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Stress-induced cardiovascular dysfunction in dilated cardiomyopathy

扩张型心肌病中应激诱发的心血管功能障碍

基本信息

批准号：
10604281
负责人：
Rasna Sabharwal
金额：
$ 50.6万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-10 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604281
关键词：
Acute Adrenal Glands Androgens Angiotensin II Anterior Pituitary Hormones Argipressin Arrhythmia Autonomic Dysfunction Basic Science Blood Pressure Brain Cardiac Cardiac Output Cardiovascular system Case Study Catecholamines Cause of Death Cell Nucleus Cessation of life Corticotropin-Releasing Hormone Data Diagnosis Dilated Cardiomyopathy Dissociation Emotional Stress Estrogen Receptors Estrogens Female Functional disorder Genetic Genetic Models Glucocorticoids Gonadal Steroid Hormones Health Heart Diseases Heart Transplantation Heart failure High Prevalence Hypertension Hypotension Hypothalamic structure Incidence Inflammation Inflammatory Interleukin-1 beta Interleukin-6 Left ventricular structure Mediating Molecular Mus Myocardial Nerve Outcome Patients Physiological Predisposition Premature Mortality Prosencephalon Renin-Angiotensin System Role Stress Sudden Death Sympathetic Nervous System TNF gene Techniques Testing Testosterone Translating Ventricular Arrhythmia Woman acute stress biological adaptation to stress clinical practice clinically relevant cytokine delta Sarcoglycan heart function male men mortality mouse model new therapeutic target novel paraventricular nucleus pharmacologic precision medicine response sex social defeat sudden cardiac death

项目摘要

PROJECT SUMMARY/ABSTRACT Dilated cardiomyopathy (DCM) defined as an enlarged left ventricle with systolic dysfunction is a leading cause of heart failure and cardiac transplantation. Sudden cardiac death accounts for ~35% of deaths in DCM, of which a significant number of the reported cases are triggered by episodes of emotional stress. Additionally, the incidence of DCM is three times greater in men than women, with reduced levels of androgens associated with poor outcomes in men with heart diseases. Despite the high prevalence and health burden, little is known about the underlying mechanisms that lead to the unexpected premature mortality in DCM, especially in males. The paraventricular nucleus of the hypothalamus (PVN) is a key cardiovascular forebrain nucleus that mediates the stress response under normal conditions and contributes to the overactivity of the sympathetic nervous system in heart failure. Angiotensin II (AngII), the excitatory component of renin-angiotensin system (RAS), and proinflammatory cytokines acting within the brain contribute to the neurohumoral excitation, cardiac remodeling and myocardial electrical instability in heart failure. Our robust preliminary results indicate that acute stress induced by social defeat decrease blood pressure, evoke ventricular arrhythmias and lead to sudden death in male, but not female, sarcoglycan delta deficient (Sgcd-/-) mouse model of DCM. Thus, our central hypothesis is that in DCM, the effects of emotional stress are superimposed upon a basal state of neurohumoral excitation which differ according to sex. We propose that while increased sympathetic outflow would normally cause hypertension, in DCM males with compromised cardiac function and reduced cardiac output, it results in hypotension, arrhythmias and sudden death. We will further determine how the reduced androgens in the DCM males contribute to their vulnerability, while estrogens in the DCM females protect against stress-induced mortality. We will test these novel hypotheses with state-of-the art physiological and molecular approaches in the ubiquitous and cardiac-specific Sgcd-/- mice, in the following two specific aims. Aim 1: To test the hypothesis that stress-induced augmentation of RAS activity and inflammation in the PVN precipitates an exaggerated neurohumoral response in males with DCM, leading to hypotension, arrhythmias and sudden death. Aim 2: To test the hypothesis that the sex hormones modulate RAS activity and inflammation in the PVN, contributing to the increased susceptibility of males with DCM to stress-induced sudden death. These studies will define underlying mechanisms of stress-mediated sudden death in male mice with DCM, and identify novel therapeutic target(s) that will enable discoveries from basic science to be translated into clinical practice for dilated cardiomyopathy and heart failure.

项目总结/文摘