carotid vulnerable lesions are related to accelerated recurrence for cerebral infarction

Original Investigations

Carotid Vulnerable Lesions Are Related toAccelerated Recurrence for Cerebral Infarction:

Magnetic Resonance Imaging Study1

Kai Lin, MS, Zhao-Qi Zhang, MD, Robert Detrano, MD, PhD, Biao Lu, MD, Zhan-Ming Fan, MD

Rationale and Objectives. We sought to test the hypothesis that magnetic resonance imaging (MRI)-defined vulnerableplaques correlate to accelerated reoccurrence of cerebrovascular events and to evaluate the potential use of MRI in sec-ondary prevention of ischemic stroke.

Materials and Methods. Fifty-three symptomatic participants were recruited from patients sustaining their second MRI-confirmed cerebral infarction. Nine participants were women and 44 were men; the mean age was 69.2 years (range,55�94 years). Patients were imaged within 7 days after the reoccurrence of cerebral infarction. The MRI diagnostic sig-nals defined a classification of lesion type. We compare the interval between two cerebral infarctions with plaque vulnera-bility defined by the MRI lesion type. We used a Cox proportional hazards model to calculate the relationship betweenvulnerable lesions and the interval of cerebral infarction, and we followed these patients for 180 days and compared therecurrent rate for the third-time cerebral infarction between patients with and without vulnerable plaque.

Results. The mean infarction recurrence interval for patients with vulnerable lesions was shorter than the mean intervalfor patients without vulnerable lesion (310.1 versus 1697.2, P� .001). In patients with recurrent cerebral infarction within1 year, vulnerable lesions were more frequently detected (76% versus 19%, P� .001). The patients with vulnerable le-sions had an 8.8-fold higher hazard risk (8.8; P� .001, 95% confidence interval, 3.9�19.7) than those without vulnerablelesions after adjustment for risk factors. For those with vulnerable plaque, the morbidity of third-time cerebral infarctionwas higher than those without (24% versus 3%, P � .023).

Conclusion. MRI-defined vulnerable lesions in carotid arteries are related to accelerated recurrent cerebral infarction andhigh recurrent rate. MRI demonstrates clinical value in the secondary prevention of cerebral infarction.

Key Words. Magnetic resonance imaging; atherosclerosis; carotid arteries; cerebral infarction.©
AUR, 2006
Stroke is a serious public health problem leading to deathand disability worldwide. Survival of stroke inclines withrecurrence. People sustaining a recurrent stroke havepoorer outcomes than those with a first-ever stroke (1,2).

Acad Radiol 2006; 13:1180–1186

1 From the Department of Radiology, Beijing Institute of Heart, Lung andBlood Vessel Diseases, and Beijing Anzhen Hospital, Anzhen Li, ChaoyangDistrict, Beijing 100029, China (K.L., Z.-Q.Z., B.L., Z.-M.F.); and the Divisionof Cardiology, Harbor UCLA Medical Center, 1124 Carson St., Bldg. E5,Torrance, CA 90502 (R.D.). Received May 26, 2006; accepted July 10,2006. Address correspondence to K.L.: e-mail: [email protected]

©
AUR, 2006doi:10.1016/j.acra.2006.07.004
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As an effective modality of diagnosis, magnetic resonanceimaging (MRI) has proved its superiority over computertomography (CT) in the analysis of ischemic cerebral le-sions because it can detect and discriminate new cerebralinfarction from former lesions (3).

Of the different causes of stroke, a large proportion ofstrokes may be caused by thromboembolism. This sug-gests that plaques resulting from thrombotic complicationsof atherosclerosis may grow to obstruct the arterial lumenor to disseminate material into the bloodstream, therebycausing ischemic stroke, mainly cerebral infarction. Theconcept of an unstable or vulnerable lesion of atheroscle-
rosis that may rupture and release thromboembolic mate-

Academic Radiology, Vol 13, No 10, October 2006 CAROTID VULNERABLE LESIONS

rial was postulated to the carotid arteries. Therefore, in-formation concerning the composition of the plaque mayenhance predictions of cerebral infarction risk. In order tomore accurately and quantity detect the contents ofplaque, high-resolution MRI has emerged as a promisingtechnique for atherosclerosis plaque imaging.

However, current research mainly focuses on identify-ing special contents of plaque with MRI. Whether plaqueMRI can offer enough information for treatment or prog-nosis determines its clinical value. To test the hypothesisof a vulnerable plaque relating to quick recurrence of ce-rebral infarction and to evaluate the potential use of MRIin the secondary prevention of stroke, we designed a pre-liminary test to analyze the relationship between carotidatherosclerotic plaques classified with MRI and intervalsof cerebral infarction.

