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

• Published in: European journal of cardio-thoracic surgery 2012-06, Vol.41 (6), p.1377-1383
• Main Authors: Kolseth, Solveig Moss, Wahba, Alexander, Kirkeby-Garstad, Idar, Aro, Sakari, Nordgaard, Håvard, Høydal, Morten, Rognmo, Øivind, Nordhaug, Dag
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cardiology. Vascular system; Cardiotonic Agents - administration & dosage; Cardiotonic Agents - pharmacology; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Heart; Heart Failure - etiology; Heart Failure - physiopathology; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Hemodynamics - drug effects; Hemodynamics - physiology; Hydrazones - administration & dosage; Hydrazones - pharmacology; Medical sciences; Mitochondria, Heart - drug effects; Mitochondria, Heart - physiology; Myocardial Contraction - drug effects; Myocardial Contraction - physiology; Oxygen Consumption - drug effects; Oxygen Consumption - physiology; Pneumology; Pyridazines - administration & dosage; Pyridazines - pharmacology; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the heart; Sus scrofa; Ventricular Function, Left - drug effects; Ventricular Function, Left - physiology
• ISSN: 1010-7940; 1873-734X
• DOI: 10.1093/ejcts/ezr201

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 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.