A single levosimendan administration has recently been shown to result in clinical and hemodynamic improvement in patients with decompensated heart failure (HF), but without survival benefits. In this study, the effects of levosimendan and dobutamine on plasma levels of proinflammatory and proapoptotic mediators in decompensated HF were compared and correlated with the concomitant effects on cardiac function and prognosis. Sixty-nine patients were randomized to received 24-hour intravenous infusions of levosimendan (n = 23), dobutamine (n = 23), or placebo (n = 23). Echocardiographic, hemodynamic, and biochemical assessments were performed at baseline, immediately after treatment, and 48 hours later. Patients were subsequently followed for 4 months for disease progression. End-systolic wall stress, the left ventricular ejection fraction, pulmonary capillary wedge pressure, and cardiac index were significantly improved in the levosimendan group but remained practically unaffected in the other groups. Plasma N-terminal-pro-B-type natriuretic peptide, tumor necrosis factor-alpha, and soluble Fas ligand levels were significantly decreased only in the levosimendan group (from 1,900 +/- 223 to 1,378 +/- 170 pg/ml, 13.4 +/- 1.0 to 12.3 +/- 1.2 pg/ml, and 68.2 +/- 3.7 to 59.8 +/- 3.6 pg/ml, respectively; p <0.05 for all); interleukin-6 was also borderline reduced (p = 0.051). Levosimendan-induced reduction in end-systolic wall stress was significantly correlated with respective decreases in N-terminal-pro-B-type natriuretic peptide (r = 0.671, p <0.01), tumor necrosis factor-alpha (r = 0.586, p <0.01), soluble Fas (r = 0.441, p <0.05), and soluble Fas ligand (r = 0.614, p <0.01). Event-free survival was significantly longer in the levosimendan group (p <0.05). In conclusion, the superiority of levosimendan over dobutamine in improving central hemodynamics and left ventricular performance in decompensated HF seems to be related to its anti-inflammatory and antiapoptotic effects.