Association of Matrix Metalloproteinase 9 and Cellular Fibronectin and Outcome in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis

Abstract

Introduction: The role of matrix metalloproteinase 9 (MMP-9) and cellular fibronectin (c-Fn) in acute ischemic stroke is controversial. We systematically reviewed the literature to investigate the association of circulating MMP-9 and c-Fn levels and MMP-9 rs3918242 polymorphism with the risk of three outcome measures after stroke. Methods: We searched English and Chinese databases to identify eligible studies. Outcomes included severe brain edema, hemorrhagic transformation, and poor outcome (modified Rankin scale score ≥3). We estimated standardized mean differences (SMDs) and pooled odds ratios (ORs) with 95% confidence intervals (CIs). Results: Totally, 28 studies involving 7,239 patients were included in the analysis of circulating MMP-9 and c-Fn levels. Meta-analysis indicated higher levels of MMP-9 in patients with severe brain edema (SMD, 0.76; 95% CI, 0.18-1.35; four studies, 419 patients) and hemorrhagic transformation (SMD, 1.00; 95% CI, 0.41-1.59; 11 studies, 1,709 patients) but not poor outcome (SMD, 0.30; 95% CI, -0.12 to 0.72; four studies, 759 patients). Circulating c-Fn levels were also significantly higher in patients with severe brain edema (SMD, 1.55; 95% CI, 1.18-1.93; four studies, 419 patients), hemorrhagic transformation (SMD, 1.75; 95% CI, 0.72-2.78; four studies, 458 patients), and poor outcome (SMD, 0.46; 95% CI, 0.16-0.76; two studies, 210 patients). Meta-analysis of three studies indicated that the MMP-9 rs3918242 polymorphism may be associated with hemorrhagic transformation susceptibility under the dominant model (TT + CT vs. CC: OR, 0.621; 95% CI, 0.424-0.908; P = 0.014). No studies reported the association between MMP-9 rs3918242 polymorphism and brain edema or functional outcome after acute stroke. Conclusion: Our meta-analysis showed that higher MMP-9 levels were seen in stroke patients with severe brain edema and hemorrhagic transformation but not poor outcome. Circulating c-Fn levels appear to be associated with all three outcomes including severe brain edema, hemorrhagic transformation, and poor functional outcome. The C-to-T transition at the MMP-9 rs3918242 gene appears to reduce the risk of hemorrhagic transformation.

Keywords: cellular fibronectin; hemorrhagic transformation; matrix metalloproteinase 9; poor outcome; severe brain edema.