MATERIALS AND METHODS

PatientsBetween November 2004 and October 2005, 53 symp-

tomatic disabled participants were recruited from patientssustaining a second-time MRI-confirmed cerebral infarc-tion. Of the 53 patients, 9 were women and 44 were men;the mean age was 69.2 years (range, 55�94 years). Thisstudy was approved by the local human studies commit-tee, and patients or their legal proxy gave written in-formed consent. Patients were excluded from the study ifthey had a cardiac valvular or rhythm disorder likely tobe associated with cardiogenic embolism; if they hadthrombi, if they had organ failure of the kidney, liver,heart, or lung or had cancer or cerebral tumor; or if theydid not have carotid images of good quality or cerebralinfarction that occurred twice and in the area of anteriorcirculation. Each of the patients had a medical historyavailable and had not received lipid-lowering treatmentfor at least 6 months.

Scanning ProtocolMRI was performed on a 1.5-T system with gradient

amplitude of 40 mT/m and a maximum slew rate of 200Tm/s (Sonata; Siemens Medical Systems, rlangen, Ger-many). A dedicated phased-array coil (Invivo, IGC, Peta-luma, CA) was used. The brain was imaged with aquadrature head coil (Siemens Medical Systems).

Patients were imaged within 7 days after reoccurrenceof cerebral infarction. Table 1 shows the imaging protocol
for carotid artery. First, a two-dimensional time-of-flight
(TOF) sequence of the carotid bifurcation was performed.The center of the bifurcation on the images were used toplan 11 consecutive axial 3-mm proton density-weightedimage (PDWI), T1-weighted image (T1WI), and T2-weighted image (T2WI) dark-blood, turbo spin-echo(TSE) sections with the carotid artery in the center of theimage. Each patient underwent MRI covering the bilateralcommon carotid artery and inner carotid artery about 2cm near the bifurcation. There were 22 slices in total.MRI of the brain consisted of T1WI, T2WI, fluid-attenu-ated inversion recovery (FLAIR), and diffusion-weightedimage (DWI). An apparent diffusion coefficient (ADC)map was constructed. Table 1 shows the scanning param-eter.

Definitions and AnalysesPrevious studies with 1.5-T units demonstrated that the

contents of each atherosclerosis lesion had its diagnosticsignal intensity (SI) in MRI. Fibrous cap, calcification,lipid or necrotic core, and hemorrhage are the main con-tents of plaque. Lipid core has a shorter T2 than that offibrous tissue, both in vitro (4) and in vivo (5). Therefore,lipid has relative lower SI on PDWI versus T2WI in com-parison to fibrous tissue. Acute and subacute mixed hem-orrhage had high SI on T1WI. Recent hemorrhage ap-pears as high signal intensity in both T1WI and TOF im-ages (6). The extended calcification of the plaque isreadily detected by MRI, showing local low SI on allcontrast-weighted images.

Using the classification of the American Heart Associ-ation (AHA) (7,8) as a template, Cai et al. (9) classifiedatherosclerosis lesion based on the current level of resolu-tion by MRI: types I and II are indistinguishable from thenear-normal carotid wall. Histologically, type III is char-acterized by a slight diffuse or eccentric thickening of thewall containing pools of extracellular lipid. In T1WI andPDWI, these pools appeared as focal, slightly high signals

Table 1MRI scanning parameter of carotid artery.

T1WI T2WI PDW

TR (ms) 810 1410 1410TE (ms) 14 42 14Field of view (mm) 120 � 120 120 � 120 120 � 120Matrix 256 � 256 256 � 256 256 � 256Slice thickness (mm) 3 3 3

in some cases. Histologically, types IV and V contain a

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LIN ET AL Academic Radiology, Vol 13, No 10, October 2006

lipid or necrotic core, which on MRI may have high SI oriso-SI on T1WI, high or iso-SI on PDWI, and varied SIon T2WI. Interpretation of SI was made with reference tothe immediately adjacent tissue, such as sternocleidomas-toid muscle. The extended calcification of the type VIIplaque is readily detected by MRI, showing irregular lowSI on all contrast-weighted images. Type VIII is a highlyfibrotic lesion that often displays moderate to severe ste-nosis.

