Antiarrhythmic mechanisms of chronic vagal nerve stimulation in sympathetic neurons

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PROJECT SUMMARY/ABSTRACT Ventricular tachycardia/fibrillation (VT/VF) occur after myocardial infarction (MI), and are a common cause of sudden cardiac death. Sympathovagal imbalance, resulting from structural and functional remodeling of cardiac sympathetic neurons, promotes the initiation of VT/VF after MI. This process remains poorly understood, and current drugs that prevent sympathetic excess are limited by significant side effects and inadequate efficacy. Vagal nerve stimulation (VNS) is a promising therapy to restore sympathovagal balance with supporting data from animal models and humans, but the mechanisms underlying its benefits are poorly understood. The goal of this proposal is to test the novel hypothesis that chronic VNS exerts its protective effects against VT/VF and progressive cardiac dysfunction primarily by impacting sympathetic neuronal dysfunction after MI. In preliminary studies, we have shown that sympathetic dysfunction encompasses several key elements that include neuronal dysfunction, satellite glial activation, neuroinflammation and aberrant spatiotemporal neural activity within sympathetic ganglia such as stellate ganglia. Pilot studies from our group show that VNS exerts a governing effect on sympathetic function acutely, independent on the level of sympathoexcitation, and chronically mitigates arrhythmogenesis following MI. We will test our hypotheses using novel tools from a multidisciplinary team of investigators in 3 specific aims in pigs with chronic MI. We will delineate the impact of chronic VNS on structural and neurochemical remodeling in sympathetic neurons (Aim 1). We will determine whether chronic VNS, with its anti-inflammatory effects, attenuates satellite glial activation and neuroinflammation in stellate ganglia (Aim 2). Finally, we will dissect the impact of chronic VNS on spatiotemporal activity of stellate ganglion neurons using novel computational tools applied to high- resolution high-fidelity in vivo extracellular neural recordings from the stellate ganglion (Aim 3). We will directly link the neuroanatomical (Aim 1), neuroinflammatory (Aim 2), and neurophysiologic (Aim 3) remodeling to spontaneous and inducible VT/VF, as well as proarrhythmic local myocardial arrhythmogenic mechanisms. The results of this proposal will 1) advance our understanding of the mechanistic underpinnings of VNS efficacy and 2) potentially uncover novel pathways by which sympathetic dysfunction can be prevented or reversed, to which new therapeutic strategies can be devised.