B-mode ultrasonographic characterization of carotid atherosclerotic plaques in symptomatic and asymptomatic patients

OBJECTIVE: To identify features on B-mode ultrasonography (US) prevalent in symptomatic plaques and correlate these findings with histopathologic markers of plaque instability. METHODS: Carotid endarterectomy (CEA) plaques from symptomatic and asymptomatic patients with critical stenoses (>70%) were qualitatively assessed using preoperative B-mode US for echolucency and calcific acoustic shadowing. US echolucency was quantitated ex vivo using computerized techniques for gray-scale median (GSM) analysis. Histopathologic correlates for US plaque echolucency (percentage of necrotic core area) and acoustic shadowing (percentage of calcification area) were determined. RESULTS: Fifty CEA plaques were collected from 48 patients (46 unilateral and two bilateral); 26 of these plaques were from symptomatic patients. Age, degree of stenosis, and atherosclerotic risk factors were similar for the symptomatic and asymptomatic patients. Using preoperative B-mode US, 58%, 35%, and 7% of symptomatic plaques and 18%, 41%, and 41% of asymptomatic plaques were found to be echolucent, echogenic, and calcific, respectively (P < .05). Using ex-vivo B-mode US and GSM analysis, symptomatic plaques were more echolucent (41 +/- 19) than asymptomatic plaques (60 +/- 13), P < .03. A strong inverse correlation was found between the percent plaque necrotic area core and GSM (R = -0.9, P < .001). Percentage of calcification area in plaques with acoustic shadowing was 66% and only 27% in those without acoustic shadowing (P < .05). CONCLUSIONS: Using B-mode US, symptomatic plaques are more echolucent and less calcified than asymptomatic plaques and are associated with a greater degree of histopathologic plaque necrosis. Such features are indicative of plaque instability and should be considered in the decision-making algorithm when selecting patients with high-grade asymptomatic carotid stenosis for intervention.     

Macrophages are associated with lipid-rich carotid artery plaques, echolucency on B-mode imaging, and elevated plasma lipid levels.

OBJECTIVE: Atherosclerosis may be regarded as an inflammatory disease dominated by macrophages. We tested whether macrophages in carotid artery atherosclerotic plaques are associated with echolucency on B-mode ultrasound imaging, lipid levels, inflammatory markers, and aspirin use. METHODS: We studied 106 patients undergoing carotid endarterectomy having >/=50% carotid artery stenosis and previous ipsilateral hemispheric neurologic symptoms. RESULTS: Macrophages were particularly common in plaques with a high content of lipid and hemorrhage and, conversely, rare in plaques dominated by calcification and fibrous tissue. Macrophage density in carotid artery plaques classified by B-mode ultrasound imaging as echolucent (n = 56), intermediate (n = 25), or echorich (n = 25) was 1.8% +/- 0.2%, 1.5% +/- 0.4%, and 1.0% +/- 0.2% (+/-SE), respectively (analysis of variance, P =.02). A computer-generated measure of plaque echolucency, gray-scale median, was associated with increased macrophage density (r = -0.31; P =.002). Furthermore, plasma and low-density lipoprotein cholesterol levels were associated with carotid artery macrophage density (r = 0.26, P =.008 and r = 0.23, P =.02); this was most pronounced in patients with lipid-rich plaques. Macrophage density was not associated with plasma levels of acute-phase reactants. Finally, macrophage density in carotid artery plaques of users (n = 55) and nonusers of aspirin (n = 51) was 1.2% +/- 0.2% and 1.8% +/- 0.2% (t test, P =.01). CONCLUSIONS: Increased macrophage density in carotid atherosclerotic plaques was associated with lipid content, plaque echolucency, and increased plasma and low-density lipoprotein cholesterol levels. Furthermore, use of aspirin was associated with reduced macrophage density in carotid artery plaques.     

Computer-assisted carotid plaque analysis: characteristics of plaques associated with cerebrovascular symptoms and cerebral infarction.

