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| REVIEW ARTICLE |
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| Year : 2015 | Volume
: 1
| Issue : 1 | Page : 38-46 |
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Imaging markers of stroke risk in asymptomatic carotid artery stenosis
Shyam Prabhakaran
Department of Neurology, Center of Healthcare Studies, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| Date of Submission | 12-Apr-2015 |
| Date of Acceptance | 08-Aug-2015 |
| Date of Web Publication | 30-Sep-2015 |
Correspondence Address:
Shyam Prabhakaran
Department of Neurology, Feinberg School of Medicine, Northwestern University, 710 N, Lakeshore Drive, #1422, Chicago, Illinois - 60611
USA
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2394-8108.166373
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 |
| Introduction | |  |
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 | | |
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 | | |
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 | | |
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].
| Plaque Morphology by Doppler and Magnetic Resonance Imaging (MRI) | | |
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
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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 | | |
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 | | |
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 | | |
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 | | |
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 | | |
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 | | |
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.
Financial support and sponsorship
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Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Hillen T, Nieczaj R, Münzberg H, Schaub R, Borchelt M, Steinhagen-Thiessen E. Carotid atherosclerosis, vascular risk profile and mortality in a population-based sample of functionally healthy elderly subjects: The Berlin Ageing Study. J Intern Med 2000;247:679-88.  |
| 2. | O'Leary DH, Polak JF, Kronmal RA, Kittner SJ, Bond MG, Wolfson SK Jr, et al. Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. The CHS Collaborative Research Group. Stroke 1992;23:1752-60. |
| 3. | Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, et al. American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Epidemiology and Prevention; Council for High Blood Pressure Research; Council on Peripheral Vascular Disease, and Interdisciplinary Council on Quality of Care and Outcomes Research. Guidelines for the primary prevention of stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:517-84. |
| 4. | Barnett HJ. Carotid endarterectomy. Lancet 2004;363:1486-7. |
| 5. | Brott T, Toole JF. Medical compared with surgical treatment of asymptomatic carotid artery stenosis. Ann Intern Med 1995;123:720-2. |
| 6. | Halliday A, Mansfield A, Marro J, Peto C, Peto R, Potter J, et al. MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: Randomised controlled trial. Lancet 2004;363:1491-502. |
| 7. | Spence JD, Coates V, Li H, Tamayo A, Muñoz C, Hackam DG, et al. Effects of intensive medical therapy on microemboli and cardiovascular risk in asymptomatic carotid stenosis. Arch Neurol 2010;67:180-6. |
| 8. | Clinical alert: Benefit of carotid endarterectomy for patients with high-grade stenosis of the internal carotid artery. National Institute of Neurological Disorders and Stroke Stroke and Trauma Division. North American Symptomatic Carotid Endarterectomy Trial (NASCET) investigators. Stroke 1991;22:816-7. |
