determinant of long-term outcome.

• Cardiac efficiency is approximately 30% lower in dyssynchronous than in synchronous hearts.

• The novel left ventricular septal, His bundle and left bundle branch pacing minimise the amount of pacing-induced dyssynchrony at least as well as biventricular pacing.

• Biventricular pacing has been shown to increase cardiac efficiency when compared to conventional right ventricular pacing.

• Information on cardiac efficiency regarding the other pacing modes is limited to a large animal study showing the value of left ventricular septal pacing in maintaining efficiency.

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

Electrophysiology & Ablation

Impact of Catheter Ablation on Quality of Life and Healthcare Utilisation Sanghamitra Mohanty

1

and Andrea Natale

1–3

1. Texas Cardiac Arrhythmia Institute, St David’s Medical Center, Austin, TX, US; 2. Interventional Electrophysiology, Scripps Clinic, San Diego, CA, US; 3. Metro Health Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, US

Abstract

Impairment of quality of life (QoL) is a well-known complication of AF. Because of the association of AF with older age and many other cardiovascular comorbidities, there are multiple factors that could influence QoL score even after successful AF intervention. However, substantial improvement in QoL has been reported following catheter ablation for AF regardless of ablation outcomes. In terms of healthcare resource utilisation, the expenses associated with AF are very high because of the hospitalisations for AF-related thromboembolic complications, aggravation of heart failure, AF interventions, and emergency room visits for incessant arrhythmia episodes, and they represent a large economic burden worldwide.

Several trials have shown a drastic reduction in healthcare costs following successful AF ablation. In this review, the authors discuss this evidence systematically.

Keywords

AF, catheter ablation, quality of life, hospitalisation Disclosure: AN is on the Arrhythmia & Electrophysiology Review editorial board; this did not influence peer review. AN has no conflicts of interest to declare.

Received: 24 August 2021 Accepted: 14 October 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(4):258–61. DOI: https://doi.org/10.15420/aer.2021.50 Correspondence: Andrea Natale, Cardiac Arrhythmia Institute, St David’s Medical Center, 3000 N I-35, Suite 720, Austin TX 78705, US. E: dr.natale@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.

Quality of life (QoL) is a subjective measure of a patient’s health perceptions and functional status.1 AF, with its unpredictable arrhythmia episodes, impairs the quality of everyday life by imposing physical, mental and social limitations. Additionally, patients experience worry and anxiety about financial concerns due to loss of workdays and the cost of AF management. Moreover, although rarely life-threatening, AF is associated with increased morbidity and mortality, predominantly through an increased risk of thromboembolic events and left ventricular dysfunction, thereby increasing the likelihood of healthcare resource utilisation such as hospitalisation and emergency room visits.2 The management of AF is centred on control of arrhythmia, and stroke prophylaxis. Catheter ablation for AF has emerged not only as a widely practised strategy to accomplish long-term sinus rhythm in drug-refractory AF cases, but also as a first-line therapy especially in younger patients with paroxysmal AF and minimal structural heart disease.3–5 The techniques, as well as the safety and efficacy of the ablation procedure in AF, have improved dramatically since they were first introduced in 1998.6 Several trials have reported significant advancement in QoL and reduction in healthcare utilisation following catheter ablation utilising advancedgeneration technology.1,2,7–23 The aim of this review is to analyse the available evidence on this subject.

Impact of Catheter Ablation on QoL in AF Patients

Eliminating subjectivity (and thereby bias) in medicine was the focus of modern-day clinical research until recently. However, the emphasis is gradually shifting towards patient-reported outcomes and QoL.24 Several generic and disease-specific tools are used to measure QoL, and the

majority of the studies assessing QoL in patients undergoing catheter ablation have shown significant improvement in this metric (Table 1).

In a consecutive series of AF patients undergoing catheter ablation, Wokhlu et al. reported post-ablation improvement in QoL regardless of ablation success.22 QoL improvement in patients with post-ablation recurrence was attributed to plausible causes such as a reduction in symptom burden, improved efficacy of drugs that were previously ineffective, and a placebo effect of the ablation procedure, among others.22 They also documented the superiority of AF-specific assessment (Atrial Fibrillation Effect on Quality of Life; AFEQT) over the generic QoL questionnaire, the 36-item Short-form Health Survey (SF-36), which most likely was not an appropriate metric to measure AF-related QoL.22 Raine et al. utilised both SF-36 and the AFEQT questionnaire to assess QoL in patients undergoing catheter ablation for AF.15 They reported improvement in QoL scores only in patients (of all AF types) who maintained sinus rhythm after ablation. Additionally, they reinstated the higher sensitivity of AFEQT over SF-36 in capturing changes after catheter ablation.15 Although the authors observed QoL improvement only in arrhythmia-free individuals, because of discontinuous arrhythmia monitoring the study was not able to rule out asymptomatic episodes in patients with sinus rhythm.15 In another prospective analysis, patients with long-standing persistent AF (LSPAF) with worse baseline QoL compared with the patients with paroxysmal AF had greater improvement in post-ablation QoL, particularly those who remained in sinus rhythm off anti-arrhythmic drugs.8 A shorter

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Impact of Catheter Ablation on QoL and Healthcare Utilisation Table 1: Studies on the Impact of Catheter Ablation on Quality of Life in Various AF Populations Study

Year

Type of Study

Main Finding

General AF Population Andrade et al.2

2020

Randomised trial

Significant improvement in AFEQT score at 6 and 12 months of follow-up

Biviano et al.

2017

US registry study

Disease-specific QoL instrument scores improved significantly and similarly for older and younger patients at 1-year follow-up

Bulková et al.8

2014

Prospective study

Magnitude of QoL improvement after ablation of LSPAF was significantly greater particularly when good arrhythmia control was achieved

Gupta et al.12

2021

Consecutive series

QOL improvement was significantly associated with impairment at baseline and with AF burden after ablation

Mark et al.13

2019

Randomised trial

Mean AFEQT and MAFSI scores for QoL were significantly better at 12 months after ablation

Blomström-Lundqvist 2019 et al.14

Randomised trial

Improvement in QoL at 12 months was greater for those treated with catheter ablation compared with anti-arrhythmic medication

7

Raine et al.15

2015

Prospective study

Summative and individual health scores for both AFEQT (51.5 ± 22.0 versus 81.3 ± 18.2; p<0.01) and SF-36 (PCS 43.3 ± 10.5 versus 47.9 ± 11.3; p<0.01 and MCS 45.0 ± 11.5 versus 51.5 ± 9.4; p<0.01) improved significantly in patients who maintained sinus rhythm after ablation, but not in those with recurrent AF

Terricabras et al.21

2020

Randomised trial

Significant QOL improvement occurred in all regardless of AF recurrence, defined as AF episodes lasting more than 30 s

Wokhlu et al.22

2010

Prospective study

Post-ablation QoL improvements measured by SF-36 were noted across ablation outcomes, including recurrent AF. However with the MAFSI survey, Those off AADs had greater post-ablation improvement than those on AADs

Subsets of the AF Population Mohanty et al.1

2011

Prospective study

QoL score improved significantly in all scales of SF-36 except physical functioning and bodily pain in overweight and obese patients

Mohanty et al.19

2012

Prospective study

QoL scores improved significantly at 1 year after ablation in all scales of SF-36 in AF patients with metabolic syndrome

Mohanty et al.20

2014

Prospective study

Successful ablation improved QoL in patients with asymptomatic LSPAF following ablation

Di Biase et al.

