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1.  Changes in Carotid Intima-Media Thickness During the Cardiac Cycle: The Multi-Ethnic Study of Atherosclerosis 
Common carotid artery intima-media thickness (IMT), a measure of subclinical cardiovascular disease, changes during the cardiac cycle. The magnitude of this effect and its implications have not been well studied.
Methods and Results
Far-wall IMT measurements of the right common carotid artery were measured at end diastole and peak systole in 5633 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA). Multivariable regression models were generated with end-diastolic IMT, peak-systolic IMT, and change in IMT during the cardiac cycle as dependent variables and traditional cardiovascular risk factors as independent variables. The average age of our population was 61.9 (45 to 84) years. Average change in carotid IMT during the cardiac cycle was 0.041 mm (95% confidence interval: 0.039 to 0.042 mm), with a mean IMT of 0.68 mm. End-diastolic IMT and peak-systolic IMT were similarly associated with risk factors. In a fully adjusted model, change in carotid IMT during the cardiac cycle was associated with ethnicity and pulse pressure (P=0.001) and not age, sex, or other risk factors. Chinese and Hispanics had less of a change in IMT than did non-Hispanic whites. With peak-systolic IMT reference values used as normative data, 31.3% more individuals were classified as being in the upper quartile of IMT and at high risk for cardiovascular disease than would be expected when IMT is measured at end diastole.
Measurable differences in IMT are seen during the cardiac cycle. This affects the interpretation of IMT measurements used for cardiovascular risk assessment, given published normative data with IMT measured at peak systole.
Clinical Trial Registration
URL: Unique identifier: NCT00063440. (J Am Heart Assoc. 2012;1:e001420 doi: 10.1161/JAHA.112.001420.)
PMCID: PMC3487346  PMID: 23130162
atherosclerosis; blood pressure; carotid arteries; diastole; epidemiology; risk factors; systole; ultrasonics
2.  Associations of edge detected and manual traced common carotid intima-media thickness (IMT) measurements with Framingham risk factors: the Multi-Ethnic Study of Atherosclerosis 
Carotid intima-media thickness (IMT) is a marker of cardiovascular disease derived from ultrasound images of the carotid artery. In most outcome studies, human readers identify and trace the key IMT interfaces. We evaluate an alternate approach using automated edge detection.
We study a subset of 5640 participants with an average age 61.7 years (48% men) of the Multi-Ethnic Study of Atherosclerosis composed of whites, Chinese, Hispanic and African-Americans that are part of the MESA IMT progression study. Manual tracing IMT (mt_IMT) and edge-detected IMT (ed_IMT) measurements of the far wall of the common carotid artery (CCA) served as outcome variables for multivariable linear regression models using Framingham cardiovascular risk factors and ethnicity as independent predictors.
Measurements of mt_IMT was obtainable in 99.9% (5633/5640) and of ed_IMT in 98.9% (5579/5640) of individuals. Average ed_IMT was 0.19 mm larger than mt_IMT. Inter-reader systematic differences (bias) in IMT measurements were apparent for mt_IMT but not ed_IMT. Based on complete data on 5538 individuals, associations of IMT with risk factors were stronger (p < 0.0001) for mt_IMT (model r2: 19.5%) than ed_IMT (model r2: 18.5%).
We conclude that this edge-detection process generates IMT values equivalent to manually traced ones since it preserves key associations with cardiovascular risk factors. It also decreases inter-reader bias, potentially making it applicable for use in cardiovascular risk assessment.
PMCID: PMC3169166  PMID: 21546477
Ultrasonography; Risk Factors; Carotid Arteries; Carotid Intima Media Thickness
3.  Pulse Pressure and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis 
American Journal of Hypertension  2013;26(5):636-642.
Brachial pulse pressure (PP) has been found to be associated with markers of subclinical cardiovascular disease, including carotid intima–media thickness and left-ventricular mass index (LVMI), but it is unclear whether these associations are independent of traditional cardiovascular risk factors and of the steady, nonpulsatile component of blood pressure (BP). Moreover, it is unknown whether these associations are modified by gender, age, or race/ethnicity.
We used multivariate linear regression models to assess the relationship between brachial PP and three markers of subclinical cardiovascular disease (CVD) (common carotid intima–media thickness (CC-IMT), internal carotid intima–media thickness (IC-IMT), and LVMI) in four race/ethnic groups in the Multi-Ethnic Study of Atherosclerosis. The models were adjusted for traditional Framingham risk factors (age, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, diabetes, smoking status), use of lipid-lowering medication, use of antihypertensive medication, study site, and mean arterial pressure (MAP).
The assessment was done on 6,776 participants (2,612 non-Hispanic white, 1,870 African-American, 1,494 Hispanic, and 800 Chinese persons). The associations between brachial PP and CC-IMT, IC-IMT, and LVMI were significant in fully adjusted models. The three subclinical markers also showed significant interactions with gender (P < 0.0001), with stronger interactions in men. There was an interaction with age for LVMI (P = 0.004) and IC-IMT (P = 0.008). Race/ethnicity modified the association of PP with CC-IMT.
Brachial PP was independently associated with subclinical CVD after adjustment for cardiovascular risk factors and mean arterial pressure (MAP). The strength of the association differed significantly for strata of gender, age, and race/ethnicity.
PMCID: PMC3657481  PMID: 23388832
pulse pressare; subclinical cardiovascular disease; carotid intima–media thickness; left ventricular mass index; aging; hypertension; arterial stiffness; blood pressure.
4.  Carotid artery plaque and progression of coronary artery calcium: the Multi-Ethnic Study of Atherosclerosis 
Carotid and coronary atherosclerosis are associated to each other in imaging and autopsy studies. We evaluated whether carotid artery plaque seen on carotid ultrasound can predict incident coronary artery calcification (CAC).