Considering the complexity of tissue components andinterobserver of different contents (different observersmay have different opinions on identifying certain con-tents in the plaque), we chose a simple classification sys-tem that divided the lesions into two types based on sig-nal, for clinical convenience. Vulnerable lesion was ofeccentric shape and appeared to have an idiosyncraticheterogeneous signal. Corresponding to AHA types IV,V, and VI, the lesion might contain a large lipid core oran incomplete fibrous cap or hemorrhage signal. Whentypes IV, V, and VI were excluded, lesions containinghomogeneously thickened artery walls with or withoutcalcification signal were defined as stable lesion, referringto types I, II, III, VII, and VIII. We defined a vulnerablelesion when two consecutive slices matched the criteria.

Cerebral infarction was defined as hyperintense lesions(regions � 5 mm) with the signal intensity of cerebrospi-nal fluid that accompanies with neurosystem syndrome.T1WI and T2WI of the brain were analyzed for the pres-ence of cerebral infarction, and FLAIR and DWI se-quence were used to identify new lesions. In some acutecases, perfusion-weighted image (PWI) was applied.

Then, after a review of the patient’s hospital chartand contact with the patient’s physician, all patientswere screened for cerebrovascular risk factors, includ-ing hypertension (average blood pressure), hypercholes-terolemia, diabetes mellitus, and lipid-lowering treat-ment. Hypertension was diagnosed when the bloodpressure measured in the hospital was higher than160/95 mm Hg or the patient was taking antihyperten-sive agents. Diabetes mellitus was diagnosed if a pa-tient was using oral hypoglycemic agents or insulinand/or if the fasting blood glucose level in the hospitalexceeded 110 mg/dl. Hypercholesterolemia was diag-nosed if a patient was taking lipid-lowering agents(e.g., a statin drug) and/or if the serum cholesterollevel exceeded 230 mg/dl or the triglyceride level ex-ceeded 160 mg/dl. Then, the interval between two cere-
bral infarctions was determined.
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Follow-up StudyWe followed these patients for 6 months (180 days)

and compared the recurrent rate for the third-time cerebralinfarction between the patients with and without vulnera-ble plaque.

Statistical AnalysisStatistical analysis of the data was performed with the

software Statistical Package for Social Sciences (SPSS)version 10.0 (SPSS Inc., Chicago, IL). Different meanintervals of cerebral infarction were compared with anindependent t test. The �2 test was used to assess differ-ences between the prevalence of vulnerable lesions inpatients with intervals of longer than 1 year and less than1 year. The recurrence rate of third-time cerebral infarc-tion was also compared by �2 test. Because atherosclero-sis evolved slowly and no participant received lipid-low-ering therapy more than 6 months, it was justifiable toassert that lesion detected shortly after recurrence, the endof the interval, mainly reflected its general status in thecourse. Thus, the hazard risk (HR) of vulnerable lesioncould be evaluated in a Cox proportional hazards modelusing age, sex, diabetes mellitus, blood pressure, lipidserum levels, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as covariates. A value of P �

.05 was considered to indicate a statistically significantdifference. No adjustments for multiple comparisons weremade.

RESULTS

MRI and Plaque DescriptionMR images of the carotid artery were of good quality

in 53 patients. The range of interval of recurrent cerebralinfarction is 3�5157 days. Twenty-two patients had avulnerable lesion. Table 2 summarizes patient’s statuswith or without vulnerable lesion. The mean recurrenceinterval of patients with vulnerable lesion was 310.1 days,while the mean interval of patients without was 1697.2days. Sixteen of 21 patients who had recurrence in 1 year(365 days) had a vulnerable lesion. Only 6 of 32 patientswho reoccurred after 1 year had a vulnerable lesion. Ta-ble 3 summarizes the status of patients with recurrent ce-rebral infarction within 1 year and after 1 year. Figures 1and 2 show images of a typical vulnerable lesion. Figure
3 shows a vessel wall without a vulnerable lesion.


Relationship between Lesion Type and CerebralInfarction Interval

The mean recurrence interval of patients with vulnera-ble lesion was shorter than the mean interval of patientswithout vulnerable lesion (310.1 versus 1697.2, P �.001). In patients have a recurrent cerebral infarction at 1year (365 days), vulnerable lesion was more frequentlydetected (76% versus 19%, P � .001). The patients withvulnerable lesion had an 8.8-fold higher HR (P� .001;95% confidence interval [CI], 3.9�19.7) than those with-out after adjustment of risk factors.

