Indeed, there was no marked exacerbation of cough or sputum in all four cases. In addition, sequential PFT (available in cases 1 and 4), and HRCT (available in cases 1, 3 and 4), and chest X-ray of the four cases did not show any see more marked worsening, thus suggesting

that parenchymal lung disease was not the primary cause of the advancing symptoms/signs. Third, respiratory infection was not indicated by symptoms/signs, blood tests or imaging studies in the four cases. We thus used PAH-specific vasodilators and had favorable outcomes in patient symptoms/signs and pulmonary hemodynamics. The degree of hemodynamic improvement was marked in the four cases. Indeed, MPAP and PVR reduced by 19 ± 15% and 45 ± 8%, respectively. In addition, CI and CMR-derived RVEF improved by 28 ± 9% and 51 ± 10%, respectively. These clinical courses suggested that PAH-specific vasodilators improved pulmonary hemodynamics along with right heart function, which subsequently appeared to improve patient symptoms such as exertional dyspnea and peripheral edema. The underlying pathophysiology of the vascular response to PAH-specific treatment was not elucidated in this observational study. However, it is of clinical interest how the vasodilators could have improved pulmonary hemodynamics. First, it can be speculated that vascular lesions appeared to have more or less reversible components. Indeed,

PAH-specific vasodilators would have been less efficacious if vessel loss or ablation Everolimus in the damaged lung parenchyma was the primary mechanism of increased PVR. Second, it can also be assumed that PAH-specific treatment was efficacious because the vasculopathy was in its early phase. In fact, pulmonary vasculopathy why would respond poorly to any vasodilator if the vascular lesion is progressed to heavily fibrotic or hyalinized phase.12 Finally, the target proteins

of vasodilators, particularly of sildenafil, might have been expressed in the diseased vessels.13 Deterioration of hypoxia is the major concern when using vasodilators in hypoxic PH patients with lung disease. Theoretically, vasodilators can dilate vessels in the poorly ventilated lung fields, leading to further deterioration of ventilation/perfusion mismatch and hypoxia.3 In this regard, PDE-5 inhibitors enhance the nitric oxide pathway in the well-ventilated lung areas,14 minimizing the worsening of perfusion/ventilation mismatch when compared with other PAH-specific agents. In addition, sildenafil is reported to better improve arterial oxygenation as compared with other PDE-5 inhibitors.15 We therefore used sildenafil as the first line agent in all four cases, whereas beraprost (case 1) and bosentan (case 3) were added for the purpose of further decreases in MPAP. Importantly, the change in pulmonary oxygenation varied among the cases. In fact, pulmonary oxygenation improved in case 2, deteriorated in case 1, and did not change markedly in cases 3 and 4.