Imaging of High-Risk Carotid Artery Plaques: Current Status and Future Directions

Neurosurg Focus 36 (1):E1, 2014 ©AANS, 2014

Imaging of high-risk carotid artery plaques: current status and future directions

J. Kevin DeMarco, M.D.,1 and John Huston III, M.D.2 1Department of Radiology, Michigan State University, East Lansing, Michigan; and 2Department of Radiology, Mayo Clinic, Rochester, Minnesota

In this paper, the authors review the definition of high-risk plaque as developed by experienced researchers in atherosclerosis, including pathologists, clinicians, molecular biologists, and imaging scientists. Current concepts of vulnerable plaque are based on histological studies of coronary and carotid artery plaque as well as natural history studies and include the presence of a lipid-rich necrotic core with an overlying thin fibrous cap, plaque inflammation, fissured plaque, and intraplaque hemorrhage. The extension of these histologically identified high-risk carotid plaque features to human in vivo MRI is reviewed as well. The authors also assess the ability of in vivo MRI to depict these vulnerable carotid plaque features. Next, the ability of these MRI-demonstrated high-risk carotid plaque features to predict the risk of ipsilateral carotid thromboembolic events is reviewed and compared with the risk assessment provided by simple carotid artery stenosis measurements. Lastly, future directions of high-risk carotid plaque MRI are discussed, including the potential for increased clinical availability and more automated analysis of carotid plaque MRI. The ultimate goal of high-risk plaque imaging is to design and run future multicenter trials using carotid plaque MRI to guide individual patient selection and decisions about optimal atherosclerotic treatment strategies. (http://thejns.org/doi/abs/10.3171/2013.10.FOCUS13384)

Key Words • carotid stenosis • stroke • carotid plaque • MRI

troke remains a leading cause of morbidity and current medical intervention alone is now best for stroke mortality. Treatment decisions are still based pre- prevention in part because high-risk patients who may dominantly on studies correlating the risk reduction benefit from additional CEA cannot be identified.1 The Sachieved from carotid endarterectomy (CEA) or carotid lack of a clear benefit from surgical versus medical ther- artery stenting (CAS) with the percentage of stenosis. apy in symptomatic patients with < 70% stenosis or in While the benefit of CEA in recently symptomatic carotid patients with asymptomatic carotid stenosis suggests that artery stenosis > 70% has been demonstrated in multiple better characterization of future stroke risk is necessary large randomized clinical trials, the role of surgical ver- to identify which patients will benefit the most from CEA sus medical treatment in symptomatic patients with less or CAS. Unfortunately, current risk stratification based significant carotid stenosis remains unclear.3 The benefit on the percentage of stenosis provides minimal patient- of CEA or CAS is even more controversial in patients specific information on the actual risk of stroke for most with asymptomatic carotid stenosis. The Asymptomatic individuals with carotid artery disease. A growing body Carotid Atherosclerosis Study (ACAS) has reported a of literature suggests that carotid plaque characteristics risk reduction following CEA in asymptomatic patients may provide a superior means of predicting future ipsi- with stenosis greater than 50%–60%.34 Since completion lateral cerebrovascular events as compared with the per- of the ACAS trial, there have been significant advances in centage of carotid artery stenosis. medical therapy for carotid atherosclerotic disease. The average annual rate of ipsilateral stroke in patients with asymptomatic carotid stenosis receiving medical therapy Correlating the American Heart Association since 2001 has fallen below the rates in patients who un- Carotid Plaque Classification With Plaque MRI derwent CEA in the ACAS.1 In a systematic review and analysis of medical intervention, Abbott concluded that Definition of Vulnerable Plaque Histological studies have demonstrated that coro- Abbreviations used in this paper: ACAS = Asymptomatic Carotid nary artery plaques with a large lipid-rich necrotic core Atherosclerosis Study; AHA = American Heart Association; CAS (LRNC) and an overlying thin fibrous cap (FC) are as- = carotid artery stenting; CE = contrast-enhanced; CEA = carotid 31 endarterectomy; FC = fibrous cap; IPH = intraplaque hemorrhage; sociated with sudden cardiac death. This finding has led LRNC = lipid-rich necrotic core; MRA = MR angiography; SNR to the concept of “vulnerable plaque.” Key features of the = signal-to-noise ratio; T1W = T1-weighted; T2W = T2-weighted; vulnerable plaque, including a large LRNC with a thin FC, TIA = transient ischemic attack; TOF = time-of-flight. active inflammation with activated macrophages, fissured

