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1.  Methylomics of gene expression in human monocytes 
Human Molecular Genetics  2013;22(24):5065-5074.
DNA methylation is one of several epigenetic mechanisms that contribute to the regulation of gene expression; however, the extent to which methylation of CpG dinucleotides correlates with gene expression at the genome-wide level is still largely unknown. Using purified primary monocytes from subjects in a large community-based cohort (n = 1264), we characterized methylation (>485 000 CpG sites) and mRNA expression (>48K transcripts) and carried out genome-wide association analyses of 8370 expression phenotypes. We identified 11 203 potential cis-acting CpG loci whose degree of methylation was associated with gene expression (eMS) at a false discovery rate threshold of 0.001. Most of the associations were consistent in effect size and direction of effect across sex and three ethnicities. Contrary to expectation, these eMS were not predominately enriched in promoter regions, or CpG islands, but rather in the 3′ UTR, gene bodies, CpG shores or ‘offshore’ sites, and both positive and negative correlations between methylation and expression were observed across all locations. eMS were enriched for regions predicted to be regulatory by ENCODE (Encyclopedia of DNA Elements) data in multiple cell types, particularly enhancers. One of the strongest association signals detected (P < 2.2 × 10−308) was a methylation probe (cg17005068) in the promoter/enhancer region of the glutathione S-transferase theta 1 gene (GSTT1, encoding the detoxification enzyme) with GSTT1 mRNA expression. Our study provides a detailed description of the epigenetic architecture in human monocytes and its relationship to gene expression. These data may help prioritize interrogation of biologically relevant methylation loci and provide new insights into the epigenetic basis of human health and diseases.
PMCID: PMC3836482  PMID: 23900078
2.  Reference ranges of PR duration and P-wave indices in individuals free of cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Journal of electrocardiology  2013;46(6):10.1016/j.jelectrocard.2013.05.006.
In this brief report, we provide normal reference ranges for PR duration [unadjusted and heart rate adjusted] and P-wave indices [duration, amplitude and terminal force in V1] in individuals free of cardiovascular disease and its risk factors. We used automatically processed digital ECG data from 1252 US participants [mean age 59 (± 10) years, 738 women, 588 whites, 207 African-Americans, 217 Hispanics, 240 Chinese] from the Multi-Ethnic Study of Atherosclerosis [MESA]. In multivariable adjusted linear regression models with PR and each P-wave variable as a separate outcome, significant age, sex and race differences in these markers were observed. Subsequently, we report reference ranges for abnormal [2nd and 98th percentiles], borderline abnormal [5th and 95th percentiles] and mean [SD] values of PR and P-wave indices stratified by age [middle age (45–64 years) and seniors (65–84 years)], sex [men and women] and race [whites, African Americans, Hispanics and Chinese].
PMCID: PMC3795794  PMID: 23806475
P-wave indices; PR interval; MESA
3.  Intakes of long-chain n-3 polyunsaturated fatty acids and fish in relation to measurements of subclinical atherosclerosis 
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.
We examined intakes of long-chain n-3 PUFAs and fish in relation to clinical measures of subclinical atherosclerosis.
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.
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.
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.  Comparison of Novel Risk Markers for Improvement in Cardiovascular Risk Assessment in Intermediate Risk Individuals. The Multi-Ethnic Study of Atherosclerosis 
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.
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.
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.
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.
PMCID: PMC4141475  PMID: 22910756
5.  DASH Eating Pattern Is Associated with Favorable Left Ventricular Function in the Multi-Ethnic Study of Atherosclerosis 
Potential associations between consistency with the Dietary Approaches to Stop Hypertension (DASH) diet and preclinical stages of heart failure (HF) in a large multiethnic cohort have not been evaluated. This study sought to determine the cross-sectional relationship between the DASH eating pattern and left ventricular (LV) function in the Multi-Ethnic Study of Atherosclerosis (MESA).
A total of 4506 men and women from four ethnic groups (40% white, 24% African American, 22% Hispanic American, and 14% Chinese American) aged 45–84 years and free of clinical cardiovascular disease (CVD) were studied. Diet was assessed using a validated food-frequency questionnaire. LV functional parameters including end-diastolic volume, stroke volume, and LV ejection fraction were measured by magnetic resonance imaging. Multivariate analyses were conducted to examine the association between LV function and DASH eating pattern (including high consumption of fruits, vegetables, whole grains, poultry, fish, nuts, and low-fat dairy products and low consumption of red meat, sweets, and sugar-sweetened beverages).
A 1-unit increase in DASH eating pattern score was associated with a 0.26 ml increase in end-diastolic volume and increases of 0.10 ml/m2 in stroke volume, adjusted for key confounders. A 1-unit increase in DASH eating pattern score was also associated with a 0.04% increase in ejection fraction, but the relationship was marginally significant (p = 0.08).
In this population, greater DASH diet consistency is associated with favorable LV function. DASH dietary patterns could be protective against HF.
PMCID: PMC4119794  PMID: 23756584
DASH diet; LV function; preclinical heart failure
6.  Characterizing Spatial Patterns of Airborne Coarse Particulate (PM10–2.5) Mass and Chemical Components in Three Cities: The Multi-Ethnic Study of Atherosclerosis 
Environmental Health Perspectives  2014;122(8):823-830.
