Ventricular arrhythmias and mechanisms of parasympathetic dysfunction following myocardial infarction

室性心律失常和心肌梗死后副交感神经功能障碍的机制

基本信息

批准号：
10652988
负责人：
Marmar Vaseghi
金额：
$ 67.83万
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：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652988
关键词：
Acceleration Acetylcholine Angiotensin-Converting Enzyme Inhibitors Animal Model Animals Anti-Arrhythmia Agents Arrhythmia Autonomic Pathways Baroreflex Bilateral Brain Stem Cardiac Cardiac ablation Cardiovascular Diseases Cervical Chest Chronic Cicatrix Clinical Trials Dangerousness Defibrillators Development Disease Electrophysiology (science)Excision Exercise Fiber Functional disorder Galanin Ganglia Heart Heart Diseases Heart failure Hospitalization Infarction Interruption Knowledge Lead Life Maps Measurement Measures Mediating Medical Morbidity - disease rate Muscle Cells Myocardial Infarction Nerve Nervous System Neuroeffector Junction Neuropeptides Neurostimulation procedures of spinal cord tissue Nociception Norepinephrine Patients Public Health Quality of life Recurrence Resiniferatoxin Risk Role Shock Signal Transduction Spinal Cord Sympathectomy Sympathetic Ganglia Tachyarrhythmias Testing Time Travel Ventricular Ventricular Arrhythmia Withdrawal beta-adrenergic receptor cardiac implant density experience galanin receptor heart rate variability heart rhythm hemodynamics improved insight interstitial mortality multi-electrode arrays myocardial injury nerve supply neural neuropeptide Y neuroregulation neurotransmission new therapeutic target novel prevent research study sudden cardiac death targeted treatment

项目摘要

ABSTRACT Ventricular arrhythmias (VT/VF) due to cardiac disease and myocardial infarction (MI) lead to sudden cardiac death. To prevent sudden cardiac death, implantable cardiac defibrillators (ICD) are used. Although defibrillators save lives by aborting dangerous arrhythmias, they neither prevent recurrence of VT/VF nor progression of the underly disease. Recurrent ICD shocks are associated with increased mortality and hospitalizations, and decreased quality of life. Despite our current therapies, including catheter ablation, 60- 75% of patients have recurrence of their VT/ICD shocks at 2 years. Additional therapies are desperately needed. Chronic sympathetic activation and reduced parasympathetic function increase risk of VT/VF and recurrent ICD shocks. MI leads to amplification of sympathetic afferent signaling, which increases sympathetic outflow to the heart and causes release of not only, norepinephrine, but several co-transmitters, including neuropeptide Y and galanin. These neuropeptides have much longer half-lives than norepinephrine, and elevated sympathetic neuropeptide levels in MI and heart failure are associated with increased mortality. It has also been known for decades that MI reduces parasympathetic function, the body's own anti-arrhythmic drug, increasing risk of VT/VF. However, clinical trials that attempted to increase vagal outflow by stimulating mixed nerves (vagal nerve stimulation, spinal cord stimulation) have had disappointing results, likely because the reasons behind chronic parasympathetic “withdrawal” remain unknown. In order develop new targeted therapies, it is critical to understand mechanisms underlying parasympathetic dysfunction and sympathetic and parasympathetic interactions that occur in the setting of cardiac disease. In this proposal, we aim to test the novel hypotheses that (1) persistent efferent sympathetic activation due to MI inhibits parasympathetic function at the nerve-myocyte interface (the neuro-effector junction) due to release of sympathetic co- transmitters and (2) sympathetic afferent activation reduces central vagal tone. In specific aim 1, we will test whether inhibition of sympathetic neuropeptides, neuropeptide Y and galanin, improves vagal tone and prove anti-arrhythmic. In aim 2, we will test whether sympathetic afferent blockade improves parasympathetic function and decreases ventricular arrhythmias. For aims 1 and 2, we will utilize hemodynamic and multi- electrode array neural recordings simultaneously with high-density electrophysiological mapping and direct interstitial norepinephrine measurements in a large animal model. Aim 3 will evaluate whether disruptions of sympathetic signaling via cardiac sympathetic denervation, the only current therapy that interrupts sympathetic afferent fibers and potentially reduces co-transmitters levels, will improve parasympathetic function in patients with scar-mediated VT. Understanding these fundamental autonomic pathways has the potential to accelerate development of disease-modifying targeted therapies for ventricular arrhythmias in the U.S. and worldwide.

