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)占所有死亡的15%至20%，约占所有死亡人数的50% 美国的心血管死亡人数。导致SCD的最常见的事件级联是急性的 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尤其困难，因为大约一半的男性和 三分之二死于SCD的女性之前没有已知的心脏病病史。自主神经失衡 是SCD的主要危险因素。交感神经活动增强导致心电复极和 降低颤动阈值有利于室颤的发生。相比之下， 增加副交感神经可显著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、安全和可行的方法来增加心脏的副交感神经活动 严重缺乏有致命心律失常风险的患者，这是一项主要的医疗需求。我们的初步结果 为识别可以恢复副交感神经的新靶点提供关键的新信息 并减少心肌梗塞后心律失常和心功能不全的发生率。我们之前的工作是 睡眠呼吸暂停患者经鼻(IN)应用催产素可增加副交感神经功能 活动。结扎冠状动脉左前降支建立急性冠脉综合征动物模型 出现类似于临床研究的缺血、心律失常和死亡率。我们证明了LAD结扎的动物 内源性兴奋性催产素介导的心脏迷走神经副交感神经传递减少 脑干的神经元(CVN)。我们进一步表明，选择性和慢性激活下丘脑 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 并大大减少心律失常、炎症、纤维化和心脏疾病的发生和发生 其他心脏不良后果。基于我们的新结果，我们的总体假设是慢性选择性 激活下丘脑室旁核催产素神经元，以及鼻腔注射催产素，可显著减少心律失常 以及在急性冠脉综合征动物模型中的心脏功能障碍。在目标1中，我们将检验这样的假设，即关键的 PVN催产素神经元至CVN的兴奋通路有助于维持保护性副交感神经活动 在左前降支结扎后，心脏的这一关键神经传递可以恢复。 鼻腔催产素治疗和慢性选择性激活下丘脑室旁核催产素神经元。在《目标2》中我们将 鼻腔催产素治疗与PVN催产素神经元慢性选择性激活的关系 增加体内对心脏的副交感神经活动，减少心律失常的发生，改善 运动负荷试验中的自主神经平衡和努力能力以及心脏功能。在目标3中，我们将量化 体外灌流心脏的电和机械功能以确定导致心脏死亡的机制 鼻腔催产素和选择性激活下丘脑室旁核催产素神经元对LAD结扎动物心脏的益处。