eplerenone and Hyperglycemia

Hyperglycemia predicts death in cardiovascular disease, but intensive glucose-lowering strategies increase mortality rates in diabetes. The present analysis investigated the prognostic value of postadmission blood glucose (BG) concentration on clinical outcomes in high-risk patients with heart failure after acute myocardial infarction.. A total of 6,496 patients from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) were categorized into 4 groups by plasma glucose concentration: ≤4.5 mmol/L (hypoglycemia), 4.5-5.5 mmol/L (normoglycemia), 5.5-8.3 mmol/L (elevated glucose level), and >8.3 mmol/L (severe hyperglycemia). We evaluated the time to all-cause death (primary end point) and time to cardiovascular death or hospitalization (secondary end point). Hypo- and severe hyperglycemia were prevalent in 509 (8%) and 1,588 (24%) patients, respectively. There was a U-shaped relationship between BG level and incidence of all-cause death (11.8% in patients with normoglycemia vs 15.1% and 19.9% in those with hypo- and severe hyperglycemia; P < .001). The incidence of the secondary end point was increased only in hyperglycemic patients (36% vs 23% in normoglycemic patients; P < .001). In multivariate Cox regression analysis, hypoglycemia (hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.06-1.81; P = .002) and severe hyperglycemia (HR 1.52, CI 1.27-1.83; P < .0001) proved to be strong predictors of all-cause death. There was no significant interaction between eplerenone treatment and blood glucose levels regarding clinical outcomes.. In heart failure after acute myocardial infarction, both hypo- and hyperglycemia at the postacute phase identify patients with increased risk of death during long-term follow-up.

Topics: Aged; Blood Glucose; Diabetes Complications; Double-Blind Method; Eplerenone; Female; Humans; Hyperglycemia; Hypoglycemia; Incidence; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Proportional Hazards Models; Risk Factors; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

Aldosterone plays a crucial role in cardiovascular disease. 'Systemic' inhibition of its mineralocorticoid receptor (MR) decreases atherosclerosis by reducing inflammation and oxidative stress. Obesity, an important cardiovascular risk factor, is an inflammatory disease associated with increased plasma aldosterone levels. We have investigated the role of the 'endothelial' MR in obesity-induced endothelial dysfunction, the earliest stage in atherogenesis.. C57BL/6 mice were exposed to a normal chow diet (ND) or a high-fat diet (HFD) alone or in combination with the MR antagonist eplerenone (200 mg/kg/day) for 14 weeks. Diet-induced obesity impaired endothelium-dependent relaxation in response to acetylcholine, whereas eplerenone treatment of obese mice prevented this. Expression analyses in aortic endothelial cells isolated from these mice revealed that eplerenone attenuated expression of pro-oxidative NADPH oxidase (subunits p22phox, p40phox) and increased expression of antioxidative genes (glutathione peroxidase-1, superoxide dismutase-1 and -3) in obesity. Eplerenone did not affect obesity-induced upregulation of cyclooxygenase (COX)-1 or prostacyclin synthase. Endothelial-specific MR deletion prevented endothelial dysfunction in obese (exhibiting high 'endogenous' aldosterone) and in 'exogenous' aldosterone-infused lean mice. Pre-incubation of aortic rings from aldosterone-treated animals with the COX-inhibitor indomethacin restored endothelial function. Exogenous aldosterone administration induced endothelial expression of p22phox in the presence, but not in the absence of the endothelial MR.. Obesity-induced endothelial dysfunction depends on the 'endothelial' MR and is mediated by an imbalance of oxidative stress-modulating mechanisms. Therefore, MR antagonists may represent an attractive therapeutic strategy in the increasing population of obese patients to decrease vascular dysfunction and subsequent atherosclerotic complications.

Topics: Adipose Tissue; Aldosterone; Animals; Antioxidants; Aorta; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Cytochrome P-450 Enzyme System; Diet, High-Fat; Endothelium, Vascular; Eplerenone; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Hyperglycemia; Inflammation; Intramolecular Oxidoreductases; Male; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Obesity; Oxidative Stress; Receptors, Mineralocorticoid; Spironolactone; Superoxide Dismutase; Superoxide Dismutase-1; Up-Regulation