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The role of calcium in atherosclerosis is controversial and the relationship between vascular calcification and plaque vulnerability is not fully understood. Although calcifications are present in ≈50% to 60% of carotid plaques, their association with cerebrovascular ischemic events remains unclear. In this review, we summarize current understanding of carotid plaque calcification. We outline the role of calcium in atherosclerotic carotid disease by analyzing laboratory studies and histopathologic studies, as well as imaging findings to understand clinical implications of carotid artery calcifications. Differences in mechanism of calcium deposition express themselves into a wide range of calcification phenotypes in carotid plaques. Some patterns, such as rim calcification, are suggestive of plaques with inflammatory activity with leakage of the vasa vasourm and intraplaque hemorrhage. Other patterns such as dense, nodular calcifications may confer greater mechanical stability to the plaque and reduce the risk of embolization for a given degree of plaque size and luminal stenosis. Various distributions and patterns of carotid plaque calcification, often influenced by the underlying systemic pathological condition, have a different role in affecting plaque stability. Modern imaging techniques afford multiple approaches to assess geometry, pattern of distribution, size, and composition of carotid artery calcifications. Future investigations with these novel technologies will further improve our understanding of carotid artery calcification and will play an important role in understanding and minimizing stroke risk in patients with carotid plaques.

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Background and Purpose- Extracellular matrix proteins are important in atherosclerotic disease by influencing plaque stability and cellular behavior but also by regulating inflammation. COMP (cartilage oligomeric matrix protein) is present in healthy human arteries and expressed by smooth muscle cells. A recent study showed that transplantation of COMP-deficient bone marrow to apoE -/- mice increased atherosclerotic plaque formation, indicating a role for COMP also in bone marrow-derived cells. Despite the evidence of a role for COMP in murine atherosclerosis, knowledge is lacking about the role of COMP in human atherosclerotic disease. Methods- In the present study, we investigated if COMP was associated with a stable or a vulnerable human atherosclerotic plaque phenotype by analyzing 211 carotid plaques for COMP expression using immunohistochemistry. Results- Plaque area that stained positive for COMP was significantly larger in atherosclerotic plaques associated with symptoms (n=110) compared with asymptomatic plaques (n=101; 9.7% [4.7-14.3] versus 5.6% [2.8-9.8]; P =0.0002). COMP was positively associated with plaque lipids ( r =0.32; P =0.000002) and CD68 cells ( r =0.15; P =0.036) but was negatively associated with collagen ( r =-0.16; P =0.024), elastin ( r =-0.14; P =0.041), and smooth muscle cells ( r =-0.25; P =0.0002). COMP was positively associated with CD163 ( r =0.37; P =0.00000006), a scavenger receptor for hemoglobin/haptoglobin and a marker of Mhem macrophages, and with intraplaque hemorrhage, measured as glycophorin A staining ( r =0.28; P =0.00006). Conclusions- The present study shows that COMP is associated to symptomatic carotid atherosclerosis, CD163-expressing cells, and a vulnerable atherosclerotic plaque phenotype in humans.

Background and Purpose- Cellular apoptosis is an important feature in atherosclerosis, contributing to necrotic core formation, and plaque vulnerability. Activation of the death receptor TRAIL-R2 (TNF [tumor necrosis factor]-related apoptosis-inducing ligand receptor 2) through its ligand tumor necrosis factor-relate apoptosis-inducing ligand (TRAIL), induces apoptosis in cells in vitro. sTRAIL-R2 (soluble TRAIL-R2) was recently shown to predict cardiovascular events in healthy individuals. In the present study, we explored if plaque levels of sTRAIL-R2 and sTRAIL reflect plaque apoptosis and vulnerability and if plasma levels of these markers predict future events in subjects with advanced atherosclerosis. Methods- Plasma from 558 patients and 202 carotid plaques from the Carotid Plaque Imaging Project biobank were used. sTRAIL-R2, sTRAIL, and caspase-8 levels were assessed using a Proseek Multiplex CVD 96×96 assay. Active caspase-3 was measured using ELISA to assess plaque apoptosis. Plaque morphology was studied by immunohistochemistry. Inflammatory cytokines were assessed by Luminex. mRNA levels were quantified by RNA sequencing. Monocytes, T cells, B cells, and human coronary artery smooth muscle cells were used to study sTRAIL-R2 and sTRAIL release on cell apoptosis and inflammatory stimuli in vitro. Results- Plaque levels of sTRAIL-R2 and sTRAIL correlated to markers of extrinsic induced apoptosis (caspase-3 and -8). sTRAIL-R2 and sTRAIL protein expression were increased in symptomatic carotid plaques and patients with higher plasma levels of sTRAIL-R2 had a higher risk of future cardiovascular events. sTRAIL-R2 and sTRAIL were released upon activation of the extrinsic apoptosis pathway in vitro. sTRAIL-R2 and sTRAIL correlated with inflammatory cytokines, to CD68 expression and inversely to α-actin in the plaque tissue. Conclusions- The present study shows that sTRAIL-R2 and sTRAIL are associated to human plaque cell apoptosis, plaque inflammatory activity, and with symptomatic carotid plaques. Furthermore, high plasma levels of sTRAIL-R2 in plasma predict, independently, future cardiovascular events in individuals with manifest atherosclerotic disease.

Background and Purpose: Cross-sectional studies suggest that chronic hemodynamic impairment may cause selective cortical neuronal damage in patients with atherosclerotic internal carotid artery or middle cerebral artery occlusive disease. The purpose of this longitudinal study was to determine whether the progression of cortical neuronal damage, evaluated as a decrease in central benzodiazepine receptors (BZRs), is associated with hemodynamic impairment at baseline or hemodynamic deterioration during follow-up., Methods: We evaluated the distribution of BZRs twice using positron emission tomography and (11)C-flumazenil over time in 80 medically treated patients with atherosclerotic internal carotid artery or middle cerebral artery occlusive disease that had no ischemic episodes during follow-up. Using 3D stereotactic surface projections, we quantified abnormal decreases in the BZRs in the cerebral cortex within the middle cerebral artery distribution and correlated changes in the BZR index with the mean hemispheric values of hemodynamic parameters obtained from (15)O gas positron emission tomography., Results: In the hemisphere affected by arterial disease, the BZR index in 40 patients (50%) was increased during follow-up (mean 26±20 months). In multivariable logistic regression analyses, increases in the BZR index were associated with the decreased cerebral blood flow at baseline and an increased oxygen extraction fraction during follow-up. Increases in the oxygen extraction fraction during follow-up were associated with a lack of statin use., Conclusions: In patients with atherosclerotic internal carotid artery or middle cerebral artery disease, the progression of cortical neuronal damage was associated with hemodynamic impairment at baseline and hemodynamic deterioration during follow-up. Statin use may be beneficial against hemodynamic deterioration and therefore neuroprotective., (© 2016 American Heart Association, Inc.)

Background and Purpose: Atherosclerosis is a leading cause of mortality worldwide, contributing to both strokes and heart attacks. Macrophages are key players in atherogenesis, promoting vascular inflammation and arterial remodeling through cysteine cathepsin proteases. We used a cathepsin-targeted activity-based probe in human carotid plaque to assess its diagnostic potential and evaluate macrophage subtypes ex vivo., Methods: Carotid plaque specimens surgically removed during endarterectomy from 62 patients (age range, 38% female, 28% symptomatic) were graded pathologically as either stable (Grade 1) or unstable (Grade 2 or 3). A cathepsin activity-based probe was used to quantify individual cathepsins in plaque tissue and macrophage subtypes., Results: Cathepsin B and S activities were increased in unstable carotid plaques. They were quantified using the probe to biochemically investigate individual cathepsins (Cathepsin B and S: 0.97 and 0.90 for grade 3 versus 0.51 and 0.59 for grade 1; P=0.006 and P=0.03 arbitrary units (AU), respectively). Higher cathepsin activity was observed in carotid plaques from symptomatic patients (Cathepsin B and S: 0.65 and 0.77 for asymptomatic, 0.99 and 1.17 for symptomatic; P=0.008 and P=0.005 AU, respectively). Additionally, it was demonstrated that M2 macrophages from unstable plaques express cathepsin activity 5-fold higher than M2 macrophages from stable plaques (25.52 versus 5.22; P=0.008 AU)., Conclusions: Targeting cathepsin activity in human carotid plaques may present a novel diagnostic tool for characterizing high-risk plaques. Novel cathepsin activity patterns within plaques and macrophage subpopulations suggest their involvement in the transition to active disease., (© 2016 American Heart Association, Inc.)

