Vessel Wall Imaging Features of Spontaneous Intracranial Carotid Artery Dissection.

BACKGROUND AND OBJECTIVES: Intracranial dissection is an important cause of stroke often with nonspecific angiographic features. Vessel wall imaging (VWI) can detect dissections, but intracranial applications remain unvalidated by pathologic specimens. We sought to determine the ability of VWI to identify the rarely reported spontaneous intracranial carotid dissection (sICD) guided by postmortem validation. METHODS: VWI features of sICD, validated by postmortem specimen analysis in 1 patient, included luminal enhancement within a hypoenhancing outer wall, narrowing the mid to distal ophthalmic (C6) segment, relatively sparing the communicating (C7) segment. VWI examinations were reviewed to identify patients (1) with matching imaging features, (2) no evidence of other vasculopathies (i.e., inflammatory, intracranial atherosclerotic disease [ICAD]), and (3) adequate image quality. These sICD VWI features were compared with those in patients with known ICAD causing similar narrowing of C6 and relative sparing of C7 by a Fisher exact test accounting for multiple samples. RESULTS: Among 407 VWI examinations, 8 patients were identified with 14 sICDs, all women aged 30-56 years, 6 (75%) bilateral. All patients with sICD had risk factors of dissection (e.g., recently postpartum, fibromuscular dysplasia, and hypertension) and 3 (37.5%) had intracranial dissections elsewhere. Seven (87.5%) were diagnosed as moyamoya syndrome on initial angiography. Enhancing lesions varied from thin flap-like defects (n = 6) to thick tissue along the superolateral wall of the internal carotid artery, within the hypoenhancing outer wall. Compared with 10 intracranial carotid plaques in 8 patients with ICAD, sICD demonstrated stronger (84.6% vs 20.0%, p = 0.003-0.025) and more homogeneous (61.5% vs 0.0%, p = 0.005-0.069) enhancement and less positive remodeling (0.0% vs 60.0%, p = 0.004-0.09). T1 hyperintensity was identified in 5 sICDs in 3 patients but not identified in ICAD. Three patients with serial imaging (8- to 39.8-month maximum intervals) revealed little to no changes in stenosis, wall thickening, or enhancement. DISCUSSION: sICD is distinguishable on VWI from ICAD by enhancement characteristics, less positive remodeling, and clinical parameters. These VWI features should raise suspicion especially in young women with risk factors of dissection. Temporal stability and a lack of T1 hyperintensity should not discourage diagnosing sICD.

Association of Dental Infections with Intracranial Atherosclerotic Stenosis.

INTRODUCTION: Periodontal disease (PD) and dental caries are oral infections leading to tooth loss that are associated with atherosclerosis and cerebrovascular disease. We assessed the hypothesis that PD and caries are associated with asymptomatic intracranial atherosclerosis (ICAS) in the Atherosclerosis Risk in Communities (ARIC) study. METHODS: Full-mouth clinical periodontal measurements (7 indices) collected at 6 sites per tooth from 6,155 subjects from the Dental Atherosclerosis Risk in Communities Study (DARIC) without prior stroke were used to differentiate seven PD stages (Periodontal Profile Class [PPC]-I to -VII) and dental caries on coronal dental surface (DS) and dental root surface (DRS). A stratified subset underwent 3D time-of-flight MR angiogram and 3D high isotropic-resolution black blood MRI. ICAS was graded according to the criteria established by the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial. We evaluated the relationship between PD stage and dental caries with asymptomatic ICAS, graded as no ICAS, <50% ICAS, and ≥50% ICAS. RESULTS: Among dentate subjects who underwent vascular imaging, 801 (70%) had no ICAS, 232 (20%) had <50% ICAS, and 112 (10%) had ≥50% ICAS. Compared to participants without gum disease (PPC-I), participants with mild-moderate tooth loss (PPC-VI), severe tooth loss (PPC-VII), and severe PD (PPC-IV) had higher odds of having <50% ICAS. Participants with extensive gingivitis (PPC-V) had significantly higher odds of having ≥50% ICAS. This association remained significant after adjusting for confounding variables: age, gender, race, hypertension, diabetes, dyslipidemia, 3-level education, and smoking status. There was no association between dental caries (DS and DRS) and ICAS <50% and ≥50%. CONCLUSION: We report significant associations between mild-moderate tooth loss, severe tooth loss, and severe PD with <50% ICAS as well as an association between extensive gingivitis and ≥50% ICAS. We did not find an association between dental caries and ICAS.

