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1.  Errors in the estimation of wall shear stress by maximum Doppler velocity 
Atherosclerosis  2013;227(2):259-266.
Wall shear stress (WSS) is an important parameter with links to vascular (dys)function. Difficult to measure directly, WSS is often inferred from maximum spectral Doppler velocity (Vmax) by assuming fully-developed flow, which is valid only if the vessel is long and straight. Motivated by evidence that even slight/local curvatures in the nominally straight common carotid artery (CCA) prevent flow from fully developing, we investigated the effects of velocity profile skewing on Vmax-derived WSS.
Velocity profiles, representing different degrees of skewing, were extracted from the CCA of image-based computational fluid dynamics (CFD) simulations carried out as part of the VALIDATE study. Maximum velocities were calculated from idealized sample volumes and used to estimate WSS via fully-developed (Poiseuille or Womersley) velocity profiles, for comparison with the actual (i.e. CFD-derived) WSS.
For cycle-averaged WSS, mild velocity profile skewing caused ±25% errors by assuming Poiseuille or Womersley profiles, while severe skewing caused a median error of 30% (maximum 55%). Peak systolic WSS was underestimated by ~50% irrespective of skewing with Poiseuille; using a Womersley profile removed this bias, but ±30% errors remained. Errors were greatest in late systole, when skewing was most pronounced. Skewing also introduced large circumferential WSS variations: ±60%, and up to ±100%, of the circumferentially averaged value.
Vmax-derived WSS may be prone to substantial variable errors related to velocity profile skewing, and cannot detect possibly large circumferential WSS variations. Caution should be exercised when making assumptions about velocity profile shape to calculate WSS, even in vessels usually considered long and straight.
PMCID: PMC4329978  PMID: 23398945
Doppler ultrasound; wall shear stress; atherosclerosis; computational fluid dynamics; common carotid artery; brachial artery; femoral artery
2.  Carotid Bifurcation Geometry is an Independent Predictor of Early Wall Thickening at the Carotid Bulb 
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.
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 non-stenotic cases having sufficient-quality angiography for 3D analysis. Group 2 (N=346) excluded cases from Group 1 having common and internal carotid artery (ICA) 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.
Multiple linear regressions showed that for Group 3 bifurcation flare and proximal curvature were independent predictors of ICA wall thickness, consistent with their previously-demonstrated roles in predicting disturbed flow. For the broadest Group 1, flare was an independent predictor of ICA wall thickness, but with a sign change in regression coefficient reflecting effects of wall thickening on lumen geometry.
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.
PMCID: PMC4321819  PMID: 24357655
Atherosclerosis; Carotid Artery; Geometry; MRI; Wall Shear Stress
3.  Association of blood lactate with carotid atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study 
Atherosclerosis  2013;228(1):249-255.
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.
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 to 7.2mg/dl, Q3: 7.3 to 9.2 mg/dl, and Q4: >9.2 mg/dl).
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, thiazolodinedione 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.
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.
PMCID: PMC3657708  PMID: 23510829
atherosclerosis; carotid arteries; plaque; epidemiology; lactate
4.  Impact of T2 Decay on Carotid Artery Wall Thickness Measurements 
To investigate the impact of T2 relaxation of the carotid wall on measurements of its thickness.
Materials and Methods
The common carotid artery wall was imaged using a spin echo sequence acquired at four echo times (17 ms to 68 ms) in 65 participants as part of VALIDATE study. Images were acquired transverse to the artery 1.5 cm proximal to the flow divider. Mean wall thickness, mean wall signal intensity, lumen area, and outer wall area were measured for each echo. Contours were also traced on the image from the fourth echo and then propagated to the images from the preceding echoes. This was repeated using the image from the first echo. Mean wall signal intensity measurements at the four echo times were fit to a mono-exponential decay curve to derive the mean T2 relaxation time for each set of contours.
Mean wall thickness decreased with increasing echo time, with an average thickness reduction of 8.6% between images acquired at the first and last echo times (TE) (0.93 mm at TE 17 ms versus 0.85 mm at TE 68 ms, P < 0.001). Average T2 relaxation time of the carotid wall decreased by 3% when the smaller contours from the last echo were used, which excluded the outer-most layer (54.3 ± 7.6 ms versus 52.7 ± 6.6 ms, P = 0.03).
