Mechanisms of Cardiac TRPV1 Afferent Remodeling in Ventricular Arrhythmias

室性心律失常中心脏 TRPV1 传入重塑的机制

• 批准号: 10278404
• 负责人: Olujimi A Ajijola
• 金额: $ 48.41万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10278404
• 关键词: Acute; Agonist; Animals; Attenuated; Axon; Bioavailable; Calcium Channel Blockers; Cardiac; Cause of Death; Chronic; Cicatrix; Clinical; Clinical Management; Data; Detection; Development; Drug Delivery Systems; Drug usage; Electrophysiology (science); Epicardium; Family suidae; Feedback; Fiber; Functional disorder; Goals; Heart; Inflammation; Intervention; Lead; Link; Modeling; Myocardial; Myocardial Infarction; Myocardial dysfunction; Myocardium; Nature; Nerve; Nerve Fibers; Neurons; Norepinephrine; Oral; Pathologic; Patient Care; Patients; Pattern; Pharmaceutical Preparations; Phase; Pilot Projects; Play; Research Personnel; Resiniferatoxin; Risk; Role; Shapes; Signal Transduction; Site; Spinal; Spinal Cord; Structure; Structure of stellate ganglion; Sympathetic Nervous System; TRPV1 gene; Testing; Time; Translating; Ventricular Arrhythmia; Ventricular Tachycardia; afferent nerve; base; beta-adrenergic receptor; clinical translation; comparative efficacy; excitotoxicity; first-in-human; glial activation; in vivo; injured; multidisciplinary; neurochemistry; neuroinflammation; neuropeptide Y; neuroregulation; neurotransmission; neurotransmitter release; novel; novel therapeutics; prevent; relating to nervous system; release factor; side effect; sudden cardiac death; tool

PROJECT SUMMARY/ABSTRACT Myocardial infarction (MI) predisposes patients to ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death. After MI, alterations within the cardiac sympathetic nervous system (SNS) have been tightly linked to VT/VF. These alterations include inflammation, structural and functional remodeling within the stellate ganglion, and heterogeneous remodeling of intramyocardial sympathetic nerves in the scar-border zone. These result in enhanced and dysfunctional cardiac sympathetic neurotransmission that lead to VT/VF. Although spinal afferent signaling is enhanced after MI, the arrhythmogenic potential of spinal afferents (via maladaptive interactions with cardiac sympathetic nerves) has not been explored. Based on novel data from our group, the goal of this proposal is to test the hypothesis that chronic enhanced cardiac afferent signaling is the primary driver of sympathetic neural remodeling and dysfunction that causes VT/VF. Pilot studies from our group using epicardial resiniferatoxin (RTX) to deplete cardiac TRPV1 afferents in porcine support the rationale that persistent afferent signaling (beyond the acute ischemic phase) plays a central role in shaping the neural and cardiac substrates that lead to VAs. We will test our hypotheses using novel tools from a multidisciplinary team of investigators in 3 aims, in porcine with MI. In aim 1, we will determine whether post-MI structural, neuroinflammatory, and functional neuronal remodeling within stellate ganglia are caused by persistent TRPV1 afferent signaling. In aim 2, we will determine whether persistent cardiac TRPV1 activation amplifies intramyocardial neurotransmitter release to increase VT/VF risk. This will be accomplished using simultaneous cardiac electrophysiologic mapping and real time in vivo detection of intramyocardial Norepinephrine and neuropeptide Y levels. We will determine whether TRPV1 afferent depletion attenuates arrhythmogenicity by normalizing neurotransmitter release patterns. In aim 3, we will define the optimal site of RTX delivery for clinical management of VT/VF [Epicardial vs. Stellate Ganglion vs. Epidural application]. This will guide clinical translation of afferent neuromodulation. The results of this proposal may shift how arrhythmogenesis is approached after MI, and guide the development of new therapies that prevent altered afferent signaling after MI to fill a major clinical gap.

项目摘要/摘要 心肌梗死（MI）使患者患有心室心动过速/金刚纤维（VT/VF）和突然 心脏死亡。 MI之后，心脏交感神经系统（SNS）内的改变已紧密 链接到VT/VF。这些改变包括炎症，结构和功能重塑。 神经节和疤痕界区域内心脏内膜神经的异质重塑。 这些导致了增强和功能障碍的心脏交感神经传递，导致VT/VF。 尽管MI后脊柱传入信号传导增强了，但脊柱传入的心律失常潜力（通过 尚未探索与心脏交感神经的不良相互作用）。基于来自 我们的小组，该提议的目的是检验以下假设：慢性增强心脏传入信号是 引起VT/VF的交感神经重塑和功能障碍的主要驱动力。 我们组的试验研究使用心外膜树脂毒素（RTX）耗尽心脏TRPV1传入 猪支持持续传入信号传导（超出急性缺血阶段）的理由。 在塑造导致VA的神经和心脏底物中的中心作用。我们将使用 来自三个目标的多学科研究人员的新工具，带有MI的猪。在AIM 1中，我们将 确定恒星结构，神经炎症和功能性神经元重塑是否 神经节是由持续的TRPV1传入信号传导引起的。在AIM 2中，我们将确定是否持续 心脏TRPV1激活放大了心脏内神经递质释放，以增加VT/VF风险。这会 可以使用同时的心脏电生理图和实时检测来实现 心膜内去甲肾上腺素和神经肽y水平。我们将确定trpv1是否传入 耗竭可通过使神经递质释放模式归一化来减轻心律失常。在AIM 3中，我们将 定义用于VT/VF的临床管理的RTX传递的最佳位点[心外膜与星状神经节VS。 硬膜外应用]。这将指导传入神经调节的临床翻译。该提议的结果 可能会改变MI之后心律失常的处理方式，并指导新疗法的发展 防止MI后传入信号的改变，以填补主要的临床间隙。