Low-Grade Carotid Stenosis

Low-Grade Carotid Stenosis

L o w - G r a d e Ca ro t i d Stenosis Implications of MR Imaging Mahmud Mossa-Basha, MDa,*, Bruce A. Wasserman, MDb KEYWORDS  MR imaging  Carotid v...

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L o w - G r a d e Ca ro t i d Stenosis Implications of MR Imaging Mahmud Mossa-Basha, MDa,*, Bruce A. Wasserman, MDb KEYWORDS  MR imaging  Carotid vessel wall imaging  Low-grade carotid stenosis  Stroke

KEY POINTS  Luminal imaging techniques do not adequately evaluate extracranial carotid atherosclerotic plaque burden and characteristics in patients with low-grade carotid stenosis.  Although multiple randomized controlled trials have not indicated an advantage to surgery over medical management in the low-grade stenosis population, there is an associated risk of stroke.  Plaque features such as intraplaque hemorrhage, fibrous cap rupture, and ulceration, among others, confer an increased risk of stroke in low-grade stenosis.  Considering that atherosclerosis is a systemic disease, vessel wall MR imaging can help determine the culprit lesion in the setting of cryptogenic stroke.  Carotid vessel wall MR imaging can be helpful in identifying likelihood of plaque and its associated risk in other vascular beds that are not as easily imaged.

Stroke is the second most common cause of mortality and a leading cause of morbidity worldwide. Approximately 80% of strokes are presumed to be ischemic in etiology, with 20% to 30% arising from extracranial carotid atherosclerosis.1 In the setting of extracranial carotid artery disease, the decision to treat symptomatic patients surgically or with carotid artery stenting has traditionally relied on the degree of luminal stenosis on catheter angiography based on the results of randomized controlled trials.2,3 Pooled data from the trials showed a 16% absolute reduced 5-year risk of future stroke events in patients with 70% or greater stenosis undergoing carotid endarterectomy in comparison with medical management.4 Over the past 10 years, however, investigation has placed less emphasis on the degree of

stenosis and more on plaque features that confer lesion vulnerability. These vulnerable plaque features support the hypothesis, as in coronary artery disease, that many cerebral infarctions result from plaque rupture and distal embolization or acute occlusion, and not long-standing hypoperfusion.5–9 Multiple studies have provided evidence that plaques resulting in moderate stenosis can rupture and result in acute ischemic events.10–12 Barnett and colleagues13 indicated a significantly increased 5-year risk of ipsilateral stroke (P 5 .045) in patients with 50% to 69% stenosis treated medically (22.2%) compared with those treated surgically (15.7%). For those with less than 50% stenosis in the North American Symptomatic Carotid Endarterectomy Trial (NASCET), the stroke rate was lower in the surgical group relative to the medically managed group, although

Disclosure Statement: The authors have nothing to disclose. a Division of Neuroradiology, University of Washington Medical Center, University of Washington School of Medicine, 1959 Northeast Pacific Street, Box 357115, Seattle, WA 98195, USA; b Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, 367 East Park Building, 600 North Wolfe Street, Baltimore, MD 21287, USA * Corresponding author. E-mail address: [email protected] Neuroimag Clin N Am - (2015) -–http://dx.doi.org/10.1016/j.nic.2015.09.010 1052-5149/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.

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INTRODUCTION

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Mossa-Basha & Wasserman this did not reach statistical significance (14.9% vs 18.7%, P 5 .16). According to pooled data from the randomized control trials,4 the 5-year reduction in ipsilateral stroke rate was 4.6% for surgical patients with moderate (50%–69%) stenosis. There was no benefit in stroke rate for patients with 30% to 49% stenosis between the surgical and medical management groups, whereas there was increased risk of stroke in the surgical group for those with less than 30% stenosis (absolute risk reduction 2.2%, P 5 .05).4,14,15 The European Carotid Surgical Trial9 reported a 1.3% rate of ipsilateral ischemic stroke lasting longer than 7 days in patients with symptomatic mild (0%–29%) stenosis during a 3-year followup (0.43% per year). Fritz and Levien16 reported an 8.6% rate of ipsilateral ischemic events during a 2-year follow-up of 35 symptomatic patients with low-grade carotid stenosis or ulcerated plaque on medical management. In the setting of carotid atherosclerosis, including lesions resulting in low-grade carotid stenosis, there may be other lesions ipsilateral to the symptomatic side including aortic and intracranial plaques. Plaquecomponent characterization can provide important information to help stratify the likelihood that the carotid plaque is indeed the culprit lesion so that an appropriate treatment strategy can be implemented, including resection of the low-grade lesion. With moderate or severe carotid stenosis the associated plaques are presumed to be the culprits, and the randomized controlled trials have indicated the value of surgical intervention. The overestimation of stroke risk by contemporary standards in the medically managed groups for these trials that predate statin treatment suggests potential overtreatment of high-grade stenosis by surgery, and MR vessel wall imaging might also help to stratify high-grade lesions for a more appropriate balance of medical versus surgical treatments. Although the rate of stroke in low-grade extracranial carotid stenosis differs based on the aforementioned trials, these trials have indicated that the benefit of surgery in low-grade stenosis may not improve the outcome over medical management when surgical risks are taken into consideration. However, these trials are based on narrowing to guide surgical management, which cannot stratify the risk of rupture for low-grade lesions and identify those at high enough risk to benefit from endarterectomy, and for this reason plaque characterization by MR imaging can potentially play an important role. Furthermore, despite a lower risk of stroke from low-grade carotid plaque compared with high-grade lesions, the chance for stroke from low-grade plaque cannot be

discounted when considering the high prevalence of this disease. The occurrence of low-grade carotid stenosis in elderly populations is frequent, as 75% of men and 62% of women older than 64 years had carotid stenosis on ultrasonography in the Cardiovascular Health Study,17 whereas only 7% of men and 5% of women had stenosis greater than 49%.