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Unauthenticated | Downloaded 10/02/21 04:47 AM UTC J. K. DeMarco and J. Huston III plaque, superficial calcified nodules, and intraplaque Plaque Inflammation hemorrhage (IPH), were defined in two consensus review Observational studies on LRNC demonstrate that articles published by a group of experienced researchers neo-angiogenesis is closely associated with plaque pro- in atherosclerosis, including pathologists, clinicians, mo- 33 15,16 gression. Intimal neovascularization is predominantly lecular biologists, and imaging scientists. The discus- thought to arise from the adventitia, where there are a sion of pathological definitions of vulnerable plaque was 22 plethora of preexisting vasa vasorum. The amount of ad- subsequently extended to MRI. The American Heart ventitial neovascularity can be quantified using dynamic Association (AHA) has proposed a detailed classification contrast-enhanced (DCE) MRI. Histological evaluation scheme of atherosclerotic plaque (Fig. 1).26 This scheme showed that adventitial Ktrans calculated from DCE-MRI has been modified for in vivo MRI to include the descrip- was significantly correlated with the amount of neovascu- tion of carotid plaques with LRNCs (AHA Type IV–V) as well as a more complex plaque with IPH, ruptured FC, larity and macrophages in the excised plaque, thus provid- and/or calcified protruding nodule (AHA Type VI).5 ing an in vivo marker of plaque inflammation, which has been described as a hallmark of the vulnerable plaque.11 Lipid-Rich Necrotic Core With Thin FC Fissured Plaque Based on the histological studies of coronary artery plaque associated with sudden cardiac death, an LRNC Virmani et al. described the fissure plaque as a region of FC rupture where the juxtaluminal thrombus was in di- has also been proposed to represent a phenotype of ath- 32 erosclerotic disease with a high risk for future cardiovas- rect communication with the underlying LRNC. Using cular events.29 The most widely accepted hypothesis is either noncontrast 3D time-of-flight (TOF) MR angiog- that lipid-lowering therapy targets the plaque rupture risk raphy (MRA) or a CE-T1W MRI series, multiple authors features such as a large LRNC, thin FC, and high level have demonstrated the ability of in vivo carotid plaque of inflammatory infiltrates and activity. The lipid deple- MRI to differentiate between a thick, intact FC and a thin tion theory suggests that plaque stability is improved and or ruptured FC. Using 3D TOF MRA, Hatsukami et al. demonstrated a high level of agreement (89%) between cardiovascular events are reduced with medical treatment 9 such as statin therapy to deplete lipids and decrease the MRI and histological findings. Cai et al. used CE-T1W LRNC size.37 Multicontrast MRI of the carotid arteries MRI series to optimally demonstrate the FC and showed has been validated with histology and shown to identify moderate-to-good correlation between carotid MRI find- and quantify various carotid plaque components includ- ings and the excised histological specimen for maximal 4,21 thickness (r = 0.78, p < 0.001), length (r = 0.73, p < 0.001), ing the LRNC, FC, and IPH (Fig. 2). Contrast-enhanced 4 (CE) T1-weighted (T1W) images improve differentiation and area (r = 0.90, p < 0.001) of the intact FC. 36 of the LRNC from fibrous tissue. Further, multicontrast Intraplaque Hemorrhage carotid plaque MRI has been shown to be capable of quantifying the LRNC volume in the clinical setting of a The cause of IPH is unclear. Some authors have sug- multicenter trial with low interscan variability.24 gested that hemorrhage into a plaque is related to rupture

Fig. 1. Different types of vulnerable plaque as the underlying cause of acute coronary events and sudden cardiac death. A, rupture-prone plaque with a large lipid core and thin FC infiltrated by macrophages; B, ruptured plaque with subocclusive thrombus and early organization; C, erosion-prone plaque with proteoglycan matrix in a smooth muscle cell–rich plaque; D, eroded plaque with subocclusive thrombus; E, IPH due to leaking vasa vasorum; F, calcific nodule protruding into the vessel lumen; G, chronically stenotic plaque with severe calcification, old thrombus, and eccentric lumen. Reprinted with permission from Naghavi M et al: From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II. Circulation 108:1772–1778, 2003.

