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1.  Baseline depressive symptoms are not associated with clinically important levels of incident hypertension during two years of follow-up: the Multi-Ethnic Study of Atherosclerosis 
Hypertension  2010;55(2):408.
Previous longitudinal cohort studies have suggested an association between baseline depressive symptoms and incident hypertension. We assessed this possible association using data from the Multi-ethnic Study of Atherosclerosis, a population-based prospective cohort study of 6,814 US adults from 4 different racial/ethnic groups. Baseline users of antihypertensive medications and participants lost to follow-up were excluded leaving 3914 participants. Patients with baseline depressive symptoms (n=622) were defined using a high score on the Center for Epidemiologic Studies Depression Scale (≥ 16) or the use of an antidepressant medication. Hypertension was defined as systolic blood pressure ≥ 140, diastolic blood pressure ≥90 or new use of antihypertensive medications plus physician diagnosis. Estimates were adjusted for known risk factors including: age, sex, baseline blood pressure, diabetes, and body mass index. Untreated blood pressure was estimated using an imputation approach. A total of 477 participants developed hypertension. Using relative risk regression, patients with baseline depressive symptoms did not have an increased risk of incident hypertension (Relative Risk = 1.02; 95% Confidence Interval (CI):0.99 to 1.05) although an association between tricyclic antidepressants and hypertension (Relative Risk 1.20; 95% CI:1.05 to 1.37) was observed in sub-group analysis. Depression, even after adjustment for covariates, was associated with small changes in systolic (+2.4 mmHG; 95% CI: 0.2 to 4.7) and diastolic (+0.8 mmHG; 95% CI: −0.6 to 2.3) blood pressure. Depressive symptoms may be associated with slight increases in blood pressure in this multi-ethnic cohort but it is premature to conclude much without longer studies in other populations.
doi:10.1161/HYPERTENSIONAHA.109.139824
PMCID: PMC2821214  PMID: 20065156
Multi-Ethnic Study of Atherosclerosis; depression; hypertension; blood pressure; imputation; censored normal regression
2.  Time trends in the use of anti-hypertensive medications: results from the Multi-Ethnic Study of Atherosclerosis 
Background
Previous research has suggested that emerging evidence from randomized controlled trials (RCTs) is often not reflected in physician selection of medication class for first-line anti-hypertensive therapy.
Objectives
To evaluate the association of RCT evidence in December 2002 from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) on use of anti-hypertensive medications over time in a multi-ethnic cohort.
Methods
The Multi-Ethnic Study of Atherosclerosis study, a prospective cohort study of 6,814 adults from 4 ethnic groups, had four separate assessments of drug use. Users of anti-hypertensive medications at baseline were excluded. We evaluated temporal changes in the medication class reported by new users of antihypertensive medications.
Results
After the exclusion of antihypertensive drug users at baseline, 32% of new users of anti-hypertensive drugs seen at exam 2 were prescribed a diuretic. The publication of ALLHAT was associated with a subsequent increase in the proportion of new users taking diuretics at exam 3 compared with exam 2 (Relative Risk (RR):1.31; 95% Confidence Interval (CI):1.09–1.59). After the report from ALLHAT, the proportion of users of diuretics seen at exam 3 rose to 44% (starting in 2004) and 39% in exam 4 (starting in 2005). This increase in the proportion of diuretic use among new users of anti-hypertensive medications declined slightly but could still be detected at exam 4 as compared to exam 2 (RR:1.28; 95% CI:1.04–1.57).
Conclusions
The randomized trial evidence from the ALLHAT study was temporally associated with a moderate increase in diuretic use.
doi:10.1002/pds.1788
PMCID: PMC2844254  PMID: 19551700
Multi-Ethnic Study of Atherosclerosis; antihypertensive medications; drug utilization; longitudinal
3.  Multiple imputation for missing cardiac magnetic resonance imaging data: Results from the Multi-Ethnic Study of Atherosclerosis (MESA) 
The Canadian Journal of Cardiology  2009;25(7):e232-e235.
BACKGROUND:
Cardiac magnetic resonance imaging (MRI) is a non-invasive technique used to accurately and reproducibly measure biological parameters such as left ventricular mass. However, some subjects either refuse or are unable to complete testing, and the impact of excluding these missing data from predictive models is unknown.
METHODS:
Multiple imputation was applied to cardiac MRI data that were previously analyzed using a complete case approach. The model variables – 10 traditional cardiovascular risk factors and five sociodemographic variables – were used as a basis for imputation. Men and women were imputed separately. The primary focus was assessing the change in the cardiovascular predictors of left ventricular geometry and systolic function.
RESULTS:
Although 27% of participants were missing cardiac MRI data, multiple imputation returned results similar to those of a complete case analysis. These results were robust to the point of including additional variables in the imputation analysis above and beyond the model variables. The degree of variance explained by the models increased marginally but the statistical inference was altered for only two predictors out of 53 cardiovascular risk factors using multiple imputation.
DISCUSSION:
The results suggest that the cardiac MRI data in the Multi-Ethnic Study of Atherosclerosis (MESA) do not substantively change when missing data are handled using multiple imputation. Future analyses of cardiac MRI data may consider the complete case approach to be adequate despite the high rate of missing data in this population.
PMCID: PMC2723032  PMID: 19584978
Comparison of methods; Complete case; Magnetic resonance imaging; Multiple imputation
4.  Mediation of Cardiovascular Risk Factor Effects Through Subclinical Vascular Disease: The Multi-Ethnic Study of Atherosclerosis 
Objective
It is unclear to what extent subclinical cardiovascular disease (CVD) such as coronary artery calcium (CAC), carotid intima-media thickness (CIMT) and brachial flow mediated dilation (FMD) are mediators of the known associations between traditional cardiovascular risk factors and incident CVD events. We assessed the portion of the effects of risk factors on incident CVD events that are mediated through CAC, CIMT and FMD.