OBJECTIVE: to correlate the echostructural characteristics of carotid plaques with neurological symptoms and cerebral infarcts. MATERIALS: one hundred and five plaques were studied in 74 patients by colour-flow duplex ultrasound: 39 were symptomatic and 37 were associated with brain infarction on CT scanning. METHODS: the images were digitalised for computer-assisted image standardisation and divided in homogenous (n=67) and heterogenous (n=38) groups. Parameters of the plaque image were analysed. RESULTS: global echogenicity was significantly lower in symptomatic and in CT(+)plaques (p<0.05). For homogenous plaques, an echogenic cap (EC) was visualised in 8.3% of symptomatic vs. 33.9% of asymptomatic (p<0. 05) and in 7.7% for plaques that were CT(+)vs. 37.7% for CT(-)(p<0. 05). Surface disruption was visualised in 50% of symptomatic vs. 8. 5% of asymptomatic (p=0.002) and in 46% of CT(+)vs. 9.4% of CT(-)plaques (p=0.002). For heterogenous plaques, the echolucent region was juxtaluminal in 67% of symptomatic and CT(+)plaques vs. 33% in asymptomatic and CT(-)(p<0.01). CONCLUSION: echolucent plaques are associated with a higher neurological risk. In homogenous plaques the absence of an echogenic cap and disruption of the plaque surface also correlates with symptoms. In heterogenous plaques, juxtaluminal location of the echolucent region is an additional marker of increased risk.     

Quantification and characterization of carotid calcium with multi-detector CT-angiography.

OBJECTIVE: The aim of this study was to assess the accuracy of CT-angiography for identification and measurement of calcification of carotid atherosclerotic plaques and to characterise the content and distribution pattern of mineral calcium (hydroxyapatite, Ca) in carotid bifurcations and investigate its relationship with neurological symptoms. METHODS: Twenty-six patients with ICA stenosis > 60% (13 symptomatic, 13 asymptomatic) were selected for study. Ca was estimated from the weight of the ashed remnants of carotid endarterectomy (CEA) specimens in 11 patients. Calcium content (calcification volume (mm3),CV), and average calcium density (Hounsfield units (HU),CD), were determined by CT-angiography. The distribution pattern of calcium within the lesion (base (posterior), shoulder or luminal surface) was assessed in all cases. RESULTS: CT-derived estimation of CV and Ca mass (modified Agatston Score, (mAS) = CV x CD) showed a good correlation with its direct measurement in CEA specimens (r = 0.911 and 0.993 respectively, p < 0,005). Asymptomatic patients with ICA stenosis > 60% showed statistically significant higher content of Ca than those who were symptomatic (mAS: 122.6 +/- 138.0 HU mm3 vs 42.8 +/- 59.1 HU mm3, p = 0.04). Calcification on the surface of the plaque was observed more commonly in asymptomatic patients (9/12 vs 3/15, p = 0.006). Non-calcified or plaques with posterior calcification were 12 times more likely to be symptomatic (OR: 12, 95%CI 1.5-91.1, p = 0.021). CONCLUSIONS: CT-angiography permits the reliable quantification of calcification of carotid plaques. A lower content of calcium in carotid plaques, as well as its distribution in the base of the lesion, was associated with a greater prevalence of neurological symptoms. These parameters may be useful to identify those patients at higher risk of stroke.     

Histologic characteristics of carotid artery plaque

Carotid plaque characteristics associated with the production of symptoms were identified with quantification of carotid plaque constituents in high-grade stenotic asymptomatic (n = 8) and symptomatic (n = 44) plaques. Asymptomatic plaques contained significantly more fibrous/collagen material (88%) than symptomatic plaques (66%) (p less than 0.05). Hemorrhage constituted 2% and 1% of asymptomatic and symptomatic plaques, respectively. The predominant nonfibrous material was a pink amorphous material mixed with cholesterol, which composed 7% of asymptomatic and 27% of symptomatic plaques (p less than 0.05). No relationship was found between plaque composition and the number of ipsilateral ischemic neurologic events, nor was there evidence of a healing process. B-mode ultrasound scanning had a sensitivity of 94% in identifying plaque with greater than 80% fibrous content. We believe that plaque composition may be a useful discriminating factor in selecting asymptomatic patients for carotid endarterectomy.     