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Fig. 2. Comparison of high-resolution MR angiography (MRA), multicontrast 3-T in vivo carotid plaque MRI, and ex vivo histological evaluation of CEA specimen. A: There is 82% carotid stenosis on the 500-µm resolution contrast-enhanced (CE) carotid MRA. B: These examples of T1-weighted (T1W), T2-weighted (T2W), 3D time-of-flight (TOF) MRA, and CE-T1W plaque images obtained at the level of the carotid artery stenosis shown in panel A demonstrate how the 3-T in vivo carotid plaque MRI identifies the LRNC (light gray outline) and loose matrix (dark gray outline) through the right carotid artery plaque. C: The region of the LRNC is dark (chevron) on these T2W images, while the area of loose matrix (arrow) is bright. D: The percent areas of plaque that were characterized as LRNC (light gray outline) and loose matrix (dark gray outline) on the histological slide is similar to that measured on the in vivo 3-T MR images. of the FC.7 Recent articles have detailed the ability of in LRNC as well as the presence of a thin or ruptured FC.8 vivo MRI to depict juxtaluminal hemorrhage adjacent to In that study, there was no correlation between carotid regions of ruptured FC.10 It has also been postulated that artery stenosis and symptoms (Figs. 3 and 4). In 2006, in rupture of the vasa vasorum or the immature neovessels a 3-year natural history study of 154 previously asympto- with “leaky” immature linings may lead to the IPH that matic individuals with 50%–79% stenosis, Takaya et al. is typically deep within the plaque.22 Carotid plaque MRI found that the presence of a thin or ruptured FC (HR 17.0, has good sensitivity with moderate-to-good specificity to p ≤ 0.001) and larger maximum percentage of LRNC (HR detect and quantify IPH, with histology as the gold stan- for 10% increase 1.6, p = 0.004) were predictors of the fu- dard.19,21 Intraplaque hemorrhage is increasingly recog- ture development of neurological ischemia.28 A multivari- nized as a potent atherogenic stimulus caused by the ac- ate analysis of clinical and carotid plaque features in a cumulation of cholesterol-rich lipid membranes, leading study of 108 individuals with 50%–79% stenosis revealed to a marked increase in the size of an LRNC and further that the size of the LRNC relative to plaque size was the plaque destabilization.12 strongest predictor of new FC rupture or ulceration after 3 years of follow-up.20 In a cross-sectional study of 334 patients from four imaging centers in the US and China, the Better Risk Depiction by Carotid Plaque MRI LRNC size was the strongest predictor of other vulnera- Than Carotid Stenosis ble plaque features such as IPH and FC rupture.29 Authors of that study proposed a 4-tier grading system for plaque Lipid-Rich Necrotic Core With a Thin FC as a Predictor of Risk burden that they termed the “Carotid Atherosclerosis Score” (CA score). Patients with a maximum wall thick- Numerous studies have demonstrated the correla- ness ≤ 2 mm had a CA Score 1. Patients with a maximum tion between LRNC size and/or the presence of a thin or wall thickness > 2 mm had a CA Score 2 if they demon- ruptured FC overlying the LRNC and recent symptoms strated < 20% maximum percentage area of LRNC, CA as well as the subsequent development of new ipsilateral Score 3 if they had 20%–40% maximum percentage area carotid thromboembolic symptoms, future carotid plaque of LRNC, and a CA Score 4 if their maximum percent- destabilization with new FC rupture or new IPH, and age area of LRNC was > 40%. The CA score was an ac- progression in carotid plaque size. In a cross-sectional curate classifier of IPH (area under curve [AUC] = 0.91) study of 97 consecutive patients with 50%–99% stenosis and FC rupture (AUC = 0.93). The simple classification referred for carotid plaque MRI, there were significant as- scheme could be easily applied clinically when reviewing sociations between recent ipsilateral carotid stroke and/ carotid plaque sequences. Compared with MRA stenosis, or transient ischemic attack (TIA) and the presence of an the CA score was a stronger classifier of both IPH and FC

