Experimental evidence for a severe proarrhythmic potential of levosimendan

Background: The calcium sensitizer levosimendan is established for therapy of acutely decompensated congestive heart failure. Clinical experience suggests a possible proarrhythmic potential. The aim of the present study was to assess possible proarrhythmic effects and underlying electrophysiological mechanisms.

Methods and results: Ten rabbit hearts were isolated and Langendorff-perfused. Thereafter, levosimendan was infused in 3 concentrations (0.5, 1, and 2μM). Eight endo- and epicardial monophasic action potentials and a 12-lead ECG showed a dose-dependent reduction of QT interval (0.5μM: -27ms, 1μM:-33ms, 2μM: -77ms; p<0.05) and action potential duration at 90% of repolarization (APD₉₀; 0.5μM: -12ms, 1μM: -12ms, 2μM: -20ms). There was no significant increase in dispersion of repolarization. The described abbreviation of myocardial repolarization was accompanied by a significant decrease of effective refractory period (ERP; 0.5μM: -16ms, 1μM: -20ms, 2μM:-27ms; p<0.05). Under baseline conditions, ventricular fibrillation was inducible by programmed stimulation and aggressive burst stimulation in 3 of 10 hearts (4 episodes). After application of 1μM levosimendan, 8 of 10 control hearts were inducible (27 episodes). Of note, in 8 of 10 hearts after infusion of up to 2μM levosimendan, incessant ventricular fibrillation that could not be terminated by multiple external defibrillations occurred.

Conclusion: In the present study, acute infusion of levosimendan resulted in an abbreviation of ventricular repolarization and a reduction of ERP. This led to a significantly elevated inducibility of ventricular fibrillation. In 8 of 10 hearts, incessant ventricular fibrillation occurred. These results suggest a proarrhythmic effect of levosimendan and might explain an increased mortality that coincided levosimendan treatment in a few small clinical studies.