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), monocyte-chemotactic 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 Delta of RVSP and 6-MWT (r2=0.5355, p<0.001) as well as between Delta-sP-S and both Delta-6-MWT and Delta-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).


CONCLUSIONS
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.
Cella
Giuseppe
G
Department of Medical Sciences, University of Padova Medical Schoo, Via Ospedale Civile 105, 35100 Padova, Italy. giuseppe.cella@unipd.it
Vianello
Fabrizio
F
Cozzi
Franco
F
Marotta
Helga
H
Tona
Francesco
F
Saggiorato
Graziella
G
Iqbal
Omer
O
Fareed
Jawed
J
D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood*; D000077300:Bosentan; D003240:Connective Tissue Diseases / Q000150:complications* / Q000503:physiopathology; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000503:physiopathology; D005080:Exercise Test; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood* / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D015415:Biomarkers; D013449:Sulfonamides; D000077300:Bosentan