Subclinical Carotid Atherosclerosis: Short-term Natural History of Lipid-rich Necrotic Core—A Multicenter Study with MR Imaging

Published Online:https://doi.org/10.1148/radiol.13121702

By using results from the placebo arm of a multicenter clinical trial with MR imaging of the carotid artery, lipid-rich necrotic core regression during a short follow-up period was observed, and intraplaque hemorrhage was identified to be associated with lipid-rich necrotic core progression.

Purpose

To use magnetic resonance (MR) imaging to examine the short-term (6 months) natural history of the lipid-rich necrotic core (LRNC) in carotid artery plaques by examining the placebo group of a multicenter clinical trial.

Materials and Methods

Study procedures and consent forms were approved by the institutional review board for this HIPAA-compliant study. Written informed consent was obtained for all enrolled subjects. Subjects in the placebo group of a multicenter clinical trial who showed LRNC at screening MR imaging had a follow-up MR imaging examination after 6 months. Lumen and wall volumes and LRNC volume and percentage were measured on images from both examinations by readers who were blinded to the time sequence. Plaque progression was calculated as annualized change in common coverage by using the carotid artery bifurcation as a landmark. Associations of clinical and imaging variables with LRNC progression were examined by using linear regression analysis.

Results

Fifty-nine of 73 (81%) subjects completed the study, with a mean interval ± standard deviation of 6.9 months ± 1.0. The mean progression rates per year ± standard deviation of LRNC volume and percentage were −5.2 mm3 ± 34.3 (P = .249) and −1.74% ± 6.27% (P = .038), respectively. Of the clinical and imaging variables examined, presence of intraplaque hemorrhage (IPH) was significantly associated with LRNC progression (P = .001). Plaques with IPH had increased LRNC volume per year (62.9 mm3 ± 46.2 vs −8.8 mm3 ± 29.9, P < .001) and percentage per year (3.67% ± 1.85% vs −2.03% ± 6.30%, P = .126) compared with those without IPH. Spearman correlation analysis showed that change in LRNC positively correlated with change in wall volume (ρ = 0.60, P < .001), but not with change in lumen volume (ρ = −0.17, P = .201).

Conclusion

Serial MR imaging of the carotid artery allowed observation of changes in LRNC over a short follow-up period and demonstrated the complexity of plaque progression patterns related to tissue composition. LRNC progression may be influenced not only by clinical characteristics, but also and to a large extent by plaque characteristics such as IPH.