Carotid wall thickness measurements decrease with echo time as expected by the fast T2 relaxation time of the outer-most layer, namely the adventitia. A short echo time is needed for thickness measurements to include adventitia, which plays an important role in plaque development.
PMCID: PMC3906925  PMID: 23172683
atherosclerosis; carotid artery; T2 relaxation; contrast-enhanced MRI
5.  Association of SERPINA9 gene variants with carotid artery atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study 
The SNP rs11628722 in the SERPINA9 gene was previously associated with incident ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. Centerin, the protein encoded by SERPINA9, is involved in maturation and maintenance of naïve B cells, which play a role in atherogenesis. We investigated whether 21 tag SNPs in the SERPINA9 gene are associated with features of carotid artery atherosclerotic plaque measured by magnetic resonance imaging (MRI). Carotid MRI data were obtained from 1,282 European Americans and 341 African Americans of the ARIC Carotid MRI study, which recruited participants from ARIC by a stratified sampling plan that over-sampled participants with carotid intima-media thickening. Five MRI measures, focused on carotid wall volume, wall thickness, and lipid core, were analyzed. Genetic associations between the MRI measurements and each of the 21 SNPs were analyzed in linear regression models with adjustment for sample weights and traditional risk factors. Rs11628722 was tested a priori. In African Americans, rs11628722 was significantly associated with carotid wall volume (p < 0.05). Among the other 20 SNPs, adjusted for multiple testing, rs4905204, which encodes an Ala to Val amino acid change, was significantly associated with maximum wall thickness (p < 0.000625) and suggestively associated with total wall volume (p < 0.0026) in European Americans. In conclusion, SNPs in the SERPINA9 gene showed race-specific associations with characteristics of carotid atherosclerotic plaques. Replications in other populations are needed to validate findings of this study and to establish the SERPINA9 gene as a candidate in the etiology of carotid atherosclerosis.
PMCID: PMC3852645  PMID: 24319541
SERPINA9 gene; carotid atherosclerosis; MRI; genetic association
6.  Improved Prediction of Disturbed Flow via Hemodynamically-Inspired Geometric Variables 
Journal of Biomechanics  2012;45(9):1632-1637.
Arterial geometry has long been considered a pragmatic alternative for inferring arterial flow disturbances and their impact on the natural history and treatment of vascular diseases. Traditionally, definition of geometric variables is based on convenient shape descriptors, with only superficial consideration of their influence on flow and wall shear stress patterns. In the present study we demonstrate that a more studied consideration of the actual (c.f., nominal) local hemodynamics can lead to substantial improvements in the prediction of disturbed flow by geometry. Starting from a well-characterized computational fluid dynamics (CFD) dataset of 50 normal carotid bifurcations, we observed that disturbed flow tended to be confined proximal to the flow divider, whereas geometric variables previously shown to be significant predictors of disturbed flow included features distal to the flow divider in their definitions. Flaring of the bifurcation leading to flow separation was redefined as the maximum relative expansion of the common carotid artery (CCA), proximal to the flow divider. The beneficial effect of primary curvature on flow inertia, via suppression of flow separation, was characterized by the in-plane tortuosity of CCA as it enters the flare region. Multiple linear regressions of these redefined geometric variables against various metrics of disturbed flow revealed R2 values approaching 0.6, better than the roughly 0.3 achieved using the conventional shape-based variables, while maintaining their demonstrated real-world reproducibility. Such a hemodynamically-inspired approach to the definition of geometric variables may reap benefits for other applications where geometry is used as a surrogate marker of local hemodynamics.
PMCID: PMC3371282  PMID: 22552156
atherosclerosis; geometric risk; hemodynamics; area ratio; tortuosity
7.  Sex-Specific Association of Age with Carotid Artery Distensibility: Multi-Ethnic Study of Atherosclerosis 
Journal of Women's Health  2012;21(5):516-520.
Older women have a higher prevalence of systolic hypertension than do men; however, whether or not this relates to arterial properties, such as distensibility coefficient (DC), is not known. We examined whether the association of carotid artery DC with age differed by sex in the Multi-Ethnic Study of Atherosclerosis (MESA).
B-mode ultrasound-measured carotid diameters and brachial pressures were obtained from 6359 participants (53% female, 38% white, 12% Chinese, 27% black, 22% Hispanic, aged 45–85 years) of the MESA baseline examination. The within-individual slopes of 2log(diameter) vs. blood pressure fit using mixed models (MM) are interpreted as the DC, and interaction terms are interpreted as differences in DC. The MM calculation allows for correction of the confounding caused by the association of age, sex, and race with blood pressure, the denominator in the calculation of DC.