Cerebral Ischemic Disease and Morphometric Analyses of Carotid Plaques

Atherosclerotic carotid plaque morphology and especially, intraplaque hemorrhage are assumed to be related to neurological symptoms. Most researchers have only investigated the incidence of intraplaque hemorrhage in symptomatic and asymptomatic patients. In the present study, the amount of intraplaque hemorrhage is determined in carotid endarterectomy specimens from 33 symptomatic and 14 asymptomatic patients that caused >70% luminal stenosis. The plaque components (fibrosis, lipids, intraplaque hemorrhage, calcification, and intraluminal thrombosis) were quantified as a percentage of the total plaque volume. A high incidence of intraplaque hemorrhage was found in both the symptomatic (94%, 31/33) and asymptomatic (71%, 10/14) patients. The amount of intraplaque hemorrhage was very small within the plaques of the symptomatic (0.39% +/- 0.70%) and asymptomatic (0.37% +/- 1.12%) patients. The plaques of the symptomatic patients contained more fibrosis than lipids (45.62% +/- 14.99% and 20.45% +/- 21.45%, respectively), as did the plaques of the asymptomatic patients (42. 51% +/- 15.28% and 15.46% +/- 15.22%, respectively). Finally, intraluminal thrombosis and calcification were rare. We conclude that the amount of intraplaque hemorrhage was very small and therefore question its direct role in the development of neurological symptoms. In general, the "unstable" plaque contained more fibrosis than lipids.     

Vascular endothelial cadherin expression in human carotid atherosclerotic plaque and its relationship with plaque morphology and clinical data.

OBJECTIVES: To determine the relationship between Vascular Endothelial (VE)-cadherin expression in carotid plaques, carotid plaque morphology and clinical findings of carotid disease. MATERIALS AND METHODS: Fifty-three formalin-fixed, paraffin embedded specimens of human carotid atherosclerotic plaque obtained by endarterectomy and 20 normal postmortem arteries (control group) were studied. Thirty patients were symptomatic and 23 asymptomatic. The expression of VE-cadherin was examined by an avidin-biotin immunoperoxidase technique using specific monoclonal antibodies against this molecule. We used a scale for the estimation of the expression of the VE-cadherin, in which negative expression was indicated by 0, weak expression by 1, and strong expression by 2. In serial sections we also determined the cellular phenotype of atherosclerotic plaques: i.e. the endothelial cells (F8), macrophage (CD68) and smooth muscle cells. Possible relations between variables in statistical analysis were examined by the chi-square test or Fisher's exact test. RESULTS: Expression of VE-cadherin was observed in small newly established vessels, particularly in areas with intense inflammatory infiltrations by macrophages and leucocytes. A strong expression of VE-cadherin was evident particularly in symptomatic instead in asymptomatic patients (43% vs. 13%, p=0.057), in high degree stenosis group (81% vs. 0%, p=0.005), and in patients with ischaemic infarct in brain scan (71% vs. 23%, p=0.021). On the other hand, there was no relation between molecule expression and plaque ultrasonic characteristics (echogenic or echolucent, p=0.499). Finally, there was a significant statistical correlation in the expression of VE-cadherin and the histological type of the plaque, namely fibrotic and complicated plaques. Strong VE-cadherin expression was observed in 64% of complicated plaques instead of 6.5% in fibrotic plaques (p=0.001). CONCLUSION: An intense expression of VE-cadherin in carotid plaques is linked with plaque instability, high degree of stenosis and clinical events. This molecule seems to be a marker of progression of the atherosclerotic plaque.     

