Mineralocorticoid receptor, coronary microvascular function, and cardiac efficiency in hypertension

ABSTRACT Hypertension is a major risk factor for cardiovascular (CV) morbidity and mortality. Increased CV risk remains even if blood pressure (BP) is controlled, suggesting there are additional factors associated with hypertension (influenced by, but independent of, BP per se), which contribute to adverse CV outcomes. This application focuses on two potentially interrelated CV pathophysiologic processes: 1) impairment in myocardial oxygen delivery (manifested as coronary microvascular dysfunction, a known predictor of CV morbidity/mortality) and 2) impairment in cardiac efficiency (manifested as inefficient coupling of myocardial oxygen consumption and cardiac work). There are no established treatments for coronary microvascular dysfunction or abnormal cardiac efficiency—a critical knowledge gap. Individuals with hypertension and left ventricular hypertrophy (LVH) have coronary microvascular dysfunction and excess mineralocorticoid receptor activity. Our overall hypothesis is that, in individuals with hypertension and LVH, mineralocorticoid receptor blockade will improve coronary microvascular function and cardiac efficiency, independent of changes in BP; and these improvements will lead to improved myocardial structure and function and ultimately to improved CV outcomes. We propose a randomized, controlled, basic experimental study involving humans. Men and women with hypertension and LVH on enalapril (angiotensin-converting enzyme (ACE) inhibitor) will be randomized to treatment for 9 months with eplerenone (mineralocorticoid receptor antagonist) or chlorthalidone (thiazide-like diuretic) + potassium. We will use cardiac PET/CT to quantify changes in coronary microvascular function (i.e. myocardial flow reserve - ratio of stress/rest myocardial blood flow) and cardiac efficiency (i.e. myocardial external efficiency - ratio of myocardial work to oxygen consumption); echocardiography to assess changes in myocardial structure and function; and 24-hr BP monitoring. This study will test the hypothesis that, in patients with hypertension and LVH on ACE inhibition, treatment with mineralocorticoid receptor antagonist, as compared with a thiazide-like diuretic, improves: • Coronary microvascular function, i.e., myocardial flow reserve (Specific Aim 1) • Cardiac efficiency, i.e., myocardial external efficiency (Specific Aim 2) We anticipate that improvements in these outcomes will associate with improvements in myocardial structure and function (peak global longitudinal strain, tissue Doppler mitral annular early diastolic relaxation velocity [e’], and ratio of mitral E velocity to e’ [E/e’]).