DC was associated with age, sex, and race (all p<0.001). Women had a greater age-related lowering of DC compared to men (2.52×10−5 vs. 2.16×10−5/mm Hg lower DC per year of age, p=0.006). Mean diameter of carotid arteries was greater with age (p<0.001); this association also was significantly stronger in women compared to men (0.24% vs. 0.14% larger mean carotid diameter per year of age, p<0.001).
Greater stiffening and enlargement of arteries are seen in older women compared to older men. This implies that the afterload on the heart of older women is likely to be greater than that among older men.
PMCID: PMC3353825  PMID: 22393881
8.  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 
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.
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.
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.
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.
PMCID: PMC3355645  PMID: 22327293
Carotid artery; Cholesterol; Lipid core; Risk factors; Stroke
9.  Relation of Cholesterol and Lipoprotein Parameters with Carotid Artery Plaque Characteristics: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study 
Atherosclerosis  2011;219(2):596-602.
There is a paucity of data regarding relations of apolipoproteins (apolipoprotein B [ApoB] and apolipoprotein A-1 [Apo A-1]), lipoprotein particle measures (low-density lipoprotein particle concentration [LDLp] and high-density lipoprotein particle concentration [HDLp]), and lipoprotein cholesterol measures (low-density lipoprotein cholesterol [LDL-C], non–high-density lipoprotein cholesterol [non– HDL-C], and high-density lipoprotein cholesterol [HDL-C]) with atherosclerotic plaque burden, plaque eccentricity, and lipid-rich core presence as a marker of high-risk plaques.
Carotid artery magnetic resonance imaging was performed in 1,670 Atherosclerosis Risk in Communities study participants. Vessel wall and lipid cores were measured; normalized wall index (NWI), standard deviation (SD) of wall thickness (measure of plaque eccentricity) were calculated; and lipid cores were detected in vessels with ≥1.5 mm thickness. Fasting concentrations of cholesterol, ApoB and Apo A-1, and LDLp and HDLp were measured.
Measures of plaque burden (carotid wall volume, wall thickness, and NWI) were positively associated with atherogenic cholesterol and lipoproteins (p<0.05 for total cholesterol, LDL-C, non–HDL-C, ApoB, and LDLp), but not with HDL-C, Apo A-1, or HDLp. SD of wall thickness was associated with total cholesterol (p 0.01) and non-HDL-C (p 0.02). Although measures of atherogenic or anti-atherogenic cholesterol or lipoprotein were not individually associated with detection of a lipid-rich core, their ratios (total cholesterol/HDL-C, non–HDL-C/ HDL-C, and LDLp/HDLp) were associated with lipid-rich core presence (p≤0.05).
Extent of carotid atherosclerosis is associated with atherogenic cholesterol and lipoproteins. Atherogenic/anti-atherogenic cholesterol or particle ratios were associated with presence of a detectable lipid-rich core.
PMCID: PMC3226845  PMID: 21868017
atherogenic lipoproteins; anti-atherogenic lipoproteins; plaque burden; lipid-rich necrotic core
10.  On the Shape of the Common Carotid Artery, with Implications for Blood Velocity Profiles 
Physiological measurement  2011;32(12):1885-1897.
Clinical and engineering studies typically assume that the common carotid artery (CCA) is straight enough to assume fully developed flow, yet recent studies have demonstrated the presence of skewed velocity profiles. Towards elucidating the influence of mild vascular curvatures on blood flow patterns and atherosclerosis, the present study aimed to characterize the three-dimensional shape of the human CCA. The left and right carotid arteries of 28 participants (62±13 years) in the VALIDATE (Vascular Aging – The Link that Bridges Age to Atherosclerosis) study were digitally segmented from 3D contrast-enhanced magnetic resonance angiograms, from the aortic arch to the carotid bifurcation. Each CCA was divided into nominal cervical and thoracic segments, for which curvatures were estimated by least squares fitting of the respective centerlines to planar arcs. The cervical CCA had mean radius of curvature of 127 mm, corresponding to a mean lumen:curvature radius ratio of 1:50. The thoracic CCA was significantly more curved at 1:16, with the plane of curvature tilted by a mean angle of 25 degrees and rotated close to 90 degrees with respect to that of the cervical CCA. The left CCA was significantly longer and slightly more curved than the right CCA, and there was a weak but significant increase in CCA curvature with age. Computational fluid dynamic (CFD) simulations carried out for idealized CCA geometries derived from these and other measured geometric parameters demonstrated that mild cervical curvature is sufficient to prevent flow from fully developing, independent of the degree of thoracic curvature. These findings reinforce the idea that fully-developed flow may be the exception rather than the rule for the CCA, and perhaps other nominally long and straight vessels.
