Neural Mechanisms of Premature Ventricular Contraction-Induced Cardiomyopathy Revealed by Targeted Neuromodulation of the Cardiac Neuraxis

Richmond Institute For Veterans Research, Richmond VA

Investigators

Abstract

Frequent premature ventricular contractions (PVCs) can cause PVC-induced cardiomyopathy (PVC-CM), precipitate arrhythmias, induce heart failure and increase cardiac mortality. However, the mechanisms remain unclear. Current therapies rely solely on PVC suppression but this may not be viable in many patients nor sufficient to reverse neuro-cardiac remodeling which may persist to induce ongoing harm through autonomic dysregulation (sympathetic overload and sympathetic/parasympathetic dysfunction). We hypothesize that PVCs induce neural remodeling which is a critical mediator that promotes cardiac remodeling (PVC-CM) and confers arrhythmogenesis via autonomic dysregulation. Neuromodulation protects against neural remodeling thereby prevents or restores PVC-CM and suppresses arrhythmias (Central Hypothesis). Through a novel chronic de-afferentation model of sino-aortic afferent denervation (SAAD), we will (Aim 1) test the hypothesis that the afferent neural mechanism of PVC-CM is an arterial baroreflex “sensory” overload triggered by frequent PVCs and mediated via SAA nerves. SAAD dampens baroreflex overload and protects against PVC- CM. We will also (Aim 2) test the hypothesis that the efferent neural mechanism of PVC-CM is an efferent sympathetic overload triggered by PVCs, hence bilateral vs unilateral efferent cardiac sympathetic denervation (CSD) incrementally protects against PVC-CM by providing graded cardiac shielding against sympathetic overload, thus re-purposing a clinically approved anti-arrhythmic treatment (CSD) to novel use of cardio- protection against sympathetic overload. As a counterpart to surgical approaches, we will (Aim 3) test the hypothesis that carvedilol protects against PVC-CM via downstream beta-blockade as well as via novel and pleiotropic neuro-modulatory effects by reducing sympathetic nerve activity, cardiac adrenergic overload and preserving baroreflex and efferent autonomic function by restoring intrinsic cardiac neurotrophy suppressed by PVCs. Translationally, we will also employ therapeutic vs pre-emptive neuromodulation approaches. In-vivo electrophysiologic studies will assess protection from cardiac electrical remodeling and arrhythmogenesis while serial echocardiography will assess impact on cardiac structural remodeling. Novel chronic ambulatory cardio- neural-BP telemetry can assess neural remodeling across 4 different neural sites correlating with BP, heart rate variability and spontaneous arrhythmogenesis. Novel provocative “dual stressor” PVC and vasopressor challenge will assess the novel contribution of dynamic baroreflexes to PVC-CM, while “dual stressor” exercise and PVC challenge will protection against efferent sympathetic and parasympathetic dysfunction. Cellular- molecular and in-vitro studies will assess the impact on intrinsic vs extrinsic neural remodeling and intracellular calcium remodeling. This study will provide novel proof-of-concept that autonomic remodeling/dysregulation causes PVC-CM and pro-arrhythmia, map critical neural signaling pathways (afferent, efferent, downstream) in the PVC-neural loop thus identify novel therapeutic targets as alternative therapies to PVC suppression.