Materials and Methods
We repeated Agatston calcium score measurements in 5445 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) (mean age 57.9 years; 62.9% female). Internal carotid artery lesions were graded as 0%, 1-24%, >25% diameter narrowing and intima-media thickness (IMT) was measured. Plaque was present for any stenosis > 0%. CAC progression was evaluated with multivariable relative risk regression in cases with CAC = 0 at baseline and with multivariable linear regression for CAC > 0 adjusting for cardiovascular risk factors, body mass index, ethnicity, and common carotid IMT.
CAC was positive at baseline in 2708/5445 (49.7%) participants and became positive in 458/2837 (16.1%) at mean interval of 2.4 years between repeat examinations. Plaque and ICA IMT were both strongly associated with presence of CAC. After statistical adjustment, presence of carotid artery plaque significantly predicted incident CAC with a relative risk(RR) of 1.37 (95% Confidence Intervals: 1.12, 1.67). Incident CAC was associated with ICA IMT with an RR of 1.13 (95% Confidence Intervals: 1.03, 1.25) for each mm increase. Progression of CAC was also significantly associated (p < 0.001) with plaque and ICA IMT.
In individuals free of cardiovascular disease, subjective and quantitative measures of carotid artery plaques by ultrasound imaging are associated with CAC incidence and progression.
PMCID: PMC4084492  PMID: 23522805
5.  Coronary Artery Calcification Compared with Carotid Intima-Media Thickness in Prediction of Cardiovascular Disease Incidence: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Archives of internal medicine  2008;168(12):1333-1339.
Coronary artery calcium (CAC) and carotid intima-media thickness (IMT) are noninvasive measures of atherosclerosis that consensus panels have recommended as possible additions to risk factor assessment for predicting the probability of cardiovascular disease (CVD) occurrence.
To assess whether maximum carotid IMT or CAC (Agatston Score) is the better predictor of incident CVD.
Design, Setting, Patients
Prospective cohort study of 45–84 year-olds initially free of CVD (n = 6,698) in four ethnic groups, with standardized carotid IMT and CAC measures at baseline, in six field centers of the Multi-Ethnic Study of Atherosclerosis (MESA).
Main Outcome Measure(s)
Incident CVD events (coronary heart disease, stroke, and fatal CVD) over a maximum of 5.3 years of follow-up.
There were 222 CVD events during follow-up. CAC was associated more strongly than carotid IMT with risk of incident CVD. After adjustment for each other and traditional CVD risk factors, the hazard of CVD increased 2.1-fold (95% CI 1.8–2.5) for each standard deviation greater level of log-transformed CAC, versus 1.3-fold (95% CI 1.1–1.4) for each standard deviation greater maximum IMT. For coronary heart disease, the hazard ratios per standard deviation increment were 2.5-fold (95% CI 2.1–3.1) for CAC and 1.2-fold (95% CI 1.0–1.4) for IMT. An ROC analysis also suggested that CAC predicted incident CVD better than IMT did.
Although whether and how to clinically use bio-imaging tests of subclinical atherosclerosis remains a topic of debate, this study found that CAC predicts subsequent CVD events better than does carotid IMT.
PMCID: PMC2555989  PMID: 18574091
6.  Relationship Between Brachial Flow - Mediated Dilation and Carotid Intima- Media Thickness in an Elderly Cohort: The Cardiovascular Health Study 
Atherosclerosis  2007;197(2):840-845.
The aim of this study was to determine the relationship between brachial flow-mediated dilation (FMD) and carotid intima-media thickness (IMT) in a large multi-ethnic elderly cohort.
Brachial flow-mediated dilation (FMD) is a physiologic measure and Carotid IMT is an anatomic structural measure of subclinical atherosclerosis. Both brachial FMD and carotid IMT have been associated with cardiovascular risk factors and cardiovascular events. The relationship between brachial FMD and carotid IMT is less clear especially in older adults.
Brachial FMD, carotid IMT and traditional cardiovascular risk factors were measured in 2338 adults, age 72–98 years who were participants in the Cardiovascular Health Study. The relationship between FMD and IMT was assessed both unadjusted and also after adjusting for age, gender, race/ethnicity. BMI, HDL, LDL, systolic and diastolic blood pressure, serum creatinine, current smoking, diabetes mellitus, hormone therapy and prior CVD.
Both brachial FMD and carotid IMT correlated significantly with age, HDL levels, waist/hip ratio, serum cholesterol and number of CV risk factors. Brachial FMD was not associated with CCA IMT in this elderly cohort (Pearson partial correlation coefficient= −0.0252, p=0.222). In the adjusted linear regression model with CCA IMT as the dependent variable, brachial FMD was also not associated with CCA IMT (beta coefficient= −0.006, p=0.470)
Brachial FMD and CCA IMT are not related in population-based older adults. Brachial FMD and CCA IMT may be distinct and independent stages in the complex atherosclerotic process.
PMCID: PMC4115586  PMID: 17804000
Brachial flow-mediated dilation; carotid intima-media thickness; endothelial function; atherosclerosis; elderly
7.  Pre-Clinical Atherosclerosis due to HIV Infection: Carotid Intima-Medial Thickness Measurements from the FRAM Study 
AIDS (London, England)  2009;23(14):1841-1849.
Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis independent of traditional CVD risk factors.
Cross-sectional study of HIV-infected and control subjects without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Pre-clinical atherosclerosis was assessed by carotid intima-medial thickness (IMT) measurements in the internal/bulb and common regions in HIV-infected and control subjects after adjusting for traditional CVD risk factors.