| 9. | Randomised trial of endarterectomy for recently symptomatic carotid stenosis: Final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998;351:1379-87. |
| 10. | Rothwell PM, Eliasziw M, Gutnikov SA, Fox AJ, Taylor DW, Mayberg MR, et al. Carotid Endarterectomy Trialists' Collaboration. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet 2003;361:107-16. |
| 11. | Barnett HJ, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1998;339:1415-25. |
| 12. | Rerkasem K, Rothwell PM. Carotid endarterectomy for symptomatic carotid stenosis. Cochrane Database Syst Rev 2011;CD001081. |
| 13. | Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, et al. American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:2160-236. |
| 14. | Nadareishvili ZG, Rothwell PM, Beletsky V, Pagniello A, Norris JW. Long-term risk of stroke and other vascular events in patients with asymptomatic carotid artery stenosis. Arch Neurol 2002;59:1162-6. |
| 15. | Norris JW, Zhu CZ, Bornstein NM, Chambers BR. Vascular risks of asymptomatic carotid stenosis. Stroke 1991;22:1485-90. |
| 16. | Meissner I, Wiebers DO, Whisnant JP, O'Fallon WM. The natural history of asymptomatic carotid artery occlusive lesions. JAMA 1987;258:2704-7. |
| 17. | Mackey AE, Abrahamowicz M, Langlois Y, Battista R, Simard D, Bourque F, et al. Outcome of asymptomatic patients with carotid disease. Asymptomatic Cervical Bruit Study Group. Neurology 1997;48:896-903. |
| 18. | Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 1995;273:1421-8. |
| 19. | Marquardt L, Geraghty OC, Mehta Z, Rothwell PM. Low risk of ipsilateral stroke in patients with asymptomatic carotid stenosis on best medical treatment: A prospective, population-based study. Stroke 2010;41:e11-7. |
| 20. | Yusuf S. Two decades of progress in preventing vascular disease. Lancet 2002;360:2-3. |
| 21. | Lima JA, Desai MY, Steen H, Warren WP, Gautam S, Lai S. Statin-induced cholesterol lowering and plaque regression after 6 months of magnetic resonance imaging-monitored therapy. Circulation 2004;110:2336-41. |
| 22. | Corti R, Fuster V, Fayad ZA, Worthley SG, Helft G, Chaplin WF, et al. Effects of aggressive versus conventional lipid-lowering therapy by simvastatin on human atherosclerotic lesions: A prospective, randomized, double-blind trial with high-resolution magnetic resonance imaging. J Am Coll Cardiol 2005;46:106-12. |
| 23. | Inzitari D, Eliasziw M, Gates P, Sharpe BL, Chan RK, Meldrum HE, et al. The causes and risk of stroke in patients with asymptomatic internal-carotid-artery stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 2000;342:1693-700. |
| 24. | Aburahma AF, Thiele SP, Wulu JT Jr. Prospective controlled study of the natural history of asymptomatic 60% to 69% carotid stenosis according to ultrasonic plaque morphology. J Vasc Surg 2002;36:437-42. |
| 25. | Nicolaides AN, Kakkos SK, Griffin M, Sabetai M, Dhanjil S, Tegos T, et al. Asymptomatic Carotid Stenosis and Risk of Stroke (ACSRS) Study Group. Severity of asymptomatic carotid stenosis and risk of ipsilateral hemispheric ischaemic events: Results from the ACSRS Study. Eur J Vasc Endovasc Surg 2005;30:275-84. |
| 26. | Liapis CD, Kakisis JD, Kostakis AG. Carotid stenosis: Factors affecting symptomatology. Stroke 2001;32:2782-6. |
| 27. | Nicolaides AN, Kakkos SK, Kyriacou E, Griffin M, Sabetai M, Thomas DJ, et al. Asymptomatic Carotid Stenosis and Risk of Stroke (ACSRS) Study Group. Asymptomatic internal carotid artery stenosis and cerebrovascular risk stratification. J Vasc Surg 2010;52:1486-96.e1-5. |
| 28. | Molloy J, Markus HS. Asymptomatic embolization predicts stroke and TIA risk in patients with carotid artery stenosis. Stroke 1999;30:1440-3. |
