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1.  Ten-Year Coronary Heart Disease Risk Prediction Using Coronary Artery Calcium and Traditional Risk Factors: Derivation in the Multi-Ethnic Study of Atherosclerosis with Validation in the Heinz Nixdorf Recall Study and the Dallas Heart Study 
Several studies have demonstrated the tremendous potential of using coronary artery calcium (CAC) in addition to traditional risk factors for coronary heart disease (CHD) risk prediction. However, to date no risk score incorporating CAC has been developed.
Our goal was to derive and validate a novel risk score to estimate 10-year CHD risk using CAC and traditional risk factors.
Algorithm development was conducted in the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective community-based cohort study of 6814 participants aged 45–84, free of clinical heart disease at baseline and followed for 10 years. MESA is gender balanced and included 39% Non-Hispanic whites, 12% Chinese American, 28% African American, and 22% Hispanic Americans. External validation was conducted in the Heinz Nixdorf Recall Study (HNR) and the Dallas Heart Study (DHS).
Inclusion of CAC in the MESA risk score offered significant improvements in risk prediction (C-statistic 0.80 versus 0.75, p<0.0001). External validation in both HNR and DHS provided evidence of very good discrimination and calibration. Harrell’s C-statistic was 0.779 in HNR, and 0.816 in DHS. Additionally the difference in estimated 10-year risk between events and non-events was approximately 8–9%, indicating excellent discrimination. Mean calibration, or calibration-in-the-large, was excellent for both studies, with average predicted 10-year risk within half a percent of the observed event rate.
An accurate estimate of 10-year CHD risk can be obtained using traditional risk factors and CAC. The MESA risk score, which is available online on the MESA web site for easy use, can be used to aid clinicians in the communication of risk to patients and when determining risk-based treatment strategies.
PMCID: PMC4603537  PMID: 26449133
coronary disease; risk prediction; epidemiology; atherosclerosis
2.  Longitudinal Associations Between Neighborhood Physical and Social Environments and Incident Type 2 Diabetes Mellitus 
JAMA internal medicine  2015;175(8):1311-1320.
Neighborhood environments may influence the risk for developing type 2 diabetes mellitus (T2DM), but, to our knowledge, no longitudinal study has evaluated specific neighborhood exposures.
To determine whether long-term exposures to neighborhood physical and social environments, including the availability of healthy food and physical activity resources and levels of social cohesion and safety, are associated with incident T2DM during a 10-year period.
We used data from the Multi-Ethnic Study of Atherosclerosis, a population-based cohort study of adults aged 45 to 84 years at baseline (July 17, 2000, through August 29, 2002). A total of 5124 participants free of T2DM at baseline underwent 5 clinical follow-up examinations from July 17, 2000, through February 4, 2012. Time-varying measurements of neighborhood healthy food and physical activity resources and social environments were linked to individual participant addresses. Neighborhood environments were measured using geographic information system (GIS)- and survey-based methods and combined into a summary score. We estimated hazard ratios (HRs) of incident T2DM associated with cumulative exposure to neighborhood resources using Cox proportional hazards regression models adjusted for age, sex, income, educational level, race/ethnicity, alcohol use, and cigarette smoking. Data were analyzed from December 15, 2013, through September 22, 2014.
Incident T2DM defined as a fasting glucose level of at least 126 mg/dL or use of insulin or oral antihyperglycemics.
During a median follow-up of 8.9 years (37 394 person-years), 616 of 5124 participants (12.0%) developed T2DM (crude incidence rate, 16.47 [95% CI, 15.22-17.83] per 1000 person-years). In adjusted models, a lower risk for developing T2DM was associated with greater cumulative exposure to indicators of neighborhood healthy food (12%; HR per interquartile range [IQR] increase in summary score, 0.88 [95% CI, 0.79-0.98]) and physical activity resources (21%; HR per IQR increase in summary score, 0.79 [95% CI, 0.71-0.88]), with associations driven primarily by the survey exposure measures. Neighborhood social environment was not associated with incident T2DM (HR per IQR increase in summary score, 0.96 [95% CI, 0.88-1.07]).
Long-term exposure to residential environments with greater resources to support physical activity and, to a lesser extent, healthy diets was associated with a lower incidence of T2DM, although results varied by measurement method. Modifying neighborhood environments may represent a complementary, population-based approach to prevention of T2DM, although further intervention studies are needed.
PMCID: PMC4799846  PMID: 26121402
3.  Ability of Reduced Lung Function to Predict Development of Atrial Fibrillation in Persons 45–84 Years of Age (From the Multi-Ethnic Study of Atherosclerosis-Lung Study) 
The American journal of cardiology  2015;115(12):1700-1704.
