No abstract

Pulmonary arterial hypertension (PAH) is a fatal disease, and the ultimate cause of death is right ventricular (RV) failure. In this study, we investigated the acute hemodynamic effects of levosimendan in two rat models of RV hypertrophy and failure. Wistar rats were randomized to receive sham surgery (n ¼ 8), pulmonary trunk banding (PTB; n ¼ 8), or monocrotaline injection (MCT; n ¼ 7). RV function was evaluated at baseline and after injection of placebo and two concentrations of levosimendan (12 and 60 μg/kg) using magnetic resonance imaging, echocardiography, and invasive pressure recordings. PTB and MCT injection caused hypertrophy, dilatation, and failure of the RV compared with sham surgery. Levosimendan increased RV end systolic pressure (sham surgery: 16.0% AE 3.8% [P ¼ 0.0038]; MCT: 9.9% AE 3.1% [P ¼ 0.018]; PTB: 24.5% AE 3.3% [P ¼ 0.0001]; mean AE SEM) compared with placebo. Levosimendan markedly increased RV stroke volume (SV) in the MCT group (29.1% AE 8.3%; P ¼ 0.012), did not change RV SV in the PTB group (0.4% AE 4.5%; P ¼ 0.93), and decreased RV SV in the sham surgery group (−10.9% AE 3.7%; P ¼ 0.020). Nitroprusside, which was used to mimic the systemic arterial vasodilator action of levosimendan, did not influence RV function. These data demonstrate that levosimendan acutely improves the failing right heart in a MCT model of PAH and that the mechanism involves a direct acute positive inotropic effect on the hypertrophic and failing RV of the rat.

Right heart function is an important predictor of morbidity and mortality in patients suffering from pulmonary arterial hypertension and congenital heart diseases. We investigated whether the prostacyclin analog iloprost has a direct inotropic effect in the pressure-overloaded hypertrophic and dysfunctional right ventricle (RV). Rats were randomized to monocrotaline injection (60 mg/kg; n ¼ 8), pulmonary trunk banding (PTB; n ¼ 8), or a sham operation (n ¼ 8). RV function was evaluated with magnetic resonance imaging, echocardiography, and invasive pressure measurements at baseline, after intravenous administration of placebo, iloprost 10 ng/kg/min, or iloprost 100 ng/kg/min (Ilo100). Infusion of Ilo100 induced a 12% AE 4% (P ¼ 0:022) increase in stroke volume in the sham group and a 12% AE 3% (P ¼ 0:005) increase in the PTB group. RV dP=dt max was elevated by 11% AE 5% (P ¼ 0:039) in the sham group and by 12% AE 3% (P ¼ 0:016) in the PTB group. An elevation in cardiac output of 14% AE 3% (P ¼ 0:0008) and an 11% AE 2% (P ¼ 0:0021) increase in RV systolic pressure were found in the PTB group. Iloprost caused a decrease in mean arterial blood pressure (MAP) in all groups of animals. An equal reduction in MAP induced by the arterial vasodilator nitroprusside did not improve any of the measured parameters of RV function. We conclude that iloprost has inotropic properties directly improving ventricular function in the hypertrophic and dysfunctional right heart of the rat.

Stimulation of soluble guanylate cyclase by BAY 41-2272 alone or in combination with sildenafil failed to prevent the development of RV hypertrophy and failure in rats subjected to pulmonary trunk banding. An increased mortality was observed in animals treated by BAY 41-2272 alone and in combination with sildenafil.

Chronic treatment with levosimendan prevents the development of right ventricular failure and improves contractility in established pressure-overload-induced right ventricular failure.