| 29. | Muluk SC, Muluk VS, Sugimoto H, Rhee RY, Trachtenberg J, Steed DL, et al. Progression of asymptomatic carotid stenosis: A natural history study in 1004 patients. J Vasc Surg 1999;29:208-16. |
| 30. | Polak JF, Shemanski L, O'Leary DH, Lefkowitz D, Price TR, Savage PJ, et al. Hypoechoic plaque at US of the carotid artery: An independent risk factor for incident stroke in adults aged 65 years or older. Cardiovascular Health Study. Radiology 1998;208:649-54. |
| 31. | Powers WJ. Cerebral hemodynamics in ischemic cerebrovascular disease. Ann Neurol 1991;29:231-40. |
| 32. | Prabhakaran S, Rundek T, Ramas R, Elkind MS, Paik MC, Boden-Albala B, et al. Carotid plaque surface irregularity predicts ischemic stroke: The Northern Manhattan Study. Stroke 2006;37:2696-701. |
| 33. | Silvestrini M, Vernieri F, Pasqualetti P, Matteis M, Passarelli F, Troisi E, et al. Impaired cerebral vasoreactivity and risk of stroke in patients with asymptomatic carotid artery stenosis. JAMA 2000;283:2122-7. |
| 34. | Balestrini S, Lupidi F, Balucani C, Altamura C, Vernieri F, Provinciali L, et al. One-year progression of moderate asymptomatic carotid stenosis predicts the risk of vascular events. Stroke 2013;44:792-4. |
| 35. | Ballotta E, Da Giau G, Meneghetti G, Barbon B, Militello C, Baracchini C. Progression of atherosclerosis in asymptomatic carotid arteries after contralateral endarterectomy: A 10-year prospective study. J Vasc Surg 2007;45:516-22. |
| 36. | Bertges DJ, Muluk V, Whittle J, Kelley M, MacPherson DS, Muluk SC. Relevance of carotid stenosis progression as a predictor of ischemic neurological outcomes. Arch Intern Med 2003;163:2285-9. |
| 37. | Conrad MF, Baloum V, Mukhopadhyay S, Garg A, Patel VI, Cambria RP. Progression of asymptomatic carotid stenosis despite optimal medical therapy. J Vasc Surg 2013;58:128-35.e1. |
| 38. | Kakkos SK, Nicolaides AN, Charalambous I, Thomas D, Giannopoulos A, Naylor AR, et al. Asymptomatic Carotid Stenosis and Risk of Stroke (ACSRS) Study Group. Predictors and clinical significance of progression or regression of asymptomatic carotid stenosis. J Vasc Surg 2014;59:956-67.e1. |
| 39. | Sabeti S, Schlager O, Exner M, Mlekusch W, Amighi J, Dick P, et al. Progression of carotid stenosis detected by duplex ultrasonography predicts adverse outcomes in cardiovascular high-risk patients. Stroke 2007;38:2887-94. |
| 40. | Silvestrini M, Altamura C, Cerqua R, Pasqualetti P, Viticchi G, Provinciali L, et al. Ultrasonographic markers of vascular risk in patients with asymptomatic carotid stenosis. J Cereb Blood Flow Metab 2013;33:619-24. |
| 41. | Webb AJ, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: A systematic review and meta-analysis. Lancet 2010;375:906-15. |
| 42. | Broderick JP, Bonomo JB, Kissela BM, Khoury JC, Moomaw CJ, Alwell K, et al. Withdrawal of antithrombotic agents and its impact on ischemic stroke occurrence. Stroke 2011;42:2509-14. |
| 43. | Elkind MS. Why now? Moving from stroke risk factors to stroke triggers. Curr Opin Neurol 2007;20:51-7. |
| 44. | Elkind MS. Inflammatory mechanisms of stroke. Stroke 2010;41(Suppl):S3-8. |
| 45. | Alvarez Garcia B, Ruiz C, Chacon P, Sabin JA, Matas M. High-sensitivity C-reactive protein in high-grade carotid stenosis: Risk marker for unstable carotid plaque. J Vasc Surg 2003;38:1018-24. |
| 46. | Businaro R, Digregorio M, Riganò R, Profumo E, Buttari B, Leone S, et al. Morphological analysis of cell subpopulations within carotid atherosclerotic plaques. Ital J Anat Embryol 2005;110(Suppl 1):109-15. |
| 47. | Lombardo A, Biasucci LM, Lanza GA, Coli S, Silvestri P, Cianflone D, et al. Inflammation as a possible link between coronary and carotid plaque instability. Circulation 2004;109:3158-63. |
