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   Table of Contents      
Year : 2015  |  Volume : 1  |  Issue : 1  |  Page : 38-46

Imaging markers of stroke risk in asymptomatic carotid artery stenosis

Department of Neurology, Center of Healthcare Studies, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

Date of Submission12-Apr-2015
Date of Acceptance08-Aug-2015
Date of Web Publication30-Sep-2015

Correspondence Address:
Shyam Prabhakaran
Department of Neurology, Feinberg School of Medicine, Northwestern University, 710 N, Lakeshore Drive, #1422, Chicago, Illinois - 60611
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2394-8108.166373

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Carotid stenosis is a major cause of ischemic stroke. While symptomatic carotid stenosis requires prompt revascularization, there is significant debate about the management of asymptomatic carotid stenosis (ACS), especially in light of recent advances in medical therapy. As a result, there is an even greater need for reliable predictors of stroke risk in asymptomatic patients. Besides clinical factors and stenosis grade, plaque morphology and cerebral hemodynamics may be suitable prognostic tools. High-risk features, using Doppler and magnetic resonance imaging (MRI) suggest that subpopulations at sufficiently high risk (10% annually) can be identified and in whom revascularization would be most beneficial. In this review, imaging tools to aid in stroke risk stratification in patients with ACS are discussed.

Keywords: Collaterals, magnetic resonance imaging (MRI), plaque morphology, ultrasound

How to cite this article:
Prabhakaran S. Imaging markers of stroke risk in asymptomatic carotid artery stenosis. Brain Circ 2015;1:38-46

How to cite this URL:
Prabhakaran S. Imaging markers of stroke risk in asymptomatic carotid artery stenosis. Brain Circ [serial online] 2015 [cited 2023 Jun 3];1:38-46. Available from: http://www.braincirculation.org/text.asp?2015/1/1/38/166373

  Introduction Top

Approximately 5-10% of the United States (US) population over the age of 65 have carotid stenosis, [1],[2] which accounts for 10-15% of all ischemic strokes. [3] While symptomatic stenosis of 70-99% [after ischemic stroke or transient ischemic attack (TIA)] has long been established as requiring revascularization, there is significant debate about the management of asymptomatic carotid stenosis (ACS). The importance of risk stratification and appropriate patient selection has been stressed, given the narrow risk-benefit margin (1% absolute risk reduction per year) and lower absolute stroke risk per year among asymptomatic versus symptomatic (2% vs 20%) patients. [4],[5],[6] More recently, advances in medical therapy have further reduced the risk of stroke in patients with ACS with estimates of <1% annual risk in modern registries. [7] Yet every symptomatic patient was once asymptomatic, underscoring the need for better appreciation of the underlying mechanisms and predictors of stroke in an individual patient that are needed to improve selection for surgical intervention.

Risk stratification based on stenosis grade alone ignores the influence of type of plaque (i.e., stable vs vulnerable) and cerebral hemodynamics, and thus may not accurately predict ipsilateral stroke risk. In addition, the underlying mechanisms that lead to the development of stable plaques in some patients and vulnerable plaques in others are poorly understood. Finally, dynamic changes in cerebral circulation may augment or reduce tolerance for ipsilateral ischemia over time.

Evaluation of ACS would thus benefit from a comprehensive review of pathophysiology, from the plaque to distal circulation, to better inform the individual patient of his/her risk of stroke. In this review, we appraise various imaging markers to predict stroke in ACS patients. Though not the focus of the review, many of the insights on patient selection in ACS can be applied to recently symptomatic patients with <70% stenosis, where there exists a similar controversy because risk-benefit differences in intervention versus medical arms are modest.

  Stroke Risk in Symptomatic Versus Asymptomatic Patients Top

The risk of stroke in patients with carotid stenosis varies significantly by symptomatic status. In those with recent ischemic stroke or TIA and severe (70-99%) stenosis, the ipsilateral stroke risk is 20-30% at 2 years. In this population, studies have clearly demonstrated the benefit (absolute risk reduction of 16%) of carotid revascularization in stroke prevention. [8],[9],[10] In symptomatic patients with moderate stenosis (50-69%) in whom the stroke risk is still appreciable at 22% when treated medically, the benefit (absolute risk reduction 4.6%) of revascularization is less certain. [11],[12] Based on these and the recently completed Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST), guidelines recommend carotid endarterectomy (CEA) or carotid artery stenting (CAS) in patients with symptomatic 70-99% carotid stenosis. However, careful patient selection is recommended as benefits were not seen in women or those over age 75. [13]

