Elsevier

Surgery

Volume 137, Issue 3, March 2005, Pages 355-363
Surgery

Original communication
Metalloproteinases and their inhibitors are markers of plaque instability

https://doi.org/10.1016/j.surg.2004.10.011Get rights and content

Background

Our aim was to investigate the release, activity, and expression of matrix metalloproteinases (MMPs)-1, -2, -3 and -9, and tissue inhibitors of metalloproteinases (TIMPs)-1 and -2 in patients undergoing carotid endarterectomy and to determine whether altered plasma levels of MMPs and TIMPs may be correlated with carotid instability.

Methods

The carotid plaques of 53 consecutive patients who underwent carotid endarterectomy were classified histologically as stable or unstable. The release of MMPs and TIMPs was analyzed in the serum of patients with stable and unstable carotid plaques, and in 15 age-matched healthy volunteers. The production, activity, and expression of MMPs and TIMPs were determined by Western blotting, zymography, and reverse transcriptase polymerase chain reaction in the carotid specimens.

Results

Twenty-nine (55%) patients had an unstable carotid plaque and 24 (45%) a stable plaque. Plasma levels of MMPs were higher in patients with unstable plaques compared to patients with stable plaques and healthy volunteers (P < .001), whereas plasma levels of TIMPs were lower in patients with unstable plaques compared to patients with stable plaques and healthy volunteers (P < .001). In the carotid specimens, we found increased activity, production, and expression of MMPs, and decreased activity, production and expression of TIMPs in unstable plaques compared to stable plaques (P < .001). After endarterectomy, plasma levels of MMPs and TIMPs in patients with unstable and stable plaques returned to the values found in healthy volunteers.

Conclusions

Our study demonstrated that an imbalance exists between MMPs and TIMPs in unstable carotid plaques, which is reflected in the plasma levels of these markers. These data may help in selecting patients at high risk for cerebral events.

Section snippets

Materials and methods

Between January 2003 and December 2003, 53 consecutive patients (32 men, 21 women; mean age, 73 ± 7 years; median, 73 years; range, 60-87 years) presenting at our institution with internal carotid artery stenosis greater than 70% and no other vascular diseases (ie, abdominal aortic aneurysm and peripheral vascular disease) were entered into this study after informed consent was obtained. To exclude the concomitant presence of peripheral vascular and/or aneurysmal diseases, we screened patients

Results

Twenty-four (45%) carotid plaques were defined echographically as stable and 29 (55%) unstable with correct histologic confirmation on all carotid specimens. Twenty-five (86%) patients affected with unstable plaques were symptomatic, whereas 6 (25%) with stable plaques were symptomatic (P < .001). Table II shows the demographics, risk factors, associated diseases, and presenting symptoms of our population.

Discussion

The atherosclerotic plaque is a dynamic structure that undergoes continuous remodeling of the extracellular matrix on which its structural integrity depends. High levels of MMPs were demonstrated at the site of the inflammatory infiltrate in the fibrous cap leading to plaque instability.19 Elevated expression of several MMP species (MMP-1, -3, -12, and -13)4, 20 were observed within plaques. Brown et al10 and Henney et al12 identified members of the metalloproteinase family of enzymes in human

Conclusion

Our study demonstrated that an imbalance exists between MMPs and their inhibitors in unstable carotid plaque that may contribute to plaque instability and be a prelude to the onset of cerebral ischemic events. This imbalance could be monitored with plasma tests. Plasma levels of MMPs and TIMPs may represent valid markers of plaque instability and atherosclerosis-related inflammation, thus identifying a cohort of patients who warrant urgent intervention because of the risk for cerebral events

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