Approach and Results
6355 out of 6814 MESA participants were included. Nonlinear implementation of structural equation modeling (STATA mediation package) were used to assess whether CAC, CIMT or FMD are mediators of the association between traditional risk factors and incident CVD event.
Mean age of 62, with 47% males, 12% diabetics and 13% current smokers. Mean follow up of 7.5 years, 539 CVD events were adjudicated. CAC showed the highest mediation while FMD showed the least. Age had the highest percent of total effect mediated via CAC for CVD outcomes while current cigarette smoking had the least percent of total effect mediated via CAC [percent (95%CI: 80.2(58.8, 126.7) % vs. 10.6(6.1, 38.5) % respectively). BMI showed the highest percent of total effect mediated via CIMT [17.7(11.6, 38.9) %], only a negligible amount of the association between traditional risk factors and CVD was mediated via FMD.
Conclusion
Many of the risk factors for incident CVD (other than age, sex and BMI) showed a modest level of mediation via CAC, CIMT and FMD suggesting that current subclinical CVD markers may not be optimal intermediaries for gauging upstream risk factor modification
doi:10.1161/ATVBAHA.114.303753
PMCID: PMC4329880  PMID: 24876350
5.  THE ASSOCIATIONS OF ADIPOKINES WITH SELECTED MARKERS OF THE RENIN-ANGIOTENSINOGEN-ALDOSTERONE SYSTEM: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS 
Journal of human hypertension  2014;29(2):127-133.
Among obese individuals, increased sympathetic nervous system activity results in increased renin and aldosterone production, as well as renal tubular sodium reabsorption. This study determined the associations between adipokines and selected measures of the reninangiotensinogen-aldosterone system (RAAS). The sample was 1,970 men and women from the Multi-Ethnic Study of Atherosclerosis who were free of clinical cardiovascular disease at baseline and had blood assayed for adiponectin, leptin, plasma renin activity (PRA) and aldosterone. The mean age was 64.7 years and 50% were female. The mean (SD) PRA and aldosterone were 1.45 (0.56) ng/ml and 150.1 (130.5) pg/ml, respectively. After multivariable adjustment, a 1-SD increment of leptin was associated with a 0.55 ng/ml higher PRA and 8.4 pg/ml higher aldosterone (p < 0.01 for both). Although adiponectin was not significantly associated with PRA levels, the same increment in this adipokine was associated with lower aldosterone levels (−5.5 pg/ml, p = 0.01). Notably, the associations between aldosterone and both leptin and adiponectin were not materially changed with additional adjustment for PRA. Exclusion of those taking anti-hypertensive medications modestly attenuated the associations. The associations between leptin and both PRA and aldosterone were not different by gender but were significantly stronger among non-Hispanic Whites and Chinese Americans than African and Hispanic Americans (p < 0.01). The findings suggest that both adiponectin and leptin may relevant to blood pressure regulation via the RAAS, that the associations appear to be robust to anti-hypertension medication use and that the associations are likely different by ethnicity.
doi:10.1038/jhh.2014.40
PMCID: PMC4265023  PMID: 24919752
Adipokines; Renin; Aldosterone; Ethnicity
6.  Association of Subsyndromal and Depressive Symptoms with Inflammatory Markers among different Ethnic groups: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Journal of affective disorders  2014;164:165-170.
Objective
Depressive symptoms are associated with inflammation yet the association between inflammation and different levels of depression remains unclear. Therefore, we studied the association of subsyndromal and depressive symptoms with inflammatory markers in a large multi-ethnic cohort.
Methods
C-reactive protein (CRP) (n=6,269), interleukin-6 (IL-6) (n=6,135) and tumor necrosis factor-alpha (TNF-α) (n=1,830) were measured in selected participants from the Multi-Ethnic Study of Atherosclerosis (MESA). Subsyndromal depressive symptoms were defined as a CES-D value from 8 to 15, depressive symptoms as a CES-D≥16 and normal as a CES-D≤7. Depressive states (subsyndromal and depressed) were entered into multivariable linear regression models incrementally adjusting for demographic, behavioral, biologic and comorbidities.
Results
Among 6,289 participants not taking antidepressants and free from CVD, the mean age was 62.2, while 52% were women, 36.4% were Caucasian, 28.9% African-American, 22.3% Hispanics and 12.4% Chinese-American. Of the total, 24.2% had subsyndromal depression and 11.8% had depressive symptoms. Compared to the non-depressed group and after controlling for demographics, there was no association between both subsyndromal and depressive symptoms with logCRP(β=−0.01, p=0.80 and β=−0.05, p=0.25; respectively), logIL-6(β=0.01, p=0.71 and β=−0.04, p=0.07; respectively) and logTNF-α(β=−0.03, p=0.29 and β=0.06, p=0.18; respectively). Moreover, fully adjusted models showed no significant associations for logIL-6 and logTNF-α and the different depressive categories. However, with full adjustment, we found a significant inverse association between depressive symptoms and lnCRP(β=−0.10; p=0.01) that was not present for subsyndromal depression (β=−0.05; p=0.11).
Conclusion
Among participants not taking anti-depressants, subsyndromal depression is not associated with inflammation. However, depressive symptoms measured by CES-D≥16 are associated with a lower inflammation (CRP).
doi:10.1016/j.jad.2014.04.018
PMCID: PMC4079665  PMID: 24856570
subsyndromal depression; inflammation; cardiovascular disease; depressive states
7.  Extending the Bayesian Adjustment for Confounding algorithm to binary treatment covariates to estimate the effect of smoking on carotid intima-media thickness: The Multi-Ethnic Study of Atherosclerosis 
Statistics in medicine  2014;33(16):2797-2813.
