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Relationship between Carotid Artery Remodeling and Plaque Vulnerability with T1-Weighted Magnetic Resonance Imaging
Relationship between Carotid Artery Remodeling and Plaque Vulnerability with T1-Weighted Magnetic Resonance Imaging Kenji Fukuda, MD,* Koji Iihara, MD, PhD,* Daisuke Maruyama, MD,* Naoaki Yamada, MD, PhD,† and Hatsue Ishibashi-Ueda, MD, PhD‡
Background: The aim of this study was to validate the relationship between carotid artery remodeling defined as the carotid remodeling index (CRI) and plaque vulnerability by comparing the degree of outward remodeling calculated using 3-dimensional inversion recovery-based T1-weighted imaging (magnetization-prepared rapid acquisition gradient echo [MPRAGE]) with the symptomatology and histology of plaques extracted during carotid endarterectomy. Methods: Sixty-one patients with 50% stenosis or more (North American Symptomatic Carotid Endarterectomy Trial criteria) were included. The average rate of stenosis was 79.8%. The CRI was determined by measuring the external cross-sectional vessel area (CSVA) at the maximum stenosis of the internal carotid artery (ICA) and dividing it by the external CSVA at the distal ICA (unaffected by atherosclerosis) using MPRAGE imaging. Results: The CRI was significantly higher in symptomatic patients compared with asymptomatic patients (1.98 6 .26 versus 1.68 6 .24, P , .0001). A higher CRI positively correlated with the necrotic core area (r 5 .57, P , .0001) and negatively correlated with the fibrous cap thickness (r 5 2.33, P 5 .01). It was also significantly associated with severe intraplaque hemorrhage (P , .0001) and the prevalence of cap inflammation with macrophage (P 5 .03) and lymphocyte (P 5 .01) infiltration. Conclusions: The larger outward remodeling of the carotid artery on MPRAGE imaging had symptomatic carotid plaques and histologically vulnerable plaques. This study indicates that MPRAGE imaging is useful for the assessment of carotid artery remodeling. Key Words: Carotid artery stenosis—outward remodeling—MR imaging—plaque vulnerability—carotid remodeling index. Ó 2014 by National Stroke Association
From the *Department of Neurosurgery, National Cerebral and Cardiovascular Center, Osaka; †Department of Radiology, National Cerebral and Cardiovascular Center, Osaka; and ‡Department of Pathology, National Cerebral and Cardiovascular Center, Osaka, Japan. Received July 16, 2013; revision received December 6, 2013; accepted December 6, 2013. Grant support: None. Disclosure: The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this article. Address correspondence to Koji Iihara, MD, PhD, Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.010
Arterial remodeling is a well-known occurrence in the progression of atherosclerosis.1 The artery enlarges initially in association with plaque accumulation to ensure an adequate luminal area, namely compensatory enlargement before luminal stenosis. This phenomenon is called expansive remodeling, positive remodeling, or outward remodeling. Several studies revealed that this process is a key factor for plaque vulnerability. In those studies, intravascular ultrasound, magnetic resonance imaging (MRI), and computed tomography (CT) were used to evaluate outward remodeling of the coronary arteries.2-8 However, only a few studies have revealed the relationship between carotid artery remodeling and plaque vulnerability.9-11 Recently, MRI has been widely used to assess the plaque component in the same manner as the degree of stenosis because it provides excellent noninvasive soft tissue
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contrast without exposure to radiation. Studies have demonstrated lipid-rich necrotic cores (NCs) and intraplaque hemorrhage (IPH) or thrombus by high signal intensity on T1-weighted imaging.12-16 Specifically, carotid plaque signal hyperintensity on 3-dimensional inversion recovery-based T1-weighted imaging (magnetizationprepared rapid acquisition gradient-echo [MPRAGE]) is associated with recent ischemic events and complicated plaques.15,17-20 MPRAGE imaging is widely used for assessing the plaque component and provides good contrast of the carotid artery structure. Therefore, it can be useful to examine the degree of carotid artery remodeling without additional sequences. In this study, we aimed to validate the relationship between carotid artery remodeling and plaque vulnerability by comparing the degree of outward remodeling calculated using MPRAGE imaging with the symptomatology and histology of plaques extracted during carotid endarterectomy (CEA).
Methods Study Population Between May 2006 and September 2008, 70 patients with significant carotid stenosis ($50%) who underwent CEA were selected. Nine patients were excluded after the histologic examination because their plaques were damaged during CEA and could not be histologically evaluated. Finally, 61 patients were included in this study: 36 patients had symptomatic carotid stenosis (32 men with a mean age of 70.5 6 8.7 years and degree of stenosis of 80.3 6 11.3%) and 25 patients had asymptomatic carotid stenosis (22 men with a mean age of 66.4 6 6.5 years and degree of stenosis of 79.0 6 10.7%). Patient characteristics were examined retrospectively by reviewing medical records. A symptomatic lesion was defined as a carotid stenosis that resulted in ipsilateral ischemic events, including cerebral infarction, transient ischemic attack, and amaurosis fugax within the previous 6 months. The degree of carotid stenosis was measured by digital subtraction angiography, CT angiography, or magnetic resonance angiography (MRA) using the North American Symptomatic Carotid Endarterectomy Trial criteria. The criteria for CEA were basically based on the guidelines of the American Heart Association. CEA was performed under general anesthesia with somatosensory evoked potential monitoring by 1 surgeon (K.I.).21 In patients with repeated cerebral infarction from carotid plaques, transcranial Doppler ultrasound was also used to monitor microembolic signals caused by the neck dissection until the plaques were extracted. Endarterectomy specimens were obtained without cutting them longitudinally.
MRI Procedures MRI was performed using a standard neck array and spine array coils in a Magnetom Sonata 1.5-T system
(Siemens, Munich, Germany). MPRAGE imaging was used to examine the carotid artery structure, including the external vessel wall and the vascular lumen, transaxially with the null blood condition (effective inversion time, 660 ms; repetition time, 1500 ms) and water excitation technique to suppress fat signals. Other scanning parameters were as follows: echo time, 5.0 ms; field of view, 180 3 180 mm; matrix, 256 3 204; section thickness, 1.25 mm; 56 partitions, covering 70 mm around the carotid bifurcation; data acquisition time, 5 minutes. Multislab 3-dimensional time-of-flight MRA was also performed to delineate the luminal shape (echo time, 4.4 ms; repetition time, 35 ms; same spatial resolution as in MPRAGE).
Carotid Artery Remodeling Measurements The MPRAGE sequence was used to calculate the degree of carotid artery remodeling. The carotid remodeling index (CRI) was determined by measuring the external cross-sectional vessel area (CSVA) at the maximum stenosis of the internal carotid artery (ICA) and dividing it by the external CSVA at the distal ICA unaffected by atherosclerosis (Figs 1 and 2). This method was based on the report by Varnava et al.2 The CRI of 20 lesions (20 patients having lacunar infarction without any carotid artery stenosis, 18 men with a mean age of 66.8 6 6.4 years) was also measured as normal controls for validation. The external CSVA at the largest part of ICA in the normal control group, which is exclusively corresponded to the carotid bulb, was supposed to the external CSVA at the maximum stenosis. A single blinded investigator (K.F.) performed all measurements. The reproducibility was assessed by measurements performed by a second investigator (D.M.) in all patients.
Plaque Component Assessments The signal intensity of plaques and the adjacent muscle (typically the sternocleidomastoid muscle) on MPRAGE was measured in each image at 5-mm intervals from the common carotid bifurcation to the ICA as described by Yamada et al.12 Then, we evaluated the signal intensity ratio (SIR) of the carotid plaque component calculated by dividing the plaque signal intensity with the muscle signal intensity. The plaques that displayed the SIR greater than 2 were categorized as having high signal intensity.
Histopathologic Evaluation of Surgically Obtained Plaques The excised plaques were immediately fixed for 48 hours in Histochoice fixative (Amresco, Cleveland, OH) and decalcified with EDTA. Each plaque was embedded in paraffin and sectioned transversely at the carotid bifurcation. Further sections were obtained at
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Figure 1. Representative images of symptomatic patients. (A) Sagittal section of carotid stenosis on time-of-flight magnetic resonance angiography (‘‘*,’’ the maximum stenosis of the internal carotid artery (ICA); ‘‘†,’’ the unaffected part of the distal ICA). The encircled regions show the external cross-sectional areas of the distal ICA (B, ‘‘†’’) and maximum stenosis of the ICA with high plaque signal intensity (C, ‘‘*’’) on magnetizationprepared rapid acquisition gradient echo. (D) Photomicrograph of the maximum stenosis of the ICA demonstrating plaque rupture, anq intramural thrombus, and a large necrotic core with fresh intraplaque hemorrhage (Masson trichrome staining, original magnification 13). (E) Photomicrograph showing that the brown areas indicate positive staining of glycophorin A as IPH at the maximum stenosis of the ICA (Immunostaining with glycophorin A, original magnification, 13).