2016

Randomised trial

Significant improvement in QoL in the ablation arm compared with the amiodarone arm in patients with coexistent AF and heart failure

25

Female AF Patients Kloosterman et al.32

2020

Randomised trial

Improvement in QoL after ablation was similar between the sexes although women had lower baseline scores

Zeitler et al.33

2021

Randomised trial

QoL benefit of catheter ablation was similar across gender even though women had lower baseline score

Healthcare Utilisation in AF Patients Andrade et al.2

2020

Randomised trial

Significant reduction in healthcare utilisation in the year following AF ablation using cryo or radiofrequency energy

Biviano et al.

2017

US Registry study

For older patients (≥65 years) undergoing catheter ablation for paroxysmal AF, healthcare utilisation parameters were lower or not significantly different than for younger patients

Dewland et al.9

2014

California Healthcare Atrial flutter ablation significantly lowered the adjusted risk of inpatient hospitalisation (HR 0.88; 95% CI [0.84–0.92]; Cost and Utilisation p<0.001), emergency department visits (HR 0.60; 95% CI [0.54–0.65]; p<0.001), and overall hospital-based healthcare Project database utilisation (HR 0.94; 95% CI [0.90–0.98]; p=0.001)

Gupta et al.12

2021

Consecutive series

Cardiovascular hospitalisations were significantly decreased after ablation (42%; p=0.001)

7

2019

National database

Overall healthcare costs were reduced by 63.5% after catheter ablation

17

Samuel et al.

2017

Consecutive series

After index catheter ablation, all-cause hospitalisations, hospitalisations for AF, emergency room visits, cardioversions, and echocardiograms were reduced 12 months after catheter ablation compared with 12 months prior.

Ladapo et al.18

2011

Consecutive series

Catheter ablation for AF reduced healthcare utilisation and expenditure for up to 3 years after ablation.

Ha et al.23

2020

Consecutive series

In the overall cohort (both paroxysmal and persistent AF), there was a 48% reduction in the rate of AF-related hospitalisation/emergency room visits in the year after versus before ablation

Di Biase et al.25

2016

Randomised trial

Unplanned hospitalisation was significantly lower in the ablation arm compared with the amiodarone arm

Field et al.

2020

US administrative database

Catheter ablation in patients with AF and heart failure resulted in significant reductions in healthcare utilisation and cost in 3 years of follow-up

Saad et al.

16

36

AAD = anti-arrhythmic drug; AFEQT = AF Effect on Quality of Life; LSPAF = long-standing persistent AF; MAFSI = Mayo AF-Specific Symptom Inventory; MCS = mental component summary; PCS = physical component summary; QoL = quality of life; SF-36 = 36-item Short-form Health Survey.

history of AF, younger age and presence of LSPAF were found to be independent predictors of QoL Improvement.8

group than in the drug therapy group.13 The CAPTAF randomised trial reported similar findings.14

Two multicentre US registry studies reported comparable improvement in post-ablation AF-specific QoL scores in patients older and younger than 65 years, at 1-year follow-up.7 In 2,204 randomised patients in the CABANA trial, both the AFEQT and MAFSI (Mayo AF-Specific Symptom Inventory) mean scores were more favourable in the catheter ablation

A secondary analysis of the STAR AF II trial demonstrated a 92% reduction in AF burden following catheter ablation and a direct association of statistically significant improvement in QoL with decrease in AF burden at 18 months following the procedure.21 The QoL improvement was detected regardless of AF recurrence, defined as AF episodes lasting >30 seconds.21

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Impact of Catheter Ablation on QoL and Healthcare Utilisation The CIRCA-DOSE randomised trial also reported the same.2 Patients free of any atrial tachyarrhythmia recurrence had a significantly greater improvement in AFEQT score compared with those with tachyarrhythmia recurrence.2 Another consecutive series documented association of QoL improvement with residual tachyarrhythmia burden following catheter ablation.12

cohort of patients from the Brazilian private healthcare system, overall healthcare cost was shown to reduce by 63% after catheter ablation compared with before.16 Biviano et al. showed comparable reduction in healthcare utilisation (hospitalisation and emergency room visits) following catheter ablation in both older and younger patients with a cut-off age at 65 years.7

Catheter ablation has also been shown to positively impact QoL in subsets of AF patients with other comorbidities. In a prospective series of 660 normal versus high BMI patients, we observed significant increase in QoL scores in high BMI patients only.1 Furthermore, patients with successful ablation had more positive change in QoL compared with those with failed ablation.1 In another study including AF patients with metabolic syndrome, the QoL improvement was observed to be greater in patients with metabolic syndrome versus without.19 In a later series with asymptomatic LSPAF patients, successful ablation was shown to be associated with substantial betterment in QoL scores.20 In the AATAC randomised trial, the Minnesota Living with Heart Failure questionnaire was used to assess the change in QoL in AF patients with congestive heart failure undergoing catheter ablation versus those remaining on amiodarone.25 Compared with the drug group (and with both cohorts having similar QoL scores at baseline), the ablation arm had significantly better QoL at follow-up.25

In a large real-world population of 33,000 patients with a diagnosis of atrial flutter, catheter ablation was shown to significantly reduce the adjusted risk of inpatient hospitalisation, emergency room visits and overall hospital-based healthcare utilisation.9 Samuel et al. demonstrated reversal of healthcare resource utilisation at 2 years following catheter ablation to lower than pre-ablation levels in 1,556 AF patients.17 The rate of all-cause admissions and AF or atrial flutter hospitalisation and emergency room visits increased significantly over the 24-month period prior to ablation and subsequently decreased below pre-procedure levels throughout the 24 months following the ablation procedure.17

Another subset of AF in terms of QoL impairment is worth mentioning.

Many trials have shown that women with AF have lower baseline QoL than men.26–31 The AXAFA-AFNET 5 trial reported similar improvement in QoL following catheter ablation, across gender.32 In a substudy of the CABANA trial population, catheter ablation was shown to be superior to drugbased therapy for improving QoL in women.33

Impact of Catheter Ablation on Healthcare Utilisation

In another study on healthcare utilisation in the general and the Medicare populations, compared with the 6 months prior to ablation, there were significant reductions in the number of outpatient appointments, inpatient days, drug treatment, and emergency room visits in the total study population and in the subset ≥65 years, at 3 years after the ablation procedure.18 In the AATAC study, unplanned hospitalisation was significantly lower in the ablation arm in patients with coexistent AF and heart failure.25 Similar findings were reported by Field et al. at 3-year follow-up in patients with AF and heart failure undergoing catheter ablation.36 In two recently published studies, the authors showed benefits of catheter ablation in terms of healthcare utilisation and cost in both paroxysmal and persistent AF.13,23

Conclusion

According to a cross-sectional study using the Nationwide Inpatient Sample database for the years between 2000 and 2010, a total of 3,960,011 hospitalisations for AF as the primary discharge diagnosis were reported in the US.34 The contemporary costs of managing AF have been estimated to account for 1.0–2.7% of total annual healthcare expenditure, with a significant proportion of these expenses attributed to the direct costs associated with hospitalisation, emergency room visits and the provision of acute care.2 In 2010 the AF-specific cost was reported to be US$6.0 billion, consisting of US$2.3 billion for inpatient admissions with AF as the primary diagnosis and US$3.7 billion for outpatient care.35 Many independent trials have reported a significant reduction in healthcare resource utilisation following AF ablation (Table 1).

Based on the above evidence, it is prudent to conclude that catheter ablation improves disease-specific QoL regardless of the ablation outcome. Furthermore, irrespective of AF type, it significantly reduces the healthcare utilisation in the post-ablation period for up to 3 years.