Atrial fibrillation (AF) occurs frequently in patients with chronic obstructive pulmonary disease (COPD). Epidemiological studies have found inconsistent associations between lung function and AF, and none have studied pulmonary emphysema, which overlaps only partially with COPD in the general population. In this study, we assessed the relationship between lung function measured by spirometry, the percent of emphysema-like lung on computed tomography and incident AF. The Multi-Ethnic Study of Atherosclerosis (MESA) study is a multicenter cohort study following 6814 subjects free of clinical cardiovascular disease including AF at baseline. Spirometry was performed in a subset of 3965 participants. Percent emphysema was defined on baseline CT scans as lung regions <950 hounsfield units. Incident AF was identified from hospital discharge diagnosis and Medicare claims data. Cox proportional hazards models were used to assess independent associations of lung volumes and percent emphysema with AF. 3811 participants with valid spirometry results were included in this study. The mean age was 64.5±9.8 years and 49.4% were men. AF developed in 149 individuals (3.8%) over a mean follow-up of 4.1 years after spirometry. Lower levels of forced expiratory volume at 1 second and forced vital capacity were associated with a higher risk of AF (HR 1.21 and 1.19 per 500ml respectively; p<0.001) after adjustment of demographic and cardiovascular risk factors. Percentage emphysema was not significantly related to AF. In conclusion, in a multi-ethnic community-based sample of individuals free of cardiovascular disease at baseline, functional airflow limitation was related to a higher risk of AF.
PMCID: PMC4450133  PMID: 25900353
Atrial Fibrillation; Lung function; Emphysema
4.  Usefulness of N-terminal Pro-brain Natriuretic Peptide and Myocardial Perfusion in Asymptomatic Adults (From The Multi-Ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2015;115(10):1341-1345.
This study sought to investigate the relationship between myocardial perfusion and N-terminal pro-brain natriuretic peptide (NT-proBNP) in asymptomatic individuals without overt coronary artery disease. NT-proBNP is a cardiac neurohormone secreted from the ventricles in response to ventricular volume expansion and pressure overload, and may also be elevated in the setting of reduced myocardial perfusion. We hypothesized that reduced myocardial perfusion reserve (MPR) would be associated with elevated NT-proBNP in individuals free of overt cardiovascular disease. MPR was measured by cardiac magnetic resonance, before and after adenosine infusion, in 184 MESA participants (mean age 60 ± 10.4, 58% white, 42% Hispanic, 44% female) without overt cardiovascular disease. MPR was modeled as hyperemic myocardial blood flow (MBF) adjusted for resting MBF. A linear regression analysis, adjusted for demographics, established cardiovascular risk factors, left ventricular mass, coronary calcium score, body mass index and medications, was used to determine the association between MPR and NT-proBNP. Individuals with low hyperemic MBF were more likely to be older, male, diabetic, have higher blood pressure and higher coronary artery calcium score. Mean hyperemic MBF was 3.04 ± 0.829 ml/min/g. MPR was inversely associated with NT-proBNP levels. In a fully adjusted model, every one standard deviation decrement in MPR was associated with a 21 % increment in NT-proBNP (p=0.04). In conclusion, MPR is inversely associated with NT-proBNP level in this cross sectional study of asymptomatic individuals free of overt coronary artery disease, suggesting that higher NT-proBNP levels may reflect subclinical myocardial microvascular dysfunction.
PMCID: PMC4414796  PMID: 25816778
myocardial perfusion; myocardial blood flow; NT-pro-BNP
5.  The Association of Menopausal Age and NT-proBrain Natriuretic Peptide: The Multi-Ethnic Study of Atherosclerosis 
Menopause (New York, N.Y.)  2015;22(5):527-533.
Menopausal age could affect the risk of developing cardiovascular disease (CVD). The purpose of this study was to investigate the associations of early menopause (menopause occurring before 45 years of age) and menopausal age with NT-pro brain natriuretic peptide (NT-proBNP), a potential risk marker of CVD and heart failure (HF).
Our cross-sectional study included 2275 postmenopausal women, aged 45–85 years, without clinical CVD (2000–2002), from the Multi-Ethnic Study of Atherosclerosis. Participants were classified as having or not having early menopause. NT-proBNP was log-transformed. Multivariable linear regression was used for analysis.
There were 561 women with early menopause. The median NT-proBNP value was 79.0 (41.1–151.6) pg/ml for all participants with values of 83.4 (41.4–164.9) pg/ml and 78.0 (40.8–148.3) pg/ml for women with and without early menopause respectively. The mean (SD) age was 65 (10.1) and 65 (8.9) years for women with and without early menopause respectively. There were no significant interactions between menopausal age and ethnicity. In multivariable analysis, early menopause was associated with a 10.7% increase in NT-proBNP while each year increase in menopausal age was associated with a 0.7% decrease in NT-proBNP.
Early menopause is associated with greater NT-proBNP levels while each year increase in menopausal age is associated with lower NT-proBNP levels in postmenopausal women.
PMCID: PMC4387119  PMID: 25290536
Menopause; NT-proBNP; Sex hormones
6.  Association of Subclinical Atherosclerosis Using Carotid Intima-Media Thickness, Carotid Plaque, and Coronary Calcium Score with Left Ventricular Dyssynchrony: The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2015;239(2):412-418.
The role of atherosclerosis in the progression of global left ventricular dysfunction and cardiovascular events has been well recognized. Left ventricular (LV) dyssynchrony is a measure of regional myocardial dysfunction. Our objective was to investigate the relationship of subclinical atherosclerosis with mechanical LV dyssynchrony in a population-based asymptomatic multi-ethnic cohort.
