title: Biomarkers of tissue remodeling predict survival in patients with pulmonary hypertension.
abstract: BACKGROUND
  Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are involved in vascular and right ventricular remodeling in pulmonary hypertension (PH). MMP2, MMP9, TIMP1, and TIMP4 were measured in plasma and their potential as biomarkers for PH was evaluated.
  
  
  METHODS
  Consecutive patients undergoing right heart catheterization for suspected PH were included in this study (patients with mPAP ≥25mmHg were classed as having PH; those with mPAP <25mmHg served as non-PH controls). In total, 160 patients with PH (idiopathic pulmonary arterial hypertension, pulmonary arterial hypertension associated with connective tissue disease, chronic thromboembolic PH, and pulmonary venous hypertension) and 44 non-PH controls were included. Plasma from the time of PH diagnosis was analyzed for levels of MMP2, MMP9, TIMP1, and TIMP4 using enzyme immunoassays. Correlation analyses were performed with Pearson's or Spearman's coefficient, as appropriate. Mortality hazard ratios were derived using Cox regression analyses.
  
  
  RESULTS
  Plasma levels of MMP2, MMP9, TIMP1, and TIMP4 showed considerable overlap between patient groups. In patients with PH, MMP2, TIMP1, and TIMP4 levels correlated with hemodynamic parameters (p<0.05) and six minute walking distance (p<0.01). Patients with high (>median) MMP2 and TIMP1 plasma levels had significantly worse 5-year survival than patients with low (≤median) plasma levels (multivariate mortality hazard ratios: 2.69 and 4.46, respectively; p<0.01).
  
  
  CONCLUSIONS
  MMP2 and TIMP1 plasma levels in patients with PH reflect disease severity and predict outcome. Though not being of diagnostic value, elevated biomarker plasma levels are strongly associated with increased risk in patients with PH.
authors: University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors: Svenja L
authors: SL
authors: Tiede
authors: University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors: Matthias
authors: M
authors: Wassenberg
authors: University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors: Katrin
authors: K
authors: Christ
authors: University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors: Ralph T
authors: RT
authors: Schermuly
authors: University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors: Werner
authors: W
authors: Seeger
authors: University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors: Friedrich
authors: F
authors: Grimminger
authors: University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors: Hossein Ardeschir
authors: HA
authors: Ghofrani
authors: University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany. Electronic address: Henning.Gall@innere.med.uni-giessen.de.
authors: Henning
authors: H
authors: Gall
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D006328:Cardiac Catheterization / Q000401:mortality / Q000639:trends; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood* / Q000175:diagnosis / Q000401:mortality*; D008297:Male; D020782:Matrix Metalloproteinases / Q000097:blood*; D008875:Middle Aged; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D015996:Survival Rate / Q000639:trends; D019714:Tissue Inhibitor of Metalloproteinases / Q000097:blood*
chemical_list: D015415:Biomarkers; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases
keywords: Biomarker; Matrix metalloproteinases (MMPs); Pulmonary hypertension; Survival; Tissue inhibitors of metalloproteinases (TIMPs)