LAUSR

AIMS Although right ventricular (RV) function is an important determinant of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), there is no treatment targeting directly the RV. We therefore evaluate the efficacy of sacubitril/valsartan (LCZ 696) as add-on therapy to bosentan in rats with severe pulmonary hypertension (PH). METHODS AND RESULTS Combination therapy of LCZ 696 and bosentan has additive vascular protective effects against the pulmonary vascular remodeling and PH in two preclinical models of severe PH. Compared with monotherapy, co-treatment of LCZ 696 (30 or 68mg/kg/day for 2 weeks, per os) and bosentan (100mg/kg/day for 2 weeks, per os) started 7-day after monocrotaline (MCT) injection substantially reduces pulmonary pressures, vascular remodeling and right ventricular hypertrophy and fibrosis in rats. Consistent with these observations, cotreatment of rats with established PH induced by sugen/hypoxia (SuHx) with LCZ 696 (30mg/kg/day for 3 weeks, per os) and bosentan (100mg/kg/day for 3 weeks, per os) started 5 weeks after sugen injection partially attenuate total pulmonary vascular resistance and cardiovascular structures. We also obtained evidence showing that LCZ 696 has anti-proliferative effect on cultured human pulmonary artery smooth muscle cells (PA-SMCs) derived from patients with idiopathic PAH, an effect that is more pronounced in presence of bosentan. Finally, we found that the plasma levels of ANP and cGMP are higher in rats co-treated with LCZ 696 (30mg/kg/day) and bosentan (100mg/kg/day) than in MCT and SuHx rats treated with vehicle. CONCLUSION Dual therapy with LCZ 696 plus bosentan proved significantly superior beneficial effect to LCZ 696 or bosentan alone on vascular remodeling and severity of experimental PH. TRANSLATIONAL PERSPECTIVE Herein, we obtained several in vivo and in vitro evidence supporting that LCZ 696 could be used as an add-on therapy to bosentan to potentially prevent or even limit the remodeling of pulmonary blood vessels and to enhance cardiac function in patients with severe PH.