Mineralocorticoid Receptor, Coronary Microvascular Function, and Cardiac Efficiency in Hypertension

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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Mineralocorticoid Receptor, Coronary Microvascular Function, and Cardiac Efficiency in Hypertension

Conditions
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Hypertension, Left Ventricular Hypertrophy

Intervention / Treatment
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* Drug: Eplerenone
* Drug: Chlorthalidone
* Drug: Potassium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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: LV mass index > 134 g/m2 For women: LV mass index > 110 g/m2 We will also allow inclusion of people with treated hypothyroidism, pre-diabetes and diabetes controlled by diet, exercise, and/or metformin. Exclusion Criteria: 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 >70 years will be excluded due to safety concerns of administering an angiotensin-II infusion in these patient groups.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants are randomized to chlorthalidone or eplerenone.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Eplerenone<br>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. | Drug: Eplerenone<br>* After the Pre-Treatment Assessment, participants in the eplerenone arm will be given 50 mg eplerenone. At 2 weeks, eplerenone will be increased to 100 mg.<br>|
| Active Comparator: Chlorthalidone + potassium<br>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. | Drug: Chlorthalidone<br>* After the Pre-Treatment Assessment, participants in the chlorthalidone arm will be given 12.5 mg chlorthalidone + 10 mEq potassium. At 2 weeks, chlorthalidone will be increased to 25 mg + 20 mEq potassium.<br>Drug: Potassium<br>* After the Pre-Treatment Assessment, participants in the chlorthalidone arm will be given 12.5 mg chlorthalidone + 10 mEq potassium. At 2 weeks, chlorthalidone will be increased to 25 mg + 20 mEq potassium.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in myocardial flow reserve | Change in myocardial flow reserve (ratio of hyperemic stress myocardial blood flow to rest myocardial blood flow) | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in myocardial external efficiency | Change in myocardial external efficiency (ratio of myocardial work to oxygen consumption) | 9 months |