PMCID: PMC3494738  PMID: 22031538
carotid artery; blood velocity profile; vascular geometry; Doppler ultrasound
11.  Association of Scavenger Receptor Class B Type I Polymorphisms with Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis 
Little is known regarding the association of scavenger receptor class B type I (SCARB1) single nucleotide polymorphisms (SNPs) and subclinical atherosclerosis (SCA), particularly in subjects of different racial/ethnic backgrounds. We examined this relationship in the Multi-Ethnic Study of Atherosclerosis (MESA).
Methods and Results
Forty-three SCARB1 tagging SNPs were genotyped. Baseline examinations included fasting lipids and SCA phenotypes (coronary artery calcium [CAC], and common and internal carotid artery thickness [CCIMT and ICIMT]). Examining SNP associations with different SCA phenotypes across multiple racial/ethnic groups with adjustment for multiple covariates, we found the C allele of SNP rs10846744 was associated with higher CCIMT in African American (P=0.03), Chinese (P=0.02), European American (P=0.05), and Hispanic participants (P=0.03), and was strongly associated in pooled analyses (P=0.0002). The results also showed that the association of this SNP with CCIMT was independent of lipids and other well-established cardiovascular risk factors. Stratifying by sex, there appeared to be a strong association of rs10846744 with CCIMT in females, but no genotype-sex interactions were observed.
Variation in SCARB1 at rs10846744 was significantly associated with CCIMT across racial/ethnic groups in MESA.
PMCID: PMC3359098  PMID: 20160195
genetics; atherosclerosis; cholesterol; lipids; prospective cohort study; genetic association
12.  Association of the platelet GPIIb/IIIa polymorphism with atherosclerotic plaque morphology. The Atherosclerosis Risk in Communities (ARIC) Study 
Atherosclerosis  2011;216(1):151-156.
Platelet activation and aggregation play an important role in the pathogenesis of cardiovascular disease. We examined the association of a single nucleotide polymorphism (SNP) in the GPIIIa platelet glycoprotein (Leu33Pro) with carotid artery plaque morphology and with expression of platelet markers using data from the Atherosclerosis Risk in Communities (ARIC) Carotid MRI study.
The study sample consisted of 1,202 Caucasian members of the ARIC study cohort recruited in 2004-2005 to participate in the Carotid MRI Substudy under stratified sampling based on maximum carotid artery wall thickness. The Leu33Pro polymorphism was identified as SNP rs5918 in the ITGB3 gene. Plaque visualization was accomplished with contrast enhanced MRI examination of the thickest segment of the carotid artery. Expression of platelet markers was measured using fasting whole blood flow cytometry.
This cross-sectional analysis based on age and gender adjusted weighted linear regression models suggests that those homozygous for the Leu33Pro risk allele (C) have decreased mean and minimum fibrous cap thickness. We did not observe differences in plaque lipid volume or maximum carotid artery wall thickness across SNP rs5918 genotypes. Carriers of the Leu33Pro polymorphism, as compared to major allele homozygotes, had greater percent of platelets expressing P-selectin, a platelet glycoprotein indicating activation status. Prevalent coronary heart disease did not affect estimates of fibrous cap thickness or of platelet activation.
Our results suggest that individuals with Leu33Pro polymorphism of the GPIIIa glycoprotein may be predisposed to increased risk of atherosclerotic plaque rupture.
PMCID: PMC3089705  PMID: 21353223
plaque; platelets; atherosclerosis; coronary heart disease; Magnetic Resonance Imaging (MRI)
To demonstrate the feasibility of rapid and reliable geometric characterization of normal carotid bifurcation geometry from routine three-dimensional (3D) contrast-enhanced MR angiograms.