| 48. | Sapienza P, di Marzo L, Borrelli V, Sterpetti AV, Mingoli A, Cresti S, et al. Metalloproteinases and their inhibitors are markers of plaque instability. Surgery 2005;137:355-63. |
| 49. | Croft RJ, Ellam LD, Harrison MJ. Accuracy of carotid angiography in the assessment of atheroma of the internal carotid artery. Lancet 1980;1:997-1000. |
| 50. | Endo S, Hirashima Y, Kurimoto M, Kuwayama N, Nishijima M, Takaku A. Acute pathologic features with angiographic correlates of the nearly or completely occluded lesions of the cervical internal carotid artery. Surg Neurol 1996;46:222-8. |
| 51. | Estol C, Claasen D, Hirsch W, Wechsler L, Moossy J. Correlative angiographic and pathologic findings in the diagnosis of ulcerated plaques in the carotid artery. Arch Neurol 1991;48:692-4. |
| 52. | Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb Vasc Biol 1995;15:1512-31. |
| 53. | Cai JM, Hatsukami TS, Ferguson MS, Small R, Polissar NL, Yuan C. Classification of human carotid atherosclerotic lesions with in vivo multicontrast magnetic resonance imaging. Circulation 2002;106:1368-73. |
| 54. | Gao T, He X, Yu W, Zhang Z, Wang Y. Atherosclerotic plaque pathohistology and classification with high-resolution MRI. Neurol Res 2011;33:325-30. |
| 55. | Gao T, Zhang Z, Yu W, Zhang Z, Wang Y. Atherosclerotic carotid vulnerable plaque and subsequent stroke: A high-resolution MRI study. Cerebrovasc Dis 2009;27:345-52. |
| 56. | Kakkos SK, Griffin MB, Nicolaides AN, Kyriacou E, Sabetai MM, Tegos T, et al. Asymptomatic Carotid Stenosis and Risk of Stroke (ACSRS) Study Group. The size of juxtaluminal hypoechoic area in ultrasound images of asymptomatic carotid plaques predicts the occurrence of stroke. J Vasc Surg 2013;57:609-18.e1. |
| 57. | Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: A comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20:1262-75. |
| 58. | Moody AR, Murphy RE, Morgan PS, Martel AL, Delay GS, Allder S, et al. Characterization of complicated carotid plaque with magnetic resonance direct thrombus imaging in patients with cerebral ischemia. Circulation 2003;107:3047-52. |
| 59. | Yuan C, Kerwin WS. MRI of atherosclerosis. J Magn Reson Imaging 2004;19:710-9. |
| 60. | Yuan C, Mitsumori LM, Ferguson MS, Polissar NL, Echelard D, Ortiz G, et al. In vivo accuracy of multispectral magnetic resonance imaging for identifying lipid-rich necrotic cores and intraplaque hemorrhage in advanced human carotid plaques. Circulation 2001;104:2051-6. |
| 61. | Esposito-Bauer L, Saam T, Ghodrati I, Pelisek J, Heider P, Bauer M, et al. MRI plaque imaging detects carotid plaques with a high risk for future cerebrovascular events in asymptomatic patients. PloS One 2013;8:e67927. |
| 62. | Takaya N, Yuan C, Chu B, Saam T, Underhill H, Cai J, et al. Association between carotid plaque characteristics and subsequent ischemic cerebrovascular events: A prospective assessment with MRI--initial results. Stroke 2006;37:818-23. |
| 63. | Singh N, Moody AR, Gladstone DJ, Leung G, Ravikumar R, Zhan J, et al. Moderate carotid artery stenosis: Mr imaging-depicted intraplaque hemorrhage predicts risk of cerebrovascular ischemic events in asymptomatic men. Radiology 2009;252:502-8. |
| 64. | Ringelstein EB, Droste DW, Babikian VL, Evans DH, Grosset DG, Kaps M, et al. Consensus on microembolus detection by TCD. International Consensus Group on Microembolus Detection. Stroke 1998;29:725-9. |
| 65. | Abbott AL, Chambers BR, Stork JL, Levi CR, Bladin CF, Donnan GA. Embolic signals and prediction of ipsilateral stroke or transient ischemic attack in asymptomatic carotid stenosis: A multicenter prospective cohort study. Stroke 2005;36:1128-33. |
