Published online before print April 10, 2008, doi: 10.1161/STROKEAHA.107.507988
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(Stroke. 2008;39:1722.)
© 2008 American Heart Association, Inc.
Original Contributions |
Critical Cap Thickness and Rupture in Symptomatic Carotid Plaques
The Oxford Plaque Study
From the Stroke Prevention Research Unit (J.N.R., J.K.L., P.M.R.), Department of Clinical Neurology, Radcliffe Infirmary, Oxford, UK; and the Department of Pathology (P.G.), Southampton General Hospital, Southampton, UK.
Correspondence to Professor P.M. Rothwell, Stroke Prevention Research Unit, Department of Clinical Neurology, Radcliffe Infirmary, Woodstock Road, Oxford, OX2 6HE. E-mail peter.rothwell{at}clneuro.ox.ac.uk
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Abstract |
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Background and Purpose— Advances in carotid plaque imaging could allow quantification of fibrous cap thickness in vivo. While a cap thickness <65 µm is the accepted definition of rupture-prone plaque in the coronary circulation, the threshold value for carotid plaques is unknown.
Methods— We made detailed histological assessments of 526 carotid plaques from consecutive patients undergoing endarterectomy for symptomatic carotid stenosis. The thickness of the fibrous cap at the thinnest and most representative part was measured.
Results— Cap thickness could be measured reliably in 428 (81%) plaques. In the ruptured plaques (n=257), the median representative cap thickness was 300 µm (IQR 200 to 500 µm) and the median minimum cap thickness was 150 µm (80 to 210 µm; mean=181 µm), which is much greater than the mean cap thickness of 23 µm at the point of rupture that has been reported for coronary plaques. For nonruptured plaques, the median cap thickness values were 500 µm (300 to 700 µm) and 250 µm (180 to 400 µm), respectively. The optimum cut-offs for discriminating between ruptured and nonruptured plaques were a minimum cap thickness <200 µm (OR 5.00, 3.26 to 7.65, P<0.001), a representative cap thickness <500 µm (OR 3.38, 2.25 to 5.08, P<0.001), or a combination of both (OR 5.11, 3.19 to 8.19, P<0.001). Minimum and representative cap thickness were only modestly correlated (r2=0.30) and were both independently associated with cap rupture.
Conclusions— Critical cap thickness is greater in carotid plaques than coronary plaques. Minimum and representative cap thicknesses were both independently associated with cap rupture. A combination of minimum cap thickness <200 µm and a representative cap thickness <500 µm identified ruptured plaques most reliably. Prospective imaging studies are required to establish whether these cut points predict clinical events in patients with asymptomatic carotid stenosis.
Key Words: atherosclerosis • carotid endarterectomy • carotid stenosis • pathology
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Introduction |
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The modified AHA classification of atherosclerotic lesions1 defines "thin fibrous cap" as one that is <65 µm thick on the basis that this was the 95th centile cap thickness at the point of rupture in a series of 41 fatally ruptured coronary plaques (mean(SD)=23 (19) µm).2 Rupture of the fibrous cap is also responsible for the majority of strokes distal to a carotid stenosis.3–5 Fibrous caps can now be visualized in carotid plaques in vivo,6,7 and a thin cap on MR-imaging is associated with recent ipsilateral ischemic symptoms7,8 and possibly with ischemic events on follow-up.9 However, the degree of cap thickness which renders a carotid plaque prone to rupture is unknown.
