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1.  Associations Between a Parental History of Premature Cardiovascular Disease and Coronary Calcium and Carotid Intima-Media Thickness: The Coronary Artery Risk Development In Young Adults (CARDIA) Study 
European journal of preventive cardiology  2012;10.1177/2047487312462801.
It is unclear if associations between a parental history of premature CVD (pCVD) and subclinical atherosclerosis are attenuated by adjustment for long-term risk factors levels through middle adulthood.
Prospective community-based cohort study
CARDIA participants who attended the year 20 exam (N=2283, mean age 45 years) were grouped by pCVD status: maternal only, paternal only, any parental, and no parental history (referent). We used separate logistic regression models, adjusted for average risk factor levels over 20 years' follow-up to assess associations of parental pCVD and subclinical atherosclerosis in offspring.
White participants with any parental history of pCVD had a higher odds of CAC>0 than participants with no parental history (OR 1.55; 95% CI, 1.01-2.37). This was largely driven by the association of a paternal history of pCVD with CAC>0 (OR 2.15; 95% CI, 1.42-3.23), which was minimally attenuated by multivariable adjustment (OR 2.09; 95% CI, 1.31-3.32). Similarly, adjusted associations between parental pCVD and IMT > 90%tile were observed in white participants with a paternal history of pCVD (OR=1.93; 95% CI, 1.10-3.39) and any parental history pCVD (OR 1.67; 95% CI, 1.02-2.74). No significant associations between a parental history of pCVD and the odds of subclinical atherosclerosis were observed in black participants.
Parental pCVD is independently associated with early development of subclinical atherosclerosis; these associations may be race-specific for participants in their 5th decade of life.
PMCID: PMC3779512  PMID: 23027592
Family History of Premature Cardiovascular Disease; Coronary Artery Calcium; Carotid Intima-Media Thickness
2.  Vascular Responses to Long- and Short-Term Exposure to Fine Particulate Matter 
This study evaluated the association of long- and short-term air pollutant exposures with flow-mediated dilation (FMD) and baseline arterial diameter (BAD) of the brachial artery using ultrasound in a large multicity cohort.
Exposures to ambient air pollution, especially long-term exposure to particulate matter <2.5 μm in aerodynamic diameter (PM2.5), are linked with cardiovascular mortality. Short-term exposure to PM2.5 has been associated with decreased FMD and vasoconstriction, suggesting that adverse effects of PM2.5 may involve endothelial dysfunction. However, long-term effects of PM2.5 on endothelial dysfunction have not been investigated.
FMD and BAD were measured by brachial artery ultrasound at the initial examination of the Multi-Ethnic Study of Atherosclerosis. Long-term PM2.5 concentrations were estimated for the year 2000 at each participant’s residence (n = 3,040) using a spatio-temporal model informed by cohort-specific monitoring. Short-term PM2.5 concentrations were based on daily central-site monitoring in each of the 6 cities.
An interquartile increase in long-term PM2.5 concentration (3 μg/m3) was associated with a 0.3% decrease in FMD (95% confidence interval [CI] of difference: −0.6 to −0.03; p = 0.03), adjusting for demographic characteristics, traditional risk factors, sonographers, and 1/BAD. Women, nonsmokers, younger participants, and those with hypertension seemed to show a greater association of PM2.5 with FMD. FMD was not significantly associated with short-term variation in PM2.5 (−0.1% per 12 μg/m3 daily increase [95% CI: −0.2 to 0.04] on the day before examination).
Long-term PM2.5 exposure was significantly associated with decreased endothelial function according to brachial ultrasound results. These findings may elucidate an important pathway linking air pollution and cardiovascular mortality.
PMCID: PMC3665082  PMID: 23103035
air pollution; atherosclerosis; cardiovascular mortality; endothelial function; flow-mediated dilation; traffic
3.  Kidney stones and subclinical atherosclerosis in young adults: Coronary Artery Risk Development in Young Adults (CARDIA) study 
The Journal of urology  2011;185(3):10.1016/j.juro.2010.10.086.
