CLINICAL PERSPECTIVE

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(Circulation. 2006;113:2320-2328.)
© 2006 American Heart Association, Inc.

Stroke

Histological Assessment of 526 Symptomatic Carotid Plaques in Relation to the Nature and Timing of Ischemic Symptoms

The Oxford Plaque Study

J.N.E. Redgrave, MRCP; J.K. Lovett, MRCP; P.J. Gallagher, PhD; P.M. Rothwell, PhD

From the Stroke Prevention Research Unit (J.N.E.R., J.K.L., P.M.R.), Department of Clinical Neurology, Radcliffe Infirmary, Oxford, United Kingdom; and Department of Pathology (P.J.G.), Southampton General Hospital, Southampton, United Kingdom.

Correspondence to Professor P.M. Rothwell, Stroke Prevention Research Unit, Department of Clinical Neurology, Radcliffe Infirmary, Woodstock Rd, Oxford, OX2 6HE, United Kingdom. E-mail peter.rothwell{at}clneuro.ox.ac.uk

Received September 15, 2005; revision received February 9, 2006; accepted March 10, 2006.

	Abstract

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Background— Atherosclerotic plaque at the carotid bifurcation is often associated with transient ischemic attack (TIA) and ischemic stroke, but the mechanisms are not completely understood. Previous histological studies have been too small or insufficiently detailed to reliably determine the temporal course of features of plaque instability or to stratify analyses by the nature of presenting symptoms.

Methods and Results— We performed the largest-ever histological study of symptomatic carotid plaques from consecutive patients (n=526) undergoing endarterectomy and related detailed reproducible histological assessments to the nature and timing of presenting symptoms. There was a high prevalence of many features of coronary-type plaque instability. Dense plaque inflammation (especially infiltration with macrophages) was the feature most strongly associated with both cap rupture (odds ratio 3.39, 95% confidence interval 2.31 to 4.98, P<0.001) and time since stroke (P=0.001). Strong negative associations with time since stroke were also seen for cap rupture (P=0.02), overall plaque inflammation (P=0.003), and "unstable plaque" (P=0.001). Although plaques removed 60 days after the most recent event were more unstable after a stroke than after a TIA, the instability persisted after a TIA, and plaques removed >180 days after most recent event were less unstable after a stroke than after a TIA (plaque inflammation: 60 days, odds ratio 2.33 [95% confidence interval 0.76 to 7.19]; >180 days, 0.36 [0.16 to 0.84]; P=0.008; unstable plaque: odds ratio 3.27 [95% confidence interval 0.93 to 11.50] versus 0.74 [0.33 to 1.69], P=0.05).

Conclusions— Pathology of recently symptomatic carotid plaques is similar to that of culprit coronary plaques, with strong correlations between macrophage infiltration and plaque instability. The tendency for plaque inflammation and overall instability to persist with time after a TIA but to decrease with time after a stroke suggests that the nature of the underlying pathology may differ.

Key Words: stroke • pathology • carotid arteries • atherosclerosis • plaque

	Introduction

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Most acute coronary syndromes are caused by thrombus formation in moderately stenosed coronary arteries at the site of a ruptured or eroded fibrous cap.^1–5 Atherosclerotic plaque also causes a substantial proportion of ischemic stroke, but the mechanisms are less well understood, and "stable" plaque that causes cerebral hypoperfusion is sometimes responsible. Indeed, the degree of carotid stenosis is strongly associated with stroke risk in symptomatic patients^6,7 and is the most important predictor of benefit from carotid endarterectomy (CEA).⁸ Nevertheless, an ulcerated appearance on carotid angiography is also a strong independent risk factor for stroke^9,10 and predicts the risk of subsequent acute coronary events.¹¹

Previous histological studies have compared symptomatic and asymptomatic carotid plaques^12–15 but have generally been small (median of 43 plaques in a recent systematic review).¹⁶ Furthermore, histology methods have been unstandardized, which has led to inconsistent results.^13,16,17 Larger studies of the gross macroscopic appearances of the excised plaque at CEA^9,18 or of noninvasive imaging techniques^9,19–22 are difficult to interpret because it is not clear which pathological features are represented by these indirect assessments.^21,23

