Neuroscientific therapies for atrial fibrillation

Abstract

The cardiac autonomic nervous system (ANS) plays an integral role in normal cardiac physiology as well as in disease states that cause cardiac arrhythmias. The cardiac ANS, comprised of a complex neural hierarchy in a nested series of interacting feedback loops, regulates atrial electrophysiology and is itself susceptible to remodelling by atrial rhythm. In light of the challenges of treating atrial fibrillation (AF) with conventional pharmacologic and myoablative techniques, increasingly interest has begun to focus on targeting the cardiac neuraxis for AF. Strong evidence from animal models and clinical patients demonstrates that parasympathetic and sympathetic activity within this neuraxis may trigger AF, and the ANS may either induce atrial remodelling or undergo remodelling itself to serve as a substrate for AF. Multiple nexus points within the cardiac neuraxis are therapeutic targets, and neuroablative and neuromodulatory therapies for AF include ganglionated plexus ablation, epicardial botulinum toxin injection, vagal nerve (tragus) stimulation, renal denervation, stellate ganglion block/resection, baroreceptor activation therapy, and spinal cord stimulation. Pre-clinical and clinical studies on these modalities have had promising results and are reviewed here.

Keywords: Atrial fibrillation; Autonomic nervous system; Neurocardiology; Neuromodulation; Vagus nerve.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1

Cardiac ANS. The cardiac ANS is composed of afferent and efferent (sympathetic and parasympathetic) components that interact at multiple levels within the hierarchy that spans the heart, intrathoracic extracardiac ganglia, and central nervous system (brain and spinal cord). DRG indicates dorsal root ganglion. Adapted from Shivkumar et al., 2016.

Figure 2

ICNS. The ICNS is composed of ganglionated plexi that cluster at the hilum of the heart, close to where the PVs enter the left atrium. Anatomy of the ganglionated plexuses (GPs) that comprise the intrinsic cardiac nervous system. These GPs are typically found on the posterior (A) and superior (B) epicardial surfaces of the heart. IVC indicates inferior vena cava; IVC-IAGP, inferior vena cava-inferior atrial ganglionated plexus; LIGP, left inferior ganglionated plexus; LSGP, left superior ganglionated plexus; RAGP, right atrial ganglionated plexus; SVC, superior vena cava. Adapted from Rajendran et al., 2017.

Figure 3

Neuroscientific interventions for AF. Multiple approaches to neuroscientific therapies for AF have been developed at multiple levels of the cardiac neuraxis and include ganglionated plexus (GP) ablation; botulinum toxin injection in the GPs; vagal nerve and tragus stimulation; renal artery denervation; stellate ganglionic blockade; spinal cord stimulation; and baroreceptor activation therapy. Baroreceptor activation therapy and spinal cord stimulation have only been evaluated in preclinical models. IVC indicates inferior vena cava; LIPV, left inferior pulmonary vein; LSPV, left superior pulmonary vein; RSPV, right superior pulmonary vein. Adapted from Zhu et al., 2019.