Materials and Methods
Repeat scans of 61 participants, acquired as part of the Atherosclerosis Risk in Communities (ARIC) Carotid MRI substudy, were digitally segmented using automated 3D level set methods, relying on an operator only to select the branch end points and thresholds for the 3D lumen surface initialization. Geometric factors characterizing the 3D lumen geometry were then extracted automatically.
Of 122 scans, 117 could be segmented within five minutes each, with 40% being of sufficiently high quality to require less than two minutes each. Irrespective of scan quality, geometric factors were found to be highly reproducible, with intraclass correlation coefficients (ICC) typically above 0.9. The reconstructed lumen surfaces were reproducible to < 0.3 mm on average, comparable to previous MRI-based reproducibility studies. Owing to the automated nature of the analysis, operator reliability was near-perfect (ICC > 0.99), with lumen surface differences < 0.1 mm.
The 3D geometry of the carotid bifurcation can be characterized rapidly and with a high degree of consistency, even for suboptimal image qualities. This bodes well for large-scale retrospective or prospective studies aimed at teasing out the influence of local vs. systemic risk factors for early atherosclerosis.
PMCID: PMC3059724  PMID: 21274992
magnetic resonance angiography; carotid bifurcation; reproducibility; geometric risk factors; atherosclerosis
14.  Relationship between circulating levels of RANTES (regulated on activation, normal T-cell expressed, and secreted) and carotid plaque characteristics: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study 
European Heart Journal  2010;32(4):459-468.
To assess the relationship between regulated on activation, normal T-cell expressed and secreted (RANTES) and carotid atherosclerotic plaque burden and plaque characteristics.
Methods and results
Gadolinium-enhanced magnetic resonance imaging (MRI) of the carotid artery was performed in 1901 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Wall thickness and volume, lipid-core volume, and fibrous cap thickness (by MRI) and plasma RANTES levels (by ELISA) were measured. Regression analysis was performed to study the associations between MRI variables and RANTES. Among 1769 inclusive participants, multivariable regression analysis revealed that total wall volume [beta-coefficient (β) = 0.09, P = 0.008], maximum wall thickness (β = 0.08, P = 0.01), vessel wall area (β = 0.07, P = 0.02), mean minimum fibrous cap thickness (β = 0.11, P = 0.03), and high-sensitivity C-reactive protein (β = 0.09, P = 0.01) were positively associated with RANTES. Total lipid-core volume showed positive association in unadjusted models (β = 0.18, P = 0.02), but not in fully adjusted models (β = 0.13, P = 0.09). RANTES levels were highest in Caucasian females followed by Caucasian males, African-American females, and African-American males (P < 0.0001). Statin use attenuated the relationship between RANTES and measures of plaque burden.
Positive associations between RANTES and carotid wall thickness and lipid-core volume (in univariate analysis) suggest that higher RANTES levels may be associated with extent of carotid atherosclerosis and high-risk plaques. Associations between fibrous cap thickness and RANTES likely reflect the lower reliability estimate for fibrous cap measurements compared with wall volume or lipid-core volume measurements. Statin use may modify the association between RANTES and carotid atherosclerosis. Furthermore, RANTES levels vary by race.
PMCID: PMC3106284  PMID: 20943669
Atherosclerosis; Magnetic resonance imaging; Inflammation; RANTES; High-sensitivity C-reactive protein
15.  Carotid Bifurcation Hemodynamics In Older Adults: Effect Of Measured vs. Assumed Flow Waveform 
Recent work has illuminated differences in carotid artery blood flow rate dynamics of older vs. young adults. To what degree flow waveform shape, and indeed the use of measured vs. assumed flow rates, affects simulated hemodynamics of older adult carotid bifurcations has not been elucidated. Image-based computational fluid dynamics models of N=9 normal, older adult carotid bifurcations were reconstructed from magnetic resonance angiography. Subject-specific hemodynamics were computed by imposing each individual’s inlet and outlet flow rates measured by cine phase contrast MRI, or by imposing characteristic young and older adult flow waveform shapes adjusted to cycle-averaged flow rates measured or allometrically-scaled to the inlet and outlet areas. Despite appreciable differences in the measured vs. assumed flow conditions, the locations and extents of low wall shear stress (WSS) and elevated relative residence time (RRT) were broadly consistent; however, the extent of elevated oscillatory shear index (OSI) was substantially underestimated, more by the use of assumed cycle-averaged flow rates than the assumed flow waveform shape. For studies of individual vessels, use of a characteristic flow waveform shape is likely sufficient, with some benefit offered by scaling to measured cycle-averaged flow rates. For larger-scale studies of many vessels, ranking of cases according to presumed hemodynamic or geometric risk is robust to the assumed flow conditions.
