Sustained Reduction of Aldosterone in Response to the Angiotensin Receptor Blocker Valsartan in Patients With Chronic Heart Failure

Abstract

MD; for the Valsartan Heart Failure Trial InvestigatorsBackground-Aldosterone has been implicated in the progression of heart failure. The Valsartan Heart Failure Trial (Val-HeFT) provided the first opportunity to examine the long-term effects of an angiotensin receptor blocker on plasma aldosterone levels in patients with NYHA class II through IV heart failure. Methods and Results-Plasma aldosterone was measured by radioimmunoassay in core laboratories at baseline and during follow-up in patients assigned to valsartan at a target dose of 160 mg twice daily or placebo. In the placebo group, aldosterone (baseline, 150Ϯ160 pg/mL, meanϮSD; nϭ2025) increased at 4, 12, and 24 months. In the valsartan group, aldosterone (baseline, 137Ϯ124 pg/mL, meanϮSD; nϭ2023) decreased at 4 months and remained suppressed for up to 2 years. At end point (last measurement in each patient), mean aldosterone increased by 17.8Ϯ3.0 pg/mL (SEM) (11.9%) in the placebo group and decreased by 23.8Ϯ3.0 pg/mL (SEM) (Ϫ17.4%) in the valsartan group (PϽ0.00001). The effect of valsartan was similar in all subgroups, including those receiving neither ACE inhibitors (ACE-I) nor ␤-blockers (BB) at baseline and those receiving concomitant ACE-I or BB. In contrast, outcome effects varied in the 4 subgroups, with a statistically significant reduction in the combined mortality/morbidity end point in those receiving neither neurohormonal inhibitor and an adverse trend in those treated with both drugs. Conclusions-Valsartan added to background therapy for heart failure produces sustained reduction in plasma aldosterone, consistent with the observed significant reduction in the combined mortality/morbidity end point. A similar reduction in all subgroups based on ACE-I or BB therapy, despite differing clinical outcomes in these subgroups, suggests that aldosterone plasma levels may not be a critical marker of the progression of heart failure. Key Words: heart failure Ⅲ angiotensin Ⅲ trials D espite the remarkable success of ACE inhibitors (ACE-I) in reducing the mortality and morbidity from heart failure (HF), the addition of the aldosterone inhibitor spironolactone was shown to cause an additional 30% decrease in mortality in the Randomized Aldactone Evaluation Study (RALES). 1 Although ACE-I might be expected to reduce aldosterone levels by reducing the stimulating effect of angiotensin II on aldosterone production, recent studies have demonstrated that neither angiotensin II nor aldosterone plasma levels are suppressed chronically by clinically prescribed doses of ACE-I. 2,3 Aldosterone has been implicated as a contributor to structural remodeling of the left ventricle, 4 -6 and the beneficial effects of spironolactone on mortality have been attributed to inhibition of the collagen-generating influence of aldosterone. 7,8 Aldosterone secretion is stimulated by several factors in addition to angiotensin II, and these alternate mechanisms may be important determinants of aldosterone production and its levels in the plasma and tissues in patients with HF. In...

Persistent Cardiac Aldosterone Synthesis in Angiotensin II Type 1A Receptor–Knockout Mice After Myocardial Infarction

“…A previous report has also shown that the cardiac, and not the adrenal, steroidogenic system is activated in MI rats. 9 These data are consistent with results from human clinical studies 25,26 showing that plasma aldosterone concen- trations were normal or decreased 1 month after the onset of renin-angiotensin system blockade and that the aldosterone escape phenomenon is generally induced only after long-term (several months or longer) treatment. Therefore, it is possible that different molecular mechanisms underlie the aldosterone escape phenomenon in adrenal glands and Ang II-independent aldosterone synthesis in post-MI hearts.…”

“…Furthermore, our results also show that a relatively low dose (20 mg/kg per day) of spironolactone, which does not affect hemodynamics, can significantly attenuate LV remodeling. Recently, Cohn et al 26 reported sustained reduction of the plasma aldosterone level after renin-angiotensin system blockade using valsartan, but such reduction was independent of the clinical outcome in CHF patients, suggesting the significance of the aldosterone level in the myocardium rather than the level in plasma. Taken together, these previous data and our present results suggest that locally produced aldosterone in post-MI hearts could play a primary role in the pathogenesis of LV remodeling in an autocrine or paracrine manner.…”

Effects of Angiotensin II Type 1 Receptor Antagonist on Smooth Muscle Cell Phenotype in Intramyocardial Arteries from Spontaneously Hypertensive Rats

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A Selective Antagonist of Mineralocorticoid Receptor Eplerenone in Cardiology Practice

“…Как уже отмечалось выше, значительную роль в патофизиологии сердечной не-достаточности играет повышение уровня альдостеро-на, а также кортизола [24,25], поэтому у таких пациентов увеличено количество рецепторов минералокорти-коидов в ткани миокарда [26,27]. Несмотря на терапию ингибиторами АПФ/АРА и бета-адреноблокаторами, у пациентов даже с «мягкими» проявлениями сердеч-ной недостаточности чаще всего наблюдаются повы-шенные уровни альдостерона и кортизола крови [28][29][30][31][32][33]. Ни ингибиторы АПФ/АРА, ни бета-адреноблока-торы не оказывают блокирующего действия на эти ре-цепторы.…”