5-mm intervals along the length of the ICA for embedding in paraffin. They were then divided into 5-mm blocks. Adjacent 5-mm transverse sections were stained with hematoxylin and eosin, Elastica van Gieson stain, and Masson trichrome for histologic evaluation. In the immunohistochemical analyses, we performed immunostaining for lymphocytes (CD3; Dako, Glostrup, Denmark) and macrophages (CD68; Dako). Immunostaining with glycophorin A (CD235a; Dako) was also performed to confirm IPH. An experienced histopathologist (H.I.U.) blinded to the clinical data evaluated the results. The histologic features of carotid plaques evaluated in this study were the ratio of the total plaque area to the vascular area surrounded by internal elastic lamina and the ratio of the NC area at the maximum luminal narrowing to the total plaque area. They were measured using WinROOF 5.0 morphometry software (Mitani Co., Kana-
Figure 2. Representative images of asymptomatic patients. (A) Sagittal section of carotid stenosis on time-of-flight magnetic resonance angiography (‘‘*,’’ the maximum stenosis of the internal carotid artery (ICA); ‘‘†,’’ the unaffected part of the distal ICA). The encircled regions show the external cross-sectional areas of the distal ICA (B, ‘‘†’’) and maximum stenosis of the ICA with low plaque signal intensity (C, ‘‘*’’) on magnetization-prepared rapid acquisition gradient echo. (D) Photomicrograph of the maximum stenosis of the ICA demonstrating a thick fibrous cap and small necrotic core (Masson trichrome staining, original magnification, 13). (E) Photomicrograph showing that the plaque is stained slightly for glycophorin A at the maximum stenosis of the ICA (Immunostaining with glycophorin A, original magnification, 13).
zawa, Japan). The prevalence of fibrous cap rupture, mural thrombus, inflammatory cells (including macrophages and lymphocytes), degree of IPH, and thickness of the fibrous cap were assessed. Plaque rupture (a break in the fibrous cap) was recorded when there was a clear interaction between the lipid core and the lumen, usually at a point of thinning and inflammation, and when the break in the cap was likely not created during surgery. An NC was defined as an amorphous material containing cholesterol crystals. As an index of the degree of IPH (IPH score), the ratio of the glycophorin A–positive area to the whole plaque area was calculated and graded into 3 scales: 3, 40% or more; 2, 20% or more; and 1, less than 20%. At this time, a fresh IPH was additionally recorded when an area of erythrocytes within the plaque caused disruption of the plaque architecture. Plaque inflammation with macrophage and lymphocyte
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Table 1. Summary of clinical findings and plaque characteristics in this study
Clinical findings Age (y) Sex, male (%) Hypertension (%) Diabetes mellitus (%) Hyperlipidemia (%) Cigarette smoking (%) Ischemic heart disease (%) Plaque characteristics Degree of stenosis (%) Ulceration (%) Echolucent plaque (%) Mobile plaque (%) Signal intensity ratio on MPRAGE
Symptomatic patients (n 5 36)
Asymptomatic patients (n 5 25)
P value
70.5 6 8.7 32 (88.9) 26 (72.2) 13 (36.1) 22 (61.1) 22 (61.1) 16 (44.4)
66.4 6 6.5 22 (88.0) 18 (72.0) 15 (60.0) 14 (56.0) 16 (64.0) 10 (40.0)
.06 1 1 .08 .79 1 .80
80.3 6 11.3 14 (38.9) 10 (27.8) 12 (33.3) 2.17 6 .74
79.0 6 10.7 6 (24.0) 4 (16.0) 2 (8.0) 1.88 6 .80
.66 .27 .36 .03 .17
Abbreviation: MPRAGE, magnetization-prepared rapid acquisition gradient echo.
infiltration was recorded according to the number of CD68-negative or CD3-positive cells: infiltration of greater than 20 inflammatory cells in the fibrous cap was defined as positive inflammation of the fibrous cap. Mural thrombus, which indicated plaque rupture, was defined as a fibrin organization of the endothelium or the fibrous cap of plaques.
Statistical Analyses Statistical analyses were performed using JMP 9.02 software (SAS Institute, Cary, NC). Independent-samples t test and Fisher exact test were used to compare continuous and categorical characteristics, respectively, between the symptomatic and asymptomatic patients. To ascertain the CRI as the cutoff point for the prediction of symptomatic carotid plaques, receiver operating characteristic analyses were also performed. Correlations between the CRI and pathologic parameters (plaque rupture, mural thrombus, fresh IPH, and macrophage and lymphocyte infiltration) were analyzed using the independent-samples t test. The correlation between the CRI and the NC proportion and the SIR of carotid plaque were analyzed using the Pearson rank correlation test (which measures the linear relationship between 2 variables) because we expected a linear relationship. The correlation between the CRI and the IPH score was analyzed using the Kruskal–Wallis test. A value of P less than .05 was considered significant. Interobserver agreement was evaluated with a Bland–Altman analysis.22 The data represent the mean 6 SD or percentages.
Results
ences in the frequency of conventional risk factors for carotid artery disease. With regard to their plaque characteristics, symptomatic patients had a higher number of mobile plaques (33.3% versus 8.0%, P 5.03). No significant difference in the existence of ulceration and echolucency by ultrasound imaging and the SIR of carotid plaques on MPRAGE imaging was noted between the groups. The SIR was positively correlated with the CRI (r 5 .38, P 5 .002).
Correlation between the CRI and the Clinical Findings The study group had a significantly higher CRI (1.90 6 .29 versus 1.52 6 .17, P , .0001) and larger external CSVA at the maximum stenosis of the ICA (73.0 6 18.5 versus 59.5 6 9.5 mm2, P 5.002) compared with the control group. However, the external CSVA at the distal ICA was almost identical in these groups (39.1 6 6.8 versus 39.2 6 4.5 mm2, P 5 .96). Figures 1 and 2 show representative images on time-of-flight MRA, MPRAGE, and histologic section from the symptomatic and asymptomatic patients. Symptomatic patients had a significantly higher CRI than asymptomatic ones (P ,.0001; Table 2 and Fig 3), and their external CSVA at the maximum stenosis of the ICA was significantly larger (P 5 .006). However, the external CSVA at the distal ICA was similar in these patients (P 5 .56). In analyses of receiver operating characteristic curves (Fig 4), a CRI of 1.69 was determined as the most reliable cutoff value for predicting symptomatology (95% confidence interval, .687-.915). Based on this cutoff, the sensitivity and specificity were 91.7% and 64.0%, respectively. The positive and negative predictive values were 78.6% and 84.2%, respectively.
Patient Characteristics The characteristics of the study population are listed in Table 1. The symptomatic and asymptomatic groups had similar demographic features and no significant differ-
Correlation between the CRI and Histologic Findings Figure 5 shows a scatter plot of the relationship between the CRI and the histologic characteristics. The
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Table 2. Comparison of outward remodeling in symptomatic and asymptomatic carotid lesions Symptomatic patients (n 5 36)
Asymptomatic patients (n 5 25)
P value
1.98 6 .26 78.5 6 19.0 39.3 6 7.0
1.68 6 .24 65.1 6 14.6 38.7 6 6.5
,.0001 .006 .56
Carotid remodeling index External CSVA at maximum stenosis of ICA (mm2) External CSVA at distal ICA (mm2)
Abbreviations: CSVA, cross-sectional vessel area; ICA, internal carotid artery.