In a small study of 44 carotid endarterectomy specimens (19 symptomatic), "fibrous cap thinning" was associated with symptomatic plaque.10 However, the precise definition of this qualitative histological assessment was not given. More recently, a study of 58 plaques (22 symptomatic), which reported good histology-imaging correlation of cap thickness in a subset of 20 plaques, found that mean cap thickness <650 µm and minimum cap thickness <460 µm on ultrasound were optimum for discriminating symptomatic from asymptomatic plaques.7 However, in that study, the discriminatory accuracy for minimum cap thickness was lower than that for mean cap thickness, which may have been because the minimum cap thickness values were close to the axial resolution of the ultrasound system. Therefore, to help define targets for carotid plaque imaging, there have been repeated calls for a quantitative pathological definition of "thin fibrous cap" at the carotid bifurcation.11–15
Cap rupture is more common in recently symptomatic carotid plaques than in asymptomatic carotid plaques10,16,17 and is strongly associated with ulceration on carotid angiography,18 which was an independent predictor of stroke on follow-up in patients with symptomatic severe carotid stenosis randomized to medical treatment in trials of endarterectomy.19,20 Therefore the identification of unstable plaque features in vivo may contribute to risk stratification of patients with asymptomatic and moderately severe symptomatic carotid stenosis. We studied minimum and representative cap thickness in 526 symptomatic carotid plaques and determined the thresholds most strongly associated with cap rupture. We also determined the interaction between representative and minimum cap thickness and cap rupture.
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Methods |
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We studied consecutive carotid plaques from patients undergoing CEA for recently symptomatic severe stenosis in Oxford, UK.21 At the time of the study, it was policy to operate on patients with symptomatic carotid stenosis of
70% according to the method of measurement used in the European Carotid Surgery Trial22 (equivalent to 50% by the North American Carotid Surgery Trial [NASCET] method). The majority of endarterectomies were done using the open (classic) surgical approach with a few eversion techniques performed in recent years. Patients undergoing CEA for restenosis or radiotherapy-induced carotid stenosis were excluded. The study was approved by the local ethics committee. All patients were reviewed before consideration of CEA by a neurologist and the nature and timing of cerebral ischemic symptoms was recorded. A stroke was defined as cerebral or retinal ischemic symptoms persisting >24 hours. Detailed clinical data were recorded for each patient, including age, sex, percentage stenosis, blood pressure, treated hypertension, diabetes, treated hyperlipidemia, and smoking within the preceding 6 months.
Histopathology
The excised plaques were fixed in formalin immediately after removal. The portion of carotid bifurcation showing 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 Geison (EVG), CD68 antibody (macrophages), and CD3 antibody (lymphocytes). A second researcher experienced in vascular pathology examined all the histology sections blind to the clinical details.
The fibrous cap was identified, and a calibrated graticule in the microscope eye-piece was used to measure the thinnest part (minimum cap thickness) and the part with a thickness considered to be most representative of the cap as a whole (representative cap thickness). The following additional features were graded on simple semiquantitative scales as published previously18,23: cap rupture, lipid core size, foam cells, vascularity, plaque and cap infiltration with macrophages and lymphocytes, proportion of fibrous tissue, intraplaque hemorrhage, and surface thrombus (Figure 1). Briefly, 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 an area of erythrocytes within the plaque causing disruption of plaque architecture or when there was clear evidence of organized hemorrhage with the accumulation of hemosiderin laden macrophages or iron deposition on plaque connective tissue.16 A hemorrhage was considered large of it measured >2 mm in circumferential length and >0.5 mm in maximum width. Plaque and cap infiltration with macrophages and lymphocytes was quantified as described previously.18 Cap rupture was recorded if there was clear communication between the lipid core and the lumen with a break in the fibrous cap which 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.3 Plaques were also classified according to the American Heart Association (AHA) classification of coronary atherosclerosis.24 We have previously shown that our histological assessments are reproducible and that there is reasonable agreement between adjacent 3-mm plaque sections.23 Furthermore, in a study of 128 plaques, we have shown that several histology features (eg, cap rupture, intraplaque hemorrhage and large lipid core) are strongly associated with plaque ulceration on angiography.18
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Statistical Analyses
A receiver operating curve analysis was used to determine the optimum cut-off cap thickness values for discrimination between ruptured and nonruptured plaques. The observer agreement for cap thickness values below these cut-offs was then calculated using data from our previous reproducibility study (2 observers, 60 plaques).23 Clinical and histology features were compared in cap thickness subgroups using t test or 
2 tests as appropriate. A linear regression analysis was used to determine the correlation between minimum and representative cap thickness. A conditional stepwise model was used to determine independent associations with cap rupture. SPSS (v 15.0) was used for analysis.
