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1.  Transferability and Fine Mapping of Type 2 Diabetes Loci in African Americans 
Diabetes  2013;62(3):965-976.
Type 2 diabetes (T2D) disproportionally affects African Americans (AfA) but, to date, genetic variants identified from genome-wide association studies (GWAS) are primarily from European and Asian populations. We examined the single nucleotide polymorphism (SNP) and locus transferability of 40 reported T2D loci in six AfA GWAS consisting of 2,806 T2D case subjects with or without end-stage renal disease and 4,265 control subjects from the Candidate Gene Association Resource Plus Study. Our results revealed that seven index SNPs at the TCF7L2, KLF14, KCNQ1, ADCY5, CDKAL1, JAZF1, and GCKR loci were significantly associated with T2D (P < 0.05). The strongest association was observed at TCF7L2 rs7903146 (odds ratio [OR] 1.30; P = 6.86 × 10−8). Locus-wide analysis demonstrated significant associations (Pemp < 0.05) at regional best SNPs in the TCF7L2, KLF14, and HMGA2 loci as well as suggestive signals in KCNQ1 after correction for the effective number of SNPs at each locus. Of these loci, the regional best SNPs were in differential linkage disequilibrium (LD) with the index and adjacent SNPs. Our findings suggest that some loci discovered in prior reports affect T2D susceptibility in AfA with similar effect sizes. The reduced and differential LD pattern in AfA compared with European and Asian populations may facilitate fine mapping of causal variants at loci shared across populations.
doi:10.2337/db12-0266
PMCID: PMC3581206  PMID: 23193183
2.  The Relationship between Measures of Obesity and Incident Heart Failure: The Multi-Ethnic Study of Atherosclerosis 
Obesity (Silver Spring, Md.)  2013;21(9):1915-1922.
Objective
To evaluate the strength of association of body mass index (BMI) and waist circumference (WC) with incident heart failure (HF), exploring our associations by ethnicity and age.
Design and Methods
We included 6,809 participants, aged 45–84 years, without clinical cardiovascular disease (2000–2002), from the Multi-Ethnic Study of Atherosclerosis. Cox-Proportional hazards models were used to examine associations of BMI and WC with incident HF. The predictive abilities of BMI and WC were compared using receiver operating characteristic curves.
Results
Over a median follow-up of 7.6 years, there were 176 cases. BMI and WC were associated with incident HF in men [1.33 (1.10–1.61) and 1.38 (1.18–1.62) respectively] and women [1.70 (1.33–2.17) and 1.64 (1.29–2.08) respectively]. These associations became non-significant after adjusting for obesity-related conditions (hypertension, dysglycemia, hypercholesterolemia, left ventricular hypertrophy, kidney disease and inflammation). The associations of BMI and WC did not vary significantly by ethnicity or age-group, but were inverse in Hispanic men. The area under the curve for BMI and WC was 0.749 and 0.750, respectively, in men and 0.782 and 0.777, respectively, in women.
Conclusions
The association between obesity and incident HF is largely mediated by obesity-related conditions. BMI and WC have similar predictive abilities for incident HF.
doi:10.1002/oby.20298
PMCID: PMC3664654  PMID: 23441088
Obesity; heart failure; body mass index and waist circumference
3.  Does Elevated Plasma Triglyceride Level Independently Predict Impaired Fasting Glucose? 
Diabetes Care  2013;36(2):342-347.
OBJECTIVE
Elevated plasma triglycerides (TGs) have been included in diabetes risk prediction models. This study examined whether elevated TGs predict risk for impaired fasting glucose (IFG).
RESEARCH DESIGN AND METHODS
This study used the baseline and longitudinal follow-up data from the Multi-Ethnic Study of Atherosclerosis (MESA). The analysis included non-Hispanic whites, African Americans, Hispanics, and Chinese Americans 45–84 years of age who had fasting glucose <100 mg/dL at baseline and who did not have clinically evident cardiovascular disease or diabetes. Cox proportional regression models were used to examine the association of elevated TGs with incidence of IFG adjusting for central obesity, low HDL cholesterol, elevated blood pressure, baseline fasting glucose, and BMI. Area under the receiver operating characteristic curve (AUC), sensitivity, and specificity of elevated TGs in predicting IFG were calculated.
RESULTS
The incidence rate of developing IFG was 59.1 per 1,000 person-years during the median 4.75 years of follow-up. African Americans and Hispanics had a higher incidence rate of IFG compared with non-Hispanic whites among people with normal TG concentrations. Elevated TGs (>150 mg/dL) at baseline were independently associated with the incidence of IFG with an adjusted hazard ratio of 1.19 (95% CI 1.04–1.37). However, its predictive value for identifying people at risk for IFG was poor, with <57% AUC. Interactions of elevated TGs with race/ethnicity in predicting IFG were not statistically significant.
CONCLUSIONS
Elevated TGs were moderately associated with risk for IFG, and it was a poor risk prediction tool for IFG.
doi:10.2337/dc12-0355
PMCID: PMC3554324  PMID: 23033247
4.  The Association of Health Professional Shortage Areas and Cardiovascular Risk Factor Prevalence, Awareