A dose-response study of levosimendan in a porcine model of acute ischaemic heart failure

Abstract

Objectives: 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 themore load-dependent contractility indicator of dP/dtmax 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. © The Author 2011. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.