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1.  Elevated Fibrinogen Levels and Subsequent Subclinical Atherosclerosis: The CARDIA Study 
Atherosclerosis  2008;202(2):623-631.
Objective
To determine whether elevated levels of hemostatic factors are associated with the subsequent development of subclinical cardiovascular disease.
Methods
Fibrinogen, factors VII (FVII) and VIII (FVIII), and von Willebrand factor (vWF) were measured in 1396 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Coronary artery calcification (CAC) and carotid intimal/medial thickness (CIMT) were determined 13 years later. The adjusted prevalence of CAC and mean CIMT across the quartiles of each hemostatic factor was computed for the total sample and for each race and gender group.
Results
The age, race, and gender-adjusted prevalences of CAC with increasing quartiles of fibrinogen were 14.4%, 15.2%, 20.0%, and 29.1% (p<0.001 for trend). This trend persisted after further adjustment for body mass index (BMI), smoking, educational level, center, systolic blood pressure (BP), diabetes, antihypertensive medication use, total and high density lipoprotein (HDL) cholesterol, and CRP. A similar trend was observed for CIMT (age, race and gender-adjusted, p<0.001; multivariable-adjusted, p=0.014). Further analyses of race and gender subgroups showed that increasing quartiles of fibrinogen were associated with CAC and CIMT in all subgroups except black men. The prevalence of CAC was not associated with increasing quartiles of FVII, FVIII or vWF, suggesting they may be less involved in plaque progression.
Conclusion
An elevated fibrinogen concentration in persons aged 25 to 37 is independently associated with subclinical cardiovascular disease in the subsequent decade.
doi:10.1016/j.atherosclerosis.2008.05.039
PMCID: PMC2662501  PMID: 18602107
hemostatic factors; coronary calcium; carotid thickness; fibrinogen; atherosclerosis
2.  Impact of Subclinical Atherosclerosis on Cardiovascular Disease Events in Individuals With Metabolic Syndrome and Diabetes 
Diabetes Care  2011;34(10):2285-2290.
OBJECTIVE
While metabolic syndrome (MetS) and diabetes confer greater cardiovascular disease (CVD) risk, recent evidence suggests that individuals with these conditions have a wide range of risk. We evaluated whether screening for coronary artery calcium (CAC) and carotid intimal-medial thickness (CIMT) can improve CVD risk stratification over traditional risk factors (RFs) in people with MetS and diabetes.
RESEARCH DESIGN AND METHODS
We assessed CAC and CIMT in 6,603 people aged 45–84 years in the Multi-Ethnic Study of Atherosclerosis (MESA). Cox regression examined the association of CAC and CIMT with coronary heart disease (CHD) and CVD over 6.4 years in MetS and diabetes.
RESULTS
Of the subjects, 1,686 (25%) had MetS but no diabetes and 881 (13%) had diabetes. Annual CHD event rates were 1.0% among MetS and 1.5% for diabetes. Ethnicity and RF-adjusted hazard ratios for CHD for CAC 1–99 to ≥400 vs. 0 in subjects with neither MetS nor diabetes ranged from 2.6 to 9.5; in those with MetS, they ranged from 3.9 to 11.9; and in those with diabetes, they ranged from 2.9 to 6.2 (all P < 0.05 to P < 0.001). Findings were similar for CVD. CAC increased the C-statistic for events (P < 0.001) over RFs and CIMT in each group while CIMT added negligibly to prediction over RFs.
CONCLUSIONS
Individuals with MetS or diabetes have low risks for CHD when CAC or CIMT is not increased. Prediction of CHD and CVD events is improved by CAC more than by CIMT. Screening for CAC or CIMT can stratify risk in people with MetS and diabetes and support the latest recommendations regarding CAC screening in those with diabetes.
doi:10.2337/dc11-0816
PMCID: PMC3177707  PMID: 21844289
3.  Intakes of long-chain n-3 polyunsaturated fatty acids and fish in relation to measurements of subclinical atherosclerosis 
Background
Data on the relations of different types of fish meals and long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) with measures of atherosclerosis are sparse.
Objective
We examined intakes of long-chain n-3 PUFAs and fish in relation to clinical measures of subclinical atherosclerosis.
Design
A cross-sectional study was conducted in 5,488 multiethnic adults aged 45–84 years and free of clinical cardiovascular disease. Diet was assessed using self-administered food frequency questionnaires. Subclinical atherosclerosis was determined by common carotid intima-media thickness (cCIMT, >80th percentile), internal CIMT (iCIMT, >80th percentile), coronary artery calcium score (CAC, >0) or ankle-brachial index (ABI, <0.90), respectively.
Results
After adjustment for potential confounders, intakes of long-chain n-3 PUFAs and non-fried (broiled, steamed, baked or raw) fish were inversely related to subclinical atherosclerosis determined by cCIMT but not iCIMT, CAC or ABI. The multivariable odds ratio comparing the highest to the lowest quartile of dietary exposures in relation to subclinical atherosclerosis determined by cCIMT was 0.69 (95% CI: 0.55, 0.86; p for trend<0.01) for n-3 PUFA intake, 0.80 (95% CI: 0.64, 1.01; p=0.054) for non-fried fish and 0.90 (95% CI: 0.73, 1.10; p=0.33) for fried fish consumption.
