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1.  Differences in Subclinical Cardiovascular Disease between African American and Caucasian Women with Systemic Lupus Erythematosus 
Racial differences exist in disease rates and mortality in both cardiovascular disease (CVD) and Systemic Lupus Erythematosus (SLE). The objective of this cross-sectional study was to compare the frequency of and risk factors for subclinical CVD in African-American (AA) and Caucasian women with SLE and no prior CVD events.
Traditional CVD risk factors and SLE-related factors were assessed in 309 SLE women. Subclinical CVD was assessed by carotid ultrasound to measure intima-medial thickness (IMT) and plaque, and electron beam computed tomography (EBCT) to measure coronary artery calcium (CAC).
AA had less education, higher body mass index, blood pressure, lipoprotein(a), CRP, fibrinogen, and ESR, but lower albumin; more and longer duration of corticosteroid use; higher SLE disease activity and damage; and more had dsDNA antibodies compared to Caucasian women, after adjustment for age and study-site. More AA had carotid plaque (adjusted OR 1.94, 95%CI 1.03, 3.65) and higher carotid IMT (0.620 vs. 0.605mm, p=0.07) compared with Caucasians, but similar CAC. Multivariate analysis included risk factor variables significantly different between the racial groups and associated with plaque: blood pressure, current corticosteroid use, SLE disease activity and damage. All factors contributed, but no individual risk factor fully accounted for the association between race and plaque.
In conclusion, the presence of carotid plaque was higher in AA compared with Caucasian women with SLE, in contrast to studies of non-SLE subjects, where AA have similar or less plaque than Caucasians. A combination of SLE-related and traditional CVD risk factors explained the racial difference in plaque burden.
PMCID: PMC2674850  PMID: 19138649
Systemic Lupus Erythematosus; Race; Cardiovascular Disease
2.  Coronary Calcification is More Predictive of Carotid Intimal Medial Thickness in Black Compared to White Middle Aged Men 
Atherosclerosis  2007;196(2):913-918.
Race-specific data for the association between coronary artery calcification (CAC) and carotid intimal medial thickness (IMT) are limited. We sought to compare black-white specific associations of these two measures.
We conducted a population-based study of 379 randomly-selected men aged 40–49 years (84 black and 295 white) from Allegheny County, US (2004–2006). Agatston CAC score was evaluated by electron-beam tomography and carotid IMT was evaluated by ultrasonography.
Compared to white men, black men had similar prevalence of CAC (p=0.56) and higher total carotid IMT (p<0.001). In black and white men, CAC score had significant positive correlations with total carotid IMT (r=0.47 & r=0.24 respectively, p<0.001 for both) as well as the IMT for the common carotid artery (CCA), internal carotid artery and carotid bulb. The associations of CAC with total and CCA IMT were significantly stronger in black (beta=0.07 & beta=0.05 respectively) than white men (beta=0.03 & beta=0.01 respectively) after adjustment for traditional coronary risk factors (p=0.046 & p=0.036 respectively).
In black and white middle-aged men, CAC score had significant positive correlations with total and segmental carotid IMT. CAC was more predictive of total and CCA IMT in black than white men independent of coronary risk factors.
PMCID: PMC3089019  PMID: 17350026
Epidemiology; atherosclerosis; coronary calcification; carotid intimal medial thickness; Caucasian; black
3.  Racial differences in the burden of coronary artery calcium and carotid intima media thickness between Blacks and Whites 
Netherlands Heart Journal  2014;23(1):44-51.
Identification of racial differences in the burden and correlates of carotid intima media thickness (CIMT) and coronary artery calcium (CAC) may provide the basis for the development of race-specific cardiovascular disease (CVD) risk prediction algorithms.
In the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study, CIMT was measured by carotid ultrasonography in 792 individuals (35 % Black). CIMT >1 mm was considered significant. CAC was quantified by electron beam computed tomography in 776 individuals (46 % Black). CAC was considered significant if the Agatston score was >100. Cross-sectional associations between race, CIMT and CAC were assessed using logistic regression models.
Blacks had greater CIMT (mean difference 0.033 mm, 95 % CI 0.005–0.06 mm; p = 0.02) and 1.5-fold (95 % CI 1.0–2.3) higher odds of having significant CIMT than Whites. Blacks had less CAC than Whites (mean Agatston score difference 66, [11–122]; p = 0.02) and 50 % lower odds of a significant CAC score compared with Whites (0.5 [0.3–0.7]). These associations were virtually unchanged after adjustment for CVD risk factors. Of the novel CVD risk markers assessed, small-dense low-density lipoprotein was independently associated with increased odds of significant CIMT, with the association being similar among Blacks and Whites (odds ratio [95 % CI]: 1.7 [1.2–2.5] and 1.4 [1.0–1.8] per 1-SD higher level, respectively). Interleukin-6 was significantly associated with CAC among Blacks (1.4 [1.0–2.0]).
Black race is independently associated with greater CIMT but less CAC than White race. CVD risk stratification strategies that incorporate these measures of subclinical atherosclerosis should consider race-specific algorithms.