Recent reports suggest that nephrolithiasis and atherosclerosis share a number of risk factors. There has been no previous examination of the relationship between kidney stones and subclinical atherosclerotic disease Here we assessed the relationship between nephrolithiasis and carotid wall thickness and carotid stenosis assessed by B-mode ultrasound in the general community using data from The Coronary Artery Risk Development in Young Adults (CARDIA) study.
CARDIA is a U.S. population-based, observational study of 5,115 white and African-American men and women between the ages of 18 and 30 years at recruitment in 1985-1986.
By the year 20 exam, 200 (3.9%) of CARDIA participants had reported ever having kidney stones. Symptomatic kidney stones were associated with greater carotid wall thickness measured at the year 20 exam, particularly of the internal carotid/bulb region. Using a composite dichotomous endpoint of carotid stenosis and/or upper quartile of internal carotid/bulb wall thickness, the association of kidney stones with carotid atherosclerosis was significant (odds ratio=1.6; 95% confidence interval 1.1-2.3; p=0.01) even after adjusting for major atherosclerotic risk factors.
The association between a history of kidney stones and subclinical carotid atherosclerosis in young adults adds further support to the notion that nephrolithiasis and atherosclerosis share common systemic risk factors and/or pathophysiology.
PMCID: PMC3827917  PMID: 21251678
urolithiasis; atherosclerosis
4.  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
5.  Association of number of live births with left ventricular structure and function. The Multi-Ethnic Study of Atherosclerosis (MESA) 
American heart journal  2012;163(3):470-476.
Pregnancy is associated with marked maternal cardiovascular/hemodynamic changes. A greater number of pregnancies may be associated with long-term subclinical changes in left ventricular (LV) remodeling.
Among 2,234 white, black, Hispanic, and Chinese women (mean age 62 years) in the MESA, we used linear regression to relate live births and cardiac magnetic resonance imaging LV measures. Covariates included age, ethnicity, height, income, education, birth country, smoking, menopause, and oral contraceptive duration. Models were additionally adjusted for potential mediators: systolic blood pressure, antihypertensive use, total/high-density lipoprotein cholesterol, triglycerides, diabetes, and body mass index. We performed sensitivity analyses excluding 763 women in the lowest socioeconomic group: annual income <$25,000 and lower high school level of education.
With each live birth, LV mass increased 1.26 g; LV end-diastolic volume, 0.74 mL; and LV end-systolic volume, 0.45 mL; LV ejection fraction decreased 0.18% (P trend <0.05). Changes were most notable for the category of women with ≥5 pregnancies. Upon adjustment for potential biologic mediators, live births remained positively associated with LV mass and end-systolic volume. Live births remained significantly associated with LV end-systolic, end-diastolic volumes, and LV mass (P trend ≤0.02) after excluding women in the lowest socioeconomic group.
Number of live births is associated with key LV structural and functional measures in middle to older ages, even after adjustment for sociodemographic factors and cardiovascular disease risk factors. Hemodynamic changes during pregnancy may be associated with cardiac structure/function beyond childbearing years.
PMCID: PMC3656723  PMID: 22424019
6.  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
7.  Associations of cardiovascular risk factors, carotid intima-media thickness and left ventricular mass with inter-adventitial diameters of the common carotid artery: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2011;218(2):344-349.
Common carotid artery inter-adventitial diameter (IAD) and intima-media thickness (IMT) are measurable by ultrasound. IAD may be associated with left ventricular mass (LV mass) while IMT is a marker of subclinical atherosclerosis. It is not clear if IAD is associated with LV mass after accounting for IMT and traditional cardiovascular risk factors.
IAD and IMT were measured on participants of the Multi-Ethnic Study of Atherosclerosis (MESA) IMT progression study. A total of 5641 of the originally enrolled 6814 MESA participants were studied. LV mass was measured by magnetic resonance imaging. Multivariable linear regression was used with IAD as the outcome and adjustment for risk factors, as well as IMT and LV mass.
Traditional cardiovascular risk factors, height, weight and ethnicity were significantly associated with IAD. After adjustment for risk factors, a one mm difference in IMT was associated with a 1.802 mm (95% CI: 1.553, 2.051) higher mean IAD. A one gm difference in LV mass was associated with a 0.006 mm (95% CI: 0.005, 0.007) higher mean IAD. LV mass was independently associated with IAD after adjusting for cardiovascular risk factors and IMT. These associations were slightly different for men and women.
