Abstract 4373: Effects of Darbepoetin-Alpha on Plasma Markers of Oxidative and Nitrosative Stress in Anemic Patients with Chronic Heart Failure

Abstract

Increased oxidative and nitrosative stress may be important pathophysiologic mechanisms that mediate cardiac and vascular dysfunction in chronic heart failure (CHF). This study investigate the effects of recombinant human erythropoietin analogue darbepoetin-alpha(α) on plasma markers of oxidative and nitrosative stress along with cardiac function and exercise capacity in patients with CHF and anemia. Thirty CHF patients [Hew York Heart Association class, II-III; LV ejection fraction (EF) <40%; hemoglobin <12.5 g/dl; serum creatinine <2.5 mg/dl] were randomized (1:1) to receive either a 3-month darbepoetin-α regimen at 1.5 μg/Kg every 20 days plus oral iron or placebo plus oral iron. Echocardiographic indices of LV function, plasma B-type natriuretic peptide (BNP) and plasma markers of oxidative [oxidative: malondyaldheyde (MDA), carbonyl proteins; anti-oxidative: glutathione) and nitrosative (nitrotyrosine) stress, and 6-min walked distance were assessed at baseline and post-treatment. A significant improvement of LV ejection fraction (p<0.01) and six min walked distance (p<0.001) was observed only in darbepoetin-treated patients. Moreover, plasma BNP (661±858 from 1102±1200 pg/ml, p<0.001), MDA (2.1±0.9 from 2.5±0.8 ng/ml, p<0.01), protein carbonyl (1.7±0.6 from 2.1±0.7 ng/ml, p<0.01) were significantly reduced, while plasma anti-oxidative enzyme glutathione (124±11 from 116±10 ng/ml, p<0.05) was increased after darbepoetin treatment. These factors remained unaffected in placebo-treated patients. Darbepoetin-induced percent changes in carbonyl protein was significantly correlated with respective changes in BNP (r=0.55, p<0.05) and LV ejection fraction (r=−0.46, p<0.05). Finally, a drug-induced percent reduction in nitrotyrosine was significantly correlated with the respective improvement in 6 min walked distance (r=−0.63 p<0.05). Darbepoetin seems to attenuate deleterious effects of oxidative and nitrosative stress into cardiovascular system of anemic patients with CHF. This beneficial action may be related with the drug-induced improvement of cardiac function and exercise capacity of these patients.