Recurrence Rate of Cerebral Infarction betweenPatients with and without Vulnerable Plaque

One patient with vulnerable plaque did not recoverfrom his second cerebral infarction and died. All otherpatients survived for 180 days after the second cerebral

Table 2Interval of cerebral infarction of patients with and without a vu

Patients with avulnerable lesion

(n � 22)

Mean age (yr) 66.9 � 5.5Systolic pressure (mm Hg) 140.7 � 18.7Diastolic pressure (mm Hg) 88.2 � 9.8Mean blood glucose (mg/dl) 107.8 � 21.1Mean triglycerides (mg/dl) 171.0 � 82.7Mean cholesterol (mg/dl) 172.3 � 55.6Mean LDL (mg/dl) 118.6 � 33.6Mean HDL (mg/dl) 39.4 � 9.9Interval (days) 310.1

Table 3Prevalence of a vulnerable lesion in patients recurring within o

Patients withrecurrence within

year (n � 21)

Mean age (yr) 67.5 � 6.4Systolic pressure (mm Hg) 144.5 � 20.6Diastolic pressure (mm Hg) 91.4 � 10.2Mean blood glucose (mg/dl) 115.0 � 30.7Mean triglycerides 161.8 � 88.2Mean cholesterol (mg/dl) 169.1 � 56.8Mean LDL (mg/dl) 113.1 � 34.7Mean HDL (mg/dl) 40.0 � 10.5Prevalence of vulnerable lesion 16 (76%)

infarction. Among 21 patients with vulnerable plaque, 5

had a third-time cerebral infarction. Among 31 patientswithout vulnerable plaque, only 1 patient reoccurred (24%versus 3%, P � .023).

DISCUSSION

There is considerable knowledge about risk factors forfirst-ever stroke and a lack of knowledge about risk fac-tors for recurrent stroke, although recurrent stroke is com-mon. Some patients have recurrence several times. Lee etal. (10) showed that the median time to first stroke recur-rence was 255 days. The cumulative probability of firstrecurrence was 5.1% at 6 months, 8.4% at 1 year, and19.8% at 4 years. Many risk factors have implications forplanning secondary prevention strategies. Muir (11) pre-sented recent evidence that reduction of blood pressureand cholesterol, regardless of baseline values, has un-

ble lesion.

Patients withouta vulnerable

lesion (n � 31) Significance (P)

70.9 � 9.0 .069146.8 � 12.0 .15792.1 � 10.1 .167

107.8 � 21.1 .590153.8 � 59.9 .396180.7 � 32.9 .525123.8 � 33.9 .58440.2 � 8.1 .738

1697.2 .000

r 1 year.

Patients withrecurrence after 1

year (n � 32) Significance (P)

70.3 � 8.7 .213144.1 � 10.8 .90789.8 � 10.1 .592

107.2 � 26.0 .324159.4 � 56.3 .946183.4 � 34.2 .309127.2 � 32.1 .13539.7 � 7.7 .895

6 (19%) .000

lnera

r afte

1

equivocal benefit in secondary prevention.

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) PD


Both as markers of generalized atherosclerosis andsources of thromboemboli, carotid plaques increase therisk of cerebral infarction. Plaques increase the risk ofinfarctions in the anterior circulation more often than inthe posterior circulation (12). Risk of thromboembolicstroke is thought to be better reflected by carotid plaquecomposition than by luminal stenosis. The compositionand morphology of the atherosclerotic plaque at the ca-rotid artery are considered important determinants of cere-brovascular events.

Traditionally, measurement of vessel stenosis by using

Figure 1. A 55-year-old patient sustained new cerebral infarctionlumen is not stenosis. High-signal material within the left commona type VI lesion, a hemorrhage (high SI on T1WI, PDWI, and T2WI)PDW). (a) T2WI. (b) PDW. (c) T1WI.

Figure 2. A 65-year-old patient sustained a new cerebral infarctiotery was stenotic. An eccentrically shaped plaque was found in thcontent varies greatly. It is considered a type V lesion. (a) T2WI. (b

ultrasonography or angiography remains the principal

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method for determining the severity of carotid atheroscle-rosis. B-mode ultrasonography is a modality to measureintima-media thickness (IMT) and to determine whetherthere is a plaque. Some follow-up research had demon-strated carotid IMT relates to morbidity of cerebral infarc-tion (13). However, there were many conflicts and lessclear findings based on this classification in patients. TheNorth American Symptomatic Carotid EndarterectomyTrial and European Carotid Surgery Trial have providedevidence of the benefit of carotid endarterectomy in thosesymptomatic patients, with a recent transient ischemic

ays after his first stroke. On multicontrast-weighted MR images,tid artery wall was covered by a low-signal layer. It is consideredred with a thin fabric cap (iso-SI to low SI in T1WI, T2WI, and

30 days after his first stroke. The lumen of right inner carotid ar-sel wall and protruded into the lumen. The signal of the plaqueW. (c) T1WI.