Inter-adventitial diameters are associated with left ventricular mass after adjusting for cardiovascular risk factors and IMT. IAD might serve as a surrogate for left ventricular mass and have predictive value for cardiovascular outcomes.
PMCID: PMC3186064  PMID: 21726862
carotid arteries; ultrasonics; hypertrophy; magnetic resonance imaging; remodeling; risk factors; left ventricle
8.  Association of Small Artery Elasticity With Incident Cardiovascular Disease in Older Adults 
American Journal of Epidemiology  2011;174(5):528-536.
Functional biomarkers like large artery elasticity (LAE) and small artery elasticity (SAE) may predict cardiovascular disease (CVD) events beyond blood pressure. The authors examined the prognostic value of LAE and SAE for clinical CVD events among 6,235 Multi-Ethnic Study of Atherosclerosis participants who were initially aged 45–84 years and without symptomatic CVD. LAE and SAE were derived from diastolic pulse contour analysis. During a median 5.8 years of follow-up between 2000 and 2008, 454 adjudicated CVD events occurred, including 256 cases of coronary heart disease (CHD), 93 strokes, and 126 heart failures (multiple diagnoses were possible). After adjustment for age, race/ethnicity, sex, clinic, height, heart rate, body mass index, systolic and diastolic blood pressure, use of antihypertensive and cholesterol-lowering medications, smoking, total cholesterol, high density lipoprotein cholesterol, triglycerides, diabetes, and high-sensitivity C-reactive protein, the hazard ratio for any CVD per standard-deviation increase in SAE was 0.71 (95% confidence interval: 0.61, 0.83; P < 0.0001). The lowest (stiffest) SAE quartile had a hazard ratio of 2.28 (95% confidence interval: 1.55, 3.36) versus the highest (most elastic) quartile. The net reclassification index, conditional on base risk, was 0.11. SAE was significantly associated with future CHD, stroke, and heart failure. After adjustment, LAE was not significantly related to CVD. In asymptomatic participants free of overt CVD, lower SAE added prognostic information for CVD, CHD, stroke, and heart failure events.
PMCID: PMC3202150  PMID: 21709134
arteries; cardiovascular diseases; elasticity; risk factors
9.  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
10.  Sex Differences in Subclinical Atherosclerosis by Race/Ethnicity in the Multi-Ethnic Study of Atherosclerosis 
American Journal of Epidemiology  2011;174(2):165-172.
Sex differences in cardiovascular disease mortality are more pronounced among non-Hispanic whites than other racial/ethnic groups, but it is unknown whether this variation is present in the earlier subclinical stages of disease. The authors examined racial/ethnic variation in sex differences in coronary artery calcification (CAC) and carotid intimal media thickness at baseline in 2000–2002 among participants (n = 6,726) in the Multi-Ethnic Study of Atherosclerosis using binomial and linear regression. Models adjusted for risk factors in several stages: age, traditional cardiovascular disease risk factors, behavioral risk factors, psychosocial factors, and adult socioeconomic position. Women had a lower prevalence of any CAC and smaller amounts of CAC when present than men in all racial/ethnic groups. Sex differences in the prevalence of CAC were more pronounced in non-Hispanic whites than in African Americans and Chinese Americans after adjustment for traditional cardiovascular disease risk factors, and further adjustment for behavioral factors, psychosocial factors, and socioeconomic position did not modify these results (for race/sex, Pinteraction = 0.047). Similar patterns were observed for amount of CAC among adults with CAC. Racial/ethnic variation in sex differences for carotid intimal media thickness was less pronounced. In conclusion, coronary artery calcification is differentially patterned by sex across racial/ethnic groups.
PMCID: PMC3167681  PMID: 21685409
calcification, physiologic; continental population groups; coronary vessels; sex; social class
11.  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
12.  Reduced Kidney Function and Preclinical Atherosclerosis in HIV-Infected Individuals: The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) 
American Journal of Nephrology  2011;33(5):453-460.