Observational data suggested that the risk of stroke in patients with ACS is 1-3%. [14],[15],[16],[17] In randomized clinical trials, the annual risk of ipsilateral stroke was 2% in medically treated patients and was lowered to 1% following CEA. [6],[18] Studies of modern or aggressive medical therapy that includes highly potent medications such as statins suggest that the annual risk may be even lower, to as low as <1% per year. [7],[19] Indeed, it is known that over the past several decades, the overall vascular risk reduction achieved by medical measures can be as high as 75% if multimodal therapies are employed. [20] Moreover, several studies have also demonstrated that plaque progression can be retarded using statin medications. [21],[22]

In this modern era, discerning which ACS patients will benefit from medical therapy alone or require CEA, therefore, becomes even more difficult. It is particularly vexing because the mechanism of stroke even in those with ipsilateral carotid stenosis may not always be related to the carotid plaque. A prior study found that 45% of strokes in patients with 60-99% ACS are due to lacunar or cardioembolic mechanisms. [23] Thus, given the heterogeneity in risk and the challenge in identifying appropriate patients for surgical management, the development of reliable measures of high-risk (i.e., heterogeneous plaque morphology and flow characteristics) are paramount. If no high-risk features are found, clinicians may not consider revascularization, offering maximal medical therapy and serial surveillance instead. If high-risk features are found, it may be more reasonable to consider CEA if technically amenable.

  Standard Predictors of Stroke in Acs Top

Identifying high-risk features of ipsilateral stroke remains challenging. Several clinical factors are associated with stroke risk in ACS patients. These include male sex, history of contralateral TIA or stroke, contralateral carotid stenosis or occlusion, and preexisting cardiac disease, hypertension, and renal disease. [24],[25],[26] In addition, the risk is linearly associated with advancing degree of stenosis, increasing from 1% in low-grade (50-80%) stenosis to >3% in high-grade (80-99%) stenosis. [27]

Other radiographic factors that influence stroke risk include rate of stenosis progression over time, the adequacy of collateral vessels and cerebrovascular reserve, and the morphological characteristics of the plaque. [28],[29],[30],[31],[32],[33] While degree of stenosis has some importance, especially when >80%, there is evidence that several plaque features as assessed by carotid ultrasound may impart risk even in low-grade stenosis. [25] For example, heterogeneous, echolucent, and ulcerated plaques increase stroke risk and serve as markers of vulnerable or unstable carotid plaques. [30],[32] Lastly, progressive stenosis over time is associated with increased stroke risk. [26],[29],[34],[35],[36],[37],[38],[39],[40] However, even with these tools, the annual risk of stroke in selected patients with high-risk features only approaches 10%.

In contrast to the risk factors that estimate long-term risk but not exactly when and in whom a stroke will occur, other temporally linked and dynamic factors such as inflammation and infection, withdrawal of antiplatelet medications and/or poor responsiveness, and hemodynamic alterations may better explain how an asymptomatic plaque becomes symptomatic at any given moment. [41],[42],[43],[44] These factors are not well studied in ACS. Thus, even with clinical and imaging predictive models, it is more likely that patients identified as being high-risk will not have a stroke than have a stroke in the follow-up period.

  Plaque Development and Rupture Top

The cascade of events leading to carotid plaque formation and rupture involves endothelial damage, lipid deposition, inflammation, and coagulation and platelet activation. Research in this area has introduced the concept of the "unstable" carotid plaque, which through in situ hemorrhage, thrombosis, and inflammation, may result in plaque rupture with secondary embolization and/or perfusion failure. [45],[46],[47],[48] It is hypothesized that plaque morphology and vulnerability leads to atherothromboembolism, which is counteracted by spontaneous dissolution of clot and clearance of emboli in the presence of robust antegrade and collateral perfusion. This complex pathophysiology is critical to understanding stroke mechanisms in ACS, and provides gold standards for imaging markers and potential targets for medical therapies to prevent stroke. Indeed, histological and immunological investigations into the underlying pathophysiology of the unstable carotid plaque have observed that echolucent and irregular plaques are associated with plaque rupture. [49],[50],[51] Imaging markers, therefore, may provide useful surrogates of the underlying biology of active or vulnerable carotid plaques and the capacity of distal cerebral vasculature to compensate [Table 1].
Table 1: Mechanisms, imaging markers, and modality in ACS

