A Prospective Multicenter Comparison Study of Risk-adapted Ultrasound-directed and Magnetic Resonance Imaging-directed Diagnostic Pathways for Suspected Prostate Cancer in Biopsy-naïve Men.

BACKGROUND: European Association of Urology guidelines recommend a risk-adjusted biopsy strategy for early detection of prostate cancer in biopsy-naïve men. It remains unclear which strategy is most effective. Therefore, we evaluated two risk assessment pathways commonly used in clinical practice. OBJECTIVE: To compare the diagnostic performance of a risk-based ultrasound (US)-directed pathway (Rotterdam Prostate Cancer Risk Calculator [RPCRC] #3; US volume assessment) and a magnetic resonance imaging (MRI)-directed pathway. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective multicenter study (MR-PROPER) with 1:1 allocation among 21 centers (US arm in 11 centers, MRI arm in ten). Biopsy-naïve men with suspicion of prostate cancer (age ≥50 yr, prostate-specific antigen 3.0-50 ng/ml, ± abnormal digital rectal examination) were included. INTERVENTION: Biopsy-naïve men with elevated risk of prostate cancer, determined using RPCRC#3 in the US arm and Prostate Imaging Reporting and Data System scores of 3-5 in the MRI arm, underwent systematic biopsies (US arm) or targeted biopsies (MRI arm). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the proportion of men with grade group (GG) ≥2 cancer. Secondary outcomes were the proportions of biopsies avoided and GG 1 cancers detected. Categorical (nonparametric) data were assessed using the Mann-Whitney U test and χ2 tests. RESULTS AND LIMITATIONS: A total of 1965 men were included in the intention-to-treat population (US arm n = 950, MRI arm n = 1015). The US and MRI pathways detected GG ≥2 cancers equally well (235/950, 25% vs 239/1015, 24%; difference 1.2%, 95% confidence interval [CI] -2.6% to 5.0%; p = 0.5). The US pathway detected more GG 1 cancers than the MRI pathway (121/950, 13% vs 84/1015, 8.3%; difference 4.5%, 95% CI 1.8-7.2%; p < 0.01). The US pathway avoided fewer biopsies than the MRI pathway (403/950, 42% vs 559/1015, 55%; difference -13%, 95% CI -17% to -8.3%; p < 0.01). Among men with elevated risk, more GG ≥2 cancers were detected in the MRI group than in the US group (52% vs 43%; difference 9.2%, 95% CI 3.0-15%; p < 0.01). CONCLUSIONS: Risk-adapted US-directed and MRI-directed pathways detected GG ≥2 cancers equally well. The risk-adapted US-directed pathway performs well for prostate cancer diagnosis if prostate MRI capacity and expertise are not available. If prostate MRI availability is sufficient, risk assessment should preferably be performed using MRI, as this avoids more biopsies and detects fewer cases of GG 1 cancer. PATIENT SUMMARY: Among men with suspected prostate cancer, relevant cancers were equally well detected by risk-based pathways using either ultrasound or magnetic resonance imaging (MRI) to guide biopsy of the prostate. If prostate MRI availability is sufficient, risk assessment should be performed with MRI to reduce unnecessary biopsies and detect fewer irrelevant cancers.

Computed tomography of aortic wall calcifications in aortic dissection patients.

OBJECTIVES: To investigate the frequency of aortic calcifications at the outer edge of the false lumen and the frequency of fully circular aortic calcifications in a consecutive series of patients with aortic dissection who underwent contrast-enhanced CT. METHODS: The study population compromised of 69 consecutive subjects aged 60 years and older with a contrast-enhanced CT scan demonstrating an aortic dissection. All CT scans were evaluated for the frequency of aortic calcifications at the outer edge of the false lumen and the frequency of fully circular aortic calcifications by two experienced observers. Between observer reliability was evaluated by using Cohen's Kappa. Differences between groups were tested using unpaired T test and Chi-square test. RESULTS: Presumed media calcifications were observed in 22 (32%) patients of 60 years and older and were found more frequently in chronic aortic dissection (N = 12/23, 52%) than in acute aortic dissection (N = 10/46, 22%). CONCLUSION: As the intima has been torn away by the aortic dissection it is highly likely that CT scans can visualize the calcifications in the tunica media of the aorta.

10-years experience with the Athero-Express study.