Reduced kidney function and albuminuria are associated with higher risk for cardiovascular disease (CVD) and mortality in HIV-infected individuals. We investigated whether reduced estimated glomerular filtration rate (eGFR) and albuminuria are associated with subclinical vascular disease, as assessed by carotid intima-medial thickness (cIMT).
Cross-sectional analysis of 476 HIV-infected individuals without clinical evidence of CVD enrolled in the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study, using multivariable linear regression. eGFRCys and eGFRCr were calculated from cystatin C and creatinine levels. Albuminuria was defined as a positive urine dipstick (≥1+) or urine albumin-to-creatinine ratio ≥30 mg/g. Common and internal cIMT were measured by high-resolution B-mode ultrasound.
In unadjusted analyses, eGFRCys and eGFRCr were strongly associated with common and internal cIMT. Each 10 ml/min/1.73 m2 decrease in eGFRCys and eGFRCr was associated with a 0.008 mm higher common cIMT (p = 0.003, p = 0.01) and a 0.024 and 0.029 mm higher internal cIMT (p = 0.003), respectively. These associations were eliminated after adjustment for age, gender, and race. Albuminuria showed little association with common or internal cIMT in all models.
In HIV-infected individuals without prior CVD, reduced kidney function and albuminuria were not independently associated with subclinical vascular disease, as assessed by cIMT. These results suggest that research should focus on searching for novel mechanisms by which kidney disease confers cardiovascular risk in HIV-infected individuals.
PMCID: PMC3100378  PMID: 21508633
Cystatin C; Intima-medial thickness; HIV; Atherosclerosis; Cardiovascular disease; Kidney
13.  Pericardial Fat is Associated with Carotid Stiffness in the Multi-Ethnic Study of Atherosclerosis 
Background and Aims
Arterial stiffness is a prominent feature of vascular aging and a risk factor for cardiovascular disease (CVD). Fat around the heart and blood vessels (i.e. pericardial fat, Pfat) may contribute to arterial stiffness via a local paracrine effect of adipose tissue on the surrounding vasculature. Thus, we determined the association between Pfat and carotid stiffness in 5,770 participants (mean age 62 yrs, 53% female, 25% African American, 24% Hispanic, and 13% Chinese) from the Multi-Ethnic Study of Atherosclerosis.
Methods and Results
Pfat was measured by computed tomography, and ultrasonography of the common carotid artery was used to calculate the distensibility coefficient (DC) and young’s modulus (YM). Lower DC and higher YM values indicate stiffer arteries. Pfat quartile was highly associated with demographic, behavioral, anthropometric, hemodynamic, metabolic, and disease variables in both men and women. After adjusting for height, clinical site, CVD risk factors, and medications, a 1-standard deviation (41.91 cm3) increment in Pfat was associated with a 0.00007±0.00002 1/mmHg lower DC (p=0.0002) in men and a 48.1±15.1 mmHg/mm higher YM in women (p=0.002). Additional adjustment for C-reactive protein, coronary artery calcification, and carotid intima-media thickness had only modest effects. More importantly, adjusting for body mass index and waist circumference did not significantly change the overall results.
Higher Pfat is associated with higher carotid stiffness, independent of traditional CVD risk factors and obesity.
PMCID: PMC2929306  PMID: 20153618
pericardial fat; arterial stiffness; distensibility; carotid artery
14.  Segment-specific association between plasma homocysteine and carotid artery intima-media thickness in the Framingham Heart Study 
Higher plasma total homocysteine (tHcy) is an established risk factor for cardiovascular disease. The relation between tHcy and carotid artery intima-media thickness (IMT) at the internal carotid artery (ICA)/bulb-IMT and common carotid artery (CCA)-IMT has not been systematically examined. Since the ICA/bulb segment is more prone to plaque formation than the CCA segment, differential associations with tHcy at these sites might suggest mechanisms of tHcy action.
We examined the cross-sectional segment-specific relations of tHcy to ICA/bulb-IMT and CCA-IMT in 2,499 participants from the Framingham Offspring Study, free of cardiovascular disease.