Vascular Involvement in Neurosarcoidosis: Early Experiences From Intracranial Vessel Wall Imaging.

BACKGROUND AND OBJECTIVES: Cerebrovascular manifestations in neurosarcoidosis (NS) were previously considered rare but are being increasingly recognized. We report our preliminary experience in patients with NS who underwent high-resolution vessel wall imaging (VWI). METHODS: A total of 13 consecutive patients with NS underwent VWI. Images were analyzed by 2 neuroradiologists in consensus. The assessment included segment-wise evaluation of larger- and medium-sized vessels (internal carotid artery, M1-M3 middle cerebral artery; A1-A3 anterior cerebral artery; V4 segments of vertebral arteries; basilar artery; and P1-P3 posterior cerebral artery), lenticulostriate perforator vessels, and medullary and deep cerebral veins. Cortical veins were not assessed due to flow-related artifacts. Brain biopsy findings were available in 6 cases and were also reviewed. RESULTS: Mean patient age was 54.9 years (33-71 years) with an M:F of 8:5. Mean duration between initial diagnosis and VWI study was 18 months. Overall, 9/13 (69%) patients had vascular abnormalities. Circumferential large vessel enhancement was seen in 3/13 (23%) patients, whereas perforator vessel involvement was seen in 6/13 (46%) patients. Medullary and deep vein involvement was also seen in 6/13 patients. In addition, 7/13 (54%) patients had microhemorrhages in susceptibility-weighted imaging, and 4/13 (31%) had chronic infarcts. On biopsy, 5/6 cases showed perivascular granulomas with vessel wall involvement in all 5 cases. DISCUSSION: Our preliminary findings suggest that involvement of intracranial vascular structures may be a common finding in patients with NS and should be routinely looked for. These findings appear concordant with previously reported autopsy literature and need to be validated on a larger scale.

Advances in Multimodality Carotid Plaque Imaging: AJR Expert Panel Narrative Review.

Contemporary imaging methods provide detailed visualization of carotid athero-sclerotic plaque, enabling a major evolution of in vivo carotid plaque imaging evaluation. The degree of luminal stenosis in the carotid artery bifurcation, as assessed by ultrasound, has historically served as the primary imaging feature for determining ischemic stroke risk and the potential need for surgery. However, stroke risk may be more strongly driven by the presence of specific characteristics of vulnerable plaque, as visualized on CT and MRI, than by traditional ultrasound-based assessment of luminal narrowing. This review highlights six promising imaging-based plaque characteristics that harbor unique information regarding plaque vulnerability: maximum plaque thickness and volume, calcification, ulceration, intraplaque hemorrhage, lipid-rich necrotic core, and thin or ruptured fibrous cap. Increasing evidence supports the association of these plaque characteristics with risk of ischemic stroke, although these characteristics have varying suitability for clinical implementation. Key aspects of CT and MRI protocols for carotid plaque imaging are also considered. Practical next steps and hurdles are explored for implementing routine imaging assessment of these plaque characteristics in addition to, or even as replacement for, traditional assessment of the degree of vascular stenosis on ultrasound, in the identification of individuals at high risk of ischemic stroke.

Association between kidney disease measures and intracranial atherosclerosis: The ARIC study.

OBJECTIVE: To test the association between reduced kidney function (assessed by estimated glomerular filtration rate [eGFR] and cystatin C [CysC]) and kidney damage (assessed by urinary albumin-to-creatinine ratio [ACR]) and intracranial atherosclerotic disease (ICAD) by high-resolution vessel wall MRI (VWMRI) in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). METHODS: We conducted a cross-sectional analysis of ARIC participants with data on kidney measures and VWMRI in 2011 to 2013. The main outcomes were presence of intracranial plaques and luminal stenosis. Multivariable models were adjusted for demographics, cardiovascular risk factors, and use of antithrombotic medications. RESULTS: A total of 1,762 participants (mean ± SD age, 76.3 ± 5.3) were included. eGFR based on CysC (eGFRcysc) <60 mL/min/1.73 m2 (vs ≥60 mL/min/1.73 m2) was associated with plaque presence (adjusted odds ratio [OR] 1.29, 95% confidence interval [CI] 1.04-1.60), any detectable stenosis (adjusted OR 1.31, 95% CI 1.04-1.63), and >70% stenosis or occlusion (adjusted OR 2.15, 95% CI 1.32-3.50). Neither ACR nor CysC showed statistically significant associations with ICAD features in adjusted models. In adjusted multinomial models, participants with eGFRcysc <60 mL/min/1.73 m2 (vs ≥60 mL/min/1.73 m2) had an increased OR of 1.41 (95% CI 1.06-1.87) for having 1 plaque (vs none) but no significant increase for multiple plaques; ACR ≥30 was associated with moderate (50%-70%) stenosis (OR 2.01, 95% CI 1.14-3.55) vs absent or less than 50% stenosis. CONCLUSION: In community-dwelling older adults, reduced kidney function or elevated kidney damage was associated with ICAD measured by VWMRI. This finding may help to better identify a population at high risk for ICAD.