Background: The long-term health effects of coarse particular matter (PM10–2.5) are challenging to assess because of a limited understanding of the spatial variation in PM10–2.5 mass and its chemical components.
Objectives: We conducted a spatially intensive field study and developed spatial prediction models for PM10–2.5 mass and four selected species (copper, zinc, phosphorus, and silicon) in three American cities.
Methods: PM10–2.5 snapshot campaigns were conducted in Chicago, Illinois; St. Paul, Minnesota; and Winston-Salem, North Carolina, in 2009 for the Multi-Ethnic Study of Atherosclerosis and Coarse Airborne Particulate Matter (MESA Coarse). In each city, samples were collected simultaneously outside the homes of approximately 40 participants over 2 weeks in the winter and/or summer. City-specific and combined prediction models were developed using land use regression (LUR) and universal kriging (UK). Model performance was evaluated by cross-validation (CV).
Results: PM10–2.5 mass and species varied within and between cities in a manner that was predictable by geographic covariates. City-specific LUR models generally performed well for total mass (CV R2, 0.41–0.68), copper (CV R2, 0.51–0.86), phosphorus (CV R2, 0.50–0.76), silicon (CV R2, 0.48–0.93), and zinc (CV R2, 0.36–0.73). Models pooled across all cities inconsistently captured within-city variability. Little difference was observed between the performance of LUR and UK models in predicting concentrations.
Conclusions: Characterization of fine-scale spatial variability of these often heterogeneous pollutants using geographic covariates should reduce exposure misclassification and increase the power of epidemiological studies investigating the long-term health impacts of PM10–2.5.
Citation: Zhang K, Larson TV, Gassett A, Szpiro AA, Daviglus M, Burke GL, Kaufman JD, Adar SD. 2014. Characterizing spatial patterns of airborne coarse particulate (PM10–2.5) mass and chemical components in three cities: the Multi-Ethnic Study of Atherosclerosis. Environ Health Perspect 122:823–830;
PMCID: PMC4123025  PMID: 24642481
7.  Relationship Between Brachial Flow - Mediated Dilation and Carotid Intima- Media Thickness in an Elderly Cohort: The Cardiovascular Health Study 
Atherosclerosis  2007;197(2):840-845.
The aim of this study was to determine the relationship between brachial flow-mediated dilation (FMD) and carotid intima-media thickness (IMT) in a large multi-ethnic elderly cohort.
Brachial flow-mediated dilation (FMD) is a physiologic measure and Carotid IMT is an anatomic structural measure of subclinical atherosclerosis. Both brachial FMD and carotid IMT have been associated with cardiovascular risk factors and cardiovascular events. The relationship between brachial FMD and carotid IMT is less clear especially in older adults.
Brachial FMD, carotid IMT and traditional cardiovascular risk factors were measured in 2338 adults, age 72–98 years who were participants in the Cardiovascular Health Study. The relationship between FMD and IMT was assessed both unadjusted and also after adjusting for age, gender, race/ethnicity. BMI, HDL, LDL, systolic and diastolic blood pressure, serum creatinine, current smoking, diabetes mellitus, hormone therapy and prior CVD.
Both brachial FMD and carotid IMT correlated significantly with age, HDL levels, waist/hip ratio, serum cholesterol and number of CV risk factors. Brachial FMD was not associated with CCA IMT in this elderly cohort (Pearson partial correlation coefficient= −0.0252, p=0.222). In the adjusted linear regression model with CCA IMT as the dependent variable, brachial FMD was also not associated with CCA IMT (beta coefficient= −0.006, p=0.470)
Brachial FMD and CCA IMT are not related in population-based older adults. Brachial FMD and CCA IMT may be distinct and independent stages in the complex atherosclerotic process.
PMCID: PMC4115586  PMID: 17804000
Brachial flow-mediated dilation; carotid intima-media thickness; endothelial function; atherosclerosis; elderly
Atherosclerosis  2007;197(2):768-776.
The association of brachial flow-mediated dilation (FMD) and cardiovascular disease (CVD) status is unclear especially in older adults whose FMD is greatly diminished. We assessed the association of FMD and the presence or absence of subclinical and clinical CVD in a population based cohort of older adults.
FMD was measured in 2971 adults aged 72–98 years (mean age 78.6 years) who participated in the Cardiovascular Health Study. Multiple linear regression analysis was used to examine the association between FMD and CVD status (clinical, subclinical and free of CVD). Out of 2791 with complete data, 82.7% were Caucasians and 59% females. 743 were classified as having clinical CVD, 607 as subclinical CVD and 1441 as neither clinical CVD nor subclinical CVD (CVD free). FMD was higher in the CVD free group compared with either the clinical (3.13 ± 0.05% vs 2.93 ± 0.07%, p=0.025) or the subclinical CVD group (3.13± 0.05% vs 2.95± 0.08%, p=0.05) after adjusting for covariates. There was no significant difference between the FMD of subjects with clinical and subclinical CVD (2.93 ± 0.07% vs 2.95 ± 0.08%, p=0.84). Similar but inverted associations were observed between height adjusted brachial artery diameter (BAD) and CVD status. However, FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD.
Among older adults, those with either clinical or subclinical CVD have lower FMD than CVD free subjects. BAD showed similar but inverted associations with CVD status in this cohort. FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD.
