Effects of Levosimendan on circulating markers of oxidative and nitrosative stress in patients with advanced heart failure

Background: Oxidative stress is associated with maladaptive cardiac remodeling and vascular dysfunction and may be an important contributor to chronic heart failure (CHF) deterioration. We sought to investigate if the calcium sensitizer levosimendan beneficially modulates circulating markers of oxidative and nitrosative stress thus lessening their deleterious effects in patients with advanced CHF. Methods: Thirty-nine patients with advanced CHF (mean NYHA 3.5 +/- 0.4; ischemic/dilated: 23/16; mean left ventricular ejection fraction: 26 +/- 7%) who were hospitalized due to syndrome worsening, were randomized (2: 1) to receive either a 24-h levosimendan infusion of 0.1 mu g/(kgmin) (n = 26) or placebo (n = 13). Plasma b-type natriuretic peptide (BNP), circulating markers of oxidative [protein carbonyls, malondialdehyde (MDA)] and nitrosative (nitrotyrosine) stress, and cyclic GMP (cGMP) were measured at baseline and 48 h after each treatment. Results: Baseline characteristics and medications were well balanced in the two treatment groups. A significant improvement in left ventricular ejection fraction (P < 0.01), NYHA class (P < 0.01), and plasma BNP (P < 0.01) was observed post-treatment only in the levosimendan group. Markers such as MDA, protein carbonyls and nitrotyrosine remained stable in the levosimendan-treated group, but significantly increased (P < 0.05) in the placebo-treated patients. Neither therapeutic intervention changed the levels of circulating cGMP. Conclusion: Levosimendan does not increase markers of oxidative and nitrosative stress in contrast to the placebo treatment, thus, exerting cardioprotective effects in advanced CHF patients. Moreover, levosimendan may exert its biologic action through non-cGMP-dependent biochemical pathways. (C) 2007 Elsevier Ireland Ltd. All rights reserved.