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

• 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
• 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

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’]).

抽象的 高血压是心血管（CV）发病和死亡的主要危险因素。心血管风险仍然增加 即使血压 (BP) 得到控制，也表明还有其他因素与高血压相关 （受血压本身影响，但独立于血压本身），这会导致不良的心血管结果。这个应用程序 重点关注两个潜在相关的 CV 病理生理过程：1）心肌氧损伤 分娩（表现为冠状动脉微血管功能障碍，已知的 CV 发病率/死亡率的预测因素）和 2) 心脏效率受损（表现为心肌耗氧量和心肌耗氧量的低效耦合） 心脏工作）。对于冠状动脉微血管功能障碍或异常，尚无确定的治疗方法 心脏效率——一个关键的知识差距。患有高血压和左心室肥厚的人 (LVH) 具有冠状动脉微血管功能障碍和盐皮质激素受体活性过度。我们的整体 假设是，在患有高血压和 LVH 的个体中，盐皮质激素受体阻断会改善 冠状动脉微血管功能和心脏效率，与血压变化无关；以及这些改进 将改善心肌结构和功能，并最终改善心血管结果。 我们提出了一项涉及人类的随机、对照、基础实验研究。男性和女性同 服用依那普利（血管紧张素转换酶 (ACE) 抑制剂）的高血压和 LVH 将被随机分组 使用依普利酮（盐皮质激素受体拮抗剂）或氯噻酮（噻嗪类药物）治疗 9 个月 利尿剂）+钾。我们将使用心脏 PET/CT 来量化冠状动脉微血管功能的变化（即 心肌血流储备 - 应激/静息心肌血流量的比率）和心脏效率（即心肌 外部效率——心肌做功与耗氧量之比）；超声心动图评估变化 心肌结构与功能；和24小时血压监测。 这项研究将检验以下假设：在高血压和 LVH 患者中，ACE 抑制作用 与噻嗪类利尿剂相比，用盐皮质激素受体拮抗剂治疗， 改进： • 冠状动脉微血管功能，即心肌血流储备（具体目标 1） • 心脏效率，即心肌外部效率（具体目标 2） 我们预计这些结果的改善将与心肌结构的改善相关 和功能（峰值全局纵向应变、组织多普勒二尖瓣环舒张早期舒张速度[e’]、 以及二尖瓣 E 速度与 e' 的比率 [E/e']）。