Background and Purpose: Leptomeningeal collateral growth is a key factor that defines the severity of ischemic stroke. Patients with stroke generally have vascular risk factors, such as diabetes mellitus; however, consensus is lacking on how diabetes mellitus affects leptomeningeal arteriogenesis. We investigate the influence of diabetes mellitus on the leptomeningeal arteriogenesis., Methods: We measured the vessel diameter of the leptomeningeal anastomoses 14 days after the common carotid artery occlusion in db/db, db/+, and streptozotocin-induced hyperglycemic mice. In another set of these mice, we measured the infarct volume attributed to subsequent middle cerebral artery occlusion 14 days after the common carotid artery occlusion. Mac-2-positive cells on the dorsal brain surface and the mRNA expression of several macrophage-related factors in the cerebral cortex were examined. Finally, we tested whether the leptomeningeal arteriogenesis could be restored by pharmaceutical intervention in the db/db mice., Results: Cerebral hypoperfusion led to significant ipsilateral leptomeningeal collateral growth in db/+ mice and streptozotocin-induced hyperglycemic mice. The collateral growth contributed to reduced infarct volume. In contrast, leptomeningeal arteriogenesis was impaired in the db/db mice. The number of Mac-2-positive cells was increased and tumor necrosis factor-α mRNA expression was induced after common carotid artery occlusion in the db/+ mice. However, these responses were not observed in the db/db mice. Administration of the tumor necrosis factor-α inhibitor etanercept before common carotid artery occlusion restored the hypoperfusion-induced leptomeningeal collateral growth in db/db mice., Conclusions: These results indicate that leptomeningeal arteriogenesis is impaired in db/db mice and that suppression of the tumor necrosis factor-α response to hypoperfusion is the major contributing factor., (© 2015 American Heart Association, Inc.)

Background and Purpose: For symptomatic patients with carotid artery stenosis, the risk benefit for surgical intervention may vary among patient groups. Various modalities of plaque imaging have been promoted as potential tools for additional risk stratification, particularly in patients with moderate stenosis. However, it remains uncertain to what extent carotid plaque components predict risk of future ipsilateral ischemic stroke., Methods: In 2 large atherosclerotic carotid plaque biobank studies, we related histological characteristics of 1640 carotid plaques with a validated risk model for the prediction of individual 1- and 5-year stroke risk., Results: No significant heterogeneity between the studies was found. Predicted 5-year stroke risk (top versus bottom quartile) was related to plaque thrombus (odds ratio, 1.42; 95% confidence interval, 1.11-1.89; P=0.02), fibrous content (0.65; 0.49-0.87; P=0.004), macrophage infiltration (1.41; 1.05-1.90; P=0.02), high microvessel density (1.49; 1.05-2.11; P=0.03), and overall plaque instability (1.40; 1.05-1.87; P=0.02). This association was not observed for cap thickness, calcification, intraplaque hemorrhage, or lymphocyte infiltration. Plaques removed within 30 days of most recent symptomatic event were most strongly correlated with predicted stroke risk., Conclusions: Features of the vulnerable carotid plaque, including plaque thrombus, low fibrous content, macrophage infiltration, and microvessel density, correlate with predicted stroke risk. This study provides a basis for plaque imaging studies focused on stroke risk stratification., (© 2014 American Heart Association, Inc.)

Background and Purpose: Neovascularization associated with plaque vulnerability, particularly in the plaque shoulder, is susceptible to rupture, causing ischemic events. We aimed to use contrast-enhanced ultrasound to evaluate neovessels in carotid plaques quantitatively, focusing on plaque shoulders., Methods: Using contrast-enhanced ultrasound with perflubutane, we analyzed 50 consecutive patients who underwent carotid endarterectomy. We measured enhanced intensity and assessed the correlation between contrast effect and histopathology, comparing symptomatic and asymptomatic plaques., Results: Enhanced intensity of the plaque shoulder was associated with neovessel density (P<0.01; ρ=0.43). Enhanced intensity of the plaque shoulder was higher in plaques with rupture than in those without (P<0.05), and in symptomatic plaques (n=31) than in asymptomatic ones (n=19; P<0.01)., Conclusions: Quantitative evaluation of the contrast effect using contrast-enhanced ultrasound enabled the assessment of neovascularization of plaque shoulders in vivo real time, which may help stratify plaque vulnerability., (© 2014 American Heart Association, Inc.)

Background and Purpose: Limited information is available on the long-term effects of interleukin-6 (IL-6) on systemic atherosclerosis. The purpose of the present study was to clarify the relationship between chronic elevation of IL-6 and the long-term progression of carotid atherosclerosis., Methods: We prospectively evaluated 210 patients with ≥1 vascular risk factors for 9.0±1.0 years. Carotid mean-maximal intima-media thickness (mmIMT), the serum high-sensitivity C-reactive protein (hs-CRP) level, and the serum IL-6 level were measured at baseline and every 3 years. The associations between the progression of mmIMT and the long-term average levels of hs-CRP and IL-6 were analyzed., Results: Carotid mmIMT increased throughout the study period (0.031±0.026 mm/y). Baseline mmIMT was significantly associated with baseline hs-CRP (P=0.002) and baseline IL-6 (P<0.001) levels. Progression of mmIMT was positively correlated with average hs-CRP (P=0.001) and average IL-6 (P<0.001) levels. When adjusted for age, sex, traditional risk factors, and baseline mmIMT, mmIMT progression remained significantly associated only with the average IL-6 level (standardized β=0.17; P=0.02), but not with the average hs-CRP level (standardized β=0.10; P=0.18)., Conclusions: Chronic elevation of serum IL-6 was associated with the progression of atherosclerosis in patients with vascular risk factors. IL-6 could be used as a quantitative marker and a potential therapeutic target for accelerated atherosclerosis., (© 2014 American Heart Association, Inc.)

Background and Purpose: The Capillary Index Score (CIS) is a simple angiography-based scale for assessing viable tissue in the ischemic territory. We retrospectively applied it to Interventional Management of Stroke (IMS) trials I and II to evaluate the predictive value for good outcomes., Methods: CIS was calculated from pretreatment diagnostic cerebral angiograms blinded to outcome. IMS I and II diagnostic cerebral angiogram images of sufficient quality were reviewed and CIS calculated for treated subjects with internal carotid artery or M1 occlusion. CIS scoring (0-3) was dichotomized into favorable (f CIS; 2 or 3) and poor (p CIS; 0 or 1). Modified thrombolysis in cerebral infarction score 2b or 3 was considered good revascularization. CIS and modified thrombolysis in cerebral infarction scores were compared with good outcome, defined as modified Rankin Scale score≤2 at 90 days., Results: Twenty-eight of 161 subjects met the inclusion criteria. Thirteen (46%) had f CIS. Good clinical outcome was significantly different between the 2 CIS groups (62% for f CIS versus 7% for p CIS; P=0.004). Good reperfusion correlated to good outcome (P=0.04). No significant differences in time to intravenous or intra-arterial treatment were identified between f CIS and p CIS groups (P>0.25)., Conclusions: A f CIS was found in ≈50% of subjects and was a virtual prerequisite for good outcome in this study subgroup of IMS I and II. We call this the 50% barrier., (© 2014 American Heart Association, Inc.)

Background and Purpose: Extravascular optical coherence tomography (OCT), as a noninvasive imaging methodology with micrometer resolution, was evaluated in a murine model of carotid atherosclerosis by way of assessing the efficacy of pravastatin therapy., Methods: An OCT device was engineered for extravascular plaque imaging. Wild-type mice and apolipoprotein E-deficient (ApoE(-/-)) mice were randomized to 3 treatment groups: (1) wild-type on a diet of standard rodent chow (n=13); (2) ApoE(-/-) on a high-fat, atherosclerotic diet (HFD; n=13); and (3) ApoE(-/-) on a HFD given daily pravastatin (n=13). Mice were anesthetized and the left common carotid was surgically exposed. Three-dimensional (3D; 2 spatial dimensions+time) and 4D (3 spatial dimensions+time) OCT images of the vessel lumen patency were evaluated. After perfusion, in situ OCT imaging was performed for statistical comparison with the in vivo results and final histology., Results: Intraoperative OCT imaging positively identified carotid plaque in 100% of ApoE(-/-) mice on HFD. ApoE(-/-) mice on HFD had a significantly decreased lumen patency when compared with that in wild-type mice (P<0.001). Pravastatin therapy was found to increase lumen patency significantly in ApoE(-/-) mice on HFD (P<0.01; compared with ApoE(-/-) on HFD). The findings were confirmed with OCT imaging after perfusion and histology., Conclusions: OCT imaging offers the potential for real-time, detailed vessel lumen evaluation, potentially improving surgical accuracy and outcomes during cerebrovascular neurosurgical procedures. Pravastatin significantly increases vessel lumen patency in the ApoE(-/-) mouse on HFD.

