Experimental evidence for a severe proarrhythmic potential of levosimendan

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• 作者：Gerrit Frommeyer^a ; ^{gerrit.frommeyer@ukmuenster.de} ; Anja Kohnke^a ; Christian Ellermann^a ; Dirk G. Dechering^a ; Simon Kochhä ; user^a ; Christian Pott^a ; Michael Fehr^b ; Lars Eckardt^a
• 关键词：Levosimendan ; Therapeutic safety ; Ventricular refractory period ; Ventricular fibrillation
• 刊名：International Journal of Cardiology
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：228
• 期：Complete
• 页码：583-587
• 全文大小：605 K
• 卷排序：228

文摘

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 resultsTen rabbit hearts were isolated and Langendorff-perfused. Thereafter, levosimendan was infused in 3 concentrations (0.5, 1, and 2 μM). Eight endo- and epicardial monophasic action potentials and a 12-lead ECG showed a dose-dependent reduction of QT interval (0.5 μM: − 27 ms, 1 μM:-33 ms, 2 μM: − 77 ms; p < 0.05) and action potential duration at 90% of repolarization (APD90; 0.5 μM: − 12 ms, 1 μM: − 12 ms, 2 μM: − 20 ms). 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; 0.5 μM: − 16 ms, 1 μM: − 20 ms, 2 μM: − 27 ms; 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 1 μM levosimendan, 8 of 10 control hearts were inducible (27 episodes). Of note, in 8 of 10 hearts after infusion of up to 2 μM 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.