The CIRCA-DOSE randomised trial reported a reduction of 75% in cardioversion, 62% in emergency room visits, 43% in hospitalisation and 86% in anti-arrhythmic drugs use following catheter ablation using either radiofrequency or cryo energy, in paroxysmal AF patients.2 In a consecutive series, Gupta et al. documented significant reduction in cardiovascular hospitalisation following AF ablation.12 In a retrospective 1. Mohanty S, Mohanty P, Di Biase L, et al. Influence of body mass index on quality of life in atrial fibrillation patients undergoing catheter ablation. Heart Rhythm 2011;8:1847–52. https://doi.org/10.1016/j.hrthm.2011.07.005; PMID: 21740879.

2. Andrade JG, Macle L, Verma A, et al; CIRCA-DOSE Study Investigators. Quality of life and health care utilization in the CIRCA-DOSE Study. JACC Clin Electrophysiol 2020;6:935–44. https://doi.org/10.1016/j.jacep.2020.04.017; PMID: 32819528.

3. Nielsen JC, Johannessen A, Raatikainen P, et al. Long-term

Clinical Perspective

• Catheter ablation improves quality of life (QoL) in AF patients, regardless of ablation outcome.

• Positive change in QoL even in the absence of achievement of

sinus rhythm is probably due to reduction in arrhythmia burden and improved efficacy of drugs that were previously ineffective.

• Significant reduction in healthcare utilisation such as hospitalisation and emergency room visits following catheter ablation has also been well documented.

• When determining the priority of catheter ablation in AF patients, the aforementioned benefits should be considered along with the success rate of the procedure in achieving arrhythmia-free survival.

efficacy of catheter ablation as first-line therapy for paroxysmal atrial fibrillation: 5-year outcome in a randomised clinical trial. Heart 2017;103:368–76. https://doi. org/10.1136/heartjnl-2016-309781; PMID: 27566295.

4. Imberti JF, Ding WY, Kotalczyk A, et al. Catheter ablation as first-line treatment for paroxysmal atrial fibrillation: a systematic review and meta-analysis. Heart 2021;107:1630– 6. https://doi.org/10.1136/heartjnl-2021-319496; PMID: 34261737.

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5. Santangeli P, Di Biase L, Natale A. Ablation versus drugs: what is the best first-line therapy for paroxysmal atrial fibrillation? Antiarrhythmic drugs are outmoded and catheter ablation should be the first-line option for all patients with paroxysmal atrial fibrillation: pro. Circ Arrhythm Electrophysiol 2014;7:739–46. https://doi.org/10.1161/CIRCEP.113.000629; PMID: 25140019.

6. Haïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the

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Bulková V, Fiala M, Havránek S, et al. Improvement in quality of life after catheter ablation for paroxysmal versus long-standing persistent atrial fibrillation: a prospective study with 3-year follow-up. J Am Heart Assoc 2014;3:e000881. https://doi.org/10.1161/JAHA.114.000881; PMID: 25037195.

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Mark DB, Anstrom KJ, Sheng S, et al. Effect of catheter ablation vs medical therapy on quality of life among patients with atrial fibrillation: the CABANA randomized clinical trial.

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17. Samuel M, Avgil Tsadok M, Joza J, et al. Catheter ablation for the treatment of atrial fibrillation is associated with a reduction in health care resource utilization. J Cardiovasc Electrophysiol 2017;28:733–41. https://doi.org/10.1111/ jce.13225; PMID: 28419594.

18. Ladapo JA, David G, Gunnarsson CL, et al. Healthcare utilization and expenditures in patients with atrial fibrillation treated with catheter ablation. J Cardiovasc Electrophysiol 2012;23:1–8. https://doi.org/10.1111/j.1540-8167.2011.02130.x; PMID: 21777324.

19. Mohanty S, Mohanty P, Di Biase L, et al. Impact of metabolic syndrome on procedural outcomes in patients with atrial fibrillation undergoing catheter ablation. J Am Coll Cardiol 2012;59:1295–301. https://doi.org/10.1016/j.jacc.2011.11.051; PMID: 22464257.

20. Mohanty S, Santangeli P, Mohanty P, et al. Catheter ablation of asymptomatic longstanding persistent atrial fibrillation: impact on quality of life, exercise performance, arrhythmia perception, and arrhythmia-free survival. J Cardiovasc Electrophysiol 2014;25:1057–64. https://doi.org/10.1111/ jce.12467; PMID: 24903064.

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Electrophysiology and Ablation

Inferior Extensions of the Atrioventricular Node Robert H Anderson ,1 Jill PJM Hikspoors ,2 Justin T Tretter ,3 Yolanda Macías ,4 Diane E Spicer ,5,6 Wouter H Lamers ,2 Damián Sánchez-Quintana 4 and Eduardo Back Sternick 7 1. Biosciences Institute, Newcastle University, Newcastle-upon-Tyne, UK; 2. Department of Anatomy and Embryology, Maastricht University, Maastricht, the Netherlands; 3. Heart Institute, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, US; 4. Department of Human Anatomy and Cell Biology, Faculty of Medicine, University of Extremadura, Badajoz, Spain; 5. Congenital Heart Center, University of Florida, Gainesville, FL, US; 6. Heart Institute, Johns Hopkins All Children’s Hospital, St Petersburg, FL, US; 7. Arrhythmia and Electrophysiology Department, Biocor Institute, Nova Lima, Brazil

Abstract

The pathways for excitation of the atrioventricular node enter either superiorly, as the so-called ‘fast’ pathway, or inferiorly as the ‘slow’ pathway.

However, knowledge of the specific anatomical details of these pathways is limited. Most of the experimental studies that established the existence of these pathways were conducted in mammalian hearts, which have subtle differences to human hearts. In this review, the authors summarise their recent experiences investigating human cardiac development, correlating these results with the arrangement of the connections between the atrial myocardium and the compact atrioventricular node as revealed by serial sectioning of adult human hearts. They discuss the contributions made from the atrioventricular canal myocardium, as opposed to the primary ring. Both these rings are incorporated into the atrial vestibules, albeit with the primary ring contributing only to the tricuspid vestibule. The atrial septal cardiomyocytes are relatively late contributors to the nodal inputs. Finally, they relate our findings of human cardiac development to the postnatal arrangement.

Keywords

Conduction tissues, animal species, fast pathway, slow pathway, development Disclosure: RHA is on the Arrhythmia & Electrophysiology Review editorial board; this did not influence peer review. All other authors have no conflicts of interest to disclose.

Received: 2 August 2021 Accepted: 2 September 2021 Citation: Arrhythmia & Electrophysiology Review 2021;10(4):262–72. DOI: https://doi.org/10.15420/aer.2021.43 Correspondence: Eduardo Sternick, Arrhythmia and Electrophysiology Department, Biocor Institute, Al. do Morro, 85 - Torre 4, Suite 1900, Vila da Serra, Nova Lima - MG, 34006-083 Brazil. E: eduardosternick@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.

It is now well established that there are two major pathways of conduction into the atrioventricular node, the so-called slow and fast pathways.1 It is also well established that ablation of one or other of the pathways can cure atrioventricular nodal re-entry. In this regard, the fast pathway is recognised as being closely related to the site of penetration of the conduction axis from the atrial to the ventricular myocardial components of the heart. For this reason, it is the slow pathway that is usually targeted during therapeutic ablation. However, the specific substrate that is ablated remains uncertain, although the site of ablation is now usually the septal vestibule of the tricuspid valve. Furthermore, atrioventricular nodal re-entry has now been shown to take various forms, which can be discriminated by electrophysiological investigations.2,3 Again, however, the specific pathways for the different circuits have yet to be established.

