Phosphodiesterase type 5 inhibitors improve microvascular dysfunction markers in pulmonary arterial hypertension associated with congenital heart disease.

ABSTRACT

BACKGROUND: Ideally, vasodilator therapies for pulmonary arterial hypertension (PAH) should have a favorable impact on markers of vascular dysfunction, in addition to their known effects on hemodynamics, cardiac function, and patient's physical capacity. METHODS: We analyzed circulating (plasma) markers of endothelial and platelet activation/dysfunction (enzyme-linked immunoassays) in the specific setting of advanced PAH associated with congenital heart disease, during the course of sildenafil and tadalafil therapies. Thirty-one patients were enrolled (age 10-54 years), most of them with chronic hypoxemia and elevated hematocrit. Drugs were administered orally for 6 months (sildenafil [n = 16], 20 mg t.i.d.; tadalafil [n = 15], single daily dose of 40 mg). Measurements were performed at baseline, and 90 and 180 days. RESULTS: Compared to controls, patients had elevated baseline ß-thromboglobulin (ß-TG, P = .002), P-selectin (P = .027), tissue-type plasminogen activator (t-PA, P = .009), and von Willebrand factor antigen (VWFAg, P = .010). Thrombomodulin was importantly reduced (TM, P < .001), while soluble CD40 Ligand was not changed (P = .320). Tadalafil administration was associated with improvement of ß-TG (P = .004), t-PA (P = .003) and TM (P = .046) levels, while P-selectin was improved by sildenafil treatment only (P = .034). VWFAg improved transiently in the sildenafil group (P = .019). Both therapies were associated with improvement of the physical capacity (functional class and distance walked during the 6-minute test, P < .05), hematocrit and hemoglobin level (P < .05), and health-related quality of life (physical and mental components, P < .05). CONCLUSION: In PAH associated with congenital heart disease, phosphodiesterase 5 inhibitors seem to have beneficial actions at microcirculatory level, beyond the proposed effects as vasodilators.