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

• 批准号: 10370369
• 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
• 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/10370369
• 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; Interleukin-1 beta; Interleukin-6; Lead; Left ventricular structure; Mediating; Molecular; Mus; Myocardial; Nerve; Outcome; Patients; Pharmacology; Physiological; Predisposition; Premature Mortality; Prosencephalon; Renin-Angiotensin System; Role; Stress; Sudden Death; Sympathetic Nervous System; TNF gene; Techniques; Testing; Testosterone; Time; Translating; Ventricular Arrhythmia; Woman; acute stress; base; biological adaptation to stress; clinical practice; clinically relevant; cytokine; delta Sarcoglycan; heart function; male; men; mortality; mouse model; new therapeutic target; novel; paraventricular nucleus; precision medicine; response; sex; social defeat; sudden cardiac death

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/摘要 扩张型心肌病（DCM）定义为左心室扩大伴收缩功能障碍，是导致心肌梗死的主要原因 心脏衰竭和心脏移植的案例心源性猝死占DCM死亡的约35%， 在报告的案件中，有相当一部分是由情绪紧张引起的。此外，本发明的目的是， 男性DCM的发病率是女性的三倍， 在患有心脏病的男性中效果不佳。尽管患病率和健康负担很高， 关于导致扩张型心肌病（尤其是男性）意外过早死亡的潜在机制。 下丘脑室旁核（PVN）是心血管前脑的关键核团， 在正常情况下介导应激反应，并导致交感神经过度活跃。 心力衰竭的神经系统血管紧张素II（AngII），肾素-血管紧张素系统的兴奋性成分 (RAS)和促炎性细胞因子在脑内的作用有助于神经体液兴奋，心脏 重构和心肌电不稳定性。我们稳健的初步结果表明， 社交失败引起的急性应激降低血压，诱发室性心律失常， 在DCM的肌聚糖δ缺陷（Sgcd-/-）小鼠模型中，雄性而非雌性突然死亡。所以我们 中心假设是，在DCM中，情绪压力的影响叠加在基础状态上， 神经体液兴奋，根据性别不同。我们认为，虽然增加交感神经流出 通常会导致高血压，在心脏功能受损和心脏功能降低的DCM男性中， 输出，它会导致低血压，心律失常和猝死。我们将进一步确定如何减少 雄激素在DCM男性有助于他们的脆弱性，而雌激素在DCM女性保护 对抗压力导致的死亡我们将用最先进的生理学和病理学方法来检验这些新的假设。 在普遍存在的和心脏特异性的Sgcd-/-小鼠中的分子方法，在以下两个具体的目标。 目的1：验证压力诱导的RAS活性增强和PVN炎症的假设 在DCM男性中引起过度的神经体液反应，导致低血压， 心律失常和猝死。 目的2：为了验证性激素调节PVN中RAS活性和炎症的假设， 导致扩张型心肌病男性患者对压力诱发的猝死的易感性增加。 这些研究将定义患有扩张型心肌病的雄性小鼠应激介导的猝死的潜在机制， 并确定新的治疗靶点，使基础科学的发现能够转化为 扩张型心肌病和心力衰竭的临床实践。