Hemodynamic and Histopathologic Benefits of Early Treatment with Macitentan in a Rat Model of Pulmonary Arterial Hypertension

Background and Objectives: Macitentan (MAC) reduces morbidity and mortality among advanced-stage pulmonary arterial hypertension (PAH) patients. However, data regarding the histopathologic and hemodynamic 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=16), MAC combined with sildenafil (SIL) (MAC+SIL, n=16), or normal saline (MCT, n=16). Twelve 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 7 weeks after MCT injection. Rats were subsequently euthanized for histopathologic analysis. Results: RV-right atrial pressure gradient on echocardiography was significantly increased 3 weeks after MCT injection, but was maintained in the Sham. RV-FAC was less deteriorated in the MAC, compared to that in the MCT ($44{\pm}3%$ vs. $25{\pm}7%$, p<0.05), and the co-administration of SIL showed no additional benefit ($45{\pm}8%$, p>0.05 vs. the MAC). On invasive hemodynamic analyses, RV end-systolic ($196{\pm}78{\mu}L$) and end-diastolic volumes ($310{\pm}86{\mu}L$), pulmonary artery systolic pressure ($89{\pm}7.2mmHg$), and end-systolic pressure-volume relationship ($-254{\pm}25.1$) were significantly worse in the MCT vs. in the MAC ($101{\pm}45{\mu}L$, $235{\pm}55{\mu}L$, $40{\pm}10.5mmHg$, and $-145{\pm}42.1$, respectively) and MAC+SIL ($109{\pm}47{\mu}L$, $242{\pm}46{\mu}L$, $38{\pm}9.2mmHg$, and $-151{\pm}39.2$, respectively) (all p<0.05). However, the MAC and MAC+SIL did not differ (all p>0.05). On histopathology, both RV and lung fibrosis were significantly reduced in the MAC and MAC+SIL vs. in the MCT (all p<0.05); the 2 treatment groups did not differ. Conclusions: MAC treatment at an earlier stage significantly attenuated experimental PAH progression hemodynamically and histopathologically.