In this animal experimental study conducted by Kim et al.,9) authors reported the hemodynamic and histopathologic benefits of macitentan. According to the study, these beneficial effects can be explained by two mechanisms. One is a potent ERA macitentan per se; another is the early initiation of treatment. PAH is known as a rapidly progressive disease, even at earlier stage and become irreversible beyond some stage of disease.3) It is reason why PAH remains an incurable and eventually fatal disease even with increased physician awareness and the relatively recent therapeutic developments. Although the concept that an early diagnosis and early therapeutic intervention are critical has been acknowledged, authors proved the benefits of the early initiation of macitentan by a well-designed protocol with monocrotaline-induced PAH rat model.9) Accurate hemodynamic assessment using a Millar conductance pressure catheter and histopathologic back-up seems to be the main power of this study. Although SERAPHIN trial has shown clinical benefit of macitentan, hemodynamic or histopathologic changes on right ventricle (RV) could not be evaluated. RV usually compensate to the pressure overload by chamber dilatation. RV dilatation can subsequently be changed to dysfunction or failure when pressure overload is prolonged and severe. Thus, RV is a final victim and main prognosticator of PAH. In this study, hemodynamic, histopathologic and Doppler echocardiographic comparisons on the RV according to the therapeutic options seem to be relevant and appropriate. Thus, the results of this study can be applied to the interpretation of survival benefit in SERAPHIN trial. However, the combination of macitentan and sildenaphil in the study could not show additive or synergistic effects compared to the macitentan monotherapy.9) The exact reasons should be answered by the subsequent experiments in near future. Despite the availability of several therapeutic options, the long-term prognosis for PAH treated in monotherapy remains unsatisfactory. An alternative approach is the combination therapy, using drugs targeting the different pathways implicated in PAH. Combination therapy appears promising for patients who are refractory to treatment or whose disease progression is not well controlled with monotherapy. The best combination regimen and the appropriate timing of combination in PAH remains debatable and further studies should be needed.

Although the monocrotaline-induced PAH in rat is not identical to human PAH, this animal disease model has been generally accepted by the most basic researchers in this field.10) And the initiation of treatment 1 week after monocrotaline injection does not quite equally reflect an early treatment to the patients with PAH. However, this study gives us the valuable evidences such as the mechanisms of clinical benefits by macitentan shown in clinical trials and the importance of treatment initiation in early stage of PAH. We still have limited number of therapeutic options for PAH. Thus, researchers and clinicians should investigate more to understand the pathophysiologic and molecular mechanisms, and develop new pharmacologic therapies to inhibit the disease progression and improve survival.