Aldosterone and Cardiovascular Disease: Research and Mentoring Program

项目总结/摘要 此K24竞争续订应用程序将为以下人员提供受保护时间支持：1）我的指导， 初级临床研究者的教学; 2）以患者为导向的研究醛固酮的作用 和盐皮质激素受体（MR）在心血管（CV）疾病的病理生理学中的作用。 醛固酮激活MR并可引起血管和心脏炎症和纤维化。的支持下 在K24资助的前五年，我们发现，在控制良好的糖尿病患者中， MR拮抗剂可改善冠状动脉血流储备，这是冠状动脉血管功能的一项指标。在这些相同 在个体中，醛固酮水平升高与心肌细胞外容积增加相关 (ECV)心脏炎症和纤维化的指标。这些发现表明，在糖尿病中， 导致冠状动脉血流储备受损和心肌ECV增加;这两者都预测增加 糖尿病的CV发病率和死亡率。此外，我们的初步数据表明， 代谢紊乱、内脏肥胖和胰岛素抵抗增加，以及艾滋病毒导致醛固酮升高 程度.艾滋病毒感染者，经过抗逆转录病毒治疗后，冠状动脉血流储备受损， 心肌ECV增加，冠状动脉斑块增加。他们患心血管疾病的风险增加， 与非艾滋病毒感染者相比。传统的心血管疾病不能解释心血管疾病风险的增加 风险因素和没有成功的治疗策略存在，以补充抗逆转录病毒治疗，以减少心血管疾病 艾滋病毒的风险。该提案检验了过度MR活动导致冠状动脉血管功能障碍的假设， 心肌炎症和纤维化，以及艾滋病毒增加冠状动脉斑块。因此，我们将执行一个 随机、双盲、安慰剂对照试验，以证明选择性MR治疗 拮抗剂依普利酮治疗12个月可改善冠状动脉血流储备（特异性目标1）、心肌ECV （具体目标2）和冠状动脉斑块（具体目标3）。我们将利用先进的放射技术 （心脏PET、心脏MRI和冠状动脉CTA）来量化这些CV结局。 这项研究是首次全面研究MR阻断对HIV患者CV疾病的影响，旨在 提供了新的机制的见解和一个有前途的策略，降低心血管疾病的风险，艾滋病毒。而且这些 这些数据应该为其他CVD负担增加的非HIV人群提供重要的见解。这些研究 将为对面向患者的研究感兴趣的学员提供一个肥沃的研究领域， 新的，有效的治疗代谢紊乱患者的心血管疾病。

PROJECT SUMMARY/ABSTRACT This K24 competitive renewal application is to provide support for protected time for: 1) my mentoring and teaching of junior clinical investigators; and 2) patient-oriented research investigating the role of aldosterone and the mineralocorticoid receptor (MR) in the pathophysiology of cardiovascular (CV) disease. Aldosterone activates the MR and can cause vascular and cardiac inflammation and fibrosis. With support from the first five years of K24 funding, we showed that, in individuals with well-controlled diabetes, treatment with a MR antagonist improves coronary flow reserve, a measure of coronary vascular function. In these same individuals, elevated aldosterone levels were associated with increases in myocardial extracellular volume (ECV), a measure of cardiac inflammation and fibrosis. These findings suggest that, in diabetes, MR activation contributes to impaired coronary flow reserve and increased myocardial ECV; both of which predict increased CV morbidity and mortality in diabetes. In addition, our preliminary data indicates that individuals with metabolic disturbances, increased visceral adiposity and insulin resistance, and HIV have elevated aldosterone levels. Individuals with HIV, well-treated with antiretroviral therapy, have impaired coronary flow reserve, increased myocardial ECV, and increased coronary plaque. They are at increased risk of CV disease as compared to non-HIV individuals. This increased risk of CV disease cannot be accounted for by traditional CV risk factors and no successful treatment strategies exist to complement antiretroviral therapy to reduce CVD risk in HIV. This proposal tests the hypothesis that excess MR activity leads to coronary vascular dysfunction, myocardial inflammation and fibrosis, and increased coronary plaque in HIV. Thus, we will perform a randomized, double blind, placebo controlled trial to demonstrate that treatment with a selective MR antagonist, eplerenone, for 12 months improves coronary flow reserve (Specific Aim 1), myocardial ECV (Specific Aim 2) and coronary plaque (Specific Aim 3). We will utilize sophisticated radiologic techniques (cardiac PET, cardiac MRI and coronary CTA) to quantify these CV outcomes. This research, which is the first comprehensive investigation of MR blockade on CV disease in HIV, aims to provide novel mechanistic insights and a promising strategy for CVD risk reduction in HIV. Moreover, these data should provide critical insight for other non-HIV populations with increased CVD burden. These studies will provide a fertile area for investigation by trainees interested in patient-oriented research and in identifying new, effective treatments of cardiovascular disease in patients with metabolic disorders.