© RSNA, 2013

Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13121702/-/DC1

References

  • 1 Nicholls SJ, Hsu A, Wolski K, et al.. Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome. J Am Coll Cardiol 2010;55(21):2399–2407.
  • 2 Stone GW, Maehara A, Lansky AJ, et al.. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011;364(3):226–235.
  • 3 Underhill HR, Yuan C, Yarnykh VL, et al.. Arterial remodeling in [corrected] subclinical carotid artery disease. JACC Cardiovasc Imaging 2009;2(12):1381–1389.
  • 4 DeFilippis AP, Blaha MJ, Ndumele CE, et al.. The association of Framingham and Reynolds risk scores with incidence and progression of coronary artery calcification in MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2011;58(20):2076–2083.
  • 5 Cannon CP, Braunwald E, McCabe CH, et al.. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350(15):1495–1504.
  • 6 Nissen SE, Tuzcu EM, Schoenhagen P, et al.. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291(9):1071–1080.
  • 7 Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987;316(22):1371–1375.
  • 8 Von Birgelen C, Hartmann M, Mintz GS, et al.. Spectrum of remodeling behavior observed with serial long-term (>/ = 12 months) follow-up intravascular ultrasound studies in left main coronary arteries. Am J Cardiol 2004;93(9):1107–1113.
  • 9 Serruys PW, García-García HM, Buszman P, et al.. Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 2008;118(11):1172–1182.
  • 10 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(7):1267–1273.
  • 11 Cai JM, Hatsukami TS, Ferguson MS, et al.. 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(22):3437–3444.
  • 12 Takaya N, Cai JM, Ferguson MS, et al.. Intra- and interreader reproducibility of magnetic resonance imaging for quantifying the lipid-rich necrotic core is improved with gadolinium contrast enhancement. J Magn Reson Imaging 2006;24(1):203–210.
  • 13 Takaya N, Yuan C, Chu BC, et al.. Presence of intraplaque hemorrhage stimulates progression of carotid atherosclerotic plaques: a high-resolution magnetic resonance imaging study. Circulation 2005;111(21):2768–2775.
  • 14 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(8):798–804.
  • 15 Boussel L, Arora S, Rapp J, et al.. Atherosclerotic plaque progression in carotid arteries: monitoring with high-spatial-resolution MR imaging—multicenter trial. Radiology 2009;252(3):789–796.
  • 16 Corti R, Fayad ZA, Fuster V, et al.. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation 2001;104(3):249–252.
  • 17 Lee JM, Wiesmann F, Shirodaria C, et al.. Early changes in arterial structure and function following statin initiation: quantification by magnetic resonance imaging. Atherosclerosis 2008;197(2):951–958.
  • 18 Corti R, Fuster V, Fayad ZA, et al.. Effects of aggressive versus conventional lipid-lowering therapy by simvastatin on human atherosclerotic lesions: a prospective, randomized, double-blind trial with high-resolution magnetic resonance imaging. J Am Coll Cardiol 2005;46(1):106–112.
  • 19 Lee JM, Robson MD, Yu LM, et al.. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol 2009;54(19):1787–1794.
  • 20 Corti R, Fuster V, Fayad ZA, et al.. Lipid lowering by simvastatin induces regression of human atherosclerotic lesions: two years’ follow-up by high-resolution noninvasive magnetic resonance imaging. Circulation 2002;106(23):2884–2887.
  • 21 Underhill HR, Yuan C, Zhao XQ, et al.. Effect of rosuvastatin therapy on carotid plaque morphology and composition in moderately hypercholesterolemic patients: a high-resolution magnetic resonance imaging trial. Am Heart J 2008;155(3):584.e1–e8.
  • 22 Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 2006;80(6):565–581.
  • 23 Li F, Yarnykh VL, Hatsukami TS, et al.. Scan-rescan reproducibility of carotid atherosclerotic plaque morphology and tissue composition measurements using multicontrast MRI at 3T. J Magn Reson Imaging 2010;31(1):168–176.
  • 24 Kerwin WS, Xu D, Liu F, et al.. Magnetic resonance imaging of carotid atherosclerosis: plaque analysis. Top Magn Reson Imaging 2007;18(5):371–378.
  • 25 Saam T, Kerwin WS, Chu BC, et al.. Sample size calculation for clinical trials using magnetic resonance imaging for the quantitative assessment of carotid atherosclerosis. J Cardiovasc Magn Reson 2005;7(5):799–808.
  • 26 Wagenknecht L, Wasserman B, Chambless L, et al.. Correlates of carotid plaque presence and composition as measured by MRI: the Atherosclerosis Risk in Communities Study. Circ Cardiovasc Imaging 2009;2(4):314–322.
  • 27 Yuan C, Mitsumori LM, Ferguson MS, et al.. In vivo accuracy of multispectral magnetic resonance imaging for identifying lipid-rich necrotic cores and intraplaque hemorrhage in advanced human carotid plaques. Circulation 2001;104(17):2051–2056.
  • 28 Saam T, Ferguson MS, Yarnykh VL, et al.. Quantitative evaluation of carotid plaque composition by in vivo MRI. Arterioscler Thromb Vasc Biol 2005;25(1):234–239.
  • 29 Zhao XQ, Dong L, Hatsukami T, et al.. MR imaging of carotid plaque composition during lipid-lowering therapy a prospective assessment of effect and time course. JACC Cardiovasc Imaging 2011;4(9):977–986.
  • 30 Pinheiro JC, Bates DM. Mixed-effects models in S and S-PLUS. New York, NY: Springer, 2000.
  • 31 Lima JA, Desai MY, Steen H, Warren WP, Gautam S, Lai S. Statin-induced cholesterol lowering and plaque regression after 6 months of magnetic resonance imaging-monitored therapy. Circulation 2004;110(16):2336–2341.
  • 32 Yonemura A, Momiyama Y, Fayad ZA, et al.. Effect of lipid-lowering therapy with atorvastatin on atherosclerotic aortic plaques detected by noninvasive magnetic resonance imaging. J Am Coll Cardiol 2005;45(5):733–742.
  • 33 Fayad ZA, Mani V, Woodward M, et al.. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet 2011;378(9802):1547–1559.
  • 34 Rodriguez-Granillo GA, Serruys PW, McFadden EP, et al.. First-in-man prospective evaluation of temporal changes in coronary plaque composition by in vivo intravascular ultrasound radiofrequency data analysis: an Integrated Biomarker and Imaging Study (IBIS) substudy. EuroIntervention 2005;1(3):282–288.
  • 35 Miyauchi K, Takaya N, Hirose T, et al.. Rationale and design of the carotid plaque in human for all evaluations with aggressive rosuvastatin therapy (CHALLENGER trial): evaluation by magnetic resonance imaging. Circ J 2009;73(1):111–115.
  • 36 Wasserman BA, Sharrett AR, Lai S, et al.. Risk factor associations with the presence of a lipid core in carotid plaque of asymptomatic individuals using high-resolution MRI: the multi-ethnic study of atherosclerosis (MESA). Stroke 2008;39(2):329–335.
  • 37 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(2):221–229.
  • 38 Yuan C, Kerwin WS, Ferguson MS, et al.. Contrast-enhanced high resolution MRI for atherosclerotic carotid artery tissue characterization. J Magn Reson Imaging 2002;15(1):62–67.
  • 39 Wasserman BA, Smith WI, Trout HH, Cannon RO, Balaban RS, Arai AE. Carotid artery atherosclerosis: in vivo morphologic characterization with gadolinium-enhanced double-oblique MR imaging initial results. Radiology 2002;223(2):566–573.
  • 40 Toussaint JF, LaMuraglia GM, Southern JF, Fuster V, Kantor HL. Magnetic resonance images lipid, fibrous, calcified, hemorrhagic, and thrombotic components of human atherosclerosis in vivo. Circulation 1996;94(5):932–938.
  • 41 Trivedi RA, U-King-Im JM, Graves MJ, et al.. MRI-derived measurements of fibrous-cap and lipid-core thickness: the potential for identifying vulnerable carotid plaques in vivo. Neuroradiology 2004;46(9):738–743.

Article History

Received July 30, 2012; revision requested September 14; revision received January 2, 2013; accepted January 10; final version accepted January 14.
Published online: July 2013
Published in print: July 2013