Background: Pulmonary arterial hypertension (PAH), is a complication of connective tissue diseases (CTD) characterized by increased pressure in the pulmonary circulation and associated dysfunction of the pulmonary vascular endothelial cells (EC). Although PAH remains a life-threatening disorder without a cure, in recent years novel drugs including bosentan, an antagonist of endothelin A and B receptors, have been shown to improve exercise capacity and pulmonary haemodynamics.
Objectives: To investigate the effects of bosentan on EC dysfunction evaluating the circulating levels of soluble markers of EC activity in a group of patients after three months of treatment.
Methods: We studied 18 patients, (13 females and 5 males), with PAH associated to CTD (systemic sclerosis in 14 cases, SLE in 2, mixed CTD in 2) before and after three months of bosentan administration and 18 healthy subjects as controls. At baseline, systolic pulmonary pressure (sPAP) evaluated by Doppler-echocardiogram was 70.8±23.4 mmHg, exercise capacity measured by 6-min walking test was 380.6±167.8 meters. Blood samples were collected to determine the circulating levels of the following soluble markers of EC activity: selectins (ES, LS, PS), thrombomodulin (TM), nitric oxide (NO) and CD40 Ligand. Bosentan was administrated orally at the dose of 62.5 mg/bid in the first month and of 125 mg/bid in the following months.
Results: At baseline the circulating levels of all soluble markers of EC activity, except LS, were significantly higher in patients when compared to controls (p<0.01). After three months of bosentan treatment ES, PS, NO and CD40Ligand decreased, TM remained unchanged and LS increased. Walking distance in 6 minutes increased in 11 patients (61.1%), sPAP decreased in 15 patients (83.3%), As expected, an inverse correlation between the changes of sPAP and 6-min-walk test before and after bosentan therapy was found. Moreover a positive correlation between variations of PS and of sPAP was observed.

Conclusion: Our data confirm a severe EC dysfunction in patients with PAH associated to CTD, demonstrated by elevated circulating levels of soluble markers of EC activity. After three months of treatment, bosentan was able to improve exercise capacity and pulmonary haemodinamics and to reduce EC dysfunction.