15 dcarocove

n 16e ves

attack or nondisabling stroke, who were found to have a

ut th


carotid artery stenosis greater than 70% of the whole lu-minal caliber (14). But in asymptomatic patients, severalgroups (Mayo Asymptomatic Carotid EndarterectomyTrial, Canadian Stroke Consortium, Veterans Affairs Co-operative Study Group) have reported no benefit fromcarotid endarterectomy (15). These controversies pro-voked a call for better methods of assessing the severityof carotid atherosclerosis. Over the past decade, notableadvances have been made in the understanding of the pa-thology and morphology of atherosclerosis. Many studieshave revealed that culprit lesions associated with the de-velopment of ischemic symptoms contain a large lipidcore and a thin fibrous cap (16). In vivo assessment ofplaque composition is a step forward in the prevention ofcerebral infarction. Yuan et al. (17,18) accurately detectedlipid core and hemorrhage in plaque with a 1.5-T systemand demonstrated that patients with ruptured fibrous caps,as assessed with MRI, were 23 times more likely to havea transient ischemic attack or ischemic stroke comparedwith patients with thick fibrous caps. Cai et al. (9) dem-onstrate that in vivo high-resolution multicontrast MRI iscapable of classifying intermediate to advanced athero-sclerotic lesions in the human carotid artery. Directthrombus MRI of the carotid vessels in patients with cere-bral ischemia had been an accurate means of identifyinghistological confirmed complicated plaque (19).

A challenge of introducing carotid MRI into clinicalpractice was to obtain a standard image and interpret it.We defined a routine examination process that is easy toconform to and accomplish. Despite much research todifferentiate the various contents of plaques, there were

Figure 3. A 62-year-old male patient had recurrence 2158 daysright common carotid artery wall thickened homogeneously witho

still many intersection among identifying different con-

tents. For example, lower SI on T2WI and higher SI onT1WI usually are considered to represent the lipid core.In addition to the lipid core, hemorrhage and thrombusare constituents of the vulnerable lesion (20). Unfortu-nately, hemorrhage and thrombosis may also cause thisdecrease of SI on T2WI and a lipid core with cholesterolcrystals may appear with a lower SI in T1WI. Differentstages of thrombosis also vary in signal. We divided thepatients into only two groups: vulnerable lesion and with-out vulnerable lesion. The possibility of misclassificationof atherosclerosis decreased. To our knowledge, our studyis the first so far to analyze the relationship betweenMRI-classified plaque type and recurrent ischemic stroke.Because a vulnerable lesion or culprit lesion got its namefrom a tight correlation between its presence and cardiac-cerebral event, we chose interval of cerebral infarction asan indicator of pathogenic effect of vulnerable lesionbased on the fact that clinical event, not histological evi-dence, is the ultimate criterion by which to evaluate criti-cality of the atherosclerotic lesion.

However, this study had several limitations. First, ourstudy focused on cerebral infarction, which accounts forthe majority of hospitalizations for stroke in our hospital.People who had a stroke but were not admitted to a hos-pital were excluded from the study automatically, andpatients who did not survive after first stroke or lacked anexact history were also excluded. Second, MRI has somepractical limitations. Although we made every effort towarrant image quality, including training swallow act anduse of a custom-designed bracket, four patients with dys-phoria were excluded from the analysis because of motion

r first cerebral infarction. The lumen is not stenotic, and thee character of a vulnerable lesion. (a) T2WI. (b) PDW. (c) T1WI.

afte

artifacts. Third, because of the limitation of equipment

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and examination time, we focused only on the carotidbifurcation and could not find lesions in other parts of thecarotid artery. Fourth, some data during the interval wereinaccessible, and part of the statistical methods werebased on a presumption that the lesion did not have sig-nificant recession during the interval of cerebral infarc-tion. According to many articles about the lipid-loweringtreatment effect on atherosclerosis in the carotid artery,we found that clinical trials that can prove a regression ofplaque lasted at least 2 years. All of our examinee did notaccept lipid-lowering treatment more than 6 months. Thestrict exclusion criteria also excluded a considerable num-ber of patients and led to a small sample size.

CONCLUSION

Despite the limitations of data obtained in a routineclinical setting, this study revealed that vulnerable lesionsin the carotid artery defined by MRI related to acceleratedrecurrent cerebral infarction and high recurrent rate. As a“one-stop” examination, MRI demonstrated a simple andconvenient method to evaluate risk of recurrence for sec-ondary prevention of cerebral infarction and may be aclue to therapy. Further massive prospective follow-upstudies are warranted to evaluate the prognostic value ofMRI-classified plaque with regard to secondary preventiveeffect for ischemic stroke.

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carotid vulnerable lesions are related to accelerated recurrence for cerebral infarction

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