Racial Differences in Prevalence and Risk for Intracranial Atherosclerosis in a US Community-Based Population.

Importance: Intracranial atherosclerotic disease (ICAD) is an important cause of stroke; however, little is known about racial differences in ICAD prevalence and its risk factors. Objective: To determine racial differences in ICAD prevalence and the risk factors (both midlife and concurrent) associated with its development in a large, US community-based cohort. Design, Setting, and Participants: Analysis of 1752 black and white participants recruited from the Atherosclerosis Risk in Communities (ARIC) cohort study who underwent 3-dimensional intracranial vessel wall magnetic resonance imaging from October 18, 2011 to December 30, 2013; data analysis was performed from October 18, 2011 to May 13, 2015. Exposures: Midlife and concurrent cardiovascular risk factors. Main Outcomes and Measures: Intracranial plaque presence, size (maximum normalized wall index) and number were assessed by vessel wall magnetic resonance imaging. Midlife and concurrent vascular risk factor associations were determined by Poisson regression (plaque presence), negative binominal regression (plaque number), and linear regression (plaque size), and compared between races. Results: Of the 1752 study participants (mean [SD] age, 77.6 [5.3] years; range, 67-90 years), 1023 (58.4%) were women and 518 (29.6%) were black. Black men had the highest prevalence (50.9% vs 35.9% for black women, 35.5% for white men, and 30.2% for white women; P < .001) and the highest frequency (22.4% vs 12.1% for black women, 10.7% for white men, and 8.7% for white women; P < .01) of multiple plaques. Prevalence increased with age, reaching 50% before ages 68, 84, and 88 years in black men, white men, and white women, respectively (ICAD prevalence remained <50% in black women). Midlife hypertension and hyperlipidemia were associated with 29% (prevalence ratio [PR], 1.29; 95% CI, 1.08-1.55) and 18% (PR, 1.18; 95% CI, 0.98-1.42), respectively, increased ICAD prevalence with no significant differences between races. Midlife hypertension was also associated with larger plaques (1.11 higher mean maximum normalized wall index; 95% CI, 0.21-2.01). Midlife smoking and diabetes were associated with increased risk of ICAD in black individuals (102% [PR, 2.02; 95% CI, 1.12-3.63] and 57% [PR, 1.57; 95% CI, 1.13- 2.19], respectively), but not in white participants (P < .05 interaction by race). Conclusions and Relevance: The prevalence of ICAD was highest in black men. Midlife smoking and diabetes were strongly associated with late-life ICAD in blacks only, whereas midlife hypertension and hyperlipidemia were associated with late-life ICAD in both races. These associations may help to explain racial differences in US stroke rates and offer insight into preventive risk-factor management strategies.

Community-based statins and advanced carotid plaque: Role of CD163 positive macrophages in lipoprotein-associated phospholipase A2 activity in atherosclerotic plaque.

BACKGROUND AND AIMS: Lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzymatic inflammatory biomarker primarily bound to low-density lipoprotein cholesterol, is associated with an approximate twofold increased risk of cardiovascular disease and stroke. Despite indications that circulating Lp-PLA2 is sensitive to statins, it remains largely unknown whether statin usage exerts local effects on Lp-PLA2 expression at the site of atheromatous plaque. METHODS: Carotid plaques (n = 38) were prospectively collected from symptomatic (n = 18) and asymptomatic (n = 20) patients with (n = 20) or without (n = 18) documented statin history. In all cases, endarterectomy was performed where the primary stenosis was removed in an undisturbed manner. Serial cryosections of the presenting lesion were assessed histologically for macrophages, Lp-PLA2, and cell death (apoptotic index). RESULTS: Symptomatic lesions exhibited less calcification, with greater inflammation characterized by increased expression of CD68+ and CD163+ macrophage subsets, and Lp-PLA2. Symptomatic plaques also exhibited greater necrotic core area and increased apoptosis, as compared with asymptomatic lesions. In contrast, statin treatment did not appear to influence any of these parameters, except for the extent of apoptosis, which was less in statin treated as compared with statin naïve lesions. Overall, Lp-PLA2 expression correlated positively with necrotic core area, CD68+ and CD163+ macrophage area, and cell death. Finally, in vitro assays and dual immunofluorescence staining confirmed CD163-expressing monocytes/macrophages are also a major source of Lp-PLA2. CONCLUSIONS: Statin treatment has no effect on local atherosclerotic lesion Lp-PLA2 activity, therefore, the addition of anti-inflammatory treatments to further decrease macrophage Lp-PLA2 expression in atherosclerotic lesions may reduce lesional inflammation and cell death, and prevent necrotic core expansion and lesion progression.

