Neural Control of Myocardial Excitability at the Nerve Myocyte Interface

神经肌细胞界面心肌兴奋性的神经控制

基本信息

批准号：
10627577
负责人：
KALYANAM SHIVKUMAR
金额：
$ 49.29万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-10 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627577
关键词：
Action Potentials Adrenergic Antagonists Animal Model Animals Anti-Arrhythmia Agents Antiinflammatory Effect Area Arrhythmia Attenuated Autonomic nervous system Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cessation of life Chronic Cicatrix Computer Assisted Computer Models Computer Vision Systems Data Set Disease Disease Progression Donor person Electrophysiology (science)Ensure Exhibits Family suidae Functional disorder Goals Health Heart Heart Diseases Heart Transplantation Heart failure Heterogeneity Human Hypertension Implant In Vitro Individual Infarction Inflammation Intervention Ischemia Kinetics Lead Left Ventricular Ejection Fraction Link Location Maps Measurement Measures Mechanics Mediating Morbidity - disease rate Muscle Cells Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Nerve Nervous System Neurons Neuropeptides Neurotransmitters Pathologic Patients Pattern Peptides Perfusion Periodicity Physiological Play Preparation Prevention therapy Process Reflex action Risk Role Scanning Signal Transduction Stimulus Structure Structure of stellate ganglion Sudden Death Sympathectomy Techniques Testing Therapeutic Therapeutic Intervention Time Tissues Transplantation United States Ventricular Ventricular Arrhythmia Ventricular Tachycardia data integration density disorder prevention in vivo individual response ischemic cardiomyopathy mortality nerve supply neural neuromechanism neuroregulation neurotransmitter release physiologic stressor protective effect response spatiotemporal stoichiometry sudden cardiac death targeted treatment therapeutic target

项目摘要

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.

摘要 – 项目 1 室性心律失常和心力衰竭导致的心源性猝死是发病率和死亡率的主要原因自主神经系统在美国的死亡率中起着重要作用。心律失常和心力衰竭是治疗的重要途径。然而，神经递质释放的结构和功能决定因素和健康和疾病中心肌中的肽，有效控制心脏兴奋性和机械性缺血性心肌损伤的功能以及心律失常的倾向仍然很大程度上未知。非缺血性心肌病在疤痕边缘区域表现出异常的神经支配和神经萌芽由于神经重塑，这与室性心律失常的病理生理学有关。建议测试“神经递质释放假说的时空异质性”—— 假设疤痕改变神经的超微结构并导致反射介导的神经递质不均匀心肌中的释放是致命性心律失常的关键/直接原因。该项目旨在研究心脏发生的结构（心肌）和功能（神经）变化由于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正常和患病心脏中的肽对生理应激源的反应，并具体定义了在目标 3 中，我们将确定神经递质的不均匀释放的潜在机制和潜力。迷走神经刺激在减轻与疤痕形成相关的病理重塑方面的益处疤痕和边缘区神经支配的区域结构和功能变化。将使用高密度电生理图和实时神经递质来研究区域神经肽测量与梗塞边界区域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。导致心律失常的潜在心肌和神经机制有可能发展和精确靶向治疗，激发预防心源性猝死和病情进展的治疗方法心脏衰竭。