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.

项目概要/摘要 扩张型心肌病 (DCM) 定义为左心室扩大并伴有收缩功能障碍，这是主要原因 心力衰竭和心脏移植。心源性猝死约占 DCM 死亡人数的 35%，其中 其中大量报告的病例是由情绪压力发作引发的。此外， DCM 的男性发病率是女性的三倍，与雄激素水平降低有关 患有心脏病的男性预后不佳。尽管患病率和健康负担很高，但人们知之甚少 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， 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) 和在大脑内作用的促炎细胞因子有助于神经体液兴奋、心脏 心力衰竭中的重构和心肌电不稳定。我们稳健的初步结果表明 社交失败引起的急性压力会降低血压，诱发室性心律失常并导致 雄性（而非雌性）肌聚糖 δ 缺陷 (Sgcd-/-) 扩张型心肌病 (DCM) 小鼠模型中突然死亡。因此，我们的 中心假设是，在 DCM 中，情绪压力的影响叠加在基础状态上 神经体液兴奋因性别而异。我们建议，虽然交感神经流出增加 对于心脏功能受损和心脏功能减退的 DCM 男性来说，通常会导致高血压。 输出，导致低血压、心律失常和猝死。我们将进一步确定如何减少 DCM 男性体内的雄激素导致其脆弱性，而 DCM 女性体内的雌激素则保护其脆弱性。 对抗压力引起的死亡。我们将用最先进的生理学和 在普遍存在的心脏特异性 Sgcd-/- 小鼠中采用分子方法，有以下两个具体目标。 目标 1：检验压力诱导 RAS 活性增强和 PVN 炎症的假设 导致患有 DCM 的男性出现过度的神经体液反应，导致低血压， 心律失常和猝死。 目标 2：检验性激素调节 PVN 中 RAS 活性和炎症的假设， 导致患有 DCM 的男性对压力引起的猝死的易感性增加。 这些研究将明确患有 DCM 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。