Conclusions
This study indicates that dietary intake of long-chain n-3 PUFAs or non-fried fish is associated with lower prevalence of subclinical atherosclerosis classified by cCIMT although significant changes in iCIMT, CAC and ABI were not observed. Our findings also suggest that the association of fish and atherosclerosis may vary depending on the type of fish meal consumed and the measures of atherosclerosis.
PMCID: PMC4151325  PMID: 18842801
long-chain n-3 polyunsaturated fatty acids; fish; fish oil; biomarker; subclinical atherosclerosis; multi-ethnicities
4.  Genetic ancestry is associated with subclinical cardiovascular disease in African Americans and Hispanics from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
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.
Conclusions
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.
doi:10.1161/CIRCGENETICS.109.876243
PMCID: PMC2795643  PMID: 20031644
atherosclerosis; calcium; ancestry; epidemiology; genetics
5.  Relationship between Common Carotid Intima-Media Thickness and Thoracic Aortic Calcification: the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2009;209(1):142-146.
Background
Mean maximum carotid intima-media thickness (CIMT) is associated with both coronary artery disease and cerebral thromboembolism. Thoracic aortic calcification (TAC) detected by computed tomography (CT) is also highly associated with vascular disease and cardiovascular risk. No previous study has examined the relationship between CIMT and TAC in a large patient cohort. We performed a cross-sectional study to determine whether, at baseline, there is a relationship between CIMT and CT-determined TAC score.
Methods
In the Multi-Ethnic Study of Atherosclerosis, the study cohort included a population based sample of four ethnic groups (Chinese, White, Hispanic and African-American) of 6814 women and men ages 45-84 years. After exclusion of 198 persons due to incomplete information, we compared results of 6616 participants with both CIMT and TAC. TAC was measured from the lower edge of the pulmonary artery bifurcation to the cardiac apex. CIMT at the common carotid artery site was represented as the mean maximal CIMT of the right and left near and far walls, respectively. Multivariable relative risk regression analysis was used to evaluate relationships between TAC and CIMT.
Results
The prevalence of TAC was 28% (n=1846) and the mean maximum (±SD) CIMT was 0.87±0.19 mm. A higher prevalence of TAC was noted across increasing CIMT quartiles (1st: 12%, 2nd: 21%, 3rd: 30%, 4th: 49%, P<0.0001). One standard deviation increase in CIMT was associated with a 16% higher likelihood for presence of TAC after adjusting for demographics and cardiovascular disease (CVD) risk factors (95% CI: 1.12-1.26). In addition, individuals with CIMT in the highest quartile, as compared to those with CIMT in the first quartile, had a 76% higher likelihood for presence of TAC (prevalence ratio [PR]: 1.76, 95% CI: 1.37-2.26). In race-ethnic stratified analyses, similar associations were seen in all groups. Among those with TAC>0, a higher CIMT was significantly associated with continuous TAC scores (log transformed) in the overall population as well as among all ethnic-racial groups.
Conclusions
Our study demonstrates that TAC is associated with increasing severity of carotid atherosclerotic burden as measured by CIMT. The combined utility of these two noninvasive measures of subclinical atherosclerosis for CVD risk assessment needs to be determined in future studies.
doi:10.1016/j.atherosclerosis.2009.09.013
PMCID: PMC2830343  PMID: 19782983
Atherosclerosis; carotid IMT; aortic calcification; ethnic; cardiac CT
6.  Factors Associated with Presence and Extent of Coronary Calcium in Individuals Predicted to be at Low Risk Based on Framingham Risk Score (From The Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2011;107(6):879-885.
Even among asymptomatic people at low risk (<10%) by Framingham Risk Score (FRS), high coronary artery calcium (CAC) scores signify higher predicted risk of coronary heart disease (CHD) events. We sought to determine non-invasive factors (without radiation exposure) significantly associated with CAC in low-risk, asymptomatic persons. In a cross-sectional analysis, we studied 3046 participants from MESA at low 10-year predicted risk (FRS <10%) for CHD events. Multivariable logistic regression was used to assess the association of novel markers with presence of any CAC (CAC >0) and advanced CAC (CAC ≥ 300). CAC >0 and CAC ≥ 300 were present in 30% and 3.5% of participants, respectively. Factor VIIIc, fibrinogen and sICAM were each associated with CAC presence (P ≤ 0.02); and C-reactive protein, D-dimer and carotid intima-media thickness (CIMT) with advanced CAC (P ≤ 0.03). The base model combining traditional risk factors had excellent discrimination for advanced CAC (C-statistic, 0.808). Addition of the 2 best-fit models combining biomarkers plus/minus CIMT improved the c-statistics to 0.822 and 0.820, respectively. All 3 models calibrated well, but were similar in estimating individual risk probabilities for advanced CAC (prevalence = 9.97%, 10.63% and 10.10% in the highest quartiles of predicted probabilities versus 0.26%, 0.26% and 0.26% in the lowest quartiles, respectively). In conclusion, in low risk individuals, traditional risk factors alone predicted advanced CAC with high discrimination and calibration. Biomarker combinations +/− CIMT were also significantly associated with advanced CAC, but improvement in prediction and estimation of clinical risk were modest compared to traditional risk factors alone.
doi:10.1016/j.amjcard.2010.10.072
PMCID: PMC3182475  PMID: 21376929
coronary calcium; biomarkers; novel markers; low-risk; risk factors
7.  Associations of SNPs in ADIPOQ and subclinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Obesity (Silver Spring, Md.)  2010;19(4):840-847.