Electronic supplementary material
The online version of this article (doi:10.1007/s12471-014-0610-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4268220  PMID: 25342280
Carotid intima media thickness; Coronary artery calcium; Subclinical atherosclerosis; Racial-disparity; Risk factor; Observational study
4.  Predictors of progression in atherosclerosis over 2 years in systemic lupus erythematosus 
Rheumatology (Oxford, England)  2011;50(11):2071-2079.
Objectives. Cardiovascular disease remains the major cause of death in SLE. We assessed the degree to which cardiovascular risk factors (CVRFs) and disease activity were associated with 2-year changes in measures of subclinical atherosclerosis.
Methods. One hundred and eighty-seven SLE patients participating in a placebo-controlled trial of atorvastatin underwent multi-detector CT [for coronary artery calcium (CAC)] and carotid duplex [for carotid intima–media thickness (IMT) and carotid plaque] twice, 2 years apart. During the 2 years, patients were assessed every 3 months for CVRF. Both groups were combined for analysis, as atorvastatin did not differ from placebo in preventing progression of coronary calcium. We examined the correlation between these clinical measures and progression of CAC, IMT and plaque during the follow-up period.
Results. In an analysis adjusting for age, gender and ethnicity, CAC progression was positively associated with total serum cholesterol measured over the 2-year period (P = 0.04) and smoking (P = 0.003). Carotid IMT progression was associated with systolic BP (P = 0.003), high-sensitivity CRP (hsCRP) (P = 0.013) and white blood cell (WBC) count (P = 0.029). Carotid plaque progression, defined as patients without carotid plaque at baseline with subsequent development of plaque at follow-up, was associated with systolic BP (P = 0.003), WBC count (P = 0.02), physician's global assessment (P = 0.05), blood lymphocyte count (P = 0.048), urine protein (P = 0.017) and duration of SLE (P = 0.019).
Conclusion. Our data did not provide evidence of an association between measures of SLE disease activity (SLEDAI, anti-dsDNA, anti-phospholipid and treatment) and progression of subclinical atherosclerosis. Age and hypertension were associated with the progression of carotid IMT and plaque. Age, smoking and cholesterol were associated with progression of CAC.
PMCID: PMC3247795  PMID: 21875880
Systemic lupus erythematosus; Helical computed tomography; Coronary artery calcium; Carotid intima–media thickness; Carotid plaque; Inflammation; Atherosclerosis; Carotid duplex; Coronary artery disease; Statins
5.  Mycophenolate mofetil (MMF) does not slow the progression of subclinical atherosclerosis in SLE over 2 years 
Rheumatology international  2011;32(9):2701-2705.
Accelerated atherosclerosis is a major cause of mortality in SLE. Mycophenolate mofetil (MMF) has been shown to suppress growth factor-induced proliferation of vascular smooth muscle and endothelial cells in animal models. We hypothesized that MMF might modify the inflammatory component of atherosclerosis in SLE. We examined the effect of MMF on atherosclerosis as measured by changes in carotid intima–media thickness (IMT) or coronary artery calcium (CAC) over 2 years. CAC and carotid IMT were measured at baseline and 2 years later in a cohort of 187 patients with SLE. The cohort was 91% women, 59% Caucasian, and 35% African-American, with a mean age of 45 ± 11 years. Of these, 12.5% (n = 25) received MMF during follow-up. The daily dose ranged from 500 to 3,000 mg/day, and duration ranged from 84 days to the entire 2 years. We divided MMF users into three groups: low exposure (<1,500 mg average daily dose), high exposure (≥1,500 average daily dose), and any exposure of MMF (<1,500 or ≥1,500 average daily dose) for 2 years. The mean CAC increased in all four groups: no MMF: 1.17–1.28, low MMF: 1.02–1.13, high MMF: 1.44–1.61, and any MMF: 1.21–1.34 log-Agatston units. Compared to no MMF, there was no statistically different change between the three groups (p = 0.99, 0.87, and 0.91). Similarly, mean carotid IMT increased in all four groups: no MMF: 0.58–0.66, low MMF: 0.55–0.60, high MMF: 0.56–0.71, and any MMF: 0.56–0.66. We then adjusted for statin use, lupus nephritis, body mass index, systolic blood pressure, cholesterol, and age during the 2-year follow-up. The association between MMF exposure and change in CAC or carotid IMT was not statistically significant (p = 0.63 for CAC, and p = 0.085 for carotid IMT). There was no evidence that MMF slowed or decreased the progression of atherosclerosis as measured by carotid IMT or CAC. Because the number of patients taking MMF was only twenty-five, larger studies for longer time periods are needed to explore any effect of MMF on subclinical atherosclerosis in SLE.
PMCID: PMC3601823  PMID: 21792642
Systemic lupus erythematosus; Mycophenolate mofetil; Atherosclerosis
6.  Serum 25-hydroxyvitamin D levels are not associated with subclinical vascular disease or C-reactive protein in the Old Order Amish 
Calcified tissue international  2009;84(3):195-202.