MODIFICATIONS IN MEDICAL MANAGEMENT Since the publication of the trials for evaluation of disease management based on luminal stenosis, there have been significant changes to the optimal medical management regimen that have modified stroke risk in medically managed patients. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), a class of cholesterol-lowering drugs, have become a staple of atherosclerosis-related stroke management. The Stroke Prevention by Aggressive Management in Cholesterol Levels Investigators (SPARCL)18 randomized 4731 patients with prior stroke or transient ischemic attack (TIA) (between 1 and 6 months from the event), no known coronary heart disease, and low-density lipoprotein cholesterol (LDL-C) between 100 and 190 mg/dL to 80 mg atorvastatin therapy or placebo. The 5-year absolute reduction in risk of major cardiovascular events was 3.5% (hazard ratio [HR] 0.8, 95% confidence interval [CI] 0.69–0.92; P 5 .002) with no significant difference in mortality rates. Of the 4731 randomized patients, 4278 were evaluated for carotid disease, and of those 1007 were found to have carotid stenosis.19 By randomization to the atorvastatin group, the incidence of any cardiovascular events was reduced by 42% relative to placebo (HR 0.58; 95% CI 0.46–0.73; P<.00001). The risk of cerebrovascular events (TIA or stroke) was reduced by 34% in the atorvastatin group (HR 0.66, 95% CI 0.5–0.89; P 5 .005). The risk of undergoing carotid revascularization was reduced by 54% (HR 0.44, 95% CI 0.24– 0.79; P 5 .006). The Heart Protective Study Collaborative Group20 randomized 20,536 patients in the United Kingdom with coronary artery disease, other occlusive artery disease, or diabetes mellitus to 40 mg simvastatin or placebo groups, and found a significant reduction in fatal and nonfatal stroke risk in the statin group (4.3% vs 5.7%, P<.0001). For the first occurrence of major vascular events, there was a 24% reduction in the event rate (19.8% vs 25.2%, P<.0001). Hegland and colleagues21 evaluated 230 patients with 318 carotid arteries with at least 40% carotid stenosis on carotid ultrasonography without occlusion or referral for carotid revascularization. Of

Low-Grade Carotid Stenosis these, 171 were not receiving statin therapy while 147 were treated with simvastatin. There was no significant difference in baseline stenosis but there was a significant difference in change in stenosis, as the group that did not receive statin therapy had a 14.9% change in stenosis while the simvastatin group had on average a stenosis change of 10% (P<.001). A meta-analysis22 that included more than 90,000 patients evaluated all trials testing the effect of statin drugs on the incidence of strokes and carotid intima-media (IMT) measurements by ultrasonography according to LDL-C reduction. The relative risk reduction for stroke was 21% (odds ratio [OR] 0.79). Statin size effect was significantly associated with LDL-C reduction, as each 10% reduction in LDL-C was estimated to reduce the risk of all strokes by 15.6% and carotid IMT by 0.73% per year. Statins have become a mainstay in the management of atherosclerosisrelated stroke events and, as already indicated, can significantly reduce stroke and stroke recurrence. However, there have been no recent randomized controlled trials comparing surgical and medical management with optimized medical therapy including statins to determine how their inclusion would modify surgical management algorithms.

EVALUATION OF PLAQUE BEYOND THE DEGREE OF LUMINAL STENOSIS Coronary angiographic studies have indicated that moderate to low-grade arterial stenoses may lead to myocardial infarction, and frequently the most stenotic artery will not be upstream from the myocardial infarction.23–25 Subsequent histopathologic studies indicated that plaque erosion and disruption were common features in symptomatic lesions.24,26 Similar findings have been made with carotid plaques and associated cerebrovascular events.10–12 Lovett and colleagues10 found a significant association between carotid plaque surface irregularity on angiography and associated plaque rupture and histologic vulnerable plaque characteristics including intraplaque hemorrhage (IPH), lipid-rich necrotic core, and plaque instability. Histologic evaluation indicated that plaque erosion and rupture were frequently seen in these culprit lesions, indicating that stenosis was not the sole predictor of stroke risk. The degree of stenosis is a poor predictor of plaque volume and extent.10,12,27 Inflammation is thought to represent an important destabilizing factor for atherosclerosis and is considered a major component of high-risk vulnerable plaque.28,29 Spagnoli and colleagues12 evaluated 269 carotid endarterectomy specimens, and