| 66. | King A, Shipley M, Markus H; ACES Investigators. Optimizing protocols for risk prediction in asymptomatic carotid stenosis using embolic signal detection: The Asymptomatic Carotid Emboli Study. Stroke 2011;42:2819-24. |
| 67. | Markus HS, King A, Shipley M, Topakian R, Cullinane M, Reihill S, et al. Asymptomatic embolisation for prediction of stroke in the Asymptomatic Carotid Emboli Study (ACES): A prospective observational study. Lancet Neurol 2010;9:663-71. |
| 68. | Madani A, Beletsky V, Tamayo A, Munoz C, Spence JD. High-risk asymptomatic carotid stenosis: Ulceration on 3d ultrasound vs TCD microemboli. Neurology 2011;77:744-50. |
| 69. | Topakian R, King A, Kwon SU, Schaafsma A, Shipley M, Markus HS. ACES Investigators. Ultrasonic plaque echolucency and emboli signals predict stroke in asymptomatic carotid stenosis. Neurology 2011;77:751-8. |
| 70. | Brott T, Tomsick T, Feinberg W, Johnson C, Biller J, Broderick J, et al. Baseline silent cerebral infarction in the Asymptomatic Carotid Atherosclerosis Study. Stroke 1994;25:1122-9. |
| 71. | Cao P, Zannetti S, Giordano G, De Rango P, Parlani G, Caputo N. Cerebral tomographic findings in patients undergoing carotid endarterectomy for asymptomatic carotid stenosis: Short-term and long-term implications. J Vasc Surg 1999;29:995-1005. |
| 72. | Kakkos SK, Sabetai M, Tegos T, Stevens J, Thomas D, Griffin M, et al. Asymptomatic Carotid Stenosis and Risk of Stroke (ACSRS) Study Group. Silent embolic infarcts on computed tomography brain scans and risk of ipsilateral hemispheric events in patients with asymptomatic internal carotid artery stenosis. J Vasc Surg 2009;49:902-9. |
| 73. | Miwa K, Hoshi T, Hougaku H, Tanaka M, Furukado S, Abe Y, et al. Silent cerebral infarction is associated with incident stroke and TIA independent of carotid intima-media thickness. Intern Med 2010;49:817-22. |
| 74. | Jayasooriya G, Thapar A, Shalhoub J, Davies AH. Silent cerebral events in asymptomatic carotid stenosis. J Vasc Surg 2011;54:227-36. |
| 75. | Liebeskind DS. Collateral circulation. Stroke 2003;34:2279-84. |
| 76. | Caplan LR, Hennerici M. Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke. Arch Neurol 1998;55:1475-82. |
| 77. | Hendrikse J, Rutgers DR, Klijn CJM, Eikelboom BC, van der Grond J. Effect of carotid endarterectomy on primary collateral blood flow in patients with severe carotid artery lesions. Stroke 2003;34:1650-4. |
| 78. | Ruland S, Ahmed A, Thomas K, Zhao M, Amin-Hanjani S, Du X, et al. Leptomeningeal collateral volume flow assessed by quantitative magnetic resonance angiography in large-vessel cerebrovascular disease. J Neuroimaging 2009;19:27-30. |
| 79. | van Everdingen KJ, Klijn CJ, Kappelle LJ, Mali WP, van der Grond J. MRA flow quantification in patients with a symptomatic internal carotid artery occlusion. The Dutch EC-IC Bypass Study Group. Stroke 1997;28:1595-600. |
| 80. | Hartkamp MJ, van Der Grond J, van Everdingen KJ, Hillen B, Mali WP. Circle of Willis collateral flow investigated by magnetic resonance angiography. Stroke 1999;30:2671-8. |
| 81. | Vanninen RL, Manninen HI, Partanen PL, Vainio PA, Soimakallio S. Carotid artery stenosis: Clinical efficacy of MR phase-contrast flow quantification as an adjunct to MR angiography. Radiology 1995;194:459-67. |
| 82. | Blankensteijn JD, van der Grond J, Mali WP, Eikelboom BC. Flow volume changes in the major cerebral arteries before and after carotid endarterectomy: An MR angiography study. Eur J Vasc Endovasc Surg 1997;14:446-50. |
| 83. | van Laar PJ, van der Grond J, Moll FL, Mali WP, Hendrikse J. Hemodynamic effect of carotid stenting and carotid endarterectomy. J Vasc Surg 2006;44:73-8. |