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Fig. 3. Coronally acquired MR angiogram and transverse images of a complicated plaque of the left carotid artery in a 75-year-old man with right-sided weakness. A: Maximum intensity projection of CE-MRA demonstrates a 55% smooth stenosis at the left internal carotid artery. The horizontal line indicates the level of the transverse carotid plaque images shown in B. B: Disrupted dark band (arrow) on the TOF angiogram and discontinuation of the high-intensity band on CE-T1W image indicate a thin FC. High intensity on TOF and precontrast T1W images indicates regions of hemorrhage (arrowheads). The low- intensity area on the CE-T1W image indicates an LRNC area occupying 31% of the wall area (chevron). Notice that the hemorrhage seen on TOF and T1W images almost completely fills the LRNC as seen on the CE-T1W image. Symptomatic plaques tend to have plaques with a hemorrhagic LRNC and a thin or ruptured FC. Reprinted with permission from Demarco JK et al: MR carotid plaque imaging and contrast-enhanced MR angiography identifies lesions associated with recent ipsilateral thromboembolic symptoms: an in vivo study at 3T. AJNR Am J Neuroradiol 31:1395–1402, 2010. © by American Society of Neuroradiology. rupture. Authors of that study proposed that the CA score of 33 patients randomized to receive low- or high-dose would complement carotid artery stenosis in classifying rosuvastatin, only patients with an LRNC at the begin- the severity of atherosclerotic disease. Subsequently, the ning of the study demonstrated a decrease in overall ca- CA score was prospectively evaluated using an indepen- rotid plaque volume and LRNC with the statin therapy.30 dent cohort of 73 asymptomatic subjects who underwent In one of the first prospective tests of the lipid depletion serial carotid MRI over a 3-year period. Applied prospec- theory, Zhao et al. enrolled 33 patients with an LRNC tively, the CA score was associated with new FC rupture who were treated with intensive lipid-lowering therapy. and greater lesion growth. Carotid stenosis was not sig- After 3 years of lipid therapy, these 33 subjects had a significantly associated with any end point (presented at nificant reduction in plaque lipid content.37 For the first the 2013 Radiological Society of North America Annual time, an understanding of the time course was provided, Meeting, Chicago, IL). The original AHA plaque classi- with statistically significant plaque lipid depletion ob- fication and these subsequent in vivo carotid plaque MRI served after 1 year of treatment and continuing into the trials suggest that the LRNC may be a useful phenotype 2nd year. The LRNC size reduction preceded the plaque of atherosclerotic disease that may predict future plaque regression, consistent with the lipid depletion therapy. It destabilization and thromboembolic events. is interesting to note that the results of this study provide Multiple drug trials have shown the ability of in vivo a possible biological explanation for the clinical benefit MRI to evaluate the effectiveness of statin treatment to in placebo-controlled drug trial studies in which the re- decrease the size of an LRNC. Corti et al. first demon- duction in cardiovascular events in actively treated sub- strated the ability of in vivo carotid plaque MRI to depict jects begins at 1–2 years. This study also demonstrated a response to statin therapy in a cohort of 21 asympto- a reduction in the plaque area within each patient only at matic hypercholesterolemic patients monitored over a the levels at which an LRNC existed at baseline. Carotid 2-year period.6 Although specific identification of plaque intima-media thickness specifically excludes regions of components was not pursued in that study, it is likely that carotid plaque and may not be able to demonstrate chang- most if not all of the patients had an LRNC given their es related to drug therapy. severity of hypercholesterolemia and their statin-naïve Taken as a whole, there is ample peer-reviewed lit- status at the beginning of the study. In a subsequent study erature to suggest that the presence of an LRNC repre-