PMCID: PMC4115610  PMID: 17714717
Brachial flow-mediated dilation; brachial artery diameter; cardiovascular disease; elderly
9.  The association of pericardial fat with calcified coronary plaque 
Obesity (Silver Spring, Md.)  2008;16(8):1914-1919.
Pericardial fat has a higher secretion of inflammatory cytokines than subcutaneous fat. Cytokines released from pericardial fat around coronary arteries may act locally on the adjacent cells.
We examined the relationship between pericardial fat and calcified coronary plaque.
Participants in the community-based Multi-Ethnic Study of Atherosclerosis underwent a computed tomography scan for the assessment of calcified coronary plaque in 2001/02. We measured the volume of pericardial fat using these scans in 159 whites and blacks without symptomatic coronary heart disease from Forsyth County, NC, aged 55–74 years.
Calcified coronary plaque was observed in 91 participants (57%). After adjusting for height, a one standard deviation increment in pericardial fat was associated with an increased odds of calcified coronary plaque (odds ratio (95% confidence interval): 1.92 (1.27, 2.90)). With further adjustment of other cardiovascular factors, pericardial fat was still significantly associated with calcified coronary plaque. This relationship did not differ by gender and ethnicity. On the other hand, body mass index and height-adjusted waist circumference were not associated with calcified coronary plaque.
Pericardial fat is independently associated with calcified coronary plaque.
PMCID: PMC4098129  PMID: 18535554
coronary heart disease; body mass index; waist circumference
10.  Low-Risk Lifestyle, Coronary Calcium, Cardiovascular Events, and Mortality: Results From MESA 
American Journal of Epidemiology  2013;178(1):12-21.
Unhealthy lifestyle habits are a major contributor to coronary artery disease. The purpose of the present study was to investigate the associations of smoking, weight maintenance, physical activity, and diet with coronary calcium, cardiovascular events, and mortality. US participants who were 44–84 years of age (n = 6,229) were followed in the Multi-Ethnic Study of Atherosclerosis from 2000 to 2010. A lifestyle score ranging from 0 to 4 was created using diet, exercise, body mass index, and smoking status. Coronary calcium was measured at baseline and a mean of 3.1 (standard deviation, 1.3) years later to assess calcium progression. Participants who experienced coronary events or died were followed for a median of 7.6 (standard deviation, 1.5) years. Participants with lifestyle scores of 1, 2, 3, and 4 were found to have mean adjusted annual calcium progressions that were 3.5 (95% confidence interval (CI): 0.0, 7.0), 4.2 (95% CI: 0.6, 7.9), 6.8 (95% CI: 2.0, 11.5), and 11.1 (95% CI: 2.2, 20.1) points per year slower, respectively, relative to the reference group (P = 0.003). Unadjusted hazard ratios for death by lifestyle score were as follows: for a score of 1, the hazard ratio was 0.79 (95% CI: 0.61, 1.03); for a score of 2, the hazard ratio was 0.61 (95% CI: 0.46, 0.81); for a score of 3, the hazard ratio was 0.49 (95% CI: 0.32, 0.75); and for a score of 4, the hazard ratio was 0.19 (95% CI: 0.05, 0.75) (P < 0.001 by log-rank test). In conclusion, a combination of regular exercise, healthy diet, smoking avoidance, and weight maintenance was associated with lower coronary calcium incidence, slower calcium progression, and lower all-cause mortality over 7.6 years.
PMCID: PMC3698994  PMID: 23733562
coronary artery disease; CT and MRI; diet; epidemiology; exercise; primary prevention; risk factors; weight reduction
11.  Stress Cardiac Magnetic Resonance Imaging Reduces Revascularization, Hospital Readmission, and Recurrent Cardiac Testing in Intermediate Risk Patients with Acute Chest Pain: A Randomized Trial 
JACC. Cardiovascular imaging  2013;6(7):785-794.
To determine the effect of stress cardiac magnetic resonance (CMR) imaging in an observation unit (OU) on revascularization, hospital readmission, and recurrent cardiac testing in intermediate risk patients with possible acute coronary syndrome (ACS).
Intermediate risk patients commonly undergo hospital admission with high rates of coronary revascularization. It is unknown whether OU-based care with CMR is a more efficient alternative.
We randomized 105 intermediate risk participants with symptoms of ACS but without definite ACS based on the first electrocardiogram and troponin to usual care provided by Cardiologists and Internists (n=53) versus OU care with stress CMR (n=52). We determined the primary composite endpoint of coronary artery revascularization, hospital readmission, and recurrent cardiac testing at 90 days. The secondary endpoint was length of stay from randomization to index visit discharge; safety was measured as ACS after discharge.
The median age of participants was 56 (range 35 to 91) years, 54% were men, and 20% had pre-existing coronary disease. Index hospital admission was avoided in 85% of the OU-CMR participants. The primary outcome occurred in 20 (38%) usual care versus 7 (13%) OU-CMR participants (hazard ratio 3.4, 95% CI 1.4 – 8.0, p = .006). The OU-CMR group experienced significant reductions in all components: revascularizations [15% vs 2%, p=0.03], hospital readmissions [23% vs 8%, p = .03], and recurrent cardiac testing [17% vs 4%, p = .03]. Median length of stay was 26 hours (IQR: 23 – 45) in the usual care group and 21 hours (IQR: 15 – 25) in the OU-CMR group (p < .001). ACS after discharge occurred in 3 (6%) usual care and no OU-CMR participants.
