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

• 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
• 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

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 由于心室心律失常和心力衰竭引起的心脏猝死是主要引起的发病率和 在美国的死亡率。自主神经系统在病理生理中起主要作用 心律不齐和心力衰竭。神经调节代表了治疗的重要途径 干涉。然而，神经递质释放的结构和功能决定者和 健康和疾病心肌中的肽，这些肽有效控制心脏兴奋性和机械性 功能以及对心律不齐的承诺仍然在很大程度上未知。在缺血中看到的心肌疤痕 非缺血性心肌病在疤痕边界区域表现出异常神经和神经发芽 由于神经沉积物，在心室心律不齐的病理生理学中已隐含。 测试“神经递质释放假设的时空异质性”的提议 - 假设疤痕会改变神经的超微结构并引起反射介导的神经递质不均匀 在心肌中释放，代表致命心律不齐的关键/近端原因。主要目标 该项目是为了研究发生的结构（心肌）和功能性（神经）的变化 由于心脏病，随后导致心室心律不齐。在目标1和2中，我们将确定 超微结构并定义神经递归和神经递质的释放曲线和释放轮廓 响应身体压力源，特别定义的区域 神经递质的不均匀释放。在AIM 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疤痕形成相关的病理重塑方面的好处 自主神经。疤痕和边界区域神经支配的区域结构和功能变化 区域将使用高密度的电生理映射和实时神经递质和 神经肽测量结果将与梗塞边界区域的结构变化相关 在相关的大动物模型和人心中使用组织清除技术。了解 导致心律不齐的潜在心肌和神经机制具有发展和 精确的靶向疗法激发了预防心脏猝死和进展的疗法 心脏衰竭。