For internal carotid, mean IMT was 1.17±0.50mm for HIV-infected participants and 1.06±0.58mm for controls (p<0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected vs. controls was +0.188mm (95%CI 0.113-0.263, p<0.0001). Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (+0.148mm, 95%CI 0.072-0.224, p=0.0001). For the common carotid, HIV infection was independently associated with greater IMT (+0.033mm, 95%CI 0.010, 0.056, p=0.005). The association of HIV infection with IMT was similar to that of smoking which was also associated with greater IMT (internal +0.173mm, common +0.020mm).
Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared to the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking.
PMCID: PMC3156613  PMID: 19455012
HIV; carotid IMT; smoking; cholesterol; diabetes; atherosclerosis
8.  Associations of occupation, job control and job demands with intima-media thickness: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Occupation has been linked to cardiovascular disease (CVD) incidence and mortality, but few studies have investigated occupation in relation to early atherosclerotic disease. This study examined associations between various occupational characteristics and carotid artery intima-media thickness (IMT) in a multi-ethnic sample.
The Multi-Ethnic Study of Atherosclerosis (MESA) recruited 6814 adults aged 45e84 years and free of clinical CVD (response rate 60%, 51% female). Questionnaire data were used to determine occupational group (managerial/professional, sales/office, service, blue-collar), psychosocial job characteristics (ie, job demands, job control) and other sociodemographic information.
Common carotid artery (CCA)-IMT was greater for blue-collar jobs than for management/professional jobs (mean difference=0.012 mm, p=0.049) after adjustment for age, sex, race, place of birth (US or foreign born) and CVD risk factors. Compared to management/professional jobs, internal carotid artery (ICA)-IMT was greater for sales/office, service and blue-collar jobs (mean difference=0.071 mm, p<0.001; 0.057 mm, p=0.009; and 0.110 mm, p<0.001, respectively) after adjustment for age, sex, race and place of birth. The difference between blue-collar jobs and management/professional jobs remained significant after additional adjustment for CVD risk factors, income and education (mean difference=0.048 mm, p=0.045). Higher levels of control at work were associated with thinner CCA-IMT (mean difference=‒0.009 mm, p=0.016, adjusted for age, sex, race and place of birth) but not with ICA-IMT. Job demands had no significant association with IMT.
Blue-collar jobs and low levels of job control were associated with the development of subclinical atherosclerosis.
PMCID: PMC3073024  PMID: 20935285
9.  Carotid intima media thickness is associated with body fat abnormalities in HIV-infected patients 
BMC Infectious Diseases  2014;14:348.
HIV-infected patients may be at increased risk of cardiovascular (CV) events, and lipodystrophy is generally associated with proatherogenic metabolic disturbances. Carotid intima-media thickness (cIMT) has been used as a surrogate marker for atherosclerosis and it has been shown to be an independent risk factor for CV disease. Our objective was to evaluate cIMT in HIV-infected patients on combined anti-retroviral therapy (cART) with and without lipodystrophy defined by fat mass ratio (L-FMR), and to determine the association of lipodystrophy and visceral obesity [(visceral (VAT), subcutaneous adipose tissue (SAT) volume and VAT/SAT ratio, objectively evaluated by CT scan] with cIMT.
Cross-sectional study of 199 HIV-infected patients. Body composition by DXA and abdominal CT, lipids, blood pressure, inflammatory markers, and cIMT by ultrasonography were performed. L-FMR was defined as the ratio of the percentage of trunk fat mass to the percentage of lower limb fat mass by DXA. Categorical variables were compared using the chi-square or Fisher’s exact test. Spearman correlation coefficients were estimated to study the association between cIMT and clinical and metabolic characteristics. Means of cIMT, adjusted for age, were calculated, using generalized linear models.
L-FMR was present in 41.2% of patients and cIMT was higher in these patients [0.81 (0.24) vs. 0.76 (0.25); p = 0.037)]. Lipodystrophic patients had higher VAT and VAT/SAT ratio and lower SAT. cIMT was associated with lipodystrophy evaluated by FMR, trunk fat, total abdominal fat, VAT and VAT/SAT ratio. No association was observed between cIMT and leg fat mass. Using generalized linear models, cIMT means were adjusted for age and no significant differences remained after this adjustment. The adjusted mean of cIMT was 0.787 (95% CI: 0.751-0.823) in patients without lipodystrophy, and 0.775 (95% CI: 0.732-0.817) in those with lipodystrophy (p = 0.671).
HIV-infected patients on cART with lipodystrophy defined by FMR, had a significantly higher cIMT. Carotid IMT was also associated with classical cardiovascular risk factors. In these patients, visceral adipose tissue had a significant impact on cIMT, although age was the strongest associated factor.
PMCID: PMC4087129  PMID: 24958511
Lipodystrophy; HIV; Carotid intima media thickness; Fat mass ratio; Body composition
10.  Association Between Carotid Intima-Media Thickness and Pericardial Fat in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Carotid intima-media thickness (IMT) is a sub-clinical marker of atherosclerosis and a strong predictor of stroke. Pericardial fat (PF), the fat depot around the heart, has been associated with several atherosclerosis risk factors. We sought to examine the association between carotid IMT and PF, and to examine whether such an association is independent from common atherosclerosis risk factors including measures of overall adiposity.
Unadjusted and multivariable adjusted linear regression analysis was used to examine associations between common (CCA-IMT) and internal (ICA-IMT) carotid IMT with PF in a random sample of 996 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent carotid ultrasound and chest CT at baseline examination.
A significant positive correlation was observed between PF and CCA-IMT (r =0.27, P<0.0001) and ICA-IMT (r =0.17, P<0.0001). In an unadjusted sex-specific linear regression analysis, there was a significant association between PF (1-SD difference) and CCA-IMT (mm) in both women (β coefficient (95% CI): 0.06 (0.04, 0.08), P<0.0001) and men (0.03 (0.01, 0.05), P<0.0002), an association that persisted after further adjusting for age and ethnicity (0.02 (+0.00, 0.04), P=0.0120 for women, and 0.02 (+0.00, 0.03), P=0.0208 for men). However, after additional adjustment for atherosclerosis risk factors and either BMI or waist circumference, these relations were no longer significant in either sex. In similar analyses, PF was significantly associated with ICA-IMT in both men (0.11 (0.06, 0.15), P<0.0001) and women (0.08 (0.02, 0.13), P=041). These relations were no longer significant in women in multivariable adjusted models, but persisted in men in all models except after adjusting for age, ethnicity and waist circumference.