CRI was positively correlated with the NC (r 5 .57, P , .0001) and was negatively correlated with the fibrous cap thickness (r 5 2.33, P 5 .01). The mean CRI was 1.68 6 .23 (n 5 18), 1.73 6 .21 (n 5 10), and 2.00 6 .28 (n 5 33) for IPH scores of 1, 2, and 3, respectively. Figure 6 shows relationships between the CRI and each histologic marker of plaque vulnerability. A higher IPH score was significantly associated with a higher CRI (P ,.0001). The prevalence of a fresh IPH was particularly associated with a higher CRI (with fresh IPH [n 5 46] versus without fresh IPH [n 5 15] 5 1.92 6 .25 versus 1.82 6 .32, P 5 .005). The prevalence of mural thrombus (with mural thrombus [n 5 40] versus without mural thrombus [n 5 21] 5 1.97 6 .24 versus 1.80 6 .31, P 5 .03) and quantity of inflammatory cells (with macrophage infiltration [n 5 42] versus without macrophage infiltration [n 5 19] 5 1.92 6 .28 versus 1.74 6 .29, P 5 .03; with lymphocyte infiltration [n 5 47] versus without lymphocyte infiltration [n 5 14] 5 1.91 6 .29 versus 1.68 6 .33, P 5 .007) were also associated with a higher CRI. However, the prevalence of plaque rupture
Figure 3. Scatter plot showing the relationship between the carotid remodeling index (CRI) and symptomatology. The CRI was significantly higher in symptomatic patients compared with asymptomatic patients.
was not associated with the CRI (with plaque rupture [n 5 38] versus without plaque rupture [n 5 23] 5 1.92 6 .25 versus 1.82 6 .32, P 5 .22).
Interobserver Agreement Interobserver agreement of CRI was assessed in all patients by using Bland–Altman plots, which demonstrated a good interobserver agreement (Fig 7).
Discussion In this study, we showed that larger outward remodeling of the carotid artery was significantly associated with symptomatic carotid plaques and markers of histologic carotid plaque vulnerability such as higher NC proportion, IPH score, prevalence of fresh IPH, mural thrombus, and inflammatory cells. This is the first report to examine the relationship between histologic markers related to the carotid plaque vulnerability and carotid artery remodeling, suggesting that CRI is a useful marker of future stroke risk in significant carotid stenosis ($50%).
Figure 4. Receiver operating characteristic curve analyses indicate that a CRI of 1.69, calculated by MPRAGE imaging, is the most reliable cutoff value for predicting symptomatic ICA lesions. Abbreviations: AUC, area under the curve; CRI, carotid remodeling index; ICA, internal carotid artery.
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Figure 5. Scatter plot showing the relationship between the carotid remodeling index (CRI) and the histologic characteristics. The CRI is positively correlated with necrotic core proportion (A) and negatively correlated with fibrous cap thickness (B).
Assessment of Outward Remodeling on Carotid Artery Because Gragov et al1 first reported expansive vessel remodeling to maintain an adequate luminal area in response to the development of atherosclerotic plaques at early stages, several studies using various imaging modalities2-8 have been published regarding outward remodeling and plaque vulnerability of the coronary artery. The Atherosclerosis Risk in the Communities study has assessed the carotid arteries of healthy individuals with B-mode ultrasound and found that, when carotid arterial enlargement accompanies increased wall thickness, there is less lumen constriction than expected, suggesting the pathogenesis of symptoms related to carotid stenosis.23 However, the incidence and clinical significance of carotid remodeling remain uncertain because only a few studies have been reported.9,10 Hardie et al10 have demonstrated significantly greater expansive carotid remodeling in pa-
tients with cerebral symptoms compared with asymptomatic patients as assessed by multidetector CT (MDCT) angiography, suggesting that MDCT is a reliable modality to measure the vascular lumen accurately. Compared with ultrasonography and MDCT angiography, MRI has the advantages of objective and excellent soft tissue contrast, no radiation exposure, availability for high cervical lesions, and noninvasively displaying the vascular lumen without a contrast medium.9,11,17,24 However, few studies have examined carotid artery remodeling with MRI.9,11 The MRI study with blackblood MRI of the Atherosclerosis Risk in the Communities examined the association between the luminal area and maximum wall thickness and found that carotid arteries can compensate for a greater degree of thickening than coronary arteries.11 However, they did not assess the carotid outward remodeling based on plaque
Figure 6. Bar chart shows relationships between the carotid remodeling index (CRI) and each histologic marker of plaque vulnerability. The average number of CRI is shown on vertical axis, and the score of intraplaque hemorrhage 1, 2, and 3, and the existence of each histologic marker are shown on horizontal axis. ‘‘*,’’ Indicates significance at P , .05 and ‘‘**,’’ indicates significance at P , .0001.
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Relationship between Outward Remodeling and Plaque Component on MRI Recent studies have demonstrated that carotid artery plaques with high-signal intensity (SIR . 2) on MPRAGE are correlated with symptomatic plaques and larger NCs with IPH.17,18 Plaque component assessment by MR plaque imaging is widely used for the assessment of carotid plaque vulnerability, leading to the prediction of subsequent ischemic events on clinical follow-up examinations and complications of CEA and carotid artery stenting.33-37 However, the findings of vulnerable plaques based on the MR signal intensity of the carotid plaque component vary among the MRI techniques.38 In this study, the CRI was correlated with SIR. So, the CRI and SIR could be complementary markers for evaluating vulnerable carotid plaques in MPRAGE imaging. Figure 7. Bland–Altman plot displaying the interobserver agreement of CRI between 2 observers.
vulnerability. Miura et al9 have evaluated the association between positive remodeling of the carotid artery and plaque vulnerability based on symptomatology and histology in 28 patients with black-blood MRI. However, details of the histologic assessments are not available because only 10 plaques extracted by CEA were examined to determine whether they were classified to stage VI according to the American Heart Association criteria.25
Relationship between Outward Remodeling and Plaque Vulnerability on Carotid Arteries Here, we clearly demonstrate using MPRAGE that a higher CRI is associated with a higher NC proportion, IPH score, and prevalence of fresh IPH, mural thrombus, and inflammatory cells (macrophages and lymphocytes), which are considered markers of plaque vulnerability.16,26-29 Previous histologic studies revealed that enlargement of the NC leads to plaque instability,26-28 and a large NC is strongly associated with fibrous cap thinning, fibrous cap rupture, mural thrombus, and IPH.16,29 Greater IPH and higher inflammatory cell counts in the fibrous cap could cause further expansion of the NC and result in plaque destabilization.2,30-32 These are consistent with the finding that greater expansive remodeling of the coronary artery is related to a significantly larger lipid core and higher macrophage count.2 Our histologic results demonstrate that larger outward remodeling of the carotid artery indicates the progression of histologic plaque vulnerability. In addition, the correlation between greater expansive remodeling of carotid plaques and the clinical symptomatic presentation is similar to the findings that positive remodeling of coronary plaques was associated with unstable clinical presentation.3 To evaluate outward remodeling on carotid arteries and on coronary arteries could be important in assessing plaque vulnerability.
Study Strengths and Limitations A strength of this study is that the CRI was evaluated by MPRAGE imaging. The usefulness of MPRAGE imaging for the assessment of clinical significance and histologic characterization in patients with carotid stenosis has been established in previous studies.17,18 So, we could evaluate plaque vulnerability using both CRI and SIR in MPRAGE imaging without additional sequence efficiently in clinical use. In addition, this study clearly demonstrates the close correlation between outward remodeling and plaque vulnerability in high-grade stenosis ($50%) although the clinical significance of plaque vulnerability and outward remodeling in future stroke risk has been emphasized in low-grade carotid stenosis.39 This is important because in contrast to symptomatic stenosis, there is little evidence that the risk of stroke in asymptomatic stenosis increases with the degree of stenosis across the 50%-99% range.40 A CRI of 1.69 was determined as the most reliable cutoff value for predicting symptomatology. In this analysis, the specificity was relatively low (64%). Indeed, 9 of 25 (36%) asymptomatic patients had the value of CRI greater than 1.69. However, 7 of these 9 patients with the value of CRI greater than 1.69 had vulnerable plaque component with an SIR greater than 2. The CRI was significantly correlated with SIR in this study. These results indicate that the CRI may be a useful marker to predict future stroke risk in asymptomatic patients. Because of the low risk of stroke in patients with asymptomatic carotid stenosis and the progress of intensive medical treatment,41 there is the potential to explore the need for CEA and carotid artery stenting especially in asymptomatic patients using CRI. The methods of calculating outward remodeling of the carotid artery deserve some mention. Previous studies proposed 2 parameters to demonstrate the degree of outward remodeling in the coronary artery: remodeling index calculated as the ratio of external CSVA at the maximal vessel stenosis to the mean reference external
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CSVA and remodeling ratio as the ratio of CSVA at the maximal vessel stenosis to CSVA at the distal portion.3 In this study, CRI was defined as the ratio of the external CSVA at the maximum stenosis of the ICA to the external CSVA at the distal ICA unaffected by atherosclerosis. Although the method based on the North American Symptomatic Carotid Endarterectomy Trial criteria used in this study may be affected by flow reduction beyond the critical stenosis, the external CSVA at the distal ICA of our study was comparable with the control group, suggesting a negligible effect of flow reduction. In addition, Miura et al9 reported that both these methods significantly correlated with the signal intensity of carotid plaques on MRI and a higher prevalence of stroke. Another limitation is the retrospective nature of this study regarding case selection bias. Despite these limitations, our results indicate that the CRI calculated using MPRAGE imaging, as a noninvasive and objective modality, is a reliable marker of plaque vulnerability determined based on symptomatology and histology. A prospective large study remains necessary to conclude which parameters are more likely to predict the plaque vulnerability of the carotid plaques.