In multivariable linear regression analysis, ICA/bulb-IMT was significantly higher in the fourth tHcy quartile category compared to the other quartile categories, in both the age- and sex-adjusted and in the multivariable-adjusted model (P for trend <0.0001 and <0.01, respectively). We observed a significant age by tHcy interaction for ICA/bulb-IMT (P=0.03) and therefore stratified the analyses by median age (58 years). There was a significant positive trend between tHcy and ICA/bulb-IMT in individuals 58 years of age or older (P-trend <0.01), but not in the younger individuals (P-trend=0.24). For CCA-IMT, no significant trends were observed in any of the analyses.
The segment-specific association between elevated tHcy levels and ICA/bulb-IMT suggests an association between tHcy and plaque formation.
PMCID: PMC3011043  PMID: 20580253
carotid artery; intima-media thickness; homocysteine; atherosclerosis; Framingham Offspring Study
15.  Progression of Carotid Artery Intima-Media Thickness During 12 Years in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study 
Diabetes  2011;60(2):607-613.
This study investigated the long-term effects of intensive diabetic treatment on the progression of atherosclerosis, measured as common carotid artery intima-media thickness (IMT).
A total of 1,116 participants (52% men) in the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, a long-term follow-up of the Diabetes Control and Complications Trial (DCCT), had carotid IMT measurements at EDIC years 1, 6, and 12. Mean age was 46 years, with diabetes duration of 24.5 years at EDIC year 12. Differences in IMT progression between DCCT intensive and conventional treatment groups were examined, controlling for clinical characteristics, IMT reader, and imaging device.
Common carotid IMT progression from EDIC years 1 to 6 was 0.019 mm less in intensive than in conventional (P < 0.0001), and from years 1 to 12 was 0.014 mm less (P = 0.048); but change from years 6 to 12 was similar (intensive − conventional = 0.005 mm, P = 0.379). Mean A1C levels during DCCT and DCCT/EDIC were strongly associated with progression of IMT, explaining most of the differences in IMT progression between DCCT treatment groups. Albuminuria, older age, male sex, smoking, and higher systolic blood pressure were significant predictors of IMT progression.
Intensive treatment slowed IMT progression for 6 years after the end of DCCT but did not affect IMT progression thereafter (6–12 years). A beneficial effect of prior intensive treatment was still evident 13 years after DCCT ended. These differences were attenuated but not negated after adjusting for blood pressure. These results support the early initiation and continued maintenance of intensive diabetes management in type 1 diabetes to retard atherosclerosis.
PMCID: PMC3028362  PMID: 21270271
16.  Carotid-Wall Intima–Media Thickness and Cardiovascular Events 
The New England journal of medicine  2011;365(3):213-221.
Intima–media thickness of the walls of the common carotid artery and internal carotid artery may add to the Framingham risk score for predicting cardiovascular events.
We measured the mean intima–media thickness of the common carotid artery and the maximum intima–media thickness of the internal carotid artery in 2965 members of the Framingham Offspring Study cohort. Cardiovascular-disease outcomes were evaluated for an average follow-up of 7.2 years. Multivariable Cox proportional-hazards models were generated for intima–media thickness and risk factors. We evaluated the reclassification of cardiovascular disease on the basis of the 8-year Framingham risk score category (low, intermediate, or high) after adding intima–media thickness values.
A total of 296 participants had a cardiovascular event. The risk factors of the Framingham risk score predicted these events, with a C statistic of 0.748 (95% confidence interval [CI], 0.719 to 0.776). The adjusted hazard ratio for cardiovascular disease with a 1-SD increase in the mean intima–media thickness of the common carotid artery was 1.13 (95% CI, 1.02 to 1.24), with a nonsignificant change in the C statistic of 0.003 (95% CI, 0.000 to 0.007); the corresponding hazard ratio for the maximum intima–media thickness of the internal carotid artery was 1.21 (95% CI, 1.13 to 1.29), with a modest increase in the C statistic of 0.009 (95% CI, 0.003 to 0.016). The net reclassification index increased significantly after addition of intima–media thickness of the internal carotid artery (7.6%, P<0.001) but not intima–media thickness of the common carotid artery (0.0%, P = 0.99). With the presence of plaque, defined as intima–media thickness of the internal carotid artery of more than 1.5 mm, the net reclassification index was 7.3% (P = 0.01), with an increase in the C statistic of 0.014 (95% CI, 0.003 to 0.025).