In the general population PF is associated with carotid IMT, an association that possibly not independent from markers of overall adiposity or common atherosclerosis risk factors.
PMCID: PMC2817960  PMID: 20123228
11.  B-mode ultrasound common carotid artery intima-media thickness and external diameter: cross-sectional and longitudinal associations with carotid atherosclerosis in a large population sample 
Arterial diameter and intima-media thickness (IMT) enlargement may each be related to the atherosclerotic process. Their separate or combined enlargement may indicate different arterial phenotypes with different atherosclerosis risk.
We investigated cross-sectional (baseline 1987–89: n = 7956) and prospective (median follow-up = 5.9 years: n = 4845) associations between baseline right common carotid artery (RCCA) external diameter and IMT with existing and incident carotid atherosclerotic lesions detected by B-mode ultrasound in any right or left carotid segments. Logistic regression models (unadjusted, adjusted for IMT, or adjusted for IMT and risk factors) were used to relate baseline diameter to existing carotid lesions while comparably adjusted parametric survival models assessed baseline diameter associations with carotid atherosclerosis progression (incident carotid lesions). Four baseline arterial phenotypes were categorized as having 1) neither IMT nor diameter enlarged (reference), 2) isolated IMT thickening, 3) isolated diameter enlargement, and 4) enlargement of both IMT and diameter. The association between these phenotypes and progression to definitive carotid atherosclerotic lesions was assessed over the follow-up period.
Each standard deviation increment of baseline RCCA diameter was associated with increasing carotid lesion prevalence (unadjusted odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.47–1.62) and with progression of carotid atherosclerosis (unadjusted hazards ratio (HR) = 1.37, 95% CI = 1.28–1.46); and the associations remained significant even after adjustment for IMT and risk factors (prevalence OR = 1.11, 95% CI = 1.04–1.18; progression HR = 1.11, 95% CI = 1.03–1.19). Controlling for gender, age and race, persons with both RCCA IMT and diameter in the upper 50th percentiles had the greatest risk of progressing to clearly defined carotid atherosclerotic lesions (all HR = 1.71, 95% CI = 1.47–2.0; men HR = 1.88, 95% CI = 1.48–2.39; women HR = 1.59, 95% CI = 1.31–1.95) while RCCA IMT or diameter alone in the upper 50th percentile produced significantly lower estimated risks.
RCCA IMT and external diameter provide partially overlapping information relating to carotid atherosclerotic lesions. More importantly, the RCCA phenotype of coexistent wall thickening with external diameter enlargement indicates higher atherosclerotic risk than isolated wall thickening or diameter enlargement.
PMCID: PMC2277382  PMID: 18321381
12.  Variations in Common Carotid Artery Intima-Media Thickness (cIMT) during the Cardiac Cycle: Implications for Cardiovascular Risk Assessment 
Common carotid artery (CCA) intima-media thickness (cIMT), a measure of atherosclerosis, varies between peak-systole (PS) and end-diastole (ED). This difference might affect cardiovascular risk assessment.
Materials and methods
IMT measurements of the right and left CCA were synchronized with an electrocardiogram: R-wave for ED and T-wave for PS. IMT was measured in 2930 members of the Framingham Offspring Study. Multivariable regression models were generated with ED-IMT, PS-IMT and change in IMT as dependent variables and Framingham risk factors as independent variables. ED-IMT estimates were compared to the upper quartile of IMT based on normative data obtained at PS.
The average age of our population was 57.9 years. Average difference in IMT during the cardiac cycle was 0.037 mm (95% CI: 0.035–0.038 mm). ED-IMT and PS-IMT had similar associations with Framingham risk factors (total R2= 0.292 versus 0.275) and were significantly associated with all risk factors. In a fully adjusted multivariable model, a thinner IMT at peak-systole was associated with pulse pressure (p < 0.0001), LDL-cholesterol (p = 0.0064), age (p = 0.046), and no other risk factors. Performing ED-IMT measurements while using upper quartile PS-IMT normative data lead to inappropriately increasing by 42.1% the number of individuals in the fourth IMT quartile (high cardiovascular risk category).
The difference in IMT between peak-systole and end-diastole is associated with pulse pressure, LDL-cholesterol, and age. In our study, mean IMT difference during the cardiac cycle lead to an overestimation by 42.1% of individuals at high risk for cardiovascular disease.
PMCID: PMC3544292  PMID: 22721828
Ultrasonics; Risk Factors; Carotid Arteries; Blood Pressure; systole; diastole
13.  Common carotid artery intima-media thickness (IMT) progression as a predictor of stroke in MESA (Multi-Ethnic Study of Atherosclerosis) 
Carotid artery intima-media thickness (IMT) is a marker of cardiovascular disease associated with incident stroke. We study whether IMT rate-of-change is associated with stroke.
Materials and Methods
We studied 5028 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) composed of whites, Chinese, Hispanic and African-Americans free of cardiovascular disease. In this MESA IMT progression study, IMT rate-of-change (mm/year) was the difference in right common carotid artery (CCA) far-wall IMT (mm) divided by the interval between two ultrasound examinations (median interval of 32 months). CCA IMT was measured in a region free of plaque. Cardiovascular risk factors and baseline IMT were determined when IMT rate-of-change was measured. Multivariable Cox proportional hazards models generated Hazard risk Ratios (HR) with cardiovascular risk factors, ethnicity and education level/income as predictors.