Intracranial atherosclerosis and dementia: The Atherosclerosis Risk in Communities (ARIC) Study.

OBJECTIVE: To explore the association of intracranial atherosclerotic disease (ICAD) with mild cognitive impairment (MCI) and dementia. METHODS: From 2011 to 2013, 1,744 participants completed high-resolution vessel wall MRI from the population-based Atherosclerosis Risk in Communities Study by a sampling strategy that allowed weighting back to the cohort. We defined ICAD by plaque features (presence, territory, stenosis, number). Trained clinicians used an algorithm incorporating information from interviews and neuropsychological and neurologic examinations to adjudicate for MCI and dementia. We determined the relative prevalence ratio (RPR) of MCI or dementia after adjusting for risk factors at midlife using multinomial logistic regression. RESULTS: A total of 601 (34.5%) participants had MCI (mean age ± SD, 76.6 ± 5.2 years), 83 (4.8%) had dementia (79.1 ± 5.3 years), and 857 (49.1%) were current or former smokers. Anterior cerebral artery (ACA) plaque (adjusted RPR 3.81, 95% confidence interval [CI] 1.57-9.23), >2 territories with plaque (adjusted RPR 2.12, 95% CI 1.00-4.49), and presence of stenosis >50% (adjusted RPR 1.92, 95% CI 1.01-3.65) were associated with increased prevalence of dementia in separate models. Posterior cerebral artery plaque was associated with MCI but did not reach statistical significance for dementia (adjusted RPR MCI 1.43, 95% CI 1.04-1.98; adjusted RPR dementia 1.58, 95% CI 0.79-2.85). There were no associations with middle cerebral artery atherosclerotic lesions or cognitive impairment. Many participants had plaque in >1 territory (n = 291, 46%) and participants with ACA plaques (n = 69) had the greatest number of plaques in other territories (mean 6.0, SD 4.4). CONCLUSIONS: This study demonstrates associations between ICAD and clinical MCI and dementia.

Prevalence of Intracranial Atherosclerotic Stenosis Using High-Resolution Magnetic Resonance Angiography in the General Population: The Atherosclerosis Risk in Communities Study.

BACKGROUND AND PURPOSE: Intracranial atherosclerotic stenosis (ICAS) is a common cause of stroke, but little is known about its epidemiology. We studied the prevalence of ICAS and its association with vascular risk factors using high-resolution magnetic resonance angiography in a US cardiovascular cohort. METHODS: The Atherosclerosis Risk in Communities (ARIC) study recruited participants from 4 US communities from 1987 to 1989. Using stratified sampling, we selected 1980 participants from visit 5 (2011-2013) for high-resolution 3T-magnetic resonance angiography. All images were analyzed in a centralized laboratory, and ICAS was graded as: no stenosis, <50% stenosis, 50% to 69% stenosis, 70% to 99% stenosis, and complete occlusion. We calculated per-vessel and per-person prevalence of ICAS (weighted for n=6538 visit 5 participants) and also estimated the US prevalence. We used multivariable logistic regression to identify variables independently associated with ICAS. RESULTS: Subjects who had an adequate magnetic resonance angiography (n=1765) were aged 67 to 90 years, 41% were men, 70% were white, and 29% were black. ICAS was prevalent in 31% of participants and 9% had ICAS ≥50%. Estimated US prevalence of ICAS ≥50% for 65 to 90 years old was 8% for whites and 12% for blacks. Older age, black race, higher systolic blood pressure, and higher low-density lipoprotein cholesterol levels were associated with increased odds of ICAS, whereas higher levels of high-density lipoprotein cholesterol and use of cholesterol-lowering medications were associated with decreased odds of ICAS. Body mass index and smoking were not associated with ICAS. CONCLUSIONS: The prevalence of ICAS in older adults is high, and it could be a target for primary prevention of stroke and dementia in this population.