Click here to view

  Plaque Morphology by Doppler and Magnetic Resonance Imaging (MRI) Top

Atherosclerotic plaque can be classified based on characteristics of the lipid core, fibrous cap, associated hemorrhage, surface ulceration, and thrombus adhesion. The various types or stages of atherosclerotic plaques and their relative stability and risk of atherothrombosis has been well described. [52] According to the American Heart Association (AHA) classification scheme, types I-III and types VII-VIII are stable, while types IV-VI are unstable plaques, consisting of lipid-rich cores and thin fibrous caps. It is estimated that approximately 50% of lesions are vulnerable (types IV, V, and VI). [53],[54],[55]

Using ultrasonography, plaques that are heterogeneous, are lipid-rich (echolucent), and/or have surface irregularity or ulceration can be identified reliably and have been associated with high risk of embolic stroke due to plaque rupture and thrombosis. [24],[30],[32] A recent finding is that a juxtaluminal black area of >8 mm 2 in a carotid plaque (indicating a thrombus or a thin/absent fibrous cap) was seen in 86% of all strokes that occurred in follow-up despite being present in only 21% of the cohort. [56] While plaque morphology and associated features have been described using visual inspection, the use of computerized analysis or grayscale median (GSM) provides an objective measurement of morphology. Low GSM values (<15, i.e., echolucent or type I plaques) are associated with higher annual rates of stroke than higher values. [27] Similarly, plaque area can be calculated and used to gauge risk with highest annual stroke rates in patients with >80 mm 2 plaque thickness. Using a combination of history of contralateral TIA, degree of stenosis, plaque area, and GSM values, the annual risk of stroke in patients with ACS can be calculated, with the highest-risk group having approximately 10% annual risk. [27]

Other imaging technologies, including MRI of carotid plaque, may also help in risk stratification by identification of vulnerable plaques. In addition to the assessment of the degree of stenosis, high-resolution multicontrast (time-of flight, T 1 , T 2 , and PD weighting) MRI can characterize carotid plaque composition and identify vulnerable plaques, which are susceptible to embolism [Figure 1]. Previous studies have shown that plaque classification obtained by MRI correlate well with AHA classifications based on histopathology [I-VIII, Cohen's kappa 0.74, 95% confidence interval (CI) 0.67-0.82]. [53] In vivo high-resolution multicontrast MRI is therefore capable of classifying intermediate to advanced atherosclerotic lesions in the human carotid artery and distinguishing vulnerable from stable atherosclerotic plaques. [57] Recent studies have demonstrated sensitivity and specificity in the range of 81-90% and 74-92%, respectively, for the MRI detection of high-risk plaque components. [58],[59],[60] In one study of 77 ACS patients, only patients with AHA classification IV-VI had ischemic events. [61] Intraplaque hemorrhage using MRI has also been shown to predict symptoms. [62],[63]
Figure 1: 68-year old man with left ICA plaque causing approximately 50% stenosis by MRA Vulnerable plaque is detected by high-resolution carotid MRI: T1 (top), proton density (middle) and T2 weighted imaging (bottom) on black-blood acquisition showing vulnerable plaque with intra-plaque hemorrhage

Click here to view

Thus, carotid high-resolution MRI and Doppler may be able to distinguish advanced and vulnerable plaques from more stable, early, and/or intermediate atherosclerotic plaques. Given the higher costs and limited availability of MRI, Doppler is the more widely used technique. While low of cost and widely available, identification of plaque features by Doppler does require experienced interpretation and high-quality technologists for their reliable use in clinical practice.