found a significantly higher rate of inflammatory infiltrate and acute thrombus formation with associated fibrous cap rupture in patients with acute infarct when compared with patients with TIA or no symptoms. Seventy-four percent of infarct patients had a thrombotically active plaque (fresh clot composed of platelets and fibrin on the plaque surface) compared with 35% with TIA (P<.001) and 14% of asymptomatic (P<.001) patients. There was also a significant difference in the presence of cap rupture between stroke and TIA patients (67% vs 23%, P<.001), stroke and asymptomatic patients (67% vs 13%, P<.001) and TIA and asymptomatic patients (23% vs 13%, P 5 .004). The study also found that ruptured plaques in stroke patients had inflammation that was twice as dense as that seen in TIA (P 5 .001) and asymptomatic (P 5 .001) patients. Redgrave and colleagues11 evaluated 526 consecutive endarterectomy specimens, and found that dense plaque inflammation (with macrophage infiltration) was the feature most strongly associated with fibrous cap rupture (OR 3.9, P<.001) and time since stroke (P 5 .001). There were significant negative associations between time since stroke and multiple plaque histologic features, including plaque macrophages (P 5 .007), overall plaque inflammation (P 5 .003), cap rupture (P 5 .02), and overall plaque instability (P 5 .001). There has been recent investigation of plaque inflammation and its correlation with plaque characteristics using PET/MR imaging.30–33 In the evaluation of 31 patients there was progressively significantly increased 18Ffluorodeoxyglucose activity on PET imaging between thick, thin, and ruptured fibrous caps.31 Plaques with lipid-rich necrotic cores or IPH also had significantly higher metabolic activity than those predominantly composed of collagen or calcification.31,33

LIMITATIONS OF LUMINAL IMAGING IN EVALUATION OF PLAQUE VOLUME Atherosclerotic lesions frequently remodel outwardly in their early development, which allows for maintenance of luminal size even for prominent lesions. Glagov and colleagues34 showed that luminal encroachment occurs in coronary arteries once plaque occupies 40% of the area encapsulated by the internal elastic lamina. For this reason, luminal imaging is limited in its ability to detect early lesions and frequently underestimates plaque burden in more advanced disease. Underestimation of plaque burden by angiography has been confirmed by correlation with endarterectomy specimens.15,35 Furthermore, luminal imaging evaluates disease at the point of maximum

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Mossa-Basha & Wasserman stenosis in comparison with adjacent “normal” segments. However, this does not take into account the diffuse nature of atherosclerotic disease, which further contributes to the underestimation of disease burden.36 Low-grade carotid lesions are often overlooked as a source of cerebral infarcts because of coexistent disease elsewhere, making it difficult to determine which lesion is the culprit and because plaque size is underestimated as a result of vascular remodeling. Identifying a plaque as having been the source of a stroke may change its risk profile for future events. Inzitari and colleagues37 showed that stroke risk in the territory of an asymptomatic carotid artery is substantially less than stroke risk in the territory of a symptomatic artery with a similar degree of stenosis. Dennis and colleagues38 showed that patients who experienced a TIA had a 13-fold excess stroke risk during the first year and a 7-fold excess risk over the first 7 years compared with those without TIAs. TIA

Fig. 1. Illustration of plaque characteristics.

might therefore be considered a warning for an impending cerebrovascular event and should warrant investigation of the culprit lesion. There is a growing body of literature indicating that plaque features and lesion volume play an important role in the assessment of stroke risk, especially when there is little to no narrowing. Fig. 1 illustrates carotid plaque characteristics to be further discussed herein. Freilinger and colleagues39 prospectively evaluated 32 consecutive stroke patients with less than 50% ipsilateral carotid stenosis with vessel wall MR imaging. American Heart Association (AHA) type VI plaques were found in 37.5% of plaques ipsilateral to the symptomatic side, with none on the contralateral side (P 5 .001). The most frequent vulnerable plaque features visualized included IPH (75%), fibrous cap rupture (50%), and intraluminal thrombus (33%). In reviewing 217 symptomatic patients with bilateral low-grade carotid stenosis, Cheung and colleagues40 found that the symptomatic

Low-Grade Carotid Stenosis side showed a significantly higher prevalence of IPH on T1-weighted vessel wall MR imaging than the contralateral side (13% vs 7%, P<.05). Altaf and colleagues41 evaluated patients with symptomatic mild carotid stenosis (30%–49%) and found that recurrence rates of ipsilateral stroke differed between patients with IPH represented by T1 hyperintensity (25%) compared with those without (10%). Yoshida and colleagues42 evaluated 25 patients with symptomatic low-grade (<50%) carotid stenosis and atherosclerotic plaque with high T1 signal and expansive remodeling on MR imaging. Eleven of the 25 patients had 30 recurrent infarcts on diffusion-weighted imaging (46% per patient-year) refractory to medical therapy, and were treated with carotid endarterectomy. Seven of the 11 patients in the recurrence group had no further stroke events in the postoperative follow-up period of 19.1  14.6 months. Weinstein43 found that IPH and plaque ulceration on ultrasonography were strongly associated with symptoms despite many lesions showing less than 50% luminal stenosis. In the review of vessel wall MR imaging of 47 patients, Qiao and colleagues44 found that symptoms were significantly associated with IPH (OR 10.18, P 5 .03). There was a progressively increasing significant association between symptoms and extent of neovascularity as indicated by grades of adventitial enhancement (0 5 absent, 1 5 <50%, 2 5 50%) (P 5 .02). The degree of stenosis did not correlate with ischemic events. These studies indicate how in the setting of low-grade or no stenosis, vulnerable plaque characteristics can determine the likelihood of symptoms and future events. There is continued investigation with multicenter trials to determine the role of vessel wall MR imaging in plaque characterization in the setting of cryptogenic stroke.45 Plaque surface irregularity or ulceration has been found to be an important plaque vulnerability factor, significantly increasing the risk of stroke (Fig. 2).46–49 In the analysis of 3007 patient angiograms from the European Carotid Surgery Trial,49 plaque surface irregularity was an independent predictor of ipsilateral ischemic stroke on medical treatment at all degrees of stenosis (HR 1.80, 95% CI 1.14–2.83; P 5 .01). In the evaluation of 659 patients who were found to have severe stenosis on angiography in NASCET, the risk of ipsilateral stroke at 24 months for medically treated patients with ulcerated plaques increased incrementally from 26.3% to 73.2% as the degree of stenosis increased from 75% to 95%. For patients with no ulcer, the risk of stroke remained constant at 21.3% for all degrees of stenosis. The net result yielded relative risks of stroke (ulcer vs no ulcer)

