title: Patients with pulmonary hypertension related to congenital systemic-to-pulmonary shunts are characterized by inflammation involving endothelial cell activation and platelet-mediated inflammation.
abstract: OBJECTIVE
  We examined inflammatory mediators in patients with pulmonary hypertension related to congenital systemic-to-pulmonary shunts and the change in these markers during treatment with bosentan.
  
  
  BACKGROUND
  Inflammatory mechanisms probably play a pathogenic role in idiopathic pulmonary arterial hypertension. Their involvement in pulmonary hypertension related to congenital systemic-to-pulmonary shunts is largely unknown.
  
  
  METHODS
  Plasma levels of several inflammatory mediators were determined by enzyme immunoassays in 14 children and adolescents with pulmonary hypertension related to congenital systemic-to-pulmonary shunts before and after 12 months treatment with bosentan, and compared with levels in 54 healthy controls.
  
  
  RESULTS
  The patients were characterized by increased plasma levels of von Willebrand factor ( approximately 2.5-fold), C-reactive protein ( approximately 3.5-fold), and soluble CD40 ligand ( approximately 2.5-fold) as compared with controls, representing markers of endothelial cell activation, systemic inflammation, and platelet-mediated inflammation, respectively. Patients also had significantly elevated plasma levels of osteoprotegerin ( approximately 1.6-fold). Within the study group, N-terminal pro-brain natriuretic peptide levels correlated significantly with the concentrations of C-reactive protein (r= 0.61, P < .027) and von Willebrand factor (r= 0.74, P= .004). Except for a decline in monocyte chemoattractant protein-1 and receptor activator of nuclear factor-kappaB ligand, bosentan therapy did not attenuate the systemic inflammation.
  
  
  CONCLUSIONS
  Children and adolescents with pulmonary hypertension related to congenital systemic-to-pulmonary shunts are characterized by enhanced systemic inflammation involving increased endothelial cell activation and platelet-mediated inflammation. These inflammatory responses seem essentially to be unmodified by bosentan, potentially representing new targets for therapy in this disorder.
authors.affiliation: Unit for Pediatric Heart Lung and Allergic Diseases, Rikshospitalet University Hospital, Oslo, Norway. henrik.brun@rikshospitalet.no
authors.forename: Henrik
authors.initials: H
authors.lastname: Brun
authors.forename: Henrik
authors.initials: H
authors.lastname: Holmstrøm
authors.forename: Erik
authors.initials: E
authors.lastname: Thaulow
authors.forename: Jan Kristian
authors.initials: JK
authors.lastname: Damås
authors.forename: Arne
authors.initials: A
authors.lastname: Yndestad
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
mesh_terms: D000293:Adolescent; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D000077300:Bosentan; D002648:Child; D002675:Child, Preschool; D003326:Coronary Circulation; D004314:Down Syndrome / Q000097:blood / Q000150:complications / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006330:Heart Defects, Congenital / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D007249:Inflammation / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000097:blood*; D008297:Male; D011652:Pulmonary Circulation; D013449:Sulfonamides / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D015415:Biomarkers; D018836:Inflammation Mediators; D013449:Sulfonamides; D000077300:Bosentan