The relationship between vitamin D metabolites and subclinical vascular disease is controversial. Because low serum levels of 25-hydroxyvitamin D [25(OH)D] have been associated with many cardiovascular disease (CVD) risk factors, we hypothesized that serum 25(OH)D levels would be inversely associated with inflammation as measured by C-reactive protein (CRP) and with subclinical vascular disease as measured by carotid intimal medial thickness (cIMT) and coronary artery calcification (CAC).
We measured 25(OH)D levels in 650 Amish participants. CAC was measured by computed tomography, and cIMT by ultrasound. The associations of 25(OH)D levels with natural log(CAC+1), cIMT, and natural log(CRP) levels were estimated following adjustment for age, sex, family structure, and season of examination. Additional analyses were carried out adjusting for body mass index (BMI) and other CVD risk factors.
25(OH)D deficiency (<20 ng/ml) and insufficiency (21-30 ng/ml) were common among the Amish (38.2% and 47.7%, respectively). 25(OH)D levels were associated with season, age, BMI, and parathyroid hormone levels. In neither the minimally or fully adjusted analyses were significant correlations observed between 25(OH)D levels and CAC, cIMT, or CRP (R2 < 0.01 for all).
Contrary to our hypothesis, this study failed to detect a cross-sectional association between serum 25(OH)D levels and CAC, cIMT, or CRP. Either there is no causal relationship between 25(OH)D and CVD risk, or, if there is, it may be mediated through mechanisms other than subclinical vascular disease severity.
PMCID: PMC2908302  PMID: 19148561
Little is known about whether the childhood family psychosocial environment (characterized by cold, unaffectionate interactions, conflict, aggression, neglect and/or low nurturance) affects coronary heart disease (CHD) risk. Objectives were to evaluate associations of childhood family psychosocial environment with carotid intima media thickness (IMT), a subclinical measure of atherosclerosis. The study population included 2,659 CARDIA study participants, aged 37-52 years. Childhood family psychosocial environment was measured using a risky family questionnaire via self-report. Carotid IMT was calculated using the average of 20 measurements of mean common carotid, bulb and internal carotid IMT, assessed using high-resolution B-mode ultrasound images. Utilizing linear regression analyses adjusted for age, a 1-unit (range 0-21) increase in risky family score was associated with 0.0036 (95% CI:0.0006,0.0066 mm) and 0.0020 (95% CI:0.0002,0.0038) mm increase in mean IMT in white males and females, respectively. Formal mediation analyses and covariate adjustments suggested childhood socioeconomic position and smoking may be important mechanisms in white males and females, as well as education and depressive symptomatology in white males. No associations were found in black participants. Formal statistical tests for interaction between risky family score and sex, and between risky family score and race/ethnicity, demonstrated borderline evidence of interactions for both sex (p=0.12) and race/ethnicity (p=0.14) with risky family score for associations with mean IMT. In conclusion, childhood family psychosocial environment was positively associated with IMT in white participants, with little evidence of association in black participants. Mechanisms in white participants may include potential negative impacts of socioeconomic constraints on parenting quality, potentially influencing offspring's cardiovascular risk factors (e.g. smoking), socioeconomic position (e.g. education), and/or psychosocial functioning (e.g. depression), which may in turn lead to atherosclerotic processes. Borderline racial/ethnic differences in findings should be replicated, but add to literature exploring race/ethnicity-specific associations of parenting approaches with health outcomes.
PMCID: PMC4017861  PMID: 24581057
8.  Genetic ancestry is associated with subclinical cardiovascular disease in African Americans and Hispanics from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Differences in cardiovascular disease (CVD) burden exist among racial/ethnic groups in the United States, with African Americans having the highest prevalence. Subclinical CVD measures have also been shown to differ by race/ethnicity. In the United States, there has been significant intermixing among racial/ethnic groups creating admixed populations. Very little research exists on the relationship of genetic ancestry and subclinical CVD measures.
Methods and Results
These associations were investigated in 712 African-American and 705 Hispanic participants from the MESA candidate gene sub-study. Individual ancestry was estimated from 199 genetic markers using STRUCTURE. Associations of ancestry and coronary artery calcium (CAC) and common and internal carotid intima media thickness (cIMT) were evaluated using log-binomial and linear regression models. Splines indicated linear associations of ancestry with subclinical CVD measures in African-Americans, but presence of threshold effects in Hispanics. Among African Americans, each standard deviation (SD) increase in European ancestry was associated with an 8% (95% CI (1.02, 1.15), p=0.01) greater CAC prevalence. Each SD increase in European ancestry was also associated with a 2% (95% CI (−3.4%, −0.5%), p=0.008) lower common cIMT in African Americans. Among Hispanics, the highest tertile of European ancestry was associated with a 34% greater CAC prevalence, p=0.02 as compared to lowest tertile.
The linear association of ancestry and subclinical CVD suggests that genetic effects may be important in determining CAC and cIMT among African-Americans. Our results also suggest that CAC and common cIMT may be important phenotypes for further study with admixture mapping.