| 84. | Patrick JT, Fritz JV, Adamo JM, Dandonna P. Phase-contrast magnetic resonance angiography for the determination of cerebrovascular reserve. J Neuroimaging 1996;6:137-43. |
| 85. | de Boorder MJ, Hendrikse J, van der Grond J. Phase-contrast magnetic resonance imaging measurements of cerebral autoregulation with a breath-hold challenge: A feasibility study. Stroke 2004;35:1350-4. |
| 86. | Henderson RD, Eliasziw M, Fox AJ, Rothwell PM, Barnett HJ. Angiographically defined collateral circulation and risk of stroke in patients with severe carotid artery stenosis. North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group. Stroke 2000;31:128-32. |
| 87. | Bagan P, Vidal R, Martinod E, Destable MD, Tremblay B, Dumas JL, et al. Cerebral ischemia during carotid artery cross-clamping: Predictive value of phase-contrast magnetic resonance imaging. Ann Vasc Surg 2006;20:747-52. |
| 88. | Rutgers DR, Blankensteijn JD, van der Grond J. Preoperative MRA flow quantification in CEA patients: Flow differences between patients who develop cerebral ischemia and patients who do not develop cerebral ischemia during cross-clamping of the carotid artery. Stroke 2000;31:3021-8. |
| 89. | Schomer DF, Marks MP, Steinberg GK, Johnstone IM, Boothroyd DB, Ross MR, et al. The anatomy of the posterior communicating artery as a risk factor for ischemic cerebral infarction. N Engl J Med 1994;330:1565-70. |
| 90. | Grubb RL, Derdeyn CP, Fritsch SM, Carpenter DA, Yundt KD, Videen TO, et al. Importance of hemodynamic factors in the prognosis of symptomatic carotid occlusion. JAMA 1998;280:1055-60. |
| 91. | Nemoto EM, Yonas H, Chang Y. Stages and thresholds of hemodynamic failure. Stroke 2003;34:2-3. |
| 92. | Gupta A, Baradaran H, Schweitzer AD, Kamel H, Pandya A, Delgado D, et al. Oxygen extraction fraction and stroke risk in patients with carotid stenosis or occlusion: A systematic review and meta-analysis. AJNR Am J Neuroradiol 2014;35:250-5. |
| 93. | Grubb RL Jr, Powers WJ, Derdeyn CP, Adams HP Jr, Clarke WR. The carotid occlusion surgery study. Neurosurg Focus 2003;14:e9. |
| 94. | Powers WJ, Derdeyn CP, Fritsch SM, Carpenter DA, Yundt KD, Videen TO, et al. Benign prognosis of never-symptomatic carotid occlusion. Neurology 2000;54:878-82. |
| 95. | Ringelstein EB, Weiller C, Weckesser M, Weckesser S. Cerebral vasomotor reactivity is significantly reduced in low-flow as compared to thromboembolic infarctions: The key role of the circle of Willis. J Neurol Sci 1994;121:103-9. |
| 96. | Apruzzese A, Silvestrini M, Floris R, Vernieri F, Bozzao A, Hagberg G, et al. Cerebral hemodynamics in asymptomatic patients with internal carotid artery occlusion: A dynamic susceptibility contrast MR and transcranial Doppler study. AJNR Am J Neuroradiol 2001;22:1062-7. |
| 97. | Reinhard M, Gerds TA, Grabiak D, Zimmermann PR, Roth M, Guschlbauer B, et al. Cerebral dysautoregulation and the risk of ischemic events in occlusive carotid artery disease. J Neurol 2008;255:1182-9. |
| 98. | Reinhard M, Schwarzer G, Briel M, Altamura C, Palazzo P, King A, et al. Cerebrovascular reactivity predicts stroke in high-grade carotid artery disease. Neurology 2014;83:1424-31. |
| 99. | Kuroda S, Houkin K, Kamiyama H, Mitsumori K, Iwasaki Y, Abe H. Long-term prognosis of medically treated patients with internal carotid or middle cerebral artery occlusion: Can acetazolamide test predict it? Stroke 2001;32:2110-6. |
| 100. | King A, Serena J, Bornstein NM, Markus HS. ACES Investigators. Does impaired cerebrovascular reactivity predict stroke risk in asymptomatic carotid stenosis? A prospective substudy of the asymptomatic carotid emboli study. Stroke 2011;42:1550-5. |
