Novel Mechanisms that Restore Cardiac Parasympathetic Activity Limits Arrhythmias and Cardiac Dysfunction After Myocardial Infarction

恢复心脏副交感神经活动的新机制可限制心肌梗死后的心律失常和心脏功能障碍

• 批准号: 10366054
• 负责人: Matthew W. Kay
• 金额: $ 57.92万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-10 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10366054
• 关键词: Action Potentials; Acute; Adrenergic Agents; Animal Model; Animals; Anterior Descending Coronary Artery; Arrhythmia; Autonomic Pathways; Biosensor; Brain Stem; Cardiac; Cardiovascular system; Cessation of life; Chinese Hamster Ovary Cell; Chronic; Clinical; Clinical Research; Clinical Trials; Echocardiography; Electrocardiogram; Electrophysiology (science); Engineering; Equilibrium; Event; Exercise stress test; Fibrosis; Generations; Goals; Heart; Heart Arrest; Heart Diseases; Hour; Incidence; Infarction; Inflammation; Ischemia; Left; Ligation; Light; Mechanics; Mediating; Medical; Modeling; Muscarinics; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Neurons; Nose; Outcome; Oxytocin; Pathway interactions; Patients; Proteins; Rattus; Recording of previous events; Risk; Risk Factors; Sleep Apnea Syndromes; Synapses; Testing; Time; United States; Ventricular; Ventricular Arrhythmia; Ventricular Fibrillation; Ventricular Tachycardia; Western World; Woman; Work; acute coronary syndrome; base; designer receptors exclusively activated by designer drugs; field study; heart function; improved; improved functioning; in vivo; innovation; men; mortality; neurotransmission; novel; paraventricular nucleus; patch clamp; prevent; selective expression; sudden cardiac death

Sudden Cardiac Death (SCD) is responsible for between 15 and 20% of all deaths, and ~50% of all cardiovascular deaths in the United States. The most common cascade of events leading to SCD is acute coronary syndrome (ACS) progressing to acute myocardial ischemia and/or inflammation that triggers electrical instability and lethal arrhythmias. Preventing SCD is particularly difficult as approximately one-half of men and two-thirds of women who succumb to SCD had no known history of prior heart disease. Autonomic imbalance is a major risk factor for SCD. Augmented sympathetic activity induces changes in ECG repolarization and reduction of fibrillation threshold facilitating the initiation of ventricular fibrillation (VF). In contrast, the generation of fatal ventricular arrhythmias and risk of SCD is markedly reduced by increasing parasympathetic activity. However a rapid, safe and feasible approach to increase parasympathetic activity to the heart in patients at risk for fatal arrhythmias is severely lacking and is a major medical need. Our preliminary results provide critical new information for the field that identifies a novel target that could restore parasympathetic cardiac tone and reduce the incidence of arrhythmias and cardiac dysfunction following a MI. Our prior work in subjects with sleep apnea has shown intranasal (IN) application of oxytocin increases parasympathetic cardiac activity. In an animal model of ACS with ligation of the left anterior descending coronary artery (LAD) animals develop ischemia, arrhythmias and mortality similar to clinical studies. We show that LAD-ligated animals have reduced endogenous excitatory oxytocin-mediated neurotransmission to parasympathetic cardiac vagal neurons (CVNs) in the brainstem. We further show that selective and chronic activation of hypothalamic paraventricular nucleus (PVN) oxytocin neurons restores oxytocin release, increases parasympathetic activity to the heart and substantially reduces the incidence and initiation of arrhythmias, inflammation, fibrosis and other adverse cardiac outcomes. Based upon our novel results, our overall hypothesis is that chronic selective activation of PVN oxytocin neurons, as well as nasal oxytocin administration, markedly reduces arrhythmias and cardiac dysfunction in an animal model of ACS. In Aim 1 we will test the hypothesis that the critical excitatory pathway from PVN oxytocin neurons to CVNs that helps maintain protective parasympathetic activity to the heart is blunted in animals following LAD ligation, and that this key neurotransmission can be restored with nasal oxytocin treatment and chronic and selective activation of PVN oxytocin neurons. In Aim 2 we will test whether treatment by nasal oxytocin and chronic and selective activation of PVN oxytocin neurons increases parasympathetic activity to the heart in-vivo, reduce the incidence of arrhythmias, improves autonomic balance and effort capacity in exercise stress tests and cardiac function. In Aim 3 we will quantify the electrical and mechanical function of ex-vivo perfused hearts to identify the mechanisms responsible for the cardiac benefits of nasal oxytocin and selective activation of PVN oxytocin neurons in LAD-ligated animals.

心源性猝死（SCD）占所有死亡人数的15%至20%，约占所有死亡人数的50%