PMCID: PMC2795643  PMID: 20031644
atherosclerosis; calcium; ancestry; epidemiology; genetics
9.  Carotid Plaque, Carotid Intima-Media Thickness, and Coronary Calcification Equally Discriminate Prevalent Cardiovascular Disease in Kidney Disease 
American journal of nephrology  2012;36(4):342-347.
Despite the significant morbidity and mortality attributable to cardiovascular disease (CVD), risk stratification remains an important challenge in the chronic kidney disease(CKD) population. We examined the discriminative ability of non-invasive measures of atherosclerosis, including carotid intima-media thickness(cIMT), carotid plaque, coronary artery calcification(CAC) and ascending and descending thoracic aorta calcification(TCAC), and Framingham Risk Score (FRS) to predict self-reported prevalent CVD.
Methods and Results
Participants were enrolled in the cIMT ancillary study of the Chronic Renal Insufficiency Cohort(CRIC) Study and also had all of the above measures within an 18 month period. CVD was present in 21% of study participants. C-statistics were used to ascertain the discriminatory power of each measure of atherosclerosis. The study population (n=220) was 64% male; 51% black and 45% white. The proportion of individuals with estimated glomerular filtration rate ≥60, 45–59, 30–44, and <30ml/min/1.73m2 was 21%, 41%, 28%, and 11%, respectively. In multivariable analyses adjusting for demographic factors, we failed to find a difference between CAC, carotid plaque, and cIMT as predictors of self-reported prevalent CVD (c-statistic 0.70, 95% confidence interval [CI]: 0.62–0.78; c-statistic 0.68, 95% CI: 0.60–0.75, and c-statistic 0.64, CI: 0.56–0.72, respectively). CAC was statistically better than FRS. FRS was the weakest discriminator of self-reported prevalent CVD (c-statistic 0.58).
There was a significant burden of atherosclerosis among individuals with CKD, ascertained by several different imaging modalities. We were unable to find a difference in the ability of CAC, carotid plaque, and cIMT to predict self-reported prevalent CVD.
PMCID: PMC3538165  PMID: 23107930
carotid intima media thickness; coronary artery calcification; kidney; plaque
10.  Coronary Artery Calcium, Carotid Artery Wall Thickness and Cardiovascular Disease Outcomes in Adults 70 to 99 Years Old 
The American journal of cardiology  2008;101(2):186-192.
Few population studies have evaluated the associations of both coronary artery calcium (CAC) and carotid ultrasound with cardiovascular events, especially in adults > 70 years of age. At the Pittsburgh Field Center of the Cardiovascular Health Study, 559 men and women, mean age 80.2 (SD 4.1) years had CAC score assessed by electron beam computerized tomography scan and common and internal carotid intimal-medial wall thickness (CCA-IMT and ICA-IMT) by carotid ultrasound between 1998−2000 and were followed for total and incident cardiovascular disease events through June 2003. Crude rates and hazard ratios for total and incident events were examined with and without adjustment for cardiovascular risk factors. After 5 years, there were 127 cardiovascular disease events, 48 myocardial infarctions or cardiovascular disease deaths and 28 strokes or stroke deaths. Total and incident cardiovascular disease event rates were higher in each quartile of CAC and CCA-IMT, but not ICA-IMT. For total cardiovascular disease, the adjusted hazard ratio for the 4th vs. 1st quartile of CAC was 2.1 (95% CI = 1.2−3.9) and for CCA-IMT was 2.3 (95% CI = 1.3−4.1). The CCA-IMT was more strongly related to stroke risk than was CAC, though CAC was also an important predictor of stroke. No significant sex differences were found, though relative risks appeared to be stronger in women, especially for stroke. In conclusion, in these adults > 70 years of age, CAC and CCA-IMT had similar hazard ratios for total cardiovascular disease and coronary heart disease. The CCA-IMT was more strongly related to stroke than was CAC, but CAC was also a predictor of stroke.
PMCID: PMC2213559  PMID: 18178404
calcium; cardiovascular diseases; coronary disease; prognosis
11.  A Comparison of Coronary Artery Calcium Presence, Carotid Plaque Presence, and Carotid Intima-Media Thickness for Cardiovascular Disease Prediction in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Presence of coronary artery calcium (CAC), carotid plaque, and increased carotid intima media thickness (IMT) may indicate elevated cardiovascular disease (CVD) risk; however, no large studies have compared them directly. This study compares predictive utilities of CAC presence, carotid artery plaque presence, and high IMT for incident CVD events.