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Fig. 4. Transverse carotid plaque images and coronally acquired CE-MR angiogram of the left carotid artery in an asymptomatic 61-year-old woman. A: Maximum-intensity projection of the CE-MRA demonstrates 74% stenosis at the left internal carotid artery. The horizontal line indicates the level of the transverse carotid plaque images shown in B. B: Transverse image of a TOF angiogram demonstrates a smooth luminal surface and a dark juxtaluminal band indicating an intact thick FC. The thick FC is easier to appreciate as a high-intensity band (arrows) on the CE-T1W and T2W images. An isointense area on TOF and T1W images, an isointense to low-intensity area on the T2W image, and a low-intensity area on the CE-T1W image indicate an LRNC without hemorrhage occupying 29% of the wall area (arrowheads). Notice that the LRNC is easiest to appreciate on the CE-T1W image. Asymptomatic plaques tend to have a smaller LRNC without hemorrhage as well as a thick FC. Reprinted with permission from Demarco JK et al: MR carotid plaque imaging and contrast-enhanced MR angiography identifies lesions associated with recent ipsilateral thromboembolic symptoms: an in vivo study at 3T. AJNR Am J Neuroradiol 31:1395–1402, 2010. © by American Society of Neuroradiology. sents a phenotype of atherosclerotic disease with a high cause they provide a single time point in the evolution risk for future cardiovascular events, that in vivo MRI of carotid plaque atherosclerosis. Noninvasive carotid is capable of identifying and quantifying the size of an plaque MRI gives us the ability to better understand both LRNC, that the presence and size of an LRNC provide the evolution of carotid plaque disease and our ability to reasonable selection criteria to identify patients suitable alter the natural history of atherosclerosis. for additional intensive lipid-lowering therapy, and that Intraplaque hemorrhage at baseline alone or in com- in vivo MRI provides a reproducible technique to mea- bination with other plaque features has been correlated sure the effectiveness of lipid-lowering therapies. Thus, with the subsequent development of new ipsilateral ca- carotid plaque MRI detection and/or quantification of an rotid thromboembolic symptoms and a progression in LRNC, as compared with simple carotid stenosis mea- carotid plaque size. During a mean follow-up of 38.2 surements, may provide improved risk stratification with months in 154 patients with asymptomatic moderate ca- better patient selection for additional treatment as well as rotid artery stenosis, 12 carotid cerebrovascular events a mechanism for evaluating the effectiveness of the ad- occurred. Both the presence and size of IPH correlated ditional treatment. with a new ipsilateral carotid stroke or TIA.28 In a longitudinal study of 98 patients with asymptomatic moder- Intraplaque Hemorrhage as a Predictor of Risk ate carotid artery stenosis, slightly more than one-third During IPH, there is extravasation of lipid-rich mem- of the patients demonstrated IPH, but all 6 future ipsilat- branes of the red blood cells plus deposition of iron into eral carotid events occurred in these patients.25 Altaf et the carotid plaque. Both are proinflammatory processes al. enrolled 64 recently symptomatic patients who dem- resulting in carotid plaque destabilization.12,15 A recent onstrated 30%–69% carotid stenosis in a prospective trial prospective longitudinal MRI investigation of 31 patients of carotid plaque MRI. On the initial carotid plaque MRI showed that carotid plaque IPH was associated with ac- study of the 64 recently symptomatic carotid arteries, 39 celerated plaque progression in a period of 18 months.27 (61%) demonstrated IPH. After a mean follow-up of 28 The presence of IPH is also associated with future ad- months, 14 new ipsilateral carotid events occurred. Thir- ditional carotid plaque IPH, suggesting that IPH is an teen of the 14 events occurred in arteries with IPH on the important transition point from stable to unstable carotid initial carotid plaque MRI study.2 plaque morphology. Previous histological studies have In a meta-analysis of 8 longitudinal studies of IPH de- had a very limited ability to illustrate this transition be- tected on in vivo MRI, including the 3 articles cited in the

