Antiarrhythmic mechanisms of chronic vagal nerve stimulation in sympathetic neurons

项目概要/摘要-项目3 室性心动过速/颤动（VT/VF）发生在心肌梗死（MI）后，是心肌梗死的常见原因。 心源性猝死交感迷走神经失衡，由结构和功能重塑引起， 心脏交感神经元，促进MI后VT/VF的起始。这一进程仍然很差 目前，预防交感神经过度的药物受到严重副作用的限制， 功效不足。迷走神经刺激（VNS）是一种很有前途的恢复交感-迷走神经平衡的治疗方法 动物模型和人类的支持数据，但其益处背后的机制很差 明白这项提议的目的是为了验证慢性迷走神经刺激发挥其保护作用的新假设。 主要通过影响交感神经元对VT/VF和进行性心功能不全的作用 MI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， 包括神经元功能障碍、卫星胶质细胞活化、神经炎症和异常的 交感神经节如星状神经节内的时空神经活动。我们小组的试点研究 表明VNS对交感神经功能具有急性的控制作用，不依赖于VNS水平。 交感神经兴奋，并长期减轻心肌梗死后的心肌梗死。我们将测试我们的假设 使用来自多学科研究小组的新工具，在慢性MI猪中进行3个特定目标。我们 将描述慢性迷走神经刺激对交感神经元结构和神经化学重塑的影响 (Aim 1）。我们将确定慢性VNS是否具有抗炎作用， 激活和神经炎症的星状神经节（目的2）。最后，我们将剖析慢性迷走神经综合征的影响 星状神经节神经元的时空活动，使用新的计算工具，适用于高- 星状神经节的高分辨率高保真体内细胞外神经记录（Aim 3）。我们会直接 将神经解剖学（Aim 1）、神经炎症（Aim 2）和神经生理学（Aim 3）重塑与 自发性和诱导性VT/VF，以及预防性局部心肌缺血机制。 这项建议的结果将1）推进我们对VNS机制基础的理解 有效性和2）潜在地揭示了可以预防交感神经功能障碍新途径，或 逆转，可以设计新的治疗策略。

PROJECT SUMMARY/ABSTRACT – Project 3 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.