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.

项目总结/摘要 心肌梗死（MI）易使患者发生室性心动过速/室颤（VT/VF）和突发性室性心动过速/室颤。 心源性死亡心肌梗死后，心脏交感神经系统（SNS）内的变化已被密切关注。 与VT/VF有关。这些改变包括炎症，结构和功能重塑内的星状 神经节和瘢痕边缘区心肌内交感神经的异质性重塑。 这些导致心脏交感神经传递增强和功能障碍，导致VT/VF。 虽然脊髓传入信号在MI后增强，但脊髓传入神经（通过 与心脏交感神经的适应不良的相互作用）尚未被探索。基于来自 我们的小组，这个建议的目标是测试假设，慢性增强心脏传入信号是 交感神经重塑和功能障碍的主要驱动因素，导致VT/VF。 我们小组的初步研究使用心外膜树脂毒素（RTX）消耗心脏TRPV 1传入， 猪支持持续的传入信号（超过急性缺血期）发挥作用的基本原理， 在形成导致VA的神经和心脏基质中起核心作用。我们将使用以下方法来检验我们的假设： 来自多学科研究小组的新工具，用于3个目标，在猪MI中。在目标1中， 确定心肌梗死后星状核内的结构、神经炎症和功能性神经元重塑是否与心肌梗死相关。 神经节是由持续的TRPV 1传入信号引起的。在目标2中，我们将确定是否持久 心脏TRPV 1激活放大心肌内神经递质释放以增加VT/VF风险。这将 使用同时的心脏电生理标测和真实的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TRPV 1传入 耗尽通过使神经递质释放模式正常化来减弱致心律失常性。在目标3中，我们 定义用于VT/VF临床管理的RTX输送的最佳部位[心外膜vs.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。这一提议的结果 可能会改变MI后的血管生成方式，并指导新疗法的开发， 防止MI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.