The maximum internal and mean common carotid-artery intima–media thicknesses both predict cardiovascular outcomes, but only the maximum intima–media thickness of (and presence of plaque in) the internal carotid artery significantly (albeit modestly) improves the classification of risk of cardiovascular disease in the Framingham Offspring Study cohort. (Funded by the National Heart, Lung, and Blood Institute.)
PMCID: PMC3153949  PMID: 21774709
17.  Cardiovascular Imaging for Assessing Cardiovascular Risk in Asymptomatic Men Versus Women 
Coronary artery calcium (CAC), carotid intima-media thickness, and left ventricular (LV) mass and geometry offer the potential to characterize incident cardiovascular disease (CVD) risk in clinically asymptomatic individuals. The objective of the study was to compare these cardiovascular imaging measures for their overall and sex-specific ability to predict CVD.
Methods and Results
The study sample consisted of 4965 Multi-Ethnic Study of Atherosclerosis participants (48% men; mean age, 62±10 years). They were free of CVD at baseline and were followed for a median of 5.8 years. There were 297 CVD events, including 187 coronary heart disease (CHD) events, 65 strokes, and 91 heart failure (HF) events. CAC was most strongly associated with CHD (hazard ratio [HR], 2.3 per 1 SD; 95% CI, 1.9 to 2.8) and all CVD events (HR, 1.7; 95% CI, 1.5 to 1.9). Most strongly associated with stroke were LV mass (HR, 1.3; 95% CI, 1.1 to 1.7) and LV mass/volume ratio (HR, 1.3; 95% CI, 1.1 to 1.6). LV mass showed the strongest association with HF (HR, 1.8; 95% CI, 1.6 to 2.1). There were no significant interactions for imaging measures with sex and ethnicity for any CVD outcome. Compared with traditional risk factors alone, overall risk prediction (C statistic) for future CHD, HF, and all CVD was significantly improved by adding CAC, LV mass, and CAC, respectively (all P<0.05).
There was no evidence that imaging measures differed in association with incident CVD by sex. CAC was most strongly associated with CHD and CVD; LV mass and LV concentric remodeling best predicted stroke; and LV mass best predicted HF.
PMCID: PMC3037859  PMID: 21068189
imaging; cardiovascular diseases; sex
18.  Associations of Carotid Artery Intima-Media Thickness (IMT) With Risk Factors and Prevalent Cardiovascular Disease 
The goal of this study was to compare internal carotid artery (ICA) intima-media thickness (IMT) with common carotid artery (CCA) IMT as global markers of cardiovascular disease (CVD).
Cross-sectional measurements of the mean CCA IMT and maximum ICA IMT were made on ultrasound images acquired from the Framingham Offspring cohort (n = 3316; mean age, 58 years; 52.7% women). Linear regression models were used to study the associations of the Framingham risk factors with CCA and ICA IMT. Multivariate logistic regression models and receiver operating characteristic (ROC) curve analysis were used to compare the associations of prevalent CVD with CCA and ICA IMT and determine sensitivity and specificity.
The association between age and the mean CCA IMT corresponded to an increase of 0.007 mm/y; the increase was 0.037 mm/y for the ICA IMT. Framingham risk factors accounted for 28.6% and 27.5% of the variability in the CCA and ICA IMT, respectively. Age and gender contributed 23.5% to the variability of the CCA IMT and 22.5% to that of the ICA IMT, with the next most important factor being systolic blood pressure (1.9%) for the CCA IMT and smoking (1.6%) for the ICA IMT. The CCA IMT and ICA IMT were statistically significant predictors of prevalent CVD, with the ICA IMT having a larger area under the ROC curve (0.756 versus 0.695).
Associations of risk factors with CCA and ICA IMT are slightly different, and both are independently associated with prevalent CVD. Their value for predicting incident cardiovascular events needs to be compared in outcome studies.
PMCID: PMC3186063  PMID: 21098848
atherosclerosis; carotid artery; disease prevalence; intima-media thickness; risk factors
19.  Associations of antiretroviral drug use and HIV-specific risk factors with carotid intima–media thickness 
AIDS (London, England)  2010;24(14):2201-2209.
