Background: There is a growing amount of evidence suggesting that the composition of carotid atherosclerotic plaques may be of clinical relevance. Yet, little is known on the coexistence of potentially vulnerable and stabilizing components within asymptomatic plaques. Therefore, in this study we set out to investigate the coexistence of intraplaque calcification, hemorrhage and lipid core within the carotid artery using a multi-modality imaging approach. Methods: In 329 subjects from the population-based Rotterdam Study, all with ultrasound-confirmed carotid wall thickening, we performed a multi-detector CT and a high-resolution MRI of the carotid artery bifurcation at both sides. On the CT examinations, we quantified the volume of intraplaque calcification, and using the MRI examinations we rated the presence of intraplaque hemorrhage and of lipid core. In total, we investigated 611 carotid arteries with plaques. With logistic regression models we investigated the relationship of calcification volume - as a potential stabilizing component - with the presence of potential vulnerable components (intraplaque hemorrhage and lipid core) within each carotid plaque. We adjusted all analyses for age, sex and maximal plaque thickness. Next, we stratified on degree of stenosis (≤ or >30%) to evaluate effect modification by atherosclerotic burden. Results: We found that a larger calcification volume was associated with a higher prevalence of intraplaque hemorrhage, and a lower prevalence of lipid core (fully-adjusted odds ratio (OR) per standard deviation (SD) increase in calcification volume: 2.04 (95% confidence intervals (CI): 1.49; 2.78) and 0.72 (95% CI: 0.58; 0.90), respectively). Stratification on the degree of stenosis showed no difference in the association between calcification volume and hemorrhage over strata, while the relationship between a larger calcification volume and a lower prevalence of lipid seemed more pronounced in persons with a high degree of stenosis. Conclusions: In this population-based setting, we found that there is a complex relationship between calcification, intraplaque hemorrhage and lipid core within the carotid atherosclerotic plaque. Plaques with a higher load of calcification contain more often hemorrhagic components, but less often lipid core. Our results suggest that both in small and large plaques, intraplaque calcification may not be a stabilizing factor per se. These findings create an urge for conducting prospective studies investigating the interrelation of these different plaque components with regard to future cerebrovascular events.

1.
Libby P, Ridker PM, Hansson GK: Progress and challenges in translating the biology of atherosclerosis. Nature 2011;473:317-325.
2.
Lusis AJ: Atherosclerosis. Nature 2000;407:233-241.
3.
Donnan GA, Fisher M, Macleod M, Davis SM: Stroke. Lancet 2008;371:1612-1623.
4.
Owen DR, Lindsay AC, Choudhury RP, Fayad ZA: Imaging of atherosclerosis. Annu Rev Med 2011;62:25-40.
5.
Polak JF, Pencina MJ, Pencina KM, O'Donnell CJ, Wolf PA, D'Agostino RB Sr: Carotid-wall intima-media thickness and cardiovascular events. N Engl J Med 2011;365:213-221.
6.
Naghavi M, Falk E, Hecht HS, Jamieson MJ, Kaul S, Berman D, Fayad Z, Budoff MJ, Rumberger J, Naqvi TZ, Shaw LJ, Faergeman O, Cohn J, Bahr R, Koenig W, Demirovic J, Arking D, Herrera VL, Badimon J, Goldstein JA, Rudy Y, Airaksinen J, Schwartz RS, Riley WA, Mendes RA, Douglas P, Shah PK: From vulnerable plaque to vulnerable patient - part III: executive summary of the screening for heart attack prevention and education (SHAPE) task force report. Am J Cardiol 2006;98:2H-15H.
7.
Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS, de Korte CL, Aikawa M, Airaksinen KE, Assmann G, Becker CR, Chesebro JH, Farb A, Galis ZS, Jackson C, Jang IK, Koenig W, Lodder RA, March K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A, Boerwinkle E, Ballantyne C, Insull W Jr, Schwartz RS, Vogel R, Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT: From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part II. Circulation 2003;108:1772-1778.
8.
Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS, de Korte CL, Aikawa M, Juhani Airaksinen KE, Assmann G, Becker CR, Chesebro JH, Farb A, Galis ZS, Jackson C, Jang IK, Koenig W, Lodder RA, March K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A, Boerwinkle E, Ballantyne C, Insull W Jr, Schwartz RS, Vogel R, Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT: From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part I. Circulation 2003;108:1664-1672.
9.
Alsheikh-Ali AA, Kitsios GD, Balk EM, Lau J, Ip S: The vulnerable atherosclerotic plaque: scope of the literature. Ann Intern Med 2010;153:387-395.
10.