There were 42 first time strokes seen during a mean follow-up of 3.22 years (median 3.0 years). Average age was 64.2 years, with 48% males. In multivariable models, age (HR: 1.05 per year), systolic blood pressure (HR 1.02 per mmHg), lower HDL cholesterol levels (HR: 0.96 per mg/dL) and IMT rate-of-change (HR 1.23 per 0.05 mm/year; 95% C.L. 1.02, 1.48) were significantly associated with incident stroke. The upper quartile of IMT rate-of-change had an HR of 2.18 (95% C.L.: 1.07, 4.46) compared to the lower three quartiles combined.
Common carotid artery IMT progression is associated with incident stroke in this cohort free of prevalent cardiovascular disease and atrial fibrillation at baseline.
PMCID: PMC3202068  PMID: 21885840
Ultrasonography; Risk Factors; Carotid Arteries; Carotid Intima Media Thickness; stroke
14.  Effect of inter-reader variability on outcomes in studies using carotid intima media thickness quantified by carotid ultrasonography 
European journal of epidemiology  2010;25(6):385-392.
Systematic differences between readers or equipment in imaging studies are not uncommon; failure to account for such differences when using Carotid Ultrasonography may introduce bias into associations between carotid intima media thickness (cIMT) and outcomes. We demonstrate the impact of this source of systematic measurement error (SME) using data on 5,521 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and 661 participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Participants were between 37 and 78 years old. Two outcomes were considered: (1) the effect of HIV infection on cIMT (between study) and (2) the association of cIMT with cardiovascular events (within study). All estimates were adjusted for demographics (age, gender, and ethnicity) and for traditional cardiovascular disease risk factors (smoking, blood pressure, diabetes and cholesterol). When comparing the FRAM and MESA cohorts to estimate the association of HIV infection on common cIMT, accounting for machine and reader variability (between study variability) reduced the difference associated with HIV infection from +0.080 mm (95% Confidence Interval (CI):0.065–0.095) to +0.037 mm (95% CI:0.003 to 0.072) while internal cIMT declined from +0.254 mm (95% CI:0.205–0.303) to +0.192 mm (95% CI:0.076–0.308). Attenuation of the association between cIMT and cardiovascular endpoints occurred when within study reader variability was not accounted for. The effect of SME due to use of multiple readers or machines is most important when comparisons are made between two different study populations. Within-cohort measurement error dilutes the association with events.
PMCID: PMC3161119  PMID: 20309612
Carotid intima media thickness; Measurement error; Bias; Carotid ultrasonography
15.  A High Ankle Brachial Index is Associated with Greater Left Ventricular Mass: The Multi-Ethnic Study of Atherosclerosis 
Arterial stiffness leads to left ventricular (LV) mass through non-atherosclerotic pathways in mice. In humans, a high ankle brachial index (ABI) indicates stiff peripheral arteries, and is associated with cardiovascular disease (CVD) events. Whether high ABI is associated with LV mass in humans, and whether this may reflect consequences of arterial stiffness, atherosclerosis, or both is unknown.
Among 4,972 MESA participants without clinical CVD, we used linear regression to evaluate the association of low (< 0.90) and high (>1.40 or incompressible) ABI with LV mass by cardiac magnetic resonance imaging (MRI). Intermediate ABIs served as the reference category. To determine the effect of subclinical atherosclerosis, models were adjusted for common and internal carotid intima media thickness (cIMT) and log-transformed coronary artery calcification (Ln[CAC+1]).
Compared to subjects with intermediate ABI, LV mass was higher with either low (2.70g/m2 higher, 95% CI 0.65–4.75) or high ABI (6.84 g/m2 higher, 95% CI 3.2–10.47) after adjustment for traditional CVD risk factors, kidney function, and CRP. However, further adjustment for cIMT and CAC substantially attenuated the association of low ABI with LVMI (1.24 g/m2 higher, 95% CI −0.84–3.33), whereas the association of high ABI was minimally altered (6.01 g/m2 higher, 95% CI 2.36–9.67).
High ABI is associated with greater LV mass; an association that is not attenuated with adjustment for subclinical atherosclerosis in non-peripheral arterial beds. High ABI may lead to greater LV mass through non-atherosclerotic pathways.
PMCID: PMC2837506  PMID: 20117440
vascular stiffness; medial arterial calcification; left ventricular mass; heart failure; cardiovascular disease
16.  Lipids and lipoprotein ratios: The contribution to carotid intima media thickness in adolescents and young adults with type 2 diabetes mellitus 
Journal of clinical lipidology  2013;7(5):441-445.
Dyslipidemia is common among adolescents with type 2 diabetes (T2D).
To assess whether the lipoprotein ratios LDL/HDL or TG/HDL (low density lipoprotein cholesterol/ high density lipoprotein cholesterol or triglycerides/HDL) or non-HDL cholesterol are more useful than the traditional lipid panel to predict increased arterial thickness in adolescents and young adults T2D. .
We evaluated 244 T2D adolescents and young adults in a cross sectional study (mean age 18 years, 56% African American, 65% female). Demographics, anthropometrics, and laboratory data were collected. Arterial thickness was assessed using carotid intima media thickness (IMT). Bivariate correlations and general linear models were used to determine the independent contributions of the various lipid parameters to carotid IMT.
Bivariate correlations revealed LDL/HDL ratio was the strongest predictor carotid IMT (p<0.02). After adjustment for potential covariates LDL/HDL was no longer significant. HDL cholesterol was the only lipid to independently (negatively) contribute to carotid IMT. Other risk factors that were independently associated with carotid IMT included age, race, sex and body mass index z score and hemoglobin A1C. Together these cardiovascular risk factors explained less than 20% of the variance in carotid IMT.
