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

Mattias Arvidsson; Abdulla Ahmed; Joanna Säleby; Roger Hesselstrand; Göran Rådegran

doi:10.1002/pul2.12041

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

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

Authors

Mattias Arvidsson^{1

2}, Abdulla Ahmed^{1

2}, Joanna Säleby^{1

2}, Roger Hesselstrand^{3

4}, Göran Rådegran^{1

2}

Affiliations

¹ Department of Clinical Sciences Lund, Cardiology, Faculty of Medicine Lund University Lund Sweden.
² The Hemodynamic Lab, The Section for Heart Failure and Valvular Disease, VO Heart and Lung Medicine Skåne University Hospital Lund Sweden.
³ Department of Clinical Sciences Lund, Rheumatology, Faculty of Medicine Lund University Lund Sweden.
⁴ The Department of Rheumatology Skåne University Hospital Lund Sweden.

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.