PMCID: PMC2943211  PMID: 20590284
atherosclerosis; waveform; stroke; hemodynamics; imaging; CFD; carotid artery
16.  Association of Circulating Matrix Metalloproteinases with Carotid Artery Characteristics: The ARIC Carotid MRI Study 
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 magnetic resonance imaging (MRI) in a cross-sectional investigation among Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study participants.
Methods and Results
A stratified random sample was recruited based on intima-media thickness (IMT) from a previous ultrasound examination. A high-resolution gadolinium-enhanced MRI exam of the carotid artery was performed in 2004–2005 on 1,901 ARIC 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 MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9 and TIMP-1.
Plasma MMP-1, MMP-3, and MMP-7 were significantly higher among participants in the high IMT group compared to those in the low IMT group. Normalized wall index was independently associated with MMP-3, MMP-7, and TIMP-1. MMP-7 was positively associated with carotid calcification. 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.
Circulating levels of specific MMPs and TIMP-1 were associated with carotid wall remodeling and structural changes related to plaque burden in the elderly.
PMCID: PMC2860383  PMID: 20167662
Atherosclerosis; Carotid; MRI; MMP; TIMP-1; IMT; Luminex; Multianalyte Profiling
17.  MMP2 Genetic Variation Is Associated With Measures of Fibrous Cap Thickness: The Atherosclerosis Risk in Communities Carotid MRI Study 
Atherosclerosis  2009;210(1):188-193.
Genetic variation in matrix metalloproteinase (MMP) promoter regions alters the transcriptional activity of MMPs and has been consistently associated with CHD, presumably through plaque degradation and remodeling. We examined the association of MMP promoter variation with multiple plaque characteristics measured by gadolinium-enhanced MRI among 1,700 participants in the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study.
For the analyses presented here, 1,700 participants of the biracial ARIC Carotid MRI Study (~1,000 participants with thick carotid artery walls and ~700 randomly sampled participants) were evaluated for associations of MMP genetic variation with multiple plaque characteristics, including carotid artery wall thickness, lipid core and fibrous cap measures. MRI studies were performed on a 1.5T scanner equipped with a bilateral 4-element phased array carotid coil.
Fifty-one percent of the participants were female, 77% white, 23% African American, and the mean age was 70 years. MMP2 C-1306T variant genotypes (CT+TT) were significantly associated with higher cap thickness measures, but not with wall thickness or lipid core measures. Individuals with the CC genotype had approximately 0.1 mm thinner cap thickness compared to those carrying a T allele (p=0.02).
Genetic variation within the MMP2 promoter region was associated with cap thickness and therefore may influence the role of MMP2 in plaque vulnerability.
PMCID: PMC2862087  PMID: 20064641
Atherosclerosis; Carotid MRI; Vulnerable Plaque; MMP; Genetics
18.  Characterization of volumetric flow rate waveforms at the carotid bifurcations of older adults 
Physiological measurement  2010;31(3):291-302.
While it is widely appreciated that volumetric blood flow rate (VFR) dynamics change with age, there has been no detailed characterization of the typical shape of carotid bifurcation VFR waveforms of older adults. Towards this end, retrospectively gated phase contrast magnetic resonance imaging was used to measure time-resolved VFR waveforms proximal and distal to the carotid bifurcations of 94 older adults (age 68±8 yrs) with little or no carotid artery disease, recruited from the BLSA cohort of the VALIDATE study of factors in vascular aging. Timings and amplitudes of well-defined feature points from these waveforms were extracted automatically, and averaged to produce representative common, internal and external carotid artery (CCA, ICA and ECA) waveform shapes. Relative to young adults, waveforms from older adults were found to exhibit a significantly augmented secondary peak during late systole, resulting in significantly higher resistance index (RI) and flow augmentation index (FAI). Cycle-averaged VFR at the CCA, ICA and ECA were 389±74, 245±61 and 125±49 mL min−1, respectively, reflecting a significant cycle-averaged outflow deficit of 5%, which peaked at around 10% during systole. A small but significant mean delay of 13 ms between arrivals of ICA versus CCA/ECA peak VFR suggested differential compliance of these vessels. Sex and age differences in waveform shape were also noted. The characteristic waveforms presented here may serve as a convenient baseline for studies of VFR waveform dynamics or as suitable boundary conditions for models of blood flow at the carotid arteries of older adults.
