Antiarrhythmic mechanisms of chronic vagal nerve stimulation in sympathetic neurons

项目摘要/摘要 室性心动过速/室颤(VT/VF)发生在心肌梗死(MI)后，是导致 心源性猝死。交感神经迷走神经失衡，由结构和功能重塑引起 心脏交感神经元，促进心肌梗死后室速/室颤的启动。这一进程仍然很差。 了解，目前预防交感神经过度的药物受到显著副作用和 疗效不佳。迷走神经刺激(VNS)是一种很有前途的恢复交感迷走神经平衡的方法 有来自动物模型和人类的支持数据，但其益处背后的机制很差 明白了。这项提议的目的是检验慢性VNS发挥其保护性作用的新假设 主要通过冲击交感神经元对抗VT/VF和进展性心功能不全 心肌梗死后功能障碍。 在初步研究中，我们已经表明交感神经功能障碍包括几个关键因素 这些因素包括神经元功能障碍、卫星神经胶质激活、神经炎症和异常 交感神经节如星状神经节内的时空神经活动。我们小组的初步研究 结果表明，VNS对交感神经功能有显著的调控作用，且不依赖于 交感神经兴奋，并慢性减轻心肌梗塞后心律失常的发生。我们将检验我们的假设 使用来自多学科研究团队的新工具，针对慢性心肌梗死猪的3个特定目标。我们 将描述慢性VNS对交感神经元结构和神经化学重塑的影响 (目标1)。我们将确定慢性VNS是否具有抗炎作用，削弱卫星神经胶质细胞 星状神经节的激活和神经炎症(目标2)。最后，我们将剖析慢性VNS的影响 应用新的计算工具研究星状神经节神经元的时空活动 来自星状神经节的高分辨率在体细胞外神经记录(目标3)。我们会直接 将神经解剖学(目标1)、神经炎性(目标2)和神经生理学(目标3)重塑联系到 自发性和诱发性室速/室颤，以及致心律失常的局部心肌致心律失常机制。 这一提议的结果将1)促进我们对VNS机制基础的理解 疗效和2)可能发现可预防交感神经功能障碍或 逆转，可以设计出新的治疗策略。

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.