We illustrate the application of the Bayesian Adjustment for Confounding (BAC) algorithm when the treatment covariate is binary. Using data from the Multi-Ethnic Study of Atherosclerosis, we estimate the effect of ever smoking on common carotid artery intimal medial thickness (CCA IMT) among adult Caucasian participants (n = 1378). Our novel implementation of the BAC algorithm is performed first from an outcome model perspective and secondly from a treatment model perspective with both inverse-probability-weighting (IPW) and doubly-robust (DR) estimation techniques. The BAC results are compared to the results obtained using standard model averaging and full model strategies, giving a range of adjusted estimates between 45.50 μm and 65.30 μm for increased CCA IMT among ever smokers. For both perspectives, we observe that BAC offers similar performance to using the fully specified outcome and/or treatment model (the full outcome model ever smoking effect is 48.61 μm; 95% CI: (0.62, 96.60)). We then redo the analyses for the African American, Hispanic and Chinese adult participants to study the robustness of these findings with reduced sample size. For the Chinese subcohort, which corresponds to the smallest sample size (n = 436), we find that, from a treatment model perspective, BAC reduces the variability of the estimates in comparison to using a full model approach. This suggests that the use of BAC in conjunction with IPW and DR estimation can be advantageous when applied to relatively small sample sizes. This conjecture is subsequently verified on the basis of three simulated experiments.
doi:10.1002/sim.6123
PMCID: PMC4047170  PMID: 24596278
Bayesian Adjustment for Confounding; binary treatment variable; Multi-Ethnic Study of Atherosclerosis; smoking; common carotid artery intimal medial thickness
8.  Association of Renin and Aldosterone With Ethnicity and Blood Pressure: The Multi-Ethnic Study of Atherosclerosis 
American Journal of Hypertension  2014;27(6):801-810.
BACKGROUND
Although variations in plasma renin activity (PRA) and aldosterone have been examined in whites and blacks, the association of these hormones with blood pressure in multiethnic populations has not been described.
METHODS
We measured PRA and aldosterone in 1,021 participants in the Multi-Ethnic Study of Atherosclerosis not taking antihypertensives and examined the association between ethnicity and PRA/aldosterone and the association between PRA/aldosterone with systolic blood pressure (SBP).
RESULTS
Average age was 62 (SD = 9) years, and 49% of participants were women. Median PRA was 0.51 (interquartile range (IQR) = 0.29–0.87) ng/ml/hour, and median aldosterone was 12.6 (IQR = 9.1–17.1) ng/dl. After age and sex adjustment, compared with whites, blacks had 28% lower PRA and 17.4% lower aldosterone, and Hispanics had 20.1% higher PRA but similar aldosterone levels. After multivariable adjustment, compared with whites, only Hispanic ethnicity independently associated with higher PRA (0.18ng/ml/hour; 95% confidence interval (CI) = 0.06–0.31). Blacks had lower aldosterone (−1.7ng/dl; 95% CI = −3.2 to −0.2) compared with whites. After multivariable adjustment, PRA was associated with lower SBP in whites (−3.2mm Hg; 95% CI = −5.2 to −1.2 per standardized unit PRA), Chinese (−3.5mm Hg; 95% CI = −6.2 to −0.80 per standardized unit), and Hispanics (−2.3mm Hg; 95% CI = −4.1 to −0.6 per standardized unit) but not blacks. Aldosterone was associated with higher SBP only in Hispanics (2.5mm Hg; 95% CI = 0.4–4.5 per SD).
CONCLUSIONS
Compared with whites, blacks have lower aldosterone and Hispanics have higher PRA. Aldosterone had significant associations with higher SBP in Hispanics compared with other groups, a finding that may suggest a different mechanism of hypertension.
doi:10.1093/ajh/hpt276
PMCID: PMC4017931  PMID: 24436325
black; blood pressure; Chinese; cross-sectional analysis; Hispanic; hypertension; white.
9.  Lower extremity peripheral artery disease in the absence of traditional risk factors. The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2010;214(1):169-173.
Objective
Lower-extremity peripheral artery disease (LE-PAD), is strongly related to traditional risk factors (smoking, hypertension, dyslipidemia, diabetes). We hypothesized that the prevalence of LE-PAD in the absence of traditional CVD risk factors is not negligible, and that this condition would remain associated with subclinical atherosclerosis in other territories.
Methods
In the Multi-Ethnic Study of Atherosclerosis, we classified participants without any traditional risk factor according to their ankle-brachial index (ABI) into 3 groups: low (<1.00), normal (1.00–1.30) and high (>1.30) ABI. Coronary or carotid artery diseases were defined by the presence of any coronary artery calcification (CAC score > 0) or carotid plaque, respectively.
Results
Among the 6814 participants, 1932 had no traditional risk factors. A low- and high ABI were found in 176 (9%) and 149 (7.8%) cases, respectively. Lower glomerular filtration rate (OR: 0.88/10 units, p = 0.04) and higher Interleukin-6 levels (OR: 1.42/natural-log unit, p = 0.02) were associated with low ABI. Past smoking (cessation > 10 years) and pulse pressure had borderline association with low ABI. In adjusted models, low-ABI was significantly associated with CAC prevalence (OR: 1.22, p < 0.03). No significant association was found with carotid plaque.