From cross-sectional studies we have learned that composition of atherosclerotic plaques differs, and that thrombosis on top of an inflammatory lipid rich plaque is a frequently observed pathological substrate of a cerebral or coronary event. Atherosclerosis develops over decades which hampers human studies on the natural history of the diseases. Therefore, the predictive value of atherosclerotic plaque composition for development of an adverse cardiovascular event is not clear. The elucidation of markers for atherosclerotic disease progression is essential to identify patients at high risk for vascular events, to refine treatment allocation and to serve as surrogate endpoints in pharmaceutical studies. The Athero-Express study is a large scale vascular biobank that collects vascular specimens including a clinical follow-up. This study design allows the prospective study of the local atherosclerotic plaque in relation to future local and systemic vascular outcome. The readout of the study can be assessed in terms of histology as well as RNA or protein level. This paper aims to give an overview of the results of the Athero-Express biobank since its initiation in 2002. We will also discuss the clinical implications and future directions in biobanking research.

Molecular MRI of murine atherosclerotic plaque targeting NGAL: a protein associated with unstable human plaque characteristics.

AIMS: Neutrophil gelatinase-associated lipocalin (NGAL) is an effector molecule of the innate immune system. One of its actions is the prolongation of matrix metalloproteinase-9 (MMP-9) activity by the formation of a degradation-resistant NGAL/MMP-9 complex. We studied NGAL in human atherosclerotic lesions and we examined whether NGAL could act as a target for molecular imaging of atherosclerotic plaques. METHODS AND RESULTS: Increased levels of NGAL and the NGAL/MMP-9 complex were associated with high lipid content, high number of macrophages, high interleukin-6 (IL-6) and IL-8 levels, and low smooth muscle cell content in human atherosclerotic lesions obtained during carotid endarterectomy (n= 122). Moreover, plaque levels of NGAL tended to be higher when intra-plaque haemorrhage (IPH) or luminal thrombus was present (n= 77) than without the presence of IPH or thrombus (n= 30). MMP-9 and -8 activities were strongly related to NGAL levels. The enhancement on magnetic resonance (MR) images of the abdominal aorta of ApoE(-/-)/eNOS(-/-) mice was observed at 72 h after injection of NGAL/24p3-targeted micelles. The specificity of these results was validated by histology, and co-localization of micelles, macrophages, and NGAL/24p3 was observed. CONCLUSION: NGAL is highly expressed in atheromatous human plaques and associated with increased MMP-9 activity. NGAL can be detected in murine atherosclerotic arteries using targeted high-resolution MR imaging. Therefore, we conclude that NGAL might serve as a novel imaging target for the detection of high-risk plaques.

Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: a prognostic study.

BACKGROUND: Identification of patients at risk for primary and secondary manifestations of atherosclerotic disease progression is based mainly on established risk factors. The atherosclerotic plaque composition is thought to be an important determinant of acute cardiovascular events, but no prospective studies have been performed. The objective of the present study was to investigate whether atherosclerotic plaque composition is associated with the occurrence of future vascular events. METHODS AND RESULTS: Atherosclerotic carotid lesions were collected from patients who underwent carotid endarterectomy and were subjected to histological examination. Patients underwent clinical follow-up yearly, up to 3 years after carotid endarterectomy. The primary outcome was defined as the composite of a vascular event (vascular death, nonfatal stroke, nonfatal myocardial infarction) and vascular intervention. The cumulative event rate at 1-, 2-, and 3-year follow-up was expressed by Kaplan-Meier estimates, and Cox proportional hazards regression analyses were performed to assess the independence of histological characteristics from general cardiovascular risk factors. During a mean follow-up of 2.3 years, 196 of 818 patients (24%) reached the primary outcome. Patients whose excised carotid plaque revealed plaque hemorrhage or marked intraplaque vessel formation demonstrated an increased risk of primary outcome (risk difference=30.6% versus 17.2%; hazard ratio [HR] with [95% confidence interval]=1.7 [1.2 to 2.5]; and risk difference=30.0% versus 23.8%; HR=1.4 [1.1 to 1.9], respectively). Macrophage infiltration (HR=1.1 [0.8 to 1.5]), large lipid core (HR=1.1 [0.7 to 1.6]), calcifications (HR=1.1 [0.8 to 1.5]), collagen (HR=0.9 [0.7 to 1.3]), and smooth muscle cell infiltration (HR=1.3 [0.9 to 1.8]) were not associated with clinical outcome. Local plaque hemorrhage and increased intraplaque vessel formation were independently related to clinical outcome and were independent of clinical risk factors and medication use. CONCLUSIONS: The local atherosclerotic plaque composition in patients undergoing carotid endarterectomy is an independent predictor of future cardiovascular events.

