Positive inotropes used for the treatment of heart failure have been arrhythmogenic. Levosimendan is a novel calcium sensitizer with vasodilating properties and a complex mechanism of action. Its effect on ventricular arrhythmias and 24-hour Holter electrocardiographically derived prognostic autonomic nervous system-related markers, because it occurs in parallel with changes in cardiac function and neurohormonal response, has not been systematically assessed. Forty-five patients (mean age 65 +/- 1.3 years) with heart failure refractory to conventional therapy and a mean ejection fraction of 23 +/- 1.2%, randomized to levosimendan or placebo, were studied. After Holter electrocardiographic recording, 1 drug was infused for 24 hours (levosimendan at a dose of 0.1 mug/kg/min). During this period, another Holter recording was performed to assess changes in ventricular arrhythmogenesis, 24-hour heart rate variability indexes, QTc, QT variability, and QT/RR slope. Clinical evaluation, echocardiography, and B-type natriuretic peptide measurements were performed at baseline and after treatment. After levosimendan, clinical and echocardiographic improvement was observed, associated with beneficial neurohormonal modulation (mean B-type natriuretic peptide level after levosimendan 668 +/- 108 vs 1,009 +/- 122 pg/ml at baseline, p <0.05). Episodes of nonsustained ventricular tachycardia increased with levosimendan (21.9 +/- 9.6 vs 3.0 +/- 1.2, p <0.05). Levosimendan and placebo exerted a neutral effect on all autonomic markers assessed. In conclusion, levosimendan at low doses increases nonsustained ventricular arrhythmias, without affecting Holter-derived, prognostically significant autonomic markers. At the same time, it is associated with improvements in cardiac function and neurohormonal response. These findings may have important clinical and prognostic implications.