Methods and Results
Participants were from the Multi-Ethnic Study of Atherosclerosis. Predictive values of carotid plaque, IMT and CAC presence were compared using Cox proportional hazards models, c-statistics, and net reclassification indices. The 6,779 participants were mean (standard deviation) 62.2 (10.2) years old; 49.9% had CAC, 46.7% had carotid plaque. The mean left and right IMT were 0.754 (0.210) mm and 0.751 (0.187) mm, respectively. After 9.5 years (mean), 538 CVD events, 388 coronary heart disease (CHD) events, and 196 stroke/transient ischemic attacks (TIA) were observed. CAC presence was a stronger predictor of incident CVD and CHD than carotid ultrasound measures. Mean IMT ≥75th percentile (for age, sex and race) alone did not predict events. Compared to traditional risk factors, c-statistics for CVD (c=0.756) and CHD (c=0.752) increased most by adding of CAC presence (CVD 0.776, CHD, 0.784; p<0.001) followed by carotid plaque presence (CVD c=0.760, CHD 0.757; p<0.05). Compared to risk factors (c=0.782), carotid plaque presence (c=0.787, p=0.045) but not CAC (c=0.785, p=0.438) improved prediction of stroke/TIA.
In adults without CVD, CAC presence improves prediction of CVD and CHD more than carotid plaque presence or high IMT. CAC and carotid ultrasound parameters performed similarly for stroke/TIA event prediction.
PMCID: PMC4299916  PMID: 25596139
atherosclerosis; cardiovascular disease; carotid artery; imaging; risk factor
12.  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.
13.  Effects of Aging and Smoking on Carotid Intima Media Thickness in HIV-infection 
AIDS (London, England)  2013;27(1):49-57.
To investigate the effects of aging and smoking on carotid intima-media thickness (cIMT) among patients with and without HIV.
Data from a community sample of HIV-infected and HIV-uninfected participants were analyzed. Carotid intima-media thickness was measured via carotid ultrasound and smoking history was obtained via patient interview.
Data on 166male and female participants with stable HIV-infection and 152 healthy HIV-uninfected participants were analyzed. Among the HIV-infected and HIV-uninfected participants, a significant association was observed between age and cIMT [r=0.51, P<0.0001 (HIV), r=0.39, P<0.0001, (non-HIV)], and between smoking burden and cIMT [r=0.42, P<0.0001 (HIV), r=0.24, P=0.003 (non-HIV)]. In multivariate regression modeling among all participants (HIV and non-HIV), a significant three-way interaction was observed between age, smoking burden, and HIV status with respect to cIMT (P<0.010), controlling for gender, race and traditional cardiovascular disease (CVD) risk factors, such that increased cIMT was associated with increased smoking burden and age to a greater degree among HIV-infected vs. HIV-uninfected participants. Among HIV-infected participants a significant interaction between smoking burden and age with respect to cIMT was seen (P=0.027), controlling for race, gender, CVD risk factors, immunological function and antiretroviral therapy use.
A significant interaction between HIV, age and smoking on cIMT was observed, suggesting that HIV-infection modifies the relationship of age and smoking on cIMT in this population. These findings emphasize the need to encourage smoking cessation in this population, due to its deleterious effect on subclinical atherosclerosis in older HIV-infected patients.
PMCID: PMC3690796  PMID: 22874518
HIV; Aging; Cardiovascular Diseases; Smoking
14.  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
15.  Coffee, Decaffeinated Coffee, Caffeine, and Tea Consumption in Young Adulthood and Atherosclerosis Later in Life: The CARDIA Study 
Determine the association of coffee, decaffeinated coffee, caffeine, and tea consumption in young adulthood with the presence and progression of coronary artery calcified (CAC) plaque and carotid intima-media thickness (cIMT) later in life.
Methods and Results
CARDIA is a cohort of 5115 white and black adults who were 18–30 years when they completed a baseline clinic examination in 1985–1986. Subsequent examinations were conducted 2, 5, 7, 10, 15, and 20 years later. After multivariable adjustment, no association was observed between average coffee, decaffeinated coffee, or caffeine consumption (years 0 and 7) and presence of CAC [score >0 Agatston units (AU) at year 15 or 20], CAC progression (incident CAC at year 20 or an increase in CAC score ≥20 AU), or high cIMT (>80th percentile, year 20). Tea consumption, however, displayed a non-significant trend for an inverse association with CAC (ptrend0.08) and an inverse association with CAC progression (ptrend0.04), but no association with high cIMT (ptrend>0.2). Stratification of the coffee analyses by sex, race, or smoking yielded similar non-significant patterns.
We observed no substantial association between coffee or caffeine intake and coronary and carotid atherosclerosis. However, our results suggested an inverse association between tea and CAC, but not carotid atherosclerosis.
PMCID: PMC2940975  PMID: 20616310
antioxidants; atherosclerosis; carotid arteries; diet; epidemiology; nutrition
16.  Circulating soluble ICAM-1 and subclinical atherosclerosis: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Clinical chemistry  2011;58(2):10.1373/clinchem.2011.168559.
Soluble intercellular adhesion molecule-1 (sICAM-1) is associated with endothelial dysfunction and clinical cardiovascular disease. We investigated the relationship of subclinical atherosclerosis with sICAM-1 concentration.
sICAM-1 concentration was assayed at year 15 of the Coronary Artery Risk Development in Young Adults (CARDIA) Study (black and white men and women, average age 40 years). We assessed progression of coronary artery calcification through year 20 (CAC, n=2378), and both carotid artery stenosis (n=2432) and intima media thickness at year 20 (IMT, n = 2240).