Conclusions This study clearly demonstrates the relationship between carotid artery remodeling and plaque vulnerability based on symptomatology and histology in significant carotid stenosis ($50%) using MPRAGE. This study indicates that MPRAGE imaging is useful for the assessment of carotid artery remodeling. To evaluate the outward remodeling of carotid artery using MPRAGE imaging is predictive of the risk of ipsilateral ischemic events in the future. Acknowledgment: The authors thank Mayumi Oka and Yoshifumi Higashino for collecting the patient data.
References 1. Glagov S, Weisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987;316:1371-1375. 2. Varnava AM, Mills PG, Davies MJ. Relationship between coronary artery remodeling and plaque vulnerability. Circulation 2002;105:939-943. 3. Schoenhagen P, Ziada KM, Kapadia SR, et al. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: an intravascular ultrasound study. Circulation 2000;101:598-603. 4. Kim WY, Stuber M, Bornert P, et al. Three-dimensional black-blood cardiac magnetic resonance coronary vessel wall imaging detects positive arterial remodeling in patients with nonsignificant coronary artery disease. Circulation 2002;106:296-299. 5. Nakamura M, Nishikawa H, Mukai S, et al. Impact of coronary artery remodeling on clinical presentation of coronary artery disease: an intravascular ultrasound study. J Am Coll Cardiol 2001;37:63-69.
6. Pasterkamp G, Schoneveld AH, van der Wal AC, et al. Relation of arterial geometry to luminal narrowing and histologic markers for plaque vulnerability: the remodeling paradox. J Am Coll Cardiol 1998;32:655-662. 7. Pasterkamp G, Wensing PJ, Hillen B, et al. Impact of local atherosclerotic remodeling on the calculation of percent luminal narrowing. Am J Cardiol 1997;79:402-405. 8. Achenbach S, Ropers D, Hoffmann U, et al. Assessment of coronary remodeling in stenotic and nonstenotic coronary atherosclerotic lesions by multidetector spiral computed tomography. J Am Coll Cardiol 2004;43:842-847. 9. Miura T, Matsukawa N, Sakurai K, et al. Plaque vulnerability in internal carotid arteries with positive remodeling. Cerebrovasc Dis Extra 2011;1:54-65. 10. Hardie AD, Kramer CM, Raghavan P, et al. The impact of expansive arterial remodeling on clinical presentation in carotid artery disease: a multidetector ct angiography study. AJNR Am J Neuroradiol 2007;28:1067-1070. 11. Astor BC, Sharrett AR, Coresh J, et al. Remodeling of carotid arteries detected with MR imaging: atherosclerosis risk in communities carotid MRI study. Radiology 2010; 256:879-886. 12. 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;104:2051-2056. 13. Yuan C, Kerwin WS, Ferguson MS, et al. Contrastenhanced high resolution MRI for atherosclerotic carotid artery tissue characterization. J Magn Reson Imaging 2002;15:62-67. 14. Cappendijk VC, Cleutjens KB, Heeneman S, et al. In vivo detection of hemorrhage in human atherosclerotic plaques with magnetic resonance imaging. J Magn Reson Imaging 2004;20:105-110. 15. Moody AR, Murphy RE, Morgan PS, et al. Characterization of complicated carotid plaque with magnetic resonance direct thrombus imaging in patients with cerebral ischemia. Circulation 2003;107:3047-3052. 16. Cappendijk VC, Cleutjens KB, Kessels AG, et al. Assessment of human atherosclerotic carotid plaque components with multisequence MR imaging: Initial experience. Radiology 2005;234:487-492. 17. Yamada N, Higashi M, Otsubo R, et al. Association between signal hyperintensity on T1-weighted MR imaging of carotid plaques and ipsilateral ischemic events. AJNR Am J Neuroradiol 2007;28:287-292. 18. Hishikawa T, Iihara K, Yamada N, et al. Assessment of necrotic core with intraplaque hemorrhage in atherosclerotic carotid artery plaque by MR imaging with 3d gradient-echo sequence in patients with high-grade stenosis. Clinical article. J Neurosurg 2010;113:890-896. 19. Mugler JP III, Brookeman JR. Three-dimensional magnetization-prepared rapid gradient-echo imaging (3D MP rage). Magn Reson Med 1990;15:152-157. 20. Moody AR, Allder S, Lennox G, et al. Direct magnetic resonance imaging of carotid artery thrombus in acute stroke. Lancet 1999;353:122-123. 21. Iihara K, Murao K, Sakai N, et al. Outcome of carotid endarterectomy and stent insertion based on grading of carotid endarterectomy risk: a 7-year prospective study. J Neurosurg 2006;105:546-554. 22. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1:307-310. 23. Crouse JR, Goldbourt U, Evans G, et al. Arterial enlargement in the atherosclerosis risk in communities (ARIC)
ASSESSMENT OF CAROTID ARTERY REMODELING WITH MPRAGE
24.
25.
26.
27.
28. 29.
30.
31.
32.
33.
cohort. In vivo quantification of carotid arterial enlargement. The ARIC investigators. Stroke 1994;25:1354-1359. Sadat U, Teng Z, Young VE, et al. Utility of magnetic resonance imaging-based finite element analysis for the biomechanical stress analysis of hemorrhagic and non-hemorrhagic carotid plaques. Circ J 2011;75: 884-889. Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the committee on vascular lesions of the council on arteriosclerosis, american heart association. Circulation 1995; 92:1355-1374. Virmani R, Kolodgie FD, Burke AP, et al. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 2005;25:2054-2061. Nighoghossian N, Derex L, Douek P. The vulnerable carotid artery plaque: current imaging methods and new perspectives. Stroke 2005;36:2764-2772. Golledge J, Greenhalgh RM, Davies AH. The symptomatic carotid plaque. Stroke 2000;31:774-781. Redgrave JN, Lovett JK, Gallagher PJ, et al. Histological assessment of 526 symptomatic carotid plaques in relation to the nature and timing of ischemic symptoms: the oxford plaque study. Circulation 2006;113:2320-2328. Kolodgie FD, Gold HK, Burke AP, et al. Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 2003;349:2316-2325. Burke AP, Kolodgie FD, Farb A, et al. Morphological predictors of arterial remodeling in coronary atherosclerosis. Circulation 2002;105:297-303. Pasterkamp G, Galis ZS, de Kleijn DP. Expansive arterial remodeling: location, location, location. Arterioscler Thromb Vasc Biol 2004;24:650-657. Altaf N, MacSweeney ST, Gladman J, et al. Carotid intraplaque hemorrhage predicts recurrent symptoms in patients with high-grade carotid stenosis. Stroke 2007; 38:1633-1635.
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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. Altaf N, Beech A, Goode SD, et al. Carotid intraplaque hemorrhage detected by magnetic resonance imaging predicts embolization during carotid endarterectomy. J Vasc Surg 2007;46:31-36. 36. Yamada K, Yoshimura S, Kawasaki M, et al. Embolic complications after carotid artery stenting or carotid endarterectomy are associated with tissue characteristics of carotid plaques evaluated by magnetic resonance imaging. Atherosclerosis 2011;215:399-404. 37. Akutsu N, Hosoda K, Fujita A, et al. A preliminary prediction model with mr plaque imaging to estimate risk for new ischemic brain lesions on diffusion-weighted imaging after endarterectomy or stenting in patients with carotid stenosis. AJNR Am J Neuroradiol 2012;33:1557-1564. 38. Saito A, Sasaki M, Ogasawara K, et al. Carotid plaque signal differences among four kinds of t1-weighted magnetic resonance imaging techniques: a histopathological correlation study. Neuroradiology 2012;54:1187-1194. 39. Yoshida K, Sadamasa N, Narumi O, et al. Symptomatic low-grade carotid stenosis with intraplaque hemorrhage and expansive arterial remodeling is associated with a high relapse rate refractory to medical treatment. Neurosurgery 2012;70:1143-1150. discussion 1150-1141. 40. Halliday A, Mansfield A, Marro J, et al. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet 2004;363:1491-1502. 41. Marquardt L, Geraghty OC, Mehta Z, et al. Low risk of ipsilateral stroke in patients with asymptomatic carotid stenosis on best medical treatment: a prospective, population-based study. Stroke 2010;41:e11-e17. 42. Imazeki T, Sato Y, Inoue F, et al. Evaluation of coronary artery remodeling in patients with acute coronary syndrome and stable angina by multislice computed tomography. Circ J 2004;68:1045-1050.
