Antiarrhythmic mechanisms of chronic vagal nerve stimulation in sympathetic neurons

交感神经元慢性迷走神经刺激的抗心律失常机制

基本信息

批准号：
10627579
负责人：
Olujimi A Ajijola
金额：
$ 47.31万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-10 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627579
关键词：
Action Potentials Acute Adrenergic Antagonists Animal Model Animals Anti-Arrhythmia Agents Antiinflammatory Effect Attenuated Cardiac Cardiomyopathies Cause of Death Cell Communication Cells Chronic Clinical Trials Complex Coronary Data Dose Electrophysiology (science)Elements Equilibrium Family suidae Functional disorder Goals Heart Heart Injuries Heterogeneity Human Immune Infarction Inflammation Inflammatory Intervention Investigation Life Link Mediating Myocardial Myocardial Infarction Myocardial dysfunction Myocardium Nerve Nervous System control Neuroanatomy Neuronal Dysfunction Neurons Pathway interactions Pattern Pharmaceutical Preparations Pilot Projects Predisposition Prevention Process Research Personnel Resolution Signal Transduction Structure Structure of stellate ganglion Sympathetic Ganglia Sympathetic Nervous System Testing Therapeutic Vascularization Ventricular Arrhythmia Ventricular Remodeling Ventricular Tachycardia animal data cardiac device cardiac implant cardioprotection computerized tools extracellular glial activation human model immune cell infiltrate improved in vivo insight multidisciplinary neural neural network neurochemistry neuroinflammation neurophysiology neuroregulation neurotransmission novel novel strategies novel therapeutic intervention pharmacologic prevent protective effect side effect spatiotemporal sudden cardiac death tool transcriptomics

Action Potentials Acute Adrenergic Antagonists Animal Model Animals Anti-Arrhythmia Agents Antiinflammatory Effect Attenuated Cardiac Cardiomyopathies Cause of Death Cell Communication Cells Chronic Clinical Trials Complex Coronary Data Dose Electrophysiology (science)Elements Equilibrium Family suidae Functional disorder Goals Heart Heart Injuries Heterogeneity Human Immune Infarction Inflammation Inflammatory Intervention Investigation Life Link Mediating Myocardial Myocardial Infarction Myocardial dysfunction Myocardium Nerve Nervous System control Neuroanatomy Neuronal Dysfunction Neurons Pathway interactions Pattern Pharmaceutical Preparations Pilot Projects Predisposition Prevention Process Research Personnel Resolution Signal Transduction Structure Structure of stellate ganglion Sympathetic Ganglia Sympathetic Nervous System Testing Therapeutic Vascularization Ventricular Arrhythmia Ventricular Remodeling Ventricular Tachycardia animal data cardiac device cardiac implant cardioprotection computerized tools extracellular glial activation human model immune cell infiltrate improved in vivo insight multidisciplinary neural neural network neurochemistry neuroinflammation neurophysiology neuroregulation neurotransmission novel novel strategies novel therapeutic intervention pharmacologic prevent protective effect side effect spatiotemporal sudden cardiac death tool transcriptomics

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项目摘要

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.

项目摘要/摘要 - 项目3 心室心脏（VT/VF）发生心肌梗塞（MI）后发生，是发生的，是突然心脏死亡。由结构和功能重塑产生的交感神经失衡心脏交感神经元，在MI之后促进VT/VF的倡议。这个过程仍然很差理解的，并且预防交感神经超过的当前药物受到重大副作用的限制，效率不足。迷走神经刺激（VNS）是恢复交感神经平衡的有希望的疗法借助动物模型和人类的支持数据，但其益处的基础机制却很差理解齿。该提议的目的是检验慢性VNS执行保护性的新颖假设对VT/VF和进行性心脏功能障碍的影响主要通过影响交感神经元 MI后功能障碍。在初步研究中，我们表明交感神经功能障碍包括几个关键包括神经元功能障碍，卫星神经胶质激活，神经炎症和异常的元素交感神经节内的时空神经活动，例如星状神经节。我们小组的试点研究证明VNS对同情功能执行执政效应，独立于交感神经和长期减轻MI后心律失常的作用。我们将检验我们的假设在患有慢性MI的猪中，使用来自研究人员的多学科团队的新工具。我们将描述慢性VN对交感神经元中结构和神经化学重塑的影响（目标1）。我们将确定慢性VN是否具有抗炎作用，减轻了卫星的胶质星状神经节中的激活和神经炎症（AIM 2）。最后，我们将剖析慢性VN的影响使用应用于高级的新型计算工具的星状神经节神经元的时空活性从星状神经节中的体内细胞外神经记录的高保真（AIM 3）。我们将直接将神经解剖学（AIM 1），神经炎症（AIM 2）和神经生理学（AIM 3）链接到赞助和可诱导的VT/VF，以及心律失常的局部心肌心律失常机制。该提案的结果将1）提高我们对VNS机械基础的理解效率和2）可能会发现可以预防交感神经功能障碍或相反，可以设计出新的治疗策略。