Clinical Perspective p 2328

After appropriate pilot studies were conducted,^23,24 we performed the largest-ever histological study of symptomatic carotid plaques from consecutive patients undergoing CEA and studied pathological features in relation to the nature and timing of ischemic symptoms. Our first hypothesis was that if coronary-type plaque rupture is an important mechanism of stroke and transient ischemic attack (TIA) distal to carotid stenosis, then the temporal course of plaque instability should reflect that of the risk of recurrent ischemic events^25–27 and the reduction in benefit from CEA with time since the presenting event.^8,28 Our second hypothesis was that any such temporal relationship might be more marked after a stroke than after a TIA. Ulcerated plaque on angiography is a powerful predictor of recurrent stroke,^9,10 but recurrent TIA is more frequent in patients with angiographically smooth plaque,¹⁰ which is associated with more stable plaque on histology.²⁴

	Methods

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We studied consecutive carotid plaques in patients undergoing CEA for recently symptomatic severe stenosis in Oxford, United Kingdom. At the time of the study (1975 to 2002), it was policy to operate on patients with symptomatic carotid stenosis of at least 70% according to the method of measurement used in the European Carotid Surgery Trial²⁹ (equivalent to 50% by the North American Carotid Surgery Trial method). Patients undergoing CEA for restenosis or radiotherapy-induced carotid stenosis were excluded.

Detailed clinical data were recorded for each patient, including age, sex, percentage stenosis, treatment for hypertension, treatment for diabetes, treatment for hyperlipidemia, and smoking within the preceding year. All patients were reviewed before consideration of CEA by a neurologist, and the nature of symptoms was recorded. A data collection form was also completed by the responsible clinician at the time of admission for CEA. A second study neurologist reviewed the case notes to confirm the symptomatic diagnosis and obtain any missing data. The dates of the first and most recent ipsilateral carotid territory ischemic events, the number of ischemic episodes, and the duration of the longest episode before surgery were recorded. An event was classified as a stroke if cerebral or retinal ischemic symptoms persisted for >24 hours. For the first consecutive 372 patients, the surgeon recorded the presence or absence of macroscopic plaque ulceration and surface thrombus seen at CEA. The macroscopic assessments were not based on any standardized criteria, and the surgeon was not blinded to the patients’ symptoms.

Histopathology
The excised plaque was fixed in formalin immediately after removal. The portion of carotid bifurcation that showed maximum disease was divided transversely, and further sections were taken at 3-mm intervals along the length of the plaque for embedding in paraffin wax. Adjacent 5-µm transverse sections were taken from each wax block and stained with hematoxylin and eosin, elastin van Gieson, mouse antihuman monoclonal antibodies CD68 and CD3, for macrophages and lymphocytes, respectively (Dakocytomation, UK). A second researcher experienced in vascular pathology and blinded to the clinical details examined all of the histology sections.

The following features were graded on simple semiquantitative scales as published previously^23,24: cap rupture, lipid core size, foam cells, vascularity, plaque and cap infiltration with macrophages and lymphocytes (Table 1), proportion of fibrous tissue, intraplaque hemorrhage, and surface thrombus. We have previously shown that these histological assessments are reproducible and that there is good agreement between adjacent 3-mm sections.²³ Lipid core was defined as amorphous material containing cholesterol crystals and was considered "large: if it occupied >50% of the thickness of the plaque or >25% of the total cross-sectional area. Intraplaque hemorrhage was recorded if there was as an area of erythrocytes within the plaque causing disruption of plaque architecture as defined by Bassiouny et al.³⁰ Cap rupture was recorded if there was clear communication between the lipid core and the lumen with a break in the fibrous cap that did not appear to have been created during surgery. Surface thrombus was defined as an organized collection of fibrin and red blood cells in the lumen, as illustrated by Lammie et al.³¹ Plaques were also classified according to the American Heart Association classification of coronary atherosclerosis³; however, the American Heart Association grade does not take into account important determinants of plaque stability such as lipid core size or inflammation. Therefore, we also classified each plaque as being stable, predominantly stable, unstable with intact cap, and unstable with ruptured cap (Table 1). The aim of this classification was to take into account all of the potential markers of instability, and the definitions were based on widely accepted descriptions of unstable plaque in the coronary circulation.^2–4,32 Furthermore, we have shown previously in a study of 128 plaques that "unstable plaque" on histology correlates strongly with plaque ulceration on carotid angiography.²⁴

View this table: [in this window] [in a new window]   TABLE 1. Scales Used to Assess the Presence of Inflammatory Infiltrates and Overall Instability in the Plaques on Histology

Statistical Analyses
Patients whose most recent event was a stroke versus cerebral TIA versus amaurosis fugax were compared for baseline characteristics with a t test or ² test as appropriate. Patients were further subdivided by days from the most recent event to surgery (0 to 30, 31 to 90, 91 to 180, and >180 days), and the ² test was used to calculate the significance of linear association between these time categories and the prevalence of plaque histological features. In logistic regression models for the presence of histology features, the effect of time since symptoms was represented as a cubic spline with a single knot.³³ A stepwise multivariate analysis was performed to identify independent associations between cap rupture and the other histology features. Analyses were done with SPSS (version 11.0; SPSS Inc, Chicago, Ill) and S-Plus (version 6.2; Insightful Corp, Seattle, Wash).

