Levosimendan improves right ventriculovascular coupling in a porcine model of right ventricular dysfunction.
OBJECTIVE
Experimental data suggest that levosimendan has pulmonary vasodilatory properties which, in combination with its positive inotropic effects, would render it particularly attractive for the treatment of right ventricular dysfunction. To test this hypothesis, we developed an experimental model of right ventricular failure and analyzed the effects of levosimendan on ventriculovascular coupling between the right ventricle and pulmonary artery (PA).


METHODS
Prospective, randomized, placebo-controlled animal study.


METHODS
University hospital laboratory.


METHODS
Fourteen pigs (mean weight 36 +/- 1 kg).


METHODS
Pigs were instrumented with biventricular conductance catheters, a PA and right coronary artery flow probe, and a high-fidelity pulmonary pressure catheter. Right ventricular dysfunction was induced by repetitive episodes of ischemia/reperfusion in the presence of temporary PA constriction. Pigs were randomly assigned to receive levosimendan (120 mg/kg/hr [corrected] for 10 mins followed by continuous infusion of 60 mg/kg/hr [corrected] for 45 mins) or the placebo (control).


RESULTS
Induction of right ventricular dysfunction resulted in a 42% decrease in contractility (reduction in slope of preload recruitable stroke work [Mw] from 2.5 +/- 0.4 to 1.8 +/- 0.5 mW x sec x mL(-1); p = .02) and a 60% increase in right ventricular afterload (effective pulmonary arterial elastance [PA-Ea] from 0.6 +/- 0.1 to 1.0 +/- 0.3 mm Hg x mL(-1); p < .01). Right ventriculovascular coupling, as assessed by the quotient of right ventricular end-systolic elastance (E(max)) over PA-Ea, decreased from 1.23 +/- 0.38 to 0.64 +/- 0.21 (p = .03). Treatment with levosimendan improved right ventricular contractility (Mw from 1.9 +/- 0.4 to 2.9 +/- 0.5 mW x sec x mL(-1); p < .01), lowered right ventricular afterload (PA-Ea from 1.1 +/- 0.3 to 0.8 +/- 0.3 mm Hg x mL(-1); p = .02), and restored right ventriculovascular coupling to normal values (E(max)/PA-Ea = 1.54 +/- 0.51). Levosimendan also significantly increased coronary blood flow and left ventricular contractility (Mw from 7.2 +/- 3.3 to 9.5 +/- 2.9 mW x sec x mL(-1); p = .01) but did not affect biventricular diastolic function.


CONCLUSIONS
In an experimental model of acute right ventricular dysfunction, levosimendan improved global hemodynamics and optimized right ventriculovascular coupling via a moderate increase in right ventricular contractility and a mild reduction of right ventricular afterload.
Missant
Carlo
C
Center for Experimental Anesthesiology, Emergency and Intensive Care Medicine, Department of Acute Medical Sciences, Katholieke Universiteit Leuven, Belgium.
Rex
Steffen
S
Segers
Patrick
P
Wouters
Patrick F
PF
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D006835:Hydrazones / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology*; D000077464:Simendan; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*; D018497:Ventricular Dysfunction, Right / Q000503:physiopathology*; D016278:Ventricular Function, Right / Q000187:drug effects / Q000502:physiology
D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D014665:Vasodilator Agents; D000077464:Simendan