Local atherosclerotic plaques are a source of prognostic biomarkers for adverse cardiovascular events.

OBJECTIVE: Atherosclerotic cardiovascular disease is a major burden to health care. Because atherosclerosis is considered a systemic disease, we hypothesized that one single atherosclerotic plaque contains ample molecular information that predicts future cardiovascular events in all vascular territories. METHODS AND RESULTS: AtheroExpress is a biobank collecting atherosclerotic lesions during surgery, with a 3-year follow-up. The composite primary outcome encompasses all cardiovascular events and interventions, eg, cardiovascular death, myocardial infarction, stroke, and endovascular interventions. A proteomics search identified osteopontin as a potential plaque biomarker. Patients undergoing carotid surgery (n=574) served as the cohort in which plaque osteopontin levels were examined in relation to their outcome during follow-up and was validated in a cohort of patients undergoing femoral endarterectomy (n=151). Comparing the highest quartile of carotid plaque osteopontin levels with quartile 1 showed a hazard ratio for the primary outcome of 3.8 (95% confidence interval, 2.6-5.9). The outcome did not change after adjustment for plaque characteristics and traditional risk factors (hazard ratio, 3.5; 95% confidence interval, 2.0-5.9). The femoral validation cohort showed a hazard ratio of 3.8 (95% confidence interval 2.0 to 7.4) comparing osteopontin levels in quartile 4 with quartile 1. CONCLUSIONS: Plaque osteopontin levels in single lesions are predictive for cardiovascular events in other vascular territories. Local atherosclerotic plaques are a source of prognostic biomarkers with a high predictive value for secondary manifestations of atherosclerotic disease.

Biobanks and the search for predictive biomarkers of local and systemic outcome in atherosclerotic disease.

Multiple risk factors have been associated with progression of atherosclerosis. To identify the individual patient who is at risk for disruption of a vulnerable plaque, leading to a cardiovascular event, remains a major challenge. Current screening methods, based on traditional risk factors, do not allow risk stratification on an individual level. The discovery of new biomarkers would aid in identifying specific patient groups at risk for adverse cardiovascular events due to atherosclerotic disease progression. The current definition of the vulnerable plaque, e.g. atheromatous inflammatory plaque with a thin fibrous cap, has been based on cross-sectional post-mortem studies. The predictive value of these histological characteristics of the vulnerable plaque is likely to be low, because they are also frequently observed at multiple locations in symptomatic and asymptomatic patients. The Athero-express study follows a new concept to search for the atherosclerotic patient who may suffer from adverse events. In this study, we investigate the predictive value of local plaque composition for adverse events in other vascular territories, regarding the plaque as a concentrated expression of this systemic disease. First results from this longitudinal biobank study show that the local plaque hides strong predictive value for cardiovascular events elsewhere in the vascular tree. Longitudinal biobank studies will facilitate the identification of novel local plaque markers. The search for the plaque protein signature that is predictive for adverse events might enable patient stratification that will allow individualized tailor made medicine and subsequently guide the choice for therapeutic interventions.

Caveolin-1 influences vascular protease activity and is a potential stabilizing factor in human atherosclerotic disease.

Caveolin-1 (Cav-1) is a regulatory protein of the arterial wall, but its role in human atherosclerosis remains unknown. We have studied the relationships between Cav-1 abundance, atherosclerotic plaque characteristics and clinical manisfestations of atherosclerotic disease.We determined Cav-1 expression by western blotting in atherosclerotic plaques harvested from 378 subjects that underwent carotid endarterectomy. Cav-1 levels were significantly lower in carotid plaques than non-atherosclerotic vascular specimens. Low Cav-1 expression was associated with features of plaque instability such as large lipid core, thrombus formation, macrophage infiltration, high IL-6, IL-8 levels and elevated MMP-9 activity. Clinically, a down-regulation of Cav-1 was observed in plaques obtained from men, patients with a history of myocardial infarction and restenotic lesions. Cav-1 levels above the median were associated with absence of new vascular events within 30 days after surgery [0% vs. 4%] and a trend towards lower incidence of new cardiovascular events during longer follow-up. Consistent with these clinical data, Cav-1 null mice revealed elevated intimal hyperplasia response following arterial injury that was significantly attenuated after MMP inhibition. Recombinant peptides mimicking Cav-1 scaffolding domain (Cavtratin) reduced gelatinase activity in cultured porcine arteries and impaired MMP-9 activity and COX-2 in LPS-challenged macrophages. Administration of Cavtratin strongly impaired flow-induced expansive remodeling in mice. This is the first study that identifies Cav-1 as a novel potential stabilizing factor in human atherosclerosis. Our findings support the hypothesis that local down-regulation of Cav-1 in atherosclerotic lesions contributes to plaque formation and/or instability accelerating the occurrence of adverse clinical outcomes. Therefore, given the large number of patients studied, we believe that Cav-1 may be considered as a novel target in the prevention of human atherosclerotic disease and the loss of Cav-1 may be a novel biomarker of vulnerable plaque with prognostic value.