Median sICAM-1 was 145.9 ng/ml. Among a subgroup with advanced atherosclerotic plaque (either CAC or stenosis), IMT was 0.010 (95% confidence interval (CI) 0.003–0.017 mm) higher per standard deviation of sICAM-1 (44 ng/ml) in a model adjusted for age, race, sex, clinic, smoking, exercise, body size, education, blood pressure, antihypertensive medication, plasma lipids, and cholesterol lowering medication. With the same adjustment, the odds ratios (OR) for the presence of year 20 carotid artery stenosis per SD of sICAM-1 was 1.12 (CI 1.01–1.25, p<0.04), while for occurrence of CAC progression the OR was 1.16 (CI 1.04–1.31, p<0.01). The associations with CAC and carotid stenosis were strongest in the top 20th of the sICAM-1 distribution.
sICAM-1 concentration may be an early biomarker that indicates changes in the artery wall that accompany atherosclerosis, as well as the presence of advanced plaque in the coronary and carotid arteries. This finding holds in people with low total burden of atherosclerosis, decades prior to the development of clinical CVD.
PMCID: PMC3867124  PMID: 22179741
17.  Relation of Serum Phosphorus Levels to Carotid Intima-media Thickness in Asymptomatic Young Adults (from the Bogalusa Heart Study) 
The American journal of cardiology  2010;106(6):793-797.
Elevated serum phosphorus has been associated with increased mortality from cardiovascular (CV) disease. However, information is scant regarding the influence of serum phosphorus within the normal range on vascular risk in terms of subclinical atherosclerosis in asymptomatic young adults. Serum phosphorus along with other CV risk factor variables were measured in 856 white and 354 black subjects without known CV disease or renal disease. Carotid intima-media thickness (IMT) was measured by B-mode ultrasonography. Significant race and sex differences were noted for serum phosphorus (blacks>whites) and carotid IMT (black females>white females; males>females). In bivariate analyses, serum phosphorus was correlated with carotid IMT (p<0.001); and smokers showed higher phosphorus levels than nonsmokers (p=0.008). In multivariate regression analyses, carotid IMT was significantly associated with serum phosphorus (regression coefficient β=0.028, p<0.001) and smoking (β=0.032, p<0.001), adjusting for other CV risk factors and estimated glomerular filtration rate. In addition, a significant interaction effect of cigarette smoking and serum phosphorus on carotid IMT was noted, with a greater increasing trend of carotid IMT with phosphorus in smokers than that in nonsmokers (p=0.019 for interaction). In conclusion, serum phosphorus within the normal range is an important correlate of carotid IMT in asymptomatic young adults, with smoking potentiating this adverse association.
PMCID: PMC3103213  PMID: 20816119
phosphorus; carotid artery; carotid intima-media thickness; cigarette smoking; atherosclerosis
18.  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
19.  Longitudinal assessment of fibrinogen in relation to subclinical cardiovascular disease: the CARDIA study 
To examine the strength of the associations of fibrinogen with subclinical atherosclerosis in healthy persons.
A population-based, prospective, observational study of black and white men and women (Coronary Artery Risk Development in Young Adults [CARDIA]). Fibrinogen levels were measured at year 7 (ages 25–37, n = 2969), and again at year 20 (ages 38–50, n = 2832). Measures of subclinical atherosclerosis (coronary artery calcification [CAC] and carotid intimal-medial thickness [CIMT]) were recorded at year 20.
Over the 13-year study interval (1992–1993 to 2005–2006), fibrinogen rose from a mean of 3.32 to 4.05 g L−1. After adjusting for age, gender and race, fibrinogen was positively associated with greater incidence of CAC and increased CIMT cross-sectionally as well as after 13 years of follow-up (all P-trend < 0.001). After further adjustment for field center, BMI, smoking, education, systolic blood pressure, diabetes, antihypertensive medication use, total and HDL cholesterol, and CRP, significant positive relationships between fibrinogen and incidence of CAC remained for the total cohort longitudinally (P-trend = 0.037), but not cross-sectionally (P-trend = 0.147).
This 13-year study demonstrates that higher levels of fibrinogen during young adulthood are positively associated with incidence of CAC and increased CIMT in middle-age, but the strength of the association declines with increasing age.