Conclusion
In the absence of traditional CVD risk factors, LE-PAD is still common and associated with coronary artery disease.
doi:10.1016/j.atherosclerosis.2010.10.011
PMCID: PMC4415364  PMID: 21067754
Atherosclerosis; Peripheral artery disease; Risk; Subclinical
10.  CORONARY ARTERY CALCIUM IN RELATION TO INITIATION AND CONTINUATION OF CARDIOVASCULAR PREVENTIVE MEDICATIONS: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) 
Background
Whether measuring and reporting of coronary artery calcium scores (CACS) might lead to changes in cardiovascular risk management is not established. In this observational study we examined whether high baseline CACS were associated with the initiation as well continuation of new lipid lowering medication (LLM), blood pressure lowering medication (BPLM) and regular aspirin (ASA) use in a multi-ethnic population-based cohort.
Methods and Results
MESA is a prospective cohort study of 6814 participants free of clinical cardiovascular disease at entry who underwent CAC testing at baseline examination (exam 1). Information on LLM, BPLM and regular ASA usage was also obtained at baseline, and at exams 2 and 3 (average of 1.6 and 3.2 years after baseline respectively). In this study we examined: 1) initiation of these medications at exam 2 among participants not taking these medications at baseline; and 2) continuation of medication use to exam 3 among participants already on medication at baseline. Among MESA participants, initiation of LLM, BPLM and ASA was greater in those with higher CACS After taking into account age, gender, race, MESA site, LDL cholesterol, diabetes mellitus, BMI, smoking status, hypertension, systolic blood pressure, and SES (income, education and health insurance), the risk ratios for medication initiation comparing those with CACS>400 vs. CACS=0 were 1.53 (95% CI: 1.08, 2.15) for LLM, 1.55 (1.10-- 2.17) for BPLM, and 1.32 (1.03–1.69) for ASA initiation, respectively. The risk ratios for medication continuation among those with CAC>400 vs. CACS=0 were 1.10 (95% CI: 1.01–1.20) for LLM, 1.05 (1.02–1.08) for BPLM, and 1.14 (1.04- 1.25) for ASA initiation, respectively.
Conclusion
CACS>400 was associated with a higher likelihood of initiation and continuation of LLM, BPLM and ASA. The association was weaker for continuation than for initiation of these preventive therapies.
doi:10.1161/CIRCOUTCOMES.109.893396
PMCID: PMC4402976  PMID: 20371760
Coronary artery calcification; Computed tomography; Medications; Adherence; Prevention
11.  Net Reclassification Indices for Evaluating Risk-Prediction Instruments: A Critical Review 
Epidemiology (Cambridge, Mass.)  2014;25(1):114-121.
Net reclassification indices have recently become popular statistics for measuring the prediction increment of new biomarkers. We review the various types of net reclassification indices and their correct interpretations. We evaluate the advantages and disadvantages of quantifying the prediction increment with these indices. For pre-defined risk categories, we relate net reclassification indices to existing measures of the prediction increment. We also consider statistical methodology for constructing confidence intervals for net reclassification indices and evaluate the merits of hypothesis testing based on such indices. We recommend that investigators using net reclassification indices should report them separately for events (cases) and nonevents (controls). When there are two risk categories, the components of net reclassification indices are the same as the changes in the true-positive and false-positive rates. We advocate use of true- and false-positive rates and suggest it is more useful for investigators to retain the existing, descriptive terms. When there are three or more risk categories, we recommend against net reclassification indices because they do not adequately account for clinically important differences in shifts among risk categories. The category-free net reclassification index is a new descriptive device designed to avoid pre-defined risk categories. However, it suffers from many of the same problems as other measures such as the area under the receiver operating characteristic curve. In addition, the category-free index can mislead investigators by overstating the incremental value of a biomarker, even in independent validation data. When investigators want to test a null hypothesis of no prediction increment, the well-established tests for coefficients in the regression model are superior to the net reclassification index. If investigators want to use net reclassification indices, confidence intervals should be calculated using bootstrap methods rather than published variance formulas. The preferred single-number summary of the prediction increment is the improvement in net benefit.
doi:10.1097/EDE.0000000000000018
PMCID: PMC3918180  PMID: 24240655
12.  Carotid Artery Plaque Morphology and Composition in Relation to Incident Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Radiology  2014;271(2):381-389.
Our results support the concept that adverse carotid arterial remodeling and a lipid core at MR imaging confer increased risk for subsequent cardiovascular events in asymptomatic individuals.
Purpose
To determine if carotid plaque morphology and composition with magnetic resonance (MR) imaging can be used to identify asymptomatic subjects at risk for cardiovascular events.
Materials and Methods
Institutional review boards at each site approved the study, and all sites were Health Insurance Portability and Accountability Act (HIPAA) compliant. A total of 946 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) were evaluated with MR imaging and ultrasonography (US). MR imaging was used to define carotid plaque composition and remodeling index (wall area divided by the sum of wall area and lumen area), while US was used to assess carotid wall thickness. Incident cardiovascular events, including myocardial infarction, resuscitated cardiac arrest, angina, stroke, and death, were ascertained for an average of 5.5 years. Multivariable Cox proportional hazards models, C statistics, and net reclassification improvement (NRI) for event prediction were determined.
Results
Cardiovascular events occurred in 59 (6%) of participants. Carotid IMT as well as MR imaging remodeling index, lipid core, and calcium in the internal carotid artery were significant predictors of events in univariate analysis (P < .001 for all). For traditional risk factors, the C statistic for event prediction was 0.696. For MR imaging remodeling index and lipid core, the C statistic was 0.734 and the NRI was 7.4% and 15.8% for participants with and those without cardiovascular events, respectively (P = .02). The NRI for US IMT in addition to traditional risk factors was not significant.
Conclusion
The identification of vulnerable plaque characteristics with MR imaging aids in cardiovascular disease prediction and improves the reclassification of baseline cardiovascular risk.