HDL cholesterol is the only lipid to independently associate with carotid IMT. Lipoprotein ratios and non-HDL did not provide additional information. The low variance in carotid IMT explained by traditional risk factors suggests nontraditional risk factors may be important to assess to better understand the contributors to early stage atherosclerosis in adolescents and young adults with T2D.
PMCID: PMC3788355  PMID: 24079285
type 2 diabetes; lipids; lipoproteins; adolescents; pediatrics; carotid intima media thickness; vascular disease
17.  Bone mineral density and atherosclerosis: The Multi-Ethnic Study of Atherosclerosis, Abdominal Aortic Calcium Study 
Atherosclerosis  2009;209(1):283-289.
Molecular and cell biology studies have demonstrated an association between bone and arterial wall disease, but the significance of a population-level association is less clear and potentially confounded by inability to account for shared risk factors.
To test population-level associations between atherosclerosis types and bone integrity.
Main Outcome Measures
Volumetric trabecular lumbar bone mineral density (vBMD), ankle-brachial index (ABI), intima-media thickness of the common carotid (CCA-IMT) and internal carotid (ICA-IMT) arteries, and carotid plaque echogenicity.
Design, Setting and Participants
A random subset of participants from the Multi-Ethnic Study of Atherosclerosis (MESA) assessed between 2002 and 2005.
904 post-menopausal female (62.4 years; 62% non-white; 12% ABI<1; 17% CCA-IMT>1mm; 33% ICA-IMT>1mm) and 929 male (61.4 years; 58% non-white; 6% ABI<1; 25% CCA-IMT>1mm; 40% ICA-IMT>1mm) were included. In serial, sex-specific regression models adjusting for age, ethnicity, body mass index, dyslipidemia, hypertension, smoking, alcohol consumption, diabetes, homocysteine, interleukin-6, sex hormones, and renal function, lower vBMD was associated with lower ABI in men (p for trend <0.01) and greater ICA-IMT in men (p for trend <0.02). CCA-IMT was not associated with vBMD in men or women. Carotid plaque echogenicity was independently associated with lower vBMD in both men (trend p=0.01) and women (trend p<0.04). In all models, adjustment did not materially affect results.
Lower vBMD is independently associated with structural and functional measures of atherosclerosis in men and with more advanced and calcified carotid atherosclerotic plaques in both sexes.
PMCID: PMC4254856  PMID: 19819456
18.  Heritability of Carotid Intima-Media Thickness: A Twin Study 
Atherosclerosis  2007;197(2):814-820.
To estimate the heritability of carotid intima-media thickness (IMT), a surrogate marker for atherosclerosis, independent of traditional coronary risk factors.
Methods and Results
We performed a classical twin study of carotid IMT using 98 middle-aged male twin pairs, 58 monozygotic (MZ) and 40 dizygotic (DZ) pairs, from the Vietnam Era Twin Registry. All twins were free of overt cardiovascular disease. Carotid IMT was measured by ultrasound. Bivariate and multivariate analyses were used to determine the association between traditional cardiovascular risk factors and carotid IMT. Intraclass correlation coefficients and genetic modeling techniques were used to determine the relative contributions of genes and environment to the variation in carotid IMT. In our sample, the mean of the maximum carotid IMT was 0.75 ± 0.11. Age, systolic blood pressure and HDL were significantly associated with carotid IMT. The intraclass correlation coefficient for carotid IMT was larger in MZ (0.66; 95% confidence interval [CI], 0.62–0.69) than in DZ twins (0.37; 95% CI, 0.29–0.44), and the unadjusted heritability was 0.69 (95% CI, 0.54–0.79). After adjusting for traditional coronary risk factors, the heritability of carotid IMT was slightly reduced but still of considerable magnitude (0.59; 95% CI, 0.39–0.73).
Genetic factors have a substantial influence on the variation of carotid IMT. Most of this genetic effect occurs through pathways independent of traditional coronary risk factors.
PMCID: PMC2387097  PMID: 17825306
heritability; carotid intima-media thickness; twin study; atherosclerosis
19.  Carotid Intima‐Media Thickness is Associated With Incident Heart Failure Among Middle‐Aged Whites and Blacks: The Atherosclerosis Risk in Communities Study 
Increased carotid intima‐media thickness (IMT) is associated with subclinical left ventricular myocardial dysfunction, suggesting a possible role of carotid IMT in heart failure (HF) risk determination.
Methods and Results
Mean far wall carotid IMT, measured by B‐mode ultrasound, was available for 13 590 Atherosclerosis Risk in Communities study participants aged 45 to 64 years and free of HF at baseline. HF was defined using ICD‐9 428 and ICD‐10 I‐50 codes from hospitalization records and death certificates. The association between carotid IMT and incident HF was assessed using Cox proportional hazards analysis with models adjusted for demographic variables, major CVD risk factors, and interim CHD. There were 2008 incident HF cases over a median follow‐up of 20.6 years (8.1 cases per 1000 person‐years). Mean IMT was higher in those with HF than in those without (0.81 mm±0.23 versus 0.71 mm±0.17, P<0.001). Unadjusted rate of HF for the fourth compared with the first quartile of IMT was 15.4 versus 3.9 per 1000 person‐years; P<0.001. In multivariable analysis, after adjustment, each standard deviation increase in IMT was associated with incident HF (HR 1.20 [95% CI: 1.16 to 1.25]). After adjustment, the top quartile of IMT was associated with HF (HR 1.60 [95% CI: 1.37 to 1.87]). Results were similar across race and gender groups.
Increasing carotid IMT is associated with incident HF in middle‐aged whites and blacks, beyond risks explained by major CVD risk factors and CHD. This suggests that carotid IMT may be associated with HF through mechanisms different from myocardial ischemia or infarction.
