A dose-response study of levosimendan in a porcine model of acute ischaemic heart failure.
OBJECTIVE
Levosimendan is a novel inotropic agent claimed to improve myocardial contractility by a calcium-sensitizing effect. Our aim was to evaluate dose-dependent effects of levosimendan on left ventricular (LV) contractility and energetic properties in an acute, ischaemic heart failure porcine model.


METHODS
Six pigs were used in an anaesthetized in vivo open-chest model. The time points of measurements were: baseline, after heart failure induction and after dose 1-4 (D1-D4). Heart failure was induced by microembolization of the left coronary artery before infusion of four different doses (D1: 2.5 µg/kg, D2: 10 µg/kg, D3: 40 µg/kg, D4: 80 µg/kg) of levosimendan. Haemodynamics were assessed by the pressure-conductance catheter technique. LV oxygen consumption was calculated from coronary flow measurements and coronary sinus blood gases. Mitochondrial respiration was studied in biopsies of the LV.


RESULTS
Levosimendan had no significant, load-independent effect on contractile force (slope of preload recruitable stroke work was 34 mmHg immediately following failure and 39 (P = 0.406), 42 (P = 0.219), 46 (P = 0.067) and 41 (P = 0.267) at D1-D4), although the more load-dependent contractility indicator of dP/dt(max) was slightly increased at dose 4 (P < 0.05). LV energy conversion efficiency (PVA-MVO2 relationship) remained unaltered at all doses. Maximal mitochondrial respiration decreased after induction of failure and remained at an unaltered low level during levosimendan infusion.


CONCLUSIONS
Surprisingly, levosimendan had no significant effect on contractility, energy efficiency and mitochondrial respiration of the LV, in a porcine model of acute heart failure. At high doses, levosimendan induced vasodilatation and increased heart rate and cardiac output.
Department of Circulation and Medical Imaging, The Norwegian University of Science and Technology, Trondheim, Norway. moss.kolseth@gmail.com
Solveig Moss
SM
Kolseth
Alexander
A
Wahba
Idar
I
Kirkeby-Garstad
Sakari
S
Aro
Håvard
H
Nordgaard
Morten
M
Høydal
Øivind
Ø
Rognmo
Dag
D
Nordhaug
D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006835:Hydrazones / Q000008:administration & dosage* / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D011724:Pyridazines / Q000008:administration & dosage* / Q000494:pharmacology; D000077464:Simendan; D034421:Sus scrofa; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan