Joanna K. Lovett

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

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.

Critical Cap Thickness and Rupture in Symptomatic Carotid Plaques. The Oxford Plaque Study

Background and Purpose— Advances in carotid plaque imaging could allow quantification of fibrous cap thickness in vivo. While a cap thickness <65 &mgr;m 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 &mgr;m (IQR 200 to 500 &mgr;m) and the median minimum cap thickness was 150 &mgr;m (80 to 210 &mgr;m; mean=181 &mgr;m), which is much greater than the mean cap thickness of 23 &mgr;m at the point of rupture that has been reported for coronary plaques. For nonruptured plaques, the median cap thickness values were 500 &mgr;m (300 to 700 &mgr;m) and 250 &mgr;m (180 to 400 &mgr;m), respectively. The optimum cut-offs for discriminating between ruptured and nonruptured plaques were a minimum cap thickness <200 &mgr;m (OR 5.00, 3.26 to 7.65, P<0.001), a representative cap thickness <500 &mgr;m (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 &mgr;m and a representative cap thickness <500 &mgr;m 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.

Site of carotid plaque ulceration in relation to direction of blood flow: an angiographic and pathological study.

Background: Rupture of atherosclerotic plaque is the main cause of acute coronary syndromes and carotid territory ischaemic stroke. Haemodynamic stress is important in early plaque formation and may affect the stability of mature plaques. There is some evidence that macrophage infiltration and plaque rupture tend to localise to the proximal (upstream) part of the plaque where shear stress is highest. However, previous studies have been too small to assess this reliably. We studied the site of ulceration in a large number of carotid plaques. Methods: We studied angiograms of 3,007 symptomatic carotid stenoses, and the pathological appearance of 119 carotid plaques (77 asymptomatic), to identify the presence and position of plaque ulceration. Results: Angiographic ulceration, which was present in 421 patients (14%), was more likely to be proximal than distal to the point of maximum stenosis (OR = 16.6, 95% CI = 11.6–26.9, p < 0.001). This trend increased with severity of stenosis (p = 0.002). Pathological examination of the 119 carotid plaques also showed that ulceration was more likely to occur proximal to the point of maximum stenosis (OR = 6.1, 95% CI = 2.8–13.6, p < 0.001). Conclusions: Ulceration of carotid plaques, visible on angiography or on pathological examination, is seen most often in the proximal (upstream) part where shear stress is highest.

A Critical Appraisal of the Performance, Reporting, and Interpretation of Studies Comparing Carotid Plaque Imaging With Histology

Background and Purpose— Carotid plaque instability is an important determinant of stroke risk. There are now a number of different imaging techniques that provide information on carotid plaque morphology. However, it is unclear how they compare with one another or whether they can reliably assess plaque instability. Studies comparing imaging with pathology have shown highly variable results, even for similar imaging techniques. This may be because of variable pathology techniques rather than differences in imaging. Methods— We performed a systematic review of studies that compared carotid imaging with histology of the excised plaque published between January 1995 and September 2004. We assessed the quality and comparability of these studies. In particular, we determined which histology methods were used and whether observer reproducibility of the histology assessment was reported. Results— Among 73 eligible studies, histological methods were poorly reported and highly variable; 23% reported reproducibility data for imaging and only 12% reported reproducibility data for histology. Of 29 studies that reported quantitative results of blinded comparisons, there were methodological deficiencies and the results were highly variable. No study considered the extent to which the lack of reproducibility influenced the imaging-pathological correlations reported. Conclusions— Pathological correlation in studies of carotid plaque imaging cannot be reliably interpreted or compared because of incomparable and poorly reported histology methods. We make recommendations for the performance, reporting, and interpretation of imaging–pathological correlation studies and highlight the need for consensus guidelines.

Reproducibility of Histological Assessment of Carotid Plaque: Implications for Studies of Carotid Imaging

Background: Thromboembolism from carotid plaque is an important cause of stroke. Identification of unstable plaque would therefore be clinically useful. Unfortunately, studies of carotid plaque imaging have shown poor agreement with histology. However, this may be due to inconsistent methods and the variability of assessments of carotid plaque histology, rather than inadequate imaging. Methods: We assessed the reproducibility of histological assessment in 60 plaques, and section-to-section variability along the length of 26 plaques. Results: Kappa values ranged from 0.35 to 0.89 and from 0.44 to 0.68, respectively, for intra- and inter-observer reproducibility. There was considerable section-to-section variability within plaques. Conclusions: The accuracy of imaging of carotid plaque morphology will be underestimated unless variability in the histology assessment is taken into account.

Histological Features of Symptomatic Carotid Plaques in Patients with Impaired Glucose Tolerance and Diabetes (Oxford Plaque Study)

Background: Diabetes is associated with an increased risk of incident stroke and both early and late recurrent stroke after transient ischaemic attack. Some small studies have suggested that atherosclerotic plaques from diabetics have a higher prevalence of unstable features than plaques from non-diabetics but results have been inconsistent. Method: We made detailed histological assessments of 526 plaques from consecutive patients undergoing carotid endarterectomy for recently symptomatic stenosis and related these to the presence of diabetes and impaired glucose tolerance (IGT). Results: 53 (10.1%) patients had diabetes, 26 (5%) had IGT and 447 (84.9%) had normal glucose tolerance (NGT). The overall prevalence of unstable plaque features was similar across these groups. However, whereas plaques removed >60 days after last symptoms in patients with NGT had less surface thrombus (OR = 0.61, 95% CI = 0.40–0.92, p = 0.02), fewer plaque macrophages (OR = 0.78, 95% CI = 0.51–1.19, p < 0.001) and less marked overall instability (OR = 0.57, 95% CI = 0.35–0.88, p = 0.009) than plaques removed more acutely, these features tended to be more persistent in patients with diabetes/IGT (OR = 1.08, 95% CI = 0.42–2.77, OR = 1.16, 95% CI = 0.46–2.96 and OR = 1.51, 95% CI = 0.60–3.77, respectively). Conclusion: Overall, the prevalence of unstable histology features in recently symptomatic carotid plaques is similar in patients with diabetes, IGT and NGT. However, surface thrombus and plaque macrophages appear to persist for longer after ischaemic symptoms in plaques from patients with diabetes/IGT compared to plaques from patients with NGT. This may contribute to the increased risk of recurrent stroke that is associated with diabetes/IGT.

Response to Letter by Karapanayiotides

Response: We would like to thank Dr Karapanayiotides for his comments with respect to our recently published article.1 We measured representative fibrous cap thickness by visualizing three 5-μm-thick sections from each plaque (from the bifurcation or point of maximal stenosis, and from 3 mm either side) and by using a calibrated graticule in the microscope eyepiece to record the thickness of the part which was felt to be most representative of the cap as a whole. In making this measurement we took into account all 3 sections which therefore approximated to the mean cap thickness. We agree that reliable pathological assessment is vital and we have called for better reporting.2 The intraclass correlation coefficient for measurements of representative cap thickness between and within observers were 0.57 ( P =0.004) and 0.48 ( P =0.01) respectively, which are roughly in line with …