PMCID: PMC2943236  PMID: 20086276
volumetric flow rate; carotid bifurcation; magnetic resonance imaging; human studies; augmentation index
19.  Cystatin C and Carotid Intima-Media Thickness in Asymptomatic Adults: The Multi-Ethnic Study of Atherosclerosis (MESA) 
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.
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.
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 m2, had no independent association with internal and common carotid IMT.
There were few participants with severe kidney disease.
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.
PMCID: PMC3046734  PMID: 18823684
Cystatin C; intima-media thickness (IMT); atherosclerosis; cardiovascular diseases; kidney
21.  MRI Measurements of Carotid Plaque in the Atherosclerosis Risk in Communities (ARIC) Study: Methods, Reliability and Descriptive Statistics 
To measure carotid plaque components using MRI and estimate reliability in the population-based Atherosclerosis Risk in Communities (ARIC) study.
Materials and Methods
Contrast-enhanced high-resolution (0.51 × 0.58 × 2 mm3) MRI images were acquired through internal (ICA) and common carotid arteries (CCA) of 2066 ARIC participants at four sites. Sixty-one exams were repeated and 164 pairs had repeated interpretations. Plaque component thicknesses, areas and volumes over eight slices (1.6-cm segment) were measured. Intraplaque hemorrhage was recorded. Reliability was evaluated by intraclass correlations and κ statistics.
There were 1769 successful MRI exams (mean age 71 years; 57% females; 81% white; 19% African-Americans). Repeat scan reliability was highest for CCA lumen area (0.94) and maximum wall thickness (0.89), ICA lumen area (0.89) and maximum wall thickness (0.77) and total wall volume (0.79), and lowest for small structures—core volume (0.30) and mean cap thickness (0.38). Overall reliability was primarily related to reader variability rather than scan acquisition. K’s for presence of core, calcification and hemorrhage were fair to good. White men had the thickest plaques (average maximum ICA wall thickness = 2.3 mm) and the most cores (34%).
The most important limiting factor for MRI measurements of plaque components is reader variability. Measurement error depends largely on the analyzed structure’s size.
PMCID: PMC2963866  PMID: 20099354
atherosclerosis; epidemiology; magnetic resonance imaging; plaque; statistics
22.  Correlates of carotid plaque presence and composition as measured by magnetic resonance imaging: the Atherosclerosis Risk in Communities (ARIC) Study 
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 two decades later.
Methods and Results
A high-resolution contrast-enhanced MRI exam 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 average age of the sample was 70 years, 57% female, 81% white, and 19% African American. Greater age, total and LDL cholesterol, male gender, 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 ≥1.5mm. Lipid core was observed in 569 individuals (weighted percentage = 42%). Baseline age, total and LDL cholesterol were predictors of presence of lipid core 18 years later; however, these relationships were attenuated after adjustment for wall thickness. Concurrently measured LDL was associated with greater lipid core volume, independent of wall thickness. Concurrently measured glucose and body mass index were inversely associated fibrous cap thickness.
Traditional atherosclerosis risk factors are related to increased wall volume and wall thickness two decades later, but they do not discriminate characteristics of plaque composition (core and cap) independent of wall size.
PMCID: PMC2747117  PMID: 19808612
carotid arteries; epidemiology; magnetic resonance imaging; plaque
23.  Positive remodeling of the coronary arteries detected by MRI in an asymptomatic population: the Multi-Ethnic Study of Atherosclerosis (MESA) 
The purpose of this study was to assess coronary arterial remodeling as a marker of subclinical atherosclerosis using coronary wall MRI in an asymptomatic population-based cohort.
In early atherosclerosis, compensatory enlargement of both the outer wall of the vessel as well as the lumen, termed compensatory enlargement or positive remodeling, occurs before luminal narrowing.
179 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) were evaluated using black-blood coronary wall MRI. Coronary cross-sectional area (vessel size), lumen area, and mean wall thickness of the proximal coronary arteries were measured.