| 101. | Markus HS, Harrison MJ. Estimation of cerebrovascular reactivity using transcranial Doppler, including the use of breath-holding as the vasodilatory stimulus. Stroke 1992;23:668-73. |
| 102. | Bokkers RP, van der Worp HB, Mali WP, Hendrikse J. Noninvasive MR imaging of cerebral perfusion in patients with a carotid artery stenosis. Neurology 2009;73:869-75. |
| 103. | Chaves CJ, Staroselskaya I, Linfante I, Llinas R, Caplan LR, Warach S. Patterns of perfusion-weighted imaging in patients with carotid artery occlusive disease. Arch Neurol 2003;60: 237-42. |
| 104. | Gauvrit JY, Delmaire C, Henon H, Debette S, al Koussa M, Leys D, et al. Diffusion/perfusion-weighted magnetic resonance imaging after carotid angioplasty and stenting. J Neurol 2004;251:1060-7. |
| 105. | Piñero P, González A, Moniche F, Martínez E, Cayuela A, González-Marcos JR, et al. Progressive changes in cerebral perfusion after carotid stenting: A dynamic susceptibility contrast perfusion weighted imaging study. J Neurointerv Surg 2014;6:527-32. |
| 106. | Kuy S, Dua A, Desai SS, Rossi PJ, Seabrook GR, Lewis BD, et al. Carotid endarterectomy national trends over a decade: Does sex matter? Ann Vasc Surg 2014;28:887-92. |
| 107. | Arous EJ, Baril DT, Robinson WP, Aiello FA, Hevelone ND, Arous EJ, et al. Institutional differences in carotid artery duplex diagnostic criteria result in significant variability in classification of carotid artery stenoses and likely lead to disparities in care. Circ Cardiovasc Qual Outcomes 2014;7:423-9. |
| 108. | Davies PF. Flow-mediated endothelial mechanotransduction. Physiol Rev 1995;75:519-60. |
| 109. | Malek AM, Alper SL, Izumo S. Hemodynamic shear stress and its role in atherosclerosis. JAMA 1999;282:2035-42. |
| 110. | Harloff A, Albrecht F, Spreer J, Stalder AF, Bock J, Frydrychowicz A, et al. 3D blood flow characteristics in the carotid artery bifurcation assessed by flow-sensitive 4D MRI at 3T. Magn Reson Med 2009;61:65-74. |
| 111. | Markl M, Frydrychowicz A, Kozerke S, Hope M, Wieben O. 4D flow MRI. J Magn Reson Imaging 2012;36:1015-36. |
| 112. | Markl M, Wegent F, Zech T, Bauer S, Strecker C, Schumacher M, et al. In vivo wall shear stress distribution in the carotid artery: Effect of bifurcation geometry, internal carotid artery stenosis, and recanalization therapy. Circ Cardiovasc Imaging 2010;3:647-55. |
| 113. | Oshinski JN, Curtin JL, Loth F. Mean-average wall shear stress measurements in the common carotid artery. J Cardiovasc Magn Reson 2006;8:717-22. |
| 114. | Varetto G, Gibello L, Bergamasco L, Sapino A, Castellano I, Garneri P, et al. Contrast enhanced ultrasound in atherosclerotic carotid artery disease. Int Angiol 2012;31:565-71. |
| 115. | Ritter MA, Theismann K, Schmiedel M, Ringelstein EB, Dittrich R. Vascularization of carotid plaque in recently symptomatic patients is associated with the occurrence of transcranial microembolic signals. Eur J Neurol 2013;20:1218-21. |
| 116. | Saba L, Mallarini G. Carotid plaque enhancement and symptom correlations: An evaluation by using multidetector row CT angiography. AJNR Am J Neuroradiol 2011;32:1919-25. |
| 117. | Grimm JM, Schindler A, Schwarz F, Cyran CC, Bayer-Karpinska A, Freilinger T, et al. Computed tomography angiography vs 3 T black-blood cardiovascular magnetic resonance for identification of symptomatic carotid plaques. J Cardiovasc Magn Reson 2014;16:84. |
| 118. | Lovblad KO, Mendes-Pereira V, Garibotto V, Assal F, Willi JP, Stztajzel R, et al. Neuroimaging of the vulnerable plaque. Curr Vasc Pharmacol 2015;13:182-91. |
| 119. | Alonso A, Artemis D, Hennerici MG. Molecular imaging of carotid plaque vulnerability. Cerebrovasc Dis 2015;39:5-12. |
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