Cardiac Effects of Mineralocorticoid Receptor Antagonism After Preeclampsia

Preeclampsia, a condition marked by hypertension and systemic endothelial/microvascular dysfunction in late pregnancy, affects 8% of childbearing U.S. women and is associated with two-fold risk of future material cardiovascular disease (CVD). The American College of Cardiology and American Heart Association now recognize preeclampsia as a sex-specific CVD risk factor to guide prescription of preventive statin therapy. Beyond this focused recommendation, however, specific strategies for CVD risk reduction in women with preeclampsia are not yet established. Recent preclinical evidence suggests that preeclampsia induces vascular smooth muscle cell mineralocorticoid receptor (MR) sensitivity that persists postpartum, promoting hypertension and CVD. Although MR signaling is known to underlie hypertension, MR activation also promotes cardiovascular, kidney, and metabolic disease via effects that are partially independent of blood pressure. Work by this team has implicated MR signaling in coronary microvascular dysfunction, a known predictor of heart failure with preserved ejection fraction (HFpEF) and CVD mortality. The central hypothesis is that, among women with prior preeclampsia who subsequently develop chronic hypertension, MR blockade will promote favorable cardiac remodeling and improve coronary microvascular function, independent of changes in blood pressure, and thereby reduce CVD risk in affected women. To test this hypothesis, the investigators propose a randomized, double-blind clinical study in humans. Women aged <55 years with a history of preeclampsia, current chronic hypertension, and concentric left ventricular remodeling will be randomized 1:1 to receive eplerenone (mineralocorticoid receptor antagonist) or chlorthalidone (thiazide-like diuretic) with potassium supplementation for 48 weeks, targeting equivalent blood pressure control in both groups using daily home blood pressure measurement and 24-hour ambulatory blood pressure monitoring. The investigators will measure coronary microvascular function (myocardial flow reserve, i.e., hyperemic stress/rest myocardial blood flow) quantified by cardiac positron emission tomography (PET/CT) and cardiac structure and function by cardiac ultrasound at baseline and 48 weeks. It is expected that, compared with chlorthalidone, eplerenone will yield greater improvements in coronary microvascular function and myocardial diastolic function after 48 weeks of treatment. If the hypotheses are affirmed, these findings would support the targeted use of MR antagonists much earlier than recommended by current guidelines for the management of hypertension to more effectively prevent HFpEF and other CVD among women with a history of preeclampsia.

Inclusion criteria

• Female with a history of preeclampsia (defined by ACOG criteria) in a singleton pregnancy without pre-gestational chronic hypertension.
• Current chronic hypertension (stage 1 or greater).
• Evidence of concentric left ventricular (LV) remodeling, defined as relative LV wall thickness >0.42, with or without LV hypertrophy.
• Age 18-65 years at time of randomization.

Exclusion criteria

• Use of a mineralocorticoid receptor antagonist (MRA) or amiloride within the past 3 months or more than 30 days within the previous 12 months.
• Planned pregnancy, current pregnancy, or lactation.
• Systolic BP >150 mmHg and/or diastolic BP >95 mmHg while on antihypertensives, or systolic BP >160 mmHg and/or diastolic BP >100 mmHg if untreated.
• BMI >45 kg/m².
• Clinical atherosclerotic cardiovascular disease, including coronary, cerebrovascular, or peripheral artery disease.
• Diabetes mellitus.
• LV ejection fraction <40% or history of clinical heart failure (reduced or preserved ejection fraction).
• Hypertrophic or other genetic cardiomyopathy.
• Any moderate or greater valvular heart disease.
• eGFR <60 mL/min/1.73 m².
• Urine microalbumin/creatinine ratio >300 mg/g at screening.
• Abnormal electrolytes, hemoglobin, liver function tests, or TSH at screening or baseline.
• Plasma renin activity <1 mg/mL/hour and aldosterone >20 ng/dL (suggestive of primary aldosteronism).
• Use of oral contraceptives, progestin depot or implant (note: progestin-containing IUD is permitted), or menopausal hormone therapy.
• History of hypersensitivity or intolerance to calcium channel blockers, thiazides, or MRAs.
• Active substance abuse.
• Other serious medical illnesses or concerns about protocol adherence/mortality risk within 15 months.
• Participation in another interventional clinical study.
• Participants using GLP-1 receptor agonists (GLP-1RA) are eligible only if they have received continuous treatment with the same GLP-1RA agent at an unchanged maintenance dose for ≥12 months prior to enrollment. Dose changes, agent switches, or formulation changes within the 12 months preceding enrollment are not permitted. Temporary interruptions of ≤4 consecutive weeks (e.g., due to supply issues or procedural holds) are allowed, provided the same agent and dose are resumed. At the time of enrollment, there must be no planned or anticipated GLP-1RA dose escalation, dose reduction, or discontinuation. Initiation of GLP-1RA therapy after randomization is not permitted. Dose changes during follow-up are discouraged unless clinically required.
• Use of allopurinol.
• Use of lithium.