In this single center trial, management of intermediate risk patients with possible ACS in an OU with stress CMR reduced coronary artery revascularization, hospital readmissions, and recurrent cardiac testing without an increase in post-discharge ACS at 90 days.
PMCID: PMC3710522  PMID: 23664718
chest pain; acute coronary syndrome; angioplasty; balloon; coronary; magnetic resonance imaging
12.  APOM and High-Density Lipoprotein are associated with Lung Function and Percent Emphysema 
The European respiratory journal  2013;43(4):1003-1017.
Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD.
We assessed the association of lung function with 2,100 genes selected for cardiovascular diseases among 20,077 European-Americans and 6,900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with percent emphysema, and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with FEV1/FVC and percent emphysema.
We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10−6) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10−7). Both SNPs flank the gene for apolipoprotein M (apoM), a component of HDL. Both replicated in an independent cohort. SNPs in a second gene related to apoM and HDL, PCSK9, were associated with FEV1/FVC among African-Americans. rs707974 was associated with percent emphysema among European-Americans and African-Americans, and APOM expression was related to FEV1/FVC and percent emphysema. Higher HDL levels were associated with lower FEV1/FVC and greater percent emphysema.
These findings suggest a novel role for the APOM/HDL pathway in the pathogenesis of COPD and emphysema.
PMCID: PMC4041087  PMID: 23900982
Apolipoproteins; Cholesterol; Percent Emphysema; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive
13.  Statin Therapy and Levels of Hemostatic Factors in a Healthy Population: the Multi-Ethnic Study of Atherosclerosis 
HMG CoA reductase inhibitors (statins) reduce risk of venous thromboembolism (VTE) in healthy people. Statins reduce levels of inflammation biomarkers, however the mechanism for reduction in VTE risk is unknown. In a large cohort of healthy people, we studied associations of statin use with plasma hemostatic factors related to VTE risk.
Cross-sectional analyses were performed in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of 6814 healthy men and women age 45–84, free of clinical cardiovascular disease at baseline; 1001 were using statins at baseline. Twenty-three warfarin users were excluded. Age, race, and sex-adjusted mean hemostatic factor levels were compared between statin users and nonusers, and multivariable linear regression models were used to assess associations of statin use with hemostasis factors, adjusted for age, race/ethnicity, education, income, hormone replacement therapy (in women), and major cardiovascular risk factors.
Participants using statins had lower adjusted levels of D-dimer (−9%), C-reactive protein (−21%) and factor VIII (−3%) than non-users (p<0.05). Homocysteine and von Willebrand factor were non-significantly lower with statin use. Higher fibrinogen (2%) and PAI-1 (22%) levels were observed among statin users than nonusers (p<0.05). Further adjustment for LDL and triglyceride levels did not attenuate the observed differences in these factors by statin use.
Findings of lower D-dimer, factor VIII and C-reactive protein levels with statin use suggest hypotheses for mechanisms whereby statins might lower VTE risk. A prospective study or clinical trial linking these biochemical differences to VTE outcomes in statin users and nonusers is warranted.
PMCID: PMC3702638  PMID: 23565981
statins; thrombosis; risk factor; blood coagulation; inflammation; fibrinolysis
14.  Racial Variations in the Prevalence of Refractive Errors in the United States: The Multi-Ethnic Study of Atherosclerosis 
American journal of ophthalmology  2013;155(6):1129-1138.e1.
To describe racial variations in the prevalence of refractive errors among adult white, Chinese, Hispanic, and black subjects in the United States.
Cross-sectional data from a prospective cohort study—the Multi-Ethnic Study of Atherosclerosis (MESA).
A total of 6000 adults aged 45 to 84 years living in the United States participated in the study. Refractive error was assessed, without cycloplegia, in both eyes of all participants using an autorefractor. After excluding eyes with cataract, cataract surgery, or previous refractive surgery, the eye with the larger absolute spherical equivalent (SE) value for each participant was used to classify refractive error. Any myopia was defined as SE of −1.0 diopters (D) or less; high myopia was defined as SE of −5.0 D or less; any hyperopia was defined as SE of +1.0 D or more; clinically significant hyperopia was defined as SE of +3.0 D or more. Astigmatism was defined as a cylinder value of +1.0 D or more.
After excluding 508 participants with cataracts in both eyes, 838 participants with cataract surgery, 90 participants with laser refractive surgery, and 134 participants who refused to remove their contact lenses for the refraction measurement, 4430 adults with refractive error assessment in at least 1 eye contributed to the analysis. The prevalence of myopia among MESA participants was 25.1%, with lowest rates in Hispanic participants (14.2%), followed by black (21.5%) and white participants (31.0%), and highest rates in Chinese participants (37.2%). The overall rates of high myopia and astigmatism were 4.6% and 45.0%, respectively, with Chinese subjects also having the highest rates of high myopia (11.8%) and astigmatism (53.4%). The overall prevalence of any hyperopia was 38.2% and clinically significant hyperopia was 6.1%, with Hispanic participants having the highest rates of hyperopia (50.2%) and clinically significant hyperopia (8.8%). In multivariate analyses adjusting for age, sex, race, and study site, higher education level, being employed, and being taller were associated with a higher prevalence of myopia. In contrast, lower educational level and being shorter were associated with a higher prevalence of hyperopia.
