Mechanisms of Cardiac TRPV1 Afferent Remodeling in Ventricular Arrhythmias

项目摘要/摘要 心肌梗死(MI)使患者容易发生室性心动过速/室颤(VT/VF)和猝发 心源性死亡。心肌梗死后，心脏交感神经系统(SNS)内的变化一直很紧密 链接到VT/VF。这些改变包括炎症、星状核内的结构和功能重塑。 神经节和瘢痕边缘带内交感神经的异质性重构。 这些导致心脏交感神经传递增强和功能障碍，从而导致室速/室颤。 尽管心肌梗死后脊髓传入信号增强，但脊髓传入的心律失常诱发电位(VIA) 与心脏交感神经的不适应相互作用)尚未被探索。基于来自 我们小组的目标是验证慢性增强的心脏传入信号是 交感神经重塑和功能障碍的主要驱动力，导致室速/室颤。 我们小组使用心外膜树脂毒素(RTX)耗尽心脏TRPV1传入神经的初步研究 猪支持持续性传入信号(急性缺血期以外)发挥作用的理论基础 在形成导致VAS的神经和心脏底物方面发挥核心作用。我们将使用以下工具来测试我们的假设 来自3个目标的多学科调查团队的新工具，在猪与心肌梗死。在目标1中，我们将 确定心肌梗死后星状核内结构、神经炎性和功能性神经元重构 神经节是由持续的TRPV1传入信号引起的。在目标2中，我们将确定持久化 心脏TRPV1的激活增加了心肌内神经递质的释放，从而增加了VT/VF的风险。这将是 使用同步心脏电生理标测和活体实时检测 心肌内去甲肾上腺素和神经肽Y水平。我们将确定TRPV1是否传入 耗竭通过使神经递质的释放模式正常化来减少心律失常的发生。在《目标3》中，我们将 确定RTX应用于VT/VF临床治疗的最佳部位[心外膜神经节与星状神经节对比。 硬膜外应用]。这将指导临床对传入神经调节的翻译。这项提议的结果是 可能改变心肌梗死后发生心律失常的方式，并指导开发新的治疗方法 防止心肌梗塞后传入信号的改变，以填补一个主要的临床空白。

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.