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

摘要 高血压是心血管（CV）发病率和死亡率的主要风险因素。CV风险增加 即使血压（BP）得到控制，这表明还有其他因素与高血压相关 （受BP本身的影响，但独立于BP本身），这会导致不良CV结局。本申请 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，CV发病率/死亡率的已知预测因素）和2） 心脏效率的损害（表现为心肌耗氧量的无效偶联， 心脏工作）。对于冠状动脉微血管功能障碍或异常， 心脏效率-一个关键的知识缺口。高血压和左心室肥厚患者 (LVH)冠状动脉微血管功能障碍和盐皮质激素受体活性过剩。我们的整体 假设在高血压和LVH患者中，盐皮质激素受体阻滞剂将改善 冠状动脉微血管功能和心脏效率，独立于血压的变化;这些改善 将改善心肌结构和功能，并最终改善CV结局。 我们提出了一个随机的，对照的，基本的实验研究涉及人类。男性和女性 接受依那普利（血管紧张素转换酶（ACE）抑制剂）治疗的高血压和LVH患者将被随机分配至 用依普利酮（盐皮质激素受体拮抗剂）或氯噻酮（噻嗪类）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/静息心肌血流的比率）和心脏效率（即心肌血流储备 外部效率-心肌功与耗氧量的比值）;超声心动图评估 心肌结构和功能; 24小时血压监测。 本研究将检验以下假设：在高血压伴LVH患者中， 与噻嗪类利尿剂相比， 改善： ·冠状动脉微血管功能，即心肌血流储备（特定目标1） ·心脏效率，即，心肌外效率（特定目标2） 我们预期这些结果的改善将与心肌结构的改善相关 和功能（峰值整体纵向应变，组织多普勒二尖瓣环舒张早期舒张速度[e ']， 和二尖瓣E流速与e'的比值[E/e']）。

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’]).