Much of the information regarding the existence of the dual nodal pathways has been derived on the basis of experiments using preparations from species such as the rabbit or dog. However, those making correlations between these results and the clinical observations have not always taken account of the significant differences in the arrangement of the atrioventricular node and its atrial connections between non-human and human species. This is somewhat surprising, because the differences between human and dog hearts were clearly described by Tawara when

he clarified the overall arrangement of the atrioventricular conduction axis.4,5 Nonetheless, even though there are fundamental differences in morphological arrangements between species, the building blocks of the atrioventricular node are comparable.6 The differences in morphological arrangements can have a significant effect on the patterns of conduction into the atrioventricular node because they reflect the relationship between the node and the atrial vestibules and atrial septum. These differences, in turn, can now be related to the way in which the atrioventricular junctions are remodelled during normal cardiac development.

In this review, based on our recent investigations of human cardiac development and our access to a large number of serial histological sections of adult human hearts, we show how all these features can be combined to produce an understanding of the overall anatomy of the specialised atrioventricular junction.7 We are well aware that there is considerable information regarding the molecular and functional background of the specialised atrioventricular conduction axis. However, in this review we have confined ourselves to discussions of the basic template of the axis and the way in which it differs in humans compared with mammalian species used in electrophysiological experiments. It is

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Extensions of the Atrioventricular Node Figure 1: Using Serial Histological Sectioning to Define a Conducting Tract

Non-branching bundle

Branching bundle

Right bundle branch

Fasciculoventricular connection

Recess

Left bundle branch 1 mm 1 mm

A

Left bundle branch

B

1 mm 1 mm

C

1 mm 1 mm

This set of serial histological sections from the same adult human heart prepared by us using serial histological sectioning shows how, using the criteria established by Mönkeberg and Aschoff in 1910, it is possible to define a conducting tract.9,10 A: The non-branching atrioventricular bundle. B: Branching of the atrioventricular bundle to give off the left bundle branch together with a fasciculoventricular connection. C: Branching of the axis into the right and left bundle branches. Sections were stained using the trichrome technique. The axis can be traced from section to section, the cells are histologically distinct, but, most importantly, the axis itself is insulated by fibrous tissue from the adjacent working myocardium.

Figure 2: Nodes Versus Conducting Tracts Tricuspid vestibule

the same approach that remains the mainstay for current anatomical investigations, namely the careful analysis of serially sectioned histological material. Similar analyses enabled Aschoff and Mönkeberg, the giants of cardiac pathology emerging at the beginning of the 20th century, to suggest criteria based on the initial studies of Tawara for the recognition of histologically specialised tracts within the walls of the cardiac chambers.9,10 It is these criteria that we have used as the basis of our own descriptions of the serially sectioned human datasets at our disposal.7 The criteria proposed by Aschoff and Mönkeberg were that:

Mitral vestibule

Leftward inferior extension

• the structures in question should be traceable from section to

Rightward inferior extension

A

1 mm 1 mm

section;

1 mm 1 mm

B

• the myocytes under consideration should be histologically distinct to

Last septal connection

Compact atrioventricular node

the adjacent working myocardium; and

• of greatest importance for the recognition of conducting tracts, the

myocytes, at least in the postnatal human heart, should be gathered together within an insulating sheath.

C

1 mm 1 mm

D

Applying these criteria to the serially sectioned histological dataset of adult human hearts meant that it was a relatively easy matter to recognise the non-branching atrioventricular bundle (Figure 1A), the origin of the left bundle branch from the axis (Figure 1B) and the continuation of the axis as it gives rise to the right bundle branch (Figure 1C). The significance of the criteria for the recognition of insulated tracts has recently been emphasised in the context of conduction through the working atrial myocardium.11

1 mm 1 mm

Analysis of other sections from the serially sectioned human adult hearts in our dataset shows how, using two of the criteria of Aschoff and Mönckeberg, it is possible to recognise the atrioventricular node (C), its rightward and leftward extensions (A,B) and its connections with the atrial myocardium (D).9,10 Unlike the ventricular components of the conduction axis (Figure 1), the atrial components are not insulated from the atrial myocardium.

our hope that the anatomical information provided here will set the scene for ongoing studies into the circuits involved in the different forms of atrioventricular nodal re-entry.8

Prescience of Sunao Tawara

In 1906, Tawara provided a remarkably accurate account of the atrioventricular conduction axis, emphasising the different patterns to be found within several mammalian species.4 It is difficult to surpass this initial description, even with all the modern techniques at our disposal, such as immunocytochemistry and 3D reconstruction. Tawara had used

Using two of these criteria, namely the potential to follow the structures from section to section and the ability to distinguish specialised cardiomyocytes from the adjacent working myocardium, it is possible to recognise the components of the atrioventricular node (Figure 2). It is also possible to recognise cardiomyocytes that are intermediate in their staining characteristics between the working and specialised cardiomyocytes. These are the so-called ‘transitional’ cardiomyocytes.

However, interrogation of our latest datasets revealed that these zones of transitional cardiomyocytes were less extensive in adult hearts than we had anticipated based on our earlier experiences.7

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Extensions of the Atrioventricular Node Figure 3: Architectural Arrangement of the Atrioventricular Conduction Axis

Non-branching AV bundle

Tricuspid vestibule

Penetrating AV bundle Compact AV node Branching AV bundle

Mitral vestibule

A

Ventricular septum

Penetrating AV bundle

Tricuspid vestibule

Non-branching AV bundle

Compact AV node

Branching AV bundle

Base of non-coronary sinus

B

Mitral vestibule

They show the difference in the architectural arrangement of the atrioventricular conduction axis in the human heart (A) compared with the arrangement found in the canine heart (B).

AV = atrioventricular. Source: Tawara et al. 1906.4

Unlike the components of the conduction axis as seen once it has penetrated the insulating tissues of the atrioventricular junctions, the myocytes of the atrioventricular node are not insulated from the adjacent working atrial myocardium. Insulation, of course, would defeat the very purpose of the atrioventricular node, which is to delay the transmission of the cardiac impulse to the ventricular myocardium while atrial contraction serves to fill the ventricles with blood prior to ventricular contraction.

Nonetheless, it is an easy matter to recognise the compact atrioventricular node in histological sections (Figure 2C) using the criteria proposed by Aschoff and Mönckeberg.9,10 It is also possible to trace its extensions (Figures 2A and 2B) and, in particular, the arrangement of its connections with the atrial septal myocardium can be appreciated (Figure 2D).7 As emphasised above, in our initial experiences we had considered it possible to recognise discrete transitional areas between the working atrial myocardium and the specialised cardiomyocytes of the node and its extensions. We are now less convinced of the extent of such transitional cardiomyocytes.

On the basis of his own studies using serial histological sectioning, Tawara had illustrated the marked differences in terms of the short extent of the

non-branching bundle in the human heart compared with the much longer non-branching component found in the canine heart (Figure 3). There are also differences in this arrangement between the human heart and rabbit heart. In the rabbit, the most complex component of the conduction axis, in terms of its cellular architecture, is insulated from the adjacent atrial myocardium.12 We initially described this part of the axis as representing the ‘closed’ atrioventricular node.13 However, using the criterion proposed by Tawara,4 this part of the axis is properly defined as the non-branching atrioventricular bundle. Indeed, the rabbit heart does not possess a component of the atrioventricular conduction axis that can be compared in terms of its architecture with the compact atrioventricular node as observed in the human heart. Furthermore, in the canine heart, the atrial component of the conduction axis is much smaller than the structures typically found in human hearts. Therefore, it is surprising that subsequent investigators who used either dog or rabbit hearts to explore the electrophysiology of atrioventricular nodal function neglected to take note of these obvious differences, which are readily appreciated on the basis of the illustrations provided by Tawara in the first decade of the 20th century (Figure 3).

