High-Intensity Signal on Time-of-Flight Magnetic Resonance Angiography Indicates Carotid Plaques at High Risk for Cerebral Embolism During Stenting
Background and Purpose—A major disadvantage of carotid artery stenting (CAS) compared to carotid endarterectomy is the increased risk of cerebral embolism. Thus, establishing a simple method to discriminate fragile plaques on preoperative routine examination is important. The present study examined whether high-intensity signal (HIS) in the plaque on time-of-flight (TOF) MRA, performed for screening, can discriminate plaque at high risk for cerebral embolism during CAS.
Methods—In the 30 patients treated using carotid endarterectomy, relationships between pathological findings of the plaques and TOF-MRA findings were analyzed. In the 112 patients treated using CAS, postoperative ipsilateral ischemic lesions on diffusion-weighted imaging and periprocedural ischemic symptoms were analyzed.
Results—The percentage area of intraplaque hemorrhage stained by glycophorin A was significantly larger in HIS-positive plaques (51.8%±9.8%) than in HIS-negative plaques (8.6%±9.4%; P<0.001). Postoperative ischemic lesions on diffusion-weighted imaging were more frequent in the HIS-positive plaques (25/38; 65.8%) than in the HIS-negative plaques (26/74; 35.1%; P=0.002). Periprocedural ischemic symptoms were more frequently observed in HIS-positive plaques (7/38; 18.4%) than in HIS-negative plaques (1/74; 1.4%; P=0.003). Multivariate logistic regression analysis identified HIS on TOF-MRA as an independent predictor of periprocedural ischemic symptoms (odds ratio, 15.08; 95% confidence interval, 1.76–129.0).
Conclusions—HIS in the plaque on TOF-MRA performed for screening could discriminate plaques at high risk for cerebral embolism during CAS.
Although carotid endarterectomy (CEA) is the established treatment for stroke prevention, carotid artery stenting (CAS) recently has emerged as a less invasive alternative to CEA. Two randomized controlled trials have shown that CAS and CEA offer similar efficacy,1,2 whereas another 3 randomized studies have reported that CEA is superior to CAS.3–5 Indications for CAS thus remain controversial. One of the major disadvantages of CAS is a high incidence of cerebral embolism. Recent reports described that there was an association between specific plaque components evaluated by preoperative examinations and an increased number of emboli after CAS,6,7 and that multispectral MRI could identify plaque constituents, such as the necrotic core and intraplaque hemorrhage, with high sensitivity and specificity.8,9 However, this examination requiring high-resolution MRI is not always available before revascularization procedures. Establishing a simple method to discriminate plaques at high risk for cerebral embolism during CAS on preoperative routine examination is important. We focused on high-intensity signal (HIS) in the plaque on time-of-flight (TOF) MRA performed for screening. The aims of this study were to validate HIS in the plaque on TOF-MRA with histology in CEA patients and to elucidate whether the presence of HIS on TOF-MRA was a high risk for ischemic event during CAS.
Materials and Methods
This study includes validation study by pathological analysis of surgical specimens from CEA and clinical study using MRI before and after CAS. The experimental protocol for the present study was approved by the Institutional Review Board (#22–201), and informed consent was obtained from all patients for pathological analysis.
From June 2007 to August 2010, a total of 30 consecutive patients (27 men, 3 women; 74±6 years) with carotid artery stenosis received preoperative TOF-MRA followed by CEA. The obtained specimens were analyzed pathologically and compared with the findings of preoperative TOF-MRA.
All patients treated by CEA received general anesthesia. An intraluminal shunt was used in all patients. Shunt insertion was performed immediately after arterectomy before removing the atherosclerotic plaques to provide immediate reperfusion. Before skin closure, all patients underwent angiography in the operating room to confirm patency of the carotid arteries. The patients were transferred to the intensive care unit for 24 to 48 hours after surgery.
From April 2004 and August 2010, a total of 112 consecutive patients with carotid artery stenosis received CAS and underwent MRI both preoperatively and postoperatively. TOF-MRA and diffusion-weighted imaging (DWI) were performed before treatment, and postoperative new ischemic lesions were assessed by DWI within 3 days after CAS. The relationship between HIS in the plaque on TOF-MRA and clinical symptoms after the procedure were analyzed retrospectively.
Acetyl salicylic acid (100 mg) and clopidogrel (75 mg) or ticlopidine (200 mg) or cilostazol (200 mg) were administered for a minimum of 7 days before the procedure. All CAS procedures were performed under local anesthesia via the percutaneous transfemoral route. The procedures were performed by a single neurointerventional team. A heparin bolus of 100 U/kg was administered just before the procedure to increase activated clotting time to a minimum of 250 seconds. Three types of embolic protection devices were used: distal balloon protection using Guardwire (Medtronic AVE; n=56); distal filter protection using Angioguard (Cordis; n=18); or proximal balloon protection using Optimo (Tokai Medical Products) and Guardwire (n=38). Two types of stents were placed in the stenotic lesion: Precise (Cordis; n=90) or Wallstent (Boston Scientific; n=22). The patients were evaluated neurologically 2 to 7 days after CAS by independent clinicians who were blind to CAS procedures by use of National Institute of Health Stroke Scales.10
MRI Protocol: TOF-MRA
MRI was performed using a 1.5-T system (Intera Achieva Nova Dual; Philips Medical Systems) equipped with a neurovascular coil. Maximum intensity projection images from TOF-MRA were obtained using the following parameters: repetition time, 17.5 ms; echo time, 6.9 ms; flip angle, 18 degrees; field of view, 220×110 mm; matrix, 256×128 (recon 512×512); and slice thickness, 0.8 mm (slice zip 2).