Severe Cerebral Vasospasm and Childhood Arterial Ischemic Stroke After Intrathecal Cytarabine.

We report on 2 patients who developed widespread cerebral vasospasm and arterial ischemic strokes (AIS) after application of intrathecal (IT) cytarabine. In a 3-year-old child with acute lymphoblastic leukemia (ALL), left leg weakness, hyperreflexia, and clonus were noted 4 days after her first dose of IT cytarabine during the induction phase of her chemotherapy. Cerebral MRI revealed multiple acute cerebral ischemic infarcts and widespread cerebral vasospasm. A 5-year-old girl complained of right arm and leg pain and began limping 11 days after IT cytarabine. Symptoms progressed to right dense hemiplegia, left gaze deviation, headache, and speech arrest. MRI revealed 2 large cortical areas of diffusion restriction in the right frontal and left parietal lobes. Cerebral magnetic resonance angiography (MRA) showed irregular narrowing affecting much of the intracranial arterial circulation. Although the first child fully recovered from her neurologic symptoms, the second patient had persistent hemiplegia on follow-up. Including this report, there are now 4 pediatric ALL cases of severe cerebral vasospasm and AIS in the context of IT cytarabine administration, strongly suggesting a true association. Differential diagnosis and management issues are discussed. Along with the more widespread use of MRI and MRA, the true frequency of this severe adverse effect will become clearer in future. For any child with neurologic symptoms within hours or days of receiving IT cytarabine, a low threshold for cerebral imaging with MRI and MRA is recommended.

Association of blood lactate with carotid atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study.

OBJECTIVES: Cardiovascular risk factors such as aging, smoking, and insulin resistance may lead to atherosclerosis through various mechanisms of which their association with mitochondrial dysfunction may be one of them. In order to examine this hypothesis, we assessed the association between elevated blood lactate, a marker of mitochondrial dysfunction, and carotid atherosclerosis. METHODS: From a total of 2066 participants from the Atherosclerosis Risk In Communities Carotid MRI study, 1496 were included for this analysis. Wall Thickness and Lipid core presence were measured using gadolinium-enhanced MRI. Blood lactate was categorized into quartiles (Q1: <5.9 mg/dl, Q2: 5.9-7.2 mg/dl, Q3: 7.3-9.2 mg/dl, and Q4: >9.2 mg/dl). RESULTS: Of the 1496 study participants, 763 (51%) were females, 296 (19.8%) African American, 539 (36%) obese and 308 (20.6%) had diabetes. There was a strong and graded association between lactate and wall thickness [Q1: 1.08 mm (95% CI: 1.01 mm-1.15 mm), Q2: 1.33 mm (95% CI: 1.19 mm-1.47 mm), Q3: 1.44 (95% CI: 1.34 mm-1.54 mm) and Q4: 1.62 (95% CI: 1.53 mm-1.71 mm); p for trend <0.001] after adjusting for age, gender, ethnicity, stature, body mass index (BMI), waist circumference, LDL, High sensitivity C reactive protein (HsCRP), statin use, thiazolidinedione use, hypertension, and diabetes. This association was attenuated, but still significant, after adjusting for a marker of insulin resistance, the triglyceride/HDL ratio, [Q1: 0.96 mm (95% CI: 0.82 mm-1.10 mm), Q2: 1.17 mm (95% CI: 1.08 mm-1.26 mm), Q3: 1.18 mm (95% CI: 1.07 mm-1.29 mm), Q4: 1.22 mm (95% CI: 1.13 mm-1.31 mm), p for linear trend 0.039]. There was no association of lactate with lipid core presence after adjustment for wall thickness. CONCLUSIONS: Blood lactate is associated with carotid atherosclerosis. Attenuation of the association with adjustment for triglyceride/HDL ratio, a marker of insulin resistance, suggests that lactate's association with carotid atherosclerosis may be related to insulin resistance.

Cholesterol is associated with the presence of a lipid core in carotid plaque of asymptomatic, young-to-middle-aged African Americans with and without HIV infection and cocaine use residing in inner-city Baltimore, Md., USA.

