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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.)

Purpose: To investigate the short term effects of Doxycycline on MMP-2 and MMP-9., Methods: Short term effects of Doxycycline (100 mg B.I.D.) on plasma levels of MMP-2 and MMP-9 were investigated in 20 healthy subjects; the effects of Doxy, Acetylsalicylic acid, Nitrates, and Enalapril on MMP-9 release from were assessed in isolated polymorphonuclear cells., Results: In plasma, MMP-9 activity was reduced (-22%, 95% CI -32/-11; P = 0.002) starting at 12 h after doxy; in vitro, MMP-9 released from stimulated neutrophils was reduced by Doxy (-28%, 95% CI -43/-14; P = 0.001), inhibiting degranulation, and by nitrates (-52%, 95% CI -76/-28 P = 0.005), increasing three times both pro- and active-MMP-9 bound to neutrophils (P = 0.007 and 0.040, respectively)., Conclusions: Doxy decreases MMP-9 plasma levels by around 20%, within the first 12 h. The mechanism leading to such reduction seems due to the inhibition of PMN degranulation.

Introduction: Experimental models and ex-vivo studies suggest a crucial role of some matrix metalloproteinases (MMPs) in the development of acute coronary syndromes, but expression levels of MMP-2, MMP-9 and TIMP-1 in human coronary plaques causing stable angina or an acute coronary syndrome have not been reported, yet., Methods: MMP-2, -9 and TIMP-1 expressions were assessed by real-time PCR from the debris collected into distal protective vascular guards from patients with stable angina (SA-Group, n=16), acute coronary syndrome (ACS-Group, n=16) undergoing percutaneous coronary interventions (PCI). MMP-2 and -9 activities were also evaluated by gelatin-substrate zymography on plasma samples collected immediately before PCI, and compared to those of healthy subjects (Control-Group)., Results: The expression of MMP-2 was similar in ACS and SA-Groups. MMP-9 (P=0.011), but not TIMP-1, expression was higher in debris samples from patients in the ACS-Group than in SA-Group. In both groups, the expression of MMP-2 and MMP-9 were inversely correlated (rho=-0.7; P<0.004). Zymography data indicated that pro and active MMP-9 were higher in ACS than in SA-Group, while no difference in MMP-2 was found., Conclusions: MMP-9, but not TIMP-1 or MMP-2 expression is increased in plaques causing acute coronary syndrome.

Objective: The aims of this study were to compare a microsatellite polymorphism (PM) of matrix metalloproteinase (MMP)-9 in patients with carotid atherosclerosis and control population, and to assess the relationship between this PM and plaque structure., Methods and Results: One hundred fifty patients referring to vascular diagnostic centers for suspected carotid atherosclerosis (at ultrasound examination: 110 positive, 40 negative) and controls (n=110) have been genotyped for MMP-9 PM. After controlling for risk factors, allelic and genotype frequencies were significantly different among the groups, with significant prevalence of long microsatellites in patients with carotid atherosclerosis. Long microsatellites (settled as 22 to 27 repeats) were associated with carotid atherosclerosis (odds ratio [OR], 5.2; 95% confidence interval [CI], 2.9 to 9.2), compared with controls; an independent case control study on patients with coronary atherosclerosis confirmed such result. Binary logistic regression showed that hypertension, long microsatellites in MMP-9 PM and smoking habits were variables accounting for the difference between ultrasound-positive patients and controls. Long microsatellites were also associated to plaques with thin fibrous cap and echolucent core (OR, 13.1; 95% CI, 1.6 to 100). These alleles were slightly more represented in female patients (chi2 test=0.019; OR, 2.7; 95% CI, 1.2 to 6) but not associated with other risk factors. Plasma MMP-9 levels were related neither to MMP-9 PM nor to plaque type, and were related to gender and extension of atherosclerosis in carotid arteries., Conclusions: The number of repeats (> or =22 CA) in the microsatellite of MMP-9 promoter, but not MMP-9 plasma levels, is associated to carotid atherosclerosis and particularly to plaques with a thin fibrous cap.

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.

Purpose: To assess if a polymorphism (PM) of the microsatellite (CA(13-27)) in the promoter region of Matrix Metalloproteinase 9 (MMP-9) was associated with the exudative form of age-related macular degeneration (AMD) and to its risk factors., Methods: In 107 patients with AMD (AMD Group) and 223 age- and gender-matched controls (Control Group) with cataract, demographic, clinical data, and MMP-9 PM have been compared., Results: The comparison of allelic frequencies showed a different pattern of CA repeats between AMD and Control Group (P < 0.00005), in particular the prevalence of longer microsatellites (> or = 22 CA repeats) was higher in AMD than in Control Group (O.R. 2.49, 95% CI 1.71-3.37, P < 0.001). Analyses of genetic frequencies gave similar results. Logistic regression confirmed that 22 or more CA repeats are associated to AMD. The only association between MMP-9 PM and other risk factors for AMD was with BMI (Spearman's R = 0.298, P < 0.00005): all patients with both microsatellites > or = 22 CA repeats were overweight or obese (chi2 test P < 0.0005, compared to other genotypes)., Conclusions: Longer microsatellites in the promoter of MMP-9 are associated to the exudative form of AMD and to body mass index, a well-known risk factor for the disease.

A polymorphism (PM) in the microsatellite of the promoter region of matrix metalloproteinase 9 (MMP-9), modulating its expression, could play a role in susceptibility to multiple sclerosis (MS). MMP-9 PM was determined in 95 patients with MS (MS Group) and 95 age- and sex-matched controls (Control Group). Comparison of allelic frequencies showed that a higher number of CA repeats characterized the MS group (P<0.0001) and prevalence of carriers of > or =22 CA repeats was higher in the MS than in the Control Group (OR 3.4, 95% CI: 1.7-6.8, P<0.0001). An earlier age at disease onset was a characteristic of patients with >22 CA repeats (33+/-10 vs. 28+/-10, P=0.027). No differences were found in the main MRI parameters.