Methods and Results
Participants of the Multi-Ethnic Study of Atherosclerosis (MESA) at exam 5 were evaluated using 1.5T cardiac magnetic resonance (CMR) imaging, carotid ultrasound (n=2,062) for common carotid artery (CCA) and internal carotid artery (ICA) intima-media thickness (IMT), and cardiac computed tomography (n=2,039) for coronary artery calcium (CAC) assessment (Agatston method). Dyssynchrony indices were defined as the standard deviation of time to peak systolic circumferential strain (SD-TPS) and the difference between maximum and minimum (max-min) time to peak strain using harmonic phase imaging in 12 segments (3-slices × 4 segments). Multivariable regression analyses were performed to assess associations after adjusting for participant demographics, cardiovascular risk factors, LV mass, and ejection fraction. In multivariable analyses, SD-TPS was significantly related to measures of atherosclerosis, including CCA-IMT (8.7msec/mm change in IMT, p=0.020), ICA-IMT (19.2 msec/mm change in IMT, p<0.001), carotid plaque score (1.2 msec/unit change in score, p<0.001), and log transformed CAC+1 (0.66 msec/unit log-CAC+1, p=0.018). These findings were consistent with other parameter of LV dyssynchrony i.e. max-min.
In the MESA cohort, measures of atherosclerosis are associated with parameters of subclinical LV dyssynchrony in the absence of clinical coronary event and left-bundle-branch block.
PMCID: PMC4361257  PMID: 25682041
Left Ventricular Dyssynchrony; Carotid IMT; Coronary Calcium Score; Atherosclerosis
7.  Heart failure risk prediction in the Multi-Ethnic Study of Atherosclerosis 
Heart (British Cardiac Society)  2014;101(1):58-64.
Heart failure (HF) is a leading cause of mortality especially in older populations. Early detection of high-risk individuals is imperative for primary prevention. The purpose of this study was to develop a HF risk model from a population without clinical cardiac disease.
The Multi-Ethnic Study of Atherosclerosis is a multicentre observational cohort study following 6814 subjects (mean age 62±10 years; 47% men) who were free of clinical cardiovascular disease at baseline. Median follow-up was 4.7 years. HF events developed in 176 participants. Cox proportional hazards models and regression coefficients were used to determine independent risk factors and generate a 5-year risk score for incident HF. Bootstrapping with bias correction was used for internal validation.
Independent predictors for HF (HR, p value) were age (1.30 (1.10 to 1.50) per 10 years), male gender (2.27 (1.53 to 3.36)), current smoking (1.97 (1.15 to 3.36)), body mass index (1.40 (1.10 to 1.80) per 5 kg/m2), systolic blood pressure (1.10 (1.00 to 1.10) per 10 mm Hg), heart rate (1.30) (1.10 to 1.40) per 10 bpm), diabetes (2.27 (1.48 to 3.47)), N-terminal pro-B-type natriuretic peptide (NT proBNP) (2.48 (2.16 to 2.84) per unit log increment) and left ventricular mass index (1.40 (1.30 to 1.40) per 10 g/m2). A parsimonious model based on age, gender, body mass index, smoking status, systolic blood pressure, heart rate, diabetes and NT proBNP natriuretic peptide predicted incident HF risk with a c-statistic of 0.87.
A clinical algorithm based on risk factors readily available in the primary care setting can used to identify individuals with high likelihood of developing HF without pre-existing cardiac disease.
PMCID: PMC4685458  PMID: 25381326
8.  Acculturation is associated with left ventricular mass in a multiethnic sample: the Multi-Ethnic Study of Atherosclerosis 
Acculturation involves stress-related processes and health behavioral changes, which may have an effect on left ventricular (LV) mass, a risk factor for cardiovascular disease (CVD). We examined the relationship between acculturation and LV mass in a multiethnic cohort of White, African-American, Hispanic and Chinese subjects.
Cardiac magnetic resonance assessment was available for 5004 men and women, free of clinical CVD at baseline. Left ventricular mass index was evaluated as LV mass indexed by body surface area. Acculturation was characterized based on language spoken at home, place of birth and length of stay in the United States (U.S.), and a summary acculturation score ranging from 0 = least acculturated to 5 = most acculturated. Mean LV mass index adjusted for traditional CVD risk factors was compared across acculturation levels.
Unadjusted mean LV mass index was 78.0 ± 16.3 g/m2. In adjusted analyses, speaking exclusively English at home compared to non-English language was associated with higher LV mass index (81.3 ± 0.4 g/m2 vs 79.9 ± 0.5 g/m2, p = 0.02). Among foreign-born participants, having lived in the U.S. for ≥ 20 years compared to < 10 years was associated with greater LV mass index (81.6 ± 0.7 g/m2 vs 79.5 ± 1.1 g/m2, p = 0.02). Compared to those with the lowest acculturation score, those with the highest score had greater LV mass index (78.9 ± 1.1 g/m2 vs 81.1 ± 0.4 g/m2, p = 0.002). There was heterogeneity in which measure of acculturation was associated with LV mass index across ethnic groups.