BACKGROUND: Stroke remains a leading cause of death in the United States. While stroke-related mortality in the USA has declined over the past decades, stroke death rates are still higher for blacks than for whites, even at younger ages. The purpose of this study was to estimate the frequency of a lipid core and explore risk factors for its presence in asymptomatic, young-to-middle-aged urban African American adults recruited from inner-city Baltimore, Md., USA. METHODS: Between August 28, 2003, and May 26, 2005, 198 African American participants aged 30-44 years from inner-city Baltimore, Md., were enrolled in an observational study of subclinical atherosclerosis related to HIV and cocaine use. In addition to clinical examinations and laboratory tests, B-mode ultrasound for intima-media thickness of the internal carotid arteries was performed. Among these 198, 52 were selected from the top 30th percentile of maximum carotid intima-media thickness by ultrasound, and high-resolution black blood MRI images were acquired through their carotid plaque before and after the intravenous administration of gadodiamide. Of these 52, 37 with maximum segmental thickness by MRI >1.0 mm were included in this study. Lumen and outer wall contours were defined using semiautomated analysis software. The frequency of a lipid core in carotid plaque was estimated and risk factors for lipid core presence were explored using logistic regression analysis. RESULTS: Of the 37 participants in this study, 12 (32.4%) were women. The mean age was 38.7 ± 4.9 years. A lipid core was present in 9 (17%) of the plaques. Seventy percent of the study participants had a history of cigarette smoking. The mean total cholesterol level was 176.1 ± 37.3 mg/dl, the mean systolic blood pressure was 113.1 ± 13.3 mm Hg, and the mean diastolic blood pressure was 78.9 ± 9.5 mm Hg. There were 5 participants with hypertension (13.5%). Twelve (32%) participants had a history of chronic cocaine use, and 23 (62%) were HIV positive. Among the factors investigated, including age, sex, blood pressure, cigarette smoking, C-reactive protein, fasting glucose, triglycerides, serum total cholesterol, coronary calcium, cocaine use, and HIV infection, only total cholesterol was significantly associated with the presence of a lipid core. CONCLUSIONS: This study revealed an unexpectedly high rate of the presence of lipid core in carotid plaque and highlights the importance of cholesterol lowering to prevent cerebrovascular disease in this population. Further population-based studies are warranted to confirm these results.

Association of combinations of lipid parameters with carotid intima-media thickness and coronary artery calcium in the MESA (Multi-Ethnic Study of Atherosclerosis).

OBJECTIVES: The purpose of this study was to determine the association of combinations of lipid parameters with subclinical atherosclerosis. BACKGROUND: Carotid intima-media thickness (CIMT) and coronary artery calcium (CAC) are significantly associated with incident cardiovascular disease (CVD). The association between common dyslipidemias (combined hyperlipidemia, [simple] hypercholesterolemia, dyslipidemia of metabolic syndrome, isolated low high-density lipoprotein cholesterol, and isolated hypertriglyceridemia) compared with normolipemia, and CIMT and CAC has not been previously examined. METHODS: The MESA (Multi-Ethnic Study of Atherosclerosis) participants were White, Chinese, African-American, or Hispanic adults without clinical CVD. Subjects with diabetes mellitus or who were receiving lipid-lowering therapy were excluded. Every participant was classified into only 1 of 6 groups defined by specific low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglyceride cut points. Multivariate linear and relative risk regressions evaluated the cross-sectional associations with CIMT and CAC after adjusting for CVD risk factors. Interactions with race, sex, and high-sensitivity C-reactive protein were evaluated for CIMT and CAC outcomes. RESULTS: Among 4,792 participants, only those with combined hyperlipidemia and hypercholesterolemia demonstrated both increased common CIMT (combined hyperlipidemia 0.048 mm thicker, 95% confidence interval [CI]: 0.016 to 0.080 mm; hypercholesterolemia 0.048 mm thicker, 95% CI: 0.029 to 0.067 mm) and internal CIMT (combined hyperlipidemia 0.120 mm thicker, 95% CI: 0.032 to 0.208 mm; and hypercholesterolemia 0.161 mm thicker, 95% CI: 0.098 to 0.223 mm) as well as increased risk for prevalent CAC (combined hyperlipidemia relative risk: 1.22, 95% CI: 1.08 to 1.38; hypercholesterolemia relative risk: 1.22, 95% CI: 1.11 to 1.34) compared with normolipemia. The interactions between lipid parameters and race, sex, or high-sensitivity C-reactive protein were not significant for any outcomes. CONCLUSIONS: Combined hyperlipidemia and simple hypercholesterolemia were associated with increased CIMT and prevalent CAC in a relatively healthy multiethnic population.

Association of circulating matrix metalloproteinases with carotid artery characteristics: the Atherosclerosis Risk in Communities Carotid MRI Study.