ranging from 1.24 (95% CI 0.61–2.52) to 3.43 (95% CI 1.49–7.88).46 Catheter angiography is not sensitive or specific for the detection of plaque ulcerations. The sensitivity and specificity of detecting ulcerated plaques were 45.9% and 74.1%, respectively. The positive predictive value of identifying an ulcer was 71.8%.50 MR imaging/ contrast-enhanced MR angiography is a sensitive technique for the detection of ulceration.51,52

PLAQUE PROGRESSION THROUGH REPEATED SILENT RUPTURES Coronary plaques that may rupture will frequently be associated with only mild to moderate stenosis and have vulnerable plaque characteristics, similar to what can be seen with vulnerable carotid atheroma. The coronary plaques that rupture have a lipid-rich necrotic core and a thin fibrous cap rich in macrophage and T-cell infiltration with focal disruption.53 Reports of the mean necrotic core size seen with plaque rupture related to sudden coronary death range from 34%53 to 50%.54 These plaques are highly vascularized with extensive ingrowth of the vasa vasorum.55 Carotid atheromas follow a similar pattern of disruption, with fibrous cap foam cell infiltration, thinning, and neovascularity also influencing the likelihood of rupture.56,57 Morphologic studies of coronary arteries suggest that plaque progression beyond 50% crosssectional luminal narrowing occurs secondary to repeated ruptures, which may be clinically silent.58,59 The sites of healed plaque ruptures can be recognized by demonstrating a necrotic core with a discontinuous fibrous cap, which is rich in type I collagen, and an overlying neointima formed by smooth muscle cells in a matrix rich in proteoglycan and type III collagen.58 Few angiographic studies have demonstrated plaque progression, and short-term studies have suggested that thrombosis is the likely cause. Mann and Davies59 showed that the frequency of healed plaque rupture increases along with lumen narrowing. Burke and colleagues58 found healed plaque ruptures in 61% of hearts from victims of sudden coronary death. Multiple healed plaque ruptures with layering were common in segments with acute and healed ruptures, and the percentage of cross-sectional luminal narrowing was dependent on the number of healed repair sites. The underlying percentage of luminal narrowing for acute ruptures exceeded that for healed ruptures (79%  15% vs 66%  14%; P<.0001).58 Therefore, the progression of atherosclerotic disease to severe stenosis is the result of repeated ruptures. At least 40% to 50% of

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Fig. 2. A 66-year-old man with repeated TIAs referable to territory of the right middle cerebral artery (MCA). Sagittal 3-dimensional (3D) maximum-intensity projection (MIP) reformat of the right carotid bifurcation (A) shows eccentric narrowing of the right carotid bulb measuring less than 25%. There is a focal ulceration along the outer wall. Axial T1 postcontrast double-inversion recovery black-blood sequence of the right carotid bulb (B) shows an outward remodeling plaque with focal areas of plaque enhancement. On time-of-flight MR angiography at the level of the carotid bulbs (C), there is juxtaluminal hypointensity on the right consistent with juxtaluminal calcification (long arrow), and intraplaque T1 shortening compatible with IPH. Sagittal T1 postcontrast double-inversion recovery black-blood sequence (D) confirms the presence of a small ulceration along the outer wall (white arrows). Short arrow points to the proximal internal carotid artery just distal to the carotid bifurcation.

coronary rupture sites show less than 50% diameter stenosis, and the same may be true in carotid disease.5,60 Spagnoli and colleagues12 reported a higher incidence of carotid thrombosis in patients with recent stroke in comparison with asymptomatic individuals.

HIGH-RESOLUTION VESSEL WALL MR IMAGING FOR CAROTID PLAQUE COMPONENT ASSESSMENT There has been increasing acceptance of noninvasive imaging for the evaluation of vulnerable

