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

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

Lu Wang^1,2†, Linghui Deng^3†, Ruozhen Yuan¹, Junfeng Liu¹, Yuxiao Li¹ and Ming Liu^1*

• ¹Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
• ²Center of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China
• ³National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China

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.

Introduction

Ischemic stroke is one of the most severe neurological disorders and one of the leading causes of disability worldwide (1, 2). The main reasons of deterioration were neurological complications including severe brain edema and hemorrhagic transformation, which may share the common pathophysiological mechanism of blood–brain barrier (BBB) breakdown (3). At present, neuroimaging tests are the main method for diagnosing severe brain edema and hemorrhagic transformation, but these tests are usually performed in the presence of signs of neurological worsening. The neuroimaging tests may delay the effective treatment. Given the limitations of current methods for early detection, new methods are needed to identify these two neurological complications in order to optimize timing of management administration (4).

A change of biomarker levels may precede the appearance of clinical deterioration. Clinical studies have identified that biomarkers of BBB breakdown, such as matrix metalloproteinase 9 (MMP-9) and S100-B, may be associated with clinical deterioration (5–8). Among these biomarkers, MMP-9 has sparked the most interest (9). MMP-9 belongs to a family of zinc-dependent proteolytic enzymes. In animal models, MMP-9 is upregulated in the cerebral ischemic area (10) and degrades the basal lamina around blood vessels in the brain including type IV collagen, fibronectins, and lamina (11–13). As the substrate of MMP-9, fibronectins are located between cell and cell or matrix and consist of cellular fibronectin (c-Fn) and plasma fibronectin (p-Fn). C-Fn is situated nearly exclusively in the endothelium and increases rapidly when vascular damage occurs (14, 15). After stroke onset, high levels of MMP-9 and c-Fn may represent severe damage of the neurovascular unit in injured brain tissue, and when reperfusion begins in the occluded vessels, the disruption of the extracellular matrix may further cause BBB leakage, brain edema, and even hemorrhagic complications in the infarction area (16).

No uniform conclusions have been drawn thus far about associations of circulating MMP-9 levels with the risk of severe brain edema, hemorrhagic transformation, and poor outcome after acute ischemic stroke. Previous systematic reviews suggested a correlation between MMP-9 levels and risk of hemorrhagic transformation (17, 18). While a recent study did not indicate that MMP-9 plasma concentrations were associated with any outcomes including symptomatic intracerebral hemorrhage (sICH), death, and functional outcome (19). Besides, studies focused on c-Fn are very limited, although one study suggested a device that quantified the c-Fn levels was able to stratify patients who developed hemorrhagic transformation (20). In addition, previous studies reported that MMP-9 gene polymorphism, especially the rs3918242 polymorphism (at−1562 locus C/T), regulates expression and thereby influences the levels of circulating MMP-9 (21). Stroke patients with the CT and TT genotypes had significantly higher MMP-9 levels than those with the CC genotypes at the rs3918242 polymorphism (22). MMP-9 rs3918242 polymorphism has already been associated with stroke susceptibility (23–25); however, it is unclear whether or not MMP-9 rs3918242 polymorphism is associated with stroke outcome. Considering these limitations, we aimed to systematically review all the relevant data to investigate (1) whether circulating MMP-9 levels and c-Fn levels might constitute markers of severe brain edema, hemorrhagic transformation, and poor outcome after ischemic stroke; (2) whether variations in the MMP-9 rs3918242 gene were associated with susceptibility to severe brain edema, hemorrhagic transformation, and poor outcome after ischemic stroke.