CT imaging detects markers of vulnerable carotid plaque

Stroke remains a leading cause of death in the U.S. and is the principal medical cause of long-term disability, with 780,000 new or recurrent strokes occurring annually.¹ Ischemic strokes related to carotid atherosclerotic disease make up almost 30% of the total.

Luminal narrowing is the standard parameter used to report the extent and severity of carotid artery stenosis due to atherosclerosis. The widespread use of this measure is based primarily on the results of several randomized clinical trials that showed a reduction in the risk of ischemic stroke in patients with luminal stenosis of ≥50% (assessed on conventional angiograms) after carotid endarterectomy compared with medical treatment alone.^2-4

While those patients with ≥ 50% carotid stenosis, however, have a higher individual risk of developing a stroke, they represent fewer than 5% of patients. Most stroke happens in patients with < 50% carotid stenosis, who represent a large proportion of the general population (70% in men and 60% in women over 64 years of age).^5,6 In patients with < 50% carotid stenosis, assessment of the lumen provides limited insight into the associated risk of stroke.²

Better stratification of patients with

VULNERABLE PLAQUE

The term vulnerable plaque has been used to describe thrombosis-prone plaques that have high probability of undergoing rapid progression, with subsequent rupture and embolization, even in the absence of significant luminal narrowing.³ A number of carotid plaque morphological features have been suggested as potential markers of vulnerable plaque, and these are possibly associated with an increased risk of stroke. The most studied is common carotid artery intima-media thickness.^7,8

Embolic phenomena have been associated as well with thinning and subsequent ulceration of the fibrous cap on the surface of atherosclerotic plaque, resulting in release into the parent vessel of necrotic lipoid debris from the plaque substance, especially in the case of a high plaque lipid content.^4-11 Several studies have established a correlation of plaque ulceration with clinical presentation, outcome, and prognosis,^12,13 whereas calcifications appear to be protective.^14,15

These carotid wall features have been studied mainly using ultrasound^16-33 and MRI.^34-37 Although CT angiography is a well-established technique frequently used to assess the presence and degree of carotid stenosis, very few studies have evaluated characteristics of the carotid wall with CT.

Previous studies that have explored CT angiography as a method to image carotid atherosclerotic plaques were performed using older-generation single-slice CT scanners. These studies usually focused on only one component of the carotid wall, such as calcium.

CT OF CAROTID

ATHEROSCLEROTIC PLAQUES

We recently performed a prospective study to evaluate the ability of modern multislice CTA to assess the composition of carotid artery plaques, using histology as the gold standard.38 We enrolled eight patients with transient ischemic attacks scheduled to undergo carotid CTA and endarterectomy. Endarterectomy was performed according to a special en bloc technique. An ex vivo microCT study of each endarterectomy specimen was obtained, followed by histologic examination.

A systematic comparison of CTA images with histologic sections and microCT images was performed to determine the CT attenuation associated with each component of the plaques. The pathologist outlined and labeled the regions corresponding to connective tissue, lipid-rich necrotic core, hemorrhage, and calcifications on the corresponding microCT images. This allowed calculation of the average Hounsfield density of each plaque component.

A computer algorithm that was subsequently developed automatically identifies the components of the carotid atherosclerotic plaques, based on the density of each pixel. After segmenting the inner and outer contours of the carotid artery wall from the in vivo CTA data sets, this automated classifier algorithm created a color overlay that displayed the composition of the carotid wall for each CTA image (see figure). A neuroradiologist's reading of this color overlay was compared with the pathologist's interpretation of the carotid plaque characteristics within the histologic slides.

We observed an overall 72.6% agreement in carotid plaque characterization between CTA and histologic examination. Although CTA showed perfect concordance for calcifications, it had more difficulty in identifying lipid-rich necrotic core, connective tissue, and hemorrhage because of the relative overlap in their Hounsfield densities. CTA performed well, however, in detecting large lipid cores, large hemorrhages, and ulcerations, and it was also effective in measuring fibrous cap thickness.

This study provided proof of principle that the composition of atherosclerotic plaques determined by CTA accurately reflects composition of the lesion as defined by histologic examination. Compared with previous studies, this study was unique in its use of modern multislice CT scanners with rapid acquisition, no motion artifact, and better contrast profiles and enhancement. Further, automated computer analysis was used instead of observer interpretation to identify the different components of the plaque. Automated classifier algorithms, such as the one presented in this study, may improve reproducibility in characterization of plaques and may be of interest in longitudinal studies of progression of atherosclerotic disease.

CLINICAL RELEVANCE

Using the standardized computerized assessment of CTA studies described above, we performed a retrospective cross-sectional study to identify the CT features of carotid atherosclerotic plaques that are significantly associated with the occurrence of ischemic stroke.³⁹ We identified 136 consecutive patients admitted to our emergency department who had undergone CTA to evaluate their carotid arteries. These CTA studies were processed automatically using the custom automated algorithm.