Background and Purpose: Lumen geometry has long been suspected as a risk factor for atherosclerosis by virtue of its influence on blood flow disturbances. Confirmation of this geometric risk hypothesis has, however, proved challenging owing to possible effects of wall thickening on geometry and unproven links between candidate geometric variables and disturbed flow. The purpose of this study was to overcome these challenges., Methods: The study relied on imaging and risk factor data from progressively refined subsets of the Atherosclerosis Risk in Communities (ARIC) Carotid MRI study. Group 1 (n=467) included only nonstenotic cases having sufficient quality angiography for 3-dimensional analysis. Group 2 (n=346) excluded cases from group 1 having common and internal carotid artery wall thickness above previously identified thresholds for inward remodeling. Group 3 (n=294) excluded cases from group 2 having lumen irregularities and thus was least likely to include lumen geometries influenced by wall thickening., Results: Multiple linear regressions showed that for group 3, bifurcation flare and proximal curvature were independent predictors of internal carotid artery wall thickness, consistent with their previously demonstrated roles in predicting disturbed flow. For the broadest group 1, flare was an independent predictor of internal carotid artery wall thickness but with a sign change in regression coefficient reflecting effects of wall thickening on lumen geometry., Conclusions: Carotid bifurcation geometry is an independent, albeit weak, predictor of its early wall thickening, but only when assumptions about geometric factors, and the influence of disease on them, are confronted. This highlights pitfalls of previous attempts to confirm geometric risk of atherosclerosis.

Background and Purpose: Plaque hemorrhage (PH) may lead to accelerated progression of atherosclerotic disease. The presence of local PH in the carotid plaque predicts future cardiovascular events in any vascular territory. We investigated the prevalence of local PH and the predictive value of PH for the occurrence of cardiovascular events in men and women separately., Methods: Atherosclerotic plaques from 1422 patients (969 men, 453 women) who underwent carotid endarterectomy were analyzed histologically for the presence of PH. Patients were monitored for 3 years for cardiovascular events (nonfatal stroke, nonfatal myocardial infarction, vascular death, and vascular intervention)., Results: Plaques from men showed a significantly higher prevalence of PH compared with women (67% versus 54%; P<0.001). In 1353 patients with available follow-up data, with a median duration of 2.9 years, 270 events had occurred in men (29%) and 94 in women (22%). Stratified by presence of PH, the event rate was 32% in men with PH versus 23% in men without PH, and 23% in women with PH versus 21% in women without PH. A multivariable Cox proportional hazards model found a significant interaction between sex and PH. PH was significantly associated with events in men (adjusted hazard ratio, 1.9; 95% CI, 1.2-2.8) but not in women (adjusted hazard ratio, 1.0; 95% CI, 0.6-1.7)., Conclusions: Atherosclerotic carotid plaques obtained from men reveal a higher prevalence of PH compared with women. Local PH is strongly related to secondary manifestations of cardiovascular disease in men but not in women.

Background and Purpose: The effect of flow diverter (FD) on hemodynamic changes observed in aneurysms is inevitably affected by the actual structural configuration of deployed FD. We studied the resultant hemodynamic changes after implantation of FDs using computational fluid dynamic simulations based on micro-computed tomography reconstructions in rabbit aneurysm model., Methods: The FDs by micro-computed tomography images and vascular model based on rabbit-specific angiograms in 14 rabbits were reconstructed for computational fluid dynamic studies, and rabbit-specific inlet flow waveforms were used as boundary conditions. The occluded group (n=10) and unoccluded group (n=4) were divided according to the follow-up angiography. Hemodynamic parameters were separately evaluated for significance with respect to FD implantation and healing., Results: The normalized mean wall shear stress of the aneurysm sac and inflow volume were significantly reduced after FD deployment, and the relative residence time was significantly increased after treatment, without significant differences in mean pressure of aneurysm sac. When compared with the unoccluded group, the average relative residence time increment and percentage of inflow volume reduction in occluded group were higher. Additionally, the inlet of stream after FD deployment in the occluded group was more prevalent near the central region of the neck, whereas in the unoccluded group, it was more likely to occur near the proximal part of the neck., Conclusions: This study provided the real structural configurations of fully deployed FDs in vivo. We demonstrated the decrease of wall shear stress, inflow volume, increase of relative residence time, and change of inflow stream induced by FD implantation. The higher relative residence time increment, percentage of inflow volume reduction, and location of stream inlet near the central part of the neck may be closely related to healing.

Background and Purpose: The purpose of this study was to investigate whether the Framingham Cardiovascular Risk Profile and carotid artery intima-media thickness are associated with cortical volume and thickness., Methods: Consecutive subjects participating in a prospective cohort study of aging and mild cognitive impairment enriched for vascular risk factors for atherosclerosis underwent structural MRI scans at 3-T and 4-T MRI at 3 sites. Freesurfer (Version 5.1) was used to obtain regional measures of neocortical volumes (mm3) and thickness (mm). Multiple linear regression was used to determine the association of Framingham Cardiovascular Risk Profile and carotid artery intima-media thickness with cortical volume and thickness., Results: One hundred fifty-two subjects (82 men) were aged 78 (±7) years, 94 had a clinical dementia rating of 0, 58 had a clinical dementia rating of 0.5, and the mean Mini-Mental State Examination was 28±2. Framingham Cardiovascular Risk Profile score was inversely associated with total gray matter volume and parietal and temporal gray matter volume (adjusted P<0.04). Framingham Cardiovascular Risk Profile was inversely associated with parietal and total cerebral gray matter thickness (adjusted P<0.03). Carotid artery intima-media thickness was inversely associated with thickness of parietal gray matter only (adjusted P=0.04). Including history of myocardial infarction or stroke and radiological evidence of brain infarction, or apolipoprotein E genotype did not alter relationships with Framingham Cardiovascular Risk Profile or carotid artery intima-media thickness., Conclusions: Increased cardiovascular risk was associated with reduced gray matter volume and thickness in regions also affected by Alzheimer disease independent of infarcts and apolipoprotein E genotype. These results suggest a "double hit" toward developing dementia when someone with incipient Alzheimer disease also has high cardiovascular risk.

Background and Purpose: Data on risk factors for progression of intima-media thickness (IMT) and plaque are scarce. The objective was to determine long-term risk factors for total plaque area (TPA) and IMT as well as risk factors for progression (ΔTPA and ΔIMT)., Methods: Subjects were 1307 men and 1436 women who participated in a longitudinal population-based study with ultrasound examination of the right carotid artery at baseline and after 13 years of follow-up. Total cholesterol, high-density lipoprotein cholesterol, blood pressure, body mass index, and information about smoking habits, prevalent diabetes, and cardiovascular disease were obtained at baseline. Carotid atherosclerosis was assessed as TPA and mean IMT of plaque-free segments of the common carotid artery. Associations between z-scores of risk factors and carotid atherosclerosis were assessed in multiple linear regression models., Results: In multivariable models, total cholesterol, systolic blood pressure, and smoking were stronger predictors of follow-up TPA than of IMT, whereas sex and age were stronger predictors of IMT. Total cholesterol (standardized β=0.081), systolic blood pressure (standardized β=0.062), and smoking (standardized β=0.107) were significant predictors of ΔTPA, whereas only total cholesterol (standardized β=0.084) was an independent predictor of ΔIMT. The variance explained by traditional cardiovascular risk factors was somewhat greater for TPA than for IMT., Conclusions: The cardiovascular risk factors total cholesterol, smoking, and systolic blood pressure were stronger long-term predictors of TPA and TPA progression than for IMT and IMT progression.

Background and Purpose: Traditional vascular risk factors do not completely explain the asymmetry, racial, and sex differences in carotid artery disease. Carotid anatomy and geometry may play a role in the pathogenesis of internal carotid artery (ICA) stenosis, but their effects are unknown. We hypothesized that carotid artery anatomy and geometry would be independently associated with ICA stenosis., Method: This is a retrospective study of patients with CT angiography at Monash Medical Centre, 2006 to 2007. Carotid arteries were segmented using semiautomated methods to estimate measures of carotid anatomy and geometry. Measurements of carotid artery geometry were performed according to the recent article by Thomas and colleagues. ICA stenosis was dichotomized as <30% or ≥ 30% stenosis. Cluster logistic regression was used to examine the associations of anatomy and geometry with stenosis accounting for the paired arteries within subjects, adjusting for age, sex, and vascular risk factors., Results: Mean age of the sample (n=178) was 68.4 years (SD, 14 years). The following were independently associated with ICA stenosis: ICA radius at the bifurcation (OR, 0.20; 95% CI, 0.14-0.29), ICA angle (OR, 1.05 per degree increment; 95% CI, 1.04-1.07), age (OR, 1.05 per year increment; 95% CI, 1.03-1.07), male sex (OR, 1.72; 95% CI, 1.08-2.8), and ever-smoker (OR, 1.85; 95% CI, 1.15-2.96)., Conclusions: Carotid anatomy and geometry may enhance the risk of stenosis independent of traditional vascular risk factors and may be of help in very early identification of patients at high risk of developing carotid artery atherosclerosis for aggressive intervention.