Low-Grade Carotid Stenosis plaque characteristics and their contribution to patient symptoms. Although ultrasonography has been proved to be a valuable technique for evaluation of plaque components, it is limited in its ability to differentiate IPH and lipid-rich necrotic core.61 Ultrasonography is sensitive for detecting calcifications but does a poor job imaging calcified plaques, as the acoustic shadowing limits softtissue visualization deep to the calcifications.62 Computed tomography (CT) imaging techniques can be used for plaque characterization, and provide a sensitive technique for the detection of calcifications. Some investigators have attempted to use lesion component attenuation for analysis63,64; however, attenuation characteristics depend on the energy level used65 and the administration of contrast,66,67 both of which can dramatically alter attenuation of lesion components. CT can also be of limited value in depicting some plaque components, including IPH. MR imaging has shown the ability to optimally differentiate plaque characteristics that confer plaque vulnerability, owing to its improved contrast resolution in comparison with CT and ultrasonography.68 Although CT is considered the best imaging technique for calcium detection in plaques, Clarke and colleagues69 reported MR imaging sensitivity of 97.6% for calcification detection compared with micro-CT and histology as the reference standard. MR imaging evaluation of calcification with histologic comparison showed MR imaging sensitivities ranging from 76% to 84% and specificity from 86% to 94%, with substantial agreement between the 2 techniques (k 5 0.65–0.75).70–73 Saam and colleagues73 determined the presence of calcification if there was matching plaque hypointensity on T1-weighted, T2-weighted, proton density– weighted, and time-of-flight (TOF) MR angiography sequences, with sensitivity of 76% and specificity of 86% when compared with histology. The sensitivity and specificity increased to 84% and 91% when only regions measuring greater than 2 mm2 were considered. Puppini and colleagues72 used these same 4 MR sequences to evaluate for calcifications, and found strong agreement with histologic evaluation. Cappendijk and colleagues71 chose the best combination of contrast weightings from 5 different weightings to assess plaque calcifications among other plaque components, and found that on MR imaging 100% of plaque calcifications could readily be identified and differentiated from other plaque components relative to histologic evaluation. There have been multiple reports of fibrous cap imaging on MR with histologic specimen correlation.70,72,74–76 Hatsukami and colleagues75 evaluated the fibrous cap on a 3-dimensional multiple

overlapping thin-slab MR angiographic technique, and found good agreement on fibrous cap status (89% agreement, weighted k 5 0.87) with histologic findings. The fibrous cap was determined to be thick or thin based on the presence of a dark band between the bright lumen and gray wall. The cap was considered disrupted if the dark band was not visualized and there was bright gray signal adjacent to the lumen with or without an irregular luminal surface. Cai and colleagues70 used TOF MR angiography to determine fibrous cap status, differentiating between thick (>0.25 mm) or disrupted with similar determination of disrupted cap as described in the aforementioned study. There was good accuracy of MR imaging in identifying AHA type VI lesion characteristics including fibrous cap disruption, with sensitivity and specificity of 82% and 91%, respectively. Trivedi and colleagues77 defined fibrous cap as the juxtaluminal hyperintense component on short-tau inversion recovery sequences. These investigators compared MR imaging and histology-derived fibrous cap lipidrich necrotic core thickness measurement ratios, and found strong agreement between the two, with a mean difference between the ratios of 0.02  0.004. Mitsumori and colleagues76 used a multicontrast MR protocol to evaluate fibrous cap status, with an unstable cap represented by irregularity of discontinuity of the juxtaluminal hypointense band on TOF MR angiography, absence of intimal tissue between the lumen and deeper plaque structures, or focal contour abnormalities along the lumen surface. There was good agreement between imaging and histology for the evaluation of the fibrous cap. Detection of unstable fibrous cap on the multicontrast protocol had sensitivity of 81% and specificity of 90%. Wasserman and colleagues78,79 demonstrated improved detection of fibrous cap and outer wall boundary on MR imaging after contrast administration. Areas of increased enhancement within the cap may indicate areas of inflammatory infiltrate that may suggest impending rupture or neovascularity associated with plaque instability.80,81

CLINICAL IMPLICATIONS OF PLAQUE FEATURES IPH has emerged as one of the most important atherosclerotic plaque features, contributing to plaque progression and leading to cerebrovascular ischemic events (Fig. 3).40,41,82–87 In the setting of moderate asymptomatic carotid stenosis, Singh and colleagues83 reported a significant association between IPH and ipsilateral future

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Fig. 3. A 62-year-old man with a history of remote right MCA-territory infarct, as shown on axial T2-weighted image (A) (short black arrow). The patient at the time of imaging presented with TIA referable to the right MCA territory. On 3D MIP reformat of the right internal carotid artery (B), there is 0% stenosis of the right carotid bulb. On axial fat-saturated proton-density imaging (C), there is wall thickening with outer wall remodeling (short white arrow). Hyperintense signal representing IPH involving the outer wall of the right carotid bulb (long white arrow) is seen on coronal T1 magnetization-prepared rapid-acquisition gradient echo sequence (D).

cerebrovascular ischemic events (HR 3.59, 95% CI 2.48–4.71; P<.001). The presence of carotid IPH is associated with progression of plaque volume, increased lipid-rich necrotic core volume, and development of new intraplaque hemorrhages.84,85 During and after the development of IPH, the plaque growth rate is 18.3  6.5 mm3/ year, significantly higher than the plaque growth rate before IPH development ( 20.5  13.1 mm3, P 5 .018) and showed significant progression over baseline (P 5 .008 compared with a slope of 0).84 Underhill and colleagues87 longitudinally imaged 67 asymptomatic patients with 16% to 49% carotid stenosis, and found that those with IPH showed significant progressive luminal narrowing when compared with those without IPH (P 5 .005), and a progressive increase in plaque volume (P<.001).