© RSNA, 2014
doi:10.1148/radiol.14131020
PMCID: PMC4263652  PMID: 24592924
13.  New Automated Assay of Small Dense Low-Density Lipoprotein Cholesterol Identifies Risk of Coronary Heart Disease 
Objective
Coronary heart disease (CHD) is the leading cause of death in the United States, yet assessing risk of its development remains challenging. The present study evaluates a new automated assay of small dense low-density lipoprotein cholesterol content (sdLDL-C) and whether sdLDL-C is a risk factor for CHD compared with LDL-C or small LDL particle concentrations derived from nuclear magnetic resonance spectroscopy.
Approach and Results
sdLDL-C was measured using a new automated enzymatic method, and small LDL concentrations were obtained by nuclear magnetic resonance in 4387 Multi-Ethnic Study of Atherosclerosis participants. Cox regression analysis estimated hazard ratios for developing CHD for 8.5 years after adjustments for age, race, sex, systolic blood pressure, hypertension medication use, high-density lipoprotein cholesterol, and triglycerides. Elevated sdLDL-C was a risk factor for CHD in normoglycemic individuals. Those in the top sdLDL-C quartile showed higher risk of incident CHD (hazard ratio, 2.41; P=0.0037) compared with those in the bottom quartile and indicated greater CHD risk than the corresponding quartile of LDL-C (hazard ratio, 1.75; P=0.019). The association of sdLDL-C with CHD risk remained significant when LDL-C (<2.57 mmol/L) was included in a multivariate model (hazard ratio, 2.37; P=0.012). Nuclear magnetic resonance–derived small LDL concentrations did not convey a significant risk of CHD. Those with impaired fasting glucose or diabetes mellitus showed higher sdLDL-C and small LDL concentrations but neither was associated with higher CHD risk in these individuals.
Conclusions
This new automated method for sdLDL-C identifies risk for CHD that would remain undetected using standard lipid measures, but only in normoglycemic, nondiabetic individuals.
doi:10.1161/ATVBAHA.113.302401
PMCID: PMC4211254  PMID: 24233487
coronary; disease
14.  The prospective association of Chlamydia pneumoniae and four other pathogens with development of coronary artery calcium: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2013;230(2):10.1016/j.atherosclerosis.2013.07.053.
Objective
Previous basic and cross-sectional studies obtained conflicting results regarding the association of pathogens with coronary artery calcium (CAC). The aim of this study is to prospectively evaluate this association in a population-based cohort.
Methods
We examined 5,744 individuals aged 45-84 years at baseline (2000-02) who underwent repeated CAC assessment on average 2.4 years later (a half at visit 2 [2002-04] and the other half at visit 3 [2004-05]). CAC incidence was defined as newly detectable CAC at follow-up (475 cases of 2,942 participants). CAC progression was defined as annualized change in CAC Agatston score ≥10 units/year if baseline CAC score >0 to <100 or ≥10%/year if baseline score ≥100 (1,537 cases of 2,802 participants). Seropositivity was assessed in the entire cohort for Chlamydia pneumonia and in a random sample (n=873) for Helicobacter pylori, cytomegalovirus, herpes simplex virus, and hepatitis A virus.
Results
Seropositivity to Chlamydia pneumoniae was not significantly associated with CAC incidence (odds ratio [OR] 1.11 [95% CI, 0.88-1.39], P=0.371) or progression (1.14 [0.96-1.36], P=0.135) even in unadjusted models. When CAC incidence and progression were combined, we observed significant association with Chlamydia pneumoniae seropositivity before adjustment (OR 1.17 [1.03-1.33], P=0.016) but not in a model adjusting for traditional risk factors (1.04 [0.90-1.19], P=0.611). The results were consistent across subgroups according to age, sex, and race/ethnicity. None of five pathogens or their accrual was associated with CAC incidence and progression in the subsample.
Conclusion
Our prospective study does not support the pathophysiological involvement of these pathogens in CAC development.
doi:10.1016/j.atherosclerosis.2013.07.053
PMCID: PMC3815605  PMID: 24075755
Coronary Calcium; Atherosclerosis; Pathogens; Infection
15.  Obstructive Sleep Apnea and Progression of Coronary Artery Calcium: The Multi‐Ethnic Study of Atherosclerosis Study 
Background
Obstructive sleep apnea (OSA) is a common condition associated with cardiovascular disease. Its potential effect on progression of subclinical atherosclerosis is not well understood. We tested the hypothesis that self‐reported OSA is associated with progression of coronary artery calcium (CAC). We also evaluated whether traditional cardiovascular risk factors accounted for the association.
Methods and Results
In the Multi‐Ethnic Study of Atherosclerosis (MESA) prospective cohort, we studied 2603 participants who at baseline (2002–2004) completed a sleep questionnaire and underwent coronary computed tomography (CT) and, then 8 years later (2010–2011), a repeat coronary CT. Participants were categorized by symptoms of habitual snoring or reported physician diagnosis of OSA. At baseline, 102 (3.9%) reported diagnosed OSA; 666 (25.6%) reported diagnosed habitual snoring; and 1835 (70.5%) reported neither habitual snoring nor OSA (“normal”). At baseline, CAC prevalence was highest among those with OSA but similar for those with and without habitual snoring. During 8 years of follow‐up, greater progression of CAC was observed among those with OSA versus normal (mean increase of 204.2 versus 135.5 Agatston units; P=0.01), after accounting for demographics, behaviors, and body habitus. Modest attenuation was observed after adjustment for cardiovascular risk factors (188.7 versus 138.8; P=0.06). CAC progression among habitual snorers was similar to that observed in the normal group.