Background: The aim of this study was to validate the relationship between carotid artery remodeling defined as the carotid remodeling index (CRI) and plaque vulnerability by comparing the degree of outward remodeling calculated using 3-dimensional inversion recovery-based T1-weighted imaging (magnetization-prepared rapid acquisition gradient echo [MPRAGE]) with the symptomatology and histology of plaques extracted during carotid endarterectomy. Methods: Sixty-one patients with 50% stenosis or more (North American Symptomatic Carotid Endarterectomy Trial criteria) were included. The average rate of stenosis was 79.8%. The CRI was determined by measuring the external cross-sectional vessel area (CSVA) at the maximum stenosis of the internal carotid artery (ICA) and dividing it by the external CSVA at the distal ICA (unaffected by atherosclerosis) using MPRAGE imaging. Results: The CRI was significantly higher in symptomatic patients compared with asymptomatic patients (1.98 6 .26 versus 1.68 6 .24, P , .0001). A higher CRI positively correlated with the necrotic core area (r 5 .57, P , .0001) and negatively correlated with the fibrous cap thickness (r 5 2.33, P 5 .01). It was also significantly associated with severe intraplaque hemorrhage (P , .0001) and the prevalence of cap inflammation with macrophage (P 5 .03) and lymphocyte (P 5 .01) infiltration. Conclusions: The larger outward remodeling of the carotid artery on MPRAGE imaging had symptomatic carotid plaques and histologically vulnerable plaques. This study indicates that MPRAGE imaging is useful for the assessment of carotid artery remodeling. Key Words: Carotid artery stenosis—outward remodeling—MR imaging—plaque vulnerability—carotid remodeling index. Ó 2014 by National Stroke Association
From the *Department of Neurosurgery, National Cerebral and Cardiovascular Center, Osaka; †Department of Radiology, National Cerebral and Cardiovascular Center, Osaka; and ‡Department of Pathology, National Cerebral and Cardiovascular Center, Osaka, Japan. Received July 16, 2013; revision received December 6, 2013; accepted December 6, 2013. Grant support: None. Disclosure: The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this article. Address correspondence to Koji Iihara, MD, PhD, Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.010
Arterial remodeling is a well-known occurrence in the progression of atherosclerosis.1 The artery enlarges initially in association with plaque accumulation to ensure an adequate luminal area, namely compensatory enlargement before luminal stenosis. This phenomenon is called expansive remodeling, positive remodeling, or outward remodeling. Several studies revealed that this process is a key factor for plaque vulnerability. In those studies, intravascular ultrasound, magnetic resonance imaging (MRI), and computed tomography (CT) were used to evaluate outward remodeling of the coronary arteries.2-8 However, only a few studies have revealed the relationship between carotid artery remodeling and plaque vulnerability.9-11 Recently, MRI has been widely used to assess the plaque component in the same manner as the degree of stenosis because it provides excellent noninvasive soft tissue
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contrast without exposure to radiation. Studies have demonstrated lipid-rich necrotic cores (NCs) and intraplaque hemorrhage (IPH) or thrombus by high signal intensity on T1-weighted imaging.12-16 Specifically, carotid plaque signal hyperintensity on 3-dimensional inversion recovery-based T1-weighted imaging (magnetizationprepared rapid acquisition gradient-echo [MPRAGE]) is associated with recent ischemic events and complicated plaques.15,17-20 MPRAGE imaging is widely used for assessing the plaque component and provides good contrast of the carotid artery structure. Therefore, it can be useful to examine the degree of carotid artery remodeling without additional sequences. In this study, we aimed to validate the relationship between carotid artery remodeling and plaque vulnerability by comparing the degree of outward remodeling calculated using MPRAGE imaging with the symptomatology and histology of plaques extracted during carotid endarterectomy (CEA).
Methods Study Population Between May 2006 and September 2008, 70 patients with significant carotid stenosis ($50%) who underwent CEA were selected. Nine patients were excluded after the histologic examination because their plaques were damaged during CEA and could not be histologically evaluated. Finally, 61 patients were included in this study: 36 patients had symptomatic carotid stenosis (32 men with a mean age of 70.5 6 8.7 years and degree of stenosis of 80.3 6 11.3%) and 25 patients had asymptomatic carotid stenosis (22 men with a mean age of 66.4 6 6.5 years and degree of stenosis of 79.0 6 10.7%). Patient characteristics were examined retrospectively by reviewing medical records. A symptomatic lesion was defined as a carotid stenosis that resulted in ipsilateral ischemic events, including cerebral infarction, transient ischemic attack, and amaurosis fugax within the previous 6 months. The degree of carotid stenosis was measured by digital subtraction angiography, CT angiography, or magnetic resonance angiography (MRA) using the North American Symptomatic Carotid Endarterectomy Trial criteria. The criteria for CEA were basically based on the guidelines of the American Heart Association. CEA was performed under general anesthesia with somatosensory evoked potential monitoring by 1 surgeon (K.I.).21 In patients with repeated cerebral infarction from carotid plaques, transcranial Doppler ultrasound was also used to monitor microembolic signals caused by the neck dissection until the plaques were extracted. Endarterectomy specimens were obtained without cutting them longitudinally.
MRI Procedures MRI was performed using a standard neck array and spine array coils in a Magnetom Sonata 1.5-T system
(Siemens, Munich, Germany). MPRAGE imaging was used to examine the carotid artery structure, including the external vessel wall and the vascular lumen, transaxially with the null blood condition (effective inversion time, 660 ms; repetition time, 1500 ms) and water excitation technique to suppress fat signals. Other scanning parameters were as follows: echo time, 5.0 ms; field of view, 180 3 180 mm; matrix, 256 3 204; section thickness, 1.25 mm; 56 partitions, covering 70 mm around the carotid bifurcation; data acquisition time, 5 minutes. Multislab 3-dimensional time-of-flight MRA was also performed to delineate the luminal shape (echo time, 4.4 ms; repetition time, 35 ms; same spatial resolution as in MPRAGE).
Carotid Artery Remodeling Measurements The MPRAGE sequence was used to calculate the degree of carotid artery remodeling. The carotid remodeling index (CRI) was determined by measuring the external cross-sectional vessel area (CSVA) at the maximum stenosis of the internal carotid artery (ICA) and dividing it by the external CSVA at the distal ICA unaffected by atherosclerosis (Figs 1 and 2). This method was based on the report by Varnava et al.2 The CRI of 20 lesions (20 patients having lacunar infarction without any carotid artery stenosis, 18 men with a mean age of 66.8 6 6.4 years) was also measured as normal controls for validation. The external CSVA at the largest part of ICA in the normal control group, which is exclusively corresponded to the carotid bulb, was supposed to the external CSVA at the maximum stenosis. A single blinded investigator (K.F.) performed all measurements. The reproducibility was assessed by measurements performed by a second investigator (D.M.) in all patients.
Plaque Component Assessments The signal intensity of plaques and the adjacent muscle (typically the sternocleidomastoid muscle) on MPRAGE was measured in each image at 5-mm intervals from the common carotid bifurcation to the ICA as described by Yamada et al.12 Then, we evaluated the signal intensity ratio (SIR) of the carotid plaque component calculated by dividing the plaque signal intensity with the muscle signal intensity. The plaques that displayed the SIR greater than 2 were categorized as having high signal intensity.
Histopathologic Evaluation of Surgically Obtained Plaques The excised plaques were immediately fixed for 48 hours in Histochoice fixative (Amresco, Cleveland, OH) and decalcified with EDTA. Each plaque was embedded in paraffin and sectioned transversely at the carotid bifurcation. Further sections were obtained at
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Figure 1. Representative images of symptomatic patients. (A) Sagittal section of carotid stenosis on time-of-flight magnetic resonance angiography (‘‘*,’’ the maximum stenosis of the internal carotid artery (ICA); ‘‘†,’’ the unaffected part of the distal ICA). The encircled regions show the external cross-sectional areas of the distal ICA (B, ‘‘†’’) and maximum stenosis of the ICA with high plaque signal intensity (C, ‘‘*’’) on magnetizationprepared rapid acquisition gradient echo. (D) Photomicrograph of the maximum stenosis of the ICA demonstrating plaque rupture, anq intramural thrombus, and a large necrotic core with fresh intraplaque hemorrhage (Masson trichrome staining, original magnification 13). (E) Photomicrograph showing that the brown areas indicate positive staining of glycophorin A as IPH at the maximum stenosis of the ICA (Immunostaining with glycophorin A, original magnification, 13).