Men had a greater vessel size, lumen area, and mean wall thickness than women (38.3±11.3 versus 32.6±9.4 mm2, 6.7±3.2 versus 5.3±2.4 mm2, and 2.0±0.3 versus 1.9±0.3 mm, respectively, p<0.05). No significant coronary artery narrowing was present by magnetic resonance angiography. Overall, coronary vessel size increased 25.9 mm2 per millimeter increase in coronary wall thickness, while lumen area increased only slightly at 3.1 mm2 for every millimeter increase in wall thickness (difference in slopes, p<0.0001). Adjusting for age and gender, participants with Agatston score greater than zero were more likely to have wall thickness greater than 2.0 mm (odds ratio 2.0, 95% CI 1.01–3.84).
Coronary wall MRI detected positive arterial remodeling, in asymptomatic men and women with subclinical atherosclerosis.
PMCID: PMC2793325  PMID: 19406347
subclinical atherosclerosis; magnetic resonance imaging; coronary artery disease; plaque
24.  SELP and SELPLG Genetic Variation Is Associated with Cell Surface Measures of SELP and SELPLG: The Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study 
Clinical chemistry  2009;55(6):1076-1082.
P-selectin (SELP) and its ligand, P-selectin glycoprotein ligand 1 (SELPLG), play key roles in both the inflammatory response and the atherosclerotic process. Previous studies have shown genetic variation in the SELP gene [selectin P (granule membrane protein 140kDa, antigen CD62)] to be associated with plasma SELP concentrations; however, the major biological function of SELP (and SELPLG) is at the cell surface. We therefore investigated the association of SELP polymorphisms with platelet SELP measures and polymorphisms in the SELPLG gene (selectin P ligand) with lymphocyte, granulocyte, and monocyte SELPLG measures among 1870 participants in the Atherosclerosis Risk in Communities (ARIC) Carotid MRI study.
Whole-blood flow cytometry was used to analyze leukocyte and platelet markers in the ARIC Carotid MRI study. The allele frequencies for the SELP and SELPLG polymorphisms of whites and African Americans were markedly different; therefore, all analyses were race specific.
SELP T715P was significantly associated with lower values for platelet SELP measures in whites (P = 0.0001), whereas SELP N562D was significantly associated with higher values for SELP measures in African Americans (P = 0.02). SELPLG M62I was significantly associated with lower granulocyte and monocyte SEL-PLG measures in African Americans (P = 0.003 and P = 0.0002, respectively) and with lower lymphocyte SELPLG measures in whites (P = 0.01).
Specific SELP and SELPLG polymorphisms were associated with cell surface measures of SELP and SELPLG in both whites and African Americans in the ARIC Carotid MRI study. To our knowledge, this study is the first to examine the association of SELP and SELPLG genetic variation with measures of cell surface SELP and SELPLG.
PMCID: PMC2812411  PMID: 19395438
25.  ICAM1 and VCAM1 polymorphisms, coronary artery calcium, and circulating levels of soluble ICAM-1: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2008;201(2):339-344.
Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) may be important contributors to the development and progression of atherosclerosis. Using a stratified random sample of 2,880 participants of the Multi-Ethnic Study of Atherosclerosis we investigated the relationship of 12 ICAM1 and 17 VCAM1 SNPs and coronary artery calcium (CAC) and ICAM1 SNPs and circulating levels of soluble ICAM-1 (sICAM-1). There were no ICAM1 or VCAM1 SNPs significantly associated with CAC in any of the four race/ethnic groups. In a subset of 1,451 subjects with sICAM-1 measurements, we observed a significant association with rs5491 in all four race/ethnic groups corroborating previous research that has shown that the T-allele of rs5491 interferes with the monoclonal antibody used to measure sICAM-1 in this study. After excluding all rs5491 T-allele carriers, several ICAM1 SNPs were significantly associated with sICAM-1 levels; rs5496 in African Americans, rs5498 and rs3093030 in European Americans, and rs1799969 in Hispanics. Our results identified ICAM1 polymorphisms that were significantly associated with sICAM-1 level but not CAC, a subclinical marker of atherosclerosis.
PMCID: PMC2615541  PMID: 18420209
coronary artery calcium; intercellular adhesion molecule-1 (ICAM-1); vascular adhesion molecule-1 (VCAM-1); soluble intercellular adhesion molecule-1 (sICAM-1); gene; single nucleotide polymorphism (SNP); haplotypes

Results 1-25 (25)