Background and Purpose: Recent studies have investigated plaque morphology to determine patients who are at high risk of carotid atherosclerosis. In this study, we investigated whether a difference in dynamic enhancement pattern in plaque components could be useful to assess plaque stability with multidetector CT angiography., Methods: Fifty-nine lesions with moderate to severe carotid atherosclerosis in 51 patients (33 symptomatic, 18 asymptomatic) were consecutively included. Early- and delayed-phase images were obtained in 3 equivalent axial slices with multidetector CT angiography. Hounsfield units (HU) in the early phase were subtracted from those in the delayed phase in plaques (ΔHU) and compared with clinical features, MRI-based plaque characteristics, and histological findings with 20 surgical specimens acquired from carotid endarterectomy., Results: The ΔHU was significantly higher in asymptomatic than that in symptomatic presentation (P=0.02). With MRI, a higher ΔHU was negatively correlated with signal intensity on T1-weighted imaging (r=-0.56, P<0.0001). Histology confirmed that ΔHU was positively correlated with fibrous tissue (r=0.67, P=0.001) and negatively correlated with a lipid-rich necrotic core with hemorrhage (r=-0.70, P<0.001). Moreover, less neovascularization and inflammation was found in plaques with a higher ΔHU., Conclusions: Delayed-phase images provide information regarding the dynamic change in contrast media from the early arterial phase. An increase in HU from the early phase on multidetector CT angiography indicates plaque stability with more fibrous tissue and a less lipid-rich necrotic core, intraplaque hemorrhage, and neovascularization.

Background and Purpose: Rupture of atherosclerotic plaques is one of the main causes of ischemic strokes. The aim of this study was to investigate carotid plaque vulnerability markers in relation to blood flow direction and the mechanisms leading to plaque rupture at the upstream side of carotid stenoses., Methods: Frequency and location of rupture, endothelial erosion, neovascularization, and hemorrhage were determined in longitudinal sections of 80 human carotid specimens. Plaques were immunohistochemically analyzed for markers of vulnerability. Plaque geometry was measured to reconstruct shape profiles of ruptured versus stable plaques and to perform computational fluid dynamics analyses., Results: In 86% of ruptured plaques, rupture was observed upstream. In this region, neovascularization and hemorrhage were increased, along with increased immunoreactivity of vascular endothelial and connective tissue growth factor, whereas endothelial erosion was more frequent downstream. Proteolytic enzymes, mast cell chymase and cathepsin L, and the proapoptotic protein Bax showed significantly higher expression upstream as compared with the downstream shoulder of atherosclerotic lesions. Comparison of geometric profiles for ruptured and stable plaques showed increased longitudinal asymmetry of fibrous cap and lipid core thickness in ruptured plaques. The specific geometry of plaques ruptured upstream induced increased levels of shear stress and increased pressure drop between the upstream and the downstream plaque shoulders., Conclusions: Vulnerability of the upstream plaque region is associated with enhanced neovascularization, hemorrhage, and cap thinning induced by proteolytic and proapoptotic mechanisms. These processes are reflected in structural plaque characteristics, analyses of which could improve the efficacy of vascular diagnostics and prevention.

Background and Purpose: Recent studies reported the differential effect of docosahexaenoic (DHA) and eicosapentaenoic acids (EPA). We examined the differential association of DHA and EPA with carotid intima-media thickness (IMT) in Japanese individuals in Japan and in U.S. white individuals and explored whether DHA or EPA contributes to the difference in IMT between the two groups., Methods: A population-based cross-sectional study in 608 Japanese and U.S. white men aged 40 to 49 was conducted to assess IMT, serum DHA, EPA, and other cardiovascular risk factors., Results: Japanese compared to U.S. whites had significantly lower IMT (mean±SD, 618±81 and 672±94 μm for Japanese and whites, respectively; P<0.001) and had >2-fold higher levels of DHA and EPA. DHA, but not EPA, had an inverse association with IMT in both Japanese and U.S. whites. The inverse association remained only in Japanese men after adjusting for risk and other factors. The significant difference in multivariable-adjusted IMT became nonsignificant after further adjusting for DHA (mean difference, 17 μm; 95% CI, -8 to 43; P=0.177) but not EPA. In this multivariable-adjusted model, DHA but not EPA was a significant predictor of IMT (P=-0.032 versus 0.863, respectively)., Conclusions: These data suggest that DHA may have a more potent antiatherogenic effect than EPA, especially in levels observed in the Japanese, independent of risk factors.

Background and Purpose: Atherosclerotic plaque rupture is considered the most important mechanism that underlies the onset of stroke, myocardial infarction, and sudden death. Several evidences demonstrated the pivotal role of inflammatory processes in plaque destabilization. MicroRNAs (miRNAs) are small endogenous RNAs and represent a new important class of gene regulators. Nevertheless, no data exist about the expression profile of miRNAs in atherosclerotic plaques. Thus, the aim of this study was to investigate the expression level of miRNAs in human plaques and to correlate it with clinical features of plaque destabilization., Methods: Two separate groups of plaques were collected from patients who underwent carotid endarterectomy in Chieti (n=15) and Ancona (n=38) Hospitals. All the plaques were subdivided in symptomatic (n=22) and asymptomatic (n=31) according to the presence/absence of stroke., Results: First, on the plaques collected at Chieti Hospital, we performed large-scale analysis of miRNA expression. Between the 41 miRNAs examined, we discovered profound differences in the expression of 5 miRNAs (miRNA-100, miRNA-127, miRNA-145, miRNA-133a, and miRNA-133b) in symptomatic versus asymptomatic plaques. Remarkably, when we repeated the analysis on the Ancona plaque subset, all these 5 miRNAs confirmed to be significantly more expressed in the symptomatic plaques. Finally, in vitro experiments on endothelial cells transfected with miRNA-145 and miRNA-133a confirmed the importance of these miRNAs in the modulation of stroke-related proteins., Conclusions: These results are the first to report alterations in the expression of specific miRNAs in human atherosclerotic plaques and suggest that miRNAs may have an important role in regulating the evolution of atherosclerotic plaque toward instability and rupture. Furthermore, by identifying the specific miRNA signature for stroke now, we are able to use computer algorithms to identify previously unrecognized molecular targets.

Background and Purpose: The adipocytokines adiponectin and leptin have been suggested as risk factors for cardiovascular disease, including stroke, acting through atherosclerosis. However, studies have provided conflicting results in underpowered cohorts with some suggesting that the leptin:adiponectin ratio is a better predictor of risk. We examined these associations with carotid intima-media thickness (IMT), a marker of early atherosclerosis and arterial remodeling and an independent predictor of stroke. We also examined association between genetic variants in the leptin and adiponectin genes and IMT., Methods: Adiponectin and leptin levels were determined in 990 individuals from the community Carotid Atherosclerosis Progression Study. Five variants in the gene encoding adiponectin and 7 in the gene encoding leptin were genotyped and their effects on circulating levels assessed. Both were then correlated with IMT., Results: Adiponectin levels negatively correlated with IMT (-0.079, P=0.013). There was no correlation between leptin levels or leptin:adiponectin ratio and IMT. Two variants in the ADIPOQ gene encoding adiponectin were associated with altered adiponectin levels, 1 of which (rs266729) was associated with IMT. There was also an interaction with body mass index (P=0.019) with the association being present in obese subjects (P=0.02)., Conclusions: Our results support a causal role for adiponectin in early carotid IMT and suggest it may act through interaction with obesity. In contrast, we found no evidence of a role for leptin and no evidence that leptin:adiponectin ratio is a better predictor of risk that adiponectin levels alone.

