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，影响着近2300万人 全球每年约有200万名新确诊患者。心力衰竭的显著特征 自主神经失衡，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是最近出现的一种很有前途的新疗法 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 为识别可以恢复副交感神经的新靶点提供关键的新信息 进展为心力衰竭的左心室肥厚动物模型的心脏活动。这个 目前提出的首要假设是下丘脑室旁核 下丘脑(PVN)催产素神经元是激活副交感心迷走神经元所必需的 (CVN)在脑干。在经主动脉压迫(TAC)导致左心室的动物中 进展为心力衰竭的肥厚、催产素的释放和CVN的激活都会减少。 也许更重要的是，我们的初步结果表明，选择性地恢复催产素活性可以恢复 下丘脑室旁核神经元催产素的突触释放、兴奋性神经传递 CVNS，改善心脏功能，有利地改变心脏缺血和损伤的指数 在未经治疗的动物身上。在这项提案中，我们将以我们的初步成果为基础，解决三个具体目标： 1)确定下丘脑室旁神经元中催产素的释放是否减少。 心力衰竭动物的脑干和心脏迷走神经的钝性兴奋。更有甚者 检测选择性慢性激活下丘脑室旁核内催产素神经元是否能恢复脑内催产素的释放 脑干与心脏迷走神经副交感神经元的激活。 激活下丘脑室旁核催产素神经元可缓解未经治疗的心功能不全的进展 患心衰的动物。左心室(LV)发展的压力、收缩能力和电同步将 以评估改善心功能的机制。3)检测心肌缺血指标， 包括活体心电图(EKG)异常、心外膜NADH荧光增强(FNADH)、 在慢性激活的动物中，纤维化(瘢痕)组织的形成没有或钝化。 下丘脑PVN催产素神经元与未经处理的HF动物的比较。这项建议中的研究将 支持或驳斥我们的假设，即PVN催产素神经元激活可以恢复减少的副交感神经 心脏张力和钝化发生在LV动物心脏功能改变的有害进展 研究，赋予这部作品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.