5-mm intervals along the length of the ICA for embedding in paraffin. They were then divided into 5-mm blocks. Adjacent 5-mm transverse sections were stained with hematoxylin and eosin, Elastica van Gieson stain, and Masson trichrome for histologic evaluation. In the immunohistochemical analyses, we performed immunostaining for lymphocytes (CD3; Dako, Glostrup, Denmark) and macrophages (CD68; Dako). Immunostaining with glycophorin A (CD235a; Dako) was also performed to confirm IPH. An experienced histopathologist (H.I.U.) blinded to the clinical data evaluated the results. The histologic features of carotid plaques evaluated in this study were the ratio of the total plaque area to the vascular area surrounded by internal elastic lamina and the ratio of the NC area at the maximum luminal narrowing to the total plaque area. They were measured using WinROOF 5.0 morphometry software (Mitani Co., Kana-
Figure 2. Representative images of asymptomatic patients. (A) Sagittal section of carotid stenosis on time-of-flight magnetic resonance angiography (‘‘*,’’ the maximum stenosis of the internal carotid artery (ICA); ‘‘†,’’ the unaffected part of the distal ICA). The encircled regions show the external cross-sectional areas of the distal ICA (B, ‘‘†’’) and maximum stenosis of the ICA with low plaque signal intensity (C, ‘‘*’’) on magnetization-prepared rapid acquisition gradient echo. (D) Photomicrograph of the maximum stenosis of the ICA demonstrating a thick fibrous cap and small necrotic core (Masson trichrome staining, original magnification, 13). (E) Photomicrograph showing that the plaque is stained slightly for glycophorin A at the maximum stenosis of the ICA (Immunostaining with glycophorin A, original magnification, 13).
zawa, Japan). The prevalence of fibrous cap rupture, mural thrombus, inflammatory cells (including macrophages and lymphocytes), degree of IPH, and thickness of the fibrous cap were assessed. Plaque rupture (a break in the fibrous cap) was recorded when there was a clear interaction between the lipid core and the lumen, usually at a point of thinning and inflammation, and when the break in the cap was likely not created during surgery. An NC was defined as an amorphous material containing cholesterol crystals. As an index of the degree of IPH (IPH score), the ratio of the glycophorin A–positive area to the whole plaque area was calculated and graded into 3 scales: 3, 40% or more; 2, 20% or more; and 1, less than 20%. At this time, a fresh IPH was additionally recorded when an area of erythrocytes within the plaque caused disruption of the plaque architecture. Plaque inflammation with macrophage and lymphocyte
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Table 1. Summary of clinical findings and plaque characteristics in this study
Clinical findings Age (y) Sex, male (%) Hypertension (%) Diabetes mellitus (%) Hyperlipidemia (%) Cigarette smoking (%) Ischemic heart disease (%) Plaque characteristics Degree of stenosis (%) Ulceration (%) Echolucent plaque (%) Mobile plaque (%) Signal intensity ratio on MPRAGE
Symptomatic patients (n 5 36)
Asymptomatic patients (n 5 25)
P value
70.5 6 8.7 32 (88.9) 26 (72.2) 13 (36.1) 22 (61.1) 22 (61.1) 16 (44.4)
66.4 6 6.5 22 (88.0) 18 (72.0) 15 (60.0) 14 (56.0) 16 (64.0) 10 (40.0)
.06 1 1 .08 .79 1 .80
80.3 6 11.3 14 (38.9) 10 (27.8) 12 (33.3) 2.17 6 .74
79.0 6 10.7 6 (24.0) 4 (16.0) 2 (8.0) 1.88 6 .80
.66 .27 .36 .03 .17
Abbreviation: MPRAGE, magnetization-prepared rapid acquisition gradient echo.
infiltration was recorded according to the number of CD68-negative or CD3-positive cells: infiltration of greater than 20 inflammatory cells in the fibrous cap was defined as positive inflammation of the fibrous cap. Mural thrombus, which indicated plaque rupture, was defined as a fibrin organization of the endothelium or the fibrous cap of plaques.
Statistical Analyses Statistical analyses were performed using JMP 9.02 software (SAS Institute, Cary, NC). Independent-samples t test and Fisher exact test were used to compare continuous and categorical characteristics, respectively, between the symptomatic and asymptomatic patients. To ascertain the CRI as the cutoff point for the prediction of symptomatic carotid plaques, receiver operating characteristic analyses were also performed. Correlations between the CRI and pathologic parameters (plaque rupture, mural thrombus, fresh IPH, and macrophage and lymphocyte infiltration) were analyzed using the independent-samples t test. The correlation between the CRI and the NC proportion and the SIR of carotid plaque were analyzed using the Pearson rank correlation test (which measures the linear relationship between 2 variables) because we expected a linear relationship. The correlation between the CRI and the IPH score was analyzed using the Kruskal–Wallis test. A value of P less than .05 was considered significant. Interobserver agreement was evaluated with a Bland–Altman analysis.22 The data represent the mean 6 SD or percentages.
Results
ences in the frequency of conventional risk factors for carotid artery disease. With regard to their plaque characteristics, symptomatic patients had a higher number of mobile plaques (33.3% versus 8.0%, P 5.03). No significant difference in the existence of ulceration and echolucency by ultrasound imaging and the SIR of carotid plaques on MPRAGE imaging was noted between the groups. The SIR was positively correlated with the CRI (r 5 .38, P 5 .002).
Correlation between the CRI and the Clinical Findings The study group had a significantly higher CRI (1.90 6 .29 versus 1.52 6 .17, P , .0001) and larger external CSVA at the maximum stenosis of the ICA (73.0 6 18.5 versus 59.5 6 9.5 mm2, P 5.002) compared with the control group. However, the external CSVA at the distal ICA was almost identical in these groups (39.1 6 6.8 versus 39.2 6 4.5 mm2, P 5 .96). Figures 1 and 2 show representative images on time-of-flight MRA, MPRAGE, and histologic section from the symptomatic and asymptomatic patients. Symptomatic patients had a significantly higher CRI than asymptomatic ones (P ,.0001; Table 2 and Fig 3), and their external CSVA at the maximum stenosis of the ICA was significantly larger (P 5 .006). However, the external CSVA at the distal ICA was similar in these patients (P 5 .56). In analyses of receiver operating characteristic curves (Fig 4), a CRI of 1.69 was determined as the most reliable cutoff value for predicting symptomatology (95% confidence interval, .687-.915). Based on this cutoff, the sensitivity and specificity were 91.7% and 64.0%, respectively. The positive and negative predictive values were 78.6% and 84.2%, respectively.
Patient Characteristics The characteristics of the study population are listed in Table 1. The symptomatic and asymptomatic groups had similar demographic features and no significant differ-
Correlation between the CRI and Histologic Findings Figure 5 shows a scatter plot of the relationship between the CRI and the histologic characteristics. The
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Table 2. Comparison of outward remodeling in symptomatic and asymptomatic carotid lesions Symptomatic patients (n 5 36)
Asymptomatic patients (n 5 25)
P value
1.98 6 .26 78.5 6 19.0 39.3 6 7.0
1.68 6 .24 65.1 6 14.6 38.7 6 6.5
,.0001 .006 .56
Carotid remodeling index External CSVA at maximum stenosis of ICA (mm2) External CSVA at distal ICA (mm2)
Abbreviations: CSVA, cross-sectional vessel area; ICA, internal carotid artery.
CRI was positively correlated with the NC (r 5 .57, P , .0001) and was negatively correlated with the fibrous cap thickness (r 5 2.33, P 5 .01). The mean CRI was 1.68 6 .23 (n 5 18), 1.73 6 .21 (n 5 10), and 2.00 6 .28 (n 5 33) for IPH scores of 1, 2, and 3, respectively. Figure 6 shows relationships between the CRI and each histologic marker of plaque vulnerability. A higher IPH score was significantly associated with a higher CRI (P ,.0001). The prevalence of a fresh IPH was particularly associated with a higher CRI (with fresh IPH [n 5 46] versus without fresh IPH [n 5 15] 5 1.92 6 .25 versus 1.82 6 .32, P 5 .005). The prevalence of mural thrombus (with mural thrombus [n 5 40] versus without mural thrombus [n 5 21] 5 1.97 6 .24 versus 1.80 6 .31, P 5 .03) and quantity of inflammatory cells (with macrophage infiltration [n 5 42] versus without macrophage infiltration [n 5 19] 5 1.92 6 .28 versus 1.74 6 .29, P 5 .03; with lymphocyte infiltration [n 5 47] versus without lymphocyte infiltration [n 5 14] 5 1.91 6 .29 versus 1.68 6 .33, P 5 .007) were also associated with a higher CRI. However, the prevalence of plaque rupture
Figure 3. Scatter plot showing the relationship between the carotid remodeling index (CRI) and symptomatology. The CRI was significantly higher in symptomatic patients compared with asymptomatic patients.
was not associated with the CRI (with plaque rupture [n 5 38] versus without plaque rupture [n 5 23] 5 1.92 6 .25 versus 1.82 6 .32, P 5 .22).
