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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