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: 10604331
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604331
• 关键词: Acceleration; 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; Genetic; 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; designer receptors exclusively activated by designer drugs; ex vivo perfusion; field study; functional improvement; heart function; improved; 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.

心脏猝死（SCD）负责所有死亡的15％至20％，约有50％ 美国心血管死亡。导致SCD的最常见级联事件是急性 冠状动脉综合征（ACS）发展为急性心肌缺血和/或炎症，触发电气 不稳定性和致命性心律失常。防止SCD特别困难，因为大约一半的男人 屈服于SCD的女性中有三分之二没有以前的心脏病史。自主不平衡 是SCD的主要危险因素。增强交感神经活动会引起ECG复极化的变化和 降低纤维化阈值，促进心室纤启动（VF）。相反， 通过增加副交感神经，会显着降低致命性心律不齐和SCD风险 活动。但是，一种快速，安全和可行的方法，以增加心脏的副交感神经活动 有致命性心律失常的风险的患者严重缺乏，这是主要的医疗需求。我们的初步结果 为该领域提供关键的新信息，以识别可以恢复副交感神经的新型目标 心脏张力并减少心律不齐和心脏功能障碍的发生率。我们先前的工作 睡眠呼吸暂停的受试者已表现出鼻内（IN）催产素的应用增加了副交感神经心脏 活动。在AC的动物模型中，左前降冠状动脉（LAD）动物结扎的动物模型 发展与临床研究相似的缺血，心律不齐和死亡率。我们表明，小伙子的动物有 减少内源性兴奋性催产素介导的神经传递，以副交感神经迷走神经 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 副核核（PVN）催产素神经元恢复催产素的释放，增加副交感神经活性 心脏并大大减少心律不齐，炎症，纤维化和 其他不良心脏结果。基于我们的新结果，我们的总体假设是慢性选择性 PVN催产素神经元以及鼻催产素的激活显着降低心律不齐 AC动物模型中的心脏功能障碍。在AIM 1中，我们将检验至关重要的假设 从PVN催产素神经元到有助于维持保护性副交感活动的CVN的兴奋性途径 小伙子结束后，动物对心脏钝了，可以恢复这种关键的神经递质 鼻催产素治疗以及PVN催产素神经元的慢性和选择性激活。在目标2中，我们将 测试PVN催产素神经元的鼻催产素和慢性和选择性激活是否治疗 增加对心脏的副交感活性，减少心律不齐的发生率，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AIM 3中，我们将量化 Ex-Vivo灌注心脏的电气和机械功能，以识别负责的机制 鼻催产素的心脏益处和PVN催产素神经元在LAD绑扎动物中的选择性激活。