Stress-induced cardiovascular dysfunction in dilated cardiomyopathy

项目摘要/摘要 扩张型心肌病(DCM)定义为左心室增大并伴有收缩功能障碍，是主要原因 心力衰竭和心脏移植。心脏性猝死约占DCM死亡的35%， 在报告的病例中，有相当一部分是由情绪压力引发的。另外， 扩张型心肌炎的发病率男性是女性的三倍，与雄激素水平降低有关 在患有心脏病的男性中预后不佳。尽管发病率和健康负担很高，但人们对此知之甚少。 关于导致扩张型心肌病意外过早死亡的潜在机制，特别是在男性。 下丘脑室旁核(PVN)是重要的心血管前脑核。 调节正常情况下的应激反应，并导致交感神经过度活跃 心力衰竭中的神经系统。肾素-血管紧张素系统的兴奋性成分--血管紧张素II (RAS)，以及作用于脑内的促炎细胞因子有助于神经体液兴奋，心脏 心力衰竭时的重构和心肌电不稳定。我们强劲的初步结果表明， 由社会失败引起的急性应激降低血压，诱发室性心律失常，并导致 在雄性，而不是雌性，肌糖三角缺失(SGCD-/-)的DCM小鼠模型中猝死。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 神经体液兴奋因性别不同而不同。我们认为，虽然交感神经流出的增加 在心脏功能受损和心脏功能减退的DCM男性患者中，通常会导致高血压 输出，它会导致低血压、心律失常和猝死。我们将进一步确定减少的 DCM雄性中的雄激素有助于它们的脆弱性，而DCM雌性中的雌激素则保护 对抗压力导致的死亡。我们将用最先进的生理学和 在无处不在的和心脏特异的SGCD-/-小鼠中的分子方法，在以下两个特定的目的。 目的1：验证应激诱导下丘脑室旁核RAS活性增强和炎症反应的假说 在患有扩张性心肌病的男性患者中引发夸大的神经体液反应，导致低血压， 心律失常和猝死。 目的2：验证性激素调节下丘脑室旁核RAS活性和炎症反应的假说。 导致扩张型心肌病男性对应激引起的猝死的易感性增加。 这些研究将确定患有DCM的雄性小鼠应激介导猝死的潜在机制， 并确定新的治疗靶点(S)，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。

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.