Circulating adiponectin has been associated with both clinical and subclinical cardiovascular disease (CVD). Variants of the adiponectin gene (ADIPOQ) are associated with clinical CVD, but little is known about associations with subclinical CVD. We studied the association of 11 ADIPOQ SNPs with common and internal carotid intima media thickness (cIMT), presence of coronary artery calcification (CAC), and CAC scores (in those with CAC) in 2847 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were Caucasian (n=712), African-American (n=712), Chinese (n=718), and Hispanic (n=705). All models were adjusted for age, sex, and field site, and stratified by race/ethnic group. African-Americans with genotypes AG/GG of rs2241767 had 36% greater (95% CI (16%, 59%), p=0.0001) CAC prevalence; they also had a larger common cIMT (p=0.0043). Also in African-Americans, genotypes AG/AA of rs1063537 were associated with a 35% (95% CI (14%, 59%), p=0.0005) greater CAC prevalence. Hispanics with the AA genotype of rs11711353 had a 37% (95% CI (14%, 66%), p=0.0011), greater CAC prevalence compared to those with the GG genotype. Additional adjustment for ancestry in African-American and Hispanic participants did not change the results. No single SNP was associated with subclinical CVD phenotypes in Chinese or Caucasian participants. There appears to be an association between ADIPOQ SNPs and subclinical CVD in African-American and Hispanics. Replication as well as assessment of other ADIPOQ SNPs appears warranted.
doi:10.1038/oby.2010.229
PMCID: PMC3510267  PMID: 20930713
8.  The Association of Coronary Artery Calcification and Carotid Artery Intima-Media Thickness With Distinct, Traditional Coronary Artery Disease Risk Factors in Asymptomatic Adults 
American Journal of Epidemiology  2008;168(9):1016-1023.
Coronary artery calcification (CAC) and common carotid artery intima-media thickness (CIMT) are measures of subclinical vascular disease. This 2000–2006 study aimed to characterize the associations among coronary artery disease risk factors, CAC quantity, and CIMT and to estimate shared genetic and environmental contributions to both CAC and CIMT among 478 asymptomatic Amish adults in Lancaster County, Pennsylvania. Heritability for CAC quantity and CIMT, adjusted for age and sex, was 0.42 (P = 0.0001) and 0.29 (P = 0.003), respectively. CAC quantity and CIMT were modestly correlated (adjusted r = 0.14, P = 0.003) but showed little evidence of shared genetic or environmental factors. However, significant genetic correlations were found for CAC quantity and total cholesterol (0.44 (standard error, 0.19); P = 0.03), for CAC quantity and low density lipoprotein cholesterol (0.55 (standard error, 0.17); P = 0.005), and for CIMT and waist circumference (0.58 (standard error, 0.25); P = 0.046), suggesting shared genes for these risk factors and measures of subclinical disease. Results suggest that some of the same genes influence variation in CAC and low density lipoprotein cholesterol, whereas a different set of genes influences variation in CIMT and waist circumference.
doi:10.1093/aje/kwn211
PMCID: PMC2720772  PMID: 18805900
atherosclerosis; calcification, physiologic; carotid arteries; coronary vessels; genetics; risk factors; vascular diseases
9.  The Associations of Fetuin-A with Subclinical Cardiovascular Disease in Community-Dwelling Persons: the Rancho Bernardo Study 
Objective
To determine the association of fetuin-A with subclinical CVD in community-living individuals.
Background
Fetuin-A is a hepatic secretory protein that inhibits arterial calcium deposition in vitro. Lower fetuin-A levels are associated with arterial calcification and death in end-stage renal disease populations. The association of fetuin-A with subclinical cardiovascular disease (CVD) in the general population is unknown.
Methods
Among 1,375 community-living individuals without prevalent clinical CVD, we measured plasma fetuin-A concentrations measured by ELISA. Peripheral arterial disease (PAD) was defined by ankle brachial index (ABI) < 0.90, coronary artery calcification (CAC) was measured by computed tomography, and common and internal intima media thickness (cIMT) were measured by carotid ultrasound. PAD was measured concurrent with fetuin-A, and CAC and cIMT was measured 4.6 years (mean) later.