Greater acculturation is associated with increased LV mass index in this multiethnic cohort. Acculturation may involve stress-related processes as well as behavioral changes with a negative effect on cardiovascular health.
PMCID: PMC4668673  PMID: 26631068
Acculturation; Left ventricular mass index; Cardiovascular risk; Ethnic disparities
9.  Effects of Weight Loss, Weight Cycling, and Weight Loss Maintenance on Diabetes Incidence and Change in Cardiometabolic Traits in the Diabetes Prevention Program 
Diabetes Care  2014;37(10):2738-2745.
This study examined specific measures of weight loss in relation to incident diabetes and improvement in cardiometabolic risk factors.
This prospective, observational study analyzed nine weight measures, characterizing baseline weight, short- versus long-term weight loss, short- versus long-term weight regain, and weight cycling, within the Diabetes Prevention Program (DPP) lifestyle intervention arm (n = 1,000) for predictors of incident diabetes and improvement in cardiometabolic risk factors over 2 years.
Although weight loss in the first 6 months was protective of diabetes (hazard ratio [HR] 0.94 per kg, 95% CI 0.90, 0.98; P < 0.01) and cardiometabolic risk factors (P < 0.01), weight loss from 0 to 2 years was the strongest predictor of reduced diabetes incidence (HR 0.90 per kg, 95% CI 0.87, 0.93; P < 0.01) and cardiometabolic risk factor improvement (e.g., fasting glucose: β = −0.57 mg/dL per kg, 95% CI −0.66, −0.48; P < 0.01). Weight cycling (defined as number of 5-lb [2.25-kg] weight cycles) ranged 0–6 times per participant and was positively associated with incident diabetes (HR 1.33, 95% CI 1.12, 1.58; P < 0.01), fasting glucose (β = 0.91 mg/dL per cycle; P = 0.02), HOMA-IR (β = 0.25 units per cycle; P = 0.04), and systolic blood pressure (β = 0.94 mmHg per cycle; P = 0.01). After adjustment for baseline weight, the effect of weight cycling remained statistically significant for diabetes risk (HR 1.22, 95% CI 1.02, 1.47; P = 0.03) but not for cardiometabolic traits.
Two-year weight loss was the strongest predictor of reduced diabetes risk and improvements in cardiometabolic traits.
PMCID: PMC4170126  PMID: 25024396
10.  Lifestyle and Metformin Interventions Have a Durable Effect to Lower CRP and tPA Levels in the Diabetes Prevention Program Except in Those Who Develop Diabetes 
Diabetes Care  2014;37(8):2253-2260.
We evaluate whether lifestyle and metformin interventions used to prevent diabetes have durable effects on markers of inflammation and coagulation and whether the effects are influenced by the development of diabetes.
The Diabetes Prevention Program was a controlled clinical trial of 3,234 subjects at high risk for diabetes who were randomized to lifestyle, metformin, or placebo interventions for 3.4 years. Diabetes was diagnosed semiannually by fasting glucose and annually by oral glucose tolerance testing. In addition to baseline testing, anthropometry was performed every 6 months; fasting insulin yearly; and hs-CRP, tissue plasminogen activator (tPA), and fibrinogen at 1 year and end of study (EOS).
CRP and tPA levels were unchanged in the placebo group but fell in the lifestyle and metformin groups at 1 year and remained lower at EOS. These reductions were not seen in those who developed diabetes over the course of the study despite intervention. Fibrinogen was lower at 1 year in the lifestyle group. Differences in weight and weight change explained most of the influence of diabetes on the CRP response in the lifestyle group, but only partly in the placebo and metformin groups. Weight, insulin sensitivity, and hyperglycemia differences each accounted for the influence of diabetes on the tPA response.
Lifestyle and metformin interventions have durable effects to lower hs-CRP and tPA. Incident diabetes prevented these improvements, and this was accounted for by differences in weight, insulin resistance, and glucose levels.
PMCID: PMC4113172  PMID: 24824548
11.  Age at Menopause and Incident Heart Failure: The Multi-Ethnic Study of Atherosclerosis 
Menopause (New York, N.Y.)  2014;21(6):585-591.
To evaluate associations of early menopause (menopause occurring before 45 years of age) and age at menopause with incident heart failure (HF) in post-menopausal women. We also explored associations of early, and age at menopause with left ventricular (LV) measures of structure and function in post-menopausal women.
We included 2947 post-menopausal women, aged 45-84 years, without known cardiovascular disease (2000-2002), from the Multi-Ethnic study of Atherosclerosis. Cox-Proportional hazards models were used to examine associations of early, and age at menopause with incident HF. In 2123 post-menopausal women in whom cardiac magnetic resonance imaging was obtained at baseline, we explored associations of early, and age at menopause with LV measures using multivariable linear regression.
