Spironolactone reduces mortality in severe (NYHA III-IV) heart failure with reduced ejection fraction (HFrEF). Its benefit in HFrEF extends beyond diuresis through which additional mechanism?

• A Direct negative chronotropy by blocking beta-1 receptors
• B Upregulation of SERCA2a calcium pump improving diastolic relaxation
• C Inhibition of angiotensin converting enzyme in cardiac tissue
• D Anti-fibrotic effect — aldosterone blockade in cardiomyocytes and fibroblasts reduces collagen deposition, myocardial stiffness, and ventricular remodelling ✓

Explanation

Beyond its natriuretic effect, aldosterone directly activates mineralocorticoid receptors in cardiac fibroblasts, promoting collagen synthesis and myocardial fibrosis. Chronic aldosterone excess (as in heart failure where the RAAS is activated) leads to progressive ventricular stiffness, diastolic dysfunction, and arrhythmia substrate. Spironolactone/eplerenone block these non-epithelial mineralocorticoid receptors, reducing cardiac fibrosis, normalizing collagen turnover markers, and attenuating pathological ventricular remodelling. The RALES trial demonstrated a 30% mortality reduction with spironolactone added to ACEi and loop diuretics in NYHA III-IV HFrEF.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.