Novel Mechanisms that Restore Cardiac Parasympathetic Activity Limits Arrhythmias and Cardiac Dysfunction After Myocardial Infarction

恢复心脏副交感神经活动的新机制可限制心肌梗死后的心律失常和心脏功能障碍

• 批准号: 10366054
• 负责人: Matthew W. Kay
• 金额: $ 57.92万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-10 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10366054
• 关键词: Action Potentials; Acute; Adrenergic Agents; Animal Model; Animals; Anterior Descending Coronary Artery; Arrhythmia; Autonomic Pathways; Biosensor; Brain Stem; Cardiac; Cardiovascular system; Cessation of life; Chinese Hamster Ovary Cell; Chronic; Clinical; Clinical Research; Clinical Trials; Echocardiography; Electrocardiogram; Electrophysiology (science); Engineering; Equilibrium; Event; Exercise stress test; Fibrosis; Generations; Goals; Heart; Heart Arrest; Heart Diseases; Hour; Incidence; Infarction; Inflammation; Ischemia; Left; Ligation; Light; Mechanics; Mediating; Medical; Modeling; Muscarinics; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Neurons; Nose; Outcome; Oxytocin; Pathway interactions; Patients; Proteins; Rattus; Recording of previous events; Risk; Risk Factors; Sleep Apnea Syndromes; Synapses; Testing; Time; United States; Ventricular; Ventricular Arrhythmia; Ventricular Fibrillation; Ventricular Tachycardia; Western World; Woman; Work; acute coronary syndrome; base; designer receptors exclusively activated by designer drugs; field study; heart function; improved; improved functioning; in vivo; innovation; men; mortality; neurotransmission; novel; paraventricular nucleus; patch clamp; prevent; selective expression; sudden cardiac death

Sudden Cardiac Death (SCD) is responsible for between 15 and 20% of all deaths, and ~50% of all cardiovascular deaths in the United States. The most common cascade of events leading to SCD is acute coronary syndrome (ACS) progressing to acute myocardial ischemia and/or inflammation that triggers electrical instability and lethal arrhythmias. Preventing SCD is particularly difficult as approximately one-half of men and two-thirds of women who succumb to SCD had no known history of prior heart disease. Autonomic imbalance is a major risk factor for SCD. Augmented sympathetic activity induces changes in ECG repolarization and reduction of fibrillation threshold facilitating the initiation of ventricular fibrillation (VF). In contrast, the generation of fatal ventricular arrhythmias and risk of SCD is markedly reduced by increasing parasympathetic activity. However a rapid, safe and feasible approach to increase parasympathetic activity to the heart in patients at risk for fatal arrhythmias is severely lacking and is a major medical need. Our preliminary results provide critical new information for the field that identifies a novel target that could restore parasympathetic cardiac tone and reduce the incidence of arrhythmias and cardiac dysfunction following a MI. Our prior work in subjects with sleep apnea has shown intranasal (IN) application of oxytocin increases parasympathetic cardiac activity. In an animal model of ACS with ligation of the left anterior descending coronary artery (LAD) animals develop ischemia, arrhythmias and mortality similar to clinical studies. We show that LAD-ligated animals have reduced endogenous excitatory oxytocin-mediated neurotransmission to parasympathetic cardiac vagal neurons (CVNs) in the brainstem. We further show that selective and chronic activation of hypothalamic paraventricular nucleus (PVN) oxytocin neurons restores oxytocin release, increases parasympathetic activity to the heart and substantially reduces the incidence and initiation of arrhythmias, inflammation, fibrosis and other adverse cardiac outcomes. Based upon our novel results, our overall hypothesis is that chronic selective activation of PVN oxytocin neurons, as well as nasal oxytocin administration, markedly reduces arrhythmias and cardiac dysfunction in an animal model of ACS. In Aim 1 we will test the hypothesis that the critical excitatory pathway from PVN oxytocin neurons to CVNs that helps maintain protective parasympathetic activity to the heart is blunted in animals following LAD ligation, and that this key neurotransmission can be restored with nasal oxytocin treatment and chronic and selective activation of PVN oxytocin neurons. In Aim 2 we will test whether treatment by nasal oxytocin and chronic and selective activation of PVN oxytocin neurons increases parasympathetic activity to the heart in-vivo, reduce the incidence of arrhythmias, improves autonomic balance and effort capacity in exercise stress tests and cardiac function. In Aim 3 we will quantify the electrical and mechanical function of ex-vivo perfused hearts to identify the mechanisms responsible for the cardiac benefits of nasal oxytocin and selective activation of PVN oxytocin neurons in LAD-ligated animals.

心脏性猝死 (SCD) 占所有死亡人数的 15% 至 20%，约占所有死亡人数的 50% 美国心血管死亡。导致 SCD 的最常见级联事件是急性的 冠状动脉综合征 (ACS) 进展为急性心肌缺血和/或炎症，引发电击 不稳定和致命性心律失常。预防 SCD 特别困难，因为大约一半的男性和 死于 SCD 的女性中有三分之二没有已知的心脏病史。自律神经失衡 是 SCD 的主要危险因素。增强的交感神经活动引起心电图复极的变化和 颤动阈值的降低有利于心室颤动（VF）的发生。相比之下， 通过增加副交感神经，显着降低致命性室性心律失常的发生和 SCD 的风险 活动。然而，一种快速、安全、可行的方法可以增加心脏的副交感神经活动 面临致命性心律失常风险的患者严重缺乏，这是一项重大的医疗需求。我们的初步结果 为该领域提供重要的新信息，确定可以恢复副交感神经的新靶点 心脏张力并减少心律失常和心功能不全的发生率。我们之前的工作 患有睡眠呼吸暂停的受试者已显示鼻内 (IN) 应用催产素会增加副交感神经的心脏功能 活动。在结扎左冠状动脉前降支 (LAD) 动物的 ACS 动物模型中 与临床研究相似，会出现缺血、心律失常和死亡。我们证明 LAD 连接的动物具有 减少内源性兴奋性催产素介导的副交感心脏迷走神经传递 脑干中的神经元（CVN）。我们进一步表明，下丘脑的选择性和慢性激活 室旁核（PVN）催产素神经元恢复催产素释放，增加副交感神经活动 心脏，大大减少心律失常、炎症、纤维化和 其他不良心脏后果。根据我们的新结果，我们的总体假设是慢性选择性 激活 PVN 催产素神经元以及鼻腔催产素给药可显着减少心律失常 ACS 动物模型中的心脏功能障碍。在目标 1 中，我们将检验以下假设： 从 PVN 催产素神经元到 CVN 的兴奋性通路有助于维持保护性副交感神经活动 在 LAD 结扎后，动物心脏的神经传递被削弱，而这一关键的神经传递可以恢复 通过鼻催产素治疗和慢性选择性激活 PVN 催产素神经元。在目标 2 中，我们将 测试是否通过鼻催产素治疗和慢性选择性激活 PVN 催产素神经元 增加体内心脏的副交感神经活动，减少心律失常的发生率，改善 运动压力测试和心脏功能中的自主平衡和努力能力。在目标 3 中，我们将量化 离体灌注心脏的电学和机械功能，以确定负责的机制 鼻催产素对心脏的益处以及 LAD 结扎动物中 PVN 催产素神经元的选择性激活。