Neural Control of Myocardial Excitability at the Nerve Myocyte Interface

摘要-项目1 由于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。 死亡率在美国。自主神经系统在脑缺血的病理生理学中起着重要作用。 心律失常和心力衰竭。神经轴调节代表了治疗性神经损伤的重要途径。 干预然而，神经递质释放的结构和功能决定因素， 肽在健康和疾病的心肌，有效地控制心脏的兴奋性和机械 功能以及心律失常的倾向在很大程度上仍然未知。缺血性心肌损伤中的心肌瘢痕 非缺血性心肌病表现为瘢痕边缘区神经支配异常和神经出芽 这是由于神经重塑，这与室性心律失常的病理生理学有关。我们 建议测试“神经递质释放的时空异质性假说”-- 假设瘢痕改变神经的超微结构，并导致不均匀的反射介导的神经递质 心肌中的释放，并且代表致死性心律失常的关键/近因。的主要目标 本项目旨在研究心脏的结构（心肌）和功能（神经）变化， 因为心脏病，并随后导致室性心律失常。在目标1和2中，我们将确定 超微结构并定义神经-肌细胞化学计量和神经递质的释放曲线， 肽在正常和患病的心脏中对生理应激源的反应，并具体定义了 神经递质的不均匀释放。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方面的益处， 自主神经支配瘢痕和边缘带神经支配的局部结构和功能变化 将使用高密度电生理标测和真实的时间神经递质研究区域， 神经肽测量，其将与梗塞边缘区的结构变化相关 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， 精确靶向治疗，激发预防心脏性猝死和 心衰

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.