Over a median follow-up of 8.5 years, we observed 71 HF events. There were no significant interactions with ethnicity for incident HF (Pinteraction>0.05). In adjusted analysis, early menopause was associated with increased risk of incident HF [1.66 (1.01-2.73)], while each year increase in age at menopause was associated with decreased risk of incident HF [0.96 (0.94-0.99)]. We observed significant interactions between early menopause and ethnicity for LV mass to volume ratio (LVMVR), Pinteraction=0.02. In Chinese-American women, early menopause was associated with higher LVMVR (+0.11, p=0.0002), while each year increase in age at menopause was associated with lower LVMVR (−0.004, p=0.04) at baseline.
An older menopausal age is independently associated with decreased risk of incident HF. Concentric LV remodelling, indicated by a higher LVMVR was present in Chinese-American women with early menopause at baseline.
PMCID: PMC4031284  PMID: 24423934
Menopause; Heart failure; Estrogen
12.  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
13.  Abdominal Aortic Calcium, Coronary Artery Calcium, and Cardiovascular Morbidity and Mortality in the Multi-Ethnic Study of Atherosclerosis 
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.
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.
PMCID: PMC4153597  PMID: 24812323
aortic diseases; calcium; cardiovascular diseases; diagnostic imaging; epidemiology
14.  A Panel of Biomarkers Is Associated With Increased Risk of the Presence and Progression of Atherosclerosis in Women With Systemic Lupus Erythematosus 
An increased frequency of atherosclerosis (ATH) in systemic lupus erythematosus (SLE) is well-documented but not fully explained by the presence of traditional cardiac risk factors. Several nontraditional biomarkers, including proinflammatory high-density lipoprotein (piHDL) and leptin, have been individually associated with subclinical ATH in SLE. The aim of this study was to examine whether these and other biomarkers can be combined into a risk profile, the Predictors of Risk for Elevated Flares, Damage Progression, and Increased Cardiovascular Disease in Patients with SLE (PREDICTS), that could be used to better predict future progression of ATH.
In total, 210 patients with SLE and 100 age-matched healthy control subjects (all women) participated in this prospective cohort study. The longitudinal presence of carotid plaque and intima-media thickness (IMT) were measured at baseline and followup (mean ± SD 29.6 ± 9.7 months).
At followup, carotid plaque was present in 29% of SLE patients. Factors significantly associated with plaque, determined using Salford Predictive Modeling and multivariate analysis, included age ≥48 years (odds ratio [OR] 4.1, P = 0.002), high piHDL function (OR 9.1, P < 0.001), leptin levels ≥34 ng/dl (OR 7.3, P = 0.001), plasma soluble TWEAK levels ≥373 pg/ml (OR 28.8, P = 0.004), and history of diabetes (OR 61.8, P < 0.001). Homocysteine levels ≥12 μmoles/liter were also a predictor. However, no single variable demonstrated an ideal combination of good negative predictive values (NPVs), positive predictive values (PPVs), sensitivity, and specificity. A high-risk PREDICTS profile was defined as ≥3 positive biomarkers or ≥1 positive biomarker plus a history of diabetes; for high-risk SLE patients, the PPV was 64%, NPV was 94%, sensitivity was 89%, and specificity was 79%. In multivariate analysis, SLE patients with the high-risk profile had 28-fold increased odds for the longitudinal presence of plaque (P < 0.001) and increased progression of IMT (P < 0.001).
A high-risk PREDICTS score confers 28-fold increased odds of the presence of any current, progressive, or acquired carotid plaque, both in patients with SLE and in control subjects, and is significantly associated with higher rates of IMT progression.
PMCID: PMC4106468  PMID: 24449580
15.  Genetic Ancestry and the Relationship of Cigarette Smoking to Lung Function and Percent Emphysema in Four Race/Ethnic Groups: a Cross-sectional Study 
Thorax  2013;68(7):634-642.
Cigarette smoking is the major cause of chronic obstructive pulmonary disease and emphysema. Recent studies suggest that susceptibility to cigarette smoke may vary by race/ethnicity; however, they were generally small and relied on self-reported race/ethnicity.
To test the hypothesis that relationships of smoking to lung function and percent emphysema differ by genetic ancestry and self-reported race/ethnicity among Whites, African-Americans, Hispanics and Chinese-Americans.
Cross-sectional population-based study of adults age 45-84 years in the United States
Principal components of genetic ancestry and continental ancestry estimated from one-million genome-wide single nucleotide polymorphisms. Pack-years calculated as years smoking cigarettes-per-day/20. Spirometry measured for 3,344 and percent emphysema on computed tomography for 8,224 participants.
The prevalence of ever-smoking was: Whites, 57.6%; African-Americans, 56.4%; Hispanics, 46.7%; and Chinese-Americans, 26.8%. Every 10 pack-years was associated with −0.73% (95% CI −0.90%, −0.56%) decrement in the forced expiratory volume in one second to forced vital capacity (FEV1/FVC) and a 0.23% (95% CI 0.08%, 0.38%) increase in percent emphysema. There was no evidence that relationships of pack-years to the FEV1/FVC, airflow obstruction and percent emphysema varied by genetic ancestry (all p>0.10), self-reported race/ethnicity (all p>0.10) or, among African-Americans, African ancestry. There were small differences in relationships of pack-years to the FEV1 among male Chinese-Americans and to the FEV1/FVC with African and Native American ancestry among male Hispanics only.
