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: 10674847
• 负责人: Olujimi A Ajijola
• 金额: $ 56.61万
• 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/10674847
• 关键词: Acute; Agonist; Animals; Anti-Arrhythmia Agents; Attenuated; Axon; Biological Availability; Calcium Channel; Cardiac; Cause of Death; Chronic; Cicatrix; Clinical; Clinical Management; Data; Detection; Development; Drug usage; Electrophysiology (science); Epicardium; Family suidae; Feedback; Fiber; Functional disorder; Goals; Heart; Inflammation; Intervention; Ischemia; Link; Maps; 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; Vertebral column; afferent nerve; beta-adrenergic receptor; clinical translation; comparative efficacy; excitotoxicity; first-in-human; glial activation; in vivo; injured; local drug delivery; multidisciplinary; neural; neurochemistry; neuroinflammation; neuropeptide Y; neuroregulation; neurotransmission; neurotransmitter release; novel; novel therapeutics; prevent; 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.

项目概要/摘要 心肌梗死 (MI) 使患者容易出现室性心动过速/颤动 (VT/VF) 和突发性心律失常 心源性死亡。 MI 后，心脏交感神经系统 (SNS) 内的变化受到密切关注。 与 VT/VF 相关。这些改变包括星状细胞内的炎症、结构和功能重塑 神经节，以及疤痕边界区心肌内交感神经的异质重塑。 这些会导致心脏交感神经传递增强和功能失调，从而导致 VT/VF。 尽管心肌梗死后脊髓传入信号增强，但脊髓传入的致心律失常潜力（通过 与心脏交感神经的适应不良相互作用）尚未被探索。基于来自的新颖数据 我们小组，该提案的目标是检验以下假设：慢性增强的心脏传入信号传导是 交感神经重塑和功能障碍导致 VT/VF 的主要驱动因素。 我们小组的初步研究使用心外膜树脂毒素 (RTX) 来消耗心脏 TRPV1 传入神经 猪支持这样的基本原理：持续传入信号（超出急性缺血期）发挥着重要作用。 在塑造导致 VA 的神经和心脏基质方面发挥着核心作用。我们将使用以下方法来检验我们的假设 由多学科研究人员组成的团队针对患有心肌梗死的猪，针对 3 个目标开发了新工具。在目标 1 中，我们将 确定 MI 后星状结构、神经炎症和功能神经元重塑是否发生 神经节是由持续的 TRPV1 传入信号引起的。在目标 2 中，我们将确定是否持续 心脏 TRPV1 激活会放大心肌内神经递质的释放，从而增加 VT/VF 风险。这将 使用同步心脏电生理图测和实时体内检测来完成 心肌内去甲肾上腺素和神经肽 Y 水平。我们将确定 TRPV1 传入 耗竭通过使神经递质释放模式正常化来减弱致心律失常。在目标 3 中，我们将 确定 VT/VF 临床管理的 RTX 递送的最佳部位 [心外膜、星状神经节与心室颤动] 硬膜外应用]。这将指导传入神经调节的临床转化。本提案的结果 可能会改变心肌梗死后心律失常发生的方式，并指导新疗法的开发 防止心肌梗死后传入信号的改变，以填补主要的临床空白。

项目成果

Metrics of high cofluctuation and entropy to describe control of cardiac function in the stellate ganglion.

• DOI: 10.7554/elife.78520
• 发表时间: 2022-11-25
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Gurel, Nil Z.;Sudarshan, Koustubh B.;Hadaya, Joseph;Karavos, Alex;Temma, Taro;Hori, Yuichi;Armour, J. Andrew;Kember, Guy;Ajijola, Olujimi A.;Zaidi, Mone
• 通讯作者: Zaidi, Mone

Afferents Nerves in Atrial Fibrillation: Going Beyond Fight or Flight.

心房颤动中的传入神经：超越战斗或逃跑。

• DOI: 10.1016/j.jacep.2022.01.013
• 发表时间: 2022
• 期刊: JACC. Clinical electrophysiology
• 作者: Hanna,Peter;Ajijola,OlujimiA
• 通讯作者: Ajijola,OlujimiA

Vagal Nerve Stimulation Reduces Ventricular Arrhythmias and Mitigates Adverse Neural Cardiac Remodeling Post-Myocardial Infarction.

迷走神经刺激可减少心室心律不齐，并减轻心肌后梗死后神经心脏重塑。

• DOI: 10.1016/j.jacbts.2023.03.025
• 发表时间: 2023-09
• 期刊: JACC-BASIC TO TRANSLATIONAL SCIENCE
• 影响因子: 9.7
• 作者: Hadaya, Joseph;Dajani, Al-Hassan;Cha, Steven;Hanna, Peter;Challita, Ronald;Hoover, Donald B.;Ajijola, Olujimi A.;Shivkumar, Kalyanam;Ardell, Jeffrey L.
• 通讯作者: Ardell, Jeffrey L.