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Extensions of the Atrioventricular Node Figure 4: Human Embryos in the Fifth Week of Development A

Atrioventricular canal myocardium

Atrioventricular canal myocardium

Outflow tract

Primary ring

Cavity of right ventricle

Cavity of left ventricle Developing right ventricle

Developing left ventricle

Inner heart curvature

Developing ventricular septum

Human embryo – Carnegie stage 12

Human embryo – Carnegie stage 14

B Atrioventricular canal myocardium

Primary ring

Atrioventricular canal myocardium

Primary ring Right bundle branch

Inferior rightward extension Developing left ventricle

Basis of compact atrioventricular node

Human embryo – Carnegie stage 20

The images have been prepared from our interactive PDFs reconstructed from serially sectioned human embryos in the fifth week of development. A: The left-hand panel shows a slightly earlier stage, graded as stage 12, or around 4–5 weeks after conception, in the system developed by workers at the Carnegie Institute in the 20th century, whereas the right-hand panel shows the ventricular cavities at a slightly later stage, around 5 weeks after conception. Both reconstructions are viewed from above and from the right, looking at the diaphragmatic surface of the developing heart. B: Similar reconstructions from our own interactive PDFs of a developing human embryo comparable to those shown in A, but in this case made from an embryo at Carnegie stage 20, when the embryo is in the seventh week of development. By this stage, the atrioventricular canal has expanded so as to provide the right ventricle with its own inlet component. The left-hand panel show how this leaves the ventricular component of the primary ring carried on the crest of the muscular ventricular septum. The right-hand panel, viewed from the anterior right-sided aspect, shows remodelling of the part of the primary ring initially occupying the inner heart curvature to surround the orifice of the tricuspid valve. C: Images prepared from our own PDFs showing reconstructions from a human embryo at Carnegie stage 23, which is at the end of the eighth week of development. The left-hand panel shows that the atrioventricular canal myocardium has retained the ovoid configuration as seen at Carnegie stage 20 (B). The primary ring of specialised cardiomyocytes, which will form the atrioventricular conduction axis, transitions from the ventricular to the atrial components of the developing heart by emerging between the inferior margins of the atrioventricular cushions, which have separated the initial common junction into the developing mitral and tricuspid valves. The transition at this stage is along the diaphragmatic surface of the heart, at the so-called ‘crux’. The right-hand panel shows how the muscularised vestibular spine overlies the primary ring as it transitions into the ring that encircles the tricuspid valvar orifice. It is only with ongoing development that the orifices expand inferiorly (arrows) to form the definitive right and left atrioventricular junctions. Note also that at this stage the aortic root is located superior to the atrioventricular canal myocardium.

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Extensions of the Atrioventricular Node Figure 4: Human Embryos in the Fifth Week of Development (cont.)

C Aortic root

Septal connections

Tricuspid valve Vestibular spine Mitral valve

Primary ring Atrioventricular canal myocardium

Mitral vestibule

Tricuspid vestibule

Human embryo – Carnegie stage 23

Developmental Considerations

Knowledge of the development of the atrioventricular conduction axis now permits important inferences to be made regarding the potential substrates for atrioventricular nodal re-entry tachycardias.8 In the early stages of cardiac development, the developing atrial chambers are joined through the myocardium of the atrioventricular canal exclusively with the cavity of the developing left ventricle. All the blood entering the left ventricle must pass through the primary interventricular communication to reach the developing right ventricle, which supports the entirety of the circumference of the developing outflow tract (Figure 4A, left).

At this early stage, when the atrioventricular canal is supported by the developing left ventricle, it is possible to record an adult-type electrocardiogram, with evidence already present of atrioventricular delay.6 It is also clear that, even at this early stage, prior to the completion of septation, there is already a pathway of preferential atrioventricular conduction. The inference can be made that it is the atrioventricular canal myocardium that is producing the delay. At a slightly later stage of development, as shown in the right-hand image in Figure 4A, it is also possible to recognise a ring of cardiomyocytes encircling the interventricular communication. The cardiomyocytes react to an antibody raised against an extract of the nodose ganglion of the chick.14 These cardiomyocytes are carried on the crest of the developing ventricular septum and occupy the inner heart curvature, which, at this early stage of development, separates the atrioventricular canal from the developing outflow tract (Figure 4A). These cardiomyocytes are known as the primary ring and they form the basis of the atrioventricular conduction axis. They also occupy the right side of the developing atrioventricular canal. With ongoing development, the atrioventricular canal itself expands rightward, providing the developing right ventricle with its own inlet component.

Concomitant with this rightward expansion, the part of the primary ring initially occupying the inner heart curvature is transformed so as to encircle the developing orifice of the tricuspid valve (Figure 5).

It is during the end of week 7 of human development and at the beginning

Figure 5: Site of Penetration of the Atrioventricular Conduction Axis

Inferoseptal recess

Atrioventricular insulating plane Left atrial vestibule

Right atrial vestibule

Inferior pyramidal space

The dissection, made using a normal adult human heart by removing the atrial wall of the triangle of Koch, shows how the diverging vestibules of the right and left atrial chambers form the walls of a canopy that will enclose the fibroadipose tissues of the inferior pyramidal space. The space itself is continuous inferiorly with the inferior atrioventricular groove. Note that the atrioventricular insulating plane is at the apex of the pyramid. This is the site of penetration of the atrioventricular conduction axis, which is no longer at the crux of the heart.

of week 8 that the persisting channel between the aortic root and the developing right ventricle is closed by tubercles derived from the atrioventricular endocardial cushions; this process serves to complete

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Extensions of the Atrioventricular Node ventricular septation.15 By this stage of development, another significant event has been the growth of a protrusion into the heart from the pharyngeal mesenchyme that muscularises, along with the mesenchymal cap carried on the leading edge of the primary atrial septum, to form the anteroinferior buttress of the atrial septum. This structure was described

by Wilhelm His Senior in the latter half of the 19th century as the ‘spina vestibuli’ and was the largely forgotten prior to the study of Kim et al.16,17 It then received further attention from Snarr et al., who described it as the ‘dorsal mesenchymal protrusion’.18 Our preference is to continue to recognise this entity as the vestibular spine.19 The importance of this structure is to help bind together the middle of the developing atrioventricular junctions. As it grows into the atrial cavities, it fuses with the atrial surface of the atrioventricular endocardial cushions and the mesenchymal cap to close the primary atrial foramen. The cushions themselves have fused by this time to separate the initially common atrioventricular canal into the developing tricuspid and mitral valve orifices. Even after the canal has been separated into the right and left atrioventricular junctions, and after the vestibular spine has fused with the atrial surface of the endocardial cushions, the canal itself retains its initial ovoid configuration (Figures 4C and 5).

