Effect of Bosentan on Plasma Markers of Endothelial Cell Activity in Patients with Secondary Pulmonary Hypertension Related to Connective Tissue Diseases.

Objective. To evaluate plasma markers of endothelial cell activity in patients with pulmonary arterial hypertension (PAH) induced by connective tissue diseases (CTD) before and after 3-month administration of bosentan. Methods. We quantified E, L and P-selectin (sE-S, sL-S, sP-S), thrombomodulin (TM), monocytechemotactic protein 1 (MCP-1), human soluble CD40 ligand (sCD40L), and nitric oxide (NO) in 18 patients and 18 controls. We evaluated right ventricular systolic pressure (RVSP) and the 6-minute walk test (6-MWT). Results. All plasma markers but sL-S and TM at Time 0 were significantly higher in patients compared with controls. After 3 months of therapy, decreased levels were noted in NO (Time 0 24.05 ± 6.01 mmol/l, Time 1 13.92 ± 3.40 mmol/l; p < 0.001) and sCD40L (Time 0 1685.33 ± 866 pg/ml, Time 1 1055.11 ± 630.6 pg/ml; p = 0.017). In contrast, sP-S was significantly increased (Time 0 88.36 ± 47.76 ng/ml, Time 1 147.21 ± 94.43 ng/ml; p = 0.021). All patients remained stable in WHO class III, and in 9 patients we noted an improvement in 6-MWT. A correlation was found between Δ of RVSP and 6-MWT (r2 = 0.5355, p < 0.001) as well as between Δ-sP-S and both Δ-6-MWT and Δ-RVSP. An increase sP-S level was found in 89% of nonresponder patients, whereas 55% of responders showed a stable or reduced sP-S level (p = 0.016 responder vs nonresponder). Conclusion. Treatment with bosentan for 3 months induced a beneficial effect by restoring endothelial function through a decrease in the markers of endothelial cell activity, leading to stabilization or improvement of severe PAH.