  Microembolic Signals (MES) and Silent Infarcts Top

MES detection is performed by monitoring the middle cerebral artery through the temporal bone acoustic window for 60 min with the use of a head fixation device. Emboli are considered present when a characteristic acoustic chirp occurs (>6 dB threshold), according to international consensus criteria. [64] Approximately 15-20% of ACS patients will show evidence of MES, increasing with duration of monitoring. [65],[66] The presence of ≥2 MES in a single 1-h recording suggests a high-risk, unstable asymptomatic plaque, or a plaque with a thrombus on its surface. A recent meta-analysis revealed that 17% of 1144 ACS patients evaluated with transcranial Dopper (TCD) recording had MES. More than half with MES developed stroke during follow-up. [67] Other studies have confirmed that MES, along with other high-risk plaque features on Doppler, increase the risk of stroke in ACS patients to about 7-9% annually. [28],[68],[69] Of note, embolization may be a mediator of stroke risk in those with echolucent plaques, [69] and medical therapy may reduce the rate of MES substantially. [7]

While MES represents active acute silent embolization, computed tomography (CT) and/or MRI of the brain can detect established or chronic silent infarcts. Moreover, infarct patterns on CT that suggest carotid stenosis mechanism such as embolic and/or borderzone patterns have been evaluated in patients with symptomatic carotid stenosis and ACS. [70],[71],[72],[73],[74] These studies have observed that the presence of silent embolic infarcts on CT, which are present in about 20% of ACS patients, may help stratify risk of clinical symptomatic stroke. Future studies should consider MRI screening in patients with ACS to ascertain its potential utility and compare with CT, given MRI's superiority over CT in visualizing small silent infarcts.

  Cerebral Hemodynamics Top

Primary or proximal collateral pathways provide routes for cerebral blood flow (CBF) to ischemic regions through existing anastomoses at the level of the circle of Willis. It is likely that collateral flow through the posterior and anterior communicating artery account for the majority of these alternative pathways in the setting of internal carotid stenosis with contributions from the external carotid artery via the ophthalmic artery in some patients. Secondary collateral pathways via leptomeningeal anastomoses constitute distal sources of perfusion to ischemic brain tissue. [75] In symptomatic carotid disease, hemodynamic compromise as a predictor of stroke has been studied extensively; however, in asymptomatic disease, the degree to which collateralization of flow can maintain normal neurologic function is unknown. Furthermore, impaired hemodynamics and perfusion may modify or interact closely with arterial embolism, as robust collaterals may enhance microemboli clearance. [76] Thus, distal perfusion and cerebrovascular reserve may be a more important or proximate predictor of stroke risk than plaque characteristics such as vulnerable plaques or embolic potential in patients with ACS.

Although leptomeningeal collaterals are difficult to visualize with noncontrast magnetic resonance angiography (MRA) due to their size and low flow states, primary collateral flow through the circle of Willis can be readily visualized and quantified using MRA techniques. Phase-contrast MRA, in particular, has been shown to be an accurate, noninvasive tool in the measurement of the presence, direction, and size of primary collateral flow in patients with carotid occlusion. [77] In addition, regional CBF from the sum of ipsilateral vessels distal to a carotid stenosis can be calculated by phase-contrast MRA and may provide a surrogate measure of ipsilateral hemodynamic compensation in response to proximal flow restriction. [78] In patients with severe carotid artery stenosis or occlusion, ipsilateral flow in the common carotid artery and distal internal and middle cerebral arteries are typically decreased and increased on the contralateral side. [79],[80],[81] After CEA, flow rates increase in the ipsilateral carotid circulation, while collateral flow through the contralateral carotid or vertebrobasilar arteries decreases. [77],[82] Likewise, phase-contrast MRA flow improvements have been noted following CAS. [83] The advantage of MRA phase-contrast volumetric flow (mL/min) measurements over TCD flow velocity-based (cm/s) measurements for the evaluation of Willisian collaterals is the integration of flow velocity over the cross-sectional vessel area, which should correlate more strongly with change in CBF at the tissue level. In addition, like TCD studies, phase-contrast MRA can be combined with a breath-holding or acetazolamide challenge to provide quantitative measures of vasoreactivity (see below). [84],[85]

Using these and other techniques, collateral flow has been shown to be a predictor of ipsilateral stroke in extracranial carotid stenosis. Significant reductions in the 2-year risk of stroke in the medically and surgically treated groups in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) were associated with the presence of intracranial collateral perfusion by angiography. [86] Patients with minimal or absent circle of Willis collaterals on phase-contrast MRA studies prior to CEA were more likely to develop cerebral ischemia during carotid cross-clamping than those with intact circle of Willis anatomy. [87],[88] The presence of a large ipsilateral posterior communicating artery (>1 mm in diameter) has been observed to be protective against watershed infarction in patients with carotid occlusions. [89] A recent study found that patients with decreased contralateral carotid, basilar, and posterior communicating artery flows were associated with increased recurrent stroke risk in patients with carotid occlusion. [88] These data clearly demonstrate that CBF through circle of Willis (primary) collateral circulation in patients with carotid occlusive disease have impact on the risk of subsequent stroke. Its application in ACS patients without occlusion requires more study.