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Results |
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Five hundred twenty-six consecutive carotid plaques were collected from patients with symptomatic carotid stenosis. In 98 plaques (19%), there was insufficient cap visible for reliable measurement (55 ruptured, 43 nonruptured) leaving 428 plaques for analysis.
Three hundred eight (72%) patients were male, mean (SD) age was 66.7 (8.7) and the mean (SD) stenosis of the operated artery was 80.6% (16.4). Two hundred forty-four (57%) patients were on antihypertensive medication, 94 (22%) were on lipid lowering therapy, 42 (9.8%) were diabetic, and 170 (39.7%) had smoked in the preceding 6 months.
Overall, the median representative cap thickness was 400 µm (IQR 220 to 600 µm) and the median minimum cap thickness was 200 µm (100 to 300 µm). Two hundred fifty-seven (60%) plaques were ruptured. The median (IQR) representative cap thickness for ruptured plaques was 300 µm (200 to 500 µm) versus 500 µm (300 to 700 µm) for nonruptured plaques (P<0.001). Equivalent values for minimum cap thickness were 150 µm (80 to 210 µm) and 250 µm (180 to 400 µm; P<0.001; Figure 2). There was no tendency for the median minimum cap thickness of ruptured plaques to vary with time since symptoms (P trend=0.54), preoperative stenosis (P trend=0.39), or mean arterial pulse pressure (P trend=0.89).
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There was a strong inverse relationship between both measures of cap thickness and cap rupture (Figure 3). In the corresponding receiver operating curve analyses, the area under the curve was nonsignificantly greater for minimum cap thickness (0.72) than for representative cap thickness (0.67). The optimum cap thickness values for predicting rupture were a minimum cap thickness <200 µm (OR 5.00, 95% CI 3.26 to 7.65, positive predictive value [PPV] 79% P<0.001), a representative cap thickness <500 µm (OR 3.38, 2.25 to 5.08, PPV 73% P<0.001), and a combination of both measurements (OR 5.11, 3.19 to 8.19, PPV 82% P<0.001; Table 1). These cut-offs were similar in men and women (data not shown).
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Kappa values for representative cap thickness <500 µm were 0.57 (intraobserver) and 0.51 (interobserver). For minimum cap <200 µm, these values were 0.50 and 0.42, respectively.
There was a strong positive correlation between minimum and representative cap thickness. However, there was a wide range of minimum cap thickness overall (10 to 1750 µm), of which only about a third was explained by the variation in representative cap thickness (linear regression r2=0.30). Moreover, in a backward conditional stepwise model of all of the histology features (except surface thrombus which is a consequence rather than a potential cause of cap rupture) cap thickness was independently associated with cap rupture when either or both representative and minimum cap thickness were entered as covariates. There was no interaction between the 2 measures of cap thickness and cap rupture (P=0.94). Thus the histology features independently associated with cap rupture were as follows: marked cap macrophages (OR 3.52, 1.98 to 6.26, P<0.001), intraplaque hemorrhage (OR 2.65, 1.56 to 4.51, P<0.001), large lipid core (OR 4.03, 2.35 to 6.09, P<0.001), minimum cap thickness <200 µm (OR 2.64, 1.53 to 4.57, P=0.001), and representative cap thickness <500 µm (OR 2.45, 1.41 to 4.25, P=0.001). These features were also independently associated with cap rupture after adjusting for age, sex, time since symptoms, and stenosis (data not shown).
Only 49 plaques (11.7%) had a minimum cap thickness <65 µm (the cut-off for thin fibrous cap atheroma in coronary plaques25), of which 40 (81.6%) were ruptured. Cut-offs with 100% sensitivity and specificity for cap rupture were a minimum cap thickness <20 µm (n=4, all ruptured) and a representative cap thickness <100 µm (n=9, all ruptured).
