What is the mechanism of action (MOA) of Angiotensin-Converting Enzyme (ACE) inhibitors in Heart Failure (HF)?

Mechanism of Action of ACE Inhibitors in Heart Failure

ACE inhibitors work through multiple complementary mechanisms: they block the conversion of angiotensin I to angiotensin II, enhance bradykinin activity, and augment prostaglandin production—effects that collectively reduce mortality and morbidity in heart failure with reduced ejection fraction. 1, 2

Primary Mechanisms

Renin-Angiotensin-Aldosterone System (RAAS) Inhibition

• ACE inhibitors block the enzyme that converts angiotensin I to angiotensin II, resulting in decreased plasma angiotensin II levels 2, 3
• Reduced angiotensin II leads to decreased vasopressor activity through diminished arterial and venous vasoconstriction 2, 3
• Aldosterone secretion decreases as angiotensin II is the primary stimulus for aldosterone release from the adrenal cortex 2, 3
• Decreased aldosterone results in reduced sodium and water retention, helping to prevent congestion 1
• Removal of angiotensin II negative feedback increases plasma renin activity, which is a compensatory response 2, 3

Kinin-Prostaglandin Pathway Enhancement

• ACE is identical to kininase, the enzyme that degrades bradykinin—therefore ACE inhibition increases bradykinin levels 2, 3
• Enhanced bradykinin action contributes to vasodilation and may play a significant role in therapeutic effects 1, 4
• Bradykinin augments prostaglandin production, providing additional vasodilatory effects 1
• In experimental models, ACE inhibitors modify cardiac remodeling more favorably than ARBs, and this advantage is abolished when a kinin receptor blocker is co-administered—demonstrating the importance of the bradykinin pathway 1

Cardiac and Vascular Effects

Hemodynamic Benefits

• Preferential efferent arteriole vasodilation in the kidney reduces glomerular filtration pressure while maintaining renal blood flow 1
• Decreased preload and afterload improve cardiac output without compensatory tachycardia 2
• Sustained arterial and venous vasodilation occurs with chronic therapy rather than acute administration 5

Cardiac Remodeling Prevention

• ACE inhibitors reduce left ventricular hypertrophy, an important risk factor for cardiovascular mortality 5
• Prevention and reversal of interstitial fibrosis in the left ventricle has been demonstrated experimentally 5
• Tissue cardiac renin-angiotensin system is suppressed in the failing heart, as evidenced by reduced ACE mRNA and angiotensinogen mRNA 5
• Long-term effects on myocardial structure emerge during chronic therapy rather than after short-term administration 5

Clinical Outcomes Related to Mechanism

Mortality and Morbidity Reduction

• ACE inhibitors reduce the risk of death and the combined risk of death or hospitalization across all severity levels of heart failure 1, 4
• Reduction in myocardial infarction incidence suggests effects on plaque stability or coronary perfusion 6
• Prevention of sudden death and progression of heart failure are both mechanisms of mortality benefit 6

Symptom Improvement

• Alleviation of dyspnea and fatigue through improved hemodynamics and reduced congestion 1, 4
• Enhanced exercise capacity develops with chronic therapy, possibly through improved skeletal muscle blood flow and endothelial function 4, 5
• Improved NYHA functional class and overall sense of well-being 1, 4

Important Mechanistic Considerations

Incomplete RAAS Suppression

• During chronic therapy, the RAAS demonstrates partial "escape" from inhibition with normalization of angiotensin II levels 1
• Alternative local pathways for angiotensin production contribute to this escape phenomenon 1
• Aldosterone "escape" occurs in approximately 23% of patients despite adequate ACE inhibition 7
• This incomplete suppression provides rationale for adding ARBs or aldosterone antagonists to ACE inhibitor therapy 1

Electrolyte Effects

• Small increases in serum potassium (approximately 0.1 mEq/L) result from decreased aldosterone 2
• Potassium and magnesium conservation occurs, reducing the need for supplementation in patients on loop diuretics 1, 8
• Approximately 15% of patients experience potassium increases >0.5 mEq/L requiring monitoring 2

Drug-Specific Differences

• Captopril may produce higher angiotensin II levels but lower aldosterone compared to longer-acting ACE inhibitors, possibly due to its short duration of action 7
• Better correlations between RAAS components occur with captopril, suggesting more fluctuating ACE inhibition 7
• Despite these differences, all ACE inhibitors demonstrate clinical benefit when dosed appropriately 1