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Unauthenticated | Downloaded 10/02/21 04:47 AM UTC J. K. DeMarco and J. Huston III above paragraph, Saam et al. demonstrated that despite IPH. If this hypothesis is proven, then rapid multicontrast a large degree of detected heterogeneity in the published carotid plaque imaging could be added to routine clinical studies, the presence of IPH on MRI is associated with carotid MRA. an approximately 5.6-fold higher risk for cerebrovascu- Improved carotid plaque coils are also being evaluat- lar events as compared with the risk in subjects without ed. First-generation 4-channel carotid coils have provided IPH.23 The authors concluded that homogenization of fu- high SNR images of the midneck with approximately 10– ture studies is warranted to allow sufficient assessment of 12 cm of coverage in the superoinferior direction. Sec- the level of evidence for future intervention trials. ond-generation carotid coils utilize a higher coil density (6–8 coils) to improve overall SNR and increase coverage Sex Differences in Carotid Plaque Components as a in the superoinferior direction to 16–18 cm. These coils Predictor of Risk are approved by the FDA and clinically available today In 131 patients with asymptomatic carotid stenosis for most MR vendors. Third-generation coils with tight > 50% on duplex ultrasonography, men had higher-risk integration of improved carotid coils into a larger neu- plaque features than women after controlling for potential rovascular coil capable of imaging from the aortic arch confounders (Figs. 5 and 6).17 Specifically, men tend to through the circle of Willis as well as the brain are being have a higher incidence of LRNC and thin or ruptured developed. Combined with new rapid 3D carotid plaque FC as well as larger LRNCs and IPHs compared with sequences, rapid 30-minute arch and carotid MRA with women. The higher prevalence of these potential vulnera- dedicated carotid plaque imaging or a 45-minute brain/ ble plaque features in men as compared with women may MRA/carotid plaque protocol would be possible. These be one reason that CEA was shown to be more effective new capabilities would greatly expand the routine clini- in reducing subsequent stroke in asymptomatic men with cal availability of carotid plaque imaging by providing carotid artery stenosis than in women. Additional studies access to plaque imaging within current scan times of have shown that these sex differences in high-risk carotid carotid MRA. plaque features exist even in patients with asymptomatic Rapid automated carotid plaque analysis would carotid stenosis < 50%.18 Thus, sex-based management greatly aid the clinician with the interpretation of mul- may be important in patients with asymptomatic carotid ticontrast carotid plaque sequences. Validation of automated carotid plaque analysis utilizing predominantly 2D atherosclerosis across all stages of carotid stenosis.18 MR sequences has been completed.13 Future work will extend the automated carotid plaque analysis to include Future Directions all 3D MR sequences. Increased Clinical Availability of in Vivo Carotid Plaque Future Multicenter Trials Using in Vivo Carotid Plaque MRI MRI to Guide Treatment Decisions An improved quality of carotid plaque MRI along By far, the most important future direction is to test with a decreased imaging time is one direction for future the hypothesis that vulnerable plaque imaging, as op- work. A novel 4- to 5-minute 3D-based MRI technique posed to simple carotid stenosis measurements, can guide called “3D SNAP,” which provides simultaneous non- therapy and improve patient outcome. It is possible that contrast MR angiography with the ability to detect IPH, vulnerable carotid plaque imaging may help guide both has been proposed.35 Recent work on 3D carotid plaque medical therapy and surgical intervention. As proposed sequences has also demonstrated an ability to improve above, patients with large LRNCs identified by carotid resolution with the good signal-to-noise ratio (SNR) that plaque MRI may be a subgroup with asymptomatic carot is inherent with 3D imaging.14 A combination of three id atherosclerosis that may benefit the most from aggres- 4-minute carotid plaque sequences (3D SNAP and 3D sive medical therapy. Additional clinical trials random- T1W pre- and postcontrast) may provide all the informa- izing patients with LRNCs to standard and aggressive tion necessary to fully characterize an LRNC, FC, and medical therapy are being proposed. Initial trials will

Fig. 5. Representative images obtained in a male patient with a large hemorrhagic LRNC with a ruptured FC. An irregular luminal surface with a protruding hyperintensity area on a TOF image indicates FC rupture or ulceration (chevron). An area with hypointensity on a CE-T1W image and with hyperintensity on an inversion recovery fast spoiled gradient recalled (IRF- SPGR) image indicates a hemorrhagic LRNC (arrows). Asterisks indicate the lumen. Reprinted with permission from Ota H et al: Sex differences in patients with asymptomatic carotid atherosclerotic plaque: in vivo 3.0-T magnetic resonance study. Stroke 41:1630–1635, 2010.