抽象的由于心脏疾病和心肌梗塞（MI）导致心脏疾病引起的心律不齐（VT/VF）导致心脏突然心脏死亡。为了防止心脏突然死亡，使用可植入的心脏除颤器（ICD）。虽然除颤器通过流产危险的心律失常来挽救生命，它们既不防止VT/VF复发反复发生的ICD冲击与死亡率的增加有关住院和改善的生活质量。尽管我们目前的疗法，包括导管消融，60- 75％的患者在2年后会复发其VT/ICD冲击。其他疗法拼命需要。慢性交感神经激活和降低的副交感神经功能会增加VT/VF的风险经常性的ICD冲击。 MI导致同情传入信号的扩增，这增加了交感神经出口到心脏，不仅会释放出去肾上腺素神经肽Y和Galanin。这些神经肽的半衰期比去甲肾上腺素更长，并且 MI和心力衰竭中的交感神经肽水平升高与死亡率增加有关。它有数十年来，MI也降低了副交感神经功能，该功能是人体自身的抗心律失常药物， VT/VF的风险增加。但是，试图通过刺激混合的临床试验来增加迷走神经出口神经（迷走神经刺激，脊髓刺激）的结果令人失望，可能是因为慢性副交感神经“戒断”背后的原因尚不清楚。为了开发新的目标疗法，了解副交感神经功能障碍和交感神经和在心脏病的情况下发生的副交感神经相互作用。在此提案中，我们旨在测试新的假设（1）由于MI引起的持续有效的交感神经激活抑制了副交感神经由于释放交感神经共同的释放，神经膜细胞界面的功能发射器和（2）交感传入激活可降低中心迷走神经音调。在特定目标1中，我们将测试抑制交感神经肽，神经肽y和galanin是否可以改善迷走神经和证明抗心律失常。在AIM 2中，我们将测试同情传入封锁是否改善副交感神经功能并降低心室心律不齐。对于目标1和2，我们将利用血液动力学和多种电极阵列神经记录仅具有高密度电生理图和直接大型动物模型中的间质去甲肾上腺素测量。 AIM 3将评估是否破坏通过心脏交感神经去神经的交感神经信号传导，这是唯一中断交感神经的疗法传入纤维和潜在降低共透射器水平，将改善患者的副交感神经功能与疤痕介导的VT。了解这些基本的自主途径有可能加速在美国和全球范围内开发针对心室心律不齐的靶向靶向疗法的发展。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Proarrhythmic Effects of Sympathetic Activation Are Mitigated by Vagal Nerve Stimulation in Infarcted Hearts.

DOI：
10.1016/j.jacep.2022.01.018
发表时间：
2022-04
期刊：
JACC-CLINICAL ELECTROPHYSIOLOGY
影响因子：
7
作者：
Hoang, Jonathan D.;Yamakawa, Kentaro;Rajendran, Pradeep S.;Chan, Christopher A.;Yagishita, Daigo;Nakamura, Keijiro;Lux, Robert L.;Vaseghi, Marmar
通讯作者：
Vaseghi, Marmar

Autonomic control of ventricular function in health and disease: current state of the art.

DOI：
10.1007/s10286-023-00948-8
发表时间：
2023-08
期刊：
CLINICAL AUTONOMIC RESEARCH
影响因子：
5.8
作者：
van Weperen, Valerie Y. H.;Ripplinger, Crystal M.;Vaseghi, Marmar
通讯作者：
Vaseghi, Marmar

Recurrent ventricular tachycardia after cardiac sympathetic denervation: Prolonged cycle length with improved hemodynamic tolerance and ablation outcomes.

DOI：
10.1111/jce.14624
发表时间：
2020-09
期刊：
Journal of cardiovascular electrophysiology
影响因子：
2.7
作者：
Hayase J;Dusi V;Do D;Ajijola OA;Vaseghi M;Lee JM;Yanagawa J;Hoftman N;Revels S;Buch EF;Khakpour H;Fujimura O;Krokhaleva Y;Macias C;Sorg J;Gima J;Pavez G;Boyle NG;Shivkumar K;Bradfield JS
通讯作者：
Bradfield JS

Arrhythmic Risk Profile and Outcomes of Patients Undergoing Cardiac Sympathetic Denervation for Recurrent Monomorphic Ventricular Tachycardia After Ablation.

DOI：
10.1161/jaha.120.018371
发表时间：
2021-01-19
期刊：
Journal of the American Heart Association
影响因子：
5.4
作者：
Dusi V;Gornbein J;Do DH;Sorg JM;Khakpour H;Krokhaleva Y;Ajijola OA;Macias C;Bradfield JS;Buch E;Fujimura OA;Boyle NG;Yanagawa J;Lee JM;Shivkumar K;Vaseghi M
通讯作者：
Vaseghi M

Editorial commentary: Confessions of a stressed heart: The brain-heart relationship is complicated.