Serum values of metalloproteinase-2 and metalloproteinase-9 as related to unstable plaque and inflammatory cells in patients with greater than 70% carotid artery stenosis

Abstract

Unstable carotid plaques, characterized by increased levels of macrophages and T lymphocytes, have high emboligenic potential and carry a risk for producing cerebral ischemic events. It has been suggested that plaque instability may be mediated by the family of metalloproteinases (MMPs). The purpose of this study was to analyze the relationship between concentrations of MMP-2 and MMP-9 and unstable carotid plaques, presence of macrophages and T-lymphocytes in the plaques, and neurologic symptoms, to establish additional risk markers in patients with greater than 70% carotid artery stenosis. This was a cross-sectional study carried out in a referral center and institutional practice in hospitalized patients. The study included 40 patients with carotid artery stenosis treated with carotid endarterectomy. Of these patients, 67.5% had experienced a previous neurologic event and 32.5% exhibited no symptoms. MMP-2 and MMP-9 levels were determined with enzyme-linked immunosorbent assay 48 hours before surgery. Histopathologic analysis (stable or unstable) and immunohistochemistry (macrophage count, T lymphocytes, activated T lymphocytes) were carried out on the plaques. Mean MMP-2 and MMP-9 serum concentrations in the population studied were 1138.27 ± 326.08 ng/mL and 1026.10 ± 412.90 ng/mL, respectively. MMP-2 levels were significantly higher in patients with symptoms compared with patients without symptoms (1247.30 ± 276.80 ng/mL vs 911.80 ± 311.84 ng/mL; P =. 001). MMP-9 was also significantly higher in the symptomatic group (1026.10 ± 412.90 ng/mL vs 377.84 ± 164.08 ng/mL; P =. 001) and in patients with unstable plaques compared with those with stable plaques (1006.98 ± 447.09 ng/mL vs 496.16 ± 292.78 ng/mL; P =. 001). In addition, we found a strong association between elevated MMP-9 concentration and presence of macrophages in plaque (Spearman rho, 0.45; P =. 004). At logistic regression analysis, variables that best predicted the presence of unstable plaque were a previous neurologic event and MMP-9 level greater than 607 ng/mL (sensitivity, 96%; specificity, 92%; negative predictive value, 94.7%; positive predictive value, 93%). Elevated MMP-9 concentration is associated with carotid plaque instability and the presence of macrophages, factors that indicate increased risk for a neurological event. Determination of this gelatinase may enable identification of high-risk subgroups of patients with carotid artery stenosis.