The same MRI system as TOF-MRA was used for DWI, applying the echoplanar method under the following conditions: repetition time, 2060 ms; echo time, 67.0 ms; slice thickness, 5 mm; spacing, 1.5 mm; b value, 1000 sec/mm2; and field of view, 24 cm.
Histological Processing and Evaluation
CEA specimens were immediately fixed in 10% buffered formalin, then embedded in paraffin. Serial 3-μm-thick sections were stained with hematoxylin-eosin and Masson's trichrome for histological evaluation. In addition, immunohistochemical staining was performed for glycophorin A, a protein specific to erythrocyte membranes, and CD68, an antibody targeted to macrophages, to identify intraplaque hemorrhage and macrophage infiltration, respectively. Each section was evaluated by an experienced histopathologist who was blinded to MRI results. The proportion of the intraplaque hemorrhage area was measured using Image J software (http://rsb.info.nih.gov/ij/download/) for all sections (glycophorin A-positive area/whole plaque area). CD68-positive cells were counted manually in 5 different fields from each section and total values were calculated. Fibrous cap was defined as a distinct layer of connective tissue completely covering the lipid core. Microscopic sections stained with Masson's trichrome were used for analysis of fibrous cap thickness.
MRI Analysis: TOF-MRA
HIS on cross-sectional TOF-MRA was reported as a sign of intraplaque hemorrhage.11,12 In the present study, we focused on HIS in the sagittal oblique maximum intensity projection images, rather than sectional images, on TOF-MRA (Figure 1A).
Baseline DWI was obtained after diagnostic angiography and before CAS in all patients. A second DWI was performed within 72 hours after CAS and only newly appearing lesions were regarded as ischemic lesions during CAS. A positive ischemic lesion was evaluated by DWI and apparent diffusion coefficient maps.13
Continuous values are expressed as the mean±standard deviation. Categorical data are summarized as percentages and were compared using Fisher exact test. Comparisons of continuous variables between cohorts were performed using an unpaired Student t test. Values of P<0.05 were considered indicative of a statistically significant difference. All variables with P<0.05 comparing postoperative ipsilateral ischemic lesion-positive (symptoms) with postoperative ipsilateral ischemic lesion-negative (symptoms) states were included in multivariate logistic regression analysis. That is, symptomatic stenosis and HIS in the plaque on TOF-MRA were analyzed for postoperative ipsilateral ischemic lesions and periprocedural ischemic symptoms. All statistical analyses were performed using StatView 5.0 software (SAS Institute).
Cohen κ values were calculated to quantify the level of agreement regarding the presence of HIS in the plaque on TOF-MRA between observers. A value of κ≥0.75 was used to indicate a high level of agreement, and 0.4<κ<0.75 indicated moderate agreement.14
A total of 30 CEA procedures were completed successfully, and no neurological complications were encountered in patients treated with CEA. Among the 30 patients, 23 had HIS-positive plaques and 7 had HIS-negative plaques on TOF-MRA. Representative cases of HIS-positive and HIS-negative plaque on TOF-MRA were shown (Figures 1, 2).
In these 30 specimens, the relationship between the presence of HIS in the plaque on TOF-MRA and glycophorin A-positive area was investigated. The percentage area stained by glycophorin A was significantly larger in HIS-positive plaques (51.8%±9.8%) than in HIS-negative plaques (8.6%±9.4%; P<0.001; Figure 3A). The glycophorin A-positive area corresponded well with the area of intraplaque hemorrhage diagnosed by Masson's trichrome staining on serial sections. This result suggested that intraplaque hemorrhage was significantly larger for HIS-positive plaques.
Next, the relationship between the presence of HIS on TOF-MRA and CD68-positive area was analyzed (Figure 3B). CD68-positive cells were more common in HIS-positive plaques (662±274 cells/5 fields) than in HIS-negative plaques (232±71 cells/5 fields; P<0.001). This indicated a greater degree of macrophage infiltration in HIS-positive plaques.
Furthermore, the relationship between the presence of HIS on TOF-MRA and thickness of the fibrous cap was also analyzed (Figure 3C). No significant difference was identified between the HIS-positive plaques (102±73 μm) and the HIS-negative plaques (134±181 μm; P=0.664). This result showed no relationship between the presence of HIS on TOF-MRA and thickness of the fibrous cap.
A total of 112 consecutive CAS procedures were successfully completed with adequate angiographic results, but 8 ipsilateral strokes (7.2%) were seen after the procedures. These 8 patients had experienced stroke before CAS, and modified Rankin Scale score at 90 days was 0 to 1 in 6 patients, 2 in 1 patient, and 3 in 1 patient.