Background and Purpose: Understanding associations of carotid atherosclerosis with stroke subtypes may contribute to more effective prevention of stroke., Methods: Between 1987 and 1989, 13 560 men and women aged 45 to 64 years and free of clinical stroke took part in the first examination of the Atherosclerosis Risk in Communities (ARIC) study. Incident strokes were ascertained by hospital surveillance., Results: During an average follow-up of 15.7 years, 82 incident hemorrhagic and 621 incident ischemic strokes (131 lacunar, 358 nonlacunar, and 132 cardioembolic strokes) occurred. The incidence rates of hemorrhagic and ischemic strokes were greater across higher carotid intima-media thickness levels. Although this positive association was observed for all stroke subtypes, the age-, gender-, and race-adjusted risk ratios were higher for cardioembolic and nonlacunar strokes than for hemorrhagic and lacunar strokes. Compared with participants in the lowest quintile (<0.61 mm), the adjusted risk ratios for those in the highest quintile (≥0.85 mm) of intima-media thickness were 2.55 (95% CI, 1.09-5.94) for hemorrhagic, 2.89 (95% CI, 1.50-5.54) for lacunar, 3.61 (95% CI, 2.33-5.99) for nonlacunar, and 6.12 (95% CI, 2.71-13.9) for cardioembolic stroke. The risk ratios were attenuated by additional adjustment for covariates but remained statistically significant for nonlacunar and cardioembolic strokes (P for trend <0.001, respectively). The association between carotid intima-media thickness and lacunar stroke was somewhat stronger in blacks than in whites (P for interaction=0.07)., Conclusions: Carotid atherosclerosis was associated with increased risk of all stroke subtypes, but the association of carotid atherosclerosis with stroke may vary by subtypes.

Background and Purpose: Parity is associated with the risk of clinical cardiovascular events and the severity of preclinical atherosclerosis in older subjects. We sought to determine whether childbearing is associated with concurrent changes in cardiovascular risk factors and the progression of carotid intima-media thickness., Methods: We examined the association between the number of children born during a 6-year period and concurrent changes in cardiovascular risk factors and progression of carotid intima-media thickness in men and women of reproductive age from the Cardiovascular Risk in Young Finns study. Complete data for parity and carotid intima-media thickness were available for 1786 subjects (1005 females, 781 males)., Results: For females, childbirth during the 6-year follow-up was associated with concurrent reductions in high-density lipoprotein cholesterol (P(trend)<0.0001), apolipoprotein A-I (P(trend)<0.0001), and apolipoprotein B (P(trend)=0.01); a redistribution of adiposity to abdominal deposits; and increased progression of carotid intima-media thickness (7.5+/-3.2 mum/birth [mean+/-SEM], P=0.02). The association of childbirth with carotid intima-media thickness progression was not greatly modified by adjustment for concurrent changes in cardiovascular risk factors (fully adjusted: P=0.05). This association was significantly stronger in females than males (P(heterogeneity)=0.001), who served as a control group exposed to the social and lifestyle influences of child-rearing but not the biological influences of childbearing., Conclusions: The progression of carotid atherosclerosis over a 6-year period is increased in females who gave birth during the same period, independent of traditional risk factors. Mechanisms that underlie this observation possibly include parity-induced changes in nontraditional risk factors or an acute influence of pregnancy itself.

Background and Purpose: Mechanical stress may contribute to plaque rupture in patients with carotid atherosclerosis. We determined longitudinal mechanical stresses in carotid atherosclerotic plaques and compared them with known markers of plaque vulnerability., Methods: Nineteen symptomatic patients scheduled for carotid endarterectomy underwent carotid MRI with a multicontrast protocol to characterize plaque morphology and geometry. Longitudinal 2-dimensional computational models were generated from the MRI data, and the mechanical stresses were calculated., Results: Peak longitudinal mechanical stresses occurred predominantly in the shoulder regions of the carotid plaque and correlated inversely with fibrous cap thickness (r(s)=-0.61; P=0.01), and increasing degrees of stenosis (r(s)=0.71; P=0.003). Peak stress levels were asymmetrically distributed longitudinally, with 50% occurring proximal to the maximal stenosis, 25% at the point of maximal stenosis, and 25% distal to the maximal stenosis., Conclusions: The peak longitudinal mechanical stresses in the fibrous caps of symptomatic patients with carotid atherosclerotic stenosis were located at known predilection sites for plaque rupture, suggesting that mechanical stresses may play a role in plaque destabilization.

Background and Purpose: The overall burden of prior infections may contribute to atherosclerosis and stroke risk. We hypothesized that serological evidence of common infections would be associated with carotid plaque thickness in a multiethnic cohort., Methods: Antibody titers to 5 common infectious microorganisms (ie, Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpesvirus 1 and 2) were measured among stroke-free community participants and a weighted index of infectious burden was calculated based on Cox models previously derived for the association of each infection with stroke risk. High-resolution carotid duplex Doppler studies were used to assess maximum carotid plaque thickness. Weighted least squares regression was used to measure the association between infectious burden and maximum carotid plaque thickness after adjusting for other risk factors., Results: Serological results for all 5 infectious organisms were available in 861 participants with maximum carotid plaque thickness measurements available (mean age, 67.2+/-9.6 years). Each individual infection was associated with stroke risk after adjusting for other risk factors. The infectious burden index (n=861) had a mean of 1.00+/-0.35 SD and a median of 1.08. Plaque was present in 52% of participants (mean, 0.90+/-1.04 mm). Infectious burden was associated with maximum carotid plaque thickness (adjusted increase in maximum carotid plaque thickness 0.09 mm; 95% CI, 0.03 to 0.15 mm per SD increase of infectious burden)., Conclusions: A quantitative weighted index of infectious burden, derived from the magnitude of association of individual infections with stroke, was associated with carotid plaque thickness in this multiethnic cohort. These results lend support to the notion that past or chronic exposure to common infections, perhaps by exacerbating inflammation, contributes to atherosclerosis. Future studies are needed to confirm this hypothesis and to define optimal measures of infectious burden as a vascular risk factor.

Background and Purpose: We propose to study possible differences in the associations between risk factors for cardiovascular disease (myocardial infarction and stroke) and carotid intima-media thickness (IMT) measurements made at 3 different levels of the carotid bifurcation., Methods: We conducted a cross-sectional study of a cohort of whites and blacks of both genders with a mean age of 45 years. Traditional cardiovascular risk factors were determined in cohort members. Carotid IMT was measured from high-resolution B-mode ultrasound images at 3 levels: the common carotid artery, the carotid artery bulb (bulb), and the internal carotid artery. Associations with risk factors were evaluated by multivariate linear regression analyses., Results: Of 3258 who underwent carotid IMT measurements, common carotid artery, bulb, and internal carotid artery IMT were measured at all 3 separate levels in 3023 (92.7%). A large proportion of the variability of common carotid artery IMT was explained by cardiovascular risk factors (26.8%) but less so for the bulb (11.2%) and internal carotid artery (8.0%). Carotid IMT was consistently associated with age, low-density lipoprotein cholesterol, smoking, and hypertension in all segments. Associations with fasting glucose and diastolic blood pressure were stronger for common carotid artery than for the other segments. Hypertension, diabetes, and current smoking had qualitatively stronger associations with bulb IMT and low-density lipoprotein cholesterol with internal carotid artery IMT., Conclusions: In our cohort of relatively young white and black men and women, a greater proportion of the variability in common carotid IMT can be explained by traditional cardiovascular risk factors than for the carotid artery bulb and internal carotid arteries.

Background and Purpose: It has been hypothesized that high structural stress in atherosclerotic plaques at critical sites may contribute to plaque disruption. To test that hypothesis, 3D fluid-structure interaction models were constructed based on in vivo MRI data of human atherosclerotic carotid plaques to assess structural stress behaviors of plaques with and without rupture., Methods: In vivo MRI data of carotid plaques from 12 patients scheduled for endarterectomy were acquired for model reconstruction. Histology confirmed that 5 of the 12 plaques had rupture. Plaque wall stress (PWS) and flow maximum shear stress were extracted from all nodal points on the lumen surface of each plaque for analysis. A critical PWS (maximum of PWS values from all possible vulnerable sites) was determined for each plaque., Results: Mean PWS from all ulcer nodes in ruptured plaques was 86% higher than that from all nonulcer nodes (123.0 versus 66.3 kPa, P<0.0001). Mean flow maximum shear stress from all ulcer nodes in ruptured plaques was 170% higher than that from all nonulcer nodes (38.9 versus 14.4 dyn/cm2, P<0.0001). Mean critical PWS from the 5 ruptured plaques was 126% higher than that from the 7 nonruptured ones (247.3 versus 108 kPa, P=0.0016 using log transformation)., Conclusion: The results of this study show that plaques with prior ruptures are associated with higher critical stress conditions, both at ulcer sites and when compared with nonruptured plaques. With further validations, plaque stress analysis may provide additional stress indicators helpful for image-based plaque vulnerability assessment.

