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

Sponsor

Brigham and Women's Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05593055

Collaborator

(none)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Hypertension Left Ventricular Hypertrophy	Drug: Eplerenone Drug: Chlorthalidone Drug: Potassium	Phase 4

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

75 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Participants are randomized to chlorthalidone or eplerenone.Participants are randomized to chlorthalidone or eplerenone.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Basic Science

Official Title:

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

Anticipated Study Start Date :

Apr 1, 2023

Anticipated Primary Completion Date :

Apr 1, 2027

Anticipated Study Completion Date :

Apr 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: Eplerenone 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.
Active Comparator: 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.	Drug: Chlorthalidone 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. Drug: Potassium 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.

Arm

Intervention/Treatment

Active Comparator: 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.

Drug: Eplerenone

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.

Active Comparator: 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.

Drug: Chlorthalidone

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.

Drug: Potassium

Outcome Measures

Primary Outcome Measures

Change in myocardial flow reserve [9 months]
Change in myocardial flow reserve (ratio of hyperemic stress myocardial blood flow to rest myocardial blood flow)

Secondary Outcome Measures

Change in myocardial external efficiency [9 months]
Change in myocardial external efficiency (ratio of myocardial work to oxygen consumption)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 69 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

History of hypertension
Seated systolic BP < 160 mmHg and diastolic < 100 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 pre-diabetes and treated hypothyroidism

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 diabetes mellitus
Documented coronary disease (prior revascularization and/or myocardial infarction
LV ejection fraction < 40%
Cerebrovascular disease
Peripheral vascular disease
Known genetic cardiomyopathy
Renal disease (eGFR < 60 mL/min/1.73m2)
Hepatic disease
Bronchospastic lung disease
Alcohol or substance abuse
Hormone replacement therapy
Abnormal values for electrolytes, liver enzymes or TSH
Hemoglobin A1c ≥ 6.5%
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.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Brigham and Women's Hospital

Investigators

Principal Investigator: Gail K Adler, MD, PhD, Brigham and Women's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

Gail Kurr Adler, Chief, Cardiovascular Endocrinology Section, Principal Investigator, Professor of Medicine, Brigham and Women's Hospital

ClinicalTrials.gov Identifier:

NCT05593055

Other Study ID Numbers:

2022P002126

First Posted:

Oct 25, 2022

Last Update Posted:

Oct 28, 2022

Last Verified:

Oct 1, 2022

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Hypertension

Hypertrophy, Left Ventricular

Hypertrophy

Eplerenone

Chlorthalidone

Study Results

No Results Posted as of Oct 28, 2022