In addition to the association between IPH and patient symptoms, several studies have evaluated the ability of intraplaque hemorrhage to detect future cerebrovascular ischemic events. Takaya and colleagues86 prospectively followed 154 consecutive patients with asymptomatic moderate carotid stenosis for a mean period of 38.2 months at 3-month intervals. Among the 12 ischemic events that occurred during follow-up ipsilateral to the index carotid artery, two plaque characteristics at baseline showed a significant association with the future events: IPH (HR 5.2, P 5 .005) and larger mean intraplaque hemorrhage area (HR 2.6 for 10-mm2 increase, P 5 .006). Kwee and colleagues88 evaluated 126 TIA/stroke patients with 30% to 69% carotid stenosis using vessel wall MR imaging, and prospectively followed them for 1 year to determine the

Low-Grade Carotid Stenosis likelihood of recurrence and its relationship to plaque characteristics. The carotid stenosis grade (30%–49% vs 50%–69%) was not associated with recurrent events, whereas the presence of lipid-rich necrotic core (HR 3.2001, P<.04), thin/ ruptured fibrous cap (HR 5.756, P 5 .002), and IPH (HR 3.542, P 5 .04) were significantly correlated with recurrence. Altaf and colleagues41 prospectively followed 64 TIA or stroke patients with 30% to 69% carotid stenosis who had undergone a black-blood MR imaging examination for a median of 28 months after MR imaging. Sixty-one percent of patients had IPH on the ipsilateral side at baseline imaging. Fourteen stroke/TIA events occurred during follow-up, 13 of which manifested in a territory downstream from carotid plaque with IPH (HR 9.8, 95% CI 1.3–75.1; P 5 .03). The same group followed 66 symptomatic patients with highgrade carotid stenosis who underwent vessel wall MR imaging until endarterectomy or for 30 days, in whom IPH was found to significantly increase the likelihood of recurrent ischemic events (HR 4.8, 95% CI 1.1–20.9; P<.05).82 These studies indicate the importance of IPH as a risk factor for future stroke events. Although carotid IPH can cause or be a result of plaque rupture, once it is detected on MR imaging it confers a poorer prognosis. The interplay between IPH and angiogenesis is an area of investigational interest,44,81,89–93 although their exact relationship is not yet clearly understood. One theory for the development of IPH is that it arises from leaky neovessels that grow into the plaque from the adventitial vasa vasorum.91,93 Sluimer and colleagues91 indicated that microvessel density was higher in advanced plaques than in early plaques. In early plaques and normal artery segments, the microvessel density was higher on the adventitial side than within the wall/plaque, whereas in advanced plaques the adventitial and intraplaque microvessel density were equivalent, suggesting inward growth of neovessels into the wall with plaque development. In autopsy evaluation, intraplaque neovessels were thin-walled with compromised endothelial integrity and basement membrane detachment, indicating increased wall permeability.91 This supports the idea that these fragile vessels would be more likely to rupture. IPH may also develop first on the intimal surface secondary to fibrous cap fissuring or disruption,94 and lead to intimal hypoxia and stimulate angiogenesis.90 Autopsy studies evaluating IPH and angiogenesis have shown their coexistence within plaques.81,89 McCarthy and colleagues81 found a significantly higher density of neovessels within symptomatic carotid plaques in comparison with asymptomatic lesions (P<.0001). The neovessels within symptomatic

plaques were also significantly larger and more irregular. IPH and fibrous cap rupture were significantly associated with neovessels within the plaque (P<.017, P<.001) and fibrous cap (P<.046, P<.004). Sun and colleagues92 evaluated carotid atherosclerotic plaques with a multicontrast MR protocol and dynamic contrast-enhanced perfusion, and found a significant relationship between IPH and Ktrans, indicating an increased endothelial surface area or increased permeability in the setting of intraplaque hemorrhage. Conversely, there was no significant difference in vp (blood supply) between the IPH and non-IPH groups, indicating that the difference in Ktrans reflects increased vasa vasorum ingrowth of capillaries and terminal arterioles. Qiao and colleagues44 demonstrated carotid IPH (OR 10.18, P 5 .03) and extent of adventitial neovascularity as indicated by grade of adventitial enhancement (grade 0 none, grade 1 <50%, grade 2 50%) (compared with grade 0: OR 14.9 for grade 1, OR 51.17 for grade 2; P 5 .02) to be independently associated with ischemic events. The status of the fibrous cap assessed on MR imaging has proved to be an important characteristic of carotid plaque vulnerability. Yuan and colleagues95 initially described the relationship between fibrous cap rupture and patient symptoms in a study where they scanned 53 consecutive patients scheduled for carotid endarterectomy, There was an increased likelihood of symptomatic than asymptomatic patients having ruptured caps (70% vs 9%, P 5 .001). Compared with patients with thick fibrous caps, those with ruptured caps were 23 times more likely to have had a recent cerebrovascular ischemic event. In the evaluation of 154 patients (52 symptomatic) with a carotid plaque measuring at least 3 mm on ultrasonography, Millon and colleagues96 found a significantly higher occurrence of cap rupture in the symptomatic group (30% vs 9%; OR 2.8, P 5 .001). However, the difference between symptomatic and asymptomatic was only appreciated during the first 15 days after the ischemic event. In the longitudinal MR evaluation of asymptomatic patients with severe carotid stenosis, percent volume increase of lipid-rich necrotic core was found to be a significant predictor of future fibrous cap rupture (per 5% increase: OR 2.6, P 5 .035).97

HIGH-RESOLUTION MR IMAGING FOR THE EVALUATION OF LOW-GRADE CAROTID STENOSIS Clinical Applications In the setting of low-grade carotid stenosis, vessel wall MR imaging can have an immediate impact on

