EMPHASIS Heart Failure Study Group. Eplerenone in patients with systolic heart failure and mild symptoms

INSERM, Centre d'Investigation Clinique 9501 and Unité 961, and the Department of Cardiology, Nancy University, Nancy, France.
New England Journal of Medicine (Impact Factor: 54.42). 11/2010; 364(1):11-21. DOI: 10.1056/NEJMoa1009492
Source: PubMed

ABSTRACT Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the effects of eplerenone in patients with chronic systolic heart failure and mild symptoms.
In this randomized, double-blind trial, we randomly assigned 2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.
The trial was stopped prematurely, according to prespecified rules, after a median follow-up period of 21 months. The primary outcome occurred in 18.3% of patients in the eplerenone group as compared with 25.9% in the placebo group (hazard ratio, 0.63; 95% confidence interval [CI], 0.54 to 0.74; P<0.001). A total of 12.5% of patients receiving eplerenone and 15.5% of those receiving placebo died (hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P=0.008); 10.8% and 13.5%, respectively, died of cardiovascular causes (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Hospitalizations for heart failure and for any cause were also reduced with eplerenone. A serum potassium level exceeding 5.5 mmol per liter occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001).
Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms. (Funded by Pfizer; number, NCT00232180.).

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    • "Mineralocorticoid receptor antagonists have also become a fundamental component of the standard care for many inpatient and ambulatory heart failure patients. They are indicated in mild to severely symptomatic systolic heart failure patients, decrease mortality by 30–37% and also significantly reduce hospitalizations (Pitt et al., 1999; Zannad et al., 2011). Newer agents such as ivabradine and myosin agonists will likely also impact patient care and outcomes (Swedberg et al., 2010; Malik et al., 2011). "
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    Life sciences 12/2013; 95(2). DOI:10.1016/j.lfs.2013.12.011 · 2.30 Impact Factor
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    • "The renin–angiotensin–aldosterone system is activated during heart failure (HF). Mineralocorticoid receptor (MR) antagonists have been shown to decrease morbidity and mortality not only in patients with severe HF [1] and after myocardial infarction [2] but also in patients with HF class II of the NYHA functional class [3]. The mechanism by which this inhibition induces beneficial effects, however, has not yet been completely clarified [4] [5]. "
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    ABSTRACT: Mineralocorticoid receptor (MR) antagonists decrease morbidity and mortality in heart failure patients for whom oxidative stress is usual; however, the underlying mechanism for this protection is unclear. Since aldosterone stimulates reactive oxygen species (ROS) production in several tissues, we explored its effect and the intracellular pathway involved in the rat myocardium. Aldosterone dose-dependently increased O2(.-) production in myocardial slices. At 10nmol/L, aldosterone increased O2(.-) to 165±8.8% of control, effect prevented not only by the MR antagonists eplerenone and spironolactone (107±7.8 and 103±5.3%, respectively) but also by AG1478 (105±8.0%), antagonist of the EGF receptor (EGFR). Similar results were obtained by silencing MR expression through the direct intramyocardial injection of a lentivirus coding for a siRNA against the MR. The aldosterone effect on O2(.-) production was mimicked by the mKATP channel opener diazoxide and blocked by preventing its opening with 5-HD and glibenclamide, implicating the mitochondria as the source for O2(.-) . Inhibiting the respiratory chain with rotenone or mitochondrial permeability transition (MPT) with cyclosporine A or bongkrekic acid also cancelled aldosterone-induced O2(.-) production. In addition, aldosterone effect depended on NADPH oxidase and phosphoinositide 3-kinase activation, as apocynin and wortmannin, respectively, inhibited it. EGF (0.1μg/mL) similarly increased O2(.-), although in this case MR antagonists had no effect, suggesting that EGFR transactivation occurred downstream from MR activation. Inhibition of mKATP channels, the respiratory chain, or MPT did not prevent Akt phosphorylation, supporting it happened upstream of the mitochondria. Importantly, cardiomyocytes were confirmed as source of aldosterone induced mitochondrial ROS production in experiments performed in isolated cardiac myocytes. These results allow us to speculate that the beneficial effects of MR antagonists in heart failure may be related to a decrease in oxidative stress.
    Journal of Molecular and Cellular Cardiology 12/2013; 67. DOI:10.1016/j.yjmcc.2013.12.004 · 5.22 Impact Factor
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    • "Aldosterone, the last component of the renin-angiotensinaldosterone system (RAAS), plays a pivotal role in the pathophysiology of cardiovascular diseases primarily through mineralocorticoid-receptor-(MR-) dependent actions [1]. Large clinical trials of patients with heart failure have shown that MR antagonists improve morbidity and mortality in conjunction with the current standard of care [2] [3] [4]. However , the circulating plasma aldosterone levels were within the physiological range in these large trials, thus suggesting the critical role of local cardiac RAAS activation in the pathogenesis of heart failure. "
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    ABSTRACT: In addition to classical adrenal cortical biosynthetic pathway, there is increasing evidence that aldosterone is produced in extra-adrenal tissues. Although we previously reported aldosterone production in the heart, the concept of cardiac aldosterone synthesis remains controversial. This is partly due to lack of established experimental models representing aldosterone synthase (CYP11B2) expression in robustly reproducible fashion. We herein investigated suitable conditions in neonatal rat cardiomyocytes (NRCMs) culture system producing CYP11B2 with considerable efficacy. NRCMs were cultured with various glucose doses for 2-24 hours. CYP11B2 mRNA expression and aldosterone concentrations secreted from NRCMs were determined using real-time PCR and enzyme immunoassay, respectively. We found that suitable conditions for CYP11B2 induction included four-hour incubation with high glucose conditions. Under these particular conditions, CYP11B2 expression, in accordance with aldosterone secretion, was significantly increased compared to those observed in the cells cultured under standard-glucose condition. Angiotensin II receptor blocker partially inhibited this CYP11B2 induction, suggesting that there is local renin-angiotensin-aldosterone system activation under high glucose conditions. The suitable conditions for CYP11B2 induction in NRCMs culture system are now clarified: high-glucose conditions with relatively brief period of culture promote CYP11B2 expression in cardiomyocytes. The current system will help to accelerate further progress in research on cardiac tissue aldosterone synthesis.
    10/2013; 2013(20):161396. DOI:10.1155/2013/161396
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