Autonomic Modulation and Cardiac Arrhythmias

Old Insights and Novel Strategies

Neal A. Chatterjee; Jagmeet P. Singh

Europace. 2021;23(11):1708-1721.

Abstract and Introduction

Abstract

The autonomic nervous system (ANS) plays a critical role in both health and states of cardiovascular disease. There has been a long-recognized role of the ANS in the pathogenesis of both atrial and ventricular arrhythmias (VAs). This historical understanding has been expanded in the context of evolving insights into the anatomy and physiology of the ANS, including dysfunction of the ANS in cardiovascular disease such as heart failure and myocardial infarction. An expanding armamentarium of therapeutic strategies—both invasive and non-invasive—have brought the potential of ANS modulation to contemporary clinical practice. Here, we summarize the integrative neuro-cardiac anatomy underlying the ANS, review the physiological rationale for autonomic modulation in atrial and VAs, highlight strategies for autonomic modulation, and finally frame future challenges and opportunities for ANS therapeutics.

Introduction

The autonomic nervous system (ANS) plays a critical role in both health and disease states of the cardiovascular system.^[1] An ever-improving understanding of the anatomy and physiology of the ANS^[2] has yielded foundational insights into its role in both the genesis and progression of cardiac disease, including heart failure (HF) and cardiac arrhythmias.^[3,4] These insights, coupled with dynamic technical improvements in autonomic modulation, frame an exciting landscape of autonomic-focused therapeutics for cardiovascular disease generally and cardiac arrhythmias specifically.

In this review, we will summarize the integrative neuro-cardiac anatomy underlying the ANS, review the physiological rationale for autonomic modulation in atrial and ventricular arrhythmias (VAs), highlight strategies for autonomic modulation, and finally frame future challenges and opportunities for ANS therapeutics in this space. In addition to reviewing contemporary modulatory therapies, this review will specifically highlight novel and experimental approaches to autonomic modulation.

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Europace. 2021;23(11):1708-1721. © 2021 Oxford University Press
Copyright 2007 European Heart Rhythm Association of the European Society of Cardiology (ESC). Published by Oxford University Press. All rights reserved.

Abstract and Introduction
Neuro-cardiac Anatomic Hierarchy of the Autonomic Nervous System
Autonomic Modulation and Ventricular Arrhythmias
Autonomic Modulation and Atrial Arrhythmias
References

