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Objective: To assess the association of matrix metalloproteinases (MMP) genetic polymorphism (PM) with plaques vulnerability and clinical outcome of acute vascular events., Methods: MMP-1 (-1607 G in/del), MMP-3 (-1171 A in/del), and MMP-9 microsatellite ((13-26) CA repeats around -90) PMs have been determined (i) in 204 patients with cerebrovascular disease to assess the association with features of vulnerability in carotid plaques and prevalence of stroke, (ii) in 208 patients with UA/NSTEMI to assess the association with in-hospital clinical outcome., Results: Plaques from carriers of MMP-1 G insertion showed significantly smaller plaques and thicker fibrous cap. In CVD patients carrying such variant, Odds Ratio for previous stroke was 0.27 (95%C.I. 0.13-0.56, P=0.0002) and, in UA/NSTEMI patients, the risk of Major Adverse Cardiac Events (MACE, persistent angina, NSTEMI, and vascular death) was 0.22 (95%C.I. 0.11-0.44, P<0.0001). No variants in MMP-3 PM were associated to differences in either plaque features or clinical outcome. Carriers of MMP-9≥22 repeats in the microsatellite had larger plaques and lipid core. In CVD patients with such variant, Odds Ratio for stroke was 2.2 (95%C.I. 1.1-4.4) and, in UA/NSTEMI patients, MACE risk was 4.1 (95%C.I. 2.3-7.4, P<0.0001). Persistent angina and NSTEMI separately provided comparable results., Conclusions: Carriers of MMP-1 G insertion show smaller and more stable plaques, as well as better prognosis in acute vascular events, while patients with ≥22 repeats in MMP-9 have larger necrotic core and worse prognosis in UA/NSTEMI., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Intima-media thickening (IMT) of carotid arteries and constrictive remodeling (CR) of atherosclerotic plaques are vascular pathologic characteristics that precede the onset of vascular events. SMC migration and proliferation are linked both to IMT and CR and are matrix metalloproteinase 9 (MMP-9) dependent. A genetic polymorphism (PM) of MMP-9, a CA (13-27) microsatellite in the promoter region, which accounts for differential expression of MMP-9, could be linked to progression of IMT and CR. Progression of IMT and CR of plaques in carotid arteries were studied in 55 consecutive patients with a 12-18 months follow-up. All patients were genotyped for MMP-9 PM. A positive linear relationship between the number of repeats and the progression of IMT (P=0.028) as well as of CR (P=0.018) was found. The analogous relationship was obtained when only the allele with longer microsatellite was considered. Carriers of more than 20 repeats in one allele showed faster both IMT growth (P=0.045) and stenosis progressions of plaques (P=0.019). In multivariate analysis, age, dyslipidemia, and MMP-9 PM were determinants of IMT progression, while MMP-9 PM was the only one of CR. In conclusion, the high number of CA repeats in MMP-9 promoter is positively correlated with faster IMT and CR progression.

Inflammatory phenomena at sites of atherosclerotic plaques are increasingly thought to be major determinants of the progression and clinical outcome of atherosclerotic disease. Therefore, attention is being paid to systemic markers/mediators which may reflect the inflammatory activity in the plaques. This study evaluates the pattern of the main proinflammatory cytokines tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6), their soluble receptors/antagonist, and a variety of inflammatory markers, in patients with peripheral arterial disease (PAD). Eight patients with PAD suffering from claudicatio intermittens (CI), eight with critical limb ischemia (CLI) and eight controls (C) were studied. Blood samples were collected at baseline in all groups and. for C and CI, immediately after and 4 h after a 30-min treadmill test. Baseline: no differences in cytokine plasma levels were detected among the three groups. In contrast, soluble receptors of TNF (type I and II) and of IL-6, and IL-1beta receptor antagonist (IL-1ra) were increased in CI and CLI patients, as compared to C. Of note, IL-Ira correlated with the occurrence and stage of the disease in a highly significant proportion of the patients, reaching a predictive value for the disease of P < 0.0001. The opposite trend was observed for the soluble receptor of IL-1beta. Notably, in the patients no alterations could be found in white blood cell counts, expression of CD11c adherence molecule by circulating monocytes or, in vitro. O2- release from zymosan-activated neutrophils. Moreover, plasma levels of platelet activating factor (PAF), of neutrophil elastase and of the acute phase reactants C-reactive protein (CRP) and alpha1-acid glycoprotein were not found to be significantly altered. In contrast, the acute-phase proteins alpha1-antitrypsin (alpha1AT) and haptoglobin (HG) were found to be increased. Effect of treadmill: IL-1beta and TNFalpha remained at baseline levels following exercise, and IL-6 dropped to undetectable levels. Among cytokine antagonists, again the most relevant changes concerned the IL-1ra, which was significantly increased immediately after the treadmill test, both in CI and C, and returned to baseline levels after 4 h. In contrast, soluble TNFalpha, IL-1beta and IL-6 receptors, PAF, and the other markers of leukocyte activation were not found to be altered. Soluble TNFalpha and IL-6 receptors were shown to inhibit the biological effects of their ligands. Similarly, IL-1ra and the acute phase proteins alpha1AT and HG have been reported to exert anti-inflammatory functions. The increased plasma levels of these agents, together with low levels of inflammatory cytokines and other pro-inflammatory mediators such as PAF and alpha1-acid glycoprotein, appear to draw an undescribed picture, so far, of upregulation of a composite systemic anti-inflammatory mechanism in atherosclerotic patients. IL-1ra appears to be a reliable marker of the state of activation of this mechanism. These results may provide a basis for developing new insights into the pathogenesis of the atherosclerotic disease.