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

• 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
• 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

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.

摘要 由于心脏病和心肌梗死（MI）引起的室性心律失常（VT/VF）导致突发性心脏病， 死亡为了防止心脏猝死，使用植入式心脏除颤器（ICD）。虽然 起搏器通过中止危险的心律失常来挽救生命，但它们既不能防止VT/VF的复发， 基础疾病的进展。反复ICD电击与死亡率增加相关， 住院和生活质量下降。尽管我们目前的治疗，包括导管消融，60- 75%的患者在2年时VT/ICD电击复发。额外的治疗方法 needed.慢性交感神经激活和副交感神经功能降低会增加VT/VF的风险， 反复ICD电击MI导致交感神经传入信号的放大，这增加了交感神经传导。 流出到心脏，并导致释放不仅是去甲肾上腺素，但几个共递质，包括 神经肽Y和甘丙肽这些神经肽的半衰期比去甲肾上腺素长得多， MI和心力衰竭中交感神经肽水平升高与死亡率增加有关。它有 几十年来，人们也知道心肌梗塞会降低副交感神经功能，副交感神经是人体自身的抗心肌梗塞药物， 增加VT/VF的风险。然而，试图通过刺激混合的迷走神经来增加迷走神经流出的临床试验， 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”背后的原因仍不清楚。为了开发新的目标 治疗，关键是要了解副交感神经功能障碍和交感神经和 在心脏病的背景下发生的副交感神经相互作用。在本提案中，我们旨在测试 新的假说，（1）持续传出交感神经激活由于MI抑制副交感神经 在神经-肌细胞界面（神经效应器连接）的功能，由于释放交感神经CO， 神经递质和（2）交感传入激活降低中枢迷走神经张力。具体目标1： 测试交感神经肽、神经肽Y和甘丙肽的抑制是否改善迷走神经张力， 证明是抗病毒的。在aim 2中，我们将测试交感神经传入阻滞是否能改善副交感神经 功能和减少室性心律失常。对于目标1和2，我们将利用血流动力学和多- 电极阵列神经记录同时具有高密度电生理标测和直接 大型动物模型中的间质去甲肾上腺素测量。目标3将评估 通过心脏交感神经去神经支配的交感神经信号传导，目前唯一的中断交感神经信号传导的治疗方法， 传入纤维，并可能降低共递质水平，将改善患者的副交感神经功能 瘢痕介导的室速了解这些基本的自主神经通路有可能加速 在美国和世界范围内开发针对室性心律失常的疾病修饰靶向疗法。

项目成果

The autonomic nervous system and ventricular arrhythmias in myocardial infarction and heart failure.

• DOI: 10.1111/pace.13856
• 发表时间: 2020-02
• 期刊: Pacing and clinical electrophysiology : PACE
• 作者: Wu P;Vaseghi M
• 通讯作者: Vaseghi M

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