The association of platelet-derived growth factor receptor expression, plaque morphology and histological features with symptoms in carotid atherosclerosis

Platelet-derived growth factor may influence smooth muscle cell migration and proliferation and, therefore, carotid plaque composition and stenosis. Platelet-derived growth factor receptor expression and histological features were compared in carotid plaques from symptomatic and asymptomatic patients. Immunocytochemistry and histology determined platelet-derived growth factor-alpha and -beta receptor expression, white blood cell infiltration, smooth muscle cell, elastin, cholesterol, collagen and intraplaque haemorrhage in carotid artery plaques removed at surgery or the post-mortem. Plaques with > 70% stenosis from asymptomatic (n = 10) and symptomatic patients (n = 27) had higher expression of platelet-derived growth factor and beta receptors and higher scores for macrophages and intraplaque haemorrhage than plaques with < 70% stenosis from asymptomatic patients (n = 33). Plaques with > 70% stenosis from symptomatic patients had significantly lower alpha receptor expression than plaques with > 70% stenosis from asymptomatic patients. The reduction of alpha receptor expression, which may inhibit smooth muscle cell migration, suggests that differential expression of platelet-derived growth factor receptor subunits in plaques may be related to symptoms.     

Structural analysis and magnetic resonance imaging predict plaque vulnerability: a study comparing symptomatic and asymptomatic individuals

BACKGROUND: More than half of all cerebral ischemic events are the result of rupture of extracranial plaques. The clinical determination of carotid plaque vulnerability is currently based solely on luminal stenosis; however, it has been increasingly suggested that plaque morphology and biomechanical stress should also be considered. We used finite element analysis based on in vivo magnetic resonance imaging (MRI) to simulate the stress distributions within plaques of asymptomatic and symptomatic individuals. METHODS: Thirty non-consecutive subjects (15 symptomatic and 15 asymptomatic) underwent high-resolution multisequence in vivo MRI of the carotid bifurcation. Stress analysis was performed based on the geometry derived from in vivo MRI of the carotid artery at the point of maximal stenosis. The finite element analysis model considered plaque components to be hyperelastic. The peak stresses within the plaques of symptomatic and asymptomatic individuals were compared. RESULTS: High stress concentrations were found at the shoulder regions of symptomatic plaques, and the maximal stresses predicted in this group were significantly higher than those in the asymptomatic group (508.2 +/- 193.1 vs 269.6 +/- 107.9 kPa; P = .004). CONCLUSIONS: Maximal predicted plaque stresses in symptomatic patients were higher than those predicted in asymptomatic patients by finite element analysis, suggesting the possibility that plaques with higher stresses may be more prone to be symptomatic and rupture. If further validated by large-scale longitudinal studies, biomechanical stress analysis based on high resolution in vivo MRI could potentially act as a useful tool for risk assessment of carotid atheroma. It may help in the identification of patients with asymptomatic carotid atheroma at greatest risk of developing symptoms or mild-to-moderate symptomatic stenoses, which currently fall outside current clinical guidelines for intervention.     

Echolucency of carotid plaques correlates with plaque cellularity.

OBJECTIVE: To analyse the relationship between carotid plaque echolucency and cellularity. METHODS: Carotid plaques (14 symptomatic and 16 asymptomatic) were snap frozen after endarterectomy and defined on the basis of their grey-scale-median (GSM), obtained from pre-operative high-definition ultrasonography, as either echolucent (<32) or echogenic (>or=32). DNA and total soluble protein were determined to assess cellularity. RESULTS: After correcting for wet weight, symptomatic plaques had significantly more DNA (0.400 +/- 0.07 vs 0.335 +/- 0.07 mg/g; p = 0.03) and soluble protein (34.1 +/- 6.6 vs 29.7 +/- 3.4 mg/g; p = 0.03) than asymptomatic plaques. Predominantly echolucent (Grey-Weale classification) plaques had more DNA (0.404 +/- 0.06 vs 0.332 +/- 0.08 mg/g; p = 0.03) than echogenic plaques. Plaques with GSM < 32 also had more DNA (0.386 +/- 0.08 vs 0.319 +/- 0.06 mg/g; p = 0.04) and soluble protein (34.7 +/- 7.3 vs 29.6 +/- 4.2 mg/g; p = 0.03) than those with GSM >or= 32. Inverse relations were found between GSM and plaque DNA (r = -0.47; p = 0.02) and soluble protein (r = -0.45; p = 0.02) as well as between age and DNA (r = 0.39; p = 0.04) and soluble protein (r = -0.50; p = 0.003). CONCLUSIONS: Echolucency of carotid plaques as assessed by ultrasonography reflects plaque cellularity. This observation support the notion that ultrasonography can be used to identify high-risk plaques and evaluate effect of interventions on plaque structure.     

