Neurol Clin 24 (2006) 661–667

Carotid Endarterectomyfor Asymptomatic Plaque

Cathy M. Helgason, MDDepartment of Neurology, University of Illinois College of Medicine at Chicago,

912 South Wood Street, Room 855N, Chicago, IL, 60612, USA

Asymptomatic carotid plaque statistically is a relatively benign conditionthat infrequently leads to stroke in the general population. For patientswhose ischemic stroke is caused by carotid artery atheromatous plaque,there may not be minimal neurologic residual deficit. Degree of stenosishas been the gold-standard marker of the need for carotid endarterectomyin symptomatic patients to prevent future stroke. Stenosis, paradoxically,is not the same risk for stroke in patients who are asymptomatic. This sug-gests that factors other than stenosis at the site of carotid artery plaquecause stroke. One of the first characteristics noted to be associated withCT-proved stroke was soft echolucent plaque defined by computer imageanalysis [1–4]. Other variables have been identified as meaningful for thedevelopment of symptoms. The key to understanding that dynamic processthat turns an asymptomatic into a symptomatic plaque lies in recognizingthe complexity of vulnerable plaque morphology and the interaction ofthese features with systemic characteristics of individual patients.

The clinical contradiction

For previously asymptomatic patients who have carotid plaque, the oc-currence of stroke suggests that the atheroma is not a totally benign condi-tion, contradicting the benign implication of its population-based risk. Thecontradiction occurs because the group-based data analysis from probabil-ity theory (PT)–founded statistics is never certain when regarding the case ofany one specific patient. Because stenosis is not the only risk factor forstroke and because certainty of occurrence in a specific individual patientis false, total clinical reliance on the axioms, postulates, and rules of thePT-based statistical tool can be called into question. This tool fails to

E-mail address: helgason@uic.edu

0733-8619/06/$ - see front matter � 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.ncl.2006.06.005 neurologic.theclinics.com

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discover the context that defines when individual asymptomatic patientshould have carotid endarterectomy. Thus, the wise conclusion of J. MaxFindlay is that this surgery should not be performed in the patient withoutsymptoms but by an expert surgeon who has a demonstrated lowcomplication rate [5].

The focus of the problem lies in the distinction and similarity betweenwhat is called ‘‘causation’’ on the one hand and ‘‘risk’’ on the other.‘‘Risk’’ is a gambling term, used in PT-based statistics. It derives from fre-quencies in group data. Statistical correlation, best when linear, portrays thesituation after variables, such as carotid stenosis or other morphology andstroke, are separated from each other, their context, and the patient andplaced into distributions. Causation sometimes is considered the factorsthat determine the observed frequencies. Causation, alternatively, mightbe defined as the reason a statistical correlation exists, but because the cor-relation does not portray any variable interaction as it must exist in any in-dividual patient, the cause of stroke for that patient may be unrelated.Causation is basic to the pathophysiology of disease and defines how andto what degree a factor or factors interact to change the condition of a pa-tient [6]. The cause, thus, may not be observed but is measurable.

Stenosis

The degree of stenosis was used in the clinical trials of carotid endarter-ectomy in asymptomatic disease because it paralleled the predictive modelconsidered in patients who had a transient ischemic attack or stroke. Con-sidering that these are two types of patients (that is, symptomatic andasymptomatic), it is not surprising that their relative prognostic importanceof stenosis is different. Consideration of the pathogenesis of thromboembo-lism and plaque characteristics may shed more light on the issue [7]. In thisregard, molecular events at the level of the plaque may be the cause for sys-temic changes in the blood and brain of a patient and relate to symptoms.

