A 65-year-old patient with heart failure with reduced ejection fraction (HFrEF, EF 30%) is already on maximally tolerated doses of ACE inhibitor, beta-blocker, and mineralocorticoid antagonist. The cardiologist now adds sacubitril-valsartan. What is the molecular rationale for replacing the ACE inhibitor with this combination?

• A Sacubitril inhibits neutral endopeptidase (neprilysin), preventing degradation of natriuretic peptides, while valsartan blocks AT1 receptors; dual neurohormonal blockade with augmented natriuretic peptide effects reduces preload, afterload, and cardiac fibrosis ✓
• B Sacubitril is an ACE inhibitor with superior potency; valsartan provides additive AT1 blockade for double renin-angiotensin blockade
• C Sacubitril inhibits aldosterone synthase while valsartan prevents aldosterone receptor activation, providing dual aldosterone blockade
• D The combination increases cardiac contractility through phosphodiesterase-III inhibition and simultaneously reduces afterload through angiotensin receptor blockade

Explanation

Sacubitril is a prodrug converted to LBQ657, which inhibits neprilysin (neutral endopeptidase, NEP). Neprilysin degrades natriuretic peptides (ANP, BNP, CNP), bradykinin, and adrenomedullin. By inhibiting neprilysin, sacubitril increases levels of these vasoactive peptides, which promote natriuresis, diuresis, vasodilation, inhibit the RAAS, reduce sympathetic activity, and have antifibrotic effects on the myocardium. Valsartan (AT1 blocker) is co-administered instead of ACE inhibitor to avoid the risk of angioedema that would occur with combined ACEi + neprilysin inhibition (since both pathways normally clear bradykinin). The PARADIGM-HF trial showed sacubitril-valsartan reduces CV mortality and HF hospitalization versus enalapril.

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

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Written and medically reviewed by the StethoPrep medical team.