OBJECTIVE: To examine the relationship of plasma levels of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase 1 (TIMP-1) with carotid artery characteristics measured by MRI in a cross-sectional investigation among Atherosclerosis Risk in Communities Carotid MRI Study participants. METHODS AND RESULTS: A stratified random sample was recruited based on intima-media thickness from a previous ultrasonographic examination. A high-resolution gadolinium-enhanced MRI examination of the carotid artery was performed from 2004 to 2005 on 1901 Atherosclerosis Risk in Communities cohort participants. Multiple carotid wall characteristics, including wall thickness, lumen area, calcium area, lipid core, and fibrous cap measures, were evaluated for associations with plasma MMPs 1, 2, 3, 7, 8, and 9 and TIMP-1. Plasma MMPs 1, 3, and 7 were significantly higher among participants in the high intima-media thickness group compared with those in the low intima-media thickness group. The normalized wall index was independently associated with MMPs 3 and 7 and TIMP-1. MMP-7 was positively associated with carotid calcification. The mean fibrous cap thickness was significantly higher in individuals with elevated TIMP-1 levels. In addition, TIMP-1 was positively associated with measures of lipid core. CONCLUSION: Circulating levels of specific MMPs and TIMP-1 were associated with carotid wall remodeling and structural changes related to plaque burden in elderly participants.

Correlates of carotid plaque presence and composition as measured by MRI: the Atherosclerosis Risk in Communities Study.

BACKGROUND: The composition of atherosclerotic plaque affects the likelihood of an atherothrombotic event, but prospective studies relating risk factors to carotid wall and plaque characteristics measured by MRI are lacking. We hypothesized that traditional risk factors are predictors of carotid wall and plaque characteristics measured 2 decades later. METHODS AND RESULTS: A high-resolution contrast-enhanced MRI examination of the carotid artery was performed in 1769 participants. Measures of carotid wall volume and maximum thickness; lipid core presence, volume and maximum area; and fibrous cap thickness were performed centrally. The sample was, on average, 70 years of age, 57% female, 81% white, and 19% black. Greater age, total and low-density lipoprotein cholesterol, male sex, white race, diabetes, hypertension, and smoking as measured at baseline were all significant predictors of increased wall volume and maximum wall thickness 18 years later. An analysis of lipid core was restricted to the 1180 participants with maximum wall thickness >/=1.5 mm. Lipid core was observed in 569 individuals (weighted percentage, 42%). Baseline age and total and low-density lipoprotein cholesterol were predictors of presence of lipid core 18 years later; however, these relationships were attenuated after adjustment for wall thickness. Concurrently measured low-density lipoprotein cholesterol was associated with greater lipid core volume, independent of wall thickness. Concurrently measured glucose and body mass index were inversely associated fibrous cap thickness. CONCLUSIONS: Traditional atherosclerosis risk factors are related to increased wall volume and wall thickness 2 decades later, but they do not discriminate characteristics of plaque composition (core and cap) independent of wall size.

Cystatin C and carotid intima-media thickness in asymptomatic adults: the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Persons with early kidney disease have an increased risk of cardiovascular events and mortality, but the importance of accelerated atherosclerosis in promoting these outcomes is unclear. We therefore explored whether serum cystatin C level is associated with carotid intima-media thickness (IMT) in ambulatory adults without clinical heart disease. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: We evaluated 6,557 ethnically diverse persons free of clinical cardiovascular disease aged 45 to 84 years at the baseline visit of the Multi-Ethnic Study of Atherosclerosis. PREDICTORS: Kidney function was estimated by using 2 methods: serum cystatin C level and estimated glomerular filtration rate, based on creatinine and cystatin C levels. OUTCOMES & MEASUREMENTS: Study outcomes were internal and common carotid IMT, measured by using high-resolution B-mode ultrasound. Multivariate linear and logistic regressions were used to evaluate the independent association of kidney function with carotid IMT. RESULTS: In unadjusted linear analysis, each SD (0.23 mg/L) greater cystatin C level was associated with 0.091-mm greater internal carotid IMT (P < 0.001), but this association was diminished by 70% after adjustment for age, sex, and race/ethnicity (0.027 mm; P < 0.001) and was no longer significant after adjustment for cardiovascular risk factors (0.005 mm; P = 0.5). Similarly, the strong unadjusted associations of cystatin C level with common carotid IMT disappeared after adjustment. Chronic kidney disease, defined by using either creatinine level or cystatin C-based estimated glomerular filtration rate less than 60 mL/min/1.73 m(2), had no independent association with internal and common carotid IMT. LIMITATIONS: There were few participants with severe kidney disease. CONCLUSIONS: Cystatin C level had no independent association with carotid IMT in a population free of clinical heart disease. This observation suggests that accelerated atherosclerosis is unlikely to be the primary mechanism explaining the independent association of cystatin C level with cardiovascular risk.