Interobserver Agreement Interobserver agreement of CRI was assessed in all patients by using Bland–Altman plots, which demonstrated a good interobserver agreement (Fig 7).
Discussion In this study, we showed that larger outward remodeling of the carotid artery was significantly associated with symptomatic carotid plaques and markers of histologic carotid plaque vulnerability such as higher NC proportion, IPH score, prevalence of fresh IPH, mural thrombus, and inflammatory cells. This is the first report to examine the relationship between histologic markers related to the carotid plaque vulnerability and carotid artery remodeling, suggesting that CRI is a useful marker of future stroke risk in significant carotid stenosis ($50%).
Figure 4. Receiver operating characteristic curve analyses indicate that a CRI of 1.69, calculated by MPRAGE imaging, is the most reliable cutoff value for predicting symptomatic ICA lesions. Abbreviations: AUC, area under the curve; CRI, carotid remodeling index; ICA, internal carotid artery.
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Figure 5. Scatter plot showing the relationship between the carotid remodeling index (CRI) and the histologic characteristics. The CRI is positively correlated with necrotic core proportion (A) and negatively correlated with fibrous cap thickness (B).
Assessment of Outward Remodeling on Carotid Artery Because Gragov et al1 first reported expansive vessel remodeling to maintain an adequate luminal area in response to the development of atherosclerotic plaques at early stages, several studies using various imaging modalities2-8 have been published regarding outward remodeling and plaque vulnerability of the coronary artery. The Atherosclerosis Risk in the Communities study has assessed the carotid arteries of healthy individuals with B-mode ultrasound and found that, when carotid arterial enlargement accompanies increased wall thickness, there is less lumen constriction than expected, suggesting the pathogenesis of symptoms related to carotid stenosis.23 However, the incidence and clinical significance of carotid remodeling remain uncertain because only a few studies have been reported.9,10 Hardie et al10 have demonstrated significantly greater expansive carotid remodeling in pa-
tients with cerebral symptoms compared with asymptomatic patients as assessed by multidetector CT (MDCT) angiography, suggesting that MDCT is a reliable modality to measure the vascular lumen accurately. Compared with ultrasonography and MDCT angiography, MRI has the advantages of objective and excellent soft tissue contrast, no radiation exposure, availability for high cervical lesions, and noninvasively displaying the vascular lumen without a contrast medium.9,11,17,24 However, few studies have examined carotid artery remodeling with MRI.9,11 The MRI study with blackblood MRI of the Atherosclerosis Risk in the Communities examined the association between the luminal area and maximum wall thickness and found that carotid arteries can compensate for a greater degree of thickening than coronary arteries.11 However, they did not assess the carotid outward remodeling based on plaque
Figure 6. Bar chart shows relationships between the carotid remodeling index (CRI) and each histologic marker of plaque vulnerability. The average number of CRI is shown on vertical axis, and the score of intraplaque hemorrhage 1, 2, and 3, and the existence of each histologic marker are shown on horizontal axis. ‘‘*,’’ Indicates significance at P , .05 and ‘‘**,’’ indicates significance at P , .0001.
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Relationship between Outward Remodeling and Plaque Component on MRI Recent studies have demonstrated that carotid artery plaques with high-signal intensity (SIR . 2) on MPRAGE are correlated with symptomatic plaques and larger NCs with IPH.17,18 Plaque component assessment by MR plaque imaging is widely used for the assessment of carotid plaque vulnerability, leading to the prediction of subsequent ischemic events on clinical follow-up examinations and complications of CEA and carotid artery stenting.33-37 However, the findings of vulnerable plaques based on the MR signal intensity of the carotid plaque component vary among the MRI techniques.38 In this study, the CRI was correlated with SIR. So, the CRI and SIR could be complementary markers for evaluating vulnerable carotid plaques in MPRAGE imaging. Figure 7. Bland–Altman plot displaying the interobserver agreement of CRI between 2 observers.
vulnerability. Miura et al9 have evaluated the association between positive remodeling of the carotid artery and plaque vulnerability based on symptomatology and histology in 28 patients with black-blood MRI. However, details of the histologic assessments are not available because only 10 plaques extracted by CEA were examined to determine whether they were classified to stage VI according to the American Heart Association criteria.25
Relationship between Outward Remodeling and Plaque Vulnerability on Carotid Arteries Here, we clearly demonstrate using MPRAGE that a higher CRI is associated with a higher NC proportion, IPH score, and prevalence of fresh IPH, mural thrombus, and inflammatory cells (macrophages and lymphocytes), which are considered markers of plaque vulnerability.16,26-29 Previous histologic studies revealed that enlargement of the NC leads to plaque instability,26-28 and a large NC is strongly associated with fibrous cap thinning, fibrous cap rupture, mural thrombus, and IPH.16,29 Greater IPH and higher inflammatory cell counts in the fibrous cap could cause further expansion of the NC and result in plaque destabilization.2,30-32 These are consistent with the finding that greater expansive remodeling of the coronary artery is related to a significantly larger lipid core and higher macrophage count.2 Our histologic results demonstrate that larger outward remodeling of the carotid artery indicates the progression of histologic plaque vulnerability. In addition, the correlation between greater expansive remodeling of carotid plaques and the clinical symptomatic presentation is similar to the findings that positive remodeling of coronary plaques was associated with unstable clinical presentation.3 To evaluate outward remodeling on carotid arteries and on coronary arteries could be important in assessing plaque vulnerability.
Study Strengths and Limitations A strength of this study is that the CRI was evaluated by MPRAGE imaging. The usefulness of MPRAGE imaging for the assessment of clinical significance and histologic characterization in patients with carotid stenosis has been established in previous studies.17,18 So, we could evaluate plaque vulnerability using both CRI and SIR in MPRAGE imaging without additional sequence efficiently in clinical use. In addition, this study clearly demonstrates the close correlation between outward remodeling and plaque vulnerability in high-grade stenosis ($50%) although the clinical significance of plaque vulnerability and outward remodeling in future stroke risk has been emphasized in low-grade carotid stenosis.39 This is important because in contrast to symptomatic stenosis, there is little evidence that the risk of stroke in asymptomatic stenosis increases with the degree of stenosis across the 50%-99% range.40 A CRI of 1.69 was determined as the most reliable cutoff value for predicting symptomatology. In this analysis, the specificity was relatively low (64%). Indeed, 9 of 25 (36%) asymptomatic patients had the value of CRI greater than 1.69. However, 7 of these 9 patients with the value of CRI greater than 1.69 had vulnerable plaque component with an SIR greater than 2. The CRI was significantly correlated with SIR in this study. These results indicate that the CRI may be a useful marker to predict future stroke risk in asymptomatic patients. Because of the low risk of stroke in patients with asymptomatic carotid stenosis and the progress of intensive medical treatment,41 there is the potential to explore the need for CEA and carotid artery stenting especially in asymptomatic patients using CRI. The methods of calculating outward remodeling of the carotid artery deserve some mention. Previous studies proposed 2 parameters to demonstrate the degree of outward remodeling in the coronary artery: remodeling index calculated as the ratio of external CSVA at the maximal vessel stenosis to the mean reference external
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CSVA and remodeling ratio as the ratio of CSVA at the maximal vessel stenosis to CSVA at the distal portion.3 In this study, CRI was defined as the ratio of the external CSVA at the maximum stenosis of the ICA to the external CSVA at the distal ICA unaffected by atherosclerosis. Although the method based on the North American Symptomatic Carotid Endarterectomy Trial criteria used in this study may be affected by flow reduction beyond the critical stenosis, the external CSVA at the distal ICA of our study was comparable with the control group, suggesting a negligible effect of flow reduction. In addition, Miura et al9 reported that both these methods significantly correlated with the signal intensity of carotid plaques on MRI and a higher prevalence of stroke. Another limitation is the retrospective nature of this study regarding case selection bias. Despite these limitations, our results indicate that the CRI calculated using MPRAGE imaging, as a noninvasive and objective modality, is a reliable marker of plaque vulnerability determined based on symptomatology and histology. A prospective large study remains necessary to conclude which parameters are more likely to predict the plaque vulnerability of the carotid plaques.