Myopia and astigmatism were most prevalent in the Chinese population, with Chinese subjects having 3 times the prevalence of myopia as Hispanic subjects. Hyperopia was most common in Hispanic subjects. These findings provide further insights into variations in refractive errors among different racial groups and have important implications for the eye care services in the United States.
PMCID: PMC3759975  PMID: 23453694
15.  Ten-Year Trends in Coronary Calcification in Individuals without Clinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis 
PLoS ONE  2014;9(4):e94916.
Coronary heart disease (CHD) incidence has declined significantly in the US, as have levels of major coronary risk factors, including LDL-cholesterol, hypertension and smoking, but whether trends in subclinical atherosclerosis mirror these trends is not known.
Methods and Findings
To describe recent secular trends in subclinical atherosclerosis as measured by serial evaluations of coronary artery calcification (CAC) prevalence in a population over 10 years, we measured CAC using computed tomography (CT) and CHD risk factors in five serial cross-sectional samples of men and women from four race/ethnic groups, aged 55–84 and without clinical cardiovascular disease, who were members of Multi-Ethnic Study of Atherosclerosis (MESA) cohort from 2000 to 2012. Sample sizes ranged from 1062 to 4837. After adjusting for age, gender, and CT scanner, the prevalence of CAC increased across exams among African Americans, whose prevalence of CAC was 52.4% in 2000–02, 50.4% in 2003–04, 60.0% is 2005–06, 57.4% in 2007–08, and 61.3% in 2010–12 (p for trend <0.001). The trend was strongest among African Americans aged 55–64 [prevalence ratio for 2010–12 vs. 2000–02, 1.59 (95% confidence interval 1.06, 2.39); p = 0.005 for trend across exams]. There were no consistent trends in any other ethnic group. Risk factors generally improved in the cohort, and adjustment for risk factors did not change trends in CAC prevalence.
There was a significant secular trend towards increased prevalence of CAC over 10 years among African Americans and no change in three other ethnic groups. Trends did not reflect concurrent general improvement in risk factors. The trend towards a higher prevalence of CAC in African Americans suggests that CHD risk in this population is not improving relative to other groups.
PMCID: PMC3990562  PMID: 24743658
16.  Left Ventricular Global Function Index By Magnetic Resonance Imaging- A Novel Marker for Assessment of Cardiac Performance for the Prediction Of Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis 
Hypertension  2013;61(4):770-778.
LV function is generally assessed independent of structural remodeling and vice versa. The purpose of this study was to evaluate a novel LV global function index (LVGFI) that integrates LV structure with global function and to assess its predictive value for cardiovascular (CV) events throughout adult life in a multi-ethnic population of men and women without history of cardiovascular diseases at baseline. A total of 5004 participants in the Multi-Ethnic Study of Atherosclerosis underwent a cardiac magnetic resonance (CMR) study and were followed up for a median of 7.2 years. The LVGFI by CMR was defined by the ratio of stroke volume divided by LV total volume defined as the sum of mean LV cavity and myocardial volumes. Cox proportional hazard models were constructed to predict the end points of heart failure (HF), hard CV events and a combined endpoint of all CV events after adjustment for established risk factors, calcium score and biomarkers. A total of 579 (11.6%) incident events were observed during the follow-up period. In adjusted models, the end points of HF, hard CV events and all events were all significantly associated with LVGFI (HF, hazard ratio [HR]= 0.64, p<0.0001; hard CV events, HR=0.79, p=0.007; all events, HR=0.79, p<0.0001). LVGFI had a significant independent predictive value in the multivariable models for all CV event categories. The LVGFI was a powerful predictor of incident heart failure, hard CV events and a composite endpoint including all events in this multiethnic cohort.
PMCID: PMC3691067  PMID: 23424238
left ventricle; ejection fraction; heart failure; LV mass; LV global function index
17.  Reduction in Observation Unit Length of Stay with Coronary Computed Tomography Angiography Depends on Time of Emergency Department Presentation 
Prior studies demonstrating shorter length of stay (LOS) from coronary computed tomography angiography (CCTA) relative to stress testing in emergency department (ED) patients have not considered time of patient presentation. The objectives of this study were to determine whether low-risk chest pain patients receiving stress testing or CCTA have differences in ED plus observation unit (OU) LOS, and if there are disparities in testing modality use, based upon the time of patient presentation to the ED.
The authors examined a cohort of low-risk chest pain patients evaluated in an ED-based OU using prospective and retrospective OU registry data. During the study period, stress testing and CCTA were both available from 08:00 to 17:00 hrs. CCTA was not available on weekends, and therefore only subjects presenting on weekdays were included. Cox regression analysis was used to model the effect of testing modality (stress testing vs. CCTA) on OU LOS. Separate models were fit based on time of patient presentation to the ED using four hour blocks beginning at midnight. The primary independent variable was testing modality: stress testing or CCTA. Age, sex, and race were included as covariates. Logistic regression was used to model testing modality choice by time period adjusted for age, sex, and race.