Previous research has demonstrated an increase in carotid intima–media thickness (cIMT) in HIV-infected individuals compared to controls. However, the reason for this increased level of subclinical vascular disease is unknown.
To identify HIV-related risk factors for increased cIMT.
We evaluated the relationship between HIV-related characteristics (including markers of HIV disease severity and use of antiretroviral therapy) and cIMT measurements in the internal/bulb and common carotid regions among 538 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). We used Bayesian model averaging to estimate the posterior probability of candidate HIV and non-HIV-related risk factors being true predictors of increased cIMT. Variables with a posterior probability of more than 50% were used to develop a selected regression model for each of the anatomic regions.
For common cIMT, the Bayesian model selection process identified age, African-American race, and systolic and diastolic blood pressure with probability more than 95%, HDL cholesterol with probability 85% and Hispanic ethnicity with probability 51%. Among the HIV-related factors included in the analysis, only tenofovir use was selected (51% probability). In the selected model, duration of tenofovir use was associated with lower common cIMT (−0.0094 mm/year of use; 95% confidence interval: −0.0177 to −0.0010). For internal cIMT, no HIV-related risk factors were above the 50% posterior probability threshold.
We observed an inverse association between duration of tenofovir use and common carotid cIMT. Whether this association is causal or due to confounding by indication needs further investigation.
PMCID: PMC3224487  PMID: 20671544
atherosclerosis; carotid intima–media thickness; HIV; tenofovir
20.  Segment-Specific Associations of Carotid IMT with Cardiovascular Risk Factors: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Background and Purpose
We propose to study possible differences in the associations between risk factors for cardiovascular disease (myocardial infarction and stroke) and Carotid Intima-Media thickness (IMT) measurements made at three different levels of the carotid bifurcation. Methods: Cross-sectional study of a cohort of Whites and African Americans of both genders with mean age 45 years. Traditional cardiovascular risk factors were determined in cohort members. Carotid IMT was measured from high-resolution B-mode ultrasound images at three levels: the common carotid artery (CCA), the carotid artery bulb (Bulb) and the internal carotid artery (ICA). Associations with risk factors were evaluated by multivariate linear regression analyses.
Of 3258 who underwent carotid IMT measurements, CCA, Bulb, and ICA IMT were measured at all three separate levels in 3023 (92.7%). A large proportion of the variability of CCA IMT was explained by cardiovascular risk factors (26.8%) but less so for the Bulb (11.2%) and ICA (8.0%). Carotid IMT was consistently associated with age, LDL-cholesterol, smoking and hypertension in all segments. Associations with fasting glucose and diastolic blood pressure were stronger for CCA than for the other segments. Hypertension, diabetes and current smoking had qualitatively stronger associations with Bulb IMT, and LDL cholesterol with ICA IMT. Conclusion: In our cohort of relatively young white and African-American men and women, a greater proportion of the variability in common carotid IMT can be explained by traditional cardiovascular risk factors than for the carotid artery bulb and internal carotid arteries.
PMCID: PMC3163306  PMID: 19910544
Carotid Intimal Medial Thickness; Risk Factors; Carotid Ultrasound
21.  Long-Term Exposure to Airborne Particles and Arterial Stiffness: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Environmental Health Perspectives  2011;119(6):844-851.
Increased arterial stiffness could represent an intermediate subclinical outcome in the mechanistic pathway underlying associations between average long-term pollution exposure and cardiovascular events.
We hypothesized that 20 years of exposure to particulate matter (PM) ≤ 2.5 and 10 μm in aerodynamic diameter (PM2.5 and PM10, respectively) would be positively associated with arterial stiffness in 3,996 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who were seen at six U.S. study sites.
We assigned pollution exposure during two decades preceding a clinical exam (2000–2002) using observed PM10 from monitors nearest participants’ residences and PM10 and PM2.5 imputed from a space-time model. We examined three log-transformed arterial stiffness outcome measures: Young’s modulus (YM) from carotid artery ultrasound and large (C1) and small (C2) artery vessel compliance from the radial artery pulse wave. All associations are expressed per 10 μg/m3 increment in PM and were adjusted for weather, age, sex, race, glucose, triglycerides, diabetes, waist:hip ratio, seated mean arterial pressure, smoking status, pack-years, cigarettes per day, environmental tobacco smoke, and physical activity. C1 and C2 models were further adjusted for heart rate, weight, and height.