Patients with a minimum cap thickness <200 µm were more likely to be male (P<0.001) than patients with a greater minimum cap thickness, but other clinical characteristics were similar in the 2 groups (Table 2). Patients with a representative cap thickness <500 µm had similar clinical characteristics to patients with greater representative cap thickness (Table 2).
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There was a highly significant trend for several other features of unstable plaque to increase with decreasing cap thickness eg, large lipid core, intraplaque hemorrhage, and marked cap macrophage infiltration (all P trend <0.001), many foam cells (P trend=0.001), and marked plaque macrophage infiltration (P trend=0.01; Table 3).
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Discussion |
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The AHA produced the first internationally accepted histological classification of atheromatous plaques,24 but this did not include detailed measurements of cap thickness or inflammation. The more recent morphological classification scheme described by Virmani et al1 incorporates inflammation and defines "thin fibrous cap atheroma" (ie, plaque prone to rupture) as one which is <65 µm thick, on the basis that this was the 95th centile cap thickness at the point of rupture (presumably the minimum cap thickness) in a series of 41 fatally ruptured coronary plaques (mean=23 µm).2 In this study, we have shown that in ruptured plaques at the carotid bifurcation, the median minimum cap thickness is 150 µm (mean=181 µm), which is almost 10 times greater than this.
We have also found that the optimum minimum cap thickness for discriminating between ruptured and nonruptured plaques was <200 µm, which is the same as that suggested by Virmani et al in a recent review,26 although the method they used to arrive at this value was different to ours. In that review, they refer to a small study of carotid plaques (44 plaques [19 symptomatic of which 14 were ruptured]10) and state that the mean cap thickness at the point of rupture was 72 µm (95th centile 165 µm).11,26,27 Although the raw data and detailed methods of cap measurement in that study have not been published, by using these results and extrapolating from their coronary plaque data the authors have also suggested a cut-off of <200 µm to define "thin fibrous cap" at the carotid bifurcation.11
The calibre of the internal carotid artery is clearly greater than that of coronary arteries, so the critical cap thickness might be expected to differ. However, there are several other reasons why the critical cap thickness might be greater for carotid plaques. First, the hemodynamic forces acting at the carotid bifurcation are greater than those at the inner curvatures of the coronary arteries.26 Second, arterial wall motion is also likely to differ between the 2 vascular beds which may affect propensity of plaques to rupture.28 Third, some data suggest that macrophages play a more important role in coronary plaque rupture than in carotid rupture and therefore the mechanisms of cap rupture may differ.26 Fourth, the importance of plaque "erosion" in symptom generation may differ between the 2 vascular beds.1,5 Fifth, most acute coronary syndromes are attributable to rupture of plaque in moderately stenosed vessels,29 whereas the carotid plaques in our study had caused severe stenosis. Sixth, the definition of thin cap in coronary plaques is based on a study of ruptured coronary plaques in men who died suddenly of presumed fatal myocardial infarction2 whereas the present study looked at consecutive patients undergoing CEA for symptomatic carotid stenosis. One previous study reported pathological features of fatally ruptured carotid plaques (n=14) but cap thicknesses were not apparently measured.3
Our findings lend support to some recently proposed mechanisms of plaque instability. First, thin fibrous cap was positively associated with inflammation of the plaque and of the cap, potentially supporting a link between matrix metalloproteinases and cap thinning.30,31 Second, we found that intraplaque hemorrhage and a large lipid core were strongly associated with both a thin cap and cap rupture4 consistent with a proposed role for erythrocyte membranes in stimulating lipid core growth.32,33 Third, the inverse relationship between cap thickness and cap rupture is consistent with the findings of a recent experimental study which used a flow-plaque interaction model to show that the thinner the fibrous cap, the lower the threshold for rupture in response to hemodynamic forces.34
In the only previous imaging study which has attempted to quantify the critical cap thickness in carotid plaques, a mean cap thickness of 650 µm and minimum cap thickness of 460 µm on ultrasound were associated with symptomatic (as opposed to asymptomatic) plaque.7 However, that study was very small (22 symptomatic plaques) and could not determine whether there was greater predictive power associated with lower cut points because of resolution limits of the imaging technique (400 to 500 µm).7,27 In a more recent study, the identification of fibrous cap using high-resolution in vivo MRI was shown to be poorly reproducible.35 Although more accurate quantification of cap thickness may be possible as imaging technology advances, it is important that future analyses of cap thickness in relation to prognosis are not "data dependent". We therefore recommend that at present, a representative cap thickness of 500 µm be used as a prespecified cut point in longitudinal imaging studies of patients with asymptomatic or moderately severe symptomatic carotid stenosis. If the identification of a minimum cap thickness <200 µm becomes possible with advances in imaging technology, the prognostic value of this latter cut-off should also be studied. Depending on the importance of specificity versus sensitivity of markers to determine high-risk plaque, the identification of both a minimum cap thickness <200 µm and a representative cap thickness <500 µm in vivo may prove most clinically useful (Table 1).