Conclusions This study clearly demonstrates the relationship between carotid artery remodeling and plaque vulnerability based on symptomatology and histology in significant carotid stenosis ($50%) using MPRAGE. This study indicates that MPRAGE imaging is useful for the assessment of carotid artery remodeling. To evaluate the outward remodeling of carotid artery using MPRAGE imaging is predictive of the risk of ipsilateral ischemic events in the future. Acknowledgment: The authors thank Mayumi Oka and Yoshifumi Higashino for collecting the patient data.
References 1. Glagov S, Weisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987;316:1371-1375. 2. Varnava AM, Mills PG, Davies MJ. Relationship between coronary artery remodeling and plaque vulnerability. Circulation 2002;105:939-943. 3. Schoenhagen P, Ziada KM, Kapadia SR, et al. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: an intravascular ultrasound study. Circulation 2000;101:598-603. 4. Kim WY, Stuber M, Bornert P, et al. Three-dimensional black-blood cardiac magnetic resonance coronary vessel wall imaging detects positive arterial remodeling in patients with nonsignificant coronary artery disease. Circulation 2002;106:296-299. 5. Nakamura M, Nishikawa H, Mukai S, et al. Impact of coronary artery remodeling on clinical presentation of coronary artery disease: an intravascular ultrasound study. J Am Coll Cardiol 2001;37:63-69.
6. Pasterkamp G, Schoneveld AH, van der Wal AC, et al. Relation of arterial geometry to luminal narrowing and histologic markers for plaque vulnerability: the remodeling paradox. J Am Coll Cardiol 1998;32:655-662. 7. Pasterkamp G, Wensing PJ, Hillen B, et al. Impact of local atherosclerotic remodeling on the calculation of percent luminal narrowing. Am J Cardiol 1997;79:402-405. 8. Achenbach S, Ropers D, Hoffmann U, et al. Assessment of coronary remodeling in stenotic and nonstenotic coronary atherosclerotic lesions by multidetector spiral computed tomography. J Am Coll Cardiol 2004;43:842-847. 9. Miura T, Matsukawa N, Sakurai K, et al. Plaque vulnerability in internal carotid arteries with positive remodeling. Cerebrovasc Dis Extra 2011;1:54-65. 10. Hardie AD, Kramer CM, Raghavan P, et al. The impact of expansive arterial remodeling on clinical presentation in carotid artery disease: a multidetector ct angiography study. AJNR Am J Neuroradiol 2007;28:1067-1070. 11. Astor BC, Sharrett AR, Coresh J, et al. Remodeling of carotid arteries detected with MR imaging: atherosclerosis risk in communities carotid MRI study. Radiology 2010; 256:879-886. 12. 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;104:2051-2056. 13. Yuan C, Kerwin WS, Ferguson MS, et al. Contrastenhanced high resolution MRI for atherosclerotic carotid artery tissue characterization. J Magn Reson Imaging 2002;15:62-67. 14. Cappendijk VC, Cleutjens KB, Heeneman S, et al. In vivo detection of hemorrhage in human atherosclerotic plaques with magnetic resonance imaging. J Magn Reson Imaging 2004;20:105-110. 15. Moody AR, Murphy RE, Morgan PS, et al. Characterization of complicated carotid plaque with magnetic resonance direct thrombus imaging in patients with cerebral ischemia. Circulation 2003;107:3047-3052. 16. Cappendijk VC, Cleutjens KB, Kessels AG, et al. Assessment of human atherosclerotic carotid plaque components with multisequence MR imaging: Initial experience. Radiology 2005;234:487-492. 17. Yamada N, Higashi M, Otsubo R, et al. Association between signal hyperintensity on T1-weighted MR imaging of carotid plaques and ipsilateral ischemic events. AJNR Am J Neuroradiol 2007;28:287-292. 18. Hishikawa T, Iihara K, Yamada N, et al. Assessment of necrotic core with intraplaque hemorrhage in atherosclerotic carotid artery plaque by MR imaging with 3d gradient-echo sequence in patients with high-grade stenosis. Clinical article. J Neurosurg 2010;113:890-896. 19. Mugler JP III, Brookeman JR. Three-dimensional magnetization-prepared rapid gradient-echo imaging (3D MP rage). Magn Reson Med 1990;15:152-157. 20. Moody AR, Allder S, Lennox G, et al. Direct magnetic resonance imaging of carotid artery thrombus in acute stroke. Lancet 1999;353:122-123. 21. Iihara K, Murao K, Sakai N, et al. Outcome of carotid endarterectomy and stent insertion based on grading of carotid endarterectomy risk: a 7-year prospective study. J Neurosurg 2006;105:546-554. 22. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1:307-310. 23. Crouse JR, Goldbourt U, Evans G, et al. Arterial enlargement in the atherosclerosis risk in communities (ARIC)
ASSESSMENT OF CAROTID ARTERY REMODELING WITH MPRAGE
24.
25.
26.
27.
28. 29.
30.
31.
32.
33.
cohort. In vivo quantification of carotid arterial enlargement. The ARIC investigators. Stroke 1994;25:1354-1359. Sadat U, Teng Z, Young VE, et al. Utility of magnetic resonance imaging-based finite element analysis for the biomechanical stress analysis of hemorrhagic and non-hemorrhagic carotid plaques. Circ J 2011;75: 884-889. Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the committee on vascular lesions of the council on arteriosclerosis, american heart association. Circulation 1995; 92:1355-1374. Virmani R, Kolodgie FD, Burke AP, et al. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 2005;25:2054-2061. Nighoghossian N, Derex L, Douek P. The vulnerable carotid artery plaque: current imaging methods and new perspectives. Stroke 2005;36:2764-2772. Golledge J, Greenhalgh RM, Davies AH. The symptomatic carotid plaque. Stroke 2000;31:774-781. Redgrave JN, Lovett JK, Gallagher PJ, et al. Histological assessment of 526 symptomatic carotid plaques in relation to the nature and timing of ischemic symptoms: the oxford plaque study. Circulation 2006;113:2320-2328. Kolodgie FD, Gold HK, Burke AP, et al. Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 2003;349:2316-2325. Burke AP, Kolodgie FD, Farb A, et al. Morphological predictors of arterial remodeling in coronary atherosclerosis. Circulation 2002;105:297-303. Pasterkamp G, Galis ZS, de Kleijn DP. Expansive arterial remodeling: location, location, location. Arterioscler Thromb Vasc Biol 2004;24:650-657. Altaf N, MacSweeney ST, Gladman J, et al. Carotid intraplaque hemorrhage predicts recurrent symptoms in patients with high-grade carotid stenosis. Stroke 2007; 38:1633-1635.
9
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. Altaf N, Beech A, Goode SD, et al. Carotid intraplaque hemorrhage detected by magnetic resonance imaging predicts embolization during carotid endarterectomy. J Vasc Surg 2007;46:31-36. 36. Yamada K, Yoshimura S, Kawasaki M, et al. Embolic complications after carotid artery stenting or carotid endarterectomy are associated with tissue characteristics of carotid plaques evaluated by magnetic resonance imaging. Atherosclerosis 2011;215:399-404. 37. Akutsu N, Hosoda K, Fujita A, et al. A preliminary prediction model with mr plaque imaging to estimate risk for new ischemic brain lesions on diffusion-weighted imaging after endarterectomy or stenting in patients with carotid stenosis. AJNR Am J Neuroradiol 2012;33:1557-1564. 38. Saito A, Sasaki M, Ogasawara K, et al. Carotid plaque signal differences among four kinds of t1-weighted magnetic resonance imaging techniques: a histopathological correlation study. Neuroradiology 2012;54:1187-1194. 39. Yoshida K, Sadamasa N, Narumi O, et al. Symptomatic low-grade carotid stenosis with intraplaque hemorrhage and expansive arterial remodeling is associated with a high relapse rate refractory to medical treatment. Neurosurgery 2012;70:1143-1150. discussion 1150-1141. 40. Halliday A, Mansfield A, Marro J, et al. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet 2004;363:1491-1502. 41. Marquardt L, Geraghty OC, Mehta Z, et al. Low risk of ipsilateral stroke in patients with asymptomatic carotid stenosis on best medical treatment: a prospective, population-based study. Stroke 2010;41:e11-e17. 42. Imazeki T, Sato Y, Inoue F, et al. Evaluation of coronary artery remodeling in patients with acute coronary syndrome and stable angina by multislice computed tomography. Circ J 2004;68:1045-1050.