Clinical meaning
The renin-angiotensin-aldosterone system (RAAS) plays a central maladaptive role in heart failure progression. Decreased cardiac output activates the RAAS: renin from juxtaglomerular cells converts angiotensinogen to angiotensin I, which is converted by angiotensin-converting enzyme (ACE) to angiotensin II. Angiotensin II causes potent vasoconstriction (increasing afterload), stimulates aldosterone release (promoting sodium/water retention and myocardial fibrosis), activates the sympathetic nervous system, and promotes pathological cardiac remodeling (myocyte hypertrophy and interstitial fibrosis). ACE inhibitors (enalapril, lisinopril, ramipril) block the conversion of angiotensin I to angiotensin II. They also prevent the breakdown of bradykinin (a vasodilator), which contributes to their vasodilatory effect but also causes the characteristic dry cough (10-20% of patients) and rare but life-threatening angioedema. ACEi reduce preload, afterload, aldosterone secretion, and cardiac remodeling, producing mortality reduction of 20-30% in HFrEF. ARBs (losartan, valsartan, candesartan) block the angiotensin II type 1 (AT1) receptor directly, providing RAAS inhibition without bradykinin accumulation — they are used when ACEi-intolerant due to cough but NOT for angioedema (cross-reactivity possible). Sacubitril/valsartan (ARNI — angiotensin receptor-neprilysin inhibitor) combines the ARB valsartan with sacubitril, which inhibits neprilysin (neutral endopeptidase), preventing the degradation of natriuretic peptides (ANP, BNP), bradykinin, and adrenomedullin. The resultant increased natriuretic peptide levels promote vasodilation, natriuresis, diuresis, and reduced cardiac fibrosis. The PARADIGM-HF trial demonstrated sacubitril/valsartan reduced cardiovascular mortality and HF hospitalization by 20% compared to enalapril. ARNI is now preferred over ACEi/ARB in HFrEF (EF ≤40%) with NYHA class II-IV symptoms. A mandatory 36-hour washout period between ACEi and ARNI is required to prevent life-threatening angioedema.