The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.

	Results

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A total of 570 consecutive symptomatic carotid plaques were collected. Of these, 27 plaques were too fragmented for histological evaluation, and in 17 cases, the nature or timing of the presenting event could not be reliably determined, which left 526 plaques (92%) from 498 consecutive patients (72.1% male, mean [SD] age 66.6 [8.7] years). Twenty-one patients underwent bilateral CEA for separate ipsilateral symptomatic events during the study period and therefore contributed 2 plaques each to the study. Baseline patient characteristics are listed in Table 2. The most recent ipsilateral ischemic event was a stroke in 159 patients and a TIA in 367. Twenty-four of the strokes were retinal artery occlusions, and 166 of the TIAs were amaurosis fugax. Three hundred TIA patients (81.7%) had multiple ischemic episodes preoperatively, whereas only 45 stroke patients (28.3%) had multiple ischemic episodes before CEA (P<0.001). Patients with stroke versus TIA were similar in relation to age, sex, percentage stenosis, and all other recorded patient characteristics except for days from the most recent ischemic event to surgery, which was greater after a stroke (median [interquartile range] 126 [76–197] versus 67 [16–125], P<0.001; Table 2). The longest symptomatic event duration was significantly greater in patients with cerebral TIA only compared with patients with amaurosis fugax only (mean [SD] hours: 3.22 [6.06] versus 0.32 [2.23], P<0.0001).

View this table: [in this window] [in a new window]   TABLE 2. Clinical Characteristics at the Time of CEA in Patients With Stroke and TIA

The majority of plaques showed cap rupture (58.1%), intraplaque hemorrhage (64.6%), and marked plaque inflammation (66.8%) on histology. A total of 50.4% were American Heart Association grade 6, and 64.1% had unstable plaque. The overall prevalence of histology features was similar in patients with stroke, cerebral TIA, and amaurosis fugax (Table 3). Dense infiltration with macrophages in the plaque and cap were more strongly associated with cap rupture than lymphocytes. Cap rupture on histology was strongly positively associated with several of the other histology features, including large lipid core (odds ratio [OR] 6.46, 95% confidence interval [CI] 4.37 to 9.55, P<0.001), hemorrhage (OR 4.38, 95% CI 2.98 to 6.42, P<0.001), and marked cap inflammation (OR 6.01, 95% CI 3.80 to 9.50, P<0.001; Table 4). In a multivariate stepwise analysis of all the histology features, intraplaque hemorrhage (OR 3.00, 95% CI 1.64 to 5.51, P<0.001) and cap inflammation (OR 4.33, 95% CI 2.27 to 8.26, P<0.001) were independently associated with cap rupture.

View this table: [in this window] [in a new window]   TABLE 3. Prevalence of Histological Features According to Most Recent Ischemic Event Type

View this table: [in this window] [in a new window]   TABLE 4. Prevalence of Other Histology Features in Plaques With Cap Rupture vs No Cap Rupture

There were strong correlations between several histological features and macroscopic appearances of the plaque at surgery (Table 5). Marked plaque and cap infiltration with macrophages was strongly positively associated with plaque ulceration and thrombus on macroscopic assessment, but there were no associations between macroscopic appearances and lymphocytes, vascularity, or foam cells on histology.

View this table: [in this window] [in a new window]   TABLE 5. Associations Between Plaque Macroscopic Appearances and Histological Features

There were strong negative associations between several histological features of instability and time since stroke, especially plaque macrophages (P=0.007), overall plaque inflammation (P=0.003), cap rupture (P=0.02), and unstable plaque (P=0.001), with a continued decline in these features in plaques removed up to 180 days after stroke (Figure; Table 6). Much weaker associations were seen between these features and time since TIA. In patients who underwent surgery 60 days after last symptoms, there were borderline statistically significant tendencies for cap rupture (OR 3.38, 95% CI 1.10 to 10.37, P=0.03), marked inflammatory infiltrate in the plaque (OR 2.33, 95% CI 0.76 to 7.19, P=0.14), and unstable plaque (OR 3.27, 95% CI 0.93 to 11.50, P=0.07) to be more frequent after a stroke than after a TIA. Conversely, in plaques removed >180 days after last symptoms, there was a lower prevalence of unstable features in patients with stroke than in those with TIA, particularly cap macrophages (OR 0.32, 95% CI 0.11 to 0.95, P=0.04) and overall cap inflammation (OR 0.30, 95% CI 0.11 to 0.83, P=0.02; Table 7).