Background and Purpose: Depression and hopelessness are associated with increased cardiovascular disease (CVD) morbidity and mortality; however, few studies have compared these constructs early in the atherogenic process, particularly in women or minorities., Methods: This cross-sectional study examined associations of hopelessness and depressive symptoms with carotid artery intimal-medial thickening (IMT) in 559 women (62% white, 38% black; mean+/-SD age, 50.2+/-2.8 years) without evidence of clinical CVD from the Study of Women's Health Across the Nation (SWAN) Heart Study. Hopelessness was measured by 2 questionnaire items; depressive symptoms were measured with the 20-item Center for Epidemiological Studies Depression Scale. Mean and maximum IMT were assessed by B-mode ultrasonography of the carotid arteries., Results: Increasing hopelessness was significantly related to higher mean (P=0.0139) and maximum (P=0.0297) IMT in regression models adjusted for age, race, site, income, and CVD risk factors. A weaker pattern of associations was noted for depressive symptoms and mean (P=0.1056) and maximum (P=0.0691) IMT. Modeled simultaneously in a risk factor-adjusted model, hopelessness was related to greater mean IMT (P=0.0217) and maximum IMT (P=0.0409), but depressive symptoms were unrelated to either outcome (P>0.4). No interactions with race or synergistic effects of depressive symptoms and hopelessness were observed., Conclusions: Among middle-aged women, higher levels of hopelessness are associated with greater subclinical atherosclerosis independent of age, race, income, CVD risk factors, and depressive symptoms.

Background and Purpose: Higher plasma concentrations of the endogenous nitric oxides synthase inhibitor asymmetrical dimethylarginine (ADMA) are associated with increased risk of cardiovascular and cerebrovascular events and death, presumably by promoting endothelial dysfunction and subclinical atherosclerosis. We hypothesized that plasma ADMA concentrations are positively related to common carotid artery intimal-media thickness (CCA-IMT) and to internal carotid (ICA)/bulb IMT., Methods: We investigated the cross-sectional relations of plasma ADMA with CCA-IMT and ICA/bulb IMT in 2958 Framingham Heart Study participants (mean age, 58 years; 55% women)., Results: In unadjusted analyses, ADMA was positively related to both CCA-IMT (beta per SD increment, 0.012; P<0.001) and ICA/bulb IMT (beta per SD increment, 0.059; P<0.001). In multivariable analyses (adjusting for age, sex, systolic blood pressure, antihypertensive treatment, smoking status, diabetes, BMI, total-to-HDL cholesterol ratio, log C-reactive protein, and serum creatinine), plasma ADMA was not associated with CCA-IMT (P=0.991), but remained significantly and positively related to ICA/bulb IMT (beta per SD increment, 0.0246; P=0.002)., Conclusions: In our large community-based sample, we observed that higher plasma ADMA concentrations were associated with greater ICA/bulb IMT, but not with CCA-IMT. These data are consistent with the notion that ADMA promotes subclinical atherosclerosis in a site-specific manner, with a greater proatherogenic influence at known vulnerable sites in the arterial tree.

Background and Purpose: The purpose of this study was to evaluate the effects of timing and extent of smoking, type of cigarettes, and concomitant vascular risk factors (VRFs) on the association between smoking and carotid intima-media thickness (C-IMT) in a lipid clinic population., Methods: 1804 patients (869 men, age 21 to 85 year) participated in the study. Smoking habits were recorded and C-IMTs were measured by B-mode ultrasound. The associations of C-IMT with smoking status (never, former, and current) and with the cigarettes' content of tar, nicotine, and carbon monoxide (alone or combined to define "light" or "regular" cigarettes) as well as the interactions between smoking status, gender, and VRFs were evaluated before and after adjustment for confounders., Results: C-IMT was highest in current smokers, lower in former, and lowest in never smokers. C-IMT of former and current smokers differed only after data adjustment for variables describing the extent and timing of smoking exposure. C-IMT was positively related to the number of pack-years (number of cigarettes smoked per day [cigarettes/d] multiplied by number of years smoked/20) in both former and current smokers. There were no differences in C-IMT between smokers of cigarettes with high or low nicotine, tar, or carbon monoxide content. Both diabetes and hypertension interacted positively with smoking in determining C-IMTs., Conclusions: In the present cross-sectional observational investigation, carried out in a cohort of patients attending a lipid clinic, consumption of light cigarettes does not reduce the atherogenic effect of smoking on C-IMT. The number of pack-years, cigarettes/d, and years of smoking are relevant covariates in evaluating the effects of smoking on vascular health. The presence of diabetes or hypertension strengthens the association between smoking and cardiovascular risk.

Background and Purpose: Carotid atherosclerosis has been associated with increased risk of stroke and poorer cognitive performance in older adults. The relation of carotid atherosclerosis to cognitive impairment and MRI indices of ischemia and aging in midlife is less clear., Methods: We studied 1975 Framingham Offspring Study participants free of stroke and dementia with available carotid ultrasound, brain MRI, and neuropsychological testing. We related common and internal carotid artery intima-media thickness and internal carotid stenosis to large white matter hyperintensity (>1 SD above age-specific mean), total brain volume, hippocampal volume, silent cerebral infarcts, and neuropsychological measures of verbal memory, executive function, and nonverbal memory measures., Results: We observed that internal carotid artery intima-media thickness, but not common carotid artery intima-media thickness, was associated with higher prevalence of silent cerebral infarcts (OR, 1.21; 95% CI, 1.03-1.43; P<0.05), large white matter hyperintensity (OR, 1.19; 95% CI, 1.03-1.38; P<0.05), lower total brain volume (-0.05 per SD; P<0.05), and poorer performance in verbal memory (-0.06 per SD; P<0.05) and nonverbal memory measures (-0.08 per SD; P<0.01), but not with hippocampal volume. Internal carotid stenosis >or=25% was associated with a higher prevalence of large white matter hyperintensity (adjusted OR, 1.77; 95% CI, 1.25-2.53) and lower total brain volume (-0.11 per SD; P=0.042) but not with silent cerebral infarcts or hippocampal volume. Internal carotid stenosis >or=50% was associated with higher prevalence of silent cerebral infarcts (OR, 2.53; 95% CI, 1.17-5.44), large white matter hyperintensity (OR, 2.35; 95% CI, 1.08-5.13), and poorer performance on executive function (-0.39 per SD; P<0.05), but not with total brain volume or hippocampal volume., Conclusions: Carotid atherosclerosis markers were associated with MRI indices of brain ischemia and aging and with cognitive impairment in a community-based sample of middle-aged adults. Our data suggest that internal carotid artery intima-media thickness may be a better marker for cognitive impairment than common carotid artery intima-media thickness.

Background and Purpose: Arterial stiffening and thickening and endothelial dysfunction may be associated with cognitive decline or white matter hyperintensities (WMH) independently of blood pressure level. We aimed to investigate, using an integrative approach, the relative contributions of structural and functional vascular factors to the degree of cognitive impairment (primary outcome) and the severity of WMH (secondary outcome) in elderly hypertensive patients with subjective memory complaints, a group prone to dementia., Methods: A prospective, dedicated, cross-sectional population of 198 elderly hypertensive patients (mean age 69.3+/-6.2 years) with subjective memory complaints underwent a full set of cognitive function assessments, brain MRI with semiquantification of WMH, carotid ultrasonography, carotid-femoral pulse wave velocity, brachial endothelial function, and plasma von Willebrand Factor measurements., Results: After adjustment for the usual cardiovascular risk factors, increased arterial stiffness (as assessed by pulse wave velocity) was significantly and independently associated with memory impairment in men. The severity of WMH was independently associated with increased carotid intima media thickness and stiffness (as assessed by augmentation index) as well as with increased age and plasma levels of von Willebrand Factor, a biomarker of endothelial dysfunction., Conclusions: Our data suggest that vascular abnormalities, independently of blood pressure levels, may play a role in the setting of subjective memory complaints as well as of WMH in elderly hypertensive patients. Arterial thickness and stiffness as well as endothelial function should be assessed simultaneously and may represent additional targets for the prevention of subjective memory complaints and WMH.

Background and Purpose: The recent finding that genetic variation in the leukotriene biosynthesis pathway may confer an increased risk of ischemic stroke and atherosclerosis has implicated the leukotriene family as potential mediators of cardiovascular disease. Using a 2-stage replication design, we have examined whether polymorphisms in 8 genes related to this pathway are associated with early atherosclerosis and remodeling as measured by carotid artery intima-media thickness., Methods: We assessed 969 individuals from the Carotid Atherosclerosis Progression Study (CAPS), a community based study of normal subjects, for 39 variants in the leukotriene pathway. Significant associations and gene-environment interactions were found for 21 variants in the initial cohort and were examined in the next 1905 consecutive cases from the same CAPS population., Results: No replicable association between any individual polymorphism and carotid intima-media thickness itself was present after correction for multiple testing. A single gene-environment interaction was replicated between rs17222814 on bifurcation intima-media thickness and alcohol consumption exceeding 30 grams per day., Conclusions: The genetic variants we examined in the leukotriene biosynthesis pathway have little effect on early atherosclerosis and remodeling risk as determined by carotid intima-media thickness. Our study cannot exclude them as being risk factors for more advanced stages in the atherosclerotic process.