Over the study period, 841 subjects presented Monday through Friday. Median LOS was 18.0 hours (IQR 11.7 to 22.9 hours). Objective cardiac testing was completed in 788 of 841 (94%) patients, with 496 (63%) receiving stress testing and 292 (37%) receiving CCTA. After adjusting for age, race, and sex, patients presenting between 08:00 and 11:59 hrs not only had a shorter LOS associated with CCTA (p < 0.0001), but also had a greater likelihood of being tested by CCTA (p = 0.001). None of the other time periods had significant differences in LOS or testing modality choice for CCTA relative to stress testing.
In an OU setting with weekday and standard business hours CCTA availability, CCTA testing was associated with shorter LOS among low-risk chest pain patients only in patients presenting to the ED between 08:00 and 11:59 hrs. That time period was also associated with a greater likelihood of being tested by CCTA, suggesting that ED providers may have intuited the inability of CCTA to shorten LOS during other times.
PMCID: PMC3607957  PMID: 23517254
18.  The Impact of Obesity on Cardiovascular Disease Risk Factors and Subclinical Vascular Disease 
Archives of internal medicine  2008;168(9):928-935.
To assess the importance of the obesity epidemic on cardiovascular disease (CVD) risk, we determined the prevalence of obesity and the relationship of obesity to CVD risk factors and subclinical vascular disease.
The Multi-Ethnic Study of Atherosclerosis is an observational cohort study involving 6814 persons aged 45 to 84 years who were free of clinical CVD at baseline (2000–2002). The study assessed the association between body size and CVD risk factors, medication use, and subclinical vascular disease (coronary artery calcium, carotid artery intimal medial thickness, and left ventricular mass).
A large proportion of white, African American, and Hispanic participants were overweight (60% to 85%) and obese (30% to 50%), while fewer Chinese American participants were overweight (33%) or obese (5%). Hypertension and diabetes were more prevalent in obese participants despite a much higher use of antihy-pertensive and/or antidiabetic medications. Obesity was associated with a greater risk of coronary artery calcium (17%), internal carotid artery intimal medial thickness greater than 80th percentile (32%), common carotid artery intimal medial thickness greater than 80th percentile (45%), and left ventricular mass greater than 80th percentile (2.7-fold greater) compared with normal body size. These associations persisted after adjustment for traditional CVD risk factors.
These data confirm the epidemic of obesity in most but not all racial and ethnic groups. The observed low prevalence of obesity in Chinese American participants indicates that high rates of obesity should not be considered inevitable. These findings may be viewed as indicators of potential future increases in vascular disease burden and health care costs associated with the obesity epidemic.
PMCID: PMC2931579  PMID: 18474756
19.  Associations of Acculturation and Socioeconomic Status with Subclinical CVD in the MultiEthnic Study of Atherosclerosis 
American journal of public health  2008;98(11):1963-1970.
To assess whether markers of acculturation (birthplace, number of U.S. generations) and socioeconomic status (SES) are associated with carotid artery plaque, internal carotid intima-media thickness (IMT), and albuminuria, in four racial/ethnic groups.
Using Multi-Ethnic Study of Atherosclerosis data (n = 6,716; age: 45-84) and race-specific binomial regression models, we computed prevalence ratios, adjusted for demographics and traditional cardiovascular risk factors.
The adjusted U.S. to foreign-born prevalence ratio (99% CI) for carotid plaque was 1.20 (0.97, 1.39) in Whites, 1.91 (0.94, 2.94) in Chinese, 1.62 (1.28, 2.06) in Blacks, and 1.23 (1.15, 1.31) in Hispanics. Greater carotid plaque prevalence was also found among Whites, Blacks, and Hispanics with more generations of US residence (p<0.001). Lower educational attainment and/or income were associated with greater carotid plaque prevalence in Whites and Blacks. Similar associations were observed with IMT. There was also some evidence of an inverse association between albuminuria and SES, in Whites and Hispanics.
Greater U.S. acculturation and lower SES were associated with a higher prevalence of carotid plaque and IMT, while little association was found with albuminuria.
PMCID: PMC2575668  PMID: 18511718
20.  Prospective Study of Particulate Air Pollution Exposures, Subclinical Atherosclerosis, and Clinical Cardiovascular Disease 
American Journal of Epidemiology  2012;176(9):825-837.
The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) was initiated in 2004 to investigate the relation between individual-level estimates of long-term air pollution exposure and the progression of subclinical atherosclerosis and the incidence of cardiovascular disease (CVD). MESA Air builds on a multicenter, community-based US study of CVD, supplementing that study with additional participants, outcome measurements, and state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, and black carbon. More than 7,000 participants aged 45–84 years are being followed for over 10 years for the identification and characterization of CVD events, including acute myocardial infarction and other coronary artery disease, stroke, peripheral artery disease, and congestive heart failure; cardiac procedures; and mortality. Subcohorts undergo baseline and follow-up measurements of coronary artery calcium using computed tomography and carotid artery intima-medial wall thickness using ultrasonography. This cohort provides vast exposure heterogeneity in ranges currently experienced and permitted in most developed nations, and the air monitoring and modeling methods employed will provide individual estimates of exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand and reduce uncertainty in health effect estimation regarding long-term exposure to air pollution and CVD.