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Mossa-Basha & Wasserman assessing plaque volume, despite compensatory outer wall remodeling, and identifying plaque composition and vulnerable characteristics that can help predict rupture. Identification of carotid atherosclerotic lesions, even with little to no stenosis, can provide insight into atherosclerosis elsewhere in the body including the intracranial arteries and the aorta. Shimizu and colleagues98 showed that increased carotid IMT measurements are associated with complex aortic atheromas that are more likely to lead to embolic events. In fact, complex descending thoracic aorta plaques are not an uncommon source for cryptogenic infarcts secondary to retrograde aortic flow.99 Retrograde descending aortic flow from the vicinity of a complex atherosclerotic plaque reached the common carotid artery on time-resolved computational flow MR imaging in 24.5% of cases, with 24.3% of cases of cryptogenic stroke attributed to these downstream aortic plaques in a study of 94 acute stroke patients with descending aortic plaque as defined on transesophageal echo. There has been a growing body of literature assessing carotid plaque characteristics in the setting of low-grade stenosis. Wang and colleagues100 evaluated MR imaging features of plaque vulnerability in 114 symptomatic patients. Lipid-rich necrotic core was found in 86.7% of plaques with 30% to 49% stenosis and 45.1% of lesions with 0% to 29% narrowing. In addition, IPH and fibrous cap rupture was seen in 26.7% and 6.7% of plaques, respectively, with 30% to 49% stenosis. There was a significant association between cerebral infarct volume and lipid-rich necrotic core volume (P<.04), and a marginal association between infarct volume and wall thickness percentage (P 5 .05) after adjusting for carotid luminal stenosis. Saam and colleagues101 found that 21.7% of carotid arteries with 16% to 49% stenosis and 8.1% of arteries with 0% to 15% stenosis will have complicating features on ultrasonography including IPH, fibrous cap rupture, and calcified nodules. Dong and colleagues102 indicated an 8.7% and 4.3% incidence of IPH and surface disruption, respectively, in carotid arteries with 0% stenosis. In low-grade stenosis (<50%), there is a significantly increased prevalence of vulnerable plaque characteristics in males compared with females, including ruptured/thinned fibrous cap, IPH, AHA type VI plaques, and significantly larger lipid-rich necrotic core volumes.103 In a separate study evaluating 181 patients, Zhao and colleagues104 found a 4.4% prevalence of IPH in patients with 0% stenosis. These studies indicate that plaques associated with low-grade carotid stenosis can and will have vulnerable plaque features that confer an

increased risk of subsequent growth and rupture that could lead to stroke.

Associations of Low-Grade Carotid Stenosis with Systemic Atherosclerosis Atherosclerosis is a systemic process that is known to involve multiple arterial beds simultaneously. Considering that specific vulnerable plaque characteristics can increase the likelihood of plaque rupture, this, in addition to systemic features, can confer an increased likelihood of symptoms. As atherosclerosis is a chronic, systemic, inflammatory disease, there is the potential for multisystemic plaque-rupture complications such as myocardial, renal, cerebral, and mesenteric infarctions, in addition to hypoperfusion complications proceeding in the same individual.105 The relationship of carotid IMT on ultrasonography and severity of coronary artery disease (CAD) has also been a topic of investigation. Graner and colleagues106 examined the association of carotid IMT on B-mode ultrasonography and the severity and extent of CAD on angiography in 108 patients with known or suspected CAD. Maximum and mean IMT were significantly correlated with CAD severity (P 5 .004 and P 5 .005, respectively), extent (P 5 .022 and P 5 .016, respectively), and atheroma burden (P 5 .008 for both). Carotid IMT was associated with disease extent in the mid and distal coronary segments, but not in proximal segments. In 558 consecutive patients who underwent carotid ultrasonography and coronary angiography, there was a significant correlation between mean IMT and advancing CAD (P<.0001), with a significant increase in carotid IMT in patients with 1-, 2-, and 3-vessel CAD.107 The investigators found that with a mean IMT greater than 1.15 mm, there was a 94% probability of having CAD, with 65% sensitivity and 80% specificity in high-risk CAD patients. Whereas 16.6% of patients with 3-vessel CAD had severe stenosis of the carotid, subclavian, or vertebral arteries, none of the patients with normal coronary arteries had severe extracranial arterial stenoses. In 224 patients, Lekakis and colleagues108 also found common carotid artery (P 5 .015) and carotid bulb (P 5 .04) IMT to be independent predictors of CAD extent. The clinical usefulness of carotid IMT assessment on ultrasonography and its added predictive risk beyond atherosclerosis risk factors identified by the Framingham Risk Score has recently come under challenge.109–111 A meta-analysis collating data from 14 population-based cohorts (45,828 participants) indicated that for every 0.1-mm

