Restoration of Cardiac Parasympathetic Activity in Heart Failure

心力衰竭（HF）是一种广泛存在的使人衰弱的心血管疾病，影响近2300万人 全球每年约有200万新患者确诊。心力衰竭的一个显著特征 是自主神经失调，包括交感神经活动增加和副交感神经张力降低。 恢复心脏的副交感神经活动最近已成为一种有前途的新疗法 抑制心力衰竭进展和心源性猝死风险的方法。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， 在进展为心力衰竭的左心室肥大动物模型中的心脏活动。的 目前的建议的首要假设是，下丘脑室旁核的 下丘脑（PVN）催产素神经元对于激活副交感心脏迷走神经元是必需的 （CVNs）在脑干。在经主动脉压迫（TAC）的动物中， 发展为心力衰竭的肥大、催产素的释放和CVN的激活减少。 也许更重要的是，我们的初步结果表明，催产素活性的选择性恢复恢复了 室旁核神经元催产素的突触释放，室旁核到副交感神经的兴奋性神经传递 CVNs，改善心脏功能，并有利地改变心脏缺血和损伤的指数， 在未经治疗的动物。在本提案中，我们将在初步结果的基础上，提出三个具体目标： 1)确定是否有减少释放催产素从室旁神经元的下丘脑纤维， 心力衰竭动物的脑干和心脏迷走神经元兴奋减弱。此外 测试PVN中催产素神经元的选择性慢性激活是否可以恢复PVN中催产素的释放， 脑干和副交感神经心脏迷走神经元的激活。2)检验慢性的假设 PVN催产素神经元的激活减轻了未治疗的心功能不全的进展， HF疾病动物。左心室（LV）的压力、收缩力和电同步将 以评估改善心脏功能的机制。3)检查是否有心肌缺血指标， 包括体内心电图（EKG）异常，心外膜NADH（fNADH）荧光增加， 和纤维化（疤痕）组织的形成是不存在的或钝化的动物慢性激活 下丘脑PVN催产素神经元与未处理的HF动物相比。本提案中的研究将 支持或反驳我们的假设，即PVN催产素神经元激活可以恢复减少的副交感神经 心张力和钝心功能改变的有害进展，发生在动物与LV 肥大、心功能不全和心力衰竭。这将为今后的临床应用提供重要的基础 研究，使这项工作具有很高的翻译潜力和意义。

Heart failure (HF) is a widespread and debilitating cardiovascular disease that affects nearly 23 million people worldwide with approximately 2 million new patients diagnosed annually. A distinctive hallmark of heart failure is autonomic imbalance, consisting of increased sympathetic activity and decreased parasympathetic tone. Restoration of parasympathetic activity to the heart has recently emerged as a promising new therapeutic approach to inhibit the progression of heart failure and risk of sudden cardiac death. Our preliminary results provide critical new information for the field that identifies a novel target that could restore parasympathetic cardiac activity in an animal model of left ventricular hypertrophy that progresses to heart failure. The overarching hypothesis of the current proposal is that hypothalamic paraventricular nucleus of the hypothalamus (PVN) oxytocin neurons are essential for activating parasympathetic cardiac vagal neurons (CVNs) in the brainstem. In animals with trans-aortic compression (TAC), which leads to left ventricular hypertrophy that progresses to heart failure, the release of oxytocin, and activation of CVNs, is diminished. Perhaps more importantly, our preliminary results indicate selective restoration of oxytocin activity restores the synaptic release of oxytocin from PVN neurons, the excitatory neurotransmission from PVN to parasympathetic CVNs, improves cardiac function and favorably alters the indices of cardiac ischemia and damage that occurs in untreated animals. In this proposal we will build upon our preliminary results to address three Specific Aims: 1) Determine if there is reduced release of oxytocin from paraventricular neurons of the hypothalamus fibers in the brainstem and blunted excitation of cardiac vagal neurons in heart failure diseased animals. Furthermore test if selective chronic activation of oxytocin neurons in the PVN acts to restore both the release of oxytocin in the brainstem and activation of parasympathetic cardiac vagal neurons. 2) Test the hypothesis that chronic activation of PVN oxytocin neurons mitigates the progression of cardiac dysfunction that occurs in untreated HF disease animals. Left ventricular (LV) developed pressure, contractility, and electrical synchronization will be measured to assess mechanisms of improved cardiac function. 3) Examine if indices of cardiac ischemia, including in-vivo electrocardiograph (EKG) abnormalities, increased fluorescence of epicardial NADH (fNADH), and the formation of fibrotic (scar) tissue are absent or blunted in animals with chronic activation of hypothalamic PVN oxytocin neurons compared to untreated HF animals. The studies in this proposal will either support, or refute our hypothesis that PVN oxytocin neuron activation can restore diminished parasympathetic cardiac tone and blunt the deleterious progression of cardiac function alterations that occur in animals with LV hypertrophy, cardiac dysfunction and heart failure. This will provide an important foundation for future clinical studies, giving this work high translational potential and significance.