title: Experimental evidence for a severe proarrhythmic potential of levosimendan.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany. Electronic address: gerrit.frommeyer@ukmuenster.de.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Frommeyer
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Kohnke
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Ellermann
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Dirk G
authors.initials: DG
authors.lastname: Dechering
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Kochhäuser
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Pott
authors.affiliation: Clinic of Exotic Pets, Reptiles, Exotic and Feral Birds, University of Hanover, Hanover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Fehr
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Eckardt
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects*; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006835:Hydrazones / Q000008:administration & dosage*; D007262:Infusions, Intravenous; D011724:Pyridazines / Q000008:administration & dosage*; D011817:Rabbits; D012720:Severity of Illness Index; D000077464:Simendan; D016896:Treatment Outcome; D014693:Ventricular Fibrillation / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan
keywords: Levosimendan; Therapeutic safety; Ventricular fibrillation; Ventricular refractory period