Long-term average particle exposure was not associated with greater arterial stiffness measured by YM, C1, or C2, and the few associations observed were not robust across metrics and adjustment schemes.
Long-term particle mass exposure did not appear to be associated with greater arterial stiffness in this study sample.
PMCID: PMC3114821  PMID: 21245016
air pollution; arterial stiffness; environmental air pollutants; epidemiology
Hypertension  2010;55(5):1210-1216.
Hypertension is associated with impaired endothelial function in cross-sectional studies. However, few longitudinal data exist on whether endothelial dysfunction precedes the development of hypertension. We examined the cross-sectional and longitudinal relationships between endothelial-dependent brachial artery flow-mediated dilation (FMD) and hypertension prevalence and incidence in 3,500 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), an ethnically diverse, community-based cohort study. At baseline, the prevalence ratios (95% CI) of hypertension from the highest to the lowest quartile of FMD were 1.00 (referent), 1.26 (1.12 – 1.40), 1.35 (1.21 – 1.52), and 1.68 (1.50 – 1.87) (linear trend P < 0.001). This association remained (P = 0.017) after adjustment for demographics (age, gender, ethnicity), MESA site, and other risk factors. Of the 1,869 participants without hypertension at baseline, 584 (31.3%) developed hypertension over a median follow-up of 4.8 years. The unadjusted relative risks (95% CI) of incident hypertension from the highest to the lowest quartile of FMD were 1.00 (referent), 1.38 (1.14 – 1.67), 1.44 (1.19 – 1.74), and 1.64 (1.36 – 1.97) (linear trend P < 0.001). However, after adjustment for demographics and MESA site, the relationship between FMD and incident hypertension was attenuated and not statistically significant: 1.00 (referent), 1.26 (1.04 – 1.52), 1.19 (0.98 – 1.44), and 1.18 (0.97 – 1.44). The longitudinal results also did not appreciably change after adjustment for additional risk factors and baseline blood pressure levels. In this sample, reduced FMD was not an independent predictor of hypertension incidence, suggesting that impaired endothelial function does not play a major role in the development of hypertension.
PMCID: PMC2896877  PMID: 20308612
hypertension; blood pressure; endothelium; atherosclerosis; epidemiology
23.  A Genome-wide Association Study of Carotid Atherosclerosis in HIV-infected Men 
AIDS (London, England)  2010;24(4):583-592.
The role of host genetics in the development of subclinical atherosclerosis in the context of HIV infected persons who are being treated with highly active antiretroviral therapy (HAART) is not well understood.
The present genome-wide association study (GWAS) is based on 177 HIV-positive Caucasian males receiving HAART who participated in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) Study. Common and internal carotid intima-media thicknesses (cIMT) measured by B-mode ultrasound were used as a subclinical measure of atherosclerosis. Single nucleotide polymorphisms (SNPs) were assayed using the Illumina HumanCNV370-quad beadchip. Copy Number Variants (CNV) were inferred using a hidden Markov Model (PennCNV). Regression analyses were used to assess the association of common and internal cIMT with individual SNPs and CNVs, adjusting for age, duration of antiretroviral treatment, and principal components to account for potential population stratification.
Two SNPs in tight linkage disequilibrium, rs2229116 (a missense, nonsynonymous polymorphism (IIe to Val)) and rs7177922, located in the Ryanodine receptor (RYR3) gene on chromosome 15 were significantly associated with common cIMT (p-value<1.61×10−7). The RYR gene family has been known to play a role in the etiology of cardiovascular disease and has been shown to be regulated by HIV TAT protein.
These results suggest that in the context of HIV infection and HAART, a functional SNP in a biologically plausible candidate gene, RYR3, is associated with increased common carotid IMT, which is a surrogate for atherosclerosis.
PMCID: PMC3072760  PMID: 20009918
HIV; HAART; atherosclerosis; GWAS; 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 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

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