A neuroradiologist reviewed the CT studies of the brain parenchyma obtained at baseline and the brain imaging studies obtained within the first week after the baseline CT for the presence or absence of an acute infarct and its distribution (unilateral or bilateral, single or multiple vascular territories, and location of vascular

territory). The neuroradiologist also reviewed the intracranial portion of the baseline CTA of the carotid arteries for the degree of completeness of the circle of Willis. Based on the brain CT or MRI findings and the anatomy of the circle of Willis, the neuroradiologist decided whether the distribution of an acute infarct was consistent with a carotid origin.

Patients were categorized into acute carotid stroke and nonacute carotid stroke groups independent of carotid wall CT features, using the Causative Classification System for Ischemic Stroke,40 which includes the neuroradiologist's review of the imaging studies of the brain parenchyma and of the degree of carotid stenosis, and charted test results (such as ECG and Holter). Univariate followed by multivariate analyses were used to build models to differentiate between acute and nonacute carotid stroke patients (see table), and to differentiate between the infarct and unaffected sides in the acute carotid stroke patients.

We found that an increased risk of stroke was associated with an increased carotid wall volume, thinner fibrous cap, higher number of lipid clusters within the carotid wall, and location of lipid clusters closer to the lumen. The number of calcium clusters within the carotid wall was a protective factor. These observations mirror the current understanding as to how a carotid plaque might rupture and cause an embolic stroke. Embolic phenomena have been previously reported as being associated with thinning and subsequent ulceration of the fibrous cap on the surface of the atherosclerotic plaque, resulting in release of necrotic lipid debris from the plaque substance into the parent vessel, especially in the case of high lipid content.

FUTURE STEPS

The originality of our research lies in the use of CT, routinely used to evaluate the degree of luminal narrowing, to assess the carotid artery wall. In order to characterize carotid wall features other than calcium from CT data, we developed an automated classifier computer algorithm and validated it against histological examination. Our work using CT is not intended to detract from other imaging techniques.

Ultrasound is noninvasive, can be performed at bedside, and gives accurate assessment of the carotid intima-media thickness. MRI, with appro¬priate sequences, affords unmatched tissue contrast between the different plaque components. CT is obtained as part of the standard of care, however, for numerous patients with cerebro¬vascular disease, as a result of its wide availability and the short duration of CT studies.

Our results show that the interpretation of CT studies of the carotid arteries should not be limited to the evaluation of the degree of luminal narrowing but should also include assessment of the carotid wall. The automated algorithm approach af¬fords a standardized 3D volumetric assessment of the carotid artery wall. Longitudinal studies are needed to demonstrate that the carotid plaque CT features we identified (wall thickness, fibrous cap thickness, number and location of lipid clusters, and number of calcium clusters) help prospectively predict the risk of stroke and identify patients who require stenting/endarterectomy, especially among those with

References

1. American Heart Association/American Stroke Association. Heart disease and stroke statistics--2006 update. Circulation 2006:113e85-e151.

2. Worthley SG, Helft G, Fuster V, et al. Serial in vivo MRI documents arterial remodeling in experimental atherosclerosis. Circulation 2000;101:586-589.

3. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 2003:1664-1672.

4. Bassiouny HS, Sakaguchi Y, Mikucki SA, et al. Juxtalumenal location of plaque necrosis and neoformation in symptomatic carotid stenosis. J Vasc Surg 1997;26:585-594.

5. Biasi GM, Froio A, Diethrich EB, et al. Carotid plaque echolucency increases the risk of stroke in carotid stenting: the Imaging in Carotid Angioplasty and Risk of Stroke (ICAROS) study. Circulation 2004;110:756-762.

6. Carr S, Farb A, Pearce WH, Virmani R, Yao JS. Atherosclerotic plaque rupture in symptomatic carotid artery stenosis. J Vasc Surg 1996;23:755-765; discussion 765-756.

7. Eliasziw M, Streifler JY, Fox AJ, et al. Significance of plaque ulceration in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial. Stroke 1994;25:304-308.

8. Gronholdt ML. Ultrasound and lipoproteins as predictors of lipid-rich, rupture-prone plaques in the carotid artery. Arterioscler Thromb Vasc Biol 1999;19:2-13.

9. Cinat M, Lane CT, Pham H, et al. Helical CT angiography in the preoperative evaluation of carotid artery stenosis. J Vasc Surg 1998;28:290-300.

10. el-Barghouty N, Nicolaides A, Bahal V, et al. The identification of the high risk carotid plaque. Eur J Vasc Endovasc Surg 1996;11:470-478.

11. Golledge J, Greenhalgh RM, Davies AH. The symptomatic carotid plaque. Stroke 2000;31:774-781.

12. Prabhakaran S, Rundek T, Ramas R, et al. Carotid plaque surface irregularity predicts ischemic stroke: the northern Manhattan study. Stroke 2006;37:2696-2701.

13. Rothwell PM, Gibson R, Warlow CP. Interrelation between plaque surface morphology and degree of stenosis on carotid angiograms and the risk of ischemic stroke in patients with symptomatic carotid stenosis. On behalf of the European Carotid Surgery Trialists' Collaborative Group. Stroke 2000;31:615-621.

