Multiple Biological Predictors for Vulnerable Carotid LesionsPelisek J.a · Rudelius M.b · Zepper P.c · Poppert H.c · Reeps C.a · Schuster T.d · Eckstein H.-H.a
Departments of aVascular Surgery, bPathology and cNeurology, and dInstitute of Epidemiology and Medical Statistics (IMSE), Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
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Background: In this study a multiscore analysis of various biomarkers including matrix metalloproteinases (MMPs), inflammatory factors and other clinical parameters was performed to establish a set of reliable biomarkers for improved detection of plaque instability in patients with advanced carotid stenosis. Methods: Study patients (n = 101) were classified as histologically stable (n = 37) or unstable (n = 64). Serum levels of MMP-1, -2, -3, -7, -8, -9, MMP inhibitors TIMP-1, -2, and inflammatory factors such as tumor necrosis factor (TNF-α), interleukin (IL)-1β, -6, -8, -10, and -12 were measured by ELISA assays. Multiscore analysis was performed using multiple receiver operating characteristics analysis and determination of appropriate cutoff values. Results: Circulating levels of MMP-1, -7, TIMP-1, TNF-α, and IL-8 were significantly enhanced in patients with unstable plaques compared to individuals with stable lesions, mean differences being 1.2 (p = 0.032), 2.5 (p = 0.004), 30.0 (p = 0.014), 1.3 (p = 0.047), and 2.2 (p = 0.033), respectively. The combination of MMP-1, -7, TIMP-1 and IL-8 demonstrated the highest positive predictive value of 89.4% and negative predictive value of 60.1% for patients correctly classified as individuals with unstable and stable carotid lesions by means of blood sample analysis. Conclusions: Multiple relevant biomarkers that play a decisive role in plaque instability can improve the correct determination of vulnerable carotid plaques in patients with advanced carotid artery stenosis.
© 2009 S. Karger AG, Basel
- Bamford J, Sandercock P, Dennis M, Burn J, Warlow C: Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 1991;337:1521–1526.
- Rothwell PM, Gutnikov SA, Warlow CP: Reanalysis of the final results of the European Carotid Surgery Trial. Stroke 2003;34:514–523.
- Virmani R, Burke AP, Farb A, Kolodgie FD: Pathology of the vulnerable plaque. J Am Coll Cardiol 2006;47:C13–C18.
- Chalela JA: Evaluating the carotid plaques: going beyond stenosis. Cerebrovasc Dis 2009;27(suppl 1):19–24.
- Wahlgren CM, Zheng W, Shaalan W, Tang J, Bassiouny HS: Human carotid plaque calcification and vulnerability: relationship between degree of plaque calcification, fibrous cap inflammatory gene expression and symptomatology. Cerebrovasc Dis 2009;27:193–200.
- Moreno PR, Purushothaman KR, Sirol M, Levy AP, Fuster V: Neovascularization in human atherosclerosis. Circulation 2006;113:2245–2252.
- Newby AC: Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev 2005;85:1–31.
- Sundström J, Vasan RS: Circulating biomarkers of extracellular matrix remodeling and risk of atherosclerotic events. Curr Opin Lipidol 2006;17:45–53.
- Ferri N, Paoletti R, Corsini A: Biomarkers for atherosclerosis: pathophysiological role and pharmacological modulation. Curr Opin Lipidol 2006;17:495–501.
- Lind L: Circulating markers of inflammation and atherosclerosis. Atherosclerosis 2003;169:203–214.
- Wu JT, Wu LL: Linking inflammation and atherogenesis: soluble markers identified for the detection of risk factors and for early risk assessment. Clin Chim Acta 2006;366:74–80.
- Takahashi W, Ohnuki T, Ohnuki Y, Kawada S, Takagi S: The role of high-sensitivity C-reactive protein in asymptomatic intra- and extracranial large artery diseases. Cerebrovasc Dis 2008;26:549–555.
- Borrelli V, di Marzo L, Sapienza P, Colasanti M, Moroni E, Cavallaro A: Role of platelet-derived growth factor and transforming growth factor beta1 in the regulation of metalloproteinase expressions. Surgery 2006;140:454–463.
- Turu MM, Krupinski J, Catena E, Rosell A, Montaner J, Alvarez-Sabin J, Cairols M, Badimon L: Intraplaque MMP-8 levels are increased in asymptomatic patients with carotid plaque progression on ultrasound. Atherosclerosis 2006;187:161–169.
- Alvarez B, Ruiz C, Chacon P, Alvarez-Sabin J, Matas M: Serum values of MMP-2 and MMP-9 as related to unstable plaque and inflammatory cells in patients with greater than 70% carotid artery stenosis. J Vasc Surg 2004;40:469–475.
- Sapienza P, di Marzo L, Borrelli V, Sterpetti AV, Mingoli A, Piagnerelli R, Cavallaro A: Basic fibroblast growth factor mediates carotid plaque instability through metalloproteinase-2 and -9 expression. Eur J Vasc Endovasc Surg 2004;28:89–97.
- 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;27:409–413.
- Bicknell CD, Peck D, Lau NM, Alkhamesi NA, Cowling MG, Clark MW, Jenkins MP, Wolfe JH, Darzi AW, Cheshire NJ: The relationship between plasma MMP-1, -7, -8 and -13 levels and embolic potential during carotid endoluminal intervention. Eur J Vasc Endovasc Surg 2004;28:500–507.
- Thakore AH, Guo CY, Larson MG, Corey D, Wang TJ, Vasan RS, D’Agostino RB Sr, Lipinska I, Keaney JF Jr, Benjamin EJ, O’Donnell CJ: Association of multiple inflammatory markers with carotid intimal medial thickness and stenosis (from the Framingham Heart Study). Am J Cardiol 2007;99:1598–1602.
Wang TJ, Gona P, Larson MG, Tofler GH, Levy D, Newton-Cheh C, Jacques PF, Rifai N, Benjamin EJ, D’Agostino RB, Vasan RS: Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med 200;355:2631–2639.
- Addabbo F, Mallamaci F, Leonardis D, Tripepi R, Tripepi G, Goligorsky MS, Zoccali C: Searching for biomarker patterns characterizing carotid atherosclerotic burden in patients with reduced renal function. Nephrol Dial Transplant 2007;22:3521–3526.
- Stary HC: Natural history and histological classification of atherosclerotic lesions: an update. Arterioscler Thromb Vasc Biol 2000;20:1177–1178.
- Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM: Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20:1262–1275.
Benjamini Y, Hochberg T: Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 1995;85:289–300.
- Dollery CM, Libby P: Atherosclerosis and proteinase activation. Cardiovasc Res 2006;69:625–635.
- Lemaitre V, D’Armiento J: Matrix metalloproteinases in development and disease. Birth Defects Res C Embryo Today 2006;78:1–10.
- Wu YW, Yang WS, Chen MF, Lee BC, Hung CS, Liu YC, Jeng JS, Huang PJ, Kao HL: High serum level of matrix metalloproteinase-1 and its rapid surge after intervention in patients with significant carotid atherosclerosis. J Formos Med Assoc 2008;107:93–98.
- Wight TN, Merrilees MJ: Proteoglycans in atherosclerosis and restenosis: key roles for versican. Circ Res 2004;94:1158–1167.
- Libby P, Sukhova G, Lee RT, Galis ZS: Cytokines regulate vascular functions related to stability of the atherosclerotic plaque. J Cardiovasc Pharmacol 1995;25(suppl 2):S9–S12.
- Ito T, Ikeda U: Inflammatory cytokines and cardiovascular disease. Curr Drug Targets Inflamm Allergy 2003;2:257–265.
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