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

心源性猝死（SCD）占所有死亡的15%至20%，占所有死亡的约50%。 美国的心血管疾病死亡人数。最常见的导致SCD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， 不稳定和致命的心律失常。预防SCD特别困难，因为大约有一半的男性和 三分之二死于SCD的女性没有已知的心脏病史。植物神经功能紊乱 是SCD的主要危险因素。增强的交感神经活动引起ECG复极和 降低纤颤阈值，促进心室纤颤（VF）的发生。而反观 通过增加副交感神经系统， 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，这是主要的医疗需求。我们的初步结果 为该领域提供了关键的新信息，确定了一个新的目标，可以恢复副交感神经系统， 心脏紧张度和降低心肌梗死后心律失常和心功能障碍的发生率。我们之前的工作 患有睡眠呼吸暂停的受试者已经显示鼻内（IN）应用催产素增加了副交感神经心脏 活动在结扎冠状动脉左前降支（LAD）的ACS动物模型中， 出现缺血、心律失常和死亡率，与临床研究相似。我们发现LAD结扎的动物 减少内源性兴奋性催产素介导的对副交感神经心脏迷走神经的神经传递 脑干中的神经元（CVNs）。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 并显著降低心律失常、炎症、纤维化和 其他不良心脏结局。基于我们的新结果，我们的总体假设是，慢性选择性 PVN催产素神经元的激活以及鼻催产素给药显著减少心律失常 和心功能障碍的研究。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性 在LAD结扎后的动物中，心脏的神经传递被钝化，并且这种关键的神经传递可以恢复， 用鼻催产素处理和PVN催产素神经元的慢性和选择性激活。在目标2中， 测试是否通过鼻催产素治疗和PVN催产素神经元的慢性和选择性激活 增加体内心脏的副交感神经活动，降低心律失常的发生率，改善 运动负荷试验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 离体灌注心脏的电和机械功能，以确定负责 在LAD结扎的动物中，鼻催产素和PVN催产素神经元的选择性激活对心脏的益处。

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.