Biomarkers of Tissue Remodeling Predict Survival in Patients with Pulmonary Hypertension

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.