Nandalur KR, Baskurt E, Hagspiel KD, Phillips CD, Kramer CM: Calcified carotid atherosclerotic plaque is associated less with ischemic symptoms than is noncalcified plaque on MDCT. AJR Am J Roentgenol 2005;184:295-298.
11.
Ulzheimer S, Kalender WA: Assessment of calcium scoring performance in cardiac computed tomography. Eur Radiol 2003;13:484-497.
12.
Kwee RM: Systematic review on the association between calcification in carotid plaques and clinical ischemic symptoms. J Vasc Surg 2010;51:1015-1025.
13.
van den Bouwhuijsen QJ, Vernooij MW, Hofman A, Krestin GP, van der Lugt A, Witteman JC: Determinants of magnetic resonance imaging detected carotid plaque components: the Rotterdam study. Eur Heart J 2012;33:221-229.
14.
Allison MA, Criqui MH, Wright CM: Patterns and risk factors for systemic calcified atherosclerosis. Arterioscler Thromb Vasc Biol 2004;24:331-336.
15.
Odink AE, van der Lugt A, Hofman A, Hunink MG, Breteler MM, Krestin GP, Witteman JC: Association between calcification in the coronary arteries, aortic arch and carotid arteries: the Rotterdam study. Atherosclerosis 2007;193:408-413.
16.
Wolff T, Guirguis-Blake J, Miller T, Gillespie M, Harris R: Screening for carotid artery stenosis: an update of the evidence for the U.S. preventive services task force. Ann Intern Med 2007;147:860-870.
17.
Hofman A, van Duijn CM, Franco OH, Ikram MA, Janssen HL, Klaver CC, Kuipers EJ, Nijsten TE, Stricker BH, Tiemeier H, Uitterlinden AG, Vernooij MW, Witteman JC: The Rotterdam Study: 2012 objectives and design update. Eur J Epidemiol 2011;26:657-686.
18.
Bos D, Portegies ML, van der Lugt A, Bos MJ, Koudstaal PJ, Hofman A, Krestin GP, Franco OH, Vernooij MW, Ikram MA: Intracranial carotid artery atherosclerosis and the risk of stroke in whites: the Rotterdam study. JAMA Neurol 2014;71:405-411.
19.
Cai J, Hatsukami TS, Ferguson MS, Kerwin WS, Saam T, Chu B, Takaya N, Polissar NL, Yuan C: In vivo quantitative measurement of intact fibrous cap and lipid-rich necrotic core size in atherosclerotic carotid plaque: comparison of high-resolution, contrast-enhanced magnetic resonance imaging and histology. Circulation 2005;112:3437-3444.
20.
Cappendijk VC, Cleutjens KB, Kessels AG, Heeneman S, Schurink GW, Welten RJ, Mess WH, Daemen MJ, van Engelshoven JM, Kooi ME: Assessment of human atherosclerotic carotid plaque components with multisequence MR imaging: initial experience. Radiology 2005;234:487-492.
21.
Yuan C, Mitsumori LM, Beach KW, Maravilla KR: Carotid atherosclerotic plaque: noninvasive MR characterization and identification of vulnerable lesions. Radiology 2001;221:285-299.
22.
Saam T, Ferguson MS, Yarnykh VL, Takaya N, Xu D, Polissar NL, Hatsukami TS, Yuan C: Quantitative evaluation of carotid plaque composition by in vivo MRI. Arterioscler Thromb Vasc Biol 2005;25:234-239.
23.
Sun J, Underhill HR, Hippe DS, Xue Y, Yuan C, Hatsukami TS: Sustained acceleration in carotid atherosclerotic plaque progression with intraplaque hemorrhage: a long-term time course study. JACC Cardiovasc Imaging 2012;5:798-804.
24.
van Gils MJ, Bodde MC, Cremers LG, Dippel DW, van der Lugt A: Determinants of calcification growth in atherosclerotic carotid arteries; a serial multi-detector CT angiography study. Atherosclerosis 2013;227:95-99.
25.
van Gils MJ, Vukadinovic D, van Dijk AC, Dippel DW, Niessen WJ, van der Lugt A: Carotid atherosclerotic plaque progression and change in plaque composition over time: a 5-year follow-up study using serial CT angiography. AJNR Am J Neuroradiol 2012;33:1267-1273.
26.
Hellings WE, Peeters W, Moll FL, Piers SR, van Setten J, Van der Spek PJ, de Vries JP, Seldenrijk KA, De Bruin PC, Vink A, Velema E, de Kleijn DP, Pasterkamp G: Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: a prognostic study. Circulation 2010;121:1941-1950.
27.
Abedin M, Tintut Y, Demer LL: Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol 2004;24:1161-1170.
28.
Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R: Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol 2010;30:1282-1292.
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