Evaluation of Serum Matrix Metalloproteinases as Biomarkers for Detection of Neurological Symptoms in Carotid Artery Disease

Abstract

Objective: Relevant soluble matrix metalloproteinases (MMPs), their inhibitors, tissue inhibitor of metalloproteinases (TIMPs), and serological factors were analyzed as possible biomarkers for neurological symptoms in patients with carotid artery stenosis. Methods and Results: Asymptomatic (n = 76) and symptomatic (n = 69) patients were evaluated. Serum levels of collagenases (MMP-1, -8), gelatinases (MMP-2, -9), stromelysin (MMP-3), matrilysin (MMP-7), and TIMP-1, -2 were determined by enzyme-linked immunosorbant assay (ELISA). Furthermore, fibrinogen, C-reactive protein (CRP), leukocytes, and further serological parameters were measured. Circulating MMP-7, -8, -9, and TIMP-1 were significantly enhanced in symptomatic individuals with P < .001 for MMP-7 and P < .05 for MMP-8, -9, and TIMP-1. Significant correlations were found between various MMPs with highest correlation coefficient of r = .749 between MMP-8 and -9. In addition, MMP-1, -3, -7, -9 correlated significantly with leukocytes, MMP-1, and TIMP-1 with thrombocytes, MMP-8 with fibrinogen, and MMP-7 with creatinine. Combination of more than one bio-marker led to significantly enhanced positive predictive value (PPV) for neurological symptom compared to single MMP (MMP-7 + MMP-9: PPV = 73.1%, MMP-7 + MMP-8 + MMP-9: PPV = 73.8% vs. PPV = 62.5%; P < .001). Conclusions: Thus, using appropriate analytical approaches, we showed for the first time the possibility to use set of relevant biomarkers as predictors of neurological symptoms. Such biomarkers together with current diagnostic techniques may further contribute to recognize vulnerable lesions to define patients at risk.

Keywords

atherosclerosis carotid artery matrix metalloproteinases vulnerable plaques

Get full access to this article

View all access options for this article.

References

Bamford J. , Sandercock P. , Dennis M. , Burn J. , Warlow C. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet. 1991;337(8756): 1521-1526.

Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet. 1998;351(9113):1379-1387.

Hollander M. , Hak AE , Koudstaal PJ , et al. Comparison between measures of atherosclerosis and risk of stroke: the Rotterdam Study. Stroke. 2003;34(10):2367-2372.

Rothwell PM , Gutnikov SA , Warlow CP for the European Carotid Surgery Trialist’s Collaboration. Reanalysis of the final results of the European Carotid Surgery Trial. Stroke. 2003;34(2):514-523.

Eckstein HH , Heider P. , Wolf O. , Barone M. , Hanke M. Controversies in the treatment of carotid stenoses. Present state of research and evidence-based medicine. Chirurg. 2004 ;75(7):672-680.

Virmani R. , Burke AP , Farb A. , Kolodgie FD Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006; 47(8 suppl):C13-C18.

Moreno PR , Purushothaman KR , Sirol M. , Levy AP , Fuster V. Neovascularization in human atherosclerosis. Circulation. 2006;113(18):2245-2252.

Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med. 1999;340(2):115-126.

Dollery CM , Libby P. Atherosclerosis and proteinase activation. Cardiovasc Res . 2006;69(3):625-635.

10.

Newby AC Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev. 2005;85(1):1-31.

11.

Lemaitre V. , D’Armiento J. Matrix metalloproteinases in development and disease. Birth Defects Res C Embryo Today. 2006;78(1):1-10.

12.

Borrelli V. , di Marzo L. , Sapienza P. , Colasanti M. , Moroni E. , Cavallaro A. Role of platelet-derived growth factor and transforming growth factor beta1 the in the regulation of metalloproteinase expressions. Surgery . 2006;140(3):454-463.

13.

Turu MM , Krupinski J. , Catena E. , et al. Intraplaque MMP-8 levels are increased in asymptomatic patients with carotid plaque progression on ultrasound. Atherosclerosis . 2006;187(1):161-169.

14.

Alvarez B. , Ruiz C. , Chacon P. , Alvarez-Sabin J. , Matas M. 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. J Vasc Surg. 2004;40(3):469-475.

15.

Sapienza P. , di Marzo L. , Borrelli V. , et al. Basic fibroblast growth factor mediates carotid plaque instability through metalloproteinase-2 and -9 expression. Eur J Vasc Endovasc Surg. 2004;28(1):89-97.

16.

Molloy KJ , Thompson MM , Schwalbe EC , Bell PR , Naylor AR , Loftus IM Elevation in plasma MMP-9 following carotid endarterectomy is associated with particulate cerebral embolisation. Eur J Vasc Endovasc Surg . 2004;27(4):409-413.

17.

Bicknell CD , Peck D. , Lau NM , et al. The relationship between plasma MMP-1, -7, -8 and -13 levels and embolic potential during carotid endoluminal intervention . Eur J Vasc Endovasc Surg. 2004;28(5):500-507.

18.

Loftus IM , Naylor AR , Bell PR , Thompson MM. Plasma MMP-9 - a marker of carotid plaque instability. Eur J Vasc Endovasc Surg. 2001;21(1):17-21.

19.

Akoberg AK Understanding diagnostic tests 3: receiver operating characteristic curves . Acta Paediatrica. 2007;96(5):644-647.

20.

Kunz J. Matrix metalloproteinases and atherogenesis in dependence of age. Gerontology. 2007;53(2): 63-73.

21.

Wight TN , Merrilees MJ Proteoglycans in atherosclerosis and restenosis: key roles for versican. Circ Res. 2004;94(9):1158-1167.

22.

Heider P. , Poppert H. , Wolf O. , et al. Fibrinogen and high-sensitive C-reactive protein as serological predictors for perioperative cerebral microembolic lesions after carotid endarterectomy . J Vasc Surg. 2007;46(3):449-454.