14. McKinney AM, Casey SO, Teksam M, et al. Carotid bifurcation calcium and correlation with percent stenosis

of the internal carotid artery on CT angiography. Neuroradiology 2005;47:1-9.

15. Nandalur KR, Hardie AD, Raghavan P, et al. Composition of the stable carotid plaque: insights from a multidetector computed tomography study of plaque volume. Stroke 2007;38:935-940.

16. Ebrahim S, Papacosta O, Whincup P, et al. Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke 1999;30:841-850.

17. O'Leary DH, Polak JF, Kronmal RA, et al. Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. The CHS Collaborative Research Group. Stroke 1992;23:1752-1760.

18. Touboul PJ, Elbaz A, Koller C, et al. Common carotid artery intima-media thickness and brain infarction: the Etude du Profil Genetique de l'Infarctus Cerebral (GENIC) case-control study. The GENIC Investigators. Circulation 2000;102:313-318.

19. Bonithon-Kopp C, Touboul PJ, Berr C, et al. Relation of intima-media thickness to atherosclerotic plaques in carotid arteries. The Vascular Aging (EVA) Study. Arterioscler Thromb Vasc Biol 1996;16:310-316.

20. Burke GL, Evans GW, Riley WA, et al. Arterial wall thickness is associated with prevalent cardiovascular disease

in middle-aged adults. The Atherosclerosis Risk in Communities (ARIC) Study. Stroke 1995;26:386-391.

21. Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987-1993. Am J Epidemiol 1997;146:483-494.

22. Hodis HN, Mack WJ, LaBree L, et al. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med 1998;128:262-269.

23. Salonen JT, Salonen R. Ultrasonographically assessed carotid morphology and the risk of coronary heart disease. Arterioscler Thromb 1991;11:1245-1249.

24. Bonithon-Kopp C, Scarabin PY, Taquet A, et al. Risk factors for early carotid atherosclerosis in middle-aged French women. Arterioscler Thromb 1991;11:966-972.

25. Zureik M, Touboul PJ, Bonithon-Kopp C, et al. Cross-sectional and 4-year longitudinal associations between brachial pulse pressure and common carotid intima-media thickness in a general population. The EVA study. Stroke 1999;30:550-555.

26. O'Leary DH, Polak JF, Kronmal RA, et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. NEJM 1999;340:14-22.

27. Pitt B, Byington RP, Furberg CD, et al. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT Investigators. Circulation 2000;102:1503-1510.

28. Zanchetti A, Bond MG, Hennig M, et al. Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclerosis: principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind, long-term trial. Circulation 2002;106:2422-2427.

29. MacMahon S, Sharpe N, Gamble G, et al. Effects of lowering average of below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID Atherosclerosis Substudy. LIPID Trial Research Group. Circulation 1998;97:1784-1790.

30. Smilde TJ, van Wissen S, Wollersheim H, et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP):

a prospective, randomised, double-blind trial. Lancet 2001;357:577-581.

31. Nathan DM, Lachin J, Cleary P, et al. Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. NEJM 2003;348:2294-2303.

32. Lorenz MW, von Kegler S, Steinmetz H, et al. Carotid intima-media thickening indicates a higher vascular risk across a wide age range: prospective data from the Carotid Atherosclerosis Progression Study (CAPS). Stroke 2006;37:87-92.

33. Mathiesen EB, Bonaa KH, Joakimsen O. Echolucent plaques are associated with high risk of ischemic cerebrovascular events in carotid stenosis: the tromso study. Circulation 2001;103:2171-2175.

34. Takaya N, Yuan C, Chu B, et al. Association between carotid plaque characteristics and subsequent ischemic cerebrovascular events: a prospective assessment with MRI--initial results. Stroke 2006;37:818-823.

35. Troyer A, Saloner D, Pan XM, et al. Major carotid plaque surface irregularities correlate with neurologic symptoms. J Vasc Surg 2002;35:741-747.

36. Yuan C, Zhang SX, Polissar NL, et al. Identification of fibrous cap rupture with magnetic resonance imaging is highly associated with recent transient ischemic attack or stroke. Circulation 2002;105:181-185.

37. Furie KL, Topcuoglu MA, Kelly PJ, et al. Asymptomatic Internal Carotid Artery Origin Stenosis. Curr Treat Options Cardiovasc Med 2001;3:441-447.

38. Wintermark M, Jawadi SS, Rapp JH, et al. High-resolution CT imaging of carotid artery atherosclerotic plaques. AJNR 2008;29:875-882.

39. Wintermark M, Arora S, Tong E, et al. Carotid plaque CT imaging in stroke and non-stroke patients. In publication.

40. Ay H, Furie KL, A S, et al. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol 2005;58:688-697.

Mr. Magge is a Doris Duke medical student, Mr. Sandeep is a research fellow, Dr. Soares is a research fellow, Mr. Lau is a research assistant, Ms. Tong is a medical student, and Dr. Wintermark is an assistant professor of radiology, all in the Neuro¬CardioVascular Imaging Lab of the radiology department at the University of California, San Francisco.