Angiogenesis in atherosclerotic plaque obtained from carotid endarterectomy: association between symptomatology and plaque morphology

Carotid plaque with hemorrhage leads to cerebral embolism and ischemic stroke. Plaque angiogenesis and angiogenetic factors such as vascular endothelial growth factor (VEGF) are critical in the progression of atherosclerotic carotid plaque and intraplaque hemorrhage. The correlation between plaque angiogenesis and presence of clinical symptoms was studied in 41 specimens obtained during carotid endarterectomy from 20 symptomatic and 21 asymptomatic patients treated for carotid artery stenosis. Histological findings using hematoxylin-eosin and immunohistochemical staining against von Willebrand factor and VEGF were examined. Intraplaque hemorrhage, calcification, necrosis, and invasion of foam cells were frequently observed in the carotid plaques from symptomatic patients compared with asymptomatic patients. Higher microvessel density was found in the carotid plaques with necrosis and invasion of foam cells compared with plaques without necrosis and/or foam cell invasion, and higher expression of VEGF was found from symptomatic patients compared with asymptomatic patents. These results suggest that plaque angiogenesis and higher level of VEGF expression may enhance the progression of ischemic symptoms in patients with carotid artery stenosis. Invasive macrophages in the plaque of symptomatic patients increase levels of VEGF and might enhance plaque angiogenesis and atherosclerosis progression.     

Angiogenesis and the atherosclerotic carotid plaque: an association between symptomatology and plaque morphology.

PURPOSE: Symptomatic carotid disease resulting from generation of thromboemboli has been associated with plaque instability and intraplaque hemorrhage. These features of the lesion could be influenced by the fragility and position of neovessels within the plaque. The purpose of this study was to determine whether any association exists between neovessel density, position, morphology, and thromboembolic sequelae. METHODS: Carotid endarterectomy samples were collected from 15 asymptomatic patients with greater than 80% stenoses and from 13 highly symptomatic patients who had suffered ipsilateral carotid stenotic events within 1 month of surgery. Both groups were matched for gender, age, risk factors, degree of carotid artery stenosis, and plaque size. Samples were stained with hematoxylin/eosin and van Geison. Immunohistochemistry was performed by using an endothelial specific antibody to CD31. Plaques were assessed for histologic characteristics, and neovessels were counted and characterized by size, site, and shape. RESULTS: There were significantly more neovessels in plaques (P <.00001) and fibrous caps (P <.0001) in symptomatic compared with asymptomatic plaques. Neovessels in symptomatic plaques were larger (P <.004) and more irregular. There was a significant increase in plaque necrosis and rupture in symptomatic plaques. Plaque hemorrhage and rupture were associated with more neovessels within the plaque (P <.017, P <.001) and within the fibrous cap (P <.046, P <.004). Patients with preoperative and intraoperative embolization had significantly more plaque and fibrous cap neovessels (P <.025, P <.001). CONCLUSION: Symptomatic carotid disease is associated with increased neovascularization within the atherosclerotic plaque and fibrous cap. These vessels are larger and more irregular and may contribute to plaque instability and the onset of thromboembolic sequelae.     

Macrophage accumulation within the cap of carotid atherosclerotic plaques is associated with the onset of cerebral ischemic events.

