Acute Effects of Levosimendan in Experimental Models of Right Ventricular Hypertrophy and Failure

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.

Efficacy and safety of a calcium sensitizer, levosimendan, in patients with right heart failure due to pulmonary hypertension

“…Levosimendan is currently indicated as an inotrope for acutely decompensated left heart failure patients with low cardiac output . Levosimendan has been shown to acutely improve the failing right heart in monocrotaline models of pulmonary arterial hypertension (PAH) . A variety of preclinical and clinical studies suggest that levosimendan attenuates in pulmonary vascular remodelling and has antiproliferative and anti‐inflammatory effects .…”

“…Preliminary data has shown that it possesses beneficial haemodynamic effects and improves right ventriculovascular coupling in patients with PH. Levosimendan has been reported to be a novel calcium‐sensitizing drug and a promising agent for PAH therapy …”

Acute decompensated pulmonary hypertension

“…In some studies, milrinone has been shown to reduce PVR [38]. Data on levosimendan are entirely experimental; however, it has been shown to be more effective than dobutamine for improving ventriculo-arterial coupling in preclinical studies [39,40].…”

Utilisation du levosimendan chez l’enfant

“…En cas d'insuffisance cardiaque aiguë, l'augmentation du débit cardiaque est due à une meilleure fonction ventriculaire gauche mais également à une amélioration de la fonction ventriculaire droite. En effet, sur un modèle murin d'augmentation brutale de la post-charge ventriculaire droite (par cerclage de l'artère pulmonaire ou injection de monocrotaline), le levosimendan a permis une amélioration et une restauration de l'état hémodynamique initial [48]. Ceci est dû à la fois à l'effet inotrope positif mais aussi à la baisse significative des résistances pulmonaires.…”