Neural Control of Myocardial Excitability at the Nerve Myocyte Interface

摘要-项目1 室性心律失常和心力衰竭引起的心源性猝死是发病率和死亡率的主要原因。 美国的死亡率。自主神经系统在脑血管病的病理生理学中起重要作用。 心律失常和心力衰竭。神经轴调节是治疗的重要途径 干预。然而，神经递质释放的结构和功能决定因素和 健康和疾病心肌中的多肽，它们有效地调节心脏的兴奋性和机械性 功能，以及心律失常的倾向，在很大程度上仍不清楚。心肌梗死后可见的疤痕 非缺血性心肌病在瘢痕的边缘区域表现为异常的神经支配和神经发芽 由于神经重构，已涉及室性心律失常的病理生理学。我们 提出检验“神经递质释放时空异质性假说”-- 假设疤痕改变神经的超微结构并导致不均匀的反射介导性神经递质 在心肌中释放，是致死性心律失常的关键/近因。的主要目标是 这个项目是为了研究心脏结构(心肌)和功能(神经)的变化 因心脏病，继而导致室性心律失常。在目标1和目标2中，我们将确定 观察神经递质的超微结构，确定神经-肌细胞的化学计量和释放谱。 正常和疾病心脏中的多肽对生理应激源的响应并特异性地定义 神经递质释放不均匀。在目标3中，我们将确定潜在的机制和潜力 迷走神经刺激在减轻与瘢痕形成相关的病理性重塑和 自主神经支配。瘢痕及交界区神经支配的区域结构和功能变化 将使用高密度电生理标测和实时神经递质和 与脑梗塞边缘带结构变化相关的神经肽测定 在相关的大型动物模型和人类心脏中使用组织清除技术。了解 导致心律失常的潜在心肌和神经机制有可能发展为 精确的靶向治疗，启发预防心脏性猝死和进展的治疗 心力衰竭。

ABSTRACT – Project 1 Sudden cardiac death due to ventricular arrhythmias and heart failure are the leading causes morbidity and mortality in the United States. The autonomic nervous system plays a major role in the pathophysiology of arrhythmias and heart failure. Neuraxial modulation represents an important avenue for therapeutic intervention. However, the structural and functional determinants of the release of neurotransmitters and peptides in the myocardium in health and disease, which effectively govern cardiac excitability and mechanical function, as well as propensity toward arrhythmias, remain largely unknown. Myocardial scars seen in ischemic and nonischemic cardiomyopathy show abnormal innervation and nerve sprouting at the border zone of scars due to neural remodeling, which have been implicated in the pathophysiology of ventricular arrhythmias. We propose to test “The Spatiotemporal Heterogeneity of Neurotransmitter Release Hypothesis’ – which postulates that scars alter the ultrastructure of nerves and cause non-uniform reflex-mediated neurotransmitter release in the myocardium and represents a crucial/proximate cause of lethal arrhythmias. The major goal of this project is to investigate the structural (myocardial) and functional (neural) changes in the heart that occur because of heart disease and subsequently lead to ventricular arrhythmias. In aims 1 and 2, we will determine the ultrastructure and define the nerve-myocyte stoichiometry and release profiles of neurotransmitters and peptides in normal and diseased hearts in response to physiological stressors and specifically define areas of non-uniform release of neurotransmitters. In aim 3, we will determine the underlying mechanism and potential benefit of vagal nerve stimulation in mitigating the pathological remodeling related to scar formation and autonomic innervation. Regional structural and functional changes in innervation of scar and border zone regions will be studied using high density electrophysiological mapping and real time neurotransmitter and neuropeptide measurements which will be correlated with structural changes at the border zones of infarcts using tissue clearing techniques in a relevant large animal model and in human hearts. Understanding the underlying myocardial and neural mechanisms leading to arrhythmias has the potential to develop and precisely target therapies that inspire therapies for the prevention of sudden cardiac death and progression of heart failure.