Low-Grade Carotid Stenosis increase in the common carotid IMT, the HR of first-time myocardial infarction or stroke was 1.09 (95% CI 1.07–1.12),109 with minor improvement in prediction when added to the Framingham Risk Score. This finding suggests that current evidence does not support the routine use of carotid IMT in the general population to screen for cardiovascular disease because the added value is too small to result in health benefits. Carotid IMT has typically been measured in the common carotid artery because it is easily visualized perpendicular to the ultrasound beam and provides more accurate, reproducible, and quantitative measurements112; however, the appropriateness of carotid IMT as a marker of atherosclerosis has been questioned because the main determinants of medial hypertrophy of the common carotid artery are age and hypertension, which do not necessarily reflect atherosclerotic plaque formation. Atherosclerosis of the carotid arteries typically first develops in the carotid bulb, and rarely occurs in the common carotid artery except in advanced disease.113 A meta-analysis of 11 population-based studies (54,336 patients) found that the presence of carotid bulb plaque on ultrasonography in comparison with common carotid IMT had a significantly higher diagnostic accuracy for the prediction of future myocardial infarction.114 IMT measurement in the carotid bulb was found to be a significantly stronger predictor of cardiovascular events than IMT measurements in the common carotid artery; however, the presence of carotid plaque was a significantly stronger predictor than IMT measurement at either site.114 Considering that atherosclerosis is a chronic, systemic inflammatory process and that plaque develops multifocally and simultaneously, it would stand to reason that similar vulnerable plaque features might be found in plaques in various arterial beds. Zhao and colleagues115 evaluated the association between coronary plaque characteristics on CT angiography and carotid plaque morphology on vessel wall MR imaging in 123 suspected CAD patients who underwent both examinations. Coronary plaques were identified as calcified, mixed, and noncalcified, and carotid plaques were evaluated for the presence of IPH, lipidrich necrotic core, and calcification. There was a significant correlation between the presence of a mixed coronary plaque and carotid IPH (OR 1.5, P<.05). In addition, the mixed coronary plaque had the highest likelihood of predicting carotid IPH (area under the curve 5 0.74). This result led the investigators to conclude that mixed calcified and noncalcified coronary plaques may indicate the presence of vulnerable carotid plaques, given their association with carotid IPH. In a separate

article, Zhao and colleagues116 indicated that 98.2% and 28.6% of patients with less than 50% coronary artery stenosis had carotid atherosclerotic disease with a lipid-rich necrotic core and IPH, respectively. Underhill and colleagues117 compared carotid plaque morphologic characteristics between 97 patients with obstructive CAD (50% stenosis on coronary angiogram) and 94 with normal coronary angiograms (controls). In male CAD patients compared with male controls, there was a significantly smaller lumen area (P<.001 and P 5 .006, respectively) and smaller total vessel area (P<.001 and P 5 .04, respectively) in the distal carotid bulb and internal carotid artery. For the distal bulb, there was also a significantly larger mean wall thickness (P 5 .002). There was no significant difference in plaque characteristics for females at any arterial segment, and no significant difference in the common carotid arteries for males. The presence of extracranial carotid artery atherosclerosis was significantly associated with incidence and progression of coronary artery calcification in a prospective cohort study of 5445 subjects.118 Extracranial carotid arteries are amenable to cross-sectional imaging, in particular MR imaging, considering their large size, linear anatomy, superficial location, and relative immobility; this is in contradistinction to the coronary arteries, which are very difficult to image because of their small size, cardiac and respiratory motion, and tortuous courses. For these reasons and considering the propensity of coronary plaques to outwardly remodel, thus limiting the ability to estimate plaque burden on luminal imaging, cross-sectional carotid plaque composition evaluation using MR imaging or ultrasonography may be a useful way to predict the presence and risk of CAD noninvasively.

LIMITATIONS OF MR IMAGING OF THE CAROTID ARTERIES The clinical applicability of MR imaging of plaque must be considered in light of several limitations of this modality. The resolution of MR imaging is limited by the available signal of the tissue of interest. Dedicated carotid surface coils and higherfield MR imaging scanners, however, can provide a substantially improved signal. MR imaging examinations are typically more expensive, and MR imaging has limited accessibility in comparison with other cross-sectional imaging modalities, and for these reasons MR imaging likely cannot serve as a first-line screening tool for asymptomatic carotid atherosclerotic disease. MR imaging suffers from longer scan times, and for this reason is susceptible to motion artifacts.119 Safety

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Mossa-Basha & Wasserman concerns also must be considered with MR imaging scanners, especially contraindications to magnetic-field exposure. Such concerns include metallic foreign bodies in the orbit or near vital structures, cochlear implants, and pacemakers. Local heating with skin burns can occur from certain medicine patches, tattoos, or permanent cosmetics. More commonly, claustrophobia poses a relative contraindication, although most patients are able to tolerate the examination with sedation or by using an open or wide-bore system. There has been recent concern with administration of gadolinium-based MR imaging contrast agents and evidence of intracranial tissue deposition, although the long-term significance of this is still unknown.120–123

SUMMARY MR imaging has emerged as a tool capable of uncovering and characterizing atherosclerotic plaque before it has a hemodynamic effect on the lumen, allowing a means to study plaque characteristics associated with risk for rupture. Identifying and characterizing lesions that have gone unrecognized by angiography forces clinicians reconsider the guidelines for managing lowgrade carotid stenosis. At present, MR imaging offers a tool that can identify the culprit lesion, a particular challenge with low-grade disease, creating management decisions not previously faced. Considering that atherosclerosis is a systemic disease, MR imaging can allow determination of the presence of disease within other parts of the cardiovascular system. Ultimately, understanding the nature of atherosclerosis formation in the extracranial carotid artery may allow clinicians to identify the vulnerable patient in whom systemic intervention could be initiated to prevent cardiovascular events.

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