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Fig. 6. Representative images obtained in a female patient with calcified plaque. An area of hypointensity seen on all of the images (arrows) indicates the calcified plaque. Asterisks indicate the lumen. Reprinted with permission from Ota H et al: Sex differences in patients with asymptomatic carotid atherosclerotic plaque: in vivo 3.0-T magnetic resonance study. Stroke 41:1630–1635, 2010. likely use a decrease in the LRNC size as a surrogate ing the article: both authors. Critically revising the article: both marker for improved atherosclerotic treatment, although authors. Reviewed submitted version of manuscript: both authors. larger multicenter trials with enough patients to test for a Approved the final version of the manuscript on behalf of both statistically significant improvement in hard end points, authors: DeMarco. such as stroke and TIA, will be needed to fully test the hypothesis. Improved availability of clinical MRI to de- References tect vulnerable carotid plaque will greatly facilitate these 1. Abbott AL: Medical (nonsurgical) intervention alone is now studies. Likewise, vulnerable plaque imaging in patients best for prevention of stroke associated with asymptomatic se- with recently symptomatic carotid artery stenosis may vere carotid stenosis: results of a systematic review and analy- better stratify risk and identify additional patients who sis. Stroke 40:e573–e583, 2009 would benefit from surgical intervention (CEA or CAS) 2. Altaf N, Daniels L, Morgan PS, Auer D, MacSweeney ST, and are currently not being offered these procedures. It Moody AR, et al: Detection of intraplaque hemorrhage by magnetic resonance imaging in symptomatic patients with is likely that the presence, size, location, and/or type of mild to moderate carotid stenosis predicts recurrent neuro- IPH can identify patients with mild-to-moderate carotid logical events. J Vasc Surg 47:337–342, 2008 artery stenosis who are at an increased risk of ipsilateral 3. Barnett HJ, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, stroke and/or TIA and who may benefit from surgical Haynes RB, et al: Benefit of carotid endarterectomy in patients intervention. Future large multicenter trials will clarify with symptomatic moderate or severe stenosis. N Engl J Med the risk of future ipsilateral events in patients with re- 339:1415–1425, 1998 cent stroke and/or TIA and form the basis for designing 4. Cai J, Hatsukami TS, Ferguson MS, Kerwin WS, Saam T, Chu follow-up surgical trials. B, et al: In vivo quantitative measurement of intact fibrous cap and lipid-rich necrotic core size in atherosclerotic carotid plaque: comparison of high-resolution, contrast-enhanced mag- Conclusions netic resonance imaging and histology. Circulation 112:3437– 3444, 2005 A cornerstone of stroke prevention has been the 5. Cai JM, Hatsukami TS, Ferguson MS, Small R, Polissar NL, identification of risk factors. While great strides have Yuan C: Classification of human carotid atherosclerotic le- been made with the treatment of hypertension and hy- sions with in vivo multicontrast magnetic resonance imaging. perlipidemia, future reductions in stroke may require the Circulation 106:1368–1373, 2002 6. Corti R, Fuster V, Fayad ZA, Worthley SG, Helft G, Smith identification of individual risk factors. In this paper we D, et al: Lipid lowering by simvastatin induces regression of have reviewed current concepts of vulnerable plaque and human atherosclerotic lesions: two years’ follow-up by high- demonstrated the ability of in vivo MRI to depict these resolution noninvasive magnetic resonance imaging. Circula- vulnerable carotid plaque features. Multiple single-center tion 106:2884–2887, 2002 studies have shown the ability of MRI-defined carotid 7. Davies MJ, Thomas AC: Plaque fissuring—the cause of acute plaque features to predict future events better than simple myocardial infarction, sudden ischaemic death, and crescendo carotid artery stenosis measurements. Ongoing and pro- angina. Br Heart J 53:363–373, 1985 posed multicenter trials across North America and Eu- 8. Demarco JK, Ota H, Underhill HR, Zhu DC, Reeves MJ, Potchen MJ, et al: MR carotid plaque imaging and contrast- rope will test the feasibility of vulnerable plaque imag- enhanced MR angiography identifies lesions associated with ing to accurately predict the risk of new thromboembolic recent ipsilateral thromboembolic symptoms: an in vivo study symptoms. Future interventional and drug trials using at 3T. AJNR Am J Neuroradiol 31:1395–1402, 2010 vulnerable plaque imaging to guide individual patient se- 9. Hatsukami TS, Ross R, Polissar NL, Yuan C: Visualization of lection and treatment are now being proposed. fibrous cap thickness and rupture in human atherosclerotic carotid plaque in vivo with high-resolution magnetic resonance Disclosure imaging. Circulation 102:959–964, 2000 10. Kampschulte A, Ferguson MS, Kerwin WS, Polissar NL, Chu The authors report no conflict of interest concerning the mate- B, Saam T, et al: Differentiation of intraplaque versus jux- rials or methods used in this study or the findings specified in this taluminal hemorrhage/thrombus in advanced human carotid paper. atherosclerotic lesions by in vivo magnetic resonance imag- Author contributions to the study and manuscript preparation ing. Circulation 110:3239–3244, 2004 include the following. Conception and design: both authors. Draft- 11. Kerwin WS, Oikawa M, Yuan C, Jarvik GP, Hatsukami TS:

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