PMCID: PMC3571256  PMID: 23043127
air pollution; atherosclerosis; cardiovascular diseases; environmental exposure; epidemiologic methods; particulate matter
21.  Genome-Wide Association of Body Fat Distribution in African Ancestry Populations Suggests New Loci 
Liu, Ching-Ti | Monda, Keri L. | Taylor, Kira C. | Lange, Leslie | Demerath, Ellen W. | Palmas, Walter | Wojczynski, Mary K. | Ellis, Jaclyn C. | Vitolins, Mara Z. | Liu, Simin | Papanicolaou, George J. | Irvin, Marguerite R. | Xue, Luting | Griffin, Paula J. | Nalls, Michael A. | Adeyemo, Adebowale | Liu, Jiankang | Li, Guo | Ruiz-Narvaez, Edward A. | Chen, Wei-Min | Chen, Fang | Henderson, Brian E. | Millikan, Robert C. | Ambrosone, Christine B. | Strom, Sara S. | Guo, Xiuqing | Andrews, Jeanette S. | Sun, Yan V. | Mosley, Thomas H. | Yanek, Lisa R. | Shriner, Daniel | Haritunians, Talin | Rotter, Jerome I. | Speliotes, Elizabeth K. | Smith, Megan | Rosenberg, Lynn | Mychaleckyj, Josyf | Nayak, Uma | Spruill, Ida | Garvey, W. Timothy | Pettaway, Curtis | Nyante, Sarah | Bandera, Elisa V. | Britton, Angela F. | Zonderman, Alan B. | Rasmussen-Torvik, Laura J. | Chen, Yii-Der Ida | Ding, Jingzhong | Lohman, Kurt | Kritchevsky, Stephen B. | Zhao, Wei | Peyser, Patricia A. | Kardia, Sharon L. R. | Kabagambe, Edmond | Broeckel, Ulrich | Chen, Guanjie | Zhou, Jie | Wassertheil-Smoller, Sylvia | Neuhouser, Marian L. | Rampersaud, Evadnie | Psaty, Bruce | Kooperberg, Charles | Manson, JoAnn E. | Kuller, Lewis H. | Ochs-Balcom, Heather M. | Johnson, Karen C. | Sucheston, Lara | Ordovas, Jose M. | Palmer, Julie R. | Haiman, Christopher A. | McKnight, Barbara | Howard, Barbara V. | Becker, Diane M. | Bielak, Lawrence F. | Liu, Yongmei | Allison, Matthew A. | Grant, Struan F. A. | Burke, Gregory L. | Patel, Sanjay R. | Schreiner, Pamela J. | Borecki, Ingrid B. | Evans, Michele K. | Taylor, Herman | Sale, Michele M. | Howard, Virginia | Carlson, Christopher S. | Rotimi, Charles N. | Cushman, Mary | Harris, Tamara B. | Reiner, Alexander P. | Cupples, L. Adrienne | North, Kari E. | Fox, Caroline S.
PLoS Genetics  2013;9(8):e1003681.
Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0×10−6 were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10−8 for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10−8 for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5×10−8; RREB1: p = 5.7×10−8). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.
Author Summary
Central obesity is a marker of body fat distribution and is known to have a genetic underpinning. Few studies have reported genome-wide association study (GWAS) results among individuals of predominantly African ancestry (AA). We performed a collaborative meta-analysis in order to identify genetic loci associated with body fat distribution in AA individuals using waist circumference (WC) and waist to hip ratio (WHR) as measures of fat distribution, with and without adjustment for body mass index (BMI). We uncovered 2 genetic loci potentially associated with fat distribution: LHX2 in association with WC-adjusted-for-BMI and at RREB1 for WHR-adjusted-for-BMI. Six of fourteen previously reported loci for waist in EA populations were significant in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). These findings reinforce the concept that there are loci for body fat distribution that are independent of generalized adiposity.
PMCID: PMC3744443  PMID: 23966867
22.  Statins, Risk of Dementia and Cognitive Function: Secondary Analysis of the Ginkgo Evaluation of Memory Study (GEMS) 
To examine whether lipid lowering medications (LLMs) and especially statin drugs can delay cognitive decline and dementia onset in individuals with and without Mild Cognitive Impairment (MCI) at baseline.
Longitudinal, observational study of 3,069 cognitively healthy elderly, ages 75 years and older, who were enrolled in the Ginkgo Evaluation of Memory Study. Primary outcome measure was the time to adjudicated all-cause dementia and Alzheimer dementia (AD). Secondary outcome measure was the change in global cognitive function over time measured by 3MSE and ADAS-cog scores.
Among participants without MCI at baseline current use of statins was consistently associated with a reduced risk of all cause dementia (HR 0. 79, 95% confidence interval, 0.65–0.96, p=0.021) and AD (HR 0.57, 95% confidence interval, 0.39–0.85, p= 0.005). In participants who initiated statin therapy lipophilic statins tended to reduce dementia risk more than nonlipophilic agents. In contrast there was no significant association between LLM use (including statins), dementia onset or cognitive decline in individuals with baseline MCI. However, in individuals without MCI at baseline there was a trend for a neuroprotective effect of statins on cognitive decline.
