Aldosterone and Cardiovascular Disease: Research and Mentoring Program

项目摘要/摘要 此K24竞争续订申请旨在为以下方面提供受保护时间支持：1)我的指导和 对初级临床研究人员的教学；以及2)以患者为中心的研究，调查醛固酮的作用 心血管疾病病理生理学中的盐皮质激素受体(MR)。 醛固酮激活MR，可引起血管和心脏炎症和纤维化。在来自 在K24资助的头五年，我们表明，在糖尿病得到很好控制的个人中，使用 MR拮抗剂可改善冠状动脉血流储备，这是一种衡量冠状动脉血管功能的指标。在这些相同的地方 个体中，升高的醛固酮水平与心肌细胞外体积的增加有关 (ECV)，这是一种衡量心脏炎症和纤维化的指标。这些发现表明，在糖尿病患者中，MR激活 导致冠状动脉血流储备受损和心肌ECV增加；这两者都预示着增加 糖尿病的心血管发病率和死亡率。此外，我们的初步数据表明，患有 代谢紊乱、内脏肥胖症和胰岛素抵抗增加，以及艾滋病毒导致醛固酮升高 级别。艾滋病病毒携带者，经过良好的抗逆转录病毒治疗，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，因为 与非艾滋病毒携带者相比。这种增加的心血管疾病风险不能用传统的心血管疾病来解释 危险因素和没有成功的治疗策略来补充抗逆转录病毒治疗以减少心血管疾病 感染艾滋病毒的风险。这项提议检验了MR过度活动会导致冠状动脉血管功能障碍的假说， HIV患者的心肌炎症和纤维化，以及冠状动脉斑块的增加。因此，我们将执行一个 随机、双盲、安慰剂对照试验，证明选择性磁共振治疗 拮抗剂依普利酮12个月改善冠脉血流储备(特定目标1)，心肌ECV (特异靶2)和冠状动脉斑块(特异靶3)。我们将利用先进的放射学技术 (心脏正电子发射计算机断层扫描、心脏核磁共振和冠状动脉CTA)以量化这些心血管结果。 这项研究是MR阻滞剂对HIV中CV疾病的首次全面调查，旨在 为减少艾滋病毒的心血管疾病风险提供新的机械性见解和有前景的战略。此外，这些 数据应该为心血管疾病负担增加的其他非艾滋病毒人群提供重要的洞察力。这些研究 将提供一个肥沃的领域，供对以患者为导向的研究感兴趣的受训人员进行调查并确定 代谢紊乱患者心血管疾病的新的有效治疗方法。

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.