Background and Purpose: Extracranial atherosclerosis, proximal to the carotid bifurcation and V3 segment of the vertebral artery, is considered to be an infrequent condition with a benign prognosis. However, its prevalence may be underestimated due to lack of data. We aimed to determine the prevalence of proximal extracranial plaques and stenosis in the common carotid artery, innominate and subclavian arteries, and proximal vertebral artery., Methods: We performed a systematic analysis of intra- and extracranial arteries, the aortic arch, and the heart in 339 consecutive autopsies of patients with stroke; 259 patients had brain infarction; 80 patients had brain hemorrhage and were used as control subjects. Clinical history, risk factors, imaging data, and general autopsy reports were analyzed., Results: Proximal extracranial plaques and stenosis were present in the arteries of 46.9% and 19.8% of patients, respectively, without a significant difference between brain infarction and brain hemorrhage groups. Proximal extracranial atherosclerosis occurred more frequently in the proximal vertebral artery than in other arteries (stenosis prevalence 12.7% versus 5.3% in the common carotid artery) and in patients with posterior circulation brain infarction (except for the posterior cerebral artery territory). More specifically, atherosclerosis in the proximal vertebral artery was significantly associated with posterior circulation brain infarction (age- and sex-adjusted OR, 2.31; 95% CI, 1.28 to 4.17 for plaques and 2.10; 95% CI, 1.01 to 4.38 for stenosis) using patients with isolated anterior circulation infarctions as control subjects., Conclusions: Proximal extracranial atherosclerosis was frequent and was significantly associated with brainstem infarcts. These findings support the importance of a systematic workup, including the evaluation of proximal extracranial atherosclerotic lesions.

Background and Purpose: Impaired baroreflex sensitivity (BRS) has been previously shown to be of prognostic value in patients with cardiovascular disease and stroke. Because baroreflex seems to be blunted by both carotid atherosclerosis and by lesions affecting central processing, controversy exists regarding the etiology of stroke-related baroreflex changes. The insula may play a central role in baroreflex modulation. The aim of the study was therefore to examine BRS in patients with acute stroke with regard to carotid atherosclerosis and insular involvement., Methods: We evaluated spontaneous BRS in 96 patients with acute stroke within 72 hours of ictus and 41 control subjects using a sequential crosscorrelation method., Results: Fifty-two patients with ischemic stroke and 44 patients with intracerebral hemorrhage, mean age 58.4 years, were included. With comparable carotid atherosclerosis profiles, patients with stroke had significantly lower BRS than control subjects (3.3 versus 5.3, P<0.001). Carotid atherosclerosis had no influence on variance of the BRS values in the acute stroke group. Patients with insular involvement had significantly lower BRS than patients with no insular involvement (2.55 versus 4.35, P=0.001) or control subjects (2.55 versus 5.3, P<0.001). Furthermore, patients with left insular involvement had significantly lower BRS than patients with right insular involvement (2.3 versus 3.5, P=0.049). There was no significant difference between patients with no insular lesions and control subjects (P=0.263)., Conclusions: We demonstrated that baroreflex impairment in acute stroke is not associated with carotid atherosclerosis but with insular involvement. Both insulae seem to participate in processing the baroreceptor information with the left insula being more dominant.

Background and Purpose: Cerebral microembolic signals detected by transcranial Doppler are frequent during carotid angioplasty with stenting and carotid endarterectomy (CEA). Their potential harmful effects on the brain are, however, unclear. The aim of this study was to relate the frequency and type of per-procedural microembolic signals to procedure-related ipsilateral ischemic strokes and new ipsilateral ischemic lesions on diffusion-weighted cerebral MRI., Methods: Eighty-five patients who were prospectively treated with CEA (61) or carotid angioplasty with stenting (30) for high-grade (>/=70%) internal carotid artery stenoses were monitored during the procedures using multifrequency transcranial Doppler with embolus detection and differentiation. Pre- and postprocedural cerebral diffusion-weighted cerebral MRIs were performed on a subset of patients., Results: Solid and gaseous microemboli were independently associated with procedure-related ipsilateral ischemic strokes (solid: P=0.027, gaseous: P=0.037) or new ipsilateral diffusion-weighted cerebral MRI lesions (solid: P=0.043, gaseous: P=0.026). Microembolic signals were detected during all procedures except one (CEA); 17% and 21% of all emboli were solid during carotid angioplasty with stenting and CEA, respectively. Patients undergoing carotid angioplasty with stenting had more solid (P<0.001) and gaseous (P<0.001) emboli and more new ipsilateral ischemic strokes (P=0.033) compared with patients undergoing CEA. Echolucent plaques (P=0.020) and preprocedural diffusion-weighted cerebral MRI ischemic lesions (P=0.002) were associated with increased numbers of solid emboli., Conclusions: Solid and gaseous microemboli were increased in patients with procedure-related ipsilateral ischemic strokes or new diffusion-weighted cerebral MRI lesions, which suggests that both solid and gaseous emboli may be harmful to the brain during CEA and carotid angioplasty with stenting.

Background and Purpose: The Ministry of Health, Labor, and Welfare of Japan approved the use of recombinant tissue-type plasminogen activator (rt-PA) for the treatment of acute ischemic stroke in October 2005. The impact of the regulatory approval of rt-PA on the processes of acute stroke management was examined., Methods: A prospective, multicenter, observational study was conducted between December 2004 and December 2005 in 84 Japanese institutes, including 24 institutes with a stroke unit. We enrolled 4620 consecutive patients who were hospitalized within 72 hours after the onset of completed ischemic stroke; 1089 of them were hospitalized after rt-PA was approved. The patients' characteristics and the processes of stroke management were compared before and after rt-PA approval., Results: Age, gender, stroke subtype, time from onset to hospital visit, and National Institutes of Health Stroke Scale score on admission were similar between the 2 periods. With approval, the percentage of patients treated with intravenous rt-PA therapy increased from 0.7% to 2.6% (P<0.001). The rate increased from 0.9% to 5.2% in institutes with a stroke unit (P<0.001) but did not increase in other institutes (P=0.587). Within 24 hours of stroke onset, conventional MRI (P=0.003), diffusion-weighted MRI (P<0.001), magnetic resonance angiography (P=0.001), carotid ultrasound (P=0.004), measurement of prothrombin time or activated partial thromboplastin time (P=0.034), and measurement of blood sugar (P=0.015) were performed more frequently after rt-PA approval., Conclusions: The present results indicate that the approval of intravenous rt-PA therapy resulted in dramatic changes in the processes of management for acute stroke patients.

Background and Purpose: The benefit of carotid endarterectomy is heavily influenced by the risk of perioperative death or stroke. This study developed a multivariable model predicting the risk of death or stroke within 30 days of carotid endarterectomy., Methods: The New York Carotid Artery Surgery (NYCAS) Study is a population-based cohort of 9308 carotid endarterectomies performed on Medicare patients from January 1998 through June 1999 in New York State. Detailed clinical data were abstracted from medical charts to assess sociodemographic, neurological, and comorbidity risk factors. Deaths and strokes within 30 days of surgery were confirmed by physician overreading. Multivariable logistic regression was used to identify independent patient risk factors., Results: The 30-day rate of death or stroke was 2.71% among asymptomatic patients with no history of stroke/transient ischemic attack (TIA), 4.06% among asymptomatic ones with a distant history of stroke/TIA, 5.62% among those operated on for carotid TIA, 7.89% of those with stroke, and 13.33% in those with crescendo TIA/stroke-in-evolution. Significant multivariable predictors of death or stroke included: age >/=80 years (OR, 1.30; 95% CI, 1.03 to 1.64), nonwhite (OR, 1.83; 1.23 to 2.72), admission from the emergency department (OR, 1.95; 1.50 to 2.54), asymptomatic but distant history of stroke/TIA (OR, 1.40; 1.02 to 1.94), TIA as an indication for surgery (OR, 1.81; 1.39 to 2.36), stroke as the indication (OR, 2.40; 1.74 to 3.31), crescendo TIA/stroke-in-evolution (OR, 3.61; 1.15 to 11.28), contralateral carotid stenosis >/=50% (OR, 1.44; 1.15 to 1.79), severe disability (OR, 2.94; 1.91 to 4.50), coronary artery disease (OR, 1.51; 1.20 to 1.91), and diabetes on insulin (OR, 1.55; 1.10 to 2.18). Presence of a deep carotid ulcer was of borderline significance (OR, 2.08; 0.93 to 4.68)., Conclusions: Several sociodemographic, neurological, and comorbidity risk factors predicted perioperative death or stroke after carotid endarterectomy. This information may help inform decisions about appropriate patient selection, assessments about the impact of different surgical processes of care on outcomes, and facilitate comparisons of risk-adjusted outcomes among providers.