Atherosclerotic plaque composition and occurrence of restenosis after carotid endarterectomy.

CONTEXT: Previous studies have assessed the predictive value of clinical and angiographic parameters for development of restenosis after vascular interventions. The composition of the atherosclerotic plaque at the intervention site has had limited evaluated as a marker for restenosis [corrected]. OBJECTIVE: To investigate the relationship between atherosclerotic plaque histology and the occurrence of restenosis after carotid endarterectomy. DESIGN, SETTING, AND PATIENTS: The Athero-Express study is a longitudinal vascular biobank study that includes the collection of atherosclerotic plaques of patients undergoing primary carotid endarterectomy. Five hundred patients were prospectively followed up between April 1, 2002, and March 14, 2006, to assess carotid artery restenosis measured by duplex ultrasound 1 year after the intervention. MAIN OUTCOME MEASURES: Risk of carotid restenosis in relation to predefined histological characteristics (macrophage and smooth muscle cell infiltration, collagen, calcifications, intraplaque bleeding, luminal thrombus, and lipid core size), adjusted for clinical characteristics (multivariate logistic regression analysis). RESULTS: At 1 year, 85 patients (17%) developed 50% or greater restenosis, including 40 patients (8%) who developed 70% or greater restenosis of the target vessel. Patients whose histological examination of the plaque revealed marked macrophage infiltration (n = 286) had a lower risk than those with none or minor macrophage infiltration (n = 214) of developing 50% or greater restenosis (risk difference, 11.5% vs 24.3%; adjusted odds ratio [OR], 0.43; 95% confidence interval [CI], 0.26-0.72) and a lower risk of developing 70% or greater restenosis (risk difference, 4.5% vs 12.6%; adjusted OR, 0.36; 95% CI, 0.17-0.74). Patients (n = 177) with a plaque having a large lipid core size (>40%) had a lower risk than those (n = 94) with a plaque having a lipid core size of less than 10% of developing 50% or greater restenosis (risk difference, 11.3% vs 25.5%; adjusted OR, 0.40; 95% CI, 0.19-0.81) and a lower risk of developing 70% or greater restenosis (risk difference, 5.6% vs 14.9%; adjusted OR, 0.42; 95% CI, 0.17-1.04), independent of clinical characteristics. CONCLUSIONS: Plaque composition is an independent predictor of restenosis after carotid endarterectomy. The dissection of a lipid-rich, inflammatory plaque is associated with reduced risk of restenosis.

Histological characterization of restenotic carotid plaques in relation to recurrence interval and clinical presentation: a cohort study.

UNLABELLED: Backgrounds and Purpose- Restenosis is an important complication after carotid endarterectomy, but little is known about plaque composition in early versus late restenosis and which plaque characteristics are associated with symptomatic clinical presentation of restenotic lesions. METHODS: Endarterectomy specimens of 822 consecutive patients undergoing carotid endarterectomy (33 restenotic; 789 primary) were subjected to histological examination for the presence of macrophages, smooth muscle cells, collagen, calcifications, luminal thrombus, intraplaque bleeding and lipid core size. RESULTS: Early restenotic plaques showed marked accumulation of smooth muscle cells and fibrous tissue, whereas late restenotic plaques demonstrated increased macrophage infiltration, calcification and lipid core (P trend <0.05), resembling primary plaques. Patients with symptomatic restenosis had plaques with higher macrophage infiltration (P=0.01) and a larger lipid core (P=0.02) than asymptomatic patients, independent of recurrence interval. CONCLUSIONS: Restenosis occurring >5 years after primary carotid endarterectomy resembles primary plaques. Symptomatic presentation of restenotic lesions is independently associated with an unstable plaque phenotype.

Intraobserver and interobserver variability and spatial differences in histologic examination of carotid endarterectomy specimens.