PMCID: PMC4309069  PMID: 24815496
carotid intima‐media thickness; heart failure; subclinical atherosclerosis
20.  Inter-arm Differences in Simultaneous Blood Pressure Measurements in Ambulatory Patients without Cardiovascular Diseases 
It has traditionally been known that there is normally a difference in blood pressure (BP) between the two arms; there is at least 20 mm Hg difference in the systolic blood pressure (SBP) and 10 mm Hg difference in the diastolic blood pressure (DBP). However, recent epidemiologic studies have shown that there are between-arm differences of < 5 mm Hg in simultaneous BP measurements. The purposes of this study is to examine whether there are between-arm differences in simultaneous BP measurements obtained from ambulatory patients without cardiovascular diseases and to identify the factors associated these differences.
We examined 464 patients who visited the outpatient clinic of Gangneung Asan Hospital clinical department. For the current analysis, we excluded patients with ischemic heart disease, stroke, arrhythmia, congestive heart failure, or hyperthyroidism. Simultaneous BP measurements were obtained using the Omron MX3 BP monitor in both arms. The inter-arm difference (IAD) in BP was expressed as the relative difference (right-arm BP [R] minus left-arm BP [L]: R - L) and the absolute difference (|R - L|).
The mean absolute IAD in SBP and DBP were 3.19 ± 2.38 and 2.41 ± 1.59 mm Hg, respectively, in men and 2.61 ± 2.18 and 2.25 ± 2.01 mm Hg, respectively, in women. In men, there were 83.8% of patients with the IAD in SBP of ≤ 6 mm Hg, 98.1% with the IAD in SBP of ≤ 10 mm Hg, 96.5% with the IAD in DBP of ≤ 6 mm Hg and 0% with the IAD in DBP of > 10 mm Hg. In women, 89.6% of patients had IAD in SBP of ≤ 6 mm Hg, 92.1% with IAD in DBP of ≤ 6 mm Hg, and 0% with IAD in SBP of > 10 mm Hg or IAD in DBP of > 10 mm Hg. Gangneung Asan Hospital clinical series of patients showed that the absolute IAD in SBP had a significant correlation with cardiovascular risk factors such as the 10-year Framingham cardiac risk scores and higher BP in men and higher BP in women. However, the absolute IAD in SBP and DBP had no significant correlation with the age, obesity, smoking, drinking, hyperlipidemia, diabetes, metabolic syndrome, and renal function.
Our results showed that there were no significant between-arm differences in simultaneous BP measurements. It was also shown that most of the ambulatory patients without cardiovascular diseases had an IAD in SBP of < 10 mm Hg and an IAD in DBP of < 6 mm Hg.
PMCID: PMC3611109  PMID: 23560208
Blood Pressure Determination; Arm; Risk Factors; Adults
21.  T-Cell Phenotypes, Apoptosis and Inflammation in HIV+ Patients on Virologically Effective cART with Early Atherosclerosis 
PLoS ONE  2012;7(9):e46073.
We investigated the potential relationship between T-cell phenotype, inflammation, endotoxemia, and atherosclerosis evaluated by carotid intima-media thickness (IMT) in a cohort of HIV-positive patients undergoing long-term virologically suppressive combination antiretroviral therapy (cART).
We studied 163 patients receiving virologically suppressive cART.
We measured IMT (carotid ultrasound); CD4+/CD8+ T-cell activation (CD38, CD45R0), differentiation (CD127), apoptosis (CD95), and senescence (CD28, CD57) (flow cytometry); plasma sCD14, IL-6, TNF- α, sVCAM-1, hs-CRP, anti-CMV IgG (ELISA); LPS (LAL). The results were compared by Mann-Whitney, Kruskal-Wallis or Chi-square tests, and factors associated with IMT were evaluated by multivariable logistic regression.
Of 163 patients, 112 demonstrated normal IMT (nIMT), whereas 51 (31.3%) had pathological IMT (pIMT: ≥1 mm). Of the patients with pIMT, 22 demonstrated an increased IMT (iIMT), and 29 were shown to have plaques. These patient groups had comparable nadir and current CD4+, VLs and total length of time on cART. Despite similar proportions of CD38-expressing CD8+ cells (p = .95), pIMT patients exhibited higher activated memory CD8+CD38+CD45R0+ cells (p = .038) and apoptotic CD4+CD95+ (p = .01) and CD8+CD95+ cells (p = .003). In comparison to nIMT patients, iIMT patients tended to have lower numbers of early differentiated CD28+CD57− memory CD4+ (p = .048) and CD28–CD57−CD8+ cells (p = .006), both of which are associated with a higher proliferative potential. Despite no differences in plasma LPS levels, pIMT patients showed significantly higher circulating levels of sCD14 than did nIMT patients (p = .046). No differences in anti-CMV IgG was shown. Although circulating levels of sCD14 seemed to be associated with a risk of ATS in an unadjusted analysis, this effect was lost after adjusting for classical cardiovascular predictors.
Despite the provision of full viral suppression by cART, a hyperactivated, pro-apoptotic T-cell profile characterizes HIV-infected patients with early vascular damage, for whom the potential contribution of subclinical endotoxemia and anti-CMV immunity should be investigated further.
PMCID: PMC3459872  PMID: 23029393
22.  Alcohol consumption and carotid artery structure in Korean adults aged 50 years and older 
BMC Public Health  2009;9:358.
Epidemiologic studies of the association between alcohol consumption and carotid artery structure have reported conflicting results. We investigated the association between alcohol consumption and carotid atherosclerosis by evaluating the effects of alcohol intake on carotid artery enlargement.
