Abstract 181: Anti-inflammatory Effects of Macitentan on Monocrotaline-induced Pulmonary Hypertension in a Rat Model

Abstract

Background: Inflammation is closely linked to pulmonary arterial hypertension (PAH). Macitentan (MAC) reduces morbidity and mortality among advanced-stage pulmonary arterial hypertension (PAH) patients. However, data regarding anti inflammatory benefits of MAC treatment at an early stage of PAH is lacking. Methods: One week after monocrotaline (MCT) injection, rats were randomly assigned to MAC (n=30), normal saline (MCT, n=30). Fourteen sham rats (Sham) were included for comparison. Right ventricular (RV) systolic function was assessed via echocardiography as the RV fractional area change (RV-FAC). An invasive pressure-volume analysis using a Millar conductance catheter was performed 8 weeks after MCT injection. Rats were subsequently euthanized for histopathologic analysis. Levels of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1,6) and nuclear factor-kappa B (NF-κB) activity in serum were determined with enzyme-linked immunosorbent assay. Results: RV-right atrial pressure gradient on echocardiography was significantly increased 3 weeks after MCT injection, but was maintained in the Sham. On invasive hemodynamic analyses, RV end-systolic (203±79 μL) and end-diastolic volumes (315±83 μL), pulmonary artery systolic pressure (90±6 mmHg), and end-systolic pressurevolume relationship (–264±23) were significantly worse in the MCT vs. in the MAC (98±45 μL, 225±35 μL, 39±12 mmHg, and –147±42, respectively, all p<0.05). On histopathology, both RV and lung fibrosis were significantly reduced in the MAC. MAC significantly ameliorated PAH by acting against pulmonary vascular remodeling, decreasing macrophage infiltration, and reducing pro-inflammatory cytokine expression and nuclear factor-kappa B (NF-κB) activity in the lungs of the MCT-treated rats. Conclusions: MAC treatment improves haemodynamic parameters in established pulmonary hypertension. These results suggest that MAC saline ameliorates the progression of pulmonary hypertension induced by monocrotaline in rats, which may be associated with anti-inflammatory effects.