PURPOSE: Macrophage accumulation is associated with aortic and coronary plaque instability. The macrophage content of carotid plaques removed at carotid endarterectomy (CE) was assessed, and the relevance to the onset of ipsilateral cerebral ischemic events (CIE) was examined. METHODS: Carotid plaques from patients undergoing CE were examined (group I, symptomatic stenoses, n = 28; group II, high-grade asymptomatic stenosis, n = 7). The plaques were stained with monoclonal antimacrophage antibody (HAM56), and the interval since the last CIE was recorded. The percentage area of the cap, shoulder, and entire sclerotic region was quantified by computerized planimetry. RESULTS: The macrophage content of the cap, shoulder, and sclerotic region in all 35 plaques was 1.14% (interquartile range, 0.56 to 3.86), 1.03% (0.51 to 2.15), and 0.49% (0.27 to 0.63), respectively (cap vs sclerotic, P <.01; shoulder vs sclerotic, P <. 01; cap vs shoulder, P =.23). In 18 plaques that were removed less than 180 days after the last CIE, the macrophage content of the cap, shoulder, and entire sclerotic region was 2.41% (0.95 to 4.81), 0. 83% (0.40 to 2.52), and 0.53% (0.38 to 0.71), respectively (cap vs sclerotic, P =.01; cap vs shoulder, P =.01). The content in the cap of these plaques was greater than in plaques removed more than 180 days after symptoms, or asymptomatic plaques (n = 17; 0.62% [0.44 to 1.25], P =.01). The cap macrophage content was inversely related to the time since the last CIE (r = -0.414, P =.029). CONCLUSION: In patients requiring CE, macrophage accumulation was maximal within the cap of carotid plaques and greatest in plaques removed less than 180 days after the last CIE. These findings and the inverse relationship between macrophage content and the interval since symptoms support the hypothesis that macrophage accumulation is associated with plaque instability.     

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 plaque gross morphology and clinical presentation: a prospective study of 457 carotid artery specimens

BACKGROUND AND PURPOSE: In carotid artery disease, the relationship between carotid plaque morphology and the patient's neurologic symptoms is reportedly conflicting. The aim of this study was to correlate gross carotid plaque characteristics with the presenting symptoms in a relatively large series of patients who underwent carotid endarterectomy (CEA). METHODS: Four hundred and five patients who underwent 461 CEAs were divided into three groups: (1) transiently symptomatic [transient ischemic attack (TIA) or amaurosis fugax]; (2) prior stroke; and (3) asymptomatic. The degree of stenosis based on the preoperative angiograms was used in association with the presenting symptoms as the primary criterion in the decision to operate. Carotid plaque characteristics, including ulcerated plaque (UP), intraplaque hemorrhage (IH), uncomplicated plaque, and degree of stenosis, were recorded prospectively for 457 CEAs, since 4 CEAs were excluded from the study. All CEA specimens were grossly evaluated at surgery. RESULTS: There was a statistically higher incidence of UP in transiently symptomatic (P = 0.008) or prior stroke (P = 0.006) patients than in the asymptomatic group. When IH was considered independently, its incidence did not differ significantly between the three groups. Previously symptomatic patients tended to have higher-grade stenosis than asymptomatic patients, although the difference failed to reach statistical significance (P = 0.06). Although the incidences of UP and IH were higher in the higher-grade stenosis group, the difference was again not significant. CONCLUSIONS: Carotid UP correlates closely with an initial presentation of TIA, amaurosis fugax, or prior stroke, while the association between IH and presenting symptoms is less clear. Although there is an insignificant trend toward a correlation between the higher degrees of stenosis and the onset of transient symptoms, the degree of stenosis appears unaffected by the morphology of the plaque. These findings suggest that plaque morphology may play an important role in the presentation of carotid artery disease.     

The relationship between carotid plaque composition and neurologic symptoms

Variations in plaque composition, particularly an increased lipid concentration, could make carotid plaques unstable and prone to embolization. To investigate this hypothesis, 35 carotid bifurcation plaques from 31 patients undergoing carotid endarterectomy (20 symptomatic, 11 asymptomatic) were prospectively analyzed. Plaque total lipid, cholesterol, collagen, and Ca2+ content were determined, and the plaque collagen was fractionated into pepsin-soluble collagen (PSC) (indicative of less crosslinked, more recently synthesized collagen) and pepsin-insoluble collagen. Preoperative serum lipid and plasma lipoprotein levels were also obtained in all patients. Results revealed that plaques removed from symptomatic patients contained significantly more total lipid and cholesterol (P less than 0.001) than those removed from asymptomatic patients. There was also an increased amount of pepsin-soluble collagen in symptomatic plaques, potentially indicating increased metabolic activity (P less than 0.05). In addition, mean plasma low-density lipoprotein cholesterol was higher in symptomatic patients than in asymptomatic patients (P less than 0.05). Since lipid-laden plaques can potentially be identified by B-mode ultrasound, it may be important to remove these plaques in asymptomatic patients or, alternatively, to attempt to lower the plaque cholesterol by lipid-lowering maneuvers.     

