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. 2021 Dec 20;21(1):607.
doi: 10.1186/s12872-021-02424-5.

The role of matrix metalloproteinases in patients with pulmonary hypertension: data from a prospective study

Adriana Marc  1   2 , Calin Pop  3   4 , Adela-Viviana Sitar-Taut  5 , Liviuta Budisan  6 , Ioana Berindan-Neagoe  6 , Dana Pop  1   7
Affiliations

The role of matrix metalloproteinases in patients with pulmonary hypertension: data from a prospective study

Adriana Marc et al. BMC Cardiovasc Disord. .

Abstract

Background: Despite several therapies, pulmonary hypertension (PH) is still a severe disease which can lead to right heart failure. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are involved in cardiac and vascular remodeling in PH. Therefore, these biomarkers play an important role in PH patients. This study investigated whether TIMP-4, MMP-2, and N-terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) plasma levels are useful in assessing the severity of PH and other clinical or echocardiographic parameters.

Methods: The concentrations of MMP-2, TIMP-4, and NT-proBNP in 68 PH patients were compared with those of 12 controls without PH. All patients underwent a physical examination, echocardiography, and were checked for the presence of cardiovascular risk factors; also, plasma concentrations of MMP-2, TIMP-4, NT-proBNP, total cholesterol, and triglycerides were determined.

Results: In PH patients, significantly elevated plasma levels of TIMP-4 (PH: 2877.99 ± 1363.78 pg/ml, control: 2028.38 ± 762.67 pg/ml, p = 0.0068) and NT-proBNP ( PH: 2405.00 pg/ml-5423.47 ± 6703.38 pg/ml, control: 411.0000 pg/ml-421.75 ± 315.37 pg/ml, p = 0.01) were detected. We also observed that MMP-2 and NT-proBNP were significantly increased in patients with higher WHO functional class (p = 0.001 for MMP-2, p = 0.008 for NT-proBNP), higher pressure in the pulmonary artery (p = 0.002 for MMP-2, p = 0.001 for NT-proBNP), and more severe tricuspid regurgitation (p = 0.001 for MMP-2, p = 0.009 for NT-proBNP). TIMP-4 was elevated in patients with more severe pressure in the pulmonary artery (p = 0.006).

Conclusions: The plasma levels of TIMP-4 and NT-proBNP are higher in PH patients. MMP-2 and NT-proBNP correlates with different PH parameters severity (WHO functional class, sPAP severity, TV regurgitation severity). Therefore, plasmatic levels of MMP-2 and NT-proBNP at this kind of patients reflect disease severity and may have a prognostic role. MMP-2 can help assess the beneficial effects of PH pharmacotherapy on tissue remodeling. These remodeling biomarkers may not have a diagnostic value but they have the potential to predict survival. Nevertheless, a greater understanding of the involvement of MMPs in PH is mandatory to further explore the prognostic role and the possibilities of therapeutic MMP inhibition in PH.

Keywords: Biomarkers; Matrix metalloproteinase 2; N-terminal pro-B-Type Natriuretic peptide; Pulmonary hypertension; Right heart failure; Tissue inhibitor of matrix metalloproteinase 4.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Comparison of plasma biomarker levels. Box plots show plasma biomarker concentrations in pulmonary hypertension (PH) patients (n = 68) and controls (n = 12). a Tissue inhibitor of matrix metalloproteinase’s (TIMP-4), b Matrix metalloproteinase (MMP-2), and c N-terminal B-type natriuretic peptide (NT-proBNP)
Fig. 2
Fig. 2
Correlation between disease severity and TIMP-4 concentration. We have box plots showing biomarker levels in different patient subpopulations. Patients were grouped based on disease severity determined as a WHO classification, b systolic arterial pressure (sPAP), and c the severity of TV regurgitation
Fig. 3
Fig. 3
Linear regression analyses. No relationship between TIMP-4, MMP-2, NT-proBNP, and age has been found. a Tissue inhibitor of matrix metalloproteinases (TIMP-4), b Matrix metalloproteinase (MMP-2), and c N-terminal B-type natriuretic peptide (NT-proBNP)
Fig. 4
Fig. 4
Correlation between disease severity and MMP-2 concentration. We have box plots that show biomarker levels in different patient subpopulations. Patients were grouped based on disease severity determined as a WHO classification, b systolic arterial pressure (sPAP), and c the severity of TV regurgitation
Fig. 5
Fig. 5
Correlation between disease severity and NT-proBNP concentration. We have box plots showing biomarker levels in different patient subpopulations. Patients were grouped based on disease severity determined by a WHO classification, b systolic arterial pressure (sPAP), and c the severity of TV regurgitation
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