In this large cohort, there was little-to-no evidence that the associations of smoking to lung function and percent emphysema differed by genetic ancestry or self-reported race/ethnicity.
PMCID: PMC4020409  PMID: 23585509
cigarette smoke; genetic ancestry; lung function; chronic obstructive pulmonary disease; COPD; emphysema; FVC; Forced Vital Capacity; FEV1; Forced Expiratory Volume in 1 second
16.  Regression from Pre-diabetes to Normal Glucose Regulation is Associated with Long-term Reduction in Diabetes Risk: Results from the Diabetes Prevention Program Outcomes Study 
Lancet  2012;379(9833):2243-2251.
Our objective was to quantify and predict diabetes risk reduction during the Diabetes Prevention Program Outcomes Study (DPPOS) among those who returned to normal glucose regulation (NGR) at least once during DPP compared to those who were consistently considered to have pre-diabetes.
Diabetes cumulative incidence in DPPOS was calculated for subjects with NGR or pre-diabetes status during DPP with and without stratification by prior randomized treatment group. Cox proportional hazards modeling and generalized linear mixed models were used to quantify the impact of previous (DPP) glycemic status on risk of later (DPPOS) diabetes and NGR status, respectively, per standard deviation in change. Included in this analysis are 1990 participants of DPPOS (who had been randomized during DPP: N=736 in intensive lifestyle (ILS), N=647 to metformin (MET), and N=607 to placebo (PLB)).
Diabetes risk during DPPOS was 56% lower in NGR vs. pre-diabetes (HR=0.44, 95% CI 0.37-0.55, p<0.0001) and was unaffected by prior group assignment (interaction test for NGR*ILS, p=0.1722; NGR*MET, p=0.3304). Many, but not all, of the variables that increased diabetes risk were inversely associated with the chance of reaching NGR status in DPPOS. Specifically, having had prior NGR (OR=3.18, 95% CI 2.71-3.72, p<0.0001), higher β-cell function (OR=1.28; 95% CI 1.18-1.39, p<0.0001) and insulin sensitivity (OR=1.16, 95% CI 1.08-1.25, p<0.0001) were associated with NGR in DPPOS, whereas the opposite was true for predicting diabetes (HR=0.80, 95% CI 0.71-0.89; HR=0.83, 95% CI 0.74-0.94, respectively, p<0.0001 for both). Surprisingly, among subjects who failed to return to NGR in DPP, those randomized to ILS had a higher diabetes risk (HR=1.31, 95% CI 1.03-1.68, p=0.0304) and lower chance of NGR (OR=0.59, 95% CI 0.42-0.82, p=0.0014) vs. placebo in DPPOS.
We conclude that pre-diabetes represents a high-risk state for diabetes, especially among those who remain so despite ILS. Reversion to NGR, even if transient, is associated with a significantly lower risk of future diabetes independent of prior treatment group.
PMCID: PMC3555407  PMID: 22683134
17.  Genetic Predictors of Weight Loss and Weight Regain After Intensive Lifestyle Modification, Metformin Treatment, or Standard Care in the Diabetes Prevention Program 
Diabetes Care  2012;35(2):363-366.
We tested genetic associations with weight loss and weight regain in the Diabetes Prevention Program, a randomized controlled trial of weight loss–inducing interventions (lifestyle and metformin) versus placebo.
Sixteen obesity-predisposing single nucleotide polymorphisms (SNPs) were tested for association with short-term (baseline to 6 months) and long-term (baseline to 2 years) weight loss and weight regain (6 months to study end).
Irrespective of treatment, the Ala12 allele at PPARG associated with short- and long-term weight loss (−0.63 and −0.93 kg/allele, P ≤ 0.005, respectively). Gene–treatment interactions were observed for short-term (LYPLAL1 rs2605100, Plifestyle*SNP = 0.032; GNPDA2 rs10938397, Plifestyle*SNP = 0.016; MTCH2 rs10838738, Plifestyle*SNP = 0.022) and long-term (NEGR1 rs2815752, Pmetformin*SNP = 0.028; FTO rs9939609, Plifestyle*SNP = 0.044) weight loss. Three of 16 SNPs were associated with weight regain (NEGR1 rs2815752, BDNF rs6265, PPARG rs1801282), irrespective of treatment. TMEM18 rs6548238 and KTCD15 rs29941 showed treatment-specific effects (Plifestyle*SNP < 0.05).
Genetic information may help identify people who require additional support to maintain reduced weight after clinical intervention.
PMCID: PMC3263869  PMID: 22179955
18.  Sex Differences in Subclinical Atherosclerosis by Race/Ethnicity in the Multi-Ethnic Study of Atherosclerosis 
American Journal of Epidemiology  2011;174(2):165-172.