Conclusions
OSA was associated with CAC score progression after adjustment for demographics, behaviors, and body mass index. However, the association was not significant after accounting for cardiovascular risk factors, which may mediate the association between OSA and CAC.
doi:10.1161/JAHA.114.001241
PMCID: PMC4323795  PMID: 25261530
coronary artery calcium; obstructive sleep apnea; snoring; subclinical atherosclerosis risk factor
16.  Blood Lipids and the Incidence of Atrial Fibrillation: The Multi‐Ethnic Study of Atherosclerosis and the Framingham Heart Study 
Background
Dyslipidemia is a major contributor to the development of atherosclerosis and coronary disease. Its role in the etiology of atrial fibrillation (AF) is uncertain.
Methods and Results
We studied 7142 men and women from the Multi‐Ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study who did not have prevalent AF at baseline and were not on lipid‐lowering medications. Total cholesterol, high‐density lipoprotein and low‐density lipoprotein cholesterol, and triglycerides were measured using standard procedures. Incident AF during follow‐up was identified from hospital discharge codes; review of medical charts; study electrocardiograms; and, in MESA only, Medicare claims. Multivariable Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals of AF by clinical categories of blood lipids in each cohort. Study‐specific results were meta‐analyzed using inverse of variance weighting. During 9.6 years of mean follow‐up, 480 AF cases were identified. In a combined analysis of multivariable‐adjusted results from both cohorts, high levels of high‐density lipoprotein cholesterol were associated with lower AF risk (hazard ratio 0.64, 95% CI 0.48 to 0.87 in those with levels ≥60 mg/dL versus <40 mg/dL), whereas high triglycerides were associated with higher risk of AF (hazard ratio 1.60, 95% CI 1.25 to 2.05 in those with levels ≥200 mg/dL versus <150 mg/dL). Total cholesterol and low‐density lipoprotein cholesterol were not associated with the risk of AF.
Conclusion
In these 2 community‐based cohorts, high‐density lipoprotein cholesterol and triglycerides but not low‐density lipoprotein cholesterol or total cholesterol were associated with the risk of AF, accounting for other cardiometabolic risk factors.
doi:10.1161/JAHA.114.001211
PMCID: PMC4323837  PMID: 25292185
atrial fibrillation; cholesterol; epidemiology; lipids; risk factors
17.  Abdominal Aortic Calcium, Coronary Artery Calcium, and Cardiovascular Morbidity and Mortality in the Multi-Ethnic Study of Atherosclerosis 
Objective
To evaluate the predictive value of abdominal aortic calcium (AAC) for incident cardiovascular disease (CVD) independent of coronary artery calcium (CAC).
Approach and Results
We evaluated the association of AAC with CVD in 1974 men and women aged 45 to 84 years randomly selected from the Multi-Ethnic Study of Atherosclerosis participants who had complete AAC and CAC data from computed tomographic scans. AAC and CAC were each divided into following 3 percentile categories: 0 to 50th, 51st to 75th, and 76th to 100th. During a mean of 5.5 years of follow-up, there were 50 hard coronary heart disease events, 83 hard CVD events, 30 fatal CVD events, and 105 total deaths. In multivariable-adjusted Cox models including both AAC and CAC, comparing the fourth quartile with the ≤50th percentile, AAC and CAC were each significantly and independently predictive of hard coronary heart disease and hard CVD, with hazard ratios ranging from 2.4 to 4.4. For CVD mortality, the hazard ratio was highly significant for the fourth quartile of AAC, 5.9 (P=0.01), whereas the association for the fourth quartile of CAC (hazard ratio, 2.1) was not significant. For total mortality, the fourth quartile hazard ratio for AAC was 2.7 (P=0.001), and for CAC, it was 1.9, P=0.04. Area under the receiver operating characteristic curve analyses showed improvement for both AAC and CAC separately, although improvement was greater with CAC for hard coronary heart disease and hard CVD, and greater with AAC for CVD mortality and total mortality. Sensitivity analyses defining AAC and CAC as continuous variables mirrored these results.
Conclusions
AAC and CAC predicted hard coronary heart disease and hard CVD events independent of one another. Only AAC was independently related to CVD mortality, and AAC showed a stronger association than CAC with total mortality.
doi:10.1161/ATVBAHA.114.303268
PMCID: PMC4153597  PMID: 24812323
aortic diseases; calcium; cardiovascular diseases; diagnostic imaging; epidemiology
18.  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
19.  Calcium Density of Coronary Artery Plaque and Risk of Incident Cardiovascular Events 
Importance
Coronary artery calcium (CAC), measured by computed tomography (CT), has strong predictive value for incident cardiovascular disease (CVD) events. The standard CAC score is the Agatston, which is weighted upward for greater calcium density. However, some data suggest increased plaque calcium density may be protective for CVD.
Objective
To determine the independent associations of CAC volume and CAC density with incident CVD events.
Design, Setting, and Participants
Multicenter, prospective observational MESA study (Multi-Ethnic Study of Atherosclerosis), conducted at 6 US field centers of 3398 men and women from 4 race/ethnicity groups; non-Hispanic white, African American, Hispanic, and Chinese. Participants were aged 45-84 years, free of known CVD at baseline, had CAC greater than 0 on their baseline CT, and were followed up through October 2010.
