Determinants of increased angiotensin II levels in severe chronic heart failure patients despite ACE inhibition

Introduction: The beneficial effects of ACE inhibitors are generally ascribed to blockade of neurohormonal activation. However, especially in chronic heart failure (CHF) patients plasma angiotensin II and aldosterone levels can be elevated despite ACE inhibition, the so-called ACE escape. In the present study, we aimed to identify the frequency and determinants of ACE escape in CHF patients. Methods: We studied 99 stable chronic heart failure patients (NYHA class III and IV, 66% ischemic etiology) receiving long-term therapy with ACE inhibitors. In all patients, cardiac, renal, and neurohormonal parameters were measured. ACE escape was defined as plasma angiotensin level ≥ 16 pmol/L. Results: Mean (± SD) left ventricular ejection fraction of our 99 patients (79 men and 20 women, age 69 ± 12 years) was 28 ± 10%. In addition to an ACE inhibitor, 93% of patients received diuretics, 71% a β-blocker, and 49% spironolactone. None of the patients used an angiotensin receptor blocker. In our population, 45% of the patients had an angiotensin II plasma concentration higher than 16 pmol/L (median concentration was 14.1 pmol/L). Spironolactone use was an independent predictor of elevated plasma angiotensin II levels. Furthermore, spironolactone users had significantly higher plasma active renin protein and aldosterone levels. Plasma angiotensin II concentration was positively correlated to active renin, plasma angiotensin I and plasma aldosterone. No correlation was found between plasma angiotensin II levels and serum ACE activity, dose of ACE inhibitor, or duration of use. Conclusion: In a group of severe chronic heart failure patients, 45% had elevated plasma angiotensin II levels independent of serum ACE activity despite long-term ACE inhibitor use. Although a causal link could not be proven, an association was found between spironolactone use and active renin protein, angiotensin II and aldosterone levels, suggesting that escape from ACE is mainly caused by a feedback mechanism.

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