Results
Mean age was 70 ± 11 years and 64% were female. Fetuin-A levels were inversely associated with CAC severity. When evaluated as CAC categories (0, 1–100, 101–300, > 300) using ordinal logistic regression, each standard deviation higher fetuin-A was associated with a 31% lower odds of CAC severity (proportional odds ratio [POR] 0.69; 95% confidence interval [CI] 0.46, 0.92; p=0.008) in models adjusted for demographics, lifestyle factors, traditional CVD risk factors and kidney function. In contrast, no association of fetuin-A was observed with PAD or high common or internal cIMT in adjusted models.
Conclusions
Lower fetuin-A levels are independently associated with greater CAC severity, but not PAD or cIMT. If confirmed, fetuin-A may mark calcium deposition within the vasculature, but not atherosclerosis per se.
doi:10.1016/j.jacc.2011.08.035
PMCID: PMC3224791  PMID: 22115642
Fetuin-A; Cardiovascular Disease; Coronary Artery Calcification
10.  Abdominal Aortic Calcium and Multi-Site Atherosclerosis: The Multiethnic Study of Atherosclerosis 
Atherosclerosis  2011;214(2):436-441.
Background
Abdominal aortic calcification (AAC) is a measure of subclinical cardiovascular disease (CVD). Data are limited regarding its relation to other measures of atherosclerosis.
Methods
Among 1,812 subjects (49% female, 21% black, 14% Chinese, and 25% Hispanic) within the population-based Multiethnic Study of Atherosclerosis, we examined the cross-sectional relation of AAC with coronary artery calcium (CAC), ankle brachial index (ABI), and carotid intimal medial thickness (CIMT), as well as multiple measures of subclinical CVD.
Results
AAC prevalence ranged from 34% in those aged 45–54 to 94% in those aged 75–84 (p<0.0001), was highest in Caucasians (79%) and lowest in blacks (62%) (p<0.0001). CAC prevalence, mean maximum CIMT ≥ 1 mm, and ABI<0.9 was greater in those with vs. without AAC: CAC 60% vs 16%, CIMT 38% vs 7%, and ABI 5% vs 1% for women and CAC 80% vs 37%, CIMT 43% vs 16%, and ABI 4% vs 2% for men (p<0.01 for all except p<0.05 for ABI in men). The presence of multi-site atherosclerosis (≥ 3 of the above) ranged from 20% in women and 30% in men (p<0.001), was highest in Caucasians (28%) and lowest in Chinese (16%) and ranged from 5% in those aged 45–54 to 53% in those aged 75–84 (p<0.01 to p<0.001). Finally, increased AAC was associated with 2 to 3-fold relative risks for the presence of increased CIMT, low ABI, or CAC.
Conclusions
AAC is associated with an increased likelihood of other vascular atherosclerosis. Its additive prognostic value to these other measures is of further interest.
doi:10.1016/j.atherosclerosis.2010.09.011
PMCID: PMC3040451  PMID: 21035803
atherosclerosis; calcification; cardiovascular disease; epidemiology
11.  Comparison of Novel Risk Markers for Improvement in Cardiovascular Risk Assessment in Intermediate Risk Individuals. The Multi-Ethnic Study of Atherosclerosis 
Context
Risk markers including coronary artery calcium (CAC), carotid intima-media thickness (CIMT), ankle-brachial Index (ABI), brachial flow-mediated dilation (FMD), high sensitivity C -reactive protein (hs-CRP) and family history (FH) of coronary heart disease (CHD) have been reported to improve on the Framingham risk score (FRS) for prediction of CHD. However, there are no direct comparisons of these markers for risk prediction in a single cohort.
Objective
We compared improvement in prediction of incident CHD/cardiovascular disease (CVD) of these 6 risk markers within intermediate risk participants (5 % < FRS < 20%) in the Multi-Ethnic Study of Atherosclerosis (MESA).
Design, Setting and Participants
Of 6814 MESA participants from 6 US field centers, 1330 were intermediate risk, without diabetes mellitus, and had complete data on all 6 markers. Recruitment spanned July 2000 to September 2002; follow-up extended through May 2011. Probability- weighted Cox proportional hazard models were used to estimate hazard ratios (HR). Area under the receiver operator characteristic curve (AUC) and net reclassification improvement (NRI) were used to compare incremental contributions of each marker when added to the FRS + race/ethnicity.
Main Outcome Measures
Incident CHD defined as MI, angina followed by revascularization, resuscitated cardiac arrest or CHD death. Incident CVD additionally included stroke or CVD death.
Results
After median follow-up of 7.6 years (IQR 7.3 – 7.8 years), 94 CHD and 123 CVD events occurred. CAC, ABI, hs-CRP and FH were independently associated with incident CHD in multivariable analyses [HR (95%CI: 2.60(1.94-3.50), 0.79(0.66-0.95), 1.28(1.00-1.64) and 2.18(1.38-3.42) respectively]. CIMT and FMD were not associated with incident CHD in multivariable analyses [HR (95%CI) 1.17(0.95- 1.45) and 0.95(0.78 −1.14) respectively]. Although the addition of the markers individually to the FRS +race/ethnicity improved the AUC, CAC afforded the highest increment (0.623 vs. 0.784) while FMD afforded the least [0.623 vs. 0.639]. For incident CHD, the NRI with CAC was 0.659, FMD 0.024, ABI 0.036, CIMT 0.102, FH 0.160 and hs-CRP 0.079. Similar results were obtained for incident CVD.