That impaired distal cerebral hemodynamics (i.e., leptomeningeal) is a powerful predictor of stroke in large arterial occlusive disease has also been inferred. [90] Distal to a high-grade stenosis, cerebral perfusion is reduced. Cerebral blood flow is preserved by progressive vasodilatation of resistance vessels as part of the normal cerebral autoregulatory response. Once vasodilatation is exhausted (stage I hemodynamic failure), oxygen extraction fraction (OEF) increases (stage II hemodynamic failure) to maintain normal tissue delivery of oxygen. [91] If a further decrease in perfusion pressure ensues, as may occur in the presence of high-grade carotid stenosis or systemic hypotension, compensatory mechanisms fail and cerebral ischemia and stroke symptoms occur. In the St. Louis Carotid Occlusion study, increased OEF was a strong predictor of ipsilateral stroke risk with an odds ratio (OR) of 6.04 (95% CI, 2.58-14.12) in a pooled meta-analysis. [92],[93] In patients with asymptomatic carotid occlusion, however, the prevalence of elevated OEF was lower and the association with stroke risk less clear. [94] Furthermore, limited availability of the cyclotron for positron emission tomography (PET) makes its utilization in risk stratification for ACS patients of questionable value.

Vasomotor reactivity (VMR) is the dilatory and constrictive response of cerebral resistance vessels to vasoactive stimulation, approximates stage I hemodynamic failure, and correlates with a leptomeningeal collateral flow pattern. [95],[96] In contrast to PET, VMR is easily obtained by conventional noninvasive imaging techniques such as TCD, single photon emission CT (SPECT), xenon-CT, and perfusion MRI or CT. Longitudinal studies have demonstrated that an impaired VMR identifies a subgroup of patients at high risk for both recurrent and first stroke in extracranial carotid occlusive disease. [33],[97],[98] In a study of asymptomatic high-grade (>70%) carotid artery stenosis, patients with impaired VMR had an ipsilateral TIA or stroke risk of 14% compared to only 4% in patients with preserved VMR. [33] Similarly, another study noted that impaired VMR was observed in 14% of patients and the annual rate of ipsilateral stroke in those with impaired VMR was 21.8% compared to 2.4% in those with preserved VMR. [99] A meta-analysis recently confirmed that impaired VMR predicts ipsilateral stroke with sixfold increased risk (OR, 6.14; 95% CI, 1.27-29.5) in patients with ACS. [100]

The methods available to measure cerebral VMR include responses to vasodilatory challenges with CO 2 (in the form of breath-holding or breathing enriched CO 2 ) , or with acetazolamide administration; registration of the vasodilatory response can be performed employing TCD, SPECT, or xenon-CT. At present, no one technique is considered the gold standard. VMR testing with TCD, defined as an increase in middle cerebral artery flow velocities accompanying the rise in CO 2 that occurs with breath holding, is easily performed and readily available. This response is based on the ability of TCD to record increased flow velocity after hypercarbia as a result of distal vasodilation of resistance vessels. Comparison of VMR obtained through breath-holding versus CO 2 supplementation or acetazolamide also found comparable results and good correlations. [95],[101] As noted above, a low breath-holding index (BHI) to measure VMR is an important predictor of clinical cerebral ischemic symptoms in patients with ACS. [33] As it is also TCD-based and widely available, requiring minimal training and equipment, BHI is an appealing method to measure VMR in patients with ACS. [101]

Tissue perfusion imaging using standard dynamic susceptibility-contrast MRI and arterial spin-labeling techniques have been evaluated in patients with ACS. [96],[102],[103],[104],[105] These studies indicate the following: That hypoperfusion is a mechanism of stroke in carotid occlusive disease; that perfusion abnormalities reverse with revascularization; and that cerebral blood volume inversely correlates with impaired VMR by BHI. However, there are no longitudinal data on risk prediction using perfusion imaging in ACS patients.