Table 1. Active clinical trials of autonomic modulation for atrial and ventricular arrhythmias
Intervention	Trial name	Clinical trial identifier	No. of participants/status	Description
Atrial arrhythmias
Ganglionated plexus ablation	GANGLIA-AF	NCT02487654	180/completed	Randomized study of PVI vs. GP ablation alone in patients with paroxysmal AF eligible for AF ablation
	ADD-GP	NCT03535818	60/recruiting	Randomized study evaluating efficacy of adjunctive GP ablation at time of re-do PVI in patients with paroxysmal AF
	–	NCT02035163	62/recruiting	Randomized study of the efficacy of atrial GP cryoablation at the time of cardiac surgery for prevention of post-operative AF
Epicardial botulinum toxin injection	BOTAF	NCT04075981	220/recruiting	Randomized trial of botulinum toxin to prevent AF in patients undergoing cardiac surgery
	NOVA	NCT03779841	330/recruiting	Randomized dose-ranging study to evaluate efficacy and safety of botulinum toxin injection to prevent post-operative AF at time of cardiac surgery
Vagal (tragus) nerve stimulation	–	NCT03533140	42/unknown	Randomized study of low-level tragus stimulation to prevent post-operative AF after cardiac surgery
	TraP-AF	NCT03392649	80/recruiting	Randomized study (with sham control) of tragus stimulation to prevent AF after cardiac surgery
	tVNS-POAF	NCT04514757	266/not yet recruiting	Randomized study (with sham control) of tragus stimulation to prevent AF after cardiac surgery
Spinal cord stimulation	TERMINATION-AF	NCT03539354	60/unknown	Randomized study of temporary spinal cord stimulation to prevent AF after cardiac surgery
Thoracic epidural anaesthesia	–	NCT02292030	60/unknown	Prospective cohort study of adjunctive thoracic epidural anaesthesia in heart failure patients with AF undergoing cardioversion
	–	NCT01718717	50/unknown	Randomized trial of thoracic epidural anaesthesia to prevent AF after lung resection
Stellate ganglion blockade	–	NCT03450226	40/unknown	Randomized study evaluating efficacy of stellate ganglion blockade to prevent post-cardiac surgery arrhyhmias
Renal denervation	H-FIB	NCT01635998	50/completed	Randomized study of adjunctive renal denervation during PVI for AF (paroxysmal or persistent)
	RDPAF	NCT01990911	100/active, not recruiting	Randomized study of renal denervation in patients with AF and hypertension
	ASAF	NCT02115100	138/recruiting	Randomized study of adjunctive renal denervation in patients with AF undergoing PVI
	RDN-AF	NCT01907828	61/completed	Randomized assessment of adjunctive renal denervation in patients with AF undergoing PVI
	–	NCT03246568	40/recruiting	Randomized study of adjunctive renal denervation in patients with persistent AF undergoing PVI (cryoablation)
	–	NCT01686542	100/recruiting	Randomized assessment of adjunctive renal denervation in patients with AF undergoing PVI
	ERDAF	NCT04055285	30/not yet recruiting	Randomized study of renal denervation in patients with paroxysmal AF and hypertension
	ULTRA-HFIB	NCT04182620	130/recruiting	Randomized study of renal denervation using ablative ultrasound energy at time of PVI
Ventricular arrhythmias
Vagal nerve stimulation	–	NCT04359004	10/recruiting	Prospective observational cohort study of percutaneous vagal nerve stimulation at the time of VT ablation
Stellate ganglion blockade	–	NCT02646501	20/unknown	Randomized study of stellate ganglion blockade in patients with electrical VT/VF storm
Renal denervation	RESCUE	NCT01747837	48/completed	Randomized study of renal denervation to prevent ICD therapies in patients undergoing secondary prevention ICD or primary prevention ICD with inducible VA by programmed stimulation
	RESET-VT	NCT01858194	21/completed	Randomized study of adjunctive renal denervation in patients undergoing catheter ablation for VT
Cardiac sympathetic denervation	–	NCT03071653	30/unknown	Randomized study of left cardiac sympathetic denervation in heart failure patients. Ventricular arrhythmias are component of primary outcome
	PREVENT-VT	NCT01013714	40/not yet recruiting	Randomized study of cardiac sympathetic denervation in patients with a history of ICD appropriate shock
	–	NCT04239144	30/recruiting	Randomized study of sympathetic denervation, catheter ablation, or medical therapy in patients with Chagas disease with recurrent ICD therapy
Transcutaneous magnetic stimulation	STAR-VT	NCT04043312	26/recruiting	Randomized study of transcutaneous magnetic stimulation of the left stellate ganglion for patients with electrical VT/VF storm

Status reflects the reported status of the study by study investigators as reflected in the United States National Library of Medicine public database.
ADD-GP, Adjunctive Ganglionated Plexus Ablation in Redo-Pulmonary Vein Isolation; AF, atrial fibrillation; ASAF, Treatment of Atrial Fibrillation in Patients by Pulmonary Vein Isolation in Combination with Renal Denervation or Pulmonary Vein Isolation Only; BOTAF; Prevention of Atrial Fibrillation by Botulinum Toxin Injections; ERDAF, Effect of Renal Denervation on Atrial Fibrillation; GANGLIA-AF, Ectopy Triggering Ganglionated Plexus Ablation to Prevent Atrial Fibrillation; GP, ganglionated plexus; H-FIB, Adjunctive Renal Denervation in the Treatment of Atrial Fibrillation; ICD, implantable cardioverter-defibrillator; NOVA, Botulinum Toxin Type A for the Prevention of Post-operative Atrial Fibrillation in Patients Undergoing Open-chest Cardiac Surgery; PREVENT-VT, Cardiac Sympathetic Denervation for Prevention of Ventricular Tachyarrhythmias; PVI, pulmonary vein isolation; RDN-AF, A Feasibility Study to Evaluate the Effect of Concomitant Renal Denervation and Cardiac Ablation on Atrial Fibrillation Recurrence; RDPAF, Renal Sympathetic Denervation Prevents Atrial Fibrillation in Patients with Hypertensive Heart Disease; RESCUE, Renal Sympathetic Denervation to Suppress Tachyarrhythmias in ICD Recipients; RESET-VT, Renal Sympathetic Denervation as an Adjunct to Catheter-based VT Ablation; STAR-VT, Magnetic Stimulation to Treat VT Storm; TERMINATION-AF, Temporary Spinal Cord Stimulation to Prevent Atrial Fibrillation After Cardiac Surgery.