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.

项目摘要/摘要 定义为扩大的左心室的扩张心肌病（DCM）具有收缩功能障碍是主要原因 心力衰竭和心脏移植。心脏死亡占DCM死亡的约35％， 大量报告的病例是由情绪压力发作触发的。此外， 男性的DCM发病率是女性的三倍，与雄激素相关的水平降低 心脏病男性的结果不佳。尽管患病率很高和健康负担，但鲜为人知 关于导致DCM中意外过早死亡的潜在机制，尤其是在男性中。 下丘脑（PVN）的室室核是一种钥匙心血管前脑核，它是该核 介导正常条件下的应力反应，并导致交感神经的过度活动 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）和作用在大脑内作用的促炎细胞因子有助于神经肿瘤激发，心脏 心力衰竭中的重塑和心肌不稳定性。我们强大的初步结果表明 社交失败引起的急性应激会降低血压，引起心室心律不齐，并导致 DCM的男性（sgcd - / - ）小鼠模型中的男性，但不是女性，肌肉糖三角洲的突然死亡。因此，我们的 中心假设是在DCM中，情绪压力的影响叠加在 神经肿瘤激发，根据性别有所不同。我们建议，尽管增加了交感神经流出 通常会引起高血压，在心脏功能受损和心脏降低的DCM男性中 输出，会导致低血压，心律不齐和猝死。我们将进一步确定如何减少 DCM男性中的雄激素有助于其脆弱性，而DCM女性的雌激素则保护 反对压力引起的死亡率。我们将通过最先进的生理学和 在以下两个特定目的中，无处不在和心脏特异性SGCD - / - 小鼠的分子方法。 目的1：检验以下假设：应激引起的RAS活性的增加和PVN炎症 DCM的男性中会导致夸张的神经肿瘤反应，导致低血压， 心律不齐和猝死。 目标2：测试性激素调节PVN中的RAS活性和炎症的假设， 导致DCM男性对压力引起的猝死的敏感性增加。 这些研究将定义雄性小鼠DCM，DCM的猝死的潜在机制， 并确定将使基础科学发现的新型治疗靶标被转化为 扩张心肌病和心力衰竭的临床实践。