title: Electrophysiologic effects of a calcium sensitizer inotrope levosimendan administered intravenously in patients with normal cardiac function.
abstract: Provocation of fatal cardiac arrhythmias has limited the use of inotropic agents as heart failure therapy. Calcium sensitization of the myofilaments might increase inotropy without influencing cardiac electrophysiology unless modified by ancillary properties of the drugs. Electrophysiologic effects of a calcium sensitizer inotrope levosimendan were examined in short-term intravenous administration in humans. Variables were determined in 10 patients with normal cardiac function during a preceding control phase and levosimendan infusion yielding a high therapeutic concentration of 110 (+/-22) microg/L. Levosimendan increased heart rate by 9 beats/min (p < 0.01) on average and shortened the sinus node recovery time and AH interval. At the tested cycle lengths, levosimendan shortened the effective refractory periods in the atrioventricular node by 40-63 ms (p < 0.05), in the atrium by 22-33 ms (p < 0.001), and in the ventricle by 5-9 ms (p < 0.005) on average. Levosimendan increased ventricular monophasic action potential duration by 9-17 ms at 50% (p < 0.001) and by 5-15 ms (p = 0.07) at 90% levels of repolarization on average. The QT interval during spontaneous rhythm and atrial pacing remained unchanged although increased slightly when corrected to sinus rate (p < 0.001). The observations indicate that levosimendan in short-term administration facilitates impulse formation and conduction in cardiac slow-response tissue, enhances recovery of excitability in the myocardium, and may delay ventricular repolarization. The effects on the ventricle were not substantial, and therefore the likelihood of provoking serious cardiac arrhythmias is not estimated to be high.
authors.affiliation: Division of Cardiology, Helsinki University Central Hospital, Finland. lauri.toivonen@huch.fi
authors.forename: L
authors.initials: L
authors.lastname: Toivonen
authors.forename: M
authors.initials: M
authors.lastname: Viitasalo
authors.forename: S
authors.initials: S
authors.lastname: Sundberg
authors.forename: J
authors.initials: J
authors.lastname: Akkila
authors.forename: L
authors.initials: L
authors.lastname: Lehtonen
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000328:Adult; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004594:Electrophysiology; D005260:Female; D006321:Heart / Q000187:drug effects*; D006334:Heart Function Tests; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D011724:Pyridazines / Q000494:pharmacology*; D000077464:Simendan; D014665:Vasodilator Agents / Q000494:pharmacology; D016276:Ventricular Function / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D014665:Vasodilator Agents; D000077464:Simendan; D002118:Calcium