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. 2022 Feb 4;12(1):e12041.
doi: 10.1002/pul2.12041. eCollection 2022 Jan.

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

Mattias Arvidsson  1   2 , Abdulla Ahmed  1   2 , Joanna Säleby  1   2 , Roger Hesselstrand  3   4 , Göran Rådegran  1   2
Affiliations

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

Mattias Arvidsson et al. Pulm Circ. .

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 (r s = 0.34, p = 0.019), mean right atrial pressure (r s = 0.44, p = 0.002), NT-proBNP (r s = 0.49, p ≤ 0.001), and six-minute walking distance (r s = -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.

Keywords: extracellular matrix; matrix metalloproteinase‐2; prognosis; pulmonary arterial hypertension; risk assessment.

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Conflict of interest statement

Mr. Arvidsson reports an unrestricted research grant from The Swedish Society of Pulmonary Hypertension. Mr. Ahmed, Miss Säleby, and Mr. Hesselstrand report no conflicts of interest. Dr. Rådegran reports personal lecture fees from Actelion Pharmaceuticals, Bayer Health Care, GlaxoSmithKline, Janssen‐Cilag AB, and Nordic Infucare, outside the submitted work. Dr. Rådegran has received unrestricted research grants from Actelion Pharmaceuticals, GlaxoSmithKline, and a noninterventional investigator‐initiated study research grant from Janssen‐Cilag AB. Dr. Rådegran is and has been primary‐, or co‐, investigator in; clinical PAH trials for Acceleron, Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, Janssen, Pfizer, and United Therapeutics, and in clinical heart transplantation immunosuppression trials for Novartis.

Figures

Figure 1
Figure 1
Glypican‐1 levels at PAH baseline and follow‐up. Glypican‐1 levels are significantly higher in PAH patients at follow‐up compared to baseline values. AU, arbitrary units; PAH, pulmonary arterial hypertension
Figure 2
Figure 2
Kaplan–Meier plots. Kaplan–Meier plots with Log‐rank tests for (a) MMP‐2, (b) MMP‐7, (c) MMP‐9, (d) MMP‐12, (e) perlecan, (f) TIMP‐4. p < 0.05 were considered statistically significant. Protein level threshold set as the cut‐off (as described in Table 3) yielding the highest Youden's index of sensitivity and specificity for the outcome death. MMP, matrix metalloproteinase; TIMP‐4, tissue inhibitor of metalloproteinases 4
Figure 3
Figure 3
MMP‐2 correlates with ESC/ERS risk scores and risk parameters. 6MWD, 6‐min walk distance; AU, arbitrary unit; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide; MMP‐2, matrix metalloproteinase‐2; MRAP, mean right atrial pressure; r, Spearman's correlation coefficient
See this image and copyright information in PMC

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