  Ongoing Clinical Trials Top

While CEA was previously shown to benefit patients with ACS with an absolute stroke risk reduction of 1% per year over medical management, many practitioners have challenged these results as they are inconsonant with today's intensive medical management regimen, which was not incorporated in prior trials conducted over a decade ago. The Carotid Revascularization for Primary Prevention of Stroke trial (CREST-2: NCT02089217) will evaluate the benefit of aggressive medical management versus revascularization (CEA or CAS) plus aggressive medical management on risk of stroke and cognitive decline in ACS. It plans to enroll 2,480 patients with at least 70% stenosis and randomize half to CEA versus medical management and the other half to CAS versus medical management. The primary outcome will be stroke or death within 30 days or ipsilateral ischemic stroke within 4 years of follow-up. Two other trials, the European Carotid Surgery Trial 2 (ECST-2: ISRCTN 97744893) and the Asymptomatic Carotid Surgery Trial 2 (ACST-2: ISRCTN 21144362), will also address whether revascularization is beneficial in the era of modern medical management.

  Challenges and Opportunities Top

An imaging-based approach to stratification of stroke risk in patients with ACS affords opportunities and challenges in clinical practice. It is certainly well known that asymptomatic revascularizations far outnumber (9:1) symptomatic revascularizations in the US, [106] arguably indicating a considerable overtreatment of the condition than what would be necessary, given the costs and risks associated with CEA. A more rational approach based on high-risk features might reduce unnecessary treatments while also lowering stroke risk in those who actually need it.

However, imaging comes with its own costs. Besides Doppler techniques, which have reasonably low costs in most countries, the use of more advanced techniques such as MRI could add to patient and health care costs. In addition, training of technologists and laboratories to perform specialized tests would also incur considerable costs. This latter issue further raises concerns about interrater and interlaboratory reliability, which if low can result in poor application of the technologies in routine clinical practice. [107] Thus, a rational approach using low-cost, proven imaging tools such as carotid and TCD as first-line imaging tools seems reasonable in most instances.

  Future Directions Top

While several large randomized clinical trials are ongoing and seek to answer the question of whether revascularization is superior to modern medical management in ACS patients, more work should be simultaneously done in the development of novel predictors of stroke risk in this population. Some potential innovations include the use of wall shear stress (WSS), oscillatory shear index (OSI), contrast-enhanced Doppler, and molecular labeling to further improve risk stratification.

WSS has been implicated in plaque development. [108],[109] In this context, four-dimensional (4D) flow MRI is a very promising technique that can provide WSS measurements along with flow pattern and turbulence evaluation for the entire vascular area of interest (including the common carotid artery, the bifurcation, and the external and internal carotid arteries). [110],[111],[112],[113] Another tool that could aid in risk prediction is contrast-enhanced Doppler. Using ultrasound contrast media, this technique allows for better visualization of the plaque surface and delineation of neovascularization of the plaque. [114],[115] Likewise, CT angiography can measure degree of stenosis accurately, assess surface characteristics including fissures and ulcers, and evaluate plaque composition. [116],[117] Other techniques such as molecular or labeled imaging using contrast Doppler or fluorodeoxyglucose PET can identify plaque inflammation and cellular processes that predict thromboembolic risk. [118],[119]

  Conclusions Top

The risk of stroke is relatively low in ACS patients, though high-risk features using Doppler and MRI could identify populations at sufficiently high risk (10% annually) to necessitate revascularization. Risk stratification based on stenosis grade alone is insufficient to gauge risk as it ignores the influence of plaque type (i.e., stable vs vulnerable), collateral flow (i.e., circle of Willis and leptomeningeal), and distal tissue perfusion (i.e., the severity of hemodynamic compromise). Anatomic variations in the circle of Willis and the degree of collateral perfusion can reduce the risk of stroke. Evaluation of ACS would thus benefit from risk stratification based on plaque characteristics, embolic potential, and cerebral hemodynamics. Furthermore, identification of patients with plaque neovascularization, WSS, and distal remodeling including active arteriogenesis and collateral development may identify deleterious or protective mechanisms for stroke in patients with ACS. Surveillance of ACS with advanced imaging approaches is warranted given the "needle in the haystack" challenge the disease poses to clinicians and may offer practical biomarkers readily available in clinical practice to inform treatment decisions. It is likely that imaging markers will provide the most insights and utility in ACS patients with moderate degrees of stenosis, where the most uncertainty currently exists. Ongoing clinical trials in patients with more severe stenosis are under way.

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