Main Outcomes and Measures
Incident coronary heart disease (CHD) and all CVD events
Results
During a median of 7.6 years of follow-up, there were 175 CHD events and an additional 90 other CVD events for a total of 265 CVD events. With both lnCAC volume and CAC density scores in the same multivariable model, the lnCAC volume score showed an independent association with incident CHD, with a hazard ratio (HR) of 1.81 (95% CI, 1.47-2.23) per standard deviation (SD = 1.6) increase, absolute risk increase 6.1 per 1000 person-years, and for CVD an HR of 1.68 (95% CI, 1.42-1.98) per SD increase, absolute risk increase 7.9 per 1000 person-years. Conversely, the CAC density score showed an independent inverse association, with an HR of 0.73 (95% CI, 0.58-0.91) per SD (SD = 0.7) increase for CHD, absolute risk decrease 5.5 per 1000 person-years, and an HR of 0.71 (95% CI, 0.60-0.85) per SD increase for CVD, absolute risk decrease 8.2 per 1000 person years. Area under the receiver operating characteristic curve analyses showed significantly improved risk prediction with the addition of the density score to a model containing the volume score for both CHD and CVD. In the intermediate CVD risk group, the area under the curve for CVD increased from 0.53 (95% CI, 0.48-0.59) to 0.59 (95% CI, 0.54-0.64), P = .02.
Conclusions and Relevance
CAC volume was positively and independently associated with CHD and CVD risk. At any level of CAC volume, CAC density was inversely and significantly associated with CHD and CVD risk. The role of CAC density should be considered when evaluating current CAC scoring systems.
doi:10.1001/jama.2013.282535
PMCID: PMC4091626  PMID: 24247483
20.  The Association of Framingham and Reynolds Risk Scores with Incidence and Progression of Coronary Artery Calcification in the Multi-Ethnic Study of Atherosclerosis 
Objectives
To compare the association of the Framingham Risk Score (FRS) and Reynolds Risk Score (RRS) with subclinical atherosclerosis, assessed by incidence and progression of coronary artery calcium (CAC).
Background
The comparative effectiveness of competing risk algorithms for indentifying subclinical atherosclerosis is unknown.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study of 6,814 participants free of baseline CVD. All participants underwent risk factor assessment, as well as baseline and follow-up CAC testing. We assessed the performance of the FRS and RRS to predict CAC incidence and progression using relative risk and robust linear regression.
Results
The study population included 5,140 individuals (61±10 years, 47% males, mean follow-up: 3.1±1.3 years). Among 53% of subjects (n=2,729) with no baseline CAC, 18% (n=510) developed incident CAC. Both the FRS and RRS were significantly predictive of incident CAC [RR 1.40 (95% CI 1.29 – 1.52), and RR 1.41 (95% CI 1.30 – 1.54) per 5% increase in risk, respectively] and CAC progression [mean CAC score change 6.92 (95% CI 5.31 – 8.54) and 6.82 (95% CI 5.51 – 8.14) per 5% increase]. Discordance in risk category classification (< or > 10% 10-year CHD risk) occurred in 13.7%, with only the RRS consistently adding predictive value for incidence and progression of CAC. These subclinical atherosclerosis findings are supported by a CHD events analysis over 5.6±0.7 year follow-up.
Conclusion
Both the RRS and FRS predict onset and progression of subclinical atherosclerosis. However, the RRS may provide additional predictive information when discordance between the scoring systems exists.
doi:10.1016/j.jacc.2011.08.022
PMCID: PMC4079464  PMID: 22051329
coronary artery calcium progression; subclinical atherosclerosis; risk prediction; Reynolds Risk Score; Framingham Risk Score
21.  Associations of Aortic Distensibility and Arterial Elasticity With Long-Term Visit-to-Visit Blood Pressure Variability: The Multi-Ethnic Study of Atherosclerosis (MESA) 
American Journal of Hypertension  2013;26(7):896-902.
BACKGROUND
Although higher visit-to-visit variability (VVV) of blood pressure (BP) is associated with increased cardiovascular disease risk, the physiological basis for VVV of BP is incompletely understood.
METHODS
We examined the associations of aortic distensibility (assessed by magnetic resonance imaging) and artery elasticity indices (determined by radial artery pulse contour analysis) with VVV of BP in 2,640 and 4,560 participants, respectively, from the Multi-Ethnic Study of Atherosclerosis. Arterial measures were obtained at exam 1. BP readings were taken at exam 1 and at 3 follow-up visits at 18-month intervals (exams 2, 3, and 4). VVV was defined as the SD about each participant’s mean systolic BP (SBP) across visits.
RESULTS
The mean SDs of SBP were inversely associated with aortic distensibility: 7.7, 9.9, 10.9, and 13.2mm Hg for quartiles 4, 3, 2, and 1 of aortic distensibility, respectively (P trend < 0.001). This association remained significant after adjustment for demographics, cardiovascular risk factors, mean SBP, and antihypertensive medication use (P trend < 0.01). In a fully adjusted model, lower quartiles of large artery and small artery elasticity (LAE and SAE) indices were also associated with higher mean SD of SBP (P trend = 0.02 for LAE; P trend < 0.001 for SAE).
CONCLUSIONS
In this multiethnic cohort, functional alterations of central and peripheral arteries were associated with greater long-term VVV of SBP.
doi:10.1093/ajh/hpt040
PMCID: PMC3693480  PMID: 23537891
arteries; blood pressure; epidemiology; hypertension; vasculature.
22.  Comparison of Factors Associated with Carotid Intima-Media Thickness in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR) 
Background
The measurement of carotid intima-media thickness (CIMT) is a valid method to quantify levels of atherosclerosis. The present study was conducted to compare the strengths of associations between CIMT and cardiovascular risk factors in two different populations.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR) are two population-based prospective cohort studies of subclinical cardiovascular disease. All Caucasian subjects aged 45 to 75 years from these cohorts who were free of baseline cardiovascular disease (n = 2,820 in HNR, n = 2,270 in MESA) were combined. CIMT images were obtained using B-mode sonography at the right and left common carotid artery and measured 1 cm starting from the bulb.
