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.
Subject(s)
Hypertension, Pulmonary/blood , Hypertension, Pulmonary/mortality , Matrix Metalloproteinases/blood , Tissue Inhibitor of Metalloproteinases/blood , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Cardiac Catheterization/mortality , Cardiac Catheterization/trends , Female , Humans , Hypertension, Pulmonary/diagnosis , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , Survival Rate/trendsABSTRACT
This study aimed to determine whether the vascular endothelial growth factor (VEGF) family members soluble VEGF receptor 1 (also called soluble fms-like tyrosine kinase 1 (sFlt-1)) and placental growth factor (PlGF) could be used as biomarkers for pulmonary hypertension (PH). Consecutive patients undergoing right heart catheterisation were enrolled (those with mean pulmonary arterial pressure ≥25â mmHg were classed as having PH; those with mean pulmonary arterial pressure <25â mmHg acted as non-PH controls). Plasma from the time of PH diagnosis was analysed for PlGF and sFlt-1 using enzyme immunoassays. In total, 247 patients with PH were enrolled: 62 with idiopathic pulmonary arterial hypertension (IPAH), 14 with associated pulmonary arterial hypertension (APAH), 21 with collagen vascular disease (CVD), 26 with pulmonary venous hypertension, 67 with lung disease-associated PH and 57 with chronic thromboembolic PH. The non-PH control group consisted of 40 patients. sFlt-1 plasma levels were significantly higher in patients with IPAH, APAH, CVD and lung disease-associated PH versus controls; PlGF levels were significantly higher in all PH groups versus controls. The combination of sFlt-1 and PlGF resulted in a sensitivity of 83.7% with specificity of 100% for pulmonary arterial hypertension. There was no association between sFlt-1 or PlGF and haemodynamic parameters, 6-min walking distance or survival. In summary, PlGF and sFlt-1 are promising diagnostic biomarkers for PH.
