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.

Public Health Relevance

This grant application seeks support for the training and mentoring of a new generation of physicians and investigators interested in performing patient-oriented research to understand why some individuals develop heart disease. HIV patients treated with antiretroviral medications are one such group at increased risk. The research proposed in this grant will determine whether the burden and progression of heart disease in HIV patients can be reduced by blocking a hormone, aldosterone, known to cause inflammation and damage to blood vessels.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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NHLBI Mentored Patient-Oriented Research Review Committee (MPOR)
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Scott, Jane
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Brigham and Women's Hospital
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Murphy, Caitlin A; Fitch, Kathleen V; Feldpausch, Meghan et al. (2018) Excessive Adiposity and Metabolic Dysfunction Relate to Reduced Natriuretic Peptide During RAAS Activation in HIV. J Clin Endocrinol Metab 103:1558-1565
Srinivasa, Suman; Fitch, Kathleen V; Wong, Kimberly et al. (2018) Randomized, Placebo-Controlled Trial to Evaluate Effects of Eplerenone on Metabolic and Inflammatory Indices in HIV. J Clin Endocrinol Metab 103:2376-2384
Bayomy, Omar; Rao, Ajay D; Garg, Rajesh et al. (2017) Plasminogen Activator Inhibitor-1 and Pericardial Fat in Individuals with Type 2 Diabetes Mellitus. Metab Syndr Relat Disord 15:269-275
Zaheer, Sarah; Brown, Jenifer M; Connors, Molly et al. (2017) Angiotensin-Converting Enzyme Inhibition and Parathyroid Hormone Secretion. Int J Endocrinol 2017:4138783
Tan, Jia W; Gupta, Tina; Manosroi, Worapaka et al. (2017) Dysregulated aldosterone secretion in persons of African descent with endothelin-1 gene variants. JCI Insight 2:
Seccia, Teresa M; Caroccia, Brasilina; Adler, Gail K et al. (2017) Arterial Hypertension, Atrial Fibrillation, and Hyperaldosteronism: The Triple Trouble. Hypertension 69:545-550
Srinivasa, Suman; Burdo, Tricia H; Williams, Kenneth C et al. (2016) Effects of Sodium Restriction on Activation of the Renin-Angiotensin-Aldosterone System and Immune Indices During HIV Infection. J Infect Dis 214:1336-1340
Baudrand, Rene; Pojoga, Luminita; Vaidya, Anand et al. (2016) Response to Letter Regarding Article, ""Statin Use and Adrenal Aldosterone Production in Hypertensive and Diabetic Subjects"". Circulation 133:e606
Garg, Rajesh; Adler, Gail K (2016) Differential Effects of Two Antialdosterone Agents on Glycemic Control. Endocrinology 157:3767-3768
Lopez, Diana; Luque-Fernandez, Miguel Angel; Steele, Amy et al. (2016) ""Nonfunctional"" Adrenal Tumors and the Risk for Incident Diabetes and Cardiovascular Outcomes: A Cohort Study. Ann Intern Med 165:533-542

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