Levosimendan Prevents and Reverts Right Ventricular Failure in Experimental Pulmonary Arterial Hypertension

Abstract

We investigated whether chronic levosimendan treatment can prevent and revert right ventricular (RV) failure and attenuate pulmonary vascular remodeling in a rat model of pulmonary arterial hypertension (PAH). PAH was induced in rats by exposure to SU5416 and hypoxia (SuHx). The rats were randomized to levosimendan (3 mg·kg·d) initiated before SuHx (n = 10, PREV), levosimendan started 6 weeks after SuHx (n = 12, REV), or vehicle treatment (n = 10, VEH). Healthy control rats received vehicle (n = 10, CONT). Ten weeks after SuHx, RV function was evaluated by echocardiography, magnetic resonance imaging, invasive pressure-volume measurements, histology, and biochemistry. Levosimendan treatment improved cardiac output (VEH vs. PREV 77 ± 7 vs. 137 ± 6 mL/min; P < 0.0001; VEH vs. REV 77 ± 7 vs. 117 ± 10 mL/min; P < 0.01) and decreased RV afterload compared with VEH (VEH vs. PREV 219 ± 33 vs. 132 ± 20 mm Hg/mL; P < 0.05; VEH vs. REV 219 ± 33 vs. 130 ± 11 mm Hg/mL; P < 0.01). In the PREV group, levosimendan restored right ventriculoarterial coupling (VEH vs. PREV 0.9 ± 0.1 vs. 1.8 ± 0.3; P < 0.05) and prevented the development of pulmonary arterial occlusive lesions (VEH vs. PREV 37 ± 7 vs. 15 ± 6% fully occluded lesions; P < 0.05). Chronic treatment with levosimendan prevents and reverts the development of RV failure and attenuates pulmonary vascular remodeling in a rat model of PAH.