Levosimendan improves diastolic and systolic function in failing human myocardium.
Ca(2+)-sensitizers increase myocardial contractility, but may worsen diastolic dysfunction. Levosimendan, through its unique troponin-C interaction, may preserve diastolic function. We investigated the effects of levosimendan (10(-7)-10(-5) M) on diastolic and systolic function in multicellular cardiac muscle preparations from end-stage failing human hearts (1 and 2.5 Hz, 37 degrees C, 1.25 mM [Ca(2+)], pH 7.4). Levosimendan improved systolic function: at 1 Hz, developed force (F(dev)) increased from 13.84+/-3.27 to 16.40+/-3.57 (10(-7) M, P<0.05), while diastolic force (F(dia)) decreased from 5.32+/-0.67 to 4.94+/-0.61 mN/mm(2) (P<0.05). Under control conditions, the increase in stimulation frequency from 1 to 2.5 Hz resulted in a decrease in F(dev) of -0.51+/-1.80 mN/mm(2) (negative force-frequency relationship). Levosimendan improved this relationship: at 10(-7) M, this change became positive (+1.81+/-2.06 mN/mm(2), P<0.05). Diastolic function was markedly improved in the presence of levosimendan; the increase in F(dia) of 1.56+/-0.42 mN/mm(2) (control) was attenuated to 0.70+/-0.19 mN/mm(2) (P<0.05). To allow for a more detailed analysis, preparations were sometimes divided into two groups, based on their force-frequency behavior. Twitch timing parameters were accelerated by levosimendan in preparations with a negative force-frequency relationship. Levosimendan improves both systolic and diastolic function in failing human myocardium. Effects are even more pronounced at higher heart rates and under prevailing diastolic dysfunction.
Janssen
P M
PM
Abt. Kardiologie und Pneumologie, Universität Göttingen, Göttingen, Germany. pjanssen@jhmi.edu
Datz
N
N
Zeitz
O
O
Hasenfuss
G
G
D002316:Cardiotonic Agents / Q000494:pharmacology*; D003971:Diastole / Q000187:drug effects*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D017202:Myocardial Ischemia; D009206:Myocardium; D011724:Pyridazines / Q000494:pharmacology*; D000077464:Simendan; D013599:Systole / Q000187:drug effects*
D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan