Biomarkers of tissue remodeling predict survival in patients with pulmonary hypertension

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• 作者：Svenja L. Tiede¹ ; Matthias Wassenberg¹ ; Katrin Christ¹ ; Ralph T. Schermuly¹ ; Werner Seeger¹ ; Friedrich Grimminger¹ ; Hossein Ardeschir Ghofrani¹ ; Henning Gall ; ¹ ; ^{Henning.Gall@innere.med.uni-giessen.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Pulmonary hypertension ; Biomarker ; Survival ; Matrix metalloproteinases (MMPs) ; Tissue inhibitors of metalloproteinases (TIMPs)
• 刊名：International Journal of Cardiology
• 出版年：2016
• 出版时间：15 November 2016
• 年：2016
• 卷：223
• 期：Complete
• 页码：821-826
• 全文大小：432 K

文摘

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are involved in vascular and right ventricular remodeling in pulmonary hypertension (PH). MMP2, MMP9, TIMP1, and TIMP4 were measured in plasma and their potential as biomarkers for PH was evaluated.

Methods

Consecutive patients undergoing right heart catheterization for suspected PH were included in this study (patients with mPAP ≥ 25 mm Hg were classed as having PH; those with mPAP < 25 mm Hg served as non-PH controls). In total, 160 patients with PH (idiopathic pulmonary arterial hypertension, pulmonary arterial hypertension associated with connective tissue disease, chronic thromboembolic PH, and pulmonary venous hypertension) and 44 non-PH controls were included. Plasma from the time of PH diagnosis was analyzed for levels of MMP2, MMP9, TIMP1, and TIMP4 using enzyme immunoassays. Correlation analyses were performed with Pearson's or Spearman's coefficient, as appropriate. Mortality hazard ratios were derived using Cox regression analyses.

Results

Plasma levels of MMP2, MMP9, TIMP1, and TIMP4 showed considerable overlap between patient groups. In patients with PH, MMP2, TIMP1, and TIMP4 levels correlated with hemodynamic parameters (p < 0.05) and six minute walking distance (p < 0.01). Patients with high (> median) MMP2 and TIMP1 plasma levels had significantly worse 5-year survival than patients with low (≤ median) plasma levels (multivariate mortality hazard ratios: 2.69 and 4.46, respectively; p < 0.01).

Conclusions

MMP2 and TIMP1 plasma levels in patients with PH reflect disease severity and predict outcome. Though not being of diagnostic value, elevated biomarker plasma levels are strongly associated with increased risk in patients with PH.