At the stage of development shown in Figure 4C, the primordial of the developing atrioventricular node are all in place, but are not yet in their final positions. An additional significant change is also taking place: with ongoing development, the atrioventricular canal myocardium is sequestered on the atrial aspect of the developing plane of insulation between the atrial and ventricular myocardial masses to form the vestibules of both the developing tricuspid and mitral valves.20 Subsequent to the formation of the insulating plane, the only persisting myocardial connection between the two masses is the atrioventricular conduction axis, which itself developed from the primary ring. As shown in Figure 4C, this axis transitions from the atrial to the ventricular components by passing between the inferior margins of the atrioventricular endocardial cushions. However, at the conclusion of the embryonic period of development (8 weeks in the human heart), there has been no inferior expansion of the right and left atrioventricular junctions. At this stage, the point of penetration of the axis, known as the cardiac crux, is found along the diaphragmatic surface of the developing heart. This is the point at which the primary ring, as it emerges from the ventricular mass, is overlain by the muscularising tissues of the vestibular spine and mesenchymal cap (Figure 4C, right). Therefore, at this early stage the transition from the ventricular to the atrial components (at the crux) marks the site of the formation of the atrioventricular node.

The nodal primordium then has three potential connections: with the vestibule of the tricuspid valve, with the mitral vestibule and with the atrial septal myocardium. The connection with the developing vestibule of the tricuspid valve involves not only the atrioventricular canal myocardium, which was itself sufficient initially to produce atrioventricular delay, but also the persisting parietal part of the primary ring, which is the same as the compact node itself. The second connection, with the mitral vestibule, is composed exclusively of the atrioventricular canal myocardium, because the primary ring encircles only the developing orifice of the tricuspid valve. Finally, the connection with atrial septal myocardium, formed by muscularisation of the vestibular spine and the mesenchymal cap and shown in Figure 4C, does not represent the definitive arrangement because, at the end of the embryonic period of development, there has been no expansion inferiorly of the right and left atrioventricular junctions, nor any commitment of the aortic root to the left ventricle. It is these ongoing changes taking place during the early foetal period of

development that produce the inferior pyramidal space and the inferoseptal recess of the left ventricle.

Definitive Anatomical Arrangements

It is not coincidental that the arrangement of the developing conduction axis as seen at Carnegie Stage 23 (Figure 4C) is reminiscent of the arrangement found in atrioventricular septal defect with common atrioventricular junction.21 In the ‘ostium primum’ variant of these congenital lesions, the common junction is divided into separate right and left valvar orifices, but there has been no formation of the anteroinferior buttress of the atrial septum, with all these processes being the consequence of failure of the growth of the vestibular spine. The arrangement of the conduction axis in this setting is as shown in the lefthand panel of Figure 4C. It is the ongoing expansion, subsequent to normal development, of the mitral and tricuspid valvar orifices, along with the transfer of the aortic root to the left ventricle such that it interposes between the leaflets of the mitral valve and the septum, that establishes the normal arrangement of the atrial components of the atrioventricular conduction axis. The inferior expansion of the vestibules of the right and left atrioventricular junctions produces the inferior pyramidal space (Figure 5).

The diverging vestibules of the right and left atrial chambers, themselves formed from the initial atrioventricular canal myocardium, come together superiorly at the apex of the space. The atrial margin of the space is formed by the anteroinferior buttress of the atrial septum. At the apex of the pyramid, this contains the compact atrioventricular node itself. The space is continuous inferiorly with the inferior atrioventricular groove. The coronary sinus occupies the leftward part of this groove, with its mouth within the vestibular surface of the right atrium. These relationships are now readily demonstrated by virtual dissections of living CT datasets and show the importance of the relationship between the apex of the inferior pyramidal space and the inferoseptal recess of the left ventricle (Figure 6).

It is the extent of the relationship between the inferoseptal recess of the left ventricle and the apex of the inferior pyramidal space that determines the precise location of the atrioventricular conduction axis. As we have shown, the axis penetrates so as to provide the sole transition from the atrial to the ventricular myocardial masses at the apex of the pyramidal space. This is the point at which the initial primary ring of specialised cardiomyocytes extended from beneath the atrioventricular cushions to continue within the atrioventricular canal myocardium of the tricuspid vestibule as the ‘atrioventricular ring tissue’, this particular ‘ring tissue’ being derived from the primary ring.22 It is only the tricuspid vestibule that contains the remnants of the ring tissues derived from the primary ring.

These tissues form the rightward inferior extension of the atrioventricular node. However, the compact atrioventricular node is contained within the anteroinferior buttress of the atrial septum. The vestibular spine is an interatrial and atrioventricular septal complex, rather than a right atrial structure. The septum itself, derived by muscularisation of the vestibular spine and mesenchymal cap, is supported by the roof of the inferoseptal recess of the left ventricle, formed by an area of fibrous continuity between the leaflets of the mitral and tricuspid valves (Figure 7).

The atrial component of the conduction axis penetrates the fibrous tissue, forming the roof and rightward wall of the inferoseptal recess to become the bundle of His. It then continues within the rightward wall of the recess as the non-branching atrioventricular bundle. As emphasised, the node itself, prior to penetration of the axis, is part of an atrioventricular septal complex. However, its extensions belong separately to the vestibules of

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Extensions of the Atrioventricular Node Figure 6: Fibroadipose Tissues Occupying the Inferior Pyramidal Space Membranous septum

Aortic root

Virtual basal ring

Pulmonary root

Virtual basal ring

Membranous septum

Inferoseptal recess

Inferior pyramidal space Inferoseptal recess

A

Inferior pyramidal space

B

These virtual dissections of a living CT dataset from an adult human show the extent of the fibroadipose tissues occupying the inferior pyramidal space, and the relationship between the apex of the space and the inferior extent of the inferoseptal recess of the left ventricle (orange). A: The short axis cut with a translucent myocardium. B: Right anterior oblique projection. A = anterior; F = frontal; L = left; R = right.

Figure 7: Relationship Between the Apex of the Inferior Pyramidal Space and the Inferoseptal Recess of the Left Ventricle Buttress of atrial septum

Inferoseptal recess Triangle of Koch

Atrioventricular node and extensions

Oval fossa Oval fossa

Coronary sinus

A

Coronary sinus Inferior pyramidal space

B

Septal vestibule

These dissections of a normal human heart from a child show how the inferior pyramidal space is roofed by the atrial wall of the triangle of Koch, and confirm the relationship between the apex of the space and the inferoseptal recess of the left ventricle. The heart was bisected so as to produce the slice shown in (B), which fits onto the remaining septal surfaces as shown in (A). Note that the buttress of the atrial septum, which contains the atrioventricular node, is directly adjacent to the cavity of the space that interposes between the aortic leaflet of the mitral valve and the left ventricular septal surface and is known as the inferoseptal recess. The approximate location of the atrioventricular node and its inferior extensions is shown in (B).

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Extensions of the Atrioventricular Node Figure 8: Approximate Locations Relative to the Triangle of Koch Compact AV node

Oval fossa

Fast pathway

Triangle of Koch

Insulating sheath

Septal input

Recess Penetrating bundle

Recess

1 mm 1 mm

1 mm 1 mm Last septal input

Rightward extension

Coronary sinus Recess

Leftward extension

1 mm 1 mm

Pectinate muscles

Slow pathway

Septal vestibule

1 mm 1 mm

The serial histological sections from one of our own serially sectioned datasets prepared from an adult human heart have been placed so as to demonstrate their approximate locations relative to the triangle of Koch, as shown in the middle panel. It is the last septal input, shown in the lower right-hand panel, which likely represents the so-called ‘fast pathway’. However, the so-called ‘slow pathway’ could be represented by either of the inferior nodal extensions, which are relatively balanced in this dataset, as shown by the lower left-hand panel. The rightward extension is likely to be formed from the primary ring of cardiomyocytes, which is overlain by the tricuspid vestibule, itself derived from the atrioventricular canal myocardium. The leftward inferior extension can only be formed from atrioventricular canal myocardium. Additional connections from the atrial septum feed into the axis between the levels shown by the upper left-hand and the lower right-hand panels.