Results
In both studies, age, male sex, and systolic blood pressure showed the strongest association (P < .0001 for each) for a higher CIMT. The mean of mean far wall CIMT was slightly higher in MESA participants (0.71 vs 0.67 mm). Almost all significant variables were consistent between the two cohorts in both magnitude of association with CIMT and statistical significance, including age, sex, smoking, diabetes, cholesterol levels, and blood pressure. For example, the association with systolic blood pressure was (ΔSD = 0.011; 95% confidence interval, 0.0009 to 0.014) per mm Hg in MESA and (ΔSD = 0.010; 95% confidence interval, 0.005 to 0.021) per mm Hg in HNR. This consistency persisted throughout the traditional (Framingham) risk factors.
Conclusions
A comparison of the associations between traditional cardiovascular risk factors and CIMT across two culturally diverse populations showed remarkable consistency.
doi:10.1016/j.echo.2013.03.011
PMCID: PMC3694173  PMID: 23611058
Carotid intima-media thickness; Subclinical atherosclerosis; Multi-Ethnic Study of Atherosclerosis; MESA; Heinz Nixdorf Recall Study; HNR
23.  Methods for Estimation of Disparities in Medication Use in an Observational Cohort Study: Results from the Multi-Ethnic Study of Atherosclerosis 
Purpose
Evaluating disparities in health care is an important aspect of understanding differences in disease risk. The purpose of this study is to describe methodology for estimating such disparities, with application to a large multi-ethnic cohort study.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) includes 6814 participants aged 45–84 years free of cardiovascular disease. Prevalence ratio (PR) regression was used to model baseline lipid lowering medication (LLM) or anti-hypertensive medication use at baseline as a function of gender, race, risk factors and estimated pre-treatment biomarker values.
Results
Hispanics and African-Americans had lower prevalence of medication use than non-Hispanic whites, even at the same risk factor profile. This became non-significant after adjustment for socio-economic status. Although gender did not influence the prevalence of LLM use (PR=1.09, 95% CI 0.95 to 1.25), there were differences in the association of diabetes and HDL with LLM use by gender. Men were significantly less likely to be on anti-hypertensive medications than women (PR=0.86, 95% CI 0.80 to 0.92, p<0.001) and this was not explained by risk factors or socioeconomic status. Lack of health insurance strongly influenced medication use, controlling for risk factors and other markers of socio-economic status.
Conclusions
Disparities exist in the treatment of cholesterol and hypertension. Hispanics and African Americans had less use of LLM, men had less use of anti-hypertensives. Risk factors have differential associations with medication use depending on gender. Methods described in this paper can provide improved disparity estimation in observational cohort studies.
doi:10.1002/pds.3406
PMCID: PMC3652567  PMID: 23382107
disparities; medication; statistical methods; statins; anti-hypertensives
24.  HIGHER LEPTIN IS ASSOCIATED WITH HYPERTENSION: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS 
Journal of human hypertension  2013;27(10):617-622.
Adipokines are secreted from adipose tissue, influence energy homeostasis and may contribute to the association between obesity and hypertension. Among 1,897 participants enrolled in the Multi-Ethnic Study of Atherosclerosis, we examined associations between blood pressure and leptin, tumor necrosis factor – α [TNFα], resistin and total adiponectin. The mean age and body mass index was 64.7 years and 28.1 respectively, and 50% were female. After adjustment for risk factors, a 1-standard deviation increment higher leptin level was significantly associated with higher systolic (5.0 mmHg), diastolic (1.9), mean arterial (2.8) and pulse pressures (3.6), as well as a 34% higher odds for being hypertensive (p < 0.01 for all). These associations were not materially different when the other adipokines, as well as body mass index, waist circumference or waist to hip ratio, were additionally added to the model. Notably, the associations between leptin and hypertension were stronger in men, but were not different by race/ethnic group, body mass index or smoking status. Adiponectin, resistin and TNFα were not independently associated with blood pressure or hypertension. Higher serum leptin, but not adiponectin, resistin or TNFα, is associated with higher levels of all measures of blood pressure, as well as a higher odds of hypertension, independent of risk factors, anthropometric measures and other selected adipokines.
doi:10.1038/jhh.2013.24
PMCID: PMC3735864  PMID: 23535989
adipokine; leptin; blood pressure; hypertension; ethnicity
25.  Von Willebrand Factor and the Right Ventricle (The MESA-Right Ventricle Study) 
The American journal of cardiology  2012;110(12):1846-1851.
Elevation in plasma activity of von Willebrand Factor (vWF) reflects endothelial dysfunction and predicts death in pulmonary arterial hypertension (PAH). Higher vWF activity is also associated with lower right ventricular (RV) ejection fraction in PAH. Little is known about the relationship between vWF and RV structure and function in adults without cardiovascular disease. In the current investigation, we included 1,976 participants with MRI assessment of RV structure and function and measurement of vWF activity from the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression was used to estimate the associations between vWF activity and measures of RV structure and function after adjusting for demographics, anthropometrics, smoking, diabetes mellitus, hypertension and the corresponding left ventricular (LV) parameter. The average vWF activity was 140.7 ± 57.2%. Elevated vWF activity was independently associated with lower RV mass, RV end-diastolic volume and RV stroke volume in models with and without adjustment for the corresponding LV parameter (all p < 0.05). There was no association observed between vWF activity and RV ejection fraction. In conclusion, higher vWF activity is associated with lower RV mass, RV end-diastolic volume and RV stroke volume. These associations are independent of common cardiovascular risk factors and LV morphologic changes.
doi:10.1016/j.amjcard.2012.08.022
PMCID: PMC3696516  PMID: 22995970
Cardiovascular Imaging; Biomarkers; Pulmonary Hypertension; Right Ventricle

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