Serum values of metalloproteinase-2 and metalloproteinase-9 as related to unstable plaque and inflammatory cells in patients with greater than 70% carotid artery stenosis

OBJECTIVE: Unstable carotid plaques, characterized by increased levels of macrophages and T lymphocytes, have high emboligenic potential and carry a risk for producing cerebral ischemic events. It has been suggested that plaque instability may be mediated by the family of metalloproteinases (MMPs). The purpose of this study was to analyze the relationship between concentrations of MMP-2 and MMP-9 and unstable carotid plaques, presence of macrophages and T-lymphocytes in the plaques, and neurologic symptoms, to establish additional risk markers in patients with greater than 70% carotid artery stenosis. This was a cross-sectional study carried out in a referral center and institutional practice in hospitalized patients. METHODS: The study included 40 patients with carotid artery stenosis treated with carotid endarterectomy. Of these patients, 67.5% had experienced a previous neurologic event and 32.5% exhibited no symptoms. MMP-2 and MMP-9 levels were determined with enzyme-linked immunosorbent assay 48 hours before surgery. Histopathologic analysis (stable or unstable) and immunohistochemistry (macrophage count, T lymphocytes, activated T lymphocytes) were carried out on the plaques. RESULTS: Mean MMP-2 and MMP-9 serum concentrations in the population studied were 1138.27 +/- 326.08 ng/mL and 1026.10 +/- 412.90 ng/mL, respectively. MMP-2 levels were significantly higher in patients with symptoms compared with patients without symptoms (1247.30 +/- 276.80 ng/mL vs 911.80 +/- 311.84 ng/mL; P =.001). MMP-9 was also significantly higher in the symptomatic group (1026.10 +/- 412.90 ng/mL vs 377.84 +/- 164.08 ng/mL; P =.001) and in patients with unstable plaques compared with those with stable plaques (1006.98 +/- 447.09 ng/mL vs 496.16 +/- 292.78 ng/mL; P =.001). In addition, we found a strong association between elevated MMP-9 concentration and presence of macrophages in plaque (Spearman rho, 0.45; P =.004). At logistic regression analysis, variables that best predicted the presence of unstable plaque were a previous neurologic event and MMP-9 level greater than 607 ng/mL (sensitivity, 96%; specificity, 92%; negative predictive value, 94.7%; positive predictive value, 93%). CONCLUSION: Elevated MMP-9 concentration is associated with carotid plaque instability and the presence of macrophages, factors that indicate increased risk for a neurological event. Determination of this gelatinase may enable identification of high-risk subgroups of patients with carotid artery stenosis.     

Comparison between early and late carotid endarterectomy for symptomatic carotid stenosis in relation to oxidized low-density lipoprotein and plaque vulnerability

OBJECTIVE: Although carotid endarterectomy (CEA), the gold standard in stroke prevention, has been performed in the late stage after the insult, its optimal timing remains unclear. Using biomarkers in plaque and plasma, we evaluated oxidative stress and plaque vulnerability between early and late CEA in symptomatic patients. METHODS: We compared symptomatic stroke patients who underwent early CEA within 4 weeks of the last insult (group A; n = 15) with those who received CEA in the late stage beyond 4 weeks from the last symptom (group B; n = 57). They were divided into vulnerable (group Av, n = 13; group Bv, n = 33) and stable (group As, n = 2; group Bs, n = 24) subgroups according to the pathologic findings on their plaques. We studied the relationships among their primary symptoms, clinical findings, oxidized low-density lipoprotein levels, and gelatinase A (matrix metalloproteinase [MMP]-9) activity in their plaques and plasma. RESULTS: Group A had a variety of symptoms; there was no difference in the outcome of CEA between groups A and B. The plaque and plasma oxidized low-density lipoprotein levels were higher in group A than in group B (P < .05). The incidence of pathologically vulnerable plaque was higher in group A than in group B. Plaque oxidized low-density lipoprotein levels and MMP-9 activity were similar in group Av and group Bv and were higher in those groups than in group As and Bs. CONCLUSIONS: We first demonstrated that vulnerable plaques in patients subjected to early CEA manifested a remarkable increase in oxidized low-density lipoprotein and MMP-9 activation. Our findings suggest that early CEA may be beneficial in the aspect of oxidative stress.     

