Plasma MMP2/TIMP4 Ratio at Follow-up Assessment Predicts Disease Progression of Idiopathic Pulmonary Arterial Hypertension

Purpose Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) are of particular interest in the remodeling processes of pulmonary hypertension. The aim of this study was to investigate MMP/TIMP ratios of selected biomarkers (MMP2, MMP9, TIMP1, TIMP4) at follow-up examination (V2) and their prognostic value in patients with idiopathic pulmonary arterial hypertension (iPAH). Methods Blood samples were taken from iPAH patients during right heart catheterization at diagnosis (V1, from 2003 to 2012) and first follow-up examination (V2). MMP2, MMP9, TIMP1, and TIMP4 plasma levels at V2 were determined by ELISA. Coincident with sample collection hemodynamic, laboratory, and clinical parameters were acquired. Additionally, death and clinical worsening (CW) events were listed until July 2015. Results MMP2/TIMP1 and MMP9/TIMP1 did not correlate with hemodynamic and clinical parameters. MMP2/TIMP4 showed a good correlation with mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance, estimated glomerular filtration rate (eGFR), and tricuspid annular plain systolic excursion (TAPSE). MMP9/TIMP4 shows good correlation with mPAP and eGFR. MMP2/TIMP4 showed significant results in the receiver operating characteristics analysis predicting death (AUC = 0.922; p = 0.005) and CW event (AUC = 0.818; p = 0.026). Patients above the cut-off values had a significantly higher probability to die or experience CW, respectively, estimated by log-rank test (p = 0.010 for death; p = 0.032 for CW). Conclusions MMP2/TIMP4 ratio was detected as a marker of disease severity and right ventricular function as well as a predictor for survival and time to clinical worsening and therefore might help for guidance of disease progression in iPAH patients at V2