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

盐皮质激素受体、冠状动脉微血管功能和高血压患者的心脏效率

基本信息

批准号：
10586784
负责人：
Gail Kurr Adler
金额：
$ 77.85万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586784
关键词：
Address Aftercare Albuminuria Aldosterone Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Antihypertensive Agents Blood Pressure Blood Pressure Monitors Blood Vessels Blood flow Cardiac Cardiovascular system Chlorthalidone Chronic Clinical Clinical Research Coronary Coupling Diuretics Echocardiography Enalapril Enzyme Inhibition Foundations Functional disorder Goals Guidelines Heart Heart Abnormalities Heart Diseases Human Hypertension Impairment Individual Knowledge Left Ventricular Hypertrophy Microvascular Dysfunction Mineralocorticoid Receptor Morbidity - disease rate Myocardial Non-Insulin-Dependent Diabetes Mellitus Outcome Oxygen Oxygen Consumption PET/CT scan Participant Patients Peptidyl-Dipeptidase A Placebos Positron-Emission Tomography Potassium Process Randomized Recommendation Relaxation Rest Risk Risk Factors Role Stress Structure Testing Tissues Woman Work antagonist cardiovascular risk factor eplerenone experimental study heart function hypertension treatment hypertensive improved mechanical energy men mortality prevent primary outcome receptor recruit thiazide vascular abnormality

项目摘要

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’]).

摘要