The importance of hemorrhage in the relationship between gross morphologic characteristics and cerebral symptoms in 376 carotid artery plaques.

In a prospective study 376 carotid artery plaques (275 symptomatic, 101 asymptomatic) were obtained from endarterectomies (184 unilateral and 96 bilateral) in 280 patients. The gross morphologic features of each plaque were noted at surgery and, together with the patient's clinical history, stored in computer memory. These data were analyzed in order to investigate the relationship of gross morphologic plaque characteristics with both the presence of cerebral symptoms and the degree of stenosis associated with the plaque. Ulceration was the most frequently observed of the five major gross plaque morphologic characteristics (46.0% of all plaques), but only intramural hemorrhage (30.6% of all plaques) was significantly more common in all symptomatic compared with all asymptomatic plaques (p less than 0.02). Hemorrhage was also the only gross characteristic significantly more common in focal symptomatic plaques when compared with either asymptomatic plaques (p less than 0.05) or nonfocal symptomatic plaques (p less than 0.01). When all the plaques were divided into three broad degrees of stenosis groups (0-39%, 40-69%, 70-99%) on the basis of angiographic data, only hemorrhage showed a significant correlation in incidence with increased degree of plaque stenosis, both when all plaques were considered (p less than 0.001) and when only symptomatic plaques were examined (p less than 0.001). The results indicate that intramural hemorrhage is the only carotid plaque gross morphologic characteristic significantly more frequent in symptomatic compared with asymptomatic plaques and the only characteristic significantly correlated with increased plaque size. These findings indicate that factors other than plaque ulceration and intraluminal thrombus play an important role in carotid plaque related cerebral symptoms. The data also raise questions concerning the unequivocal value of anticoagulant therapy in carotid artery disease, especially in highly stenotic lesions.     

Changes in carotid plaque echomorphology with time since a neurologic event

PURPOSE: Symptomatic carotid plaques are characterized by reduced fibrous tissue content, increased lipid content, intraplaque hemorrhage, and cap rupture. This confers an increased stroke risk. Plaque remodelling reduces this risk, however, and this study has evaluated differences in echomorphology at varying times after a neurologic event. METHODS: Gray scale medians (GSM +/- interquartile ranges) were measured using the best single longitudinal (SLV) and multiple cross-sectional views (MCSV; transverse views, 5-mm intervals throughout plaque) on B-mode ultrasound images of 61 carotid plaques (70% to 99%) causing symptoms < or =30 (n = 20), 31 to 90 (n = 10), 91 to 180 (n = 16), or >180 days (n = 15). The results were compared with those in 47 asymptomatic plaques. Plaque echolucency (SLV-GSM, MCSV(min)-GSM [cross-sectional image with lowest GSM]) and heterogeneity (MCSV(max-min)-GSM [highest minus lowest GSM of cross-sectional views]) were determined. RESULTS: In symptomatic plaques, echolucency was maximal < or =30 days of the presenting neurologic event (SLV-GSM, P = .009; MCSV(min)-GSM, P = .004). Although this diminished between 31 to 90 days, MCSV measurements in particular suggested increased echolucency (P = .042 at >180 days) and continuing heterogeneity (P = .01 at 91 to 180 days) beyond that time. CONCLUSIONS: Plaque echolucency was maximal < or =30 days of a neurologic event but diminished after 1 to 3 months, suggesting remodelling of unstable plaques. Continued features of increased echolucency and heterogeneity >91 days, however, suggests an increased stroke risk in these patients compared with that of the general population.