Mineralocorticoid Receptor, Coronary Microvascular Function, and Cardiac Efficiency in Hypertension
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 75
- 试验地点
- 2
- 主要终点
- Change in myocardial flow reserve
研究概览
简要总结
The investigators' goal is to show that in hypertensive men and women with left ventricular hypertrophy (LVH) treatment with a mineralocorticoid receptor (MR) antagonist, versus a thiazide-like diuretic, will improve coronary microvascular function and cardiac efficiency, which will associate with improvements in LV structure and function. The investigators will achieve this through a randomized, controlled, basic experimental study involving humans (BESH).
详细描述
The investigators are recruiting individuals with hypertension and LVH, as defined by echocardiography, who are on chronic angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blockade (ARB). Participants will be transitioned to enalapril, ACEi, with washout of all other anti-hypertensives and then randomized to add-on treatment for 9 months with eplerenone (MR antagonist) or chlorthalidone (thiazide-like diuretic) + potassium. The investigators will use cardiac PET to quantify changes in coronary microvascular function and cardiac efficiency; echocardiography to assess changes in cardiac function and structure. The investigators will define the impact of eplerenone as compared with chlorthalidone on coronary microvascular function (Aim 1) and cardiac efficiency (Aim 2) and determine the relationship between coronary microvascular function and cardiac efficiency. Additionally, the investigators will determine whether improvements in coronary microvascular function and/or cardiac efficiency correlate with improvements in myocardial structure and function (chamber dimensions, diastolic function, and global longitudinal strain) in individuals with hypertension and LVH.
Participants be placed on enalapril 10 mg and weaned off their other anti-hypertensives prior to the Pre-Treatment Assessment. After the Pre-Treatment Assessment, participants will be randomized to the following daily medications: 50 mg eplerenone or 12.5 mg chlorthalidone + 10 mEq potassium. At 2 weeks, eplerenone will be increased to 100 mg and chlorthalidone to 25 mg + 20 mEq potassium. Amlodipine (5 to 10 mg) will be added at 6 weeks or later if needed to achieve the BP target of <135/85 mmHg. Study outcomes will be assessed at baseline and 9 months after randomization. The primary outcome measures will be: 1) myocardial flow reserve (MFR, ratio of stress over rest myocardial blood flow); and 2) myocardial external efficiency (MEE, ratio of myocardial work over myocardial oxygen consumption and LV mass). The investigators will also measure: 1) myocardial oxygen consumption (MVO2); 2) myocardial function (peak global longitudinal strain, tissue Doppler mitral annular early diastolic relaxation velocity [e'], and the ratio of mitral E velocity to e' [E/e']) as measured by 2D echocardiography; 3) markers of cardiovascular injury and remodeling, including high sensitivity troponin and procollagen III amino terminal propeptide (PIIINP); and 4) measures of renin-angiotensin-aldosterone system under resting conditions, with upright posture, and with angiotensin-II stimulation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •History of hypertension
- •Seated systolic BP < 180 mmHg and diastolic < 110 mmHg if on antihypertensives
- •Seated systolic BP 141-200 mmHg and/or diastolic BP 90-114 mmHg if not on antihypertensives
- •LVH by echocardiogram
- •For men: interventricular septum thickness ≥ 12mm
- •For women: interventricular septum thickness ≥ 11mm
- •We will also allow inclusion of people with treated hypothyroidism, pre-diabetes and diabetes controlled by diet, exercise, and/or metformin.
排除标准
- •Use of MR antagonist (eplerenone, spironolactone, or finerenone) or amiloride (amiloride inhibits ENaC, which is a key mediator of MR's actions) within the past year
- •Orthostatic hypotension
- •Major medical illness, including uncontrolled diabetes mellitus (Hemoglobin A1c >7.5)
- •LV ejection fraction < 40%
- •New York Heart Association class III to IV congestive heart failure or unstable angina
- •A history in the prior 6 months of Q-wave myocardial infarction, stroke, transient ischemic attack, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft
- •History of secondary hypertension
- •Known genetic cardiomyopathy
- •Renal disease (seum creatinine >1.5 mg/dL for men and >1.3 mg/dL for women)
- •Hepatic disease
- •Bronchospastic lung disease
- •Alcohol or substance abuse
- •Hormone replacement therapy
- •Abnormal values for electrolytes, liver enzymes or TSH
- •Pregnancy or lactation
- •All individuals <18 and >75 years will be excluded due to safety concerns of administering an angiotensin-II infusion in these patient groups.
研究组 & 干预措施
Eplerenone
Participants be placed on enalapril 10 mg and weaned off their other anti-hypertensives prior to the Pre-Treatment Assessment. Amlodipine (5 to 10 mg) will be added if needed to control blood pressure. After the Pre-Treatment Assessment, participants randomized to this arm will receive 50 mg eplerenone . At 2 weeks, eplerenone will be increased to 100 mg. Amlodipine (5 to 10 mg) will be added at 6 weeks or later if needed to achieve the BP target of <135/85 mmHg.
干预措施: Eplerenone (Drug)
Chlorthalidone + potassium
Participants be placed on enalapril 10 mg and weaned off their other anti-hypertensives prior to the Pre-Treatment Assessment. Amlodipine (5 to 10 mg) will be added if needed to control blood pressure. After the Pre-Treatment Assessment, participants randomized to this arm will receive 12.5 mg chlorthalidone + 10 mEq potassium. At 2 weeks, chlorthalidone will be increased to 25 mg + 20 mEq potassium. Amlodipine (5 to 10 mg) will be added at 6 weeks or later if needed to achieve the BP target of <135/85 mmHg.
干预措施: Potassium (Drug)
Chlorthalidone + potassium
Participants be placed on enalapril 10 mg and weaned off their other anti-hypertensives prior to the Pre-Treatment Assessment. Amlodipine (5 to 10 mg) will be added if needed to control blood pressure. After the Pre-Treatment Assessment, participants randomized to this arm will receive 12.5 mg chlorthalidone + 10 mEq potassium. At 2 weeks, chlorthalidone will be increased to 25 mg + 20 mEq potassium. Amlodipine (5 to 10 mg) will be added at 6 weeks or later if needed to achieve the BP target of <135/85 mmHg.
干预措施: Chlorthalidone (Drug)
结局指标
主要结局
Change in myocardial flow reserve
时间窗: 9 months
Change in myocardial flow reserve (ratio of hyperemic stress myocardial blood flow to rest myocardial blood flow)
次要结局
- Change in myocardial external efficiency(9 months)
研究者
Gail Kurr Adler
Chief, Cardiovascular Endocrinology Section, Principal Investigator, Professor of Medicine
Brigham and Women's Hospital