Sex differences in cardiovascular disease mortality are more pronounced among non-Hispanic whites than other racial/ethnic groups, but it is unknown whether this variation is present in the earlier subclinical stages of disease. The authors examined racial/ethnic variation in sex differences in coronary artery calcification (CAC) and carotid intimal media thickness at baseline in 2000–2002 among participants (n = 6,726) in the Multi-Ethnic Study of Atherosclerosis using binomial and linear regression. Models adjusted for risk factors in several stages: age, traditional cardiovascular disease risk factors, behavioral risk factors, psychosocial factors, and adult socioeconomic position. Women had a lower prevalence of any CAC and smaller amounts of CAC when present than men in all racial/ethnic groups. Sex differences in the prevalence of CAC were more pronounced in non-Hispanic whites than in African Americans and Chinese Americans after adjustment for traditional cardiovascular disease risk factors, and further adjustment for behavioral factors, psychosocial factors, and socioeconomic position did not modify these results (for race/sex, Pinteraction = 0.047). Similar patterns were observed for amount of CAC among adults with CAC. Racial/ethnic variation in sex differences for carotid intimal media thickness was less pronounced. In conclusion, coronary artery calcification is differentially patterned by sex across racial/ethnic groups.
PMCID: PMC3167681  PMID: 21685409
calcification, physiologic; continental population groups; coronary vessels; sex; social class
19.  Cardiovascular Imaging for Assessing Cardiovascular Risk in Asymptomatic Men Versus Women 
Coronary artery calcium (CAC), carotid intima-media thickness, and left ventricular (LV) mass and geometry offer the potential to characterize incident cardiovascular disease (CVD) risk in clinically asymptomatic individuals. The objective of the study was to compare these cardiovascular imaging measures for their overall and sex-specific ability to predict CVD.
Methods and Results
The study sample consisted of 4965 Multi-Ethnic Study of Atherosclerosis participants (48% men; mean age, 62±10 years). They were free of CVD at baseline and were followed for a median of 5.8 years. There were 297 CVD events, including 187 coronary heart disease (CHD) events, 65 strokes, and 91 heart failure (HF) events. CAC was most strongly associated with CHD (hazard ratio [HR], 2.3 per 1 SD; 95% CI, 1.9 to 2.8) and all CVD events (HR, 1.7; 95% CI, 1.5 to 1.9). Most strongly associated with stroke were LV mass (HR, 1.3; 95% CI, 1.1 to 1.7) and LV mass/volume ratio (HR, 1.3; 95% CI, 1.1 to 1.6). LV mass showed the strongest association with HF (HR, 1.8; 95% CI, 1.6 to 2.1). There were no significant interactions for imaging measures with sex and ethnicity for any CVD outcome. Compared with traditional risk factors alone, overall risk prediction (C statistic) for future CHD, HF, and all CVD was significantly improved by adding CAC, LV mass, and CAC, respectively (all P<0.05).
There was no evidence that imaging measures differed in association with incident CVD by sex. CAC was most strongly associated with CHD and CVD; LV mass and LV concentric remodeling best predicted stroke; and LV mass best predicted HF.
PMCID: PMC3037859  PMID: 21068189
imaging; cardiovascular diseases; sex
20.  Is neighborhood racial/ethnic composition associated with depressive symptoms? The multi-ethnic study of atherosclerosis 
Social science & medicine (1982)  2010;71(3):541-550.
The racial/ethnic composition of a neighborhood may be related to residents’ depressive symptoms through differential levels of neighborhood social support and/or stressors. We used the Multi-Ethnic Study of Atherosclerosis to investigate cross-sectional associations of neighborhood racial/ethnic composition with the Center for Epidemiologic Studies-Depression (CES-D) scale in adults aged 45–84. The key exposure was a census-derived measure of the percentage of residents of the same racial/ethnic background in each participant’s census tract. Two-level multilevel models were used to estimate associations of neighborhood racial/ethnic composition with CES-D scores after controlling for age, income, marital status, education and nativity. We found that living in a neighborhood with a higher percentage of residents of the same race/ethnicity was associated with increased CES-D scores in African American men (p < 0.05), and decreased CES-D scores in Hispanic men and women and Chinese women, although these differences were not statistically significant. Models were further adjusted for neighborhood-level covariates (social cohesion, safety, problems, aesthetic quality and socioeconomic factors) derived from survey responses and census data. Adjusting for other neighborhood characteristics strengthened protective associations amongst Hispanics, but did not change the significant associations in African American men. These results demonstrate heterogeneity in the associations of race/ethnic composition with mental health and the need for further exploration of which aspects of neighborhood environments may contribute to these associations.
PMCID: PMC2922985  PMID: 20541303
Neighborhoods; Depressive symptoms; Mental health; Race/ethnicity; Ethnic density effect; USA
21.  Do socioeconomic gradients in subclinical atherosclerosis vary according to acculturation level? Analyses of Mexican-Americans in the Multi-Ethnic Study of Atherosclerosis 
Psychosomatic medicine  2009;71(7):756-762.
Although socioeconomic position (SEP) shows a consistent, inverse relationship with cardiovascular disease (CVD) risk in westernized non-Hispanic white populations, the relationship in ethnic minorities, including Hispanics, is often weak or even reversed (i.e., worse health with higher SEP). In the current study, we examined whether the association between SEP and subclinical atherosclerosis in Mexican Americans would be moderated by acculturation.