View larger version (21K): [in this window] [in a new window]   Proportion of plaques with histology features (95% CI) according to time since most recent ischemic event.

View this table: [in this window] [in a new window]   TABLE 6. No. of Plaques (%) With Histology Features in Each Symptom and Timing Subgroup

View this table: [in this window] [in a new window]   TABLE 7. ORs for Presence Versus Absence of Plaque Histological Features in Patients With Stroke Versus TIA Who Underwent Surgery 60 Days and >180 Days After the Most Recent Ischemic Event

There was a tendency for plaques removed 0 to 7 days after a TIA to be more unstable on histology than plaques removed 8 to 30 days after a TIA (eg, marked plaque macrophages 75% versus 60%, P=0.09, overall instability 74.5% versus 60.5%, P=0.12). However, this tendency was potentially confounded by the number of TIAs that occurred before surgery, as patients with TIAs within 7 days of CEA were more likely to have had multiple events, with the most recent TIA usually occurring after the date for surgery was set. Furthermore, analysis of patients with a single TIA before surgery (n=67) revealed no temporal trends in plaque features with time since symptoms.

	Discussion

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In the largest-ever study of symptomatic carotid plaque histology, we found a high prevalence of cap rupture, large lipid core, and dense macrophage infiltrate, which suggests that the mechanisms of plaque instability in the carotid circulation are similar to those in the coronary circulation.^1–5 Dense plaque macrophage infiltration was strongly associated with both cap rupture on histology and time since stroke, suggesting possible causal links between plaque inflammation and plaque instability. In contrast, plaque vascularity and plaque lymphocytes were not consistently associated with either cap rupture or time since stroke. Although evidence of previous intraplaque hemorrhage was strongly associated with cap rupture, the association with time since stroke was weak; however, we did not determine the age of hemorrhage, and an association with recent hemorrhage could therefore have been diluted.

Our findings add significantly to those of previous histological studies of carotid plaque, the majority of which simply compared symptomatic and asymptomatic plaques.¹⁶ First, previous studies have shown that macrophage infiltration is greater in symptomatic plaques^12,34–36 than in asymptomatic plaques. We have shown that macrophage infiltration is greatest in those symptomatic plaques with cap rupture. Taken together with our previous findings of a very strong association between cap rupture on histology and surface ulceration on angiography²⁴ and between angiographic ulceration and risk of subsequent stroke,⁹ we can conclude that plaques with dense infiltration with macrophages will be associated with a high risk of stroke. Second, we have further shown strong associations with time since stroke for both macrophage infiltration and cap rupture, neither of which have been reliably demonstrated previously. These observations suggest that in patients with stroke distal to severe carotid stenosis, the process of plaque disruption has an acute component. This is perhaps best illustrated by the low prevalence of features of instability in plaques from patients with stroke in whom CEA was performed >180 days after the event. Indeed, these plaques are no more unstable than the plaques that we have studied from patients who underwent surgery for asymptomatic stenosis (Redgrave, unpublished data, 2005), which suggests that the processes leading to plaque instability resulting in stroke are intermittent.

In striking contrast to the time trends observed in plaques from patients with stroke, instability tended to persist with time after TIA. These observations raise the possibility that the form of plaque instability that leads most frequently to TIA is different from that which leads most frequently to stroke in patients with carotid stenosis, the former being a more chronic process and the latter being more acute. Interestingly, plaques from patients with TIA also tended to show a greater prevalence of surface thrombus without rupture (OR 1.62, 95% CI 0.77 to 3.51, P=0.17), which possibly reflects a higher prevalence of plaque erosion.