INTRODUCTION: Studies using histologic examination and protein analysis of atherosclerotic plaques are increasingly being performed, but reproducibility of plaque histology and variation of plaque composition among different parts of the plaque, which are key to reliability of these studies, are relatively unexplored. Therefore, this study investigated the intraobserver and interobserver variability of plaque histology and spatial variability in plaque composition. METHODS: Atherosclerotic plaques (n = 100) obtained during carotid endarterectomy were divided into 0.5-cm segments. Paraffin sections were stained and semiquantitatively analyzed (four categories: no, minor, moderate, and heavy) for fat, macrophages, smooth muscle cells, collagen, calcification, thrombus, and overall phenotype. First, to determine the intraobserver and interobserver reproducibility, two independent observers independently analyzed the plaques. Second, to investigate spatial variability in plaque composition, histologic appearances of the culprit lesions (0-segment) were compared with the histologic appearances of adjacent (+5 mm) and more distant (+10 mm) plaque segments of 30 specimens. RESULTS: The kappa values for intraobserver variability of fat, macrophages, smooth muscle cells, collagen, calcifications, thrombus, and overall phenotype were 0.83, 0.85, 0.71, 0.63, 0.81, 0.80, and 0.86, respectively, and kappa values for interobserver variability were 0.68, 0.74, 0.54, 0.59, 0.82, 0.75, and 0.71, respectively. Comparison of the histologic scorings of adjacent segments revealed a mean kappa of 0.40 (range, 0.33 to 0.60). When the culprit segment was compared with the more distant segment, the mean kappa was 0.24; however, in 91% of cases, the difference between the culprit segment and the distal segment was one category or less. CONCLUSION: Semiquantitative analysis of carotid atherosclerotic plaque histology was well reproducible, both intraobserver and interobserver. Although variation between different plaque segments in histologic appearance was observed, differences were small in almost all cases. Variability in histologic examination needs to be taken into account in studies comparing plaque imaging with histopathology and plaque research studies.

From vulnerable plaque to vulnerable patient: the search for biomarkers of plaque destabilization.

There is a strong need for biomarkers to identify patients at risk for future cardiovascular events related with progressive atherosclerotic disease. Ideally, increasing knowledge of the mechanisms of atherosclerotic plaque destabilization should be translated in clinical practice. Currently, the following commonly followed strategies can be identified with the objective to detect either the local vulnerable plaque that is prone to rupture and gives rise to a thrombotic occlusion, or the systemic vulnerable patient, who has a high probability to suffer from an adverse clinical event. On the one hand, studies are ongoing to determine local atherosclerotic plaque characteristics to predict future local plaque rupture and subsequent vascular thrombosis. Newly developed imaging modalities are being developed and validated to detect these plaques in vivo. On the other hand, systemic approaches are pursued to discover serum biomarkers that are applicable to define patients at risk for future cardiovascular events. We propose a third original approach that is optional but yet unexplored, that is, to use local plaque characteristics as a biomarker not just for local plaque destabilization but for future cardiovascular events due to plaque progression in any vascular system. This review aims to provide an overview of the current standings of the identification of the vulnerable plaque and the vulnerable patient.

Low levels of Nogo-B in human carotid atherosclerotic plaques are associated with an atheromatous phenotype, restenosis, and stenosis severity.

OBJECTIVE: Reticulon-4/Nogo (Nogo-B) protects mouse arteries from lumen loss by reducing smooth muscle cell (SMC) migration and intimal thickening. Our goal was to determine plaque and circulating levels of Nogo-B in atherosclerotic and control subjects. Therefore, we studied the relationships between local Nogo-B, plaque characteristics, and clinical data in patients undergoing carotid endarterectomy. METHODS AND RESULTS: Western blot analysis showed that endarterectomy specimens from the femoral (n=19) and carotid arteries (n=145) contained significantly less Nogo-B than nonatherosclerotic mammary arteries (n=8; P<0.003) and aortas (n=15; P=0.03). Immunohistochemistry revealed that in atherosclerotic lesions, Nogo-B was expressed by macrophage/foam cells, SMC rich, and neo-vascularized areas. Atheromatous plaques (>40% fat content) showed a significant reduction in Nogo-B expression (P=0.002). Nogo-B expression levels were significantly lower in patients with more than 90% of carotid stenosis (P=0.04) or restenotic lesions after prior carotid intervention (duplex; P=0.01). In contrast, plasmatic levels of Nogo-B (soluble Nogo-B) did not differ between atherosclerotic subjects (n=68) and risk-factor matched controls (n=63; P=0.5). CONCLUSION: Our findings suggest that local reduction of Nogo-B in atherosclerotic tissue might contribute to plaque formation and/or instability triggering luminal narrowing. In contrast, plasma Nogo-B levels are not associated with clinically manifested atherosclerotic disease.