Standard tests of degree of stenosis, the carotid B mode ultrasound–Doppler and cerebral angiography is the gold standard for stenosis, donot define any characteristics of Virchow’s triad, those essential elementsfor thrombus occurrence. They do not identify molecular events at thesite of the plaque. Altered blood flow, damaged endothelium, and hyperco-agulability are at once the result and the cause of thrombus, indicating thenonlinear dynamic of the pathogenesis of thromboembolism. Quantitativeflow of blood through the carotid at the site of plaque is not defined byany of the usual tests to define carotid disease, which instead give velocityof blood flow, degree of narrowed luminal narrowing, and some plaquecharacteristics, such as ulceration and echogenicity. The plaque at highrisk for rupture and genesis of thromboembolism commonly is believed tobe that carotid plaque, which has a thin fibrous cap overlying the lipidrich necrotic core. But other factors play a role. A thrombotically active

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plaque is associated with symptoms, as is a high inflammatory infiltrate,which is associated with plaque rupture and thrombus [7]. Plaque ulcerationand thrombus are morphologies more prevalent in patients who are symp-tomatic [8,9]. Echolucent plaques have less fibrous tissue by ultrasonogra-phy and are more common in patients who are symptomatic [10].

Recent developments in technology of magnetic resonance angiography(MRA) and CT scanning may define these characteristics better. Quantita-tive MRA flow studies show that the degree of stenosis is not sufficient causefor decreased quantitative flow through an artery of the cerebral vascula-ture. Proof of principle recently has been provided in that the compositionatheromatous carotid plaque can be determined by automated classificationof high resolution ex vivo MRI, accurately reflecting the composition of theplaque by histologic confirmation [11]. The variability of histologic assess-ment affects the accuracy of imaging of carotid plaque morphology [12]. Fi-brous cap thickness and rupture can be shown in vivo by high-resolutionMRI with a 3-D multiple overlapping thin-slab angiography protocol[13–15]. Contrast-enhanced MRI can define the fibrous cap and the lipidrich necrotic core quantitatively. Multispectral MRI can identify lipid richnecrotic core in vivo reliably. Although MRI sensitively can characterizecalcification, fibrocellular tissue, the lipid core, and the necrotic core, it can-not characterize thrombus. Molecular imaging techniques by MRI, ultra-sound, and optical and nuclear methods in the future may define unstableplaque characteristics and thrombus [3]. Imaging plaque density by CTshows the correlation between carotid plaque density and neurologic eventsin asymptomatic patients [16,17]. Contrary to coronary plaques, high-riskcarotid plaques are heterogeneous, very fibrous, not lipid rich, and rupturestarting with intramural hematoma and dissection.

It is the proximity of the plaque necrotic core to the lumen and cellularindicators of microvascular neoformation and inflammation around the fi-brous cap that identify high-risk stenotic lesions of the carotid. Imagingstudies that reliably can show this as part of the routine clinical preventionof stroke have yet to arrive. In neither the North American SymptomaticCarotid Endarterectomy Trial nor the Asymptomatic Carotid Endarterec-tomy trials was quantitative flow through the stenosed vessels or plaque his-tologic vulnerability defined before randomization. Thus, in spite of largetrials having been performed, the essential information that would definethe significance of stenosis for any given patient was not known. Simplystated in the Cochrane Database of Systematic Reviews, based on three trialscomparing a group of patients receiving carotid endarterectomy and thosereceiving medical therapy, there was a reduced ‘‘risk’’ of ipsilateral andany stroke in the group of patients undergoing carotid endarterectomy.No correlation with grades of stenosis could be made that was statisticallysignificant [4]. This is because of the fact that in spite of high plaque bulkwith stenosis, the composition of that plaque can vary, sometimes betweenhigh composition of fibrous tissue or much friable atheroma with

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hemorrhage. The upshot of all of this is that although a stenotic plaque isconsidered a high-risk plaque, and possibly necessary, stenosis alone isnot sufficient and must interact dynamically with other factors before in-tramural hematoma or dissection occurs with resultant thromboembolism[17–25].