PMCID: PMC2856753  PMID: 20025644
atherosclerosis; carotid thickening; coronary calcification; fibrinogen
20.  Vitamin D Levels and Markers of Arterial Dysfunction in HIV 
HIV-infected patients have low vitamin D levels as well as an increase in cardiovascular (CVD) risk. We examined the relationship between vitamin D and three markers of arterial dysfunction among HIV-infected individuals on stable antiretroviral (ARV) therapy. Levels of 25-hydroxyvitamin D [25(OH)D] were assessed by chemiluminescent immunoassay (DiaSorin) in 100 enrollees into the Hawaii Aging with HIV-Cardiovascular Cohort Study, a cohort of HIV-infected subjects age ≥40 years on stable (≥6 months) ARV therapy. The relationships between 25(OH)D levels and brachial artery flow-mediated dilation (FMD), right common carotid artery intima-media thickness (cIMT), and coronary artery calcium (CAC) were examined. Analytical methods included Pearson's correlations, Kruskal–Wallis tests, relative risks, and linear regression models. The cohort was 86% male and 60% white with a median age of 52 years and CD4 of 510 cells/mm3. The median (Q1, Q3) level of 25(OH)D was 27.9 ng/ml (21.8, 38.3). There were 72 FMD, 50 cIMT, and 90 CAC measurements available for analyses. A significant correlation was observed between 25(OH)D levels and FMD (r=0.30, p=0.01) but not with cIMT (r=−0.05, p=0.76). In a linear regression model, Framingham risk score attenuated the relationship between FMD and 25(OH)D. Those with lower 25(OH)D levels were at slightly higher risk of having CAC (RR=1.02, p=0.04). Among those with CAC, lower 25(OH)D levels were not associated with higher CAC scores (p=0.36). Lower vitamin D levels are associated with evidence of subclinical arterial dysfunction in HIV-infected individuals. The significance of these findings warrants further investigation.
PMCID: PMC3399561  PMID: 21978287
21.  Increased prevalence of vulnerable atherosclerotic plaques and low levels of natural IgM antibodies against phosphorylcholine in patients with systemic lupus erythematosus 
Arthritis Research & Therapy  2010;12(6):R214.
The risk of cardiovascular disease (CVD) and atherosclerosis is reported to be increased in systemic lupus erythematosus (SLE). We recently reported a negative association between natural IgM-antibodies against phosphorylcholine (anti-PC) in the general population, high anti-PC levels leading to decreased atherosclerosis development and low levels to increased risk of CVD. Potential mechanisms include anti-inflammatory properties and inhibition of uptake of oxidized low density lipoprotein (LDL) in macrophages. The objective herein was to study atherosclerosis in SLE in detail and in relation to traditional and non-traditional risk factors.
A total of 114 patients with SLE were compared with 122 age- and sex-matched population-based controls. Common carotid intima-media thickness (IMT), calculated intima-media area (cIMa) and plaque occurrence were determined by B-mode ultrasound as a surrogate measure of atherosclerosis. Plaques were graded according to echogenicity and grouped as 1 to 4, with 1 being echoluscent, and considered most vulnerable. Anti-PC was studied by ELISA.
Hypertension, triglycerides and insulin resistance (determined by homeostasis model assessment of insulin resistance) and C-reactive protein (CRP) were increased in SLE (P < 0.01) while smoking, LDL, high density lipoprotein (HDL) did not differ between groups. Low levels of anti-PC IgM (lowest tertile) were more common in SLE patients than in controls (P = 0.0022). IMT and cIMa did not differ significantly between groups. However, plaques were more often found in SLE patients (P = 0.029). Age, LDL and IgM anti-PC (lowest tertile) were independently associated with plaque occurrence in SLE. Further, in the left carotid arteries echoluscent plaques (grade 1) were more prevalent in SLE as compared to controls (P < 0.016).
Plaque occurrence in the carotid arteries is increased in SLE and is independently associated with age, LDL and low anti-PC levels. Vulnerable plaques were more common in SLE. Anti-PC could be a novel risk marker also with a therapeutic potential in SLE.
PMCID: PMC3046524  PMID: 21092251
22.  Alpha-chlorofatty acid and coronary artery or aorta calcium scores in women with and without systemic lupus erythematosus. Pilot study 
The Journal of rheumatology  2014;41(9):1834-1842.
Alpha-chlorofatty acid (α-ClFA) is one product of myeloperoxidase activity in vivo during atherogenesis and may be a biomarker for cardiovascular disease (CVD). This study aims to determine if serum α-ClFA is associated with subclinical CVD as measured by coronary artery and aorta calcium scores, CAC and AC, respectively, in women with and without systemic lupus erythematosus (SLE).
This pilot project analyzes baseline data from 185 women with SLE and 186 women without SLE participating in a 5-year longitudinal study of the Study of Lupus Vascular and Bone Long-term Endpoints (SOLVABLE). Data collection included demographic information, CVD and SLE risk factors, and laboratory assessments. Alpha-ClFA was measured in stored serum by liquid chromatography-mass spectrometry. CAC and AC were measured by computed tomography. Outcome measures were the presence of high CAC and AC scores (CAC >10 or AC >100) versus low scores (CAC ≤10 or AC ≤100). Associations between risk factors and CAC or AC were tested with descriptive statistics and multivariate analyses.
SLE women had higher α-ClFA levels than women without SLE (42.2 fmol/25µl ± 36.4 vs 34.5 fmol/25µl ± 21.9, p=0.014). In analyses including individual CVD risk factors, having SLE was independently associated with high CAC and AC scores (OR 5.67, 95% CI 2.24 to 14.33 and OR 3.95, 95% CI 1.69 to 9.22, respectively). Alpha-ClFA was not associated with high CAC or AC scores in patients with SLE.
