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

Обзор

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).

Подробное описание

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.

Вмешательства

• Препарат 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.
• Препарат 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.
• Препарат 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.

Первичные конечные точки

• Change in myocardial flow reserve [Срок оценки: 9 months]

Вторичные конечные точки (1)

• Change in myocardial external efficiency [Срок оценки: 9 months]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Фундаментальное исследование

Центры проведения

США · 1 центр

• Brigham and Women's Hospital — Boston

Публикации

• Johnson K, Oparil S, Davis BR, Tereshchenko LG. Prevention of Heart Failure in Hypertension-Disentangling the Role of Evolving Left Ventricular Hypertrophy and Blood Pressure Lowering: The ALLHAT Study. J Am Heart Assoc. 2019 Apr 16;8(8):e011961. doi: 10.1161/JAHA.119.011961. PMID 30943832
• Jaffe IZ, Mendelsohn ME. Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circ Res. 2005 Apr 1;96(6):643-50. doi: 10.1161/01.RES.0000159937.05502.d1. Epub 2005 Feb 17. PMID 15718497
• Luther JM, Luo P, Wang Z, Cohen SE, Kim HS, Fogo AB, Brown NJ. Aldosterone deficiency and mineralocorticoid receptor antagonism prevent angiotensin II-induced cardiac, renal, and vascular injury. Kidney Int. 2012 Sep;82(6):643-51. doi: 10.1038/ki.2012.170. Epub 2012 May 23. PMID 22622494
• DeMarco VG, Habibi J, Jia G, Aroor AR, Ramirez-Perez FI, Martinez-Lemus LA, Bender SB, Garro M, Hayden MR, Sun Z, Meininger GA, Manrique C, Whaley-Connell A, Sowers JR. Low-Dose Mineralocorticoid Receptor Blockade Prevents Western Diet-Induced Arterial Stiffening in Female Mice. Hypertension. 2015 Jul;66(1):99-107. doi: 10.1161/HYPERTENSIONAHA.115.05674. Epub 2015 May 26. PMID 26015449
• Galmiche G, Pizard A, Gueret A, El Moghrabi S, Ouvrard-Pascaud A, Berger S, Challande P, Jaffe IZ, Labat C, Lacolley P, Jaisser F. Smooth muscle cell mineralocorticoid receptors are mandatory for aldosterone-salt to induce vascular stiffness. Hypertension. 2014 Mar;63(3):520-526. doi: 10.1161/HYPERTENSIONAHA.113.01967. Epub 2013 Dec 2. PMID 24296280
• Schiffrin EL. Effects of aldosterone on the vasculature. Hypertension. 2006 Mar;47(3):312-8. doi: 10.1161/01.HYP.0000201443.63240.a7. Epub 2006 Jan 23. No abstract available. PMID 16432039
• Maron BA, Leopold JA. Mineralocorticoid receptor antagonists and endothelial function. Curr Opin Investig Drugs. 2008 Sep;9(9):963-9. PMID 18729003
• Lieb W, Larson MG, Benjamin EJ, Yin X, Tofler GH, Selhub J, Jacques PF, Wang TJ, Vita JA, Levy D, Vasan RS, Mitchell GF. Multimarker approach to evaluate correlates of vascular stiffness: the Framingham Heart Study. Circulation. 2009 Jan 6;119(1):37-43. doi: 10.1161/CIRCULATIONAHA.108.816108. Epub 2008 Dec 22. PMID 19103986

Идентификаторы

NCT: NCT05593055 · 2022P002126

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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