Conclusion
CAC, ABI, hs-CRP and FH are independent predictors of incident CHD/CVD in intermediate risk individuals. CAC provides superior discrimination and risk reclassification compared with other risk markers.
doi:10.1001/jama.2012.9624
PMCID: PMC4141475  PMID: 22910756
12.  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.
Background
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.
Methods
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.
Results
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]).
Conclusion
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.
doi:10.1007/s12471-014-0610-4
PMCID: PMC4268220  PMID: 25342280
Carotid intima media thickness; Coronary artery calcium; Subclinical atherosclerosis; Racial-disparity; Risk factor; Observational study
13.  Longitudinal assessment of fibrinogen in relation to subclinical cardiovascular disease: the CARDIA study 
Summary
Objective
To examine the strength of the associations of fibrinogen with subclinical atherosclerosis in healthy persons.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1111/j.1538-7836.2009.03727.x
PMCID: PMC2856753  PMID: 20025644
atherosclerosis; carotid thickening; coronary calcification; fibrinogen
14.  Urine Albumin Creatinine Ratio is Associated with Carotid Atherosclerosis in a Community Based Cohort: Atherosclerosis Risk of Rural Area in Korean General Population Study 
Background
Albuminuria is a surrogate marker of endothelial dysfunction and a predictor of cardiovascular events. Data are limited with regard to the relationship between albuminuria and subclinical atherosclerosis in a community-based cohort. We determined the association between albuminuria measured by the urine albumin creatinine ratio (UACR) and carotid intima media thickness (CIMT) in a Korean rural population.
Methods
We enrolled 1,369 healthy subjects older than 40 years (857 males and 518 females) with normal renal function and measured the CIMT. We excluded subjects with overt proteinuria (> 300 mg/day) or with treatment of diabetes mellitus, hypertension, dyslipidemia, and any cardiovascular disease. The subjects were stratified into the quartile value of the UACR (lowest quartile: UACR < 4.8 and highest quartile: UACR > 17.7). And we evaluate the relationship between UACR and CIMT by linear regression and logistic regression analysis.
Results
Increasing quartile of the UACR had a stepwise increase in body mass index, blood pressure, cholesterol profile [low density lipoprotein (LDL)-cholesterol and triglyceride], glucose, homeostratic model assessment of insulin resistance (HOMA-IR), and C-reactive protein (all p values < 0.001). Maximal CIMT from the 1st to the 4th quartile values of the UACR were 0.74 ± 0.17, 0.77 ± 0.18, 0.78 ± 0.18, and 0.82 ± 0.21 mm, respectively (p < 0.001). In a multivariate regression model adjusted for age, sex, systolic blood pressure, triglyceride, LDL-cholesterol, fasting blood sugar, waist circumference, adiponectin, HOMA-IR, high sensitive C-reactive protein, smoking, UACR showed a significant association with maximal CIMT (B = 0.014, R2 = 0.145, p = 0.002).
Conclusion
Albuminuria measured by the UACR was significantly associated with both CIMT and traditional risk factors of atherosclerosis except for smoking in healthy Koreans.
doi:10.4250/jcu.2010.18.4.134
PMCID: PMC3021891  PMID: 21253362
Urine albumin creatinine ratio; Carotid intima-media thickness
15.  Signs of subclinical coronary atherosclerosis in relation to risk factor distribution in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR) 
European Heart Journal  2008;29(22):2782-2791.
Aims
Modern imaging technology allows us the visualization of coronary artery calcification (CAC), a marker of subclinical coronary atherosclerosis. The prevalence, quantity, and risk factors for CAC were compared between two studies with similar imaging protocols but different source populations: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR).
Methods and results
The measured CAC in 2220 MESA participants were compared with those in 3126 HNR participants with the inclusion criteria such as age 45–75 years, Caucasian race, and free of baseline cardiovascular disease. Despite similar mean levels of CAC of 244.6 among participants in MESA and of 240.3 in HNR (P = 0.91), the prevalence of CAC > 0 was lower in MESA (52.6%) compared with HNR (67.0%) with a prevalence rate ratio of CAC > 0 of 0.78 [95% confidence interval (CI): 0.72–0.85] after adjustment for known risk factors. Consequently, among participants with CAC > 0, the participants in MESA tended to have higher levels of CAC than those in HNR (ratio of CAC levels: 1.39; 95% CI: 1.19–1.63), since many HNR participants have small (near zero) CAC values.
Conclusions
The CAC prevalence was lower in the United States (MESA) cohort than in the German (HNR) cohort, which may be explained by more favourable risk factor levels among the MESA participants. The predictors for increased levels of CAC were, however, similar in both cohorts with the exception that male gender, blood pressure, and body mass index were more strongly associated in the HNR cohort.
doi:10.1093/eurheartj/ehn439
PMCID: PMC2582985  PMID: 18845666
Epidemiology; Atherosclerosis; Coronary artery calcium; Risk factors; Screening
16.  Is Diabetic Retinopathy Related to Subclinical Cardiovascular Disease? 
Ophthalmology  2010;118(5):860-865.