Background and Purpose: Carotid intima-media thickness (IMT) is a surrogate marker of subclinical atherosclerosis and a strong predictor of stroke and myocardial infarction. The object of this study was to determine the association between carotid IMT and 702 single nucleotide polymorphisms in 145 genes., Methods: B-mode carotid ultrasound was performed among 408 Hispanics from the Northern Manhattan Study. The common carotid artery IMT and bifurcation IMT were phenotypes of interest. Genetic effects were evaluated by the multivariate regression model adjusting for traditional vascular risk factors. For each individual, we calculated a gene risk score (GRS) defined as the total number of the significant single nucleotide polymorphisms in different genes. Subjects were then divided into 3 GRS categories using the 2 cutoff points: mean GRS +/-1 SD., Results: We identified 6 significant single nucleotide polymorphisms in 6 genes for common carotid artery IMT and 7 single nucleotide polymorphisms in 7 genes for bifurcation IMT using the probability value of 0.005 as the significant level. There were no common significant genes for both phenotypes. The most significant genes were the tissue plasminogen activator (P=0.0005 for common carotid artery IMT) and matrix metallopeptidase-12 genes (P=0.0004 for bifurcation IMT). Haplotype analysis did not yield a more significant result. Subjects with GRS >or=9 had significantly increased IMT than those with GRS

Background and Purpose: The risk for cardiovascular events is related to the composition and stability of an atherosclerotic plaque driven by inflammation and deposition of lipids. Scavenger receptors are a family of cell surface receptors involved in lipid uptake and inflammation. Recently, we found that soluble CD36 is increased in plasma from patients with diabetes strongly correlated with insulin resistance., Methods: We tested whether soluble CD36 is a marker of plaque stability in patients with high-grade internal carotid stenoses (n=62). The patients were classified according to plaque symptomatology and plaque echogenicity on ultrasound examination., Results: When patients were divided into 3 groups according to the latest clinical symptoms from plaques (ie, symptoms within the last 2 months [n=16], symptoms within the last 2 to 6 months [n=15], or asymptomatic [n=31]), the former group had significantly raised plasma levels of soluble CD36 as compared with the other 2 groups. In contrast, we found no differences in plasma levels of C-reactive protein, beta-thromboglobulin, lipid parameters, or HbA1C between these groups. The patients with echolucent carotid plaques (n=20) tended to have higher soluble CD36 levels in plasma compared with those with echogenic/heterogenic plaque (n=39; P=0.087). By immunohistochemistry, CD36 was localized to macrophages-rich area of intima within the atherosclerotic lesion., Conclusions: We propose that sCD36 may be a marker of plaque instability and symptomatic carotid atherosclerosis, possibly at least partly as a result of CD36 release to the circulation from the foam cells within the atherosclerotic lesion.

Background and Purpose: The purpose of this study was to prospectively investigate the contribution of the ipsilateral external carotid artery (ECA) to cerebral perfusion in patients with internal carotid artery occlusion., Methods: Institutional Review Board approval and informed consent were obtained. Thirty functionally independent patients (24 men, 6 women; mean age, 63 years) with an angiographically proven unilateral internal carotid artery occlusion and transient or minor disabling ischemic attacks ipsilateral to the side of the internal carotid artery occlusion were included. Grading of ECA collateral flow was performed with intraarterial digital subtraction angiography. The contribution of the ECA to regional cerebral blood flow was assessed with selective arterial spin labeling MRI. Differences in regional cerebral blood flow were analyzed with Student t test., Results: Twenty percent of the patients had ECA Grade 0 collateral flow (no filling of ophthalmic artery), 20% Grade 1 (filling of carotid siphon), and 60% Grade 2 (filling of anterior and/or middle cerebral artery) as demonstrated on digital subtraction angiography. Although in the Grade 1 group, the ECA supplied a smaller region of the brain compared with the Grade 2 group, the mean regional cerebral blood flow of the perfusion territory supplied by the ECA is similar (P=0.70) in the Grade 1 group (mean+/-SD 57+/-16 mL/min/100 g) and the Grade 2 group (60+/-12 mL/min/100g)., Conclusions: In patients with symptomatic internal carotid artery occlusion, focal brain regions may strongly depend on the contribution to cerebral perfusion of the ECA ipsilateral to the side of the internal carotid artery occlusion, even in patients with limited ECA collateral supply as demonstrated on digital subtraction angiography.

Background and Purpose: The association of carotid atherosclerosis with body composition and fat distribution is poorly understood. We aimed to test the cross-sectional association of carotid plaques and common carotid artery intima-media thickness with calf circumference (CC), representing peripheral fat and lean mass, and with waist circumference and waist-to-hip ratio, 2 markers of abdominal obesity., Methods: The study was performed on 6265 subjects aged >or=65 years recruited prospectively from the electoral rolls of 3 French cities. Ultrasound examination and anthropometric measures were performed according to a standardized protocol., Results: Carotid plaques were less frequent with increasing CC, the ORs for the second, third, and fourth quartile of CC compared with the first quartile being 0.98 (95% CI, 0.84 to 1.15), 0.85 (95% CI, 0.72 to 1.01), and 0.71 (95% CI,:0.58 to 0.86; P for trend=0.0002), respectively, independently of age, gender, body mass index, and other vascular risk factors. There was an opposite and multiplicative effect of CC and waist-to-hip ratio on the frequency of carotid plaques (55.1% of individuals in the fourth waist-to-hip ratio quartile and the first CC quartile had carotid plaques, against 31.8% in the first waist-to-hip ratio and the fourth CC quartile). Mean common carotid artery intima-media thickness was larger with increasing waist circumference, waist-to-hip ratio, and CC, but the association with CC disappeared after adjusting for body mass index., Conclusions: The present study shows, for the first time, an inverse relationship between carotid plaques and CC. Although this needs to be confirmed in other populations, it may suggest an antiatherogenic effect of large CC.

Background and Purpose: Accurate diagnosis of the degree of internal carotid artery (ICA) stenosis is needed for decisions regarding optimal stroke prevention. Noninvasive magnetic resonance angiography (MRA) is being proposed and used as a replacement for the gold standard, intra-arterial angiography. Our purpose was to perform a systematic review and diagnostic meta-analysis to determine the sensitivity and specificity of time-of-flight (TOF) MRA and contrast-enhanced (CE) MRA for the detection of (1) high-grade (> or = 70% to 99%) ICA stenoses; (2) ICA occlusions; (3) moderately severe (50% to 69%) ICA stenoses; and (4) compare the overall accuracy of the 2 MRA techniques., Methods: The medical literature on MRA and the diagnosis of ICA steno-occlusive disease was reviewed through the PubMed, EMBASE, and SCOPUS databases. All publication years were included through to November 2006. Studies were eligible for inclusion if they compared the accuracy of TOF or CE MRA for the detection of ICA disease against intra-arterial angiography and reported sufficient data., Results: The overall sensitivity of TOF MRA for the detection of > or = 70% to 99% ICA stenoses was 91.2% (95% CI: 88.9% to 93.1%) with a specificity of 88.3% (86.7% to 89.7%), whereas the sensitivity of CE MRA was 94.6% (92.4% to 96.4%) with a specificity of 91.9% (90.3% to 93.4%). For the detection of ICA occlusions, the sensitivity of TOF MRA was 94.5% (91.2% to 96.8%) and the specificity was 99.3% (98.9% to 99.6%), whereas the sensitivity and specificity values for CE MRA were 99.4% (96.8% to 100%) and 99.6% (99.2% to 99.9%), respectively. For moderately severe (50% to 69%) stenoses, TOF MRA had a sensitivity of only 37.9% (29.3% to 47.1%) and a specificity of 92.1% (89.6% to 94.1%); for CE MRA, the pooled sensitivity value was somewhat better at 65.9% (57.0% to 74.0%), whereas the specificity was 93.5% (91.3% to 95.3%)., Conclusions: TOF MRA and CE MRA showed high accuracy for the detection of high-grade ICA stenoses and occlusions with CE MRA having the edge over TOF MRA, but had only poor (TOF MRA) to fair (CE MRA) sensitivity for the detection of moderately severe stenoses.