Statins may slow the rate of cognitive decline and delay the onset of AD and all cause dementia in cognitively healthy elderly individuals whereas individuals with MCI may not have comparable cognitive protection from these agents. However, the results from this observational study need to be interpreted with caution and will require confirmation by randomized clinical trials stratifying treatment groups based on MCI status at baseline.
PMCID: PMC3140577  PMID: 21236699
Cognitive function; 3HMG-ACoA reductase inhibitors; Mild Cognitive Impairment; dementia
23.  Gender Differences Between the Minnesota Code and Novacode Electrocardiographic Prognostication of Coronary Heart Disease in the Cardiovascular Health Study 
The American journal of cardiology  2011;107(6):817-820.e1.
The Minnesota Code (MC) and Novacode (Nova) are the most widely used electrocardiographic (ECG) classification systems. The comparative strengths of their classifications for Q- and ST-T–wave abnormalities in predicting coronary heart disease (CHD) events and total mortality have not been evaluated separately by gender. We studied standard 12-lead electrocardiograms at rest from 4,988 participants in the Cardiovascular Health Study. Average age at baseline was 73 years, 60% of participants were women 85% were white, and 22% had a history of cardiovascular disease or presence of ECG myocardial infarction by MC or Nova. Starting in 1989 with an average 17-year follow-up, 65% of participants died and 33% had incident CHD in a cohort free of cardiovascular disease at baseline. Of these, electrocardiograms with major Q-wave or major ST-T abnormalities by MC or Nova predicted increased risk for CHD events and total mortality with no significant differences in predictability between men and women. The study also found that women had fewer major Q-wave changes but more major ST-T abnormalities than men. However, there were no gender differences in predicting CHD events and total mortality. In conclusion, ECG classification systems for myocardial infarction/ischemia abnormalities by MC or Nova are valuable and useful for men and women in clinical trials and epidemiologic studies.
PMCID: PMC3673724  PMID: 21247534
24.  Retinal Microvascular Signs and Disability in the Cardiovascular Health Study 
Archives of ophthalmology  2011;130(3):350-356.
Retinal microvascular signs are associated with systemic conditions and cognitive decline. We studied the associations of microvascular changes, measured by retinal signs, with disability in performing activities of daily living (ADL).
Prospective cohort study.
1487 participants in the Cardiovascular Health Study (mean age 78 years) who were free of ADL disability and had available data on retinal signs and carotid intima-media thickness (IMT) at the 1998–99 visit.
Main Outcome Measure
Incident ADL disability, defined as self-reported difficulty in performing any ADLs, by the presence of retinal signs and advanced carotid atherosclerosis, defined by carotid IMT ≥ 80th percentile or ≥ 25% stenosis; and potential mediation by cerebral microvascular disease on brain imaging or by executive dysfunction, slow gait, and depressive mood that are symptoms of frontal subcortical dysfunction.
During the median follow-up of 3.1 years (maximum 7.8 years), participants with ≥ 2 retinal signs had a higher rate of disability than those with < 2 retinal signs (10.1% versus 7.1%; adjusted hazards ratio, 1.45; 95% confidence interval, 1.24–1.69; P < 0.001). There was no evidence of interaction by advanced carotid atherosclerosis (P > 0.10). The association seemed to be partially mediated by executive dysfunction, slow gait, and depressive symptoms, but not by cerebral microvascular disease on brain imaging.
These results provide further support for the pathophysiologic and prognostic significance of microvascular disease in age-related disability. However, it remains to be determined how to best utilize retinal photography in the clinical risk prediction.
PMCID: PMC3520093  PMID: 22084159
25.  Prediction of Coronary Artery Calcium Progression in Individuals with Low Framingham Risk Score: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Jacc. Cardiovascular Imaging  2012;5(2):144-153.
We sought to determine whether novel markers not involving ionizing radiation could predict CAC progression in a low-risk population.
Increase in coronary artery calcium (CAC) scores over time (CAC progression) improves prediction of coronary heart disease (CHD) events. Due to radiation exposure, CAC measurement represents an undesirable method for repeated risk assessment, particularly in low predicted risk individuals (Framingham Risk Score [FRS] <10%).
From 6814 MESA participants, 2620 individuals were classified as low risk for CHD events (FRS <10%), and had follow-up CAC measurement. In addition to traditional risk factors [(RFs) - base model], various combinations of novel-marker models were selected based on data-driven, clinical, or backward stepwise selection techniques.
Mean follow-up was 2.5 years. CAC progression occurred in 574 participants (22% overall; 214 of 1830 with baseline CAC =0, and 360 of 790 with baseline CAC >0). Addition of various combinations of novel markers to the base model (c-statistic =0.711), showed improvements in discrimination of approximately only 0.005 each (c-statistics 0.7158, 0.7160 and 0.7164) for the best-fit models. All 3 best-fit novel-marker models calibrated well but were similar to the base model in predicting individual risk probabilities for CAC progression. The highest prevalence of CAC progression occurred in the highest compared to the lowest probability quartile groups (39.2–40.3% versus 6.4–7.1%).
In individuals at low predicted risk by FRS, traditional RFs predicted CAC progression in the short term with good discrimination and calibration. Prediction improved minimally when various novel markers were added to the model.
PMCID: PMC3310187  PMID: 22340820
coronary calcium; Framingham risk score; risk factors; progression

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