The study population consisted of 4302 community-dwelling Koreans (1577 men and 2725 women) aged 50 years and over. All the subjects had participated in the baseline survey of the Dong-gu Study conducted between 2007 and 2008. Daily alcohol consumption was determined by the number and frequency of alcoholic beverages consumed. We measured common carotid artery intima-media thickness (CCA-IMT), common carotid and bulb IMT (CB-IMT), carotid plaques, and the diameter of the common carotid artery (CCA-diameter) using high-resolution B-mode ultrasonography. We used analysis of covariance and multiple logistic regressions to determine the relationship between alcohol consumption and carotid artery parameters.
CCA-IMT and CB-IMT were negatively correlated with alcohol consumption after controlling for cardiovascular risk factors in men (p for linear trend = 0.009 and = 0.038, respectively). The multivariate-adjusted odds ratio (OR) for carotid plaques was significantly higher in men who consumed >40.0 g/d (OR = 1.81, 95% CI = 1.13-2.91), although a significant positive correlation was observed between alcohol consumption and carotid plaques (p for linear trend = 0.027). Neither carotid IMT nor carotid plaques were correlated with alcohol intake in women. Alcohol intake was positively correlated with CCA-diameter adjusted for carotid IMT and plaques in the multivariate-adjusted model in both sexes (p for linear trend <0.001 for men and 0.020 for women).
The results of our study indicate that alcohol consumption is inversely related to carotid IMT and positively related to carotid plaques in men, but not women. However, alcohol intake is positively associated with CCA-diameter in both men and women. Additional large population-based prospective studies are needed to confirm the effects of alcohol consumption on carotid artery structure.
PMCID: PMC2761892  PMID: 19775442
23.  Relationship of Epicardial Adipose Tissue Thickness with Early Indicators of Atherosclerosis and Cardiac Functional Changes in Obese Adolescents with Metabolic Syndrome 
Objective: Epicardial adipose tissue thickness (EATT) is suggested as a new cardiometabolic risk factor. Carotid intima-media thickness (IMT) is a potential indicator of subclinical atherosclerosis in patients with metabolic syndrome (MS). We investigated the association of EATT with carotid IMT and cardiac functional changes in obese adolescents with MS.
Methods: One hundred thirty-eight obese adolescents and 63 lean subjects were enrolled in the study. The obese subjects were divided into two subgroups based on the presence or absence of MS (MS group and non-MS group). All subjects underwent transthoracic echocardiographic examination for determination of left ventricular (LV) function, LV mass index (LVMI), and myocardial performance index (MPI). EATT and carotid IMT were also measured during echocardiography.
Results: The average LVMI measurements were higher in both MS and non-MS obese patients in comparison with the lean children. The MS group had significantly higher LVMI measurements than the non-MS and lean groups (88.5±23.0, 67.5±24.8 g/m2, and 62.4±18.2 g/m2, respectively; p<0.01). Carotid IMT was higher in both the MS and non-MS obese patients in comparison with the lean group. The MS group had significantly higher carotid IMT measurements than the non-MS and lean groups (0.91±0.23, 0.78±0.18, and 0.52±0.08 mm, respectively; p<0.01). The EATT was also increased significantly in patients with MS compared to lean adolescents (7.42±1.55 vs. 4.28±0.79mm; p=0.001). EATT was positively correlated with body mass index-SDS, waist circumference, fasting glucose, insulin, homeostasis model assessment-insulin resistance, triglyceride levels, LV thickness, LVMI, and MPI in the MS obese group. EATT was the only independent predictor of carotid IMT in the multivariate analysis (β= 0.69, p<0.001).
Conclusion: The findings of the present study demonstrate a close relationship of EATT with carotid IMT and early cardiac dysfunction in obese adolescents with MS. Assessment of EATT and carotid IMT in routine echocardiographic examinations is suggested as a feasible and reliable method for the evaluation of obesity with MS and its related cardiovascular risks in children and adolescents.
Conflict of interest:None declared.
PMCID: PMC3814530  PMID: 24072083
metabolic syndrome; epicardial adipose; tissue; carotid intima-media thickness
24.  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
25.  Association between Noninvasive Fibrosis Markers and Cardio-Vascular Organ Damage among Adults with Hepatic Steatosis 
PLoS ONE  2014;9(8):e104941.
Evidence suggests that advanced fibrosis, as determined by the noninvasive NAFLD fibrosis score (NFS), is a predictor of cardiovascular mortality in individuals with ultrasonography-diagnosed NAFLD. Whether the severity of histology (i.e., fibrosis stage) is associated with more pronounced cardiovascular organ damage is unsettled. In this study, we analyzed the clinical utility of NFS in assessing increased carotid intima-media thickness (cIMT), and left ventricular mass index (LVMI). In this cross-sectional study NFS, cIMT and LVMI were assessed in 400 individuals with ultrasonography-diagnosed steatosis. As compared with individuals at low probability of liver fibrosis, individuals both at high and at intermediate probability of fibrosis showed an unfavorable cardio-metabolic risk profile having significantly higher values of waist circumference, insulin resistance, high sensitivity C-reactive protein (hsCRP), fibrinogen, cIMT, and LVMI, and lower insulin-like growth factor-1 (IGF-1) levels. The differences in cIMT and LVMI remained significant after adjustment for smoking and metabolic syndrome. In a logistic regression model adjusted for age, gender, smoking, and diagnosis of metabolic syndrome, individuals at high probability of fibrosis had a 3.9-fold increased risk of vascular atherosclerosis, defined as cIMT>0.9 mm, (OR 3.95, 95% CI 1.12–13.87) as compared with individuals at low probability of fibrosis. Individuals at high probability of fibrosis had a 3.5-fold increased risk of left ventricular hypertrophy (LVH) (OR 3.55, 95% CI 1.22–10.34) as compared with individuals at low probability of fibrosis. In conclusion, advanced fibrosis, determined by noninvasive fibrosis markers, is associated with cardiovascular organ damage independent of other known factors.
PMCID: PMC4128729  PMID: 25111713

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