Participants were 801 Hispanics of Mexican origin (49.6% female; average age 60.47 years) from the Multi-Ethnic Study of Atherosclerosis cohort who underwent computed tomography of the chest for coronary artery calcium (CAC) and thoracic aortic calcium (TAC). SEP was represented by a composite of self-reported education and income. Acculturation was a composite score including language spoken at home, generation, and years of “exposure” to U.S. culture.
Small, but statistically significant SEP by acculturation interaction effects were identified in relation to prevalent CAC, prevalent TAC, and extent of TAC (all p < .05). Follow-up analyses revealed that the direction of the SEP gradient on detectable CAC changed as individuals progressed from low to high acculturation. Specifically, the association between SEP and calcification was positive at low levels of acculturation (i.e., a “reversed” gradient), and negative in circumstances of high acculturation (i.e., the expected, protective effect of higher SEP).
The findings support the utility of examining SEP and acculturation simultaneously, and of disaggregating large ethnic groupings (e.g., “Hispanic”) into meaningful subgroups to better understand health risks.
PMCID: PMC2761426  PMID: 19661194
Acculturation; calcification; coronary artery disease; Hispanics; socioeconomic status
22.  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
23.  Percent Emphysema, Airflow Obstruction, and Impaired Left Ventricular Filling 
The New England journal of medicine  2010;362(3):217-227.
Very severe chronic obstructive pulmonary disease causes cor pulmonale with elevated pulmonary vascular resistance and secondary reductions in left ventricular filling, stroke volume, and cardiac output. We hypothesized that emphysema, as detected on computed tomography (CT), and airflow obstruction are inversely related to left ventricular end-diastolic volume, stroke volume, and cardiac output among persons without very severe lung disease.
We measured left ventricular structure and function with the use of magnetic resonance imaging in 2816 persons who were 45 to 84 years of age. The extent of emphysema (expressed as percent emphysema) was defined as the percentage of voxels below −910 Hounsfield units in the lung windows on cardiac computed tomographic scans. Spirometry was performed according to American Thoracic Society guidelines. Generalized additive models were used to test for threshold effects.
Of the study participants, 13% were current smokers, 38% were former smokers, and 49% had never smoked. A 10-point increase in percent emphysema was linearly related to reductions in left ventricular end-diastolic volume (−4.1 ml; 95% confidence interval [CI], −3.3 to −4.9; P<0.001), stroke volume (−2.7 ml; 95% CI, −2.2 to −3.3; P<0.001), and cardiac output (−0.19 liters per minute; 95% CI, −0.14 to −0.23; P<0.001). These associations were of greater magnitude among current smokers than among former smokers and those who had never smoked. The extent of airflow obstruction was similarly associated with left ventricular structure and function, and smoking status had similar modifying effects on these associations. Percent emphysema and airflow obstruction were not associated with the left ventricular ejection fraction.
In a population-based study, a greater extent of emphysema on CT scanning and more severe airflow obstruction were linearly related to impaired left ventricular filling, reduced stroke volume, and lower cardiac output without changes in the ejection fraction.
PMCID: PMC2887729  PMID: 20089972
24.  Coronary Artery Calcification Compared with Carotid Intima-Media Thickness in Prediction of Cardiovascular Disease Incidence: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Archives of internal medicine  2008;168(12):1333-1339.
Coronary artery calcium (CAC) and carotid intima-media thickness (IMT) are noninvasive measures of atherosclerosis that consensus panels have recommended as possible additions to risk factor assessment for predicting the probability of cardiovascular disease (CVD) occurrence.
To assess whether maximum carotid IMT or CAC (Agatston Score) is the better predictor of incident CVD.
Design, Setting, Patients
Prospective cohort study of 45–84 year-olds initially free of CVD (n = 6,698) in four ethnic groups, with standardized carotid IMT and CAC measures at baseline, in six field centers of the Multi-Ethnic Study of Atherosclerosis (MESA).
Main Outcome Measure(s)
Incident CVD events (coronary heart disease, stroke, and fatal CVD) over a maximum of 5.3 years of follow-up.
There were 222 CVD events during follow-up. CAC was associated more strongly than carotid IMT with risk of incident CVD. After adjustment for each other and traditional CVD risk factors, the hazard of CVD increased 2.1-fold (95% CI 1.8–2.5) for each standard deviation greater level of log-transformed CAC, versus 1.3-fold (95% CI 1.1–1.4) for each standard deviation greater maximum IMT. For coronary heart disease, the hazard ratios per standard deviation increment were 2.5-fold (95% CI 2.1–3.1) for CAC and 1.2-fold (95% CI 1.0–1.4) for IMT. An ROC analysis also suggested that CAC predicted incident CVD better than IMT did.
Although whether and how to clinically use bio-imaging tests of subclinical atherosclerosis remains a topic of debate, this study found that CAC predicts subsequent CVD events better than does carotid IMT.
PMCID: PMC2555989  PMID: 18574091

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