Neuromodulation With Thoracic Dorsal Root Ganglion Stimulation Reduces Ventricular Arrhythmogenicity.

Yuki Kuwabara,Siamak Salavatian,Kimberly Howard-Quijano,Aman Mahajan,Eevanna Lundquist,Tomoki Yamaguchi

doi:10.3389/fphys.2021.713717

Abstract

Introduction: Sympathetic hyperactivity is strongly associated with ventricular arrhythmias and sudden cardiac death. Neuromodulation provides therapeutic options for ventricular arrhythmias by modulating cardiospinal reflexes and reducing sympathetic output at the level of the spinal cord. Dorsal root ganglion stimulation (DRGS) is a recent neuromodulatory approach; however, its role in reducing ventricular arrhythmias has not been evaluated. The aim of this study was to determine if DRGS can reduce cardiac sympathoexcitation and the indices for ventricular arrhythmogenicity induced by programmed ventricular extrastimulation. We evaluated the efficacy of thoracic DRGS at both low (20 Hz) and high (1 kHz) stimulation frequencies.Methods: Cardiac sympathoexcitation was induced in Yorkshire pigs (n = 8) with ventricular extrastimulation (S1/S2 pacing), before and after DRGS. A DRG-stimulating catheter was placed at the left T2 spinal level, and animals were randomized to receive low-frequency (20 Hz and 0.4 ms) or high-frequency (1 kHz and 0.03 ms) DRGS for 30 min. High-fidelity cardiac electrophysiological recordings were performed with an epicardial electrode array measuring the indices of ventricular arrhythmogenicity—activation recovery intervals (ARIs), electrical restitution curve (Smax), and Tpeak–Tend interval (Tp-Te interval).Results: Dorsal root ganglion stimulation, at both 20 Hz and 1 kHz, decreased S1/S2 pacing-induced ARI shortening (20 Hz DRGS −21±7 ms, Control −50±9 ms, P = 0.007; 1 kHz DRGS −13 ± 2 ms, Control −46 ± 8 ms, P = 0.001). DRGS also reduced arrhythmogenicity as measured by a decrease in Smax (20 Hz DRGS 0.5 ± 0.07, Control 0.7 ± 0.04, P = 0.006; 1 kHz DRGS 0.5 ± 0.04, Control 0.7 ± 0.03, P = 0.007), and a decrease in Tp-Te interval/QTc (20 Hz DRGS 2.7 ± 0.13, Control 3.3 ± 0.12, P = 0.001; 1 kHz DRGS 2.8 ± 0.08, Control; 3.1 ± 0.03, P = 0.007).Conclusions: In a porcine model, we show that thoracic DRGS decreased cardiac sympathoexcitation and indices associated with ventricular arrhythmogenicity during programmed ventricular extrastimulation. In addition, we demonstrate that both low-frequency and high-frequency DRGS can be effective neuromodulatory approaches for reducing cardiac excitability during sympathetic hyperactivity.

Highlights

Sympathetic hyperactivity is strongly associated with ventricular arrhythmias and sudden cardiac death
We evaluated the effectiveness of dorsal root ganglion stimulation (DRGS) as an alternative neuromodulation therapy by demonstrating the reduction of cardiac sympathoexcitation and ventricular arrhythmogenicity indices induced by programmed ventricular extrastimulation
We investigated the efficacy of DRGS on reducing cardiac sympathoexcitation and the indices associated with increased arrhythmogenicity in a porcine model

Summary

Introduction

Sympathetic hyperactivity is strongly associated with ventricular arrhythmias and sudden cardiac death. Neuromodulation provides therapeutic options for ventricular arrhythmias by modulating cardiospinal reflexes and reducing sympathetic output at the level of the spinal cord. We and others have previously shown that spinal cord stimulation targeting the dorsal columns reduced the cardiac sympathoexcitation, decreased ventricular arrhythmias, and improved myocardial function in the porcine model (Southerland et al, 2007; Lopshire et al, 2009; Howard-Quijano et al, 2017a). Bioelectronic dorsal root ganglion stimulation (DRGS) is a novel approach to neuromodulation therapy, targeting these neural structures that contain the axons and cell bodies of afferent neurons, located at the distal end of the dorsal root of the spinal cord (Sverrisdottir et al, 2020). Evidence suggests that DRGS is an effective treatment for some pain syndromes, clinically and preclinically (Liem et al, 2015; Deer et al, 2019; Yu et al, 2020)

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