If the pathological mechanisms underlying stroke and TIA in patients with carotid stenosis are different, then one might expect the clinical course to differ between patients presenting with TIA versus stroke. We found that patients with TIA frequently had multiple ischemic episodes in the months before CEA, whereas patients with stroke were more likely to have an isolated episode. Thus, there may be a spectrum of plaque pathology that leads to somewhat distinct clinical patterns. At one end of the spectrum, acute plaque destabilization results in an isolated, severe ischemic episode, followed by healing to a relatively quiescent state over several months, perhaps mediated by a shift in the balance of matrix-degrading enzymes and their inhibitors within the plaque.^37,38 At the other end of the spectrum, a more chronic process results in repeated, less severe ischemic symptoms over a longer period of time, which suggests perhaps that emboli are smaller or different in composition.

There are some potential alternative explanations for our findings. First, the data on timing of TIAs may have been less accurate than those for strokes either due to less accurate patient recall or because patients with TIA may be more likely to have asymptomatic plaque embolization than patients with stroke.³⁹ However, previous studies suggest that patient recall of the timing of their TIAs is usually accurate.^25,40 Second, some acute consequences of the stroke itself, which might be less marked or absent after a TIA, could cause secondary inflammation in the plaque. However, this "reverse causation" appears unlikely.

Few previous histological studies of carotid plaques have stratified analyses by time since ischemic event, and the results have been inconsistent.^12,41,42 One study found that the prevalence of "fresh" thrombus declined with time after stroke. However, the prevalence of thrombus was higher in that study than in the present study, and their definition of fresh thrombus may have overlapped with our definition of intraplaque hemorrhage. In addition, the histology analyses in that study were performed by time since the first ischemic event rather than by time since the most recent event, as we have done.⁴²

Two advantages of the present study stemmed from our long period of collection of plaques (1975 to 2002). First, because the majority of patients underwent CEA in the pre-statin era, any potential bias due to the stabilizing effect of statins on plaques was minimized. Moreover, we had sufficient power in our analysis of plaques from patients not taking statins to demonstrate the same overall results. Second, because of the historical tendency for clinicians to delay CEA after the presenting event in the hope of reducing the operative risk, there was a broad spectrum of time from last symptoms to surgery, which allowed us to identify temporal trends in plaque features more reliably.

There were, however, some potential limitations. First, we took sections at 3-mm intervals along the length of each plaque, so it is possible that some features that occurred only between the points of sectioning were missed. However, we have shown previously that there is good agreement between adjacent 3-mm sections such that even a single bifurcation section is reasonably representative of the plaque as a whole.²³ Second, the power to detect transient acute changes in pathological features in plaques from patients with stroke was limited because CEA tended to be delayed after stroke. However, a postmortem study of acutely occluded carotid arteries in 14 patients with fatal stroke showed plaque histology that was similar to our findings in patients who underwent surgery within 60 days.³¹ Furthermore, a recent study of intracoronary thrombectomy specimens removed from patients within 6 hours of ST-elevation myocardial infarction suggested that features of unstable plaque had often been present for several weeks.⁴³

In conclusion, the pathology of recently symptomatic carotid plaques is similar to that of culprit coronary plaques. Dense infiltration with macrophages is strongly associated with cap rupture and time since stroke, which supports a causal role in plaque instability. The marked temporal trends in plaque instability after stroke compared with the apparently more persistent changes after TIA raise the possibility that there is heterogeneity in the underlying mechanisms. These findings have implications not only for our understanding of the processes that lead to acute cerebral ischemia in patients with carotid stenosis but also for the interpretation of plaque appearances on imaging.

	Acknowledgments

 
This study was supported by Guarantors of Brain, the Wellcome Trust, and the Medical Research Council.

Disclosures

None.

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CLINICAL PERSPECTIVE

In the largest-ever study of the histology of recently symptomatic carotid plaques removed at endarterectomy, we related pathological features to the nature of and time since the last ischemic episode and made 3 important observations. First, we showed that the pathological features of symptomatic carotid plaques are the same as have been reported in culprit coronary plaques at postmortem analysis, which supports the concept that the therapeutic strategies that have proved effective in patients with acute coronary syndromes might also be of benefit in patients with recently symptomatic carotid stenosis. Second, we found that the prevalence of features of plaque instability fell with time since stroke but that instability was more persistent after transient ischemic attack, which suggests that the tendency for some patients with transient ischemic attack to have multiple transient episodes over a longer period of time is due to ongoing plaque instability and inflammation. Finally, plaque inflammation, especially infiltration with macrophages, was the histological feature that was most strongly associated with both cap rupture and time since stroke, which confirms the importance of macrophage infiltration as a marker of plaque instability and highlights the potential of targeted imaging for the identification of vulnerable plaques and hence the risk stratification of patients with carotid stenosis, as well as the possibility that antiinflammatory therapies might stabilize plaques.

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