OBJECTIVE
Persons with diabetic retinopathy (DR) have an increased risk of clinical cardiovascular events. Our study aimed to determine whether DR is associated with a range of measures of subclinical cardiovascular disease (CVD) in persons without clinical CVD.
DESIGN
Population-based, cross-sectional epidemiologic study
PARTICIPANTS
Nine hundred and twenty seven persons with diabetes without clinical CVD in the Multi-Ethnic Study of Atherosclerosis.
METHODS
DR was ascertained from retinal photographs according to modification of the Airlie House Classification system. Vision threatening DR (VTDR) was defined as severe non-proliferative DR, proliferative DR or clinically significant macular edema. Subclinical CVD measures were assessed and defined as follows: high coronary artery calcium (CAC) score, defined as CAC score≥400; low ankle-brachial index (ABI), defined as ABI<0.9; high ABI, defined as ABI≥1.4; high carotid intima-media thickness (IMT), defined as highest 25% of IMT; and carotid stenosis, defined as >25% stenosis or presence of carotid plaque.
MAIN OUTCOME MEASURES
Associations between DR and subclinical CVD measures.
RESULTS
The prevalence of DR and VTDR in this sample was 30.0% and 7.2%, respectively. VTDR was associated with a high CAC score (odds ratio [OR] 2.33, 95% condifence interval [CI] 1.15–4.73), low ABI (OR 2.54; 95%CI, 1.08–5.99) and high ABI (OR 12.6, 95% CI, 1.14, 140.6), after adjusting for risk factors including hemoglobin A1c level and duration of diabetes. The association between VTDR and high CAC score remained significant after further adjustment for hypoglycemic, anti-hypertensive and cholesterol-lowering medications. DR was not significantly associated with measures of carotid artery disease.
CONCLUSIONS
In persons with diabetes without a history of clinical CVD, the presence of advanced stage of DR is associated with subclinical coronary artery disease. These findings emphasize the need to be careful about the use of anti-vascular endothelial growth factor for the treatment of DR.
doi:10.1016/j.ophtha.2010.08.040
PMCID: PMC3087839  PMID: 21168222
17.  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.
Background/Aims
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1159/000327606
PMCID: PMC3100378  PMID: 21508633
Cystatin C; Intima-medial thickness; HIV; Atherosclerosis; Cardiovascular disease; Kidney
18.  Adult Height and Prevalence of Coronary Artery Calcium: The NHLBI Family Heart Study 
Background
Adult height has been hypothesized to be inversely associated with coronary heart disease but studies have produced conflicting results. We sought to examine the relationship between adult height and the prevalence of coronary artery calcium (CAC), a direct measure of subclinical atherosclerosis and surrogate marker of CHD.
Method and Results
We evaluated the relationship between adult height and CAC in 2,703 participants from the NHLBI Family Heart Study who underwent cardiac computed tomography. We used generalized estimating equations to calculate the prevalence odds ratios for the presence of CAC (CAC>0) across sex-specific quartiles of height. The mean age of the sample was 54.8 years and 60.2% were female. There was an inverse association between adult height and CAC. After adjusting for age, race, field center, waist circumference, smoking, alcohol, physical activity, systolic blood pressure, antihypertensive medications, diabetes, diabetic medications, LDL cholesterol, HDL cholesterol, lipid-lowering medications, and income, individuals in the tallest quartile had 30% lower odds of having prevalent CAC. The odds ratios (95% CI) for the presence of CAC across consecutive sex-specific quartiles of height were 1.0 (reference), 1.15 (0.86–1.53), 0.95(0.73–1.22), and 0.70 (0.53–0.93), p for trend <0.01. There was no evidence of effect modification for the relationship between adult height and CAC by age or socioeconomic status.
Conclusions
The results of our study suggest an inverse, independent association between adult height and CAC.
doi:10.1161/CIRCIMAGING.113.000681
PMCID: PMC3970195  PMID: 24336983
risk factor; imaging; epidemiology
19.  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.
Background
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).
Methods
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.
Results
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).
Conclusion
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.
doi:10.1007/s00223-008-9209-3
PMCID: PMC2908302  PMID: 19148561
20.  Effect of inter-reader variability on outcomes in studies using carotid intima media thickness quantified by carotid ultrasonography 
European journal of epidemiology  2010;25(6):385-392.