Characteristics of patients treated by CAS are shown in terms of presence or absence of HIS on TOF-MRA (Table 1). Patient characteristics with or without ischemic lesion on DWI or ischemic symptoms were shown (Supplemental Table I and II, http://stroke.ahajournals.org).
Regarding the presence of HIS in the plaque on TOF-MRA, Cohen κ values quantifying the level of agreement for the presence of HIS between observers was 0.76, indicating a high level of agreement.
To clarify the ability of HIS in the plaque on TOF-MRA to predict cerebral embolism after CAS, relationships between the presence of HIS on TOF-MRA and new ischemic lesions on DWI and periprocedural ischemic symptoms after CAS were investigated.
Among the 112 patients treated using CAS, HIS in the plaque on TOF-MRA was positive in 38 patients (33.9%) and negative in 74 patients (66.1%). Ischemic lesions were observed in 9 patients (8.0%) on baseline DWI before CAS. Postoperative new ischemic lesions on DWI were observed in the hemisphere in 51 of 112 patients (45.5%; ipsilateral lesions in 46 patients and bilateral lesions in 5 patients). Ipsilateral new ischemic lesions after CAS were detected with a higher frequency in HIS-positive groups (25/38; 65.8%) than in HIS-negative groups (26/74; 35.1%; P=0.002; Figure 4A). Furthermore, periprocedural ischemic symptoms were more frequently observed in HIS-positive groups (7/38; 18.4%) than in HIS-negative groups (1/74; 1.4%; P=0.003; Figure 4B).
Multivariate logistic regression analysis revealed that independent predictors of ischemic lesions on DWI were symptomatic stenosis and HIS in the plaque on TOF-MRA, and the only independent predictor of postoperative ischemic symptoms was HIS in the plaque on TOF-MRA (Tables 2).
The present study demonstrated that HIS on TOF-MRA was associated with intraplaque hemorrhage and that ischemic events after CAS were more frequent in HIS-positive plaques. Multivariate regression analysis showed that the only independent predictor of postoperative ischemic symptoms was the presence of HIS in the plaque. These results indicated that HIS on TOF-MRA could identify the plaques at high risk for cerebral embolism during CAS.
Previous pathological studies have shown that HIS on TOF-MRA reportedly indicates intraplaque hemorrhage.11,12 Validation study using surgical specimens in the present study found that intraplaque hemorrhage and macrophage infiltration were more frequent in HIS-positive plaques than in HIS-negative plaques. These findings suggested that HIS on TOF-MRA indicated the plaques with fragile components leading to cerebral embolism by balloon and stent compression.
This study focused on findings on TOF-MRA, which is widely available for carotid artery screening. This may be important because precise plaque imaging using high-resolution MRI is not common before revascularization procedures. With the focus on HIS in the plaque, TOF-MRA performed even for carotid artery screening could provide sufficient information about plaque composition without the need for any additional examination.
It was shown that echolucent plaques in carotid arteries diagnosed by conventional ultrasonography were associated with a high incidence of ischemic complications after CAS.6 However, MRI findings are usually more objective and reproducible than those of carotid duplex ultrasonography. Furthermore, other information on brain and intracranial and extracranial vessels can be obtained by MRI and MRA, providing important information for decision-making in carotid artery treatment. Confirmation of HIS on screening TOF-MRA seems useful before CAS to exclude lesions with large amounts of unstable components such as intraplaque hemorrhage.
Regarding clinical relevance of the results obtained in the present study, we propose performing CEA instead of CAS if the plaque is HIS-positive and the risk of CEA is not too high, and selecting more CAS than CEA if the plaque is HIS-negative. For HIS-positive plaques, modified CAS procedure with balloon cerebral protection or medical treatment without carotid revascularization might be good options when the risk of CEA is too high. A clinical study regarding the relationship between treatment selection and clinical results in patients with HIS-positive plaque would be necessary in the near future.
Several limitations must be considered for the present study. First, because this study was performed in a retrospective manner, prospective studies will be required in the future. Second, we focused on the presence of HIS in the plaque on TOF-MRA in this study, but the volume of HIS in the plaque might be another important indicator for distal embolism, because this correlates with the volume of intraplaque hemorrhage. The relationship between volume of HIS in the plaque and distal embolism attributable to CAS should also be elucidated in future analyses.
HIS in the plaques on TOF-MRA was associated with intraplaque hemorrhage and macrophage infiltration on pathological analysis, and was clinically associated with ischemic lesions on DWI and ischemic symptoms after CAS. HIS in the plaque on TOF-MRA may be useful for preoperatively identifying vulnerable plaques at high risk for CAS.
Sources of Funding
This study was supported by the Research Grant Program of Gifu University Hospital.
The authors thank Dr Hideki Ota, Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine, for his advice on editing the manuscript.
The online-only Data Supplement is available at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.111.615708/-/DC1.
- Received February 1, 2011.
- Accepted May 19, 2011.
- © 2011 American Heart Association, Inc.
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