Our study had several potential limitations. First, all of the patients underwent carotid endarterectomy for "symptomatic" carotid stenosis. However, as with all studies of this kind, a proportion of patients may have suffered thomboembolism from a source proximal or distal to the carotid bifurcation or had symptoms attributable to cerebral hypoperfusion. Certainly, previous studies in patients with symptomatic severe carotid stenosis have found that ulcerated appearances of carotid plaque on angiography are positively associated with cap rupture on histology18 as well as recurrent stroke on follow up,20 suggesting that cap rupture has prognostic value in already symptomatic individuals. Because cap rupture is the mechanism underlying the majority of strokes distal to carotid stenosis,3,5 we felt justified in determining the cap thickness values that discriminated between ruptured and nonruptured plaques to achieve the aims of this study. Second, there was considerable overlap in the distribution of cap thickness between ruptured and nonruptured plaques (Figure 2) ie, the cap thickness cut-offs were not 100% sensitive nor 100% specific for rupture. This was not unexpected as there are many factors which affect a plaques propensity to rupture, not just cap thickness. For example, hemodynamic forces,34,36,37 genetic factors,38,39 blood hyperviscosity, and a proinflammatory state are associated with increased risk of ischemic events distal to a stenosing atherosclerotic plaque and may alter the cap thickness threshold for rupture.40,41 Alternatively, some plaques may have "healed" during the interval between the last ischemic event and surgery. However, the ruptured plaques from patients operated >90 days after their last symptomatic event had similar cap thickness to ruptured plaques from patients operated <30 days (data not shown). It is also possible that some cap ruptures were missed by our sectioning technique (sections taken from the bifurcation and 3 mm either side) but in a pilot study of 26 plaques, we found this method detected the majority of features of plaque instability (including 87% cap ruptures).23 A third limitation is that because of fragmentation of the fibrous cap, we could not reliably determine the cap thickness at the exact point where the ruptures occurred. However, the positive association between minimum cap thickness and rupture was stronger than the positive association between representative cap thickness and rupture consistent with cap rupture tending to occur at its thinnest point. Finally, because it is clearly not possible to study the predictive value of plaque pathology once the plaque has been removed, our study was necessarily cross-sectional. Therefore the cut-offs we propose need to be validated in prospective studies of in vivo plaque imaging in patients with asymptomatic carotid stenosis.
In conclusion, a minimum cap thickness <200 µm is the optimum cap thickness measure for discriminating between ruptured and nonruptured symptomatic carotid plaques on histology. However, a representative cap thickness <500 µm may be a more realistic cap measurement target for studies of in vivo plaque imaging because of the resolution limits of currently available techniques. Prospective studies in patients with carotid stenosis are required to establish whether these cut points predict clinical events and how they might be incorporated into prognostic models of stroke risk in patients with carotid stenosis.
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Acknowledgments |
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Disclosures
None.
Received October 24, 2007; accepted November 14, 2007.
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