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

Background: 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). Methods and Results: PAH was induced in rats by exposure to SU5416 and hypoxia (SuHx). The rats were randomized to levosimendan (3 mg.kg(-1).d(-1)) 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). Conclusion: Chronic treatment with levosimendan prevents and reverts the development of RV failure and attenuates pulmonary vascular remodeling in a rat model of PAH.