Plasma matrix metalloproteinase 2 is associated with severity and mortality in pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a life‐threatening disease characterized by vasoconstriction and remodeling of the pulmonary vessels. Risk stratification in PAH could potentially be improved by including novel biomarkers related to PAH pathobiology. We aimed to investigate the relationship between extracellular matrix (ECM)‐related proteins, survival, and European Society of Cardiology and European Respiratory Society (ESC/ERS) risk stratification scores in patients with PAH. Plasma samples and hemodynamics were collected from PAH patients during right heart catheterizations at diagnosis (n = 48) and early follow‐up, after treatment initiation (n = 33). Plasma levels of 14 ECM‐related proteins, with altered levels in PAH compared to healthy controls, were analyzed with proximity extension assays, and related to hemodynamics, transplant‐free survival time, and ESC/ERS risk score. Glypican‐1 levels were higher before versus after treatment initiation (p = 0.048). PAH patients with high plasma levels of matrix metalloproteinase (MMP) ‐2, MMP‐7, MMP‐9, MMP‐12, perlecan, and tissue inhibitor of metalloproteinase 4 (TIMP‐4) at baseline, had worse transplant‐free survival (p < 0.03) than patients with low levels. Hazard ratio (95% confidence interval) was for MMP‐2 1.126 (1.011–1.255), perlecan 1.0099 (1.0004–1.0196), and TIMP‐4 1.037 (1.003–1.071) in age and sex‐adjusted Cox‐regression model. MMP‐2 correlated with ESC/ERS risk scores (rs = 0.34, p = 0.019), mean right atrial pressure (rs = 0.44, p = 0.002), NT‐proBNP (rs = 0.49, p ≤ 0.001), and six‐minute walking distance (rs = −0.34, p = 0.02). The present study indicates that high levels of MMP‐2, perlecan, and TIMP‐4 are associated with poor survival in PAH. High plasma MMP‐2, correlated with poor prognosis in PAH. Further validation in larger studies is needed to better determine this association.

Serum Matrix Metalloproteinase 2 (MMP-2) Levels in Children with Pulmonary Hypertension Associated with Congenital Heart Disease

“…The findings of the recent research showed that the best cutoff point of MMP-2 to differentiate cases in PAH-CHD group from CHD group without PH was ≥ 109.7 ng/ml, with sensitivity of 52 %, specificity of 96%, PPV of 96 % and NPV of 52 %, which are in line with Arvidsson et al who revealed serum MMP-2 in PAH had sensitivity of 52% and specificity of 93% [37].…”

“…Arvidsson et al [37] and Tiede et al [38] revealed an increased risk of death among PH cases with MMP-2 concentrations above the median. This highlights the possible significance of MMP-2 as a prognostic indicator, as greater MMP-2 concentrations were related with a poor outcome in PAH.…”

Circulating biomarkers of extracellular matrix dysregulation are associated with adverse post-stage 2 outcomes in infants with single ventricle heart disease

“…Our prior work additionally demonstrated an association between increased post-operative MMP 7 and post-Stage 2 hypoxemia 5 . Increased circulating MMP 7 has also been associated with pulmonary pathology in a number of clinical populations, including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and pulmonary arterial hypertension 7 , 28 – 30 . In this context, our results suggest a role for increased MMP 7 exposure as both a biomarker of disease and a potential mechanistic driver of pulmonary vascular inadequacy in SVHD.…”

“…Two additional biomarkers of interest, TIMP 4 and MMP 1, were directly associated with post-Stage 2 LOS. While the role of MMP 1 in the pulmonary vasculature is less clear, elevated TIMP 4 level has been previously identified as a biomarker of disease and indicator of poor prognosis in pulmonary arterial hypertension 30 , 32 – 34 . Although not evaluated previously in SVHD, a pediatric study linked elevated TIMP 4 levels to increased pulmonary vascular stiffness by MRI providing a potential mechanism linking TIMP 4 activity to impaired tolerance of Stage 2 physiology 20 .…”

Expression profiles of circRNAs and identification of hsa_circ_0007608 and hsa_circ_0064656 as potential biomarkers for COPD-PH patients

“…It is obvious that intracellular signal transduction is ubiquitous in the pathogenesis of PH in COPD [36] . Existing studies also show that ECM is implicated in the development of pulmonary vascular remodeling and high level of ECM-related proteins such as MMP-2 are associated with poor survival and prognosis of PH patients [37] . Additionally, release of calcium ions from the endoplasmic reticulum to the cytoplasm and mitochondria is an important mediators of cell proliferation, migration and mesenchymal transition, thereby affecting the contractility and resistance of pulmonary artery [38][39] .…”