SLE, but not serum α-ClFA, was associated with the presence of high CAC and AC scores in this pilot project.
PMCID: PMC4724198  PMID: 25086078
systemic lupus erythematosus; cardiovascular disease; coronary artery calcium; aorta calcium
23.  Cholesteryl Ester Transfer Protein Genetic Polymorphisms, HDL Cholesterol, and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2008;200(2):359-367.
The cholesteryl ester transport protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, -629C/A, Taq1B, and -2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, and carotid intimal-medial thickness (IMT) and carotid artery plaque, measured by ultrasonography. Carriers of the 451Q and 373P alleles have significantly higher CETP concentration (22.4% and 19.5%, respectively; p<0.001) and activity (13.1% and 9.4%, respectively; p<0.01) and lower HDL-C (5.6% and 6.0%, respectively; p<0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p=0.006 and p=0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p=0.036). Neither polymorphism is associated with common or internal carotid IMT. We confirmed that the -629A, Taq1B B2, and -2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p<0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p<0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p<0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.
PMCID: PMC3612981  PMID: 18243217
24.  Association of inflammatory markers with subclinical atherosclerosis in middle-aged white, Japanese-American, and Japanese men: the ERA-JUMP Study 
To examine whether the inflammatory markers, C-reactive protein (CRP) and fibrinogen, are associated with biomarkers of atherosclerosis [carotid intima-media thickness (IMT) and coronary artery calcification (CAC)] in the general male population, including Asians.
Population-based samples of 310 Japanese, 293 Japanese-American and 297 White men aged 40-49 years without clinical cardiovascular disease had IMT, CAC, CRP and fibrinogen levels, and other conventional risk factors measured using standardized methods. Statistical associations between the variables were evaluated using multiple linear or logistic regression models.
The Japanese group had significantly lower levels of inflammatory markers and subclinical atherosclerosis than the Japanese-American and White groups (P-values all <0.001). The mean levels of CRP were 0.66 vs. 1.11 and 1.47 mg/L, and fibrinogen 255.0 vs. 313.0 and 291.5 mg/dl, respectively. Mean carotid IMT was 0.61 vs. 0.73 and 0.68 mm, and the prevalence of CAC 11.6% vs. 32.1% and 26.3%, respectively. Body mass index (BMI) showed significant positive associations with both CRP and fibrinogen levels. Although CRP showed a significant positive association with IMT in Japanese men, this association became non-significant after adjustment for traditional risk factors or BMI. In all three populations, CRP was not associated significantly with the prevalence of CAC. Similarly, fibrinogen did not show a significant association with either IMT or the prevalence of CAC.
The associations of inflammatory markers with subclinical atherosclerosis may merely reflect the strong association of BMI with inflammatory markers and subclinical atherosclerosis in both Eastern and Western populations.
PMCID: PMC4449327  PMID: 25445888
obesity; C-reactive protein; fibrinogen; intima-media thickness; coronary artery calcification
25.  Coronary Artery Calcification in Obese Youth: What Are the Phenotypic and Metabolic Determinants? 
Diabetes Care  2014;37(9):2632-2639.
Obesity in adolescence has been associated with increased risk for coronary heart disease in adulthood. This study evaluated subclinical atherosclerosis in obese youth and the underlying risk factors.
Ninety obese adolescents (37 normal glucose tolerant, 27 prediabetes, and 26 type 2 diabetes) underwent evaluation of coronary artery calcifications (CACs) by electron beam computed tomography, aortic pulse wave velocity (PWV), carotid intima-media thickness (IMT), lipids, leptin, inflammatory markers, and body composition (DEXA). A total of 68 underwent evaluation of insulin sensitivity (IS) (hyperinsulinemic-euglycemic clamp) and abdominal adiposity (computed tomography).
A total of 50% had CACs (CAC+: Agatston CAC score ≥1). CAC+ youth had higher BMI, fat mass, and abdominal fat, with no difference in sex, race, IS per fat-free mass (ISFFM), glucose tolerance, PWV, or IMT compared with the CAC− group. PWV was inversely related to IS. In multiple regression analyses with age, race, sex, HbA1c, BMI (or waist circumference), ISFFM, diastolic blood pressure, non–HDL cholesterol, and leptin as independent variables, BMI (or waist) (R2 = 0.41; P = 0.001) was the significant determinant of CAC; leptin (R2 = 0.37; P = 0.034) for PWV; and HbA1c, race, and age (R2 = 0.34; P = 0.02) for IMT.
Early in the course of obesity, there is evidence of CAC independent of glycemia. The different biomarkers of subclinical atherosclerosis appear to be differentially modulated, adiposity being the major determinant of CAC, hyperglycemia, age, and race for IMT, and leptin and IS for arterial stiffness. These findings highlight the increased cardiovascular disease risk in obese youth and the need for early interventions to reverse obesity and atherosclerosis.
PMCID: PMC4392940  PMID: 25147256

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