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: 10053216
• 负责人: Marmar Vaseghi
• 金额: $ 59.3万
• 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/10053216
• 关键词: 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; Interruption; Knowledge; Lead; Life; Measurement; Measures; Mediating; Medical; Morbidity - disease rate; Muscle Cells; Myocardial Infarction; Nerve; Nervous system structure; 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; density; experience; galanin receptor; heart rate variability; heart rhythm; hemodynamics; improved; insight; interstitial; mortality; multi-electrode arrays; myocardial injury; nerve supply; neuropeptide Y; neuroregulation; neurotransmission; new therapeutic target; novel; prevent; relating to nervous system; 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 心脏病和心肌梗死引起的室性心律失常(VT/VF)可导致心脏骤停。 死亡。为了防止心脏性猝死，植入式心脏除颤器(ICD)被使用。虽然 除颤器通过终止危险的心律失常来拯救生命，它们既不能防止室速/室颤的复发，也不能防止室速/室颤的复发。 疾病的发展。反复发生的ICD休克与死亡率增加和 住院和生活质量下降。尽管我们目前的治疗方法，包括导管消融术，60- 75%的患者在2年后VT/ICD电击复发。额外的治疗方法是不顾一切的 需要的。慢性交感神经激活和副交感神经功能降低增加VT/VF和 反复发生的ICD电击。MI导致交感传入信号的放大，从而增加交感神经 外流到心脏，不仅导致去甲肾上腺素的释放，而且还引起几种共递质的释放，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，而且 心肌梗塞和心力衰竭患者交感神经肽水平升高与死亡率增加有关。它有 几十年来，人们一直知道心肌梗塞会降低副交感神经功能，这是人体自己的抗心律失常药物， 室性心动过速/室颤风险增加。然而，试图通过刺激增加迷走神经流出的临床试验好坏参半 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。为了开发新目标 治疗，关键是要了解副交感神经功能障碍和交感神经功能障碍的潜在机制。 发生在心脏病背景下的副交感神经相互作用。在这项提案中，我们的目标是测试 新的假说：(1)心肌梗塞引起的持续性传出交感神经兴奋抑制副交感神经 在神经-肌细胞界面(神经-效应器连接)的功能，由于释放交感神经协同 递质和(2)交感传入兴奋降低中枢迷走神经张力。在具体目标1中，我们将 测试抑制交感神经肽、神经肽Y和甘丙肽是否能改善迷走神经张力和迷走神经张力 证明是抗心律失常的。在目标2中，我们将测试交感传入阻断是否能改善副交感神经 功能，减少室性心律失常。对于目标1和目标2，我们将利用血流动力学和多维 电极阵列神经记录与高密度电生理标测同时进行 在大型动物模型中的间质去甲肾上腺素测量。目标3将评估是否中断了 通过心脏交感神经去神经传递交感神经信号，这是目前唯一中断交感神经的治疗方法 传入纤维和潜在的降低共递质水平，将改善患者的副交感神经功能 有SCAR介导性室速。理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。