Systematic differences between readers or equipment in imaging studies are not uncommon; failure to account for such differences when using Carotid Ultrasonography may introduce bias into associations between carotid intima media thickness (cIMT) and outcomes. We demonstrate the impact of this source of systematic measurement error (SME) using data on 5,521 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and 661 participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Participants were between 37 and 78 years old. Two outcomes were considered: (1) the effect of HIV infection on cIMT (between study) and (2) the association of cIMT with cardiovascular events (within study). All estimates were adjusted for demographics (age, gender, and ethnicity) and for traditional cardiovascular disease risk factors (smoking, blood pressure, diabetes and cholesterol). When comparing the FRAM and MESA cohorts to estimate the association of HIV infection on common cIMT, accounting for machine and reader variability (between study variability) reduced the difference associated with HIV infection from +0.080 mm (95% Confidence Interval (CI):0.065–0.095) to +0.037 mm (95% CI:0.003 to 0.072) while internal cIMT declined from +0.254 mm (95% CI:0.205–0.303) to +0.192 mm (95% CI:0.076–0.308). Attenuation of the association between cIMT and cardiovascular endpoints occurred when within study reader variability was not accounted for. The effect of SME due to use of multiple readers or machines is most important when comparisons are made between two different study populations. Within-cohort measurement error dilutes the association with events.
doi:10.1007/s10654-010-9442-8
PMCID: PMC3161119  PMID: 20309612
Carotid intima media thickness; Measurement error; Bias; Carotid ultrasonography
21.  Subclinical Atherosclerosis is Weakly Associated with Lower Cognitive Function in Healthy Hyperhomocysteinemic Adults without Clinical Cardiovascular Disease 
OBJECTIVE
Atherosclerosis is the most common pathologic process underlying cardiovascular disease (CVD). It is not well known whether subclinical atherosclerosis is an independent risk factor for lower cognitive function among individuals without clinically evident CVD.
METHODS
We examined cross-sectional associations between subclinical atherosclerosis and cognitive function in a community-based sample of otherwise healthy adults with plasma homocysteine ≥8.5 µmol/L enrolled in the BVAIT study (n=504, mean age 61 years). Carotid artery intima-media thickness (CIMT), coronary (CAC) and abdominal aortic calcium (AAC) were used to measure subclinical atherosclerosis. Cognitive function was assessed with a battery of neuropsychological tests. A principal components analysis was used to extract five uncorrelated cognitive factors from scores on individual tests, and a measure of global cognition was derived. Multivariable linear regression was used to examine the association between subclinical atherosclerosis and cognitive function, adjusting for other correlates of cognition.
RESULTS
Increasing thickness of CIMT was associated with significantly lower scores on the verbal learning factor (β = −0.07 per 0.1 mm increase CIMT [SE(β)=0.03], p=0.01). CAC and AAC were not individually associated with any of the cognitive factors.
CONCLUSIONS
This study provides evidence that increasing CIMT is weakly associated with lower verbal learning abilities but not global cognition in a population of otherwise healthy middle-to-older aged adults with elevated plasma homocysteine but without clinically evident CVD. The association between CIMT and poor verbal learning may pertain particularly to men.
doi:10.1002/gps.2134
PMCID: PMC2661006  PMID: 18836986
cognitive function; atherosclerosis; cardiovascular disease; memory; verbal learning
22.  A cross-sectional association of obesity with coronary calcium among Japanese, Koreans, Japanese Americans, and US Whites 
Aims
Conflicting evidence exists regarding whether obesity is independently associated with coronary artery calcium (CAC), a measure of coronary atherosclerosis. We examined an independent association of obesity with prevalent CAC among samples of multi-ethnic groups whose background populations have varying levels of obesity and coronary heart disease (CHD).
Methods and results
We analysed a population-based sample of 1212 men, aged 40–49 years free of clinical cardiovascular disease recruited in 2002–06; 310 Japanese in Japan (JJ), 294 Koreans in South Korea (KN), 300 Japanese Americans (JA), and 308 Whites in the USA (UW). We defined prevalent CAC as an Agatston score of ≥10. Prevalent CAC was calculated by tertile of the body mass index (BMI) in each ethnic group and was plotted against the corresponding median of tertile BMI. Additionally, logistic regression was conducted to examine whether an association of the BMI was independent of conventional risk factors. The median BMI and crude prevalence of CAC for JJ, KN, JA, and UW were 23.4, 24.4, 27.4, and 27.1 (kg/m2); 12, 11, 32, and 26 (%), respectively. Despite the absolute difference in levels of BMI and CAC across groups, higher BMI was generally associated with higher prevalent CAC in each group. After adjusting for age, smoking, alcohol, hypertension, lipids, and diabetes mellitus, the BMI was positively and independently associated with prevalent CAC in JJ, KN, UW, but not in JA.
Conclusion
In this multi-ethnic study, obesity was independently associated with subclinical stage of coronary atherosclerosis among men aged 40–49 years regardless of the BMI level.
doi:10.1093/ehjci/jet080
PMCID: PMC3738098  PMID: 23764486
Coronary artery calcium; Obesity; Body mass index; Multi-ethnic; Men; Risk factors
23.  Association between Obesity, hsCRP ≥2 mg/L, and Subclinical Atherosclerosis: Implications of JUPITER from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Objective
High-sensitivity C-reactive protein (hsCRP) levels are closely associated with abdominal obesity, metabolic syndrome, and atherosclerotic cardiovascular disease. The JUPITER trial has encouraged using hsCRP ≥2 mg/L to guide statin therapy; however the association of hsCRP to atherosclerosis, independent of obesity, remains unknown.