AV = atrioventricular.

the right and left atrial chambers. Nonetheless, its septal connections are self-evidently contained within the anteroinferior buttress of the atrial septum. These three building blocks of the nodal connections (i.e. the two inferior extensions and the septal connections) are present in all hearts.

Their specific arrangement, and extent, varies markedly. This was revealed by our analysis of the histological datasets prepared from normal adult human hearts.7 We are able to illustrate the significance of the variations using selected cases from our series.7

Variations in Nodal Building Blocks

The atrioventricular node itself varies in its position within the triangle of Koch. We had initially believed the node to be found at the apex of the triangle. This is still a good general guide to its position. However, our combined histological and electrophysiological assessment showed much greater variability in this location than we had initially anticipated.23 We also found variation in terms of whether the compact node itself was supported by a plate of fibrous tissue formed at the apex of the inferior pyramidal space or whether it was incorporated on the right wall of the inferoseptal recess as part of an atrioventricular fibromyocardial septal complex. Regardless of these considerations, the compact node itself is unequivocally a septal structure. As emphasised, it then potentially has right atrial and left atrial extensions, along with additional direct septal connections (Figure 8).

The dataset as shown in Figure 8, prepared from an adult human heart, illustrates the three basic ‘building blocks’ in regard to the atrial cardiomyocytes that make contact with the specialised cardiomyocytes forming the compact atrioventricular node. Of the 20 human datasets we

analysed in detail to assess these connections, which came from normal adult hearts, only two showed the balanced arrangement as illustrated in Figure 8.7 Most of the datasets showed dominance of the right inferior extension.7 As we have emphasised, this extension is almost certainly the remnant of the specialised cardiomyocytes derived from the primary ring and incorporated into the tricuspid vestibule. As can be seen, the extension itself is overlaid by the working myocardium of the tricuspid vestibule, which itself is a remnant of the embryonic atrioventricular canal myocardium. Even in those datasets in which the rightward inferior extension is the dominant pathway feeding the inferior part of the compact node, there is still further variation of the extension itself within the vestibule. In some of the hearts, the extension cannot be followed for any significant distance as an entity distinct from the vestibular myocardium.

In other hearts, the histologically discrete cardiomyocytes, fulfilling one of the criteria established by Aschoff and Mönckeberg for the recognition of ‘nodal’ tissue,9,10 extend within the septal vestibule towards the orifice of the coronary sinus, but are again overlaid by the vestibular myocardium (Figure 9).

In still other datasets, we found fibroadipose tissue within the inferior pyramidal space disrupting the connections between the septal cardiomyocytes and the compact node. This arrangement would potentially leave the rightward inferior extension itself as the solitary pathway into the compact atrioventricular node (Figure 10).

Composition of the ‘Ring Tissues’

In this review, we have emphasised the presence of three ‘inputs’ to the compact atrioventricular node, namely the rightward and leftward inferior

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Extensions of the Atrioventricular Node Figure 9: Dominant Rightward Inferior Extension Tendon of Todaro

Compact node

Membranous septum

Tendon of Todaro

Mitral–tricuspid continuity

Recess Septal input

Penetrating bundle Final septal input

Inferior extension

Recess Mitral vestibule

Coronary sinus

Septal vestibule

The images are taken from one of our datasets prepared from an adult human heart in which the rightward inferior extension is dominant (left-hand lower panel), with minimal connection to the compact node from the mitral vestibule (star in left-hand lower panel). The inferior extension continued in this heart within the septal vestibule towards the orifice of the coronary sinus.

Figure 10: Serial Histological Sectioning Showing Minimal Connections Between the Septum and Compact Node Septal input

Compact AV node

Penetrating AB bundle

Mitral vestibule Inferoseptal recess Inferoseptal recess 5 mm Loss of septal input Tricuspid vestibule

Compact AV node

Inferior extension

Mitral vestibule Inferoseptal recess

The histological sections in this dataset, again prepared by serial histological sectioning of an adult human heart, are comparable in many ways with those shown in Figure 9, but differ in that minimal connections were found between the septum and compact node. In this setting, the rightward inferior extension may potentially be the only pathway providing atrioventricular conduction. The star in the lower left-hand panel indicates the inferior pyramidal space.

extensions, and the direct connections from the atrial septum. We have also highlighted the need to distinguish between the findings in experimental

animals and the arrangement in the human heart. This latter point is relevant when we assess the relationships between the connections themselves

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Extensions of the Atrioventricular Node The compact atrioventricular node itself is formed at the inferior end of the transition of the primary ring from the ventricular to the atrial myocardial masses. During initial cardiac development there is a second superior transition, which is broken during ongoing development with the formation of fibrous continuity between the leaflets of the aortic and mitral valves, this process attenuating the myocardium of the inner heart curvature. The atrial remnant of this second transition forms the retroaortic node.22,27 This nodal remnant, at least in human hearts, is separated by an area of working myocardium from the compact atrioventricular node. Its precise function, if any, remains to be clarified.27,28

and the so-called ‘ring tissues’. We first described the ‘ring tissues’ in the human heart as remnants of the primary ring, pointing out that it was these remnants that almost certainly persist as the structures incorrectly judged

by Kent as producing accessory atrioventricular myocardial pathways in the normal heart.24 We subsequently showed that, on occasion, the remnants could indeed persist as part of a re-entry circuit, forming the atrial component of the pathways nowadays described as atriofascicular tracts.25 These cardiomyocytes are part of the tissues we have described as the ‘primary ring’. As we have shown, they surround the developing orifice of the tricuspid valve, forming the basis of the compact node, but significantly also its rightward inferior extension. Therefore, the cardiomyocytes of the primary ring form one of the inputs to the atrioventricular node. These cardiomyocytes are overlaid by the cardiomyocytes of the tricuspid valvar vestibule, which themselves are derived from the atrioventricular canal myocardium.17 This is another ‘specialised’ area of myocardium, because it is known that it is the atrioventricular canal that provides the necessary delay in conduction of the cardiac impulse in many animal species, as well as early during cardiac development in mammals.6

Conclusion

On the basis of our findings during cardiac development, we can predict that all hearts have the basis for the compact atrioventricular node to make contact with atrial cardiomyocytes via its right and left inferior atrial extensions, or via the cardiomyocytes of the atrial septum. It is these connections that must provide the anatomical substrates for the ‘slow’ and ‘fast’ pathways into the node. As yet, electrophysiologists have been unable to characterise the specific composition of these pathways.8 Our analysis of datasets prepared from normal adult human hearts showed marked variation in the extent of these potential substrates. Furthermore, their architecture was subtly different from the arrangements found in mammalian species used in experiments designed to reveal the physiology of these presumed pathways. The increasing ability to assess the composition of the inferior pyramidal space, combined with knowledge of potential variations, will hopefully soon lead to clarification of the different pathways underscoring nodal re-entry tachycardia.