The dynamic process of plaque and patients

That the vulnerable carotid plaque, the one that ruptures with subsequentthrombosis or distal embolization of atheromatous debris, is different fromcarotid stenosis is suggested by the Cochrane results (no correlation withstenosis) and the biophysiology of the fibrous cap, lipid core, intraplaque hem-orrhage, and plaque structure and function [4]. Biologic, genetic, andmechan-ical factors are involved in plaque rupture, thrombosis, and embolism. It maywell be that changes in gene activation relating to angiogenesis and cytokineexpression relate to the symptomatology of patients. Recent scientific litera-ture reflects the study of correlations of such factors. Histologic markers ofvulnerability include large lipid core, thin fibrous cap, intraplaque hemor-rhage, and inflammatory cells of the monocyte-macrophage lineage. Impor-tantly, patient systemic correlations of atherosclerotic plaque instabilityalso are suggested by studies showing inflammation as measured by serumhigh sensitivity C-reactive protein levels. Serologicmarkers of plaque instabil-ity may bemultiple: pregnancy-associated protein A, P-selectin, interleukin 6,interleukin 12, metalloproteinases, lipoprotein(a), and oxidation products.Matrix metalloproteinases (MMP-8 and MMP-9) and inflammatory plaqueare associated. Matrix metalloproteinase and plaque regulation and plaquedestabilization may be regulated by extracellular matrix matelloproteinaseinducer (EMMPRIN) differences in form. Tissue inhibitors of metallopro-teinases might be involved in plaque formation.Chlamydia pneumoniae infec-tion of vascular smooth muscle cells increases interleukin 6 secretion fromatheromatous plaque and could explain the presence of inflammatory serol-ogy in patients at risk for stroke.Markers of thrombophila and impaired fibri-nolysis correlate with the symptomatic characterization of carotid stenosis byplaque. Hematocrit, tissue plasminogen activator antigen levels, plasminogenactivator inhibitor-1 levels and microembolic signal activity are correlatedwith the degree of stenosis. Over time, the development or appearance of thesehematologic abnormalities could sentinel the change from asymptomatic tosymptomatic disease. In histologic samples of carotid plaque from asymptom-atic and symptomatic patients, increased density of mast cells was correlatedwith atherogenic lipid profile, high-grade stenosis, and symptoms. Unstablecharacteristics, defined as the presence of macrophages, smooth muscle cells,collagen, calcifications, thrombus, andmeasured amount of fat, matrixmetal-loproteinase activity, and cytokine expression indicate increased risk for tran-sient ischemic attack and stroke. Plaque phenotype is found similar in patientswho have stroke and transient ischemic attack but not in those with amaurosis

665CAROTID ENDARTERECTOMY FOR ASYMPTOMATIC PLAQUE

fugax whose phenotype resembles that of asymptomatic patients [18,19,25–28]. Fluorodeoxyglucose positron emission tomography identifies plaqueinflammation and correlates with serum high-sensitivity C-reactive proteinin patients who are symptomatic and have carotid artery disease [29]. Fibrouscap thickness can be detected by ultrasound showing good correlation withhistology and symptoms [30].

Thus, blood tests for thrombophilia and inflammation, ultrasound imag-ing, and CT and MRI cross-sectional studies of carotid plaque, echogenic-ity, regularity, homogeneity, location, and the thinness of the fibrous capmay indicate impending stroke. Embolic monitoring also can give prognos-tic data. Transcranial Doppler monitoring of patients who have had recentcerebral ischemia of presumed arterial origin recognizes the subgroup of pa-tients who have high risk for early recurrence [31]. But most importantly, itis not only the plaque and its histologic features that cause patients to besymptomatic but also blood components and flow abnormalities that areimportant. Hypercoagulability determines to a degree which patients willbecome symptomatic from vulnerable coronary plaque. This likely is thecase also for carotid plaque. All these facts point to the conclusion that itis within the context of individual patients that these factors assume aninteractive dynamic process, which changes over time and either leadsto symptoms or remains asymptomatic. Flow dynamics at the site of thecarotid bifurcation may produce endothelial disruption, and the microcircu-lation of the artery wall itself is important for ulceration and changes in theintima and media [32,33]. Mechanical forces from blood flow can affect geneexpression and function in endothelial cells.

Summary

Statistical correlations are linear noninteractive relationships, but the dy-namics of causation are nonlinear and involve complex interactions wherevariables change through their effect on one another and interact with thecontext of the patient over time. The discovery and interpretation of plaquevulnerable features in the individual patient are not determined for the asymp-tomatic patient being considered for carotid endarterectomy. New technolo-gies for identification of plaque chemical andmorphologic composition are onthe horizon and may be applicable to certain patients but change in their use-fulness as the plaque and patient change over time [34].

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