Methods and Results
We studied 6,760 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were stratified into 4 groups: non-obese/low hsCRP, non-obese/high hsCRP, obese/low hsCRP, and obese/high hsCRP. Using multivariable logistic and robust linear regression, we described the association with subclinical atherosclerosis, using coronary artery calcium (CAC) and carotid intima-media thickness (cIMT). Mean BMI was 28.3 ± 5.5 kg/m2, and median hsCRP was 1.9 mg/L (0.84 – 4.26). High hsCRP, in the absence of obesity, was not associated with CAC and was mildly associated with cIMT. Obesity was strongly associated with CAC and cIMT independent of hsCRP. When obesity and high hsCRP were both present, there was no evidence of multiplicative interaction. Similar associations were seen among 2,083 JUPITER-eligible individuals.
Conclusions
High hsCRP, as defined by JUPITER, was not associated with CAC and was mildly associated with cIMT in the absence of obesity. In contrast, obesity was associated with both measures of subclinical atherosclerosis independent of hsCRP status.
doi:10.1161/ATVBAHA.111.223768
PMCID: PMC3130297  PMID: 21474823
obesity; hsCRP; high sensitivity C-reactive protein; subclinical atherosclerosis; coronary artery calcium; carotid intima-media thickness
24.  The Epidemiology of Subclavian Stenosis and its Association with Markers of Subclinical Atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2010;211(1):266-270.
Background
Recent studies indicate that subclavian stenosis (SS), diagnosed by a large systolic blood pressure difference (SBPD) between the right and left brachial arteries, is associated with cardiovascular disease (CVD) risk factors and outcomes. We sought to describe the epidemiology of SS and determine its association with markers of subclinical CVD in the baseline cohort of the Multi-Ethnic Study of Atherosclerosis.
Methods
We defined SS by an absolute SBPD ≥15 mmHg. Peripheral artery disease (PAD) was defined by an ankle-brachial index ≤0.90. The coronary artery calcium score (CAC) and the common-carotid artery intima-media thickness (CCA-IMT) were measured by computed tomography and B-mode ultrasound, respectively. Odds ratios for the associations of SS with risk factors and subclinical disease were estimated using logistic regression.
Results
Of 6,743 subjects studied, 307 participants (4.6%) had SS, with a higher prevalence in women (5.1%) than men (3.9%), and in African-Americans (7.4%) and non-Hispanic whites (5.1%) than Hispanic (1.9%) or Chinese (1.0%) participants (p<0.01). In a model including age, gender, ethnicity, traditional and novel CVD risk factors, significant associations with SS were observed for C-reactive protein (highest vs. three lower quartiles: OR=1.41; 95%CI: 1.06-1.87) and brachial artery pulse pressure (OR=1.12 /10 mmHg; 95%CI: 1.03-1.21). Adjusted for age, gender, ethnicity, traditional and novel CVD risk factors, SS was significantly associated with PAD (OR=2.35; 1.55-3.56), with CCA-IMT (highest vs. the lower three quartiles: OR=1.32; 1.00-1.75), and high CAC (score >100 vs. score=0; OR=1.43; 1.03-2.01).
Conclusions
The subclavian stenosis is positively associated with other markers of subclinical atherosclerosis.
doi:10.1016/j.atherosclerosis.2010.01.013
PMCID: PMC2925848  PMID: 20138280
subclavian artery; blood pressure; atherosclerosis; epidemiology
25.  Associations of Inflammatory Markers with Coronary Artery Calcification: Results from the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2009;209(1):226-229.
Objective
Inflammatory markers predict coronary heart disease (CHD). However, associations with coronary artery calcium (CAC), a marker of subclinical CHD, are not established.
Methods
We examined cross-sectional associations of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with CAC presence (Agatston score > 0 by computed tomography) in 6,783 Multi-Ethnic Study of Atherosclerosis (MESA) participants.
Results
In all participants, those in the highest, compared to lowest, quartile of CRP had a relative risk (RR, 95% confidence interval) of 1.13 (1.06-1.19; p<0.01) for CAC in age, sex and ethnicity adjusted models. For highest versus lowest quartiles, relative risks were 1.22 (1.15-1.30; p<0.01) for IL-6 and 1.18 (1.11-1.24; p<0.01) for fibrinogen. Adjusting for CHD risk factors (smoking, diabetes, blood pressure, obesity and dyslipidemia) attenuated RRs. RRs for CAC were 1.05 (0.99-1.12; p=0.63) for CRP, 1.12 (1.06-1.20; p<0.01) for IL-6 and 1.09 (1.02-1.16; p=0.01) for fibrinogen in multivariable adjusted models. Results were similar for men and women and across ethnic groups.
Conclusion
Inflammatory markers were weakly associated with CAC presence and burden in MESA. Our data support the hypothesis that inflammatory biomarkers and CAC reflect distinct pathophysiology.
doi:10.1016/j.atherosclerosis.2009.08.037
PMCID: PMC2830357  PMID: 19766217
Atherosclerosis; Calcium; Inflammation; Population

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