Risk factor associations with the presence of a lipid core in carotid plaque of asymptomatic individuals using high-resolution MRI: the multi-ethnic study of atherosclerosis (MESA).

BACKGROUND AND PURPOSE: Atheroma vulnerability to rupture is increased in the presence of a large lipid core. Factors associated with a lipid core in the general population have not been studied. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) is a multicenter cohort study of individuals free of clinical cardiovascular disease designed to include a high proportion of ethnic minorities. We selected MESA participants from the top 15th percentile of maximum carotid intima media thickness by ultrasound and acquired high-resolution black blood MRI images through their carotid plaque before and after the intravenous administration of gadodiamide (0.1 mmol/kg). Lumen and outer wall contours were defined using semiautomated analysis software. We analyzed only plaques with a maximum thickness >or=1.5 mm by MRI (n=214) and assessed cross-sectional risk factor associations with lipid core presence by multivariable logistic regression. RESULTS: A lipid core was present in 151 (71%) of the plaques. After controlling for age, ethnicity, sex, maximum arterial wall thickness, hypertension, cigarette smoking, diabetes, and C-reactive protein, compared with participants in the lowest tertile of total plasma cholesterol, the ORs of having a lipid core for participants in the middle and highest tertiles were 2.76 (95% CI: 1.01 to 7.51) and 4.63 (95% CI: 1.56 to 13.75), respectively. None of the other risk factors was associated with lipid core. CONCLUSIONS: In persons with thickened carotid walls, plasma total cholesterol, but not other established coronary heart disease risk factors, is strongly associated with lipid core presence by MRI. High total cholesterol may be associated with rupture proneness of atherosclerotic lesions in the general population.

Correlation of hindbrain CSF flow and outcome after surgical decompression for Chiari I malformation.

OBJECTIVE: Many patients with symptomatic Chiari I malformation experience symptom recurrence after surgical decompression. Improved radiographic predictors of outcome are needed to better select patients most likely to benefit from surgical intervention. We examined whether ventral or dorsal cerebrospinal fluid (CSF) flow dynamics assessed by cine phase-contrast MRI scans could predict response to posterior fossa decompression for Chiari I malformation. METHODS: Forty-four consecutive pediatric patients undergoing pre-operative cine phase-contrast MRI followed by posterior fossa decompression for Chiari I malformation were retrospectively reviewed. The association of pre-operative ventral or dorsal CSF flow abnormalities at the foramen magnum with symptom-free survival after surgical decompression was assessed via Kaplan-Meier plots and log-rank analysis. RESULTS: Mean +/- SD age at time of surgery was 8 +/- 6 years. Sixteen (36%) patients demonstrated decreased CSF flow dorsal to the cervico-medullary brainstem alone. Fourteen (32%) patients demonstrated abnormal CSF flow both ventral and dorsal to the cervico-medullary brainstem. Fourteen (32%) had normal hindbrain CSF flow. Overall, 13 (30%) patients experienced some degree of symptom recurrence by last follow-up (mean of 27 +/- 16 months post-operatively). Symptom recurrence did not differ as a function of degree of tonsilar ectopia (p = 0.55). Abnormal CSF flow dorsal to the cervico-medullary brainstem was not associated with symptom recurrence after surgical decompression (p = 0.10). However, combined pre-operative ventral and dorsal CSF flow abnormality was associated with a significant reduction (2.6-fold) in the risk of post-operative symptom recurrence (p < 0.05). Only one patient (7%) with pre-operative ventral and dorsal CSF flow pathology experienced symptom recurrence 3.5 years after surgery versus 12 (40%) patients without ventral CSF flow pathology. There were otherwise no differences in baseline clinical, radiological, or operative variables between patients with abnormal versus normal ventral CSF flow. CONCLUSION: The presence of decreased CSF flow both ventral and dorsal to the cervico-medullary brainstem was associated with improved response to hindbrain decompression for Chiari I malformation in children. Cine phase-contrast MRI may be a useful tool for surgical risk stratification and identifying patients that may be optimal surgical candidates. Combined ventral and dorsal hindbrain CSF flow pathology may better predict response to posterior fossa decompression compared to dorsal CSF flow pathology alone.