Experimental evidence for a severe proarrhythmic potential of levosimendan

Abstract

BackgroundThe 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 resultsTen 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. ConclusionIn 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.