Gender-associated differences in plaque phenotype of patients undergoing carotid endarterectomy.

BACKGROUND: Carotid endarterectomy to prevent a stroke is less beneficial for women compared with men. This benefit is lower in asymptomatic women compared with asymptomatic men or symptomatic patients. A possible explanation for this gender-associated difference in outcome could be found in the atherosclerotic carotid plaque phenotype. We hypothesize that women, especially asymptomatic women, have more stable plaques than men, resulting in a decreased benefit of surgical plaque removal. METHODS: Carotid endarterectomy specimens of 450 consecutive patients (135 women, 315 men) were studied. The culprit lesions were semi-quantitatively analyzed for the presence of macrophages, smooth muscle cells, collagen, calcifications, and luminal thrombus. Plaques were categorized in three phenotypes according to overall presentation and the amount of fat. Protein was isolated from the plaques for determination of interleukin-6 (IL-6) and IL-8 concentrations and matrix metalloproteinase-8 (MMP-8) and MMP-9 activities. RESULTS: Atheromatous plaques (>40% fat) were less frequently observed in women than in men (22% vs 40%; P < .001). In addition, plaques obtained from women more frequently revealed low macrophage staining (11% vs 18%; P = .05) and strong smooth muscle cell staining (38% vs 24%; P = .001). Compared with men, women had a lower plaque concentration of IL-8 (P = .001) and lower MMP-8 activity (P = .01). The observed differences were most pronounced in asymptomatic women, who showed the most stable plaques, with an atheromatous plaque in only 9% of cases compared with 39% in asymptomatic men (P = .02). In addition, a large proportion of plaques obtained from asymptomatic women showed high smooth muscle cell content (53% vs 30%; P = .03) and high collagen content (55% vs 24%; P = .003). All relations between gender and plaque characteristics, except for MMP-8, remained intact in a multivariate analysis, including clinical presentation and other cardiovascular risk factors. CONCLUSION: Carotid artery plaques obtained from women have a more stable, less inflammatory phenotype compared with men, independent of clinical presentation and cardiovascular risk profile. Asymptomatic women demonstrate the highest prevalence of stable plaques. These findings could explain why women benefit less from carotid endarterectomy compared with men.

Carotid atherosclerotic plaques in patients with transient ischemic attacks and stroke have unstable characteristics compared with plaques in asymptomatic and amaurosis fugax patients.

INTRODUCTION: Atherosclerotic carotid artery disease is responsible for a variety of clinical presentations, ranging from asymptomatic to cerebral ischemic events. Considering the upcoming use of noninvasive imaging modalities, plaque characteristics could serve as a marker in the selection of patients eligible for carotid endarterectomy (CEA). This would be more likely if characteristics corresponded with clinical manifestations and were predictive of future events. In this study, we hypothesized that plaque characteristics correlate with the clinical presentation of carotid artery disease. METHODS: We included 404 patients undergoing a carotid endarterectomy (CEA). Ipsilateral clinical symptoms and duplex measurements were recorded. Patients could be asymptomatic (23.5%) or symptomatic with stroke (26.5%), transient ischemic attack (TIA) (36.1%), or amaurosis fugax (AFX) (13.9%). Plaques were stained and semi-quantitatively analyzed for the presence of macrophages, smooth muscle cells, collagen, calcifications, and thrombus. Plaques were categorized in three phenotypes by their overall presentation and the amount of fat. In addition, plaque matrix metalloproteinase (MMP) activity and cytokines expressions were measured. RESULTS: Fibrous, fibro-atheromatous, and atheromatous plaques were observed in 30.2%, 35.6%, and 34.2%, respectively. Atheromatous plaques were more prevalent in patients with stroke and TIA compared with asymptomatic patients or patients with AFX (P = .001). Collagen staining was less evident in patients with TIA and stroke compared with asymptomatic patients or patients with AFX (P < .001). Plaques of patients with TIA and stroke showed significantly higher activity levels of MMP-8 and MMP-9 and higher levels of interleukin-8 compared with asymptomatic and AFX patients. CONCLUSION: Plaque phenotype of patients with TIA is comparable to that of patients with stroke; whereas, the plaque phenotype of patients with AFX resembles the plaque phenotype of asymptomatic patients. Follow-up studies should be encouraged to determine whether plaque characteristics visualized by imaging techniques might help to identify patients most likely to benefit from CEA.