Furthermore, it is the atrioventricular canal myocardium that was identified as an additional ‘ring’ of specialised cardiac tissue in the investigation of Yanni et al.22 This second ring, identified using immunocytochemical markers in hearts from several non-human species, provides not only the tricuspid vestibular myocardium, but also the myocardium of the mitral valvar vestibule, and it is the mitral vestibule that produces the second inferior extension from the atrioventricular node. Therefore, both inferior nodal extensions are histologically specialised, but the rightward extension, derived from the primary ring, is additionally associated with the tricuspid valvar vestibule, derived from the ring derived from the atrioventricular canal myocardium. Either of these extensions may be presumed to be capable of slow conduction. Therefore, it is appropriate that one or other, or both, is believed to be a potential substrate for the slow pathway.1,8 The leftward extension may be long enough to reach the inferoposterior aspect of the mitral vestibule.26 In contrast, the septal connections of the compact node are derived by muscularisation of the vestibular spine and the mesenchymal cap. They are presumably working atrial cardiomyocytes. It is the final of these connections that is now suggested to function as the fast pathway.7 Hence, the inferences to be made from cardiac development, and the structure of the atrioventricular node, add support for developing theories regarding the potential circuits for the different types of atrioventricular nodal re-entry.

1. Katritsis DG. A unified theory for the circuit of atrioventricular nodal re-entrant tachycardia. Europace 2020;22:1763–7. https://doi.org/10.1093/europace/euaa196; PMID: 32978626.

2. Katritsis DG, Josephson ME. Classification of electrophysiological types of atrioventricular nodal re-entrant tachycardia: a reappraisal. Europace 2013;15:1231– 40. https://doi.org/10.1093/europace/eut100; PMID: 23612728.

3. Katritsis DG, Josephson ME. Differential diagnosis of regular, narrow-QRS tachycardias. Heart Rhythm 2015;12:1667–76. https://doi.org/10.1016/j.hrthm.2015.03.046; PMID: 25828600.

4. Tawara S. Das Reizleitungssystem des Säugetierherzens: eine anatomisch-histologische Studie über das Atrioventrikularbundel und die Purkinjeschen Fäden. Jena: Gustav Fischer, 1906.

5. Tawara S. The Conduction System of the Mammalian Heart: An Anatomico-histological Study of the Atrioventricular Bundle and the Purkinje Fibers. 1st English ed. London: Imperial College Press, 1998.

6. Anderson RH, Mori S, Spicer DE, et al. The anatomy, development, and evolution of the atrioventricular

7.

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12.

Clinical Perspective

• In all hearts, the compact atrioventricular node can make contact with atrial cardiomyocytes via its right and left inferior atrial extensions, or via the cardiomyocytes of the atrial septum.

• It is these connections that provide the anatomical substrates for the so-called ‘slow’ and ‘fast’ pathways into the node.

• The increasing ability to assess the composition of the inferior pyramidal space, combined with increasing knowledge of potential anatomical variations, increases the likelihood that the arrangement of the different pathways underscoring nodal re-entry tachycardia will soon be clarified.

• The role of the retroaortic node as a potential tachycardia substrate remains to be established.

conduction axis. J Cardiovasc Dev Dis 2018;5:44–61. https:// doi.org/10.3390/jcdd5030044; PMID: 30135383.

Anderson RH, Sanchez-Quintana D, Mori S, et al.

Re-evaluation of the structure of the atrioventricular node and its connections with the atrium. Europace 2020;22:821– 30. https://doi.org/10.1093/europace/euaa031; PMID: 32304217.

Katritsis DG, Marine JE, Katritsis G, et al. Spatial characterization of the tachycardia circuit of atrioventricular nodal re-entrant tachycardia. Europace 2021;23:1596–602. https://doi.org/10.1093/europace/euab130; PMID: 34240123.

Aschoff L. Lecture on cardiac disorders in their relationship to the specific muscle system of the heart. Verh Dtsch Ges Pathol 1910;14:3–35 [in German].

Mönckeberg JG. Beiträge zur normalen und pathologischen Anatomie des Herzens. Verh Dtsch Ges Pathol 1910;14:64–71.

Sternick EB, Sanchz-Quintana D. Critical assessment of the concepts and misconceptions of the cardiac conduction system over the last 100 years: the personal quest of Robert H. Anderson. J Cardiovasc Dev Dis 2021;8:5–17. https://doi. org/10.3390/jcdd8010005; PMID: 33477750.

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Anderson RH, Janse MJ, Van Capelle FJL, et al. A combined morphological and electrophysiological study of the atrioventricular node of the rabbit heart. Circ Res 1974;35:909–22. https://doi.org/10.1161/01.RES.35.6.909; PMID: 4430083.

Wessels A, Vermeulen JLM, Verbeek FJ, et al. Spatial distribution of ‘tissue-specific’ antigens in the developing human heart and skeletal muscle III. An immunohistochemical analysis of the distribution of the neural tissue antigen G1N2 in the embryonic heart; implications for the development of the atrioventricular conduction system. Anat Rec 1992;232:97–111. https://doi. org/10.1002/ar.1092320111; PMID: 1536469.

Anderson RH, Spicer DE, Brown NA, Mohun TJ. The development of septation in the four-chambered heart. Anat Rec 2014;297:1414–29. https://doi.org/10.1002/ar.22949; PMID: 24863187.

His W. Das Herz. In: His W, ed. Anatomie Menschlicher

Extensions of the Atrioventricular Node Embryonen. Vol. 3: Zeur Geschichte der Organe. Leipzig: Vogel, 1885;129–84.

17. Kim JS, Viragh S, Moorman AFM, et al. Development of the myocardium of the atrioventricular canal and the vestibular spine in the human heart. Circ Res 2001;88:395–402. https:// doi.org/10.1161/01.RES.88.4.395; PMID: 11230106.

18. Snarr BS, O’Neal JL, Chintalapudi MR, et al. Isl1 expression at the venous pole identifies a novel role for the second heart field in cardiac development. Circ Res 2007;101:971–4. https://doi.org/10.1161/CIRCRESAHA.107.162206; PMID: 17947796.

19. Jensen B, Spicer DE, Sheppard MN, Anderson RH. Development of the atrial septum in relation to postnatal anatomy and interatrial communications. Heart 2017;103:456–62. https://doi.org/10.1136/ heartjnl-2016-310660; PMID: 28003417.

20. Wessels A, Markman MWM, Vermeulen JLM, et al. The development of the atrioventricular junction in the human heart. Circ Res 1996;78:110–7. https://doi.org/10.1161/01.

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21. Yoshitake S, Kaneko Y, Morita K, et al. Reassessment of the location of the conduction system in atrioventricular septal defect using phase-contrast computed tomography. Semin Thorac Cardiovasc Surg 2020;32:960–8. https://doi. org/10.1053/j.semtcvs.2020.03.011; PMID: 32450213.

22. Yanni J, Boyett MR, Anderson RH, Dobrzynski H. The extent of the specialized atrioventricular ring tissues. Heart Rhythm 2009;6:672–80. https://doi.org/10.1016/j.hrthm.2009.01.021; PMID: 19328044.

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

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25. Anderson RH, Ho SY, Gillette PC, Becker AE. Mahaim, Kent

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26. Stavrakis S, Jackman WM, Lockwood D, et al. Slow/fast atrioventricular nodal reentrant tachycardia using the inferolateral left atrial slow pathway: role of the resetting response to select the ablation target. Circ Arrhythm Electrophysiol 2018;11:e006631. https://doi.org/10.1161/ CIRCEP.118.006631; PMID: 30354287.

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28. Cheung CC, Kim E, Tseng ZH, et al. Atrial tachycardia ablation at the pulmonic valve in a patient with congenitally corrected transposition of great arteries. JACC Clin Electrophysiol 2021;7:1473–81. https://doi.org/10.1016/j. jacep.2021.06.017; PMID: 34330669.

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Call for Submissions Arrhythmia & Electrophysiology Review publishes invited contributions from prominent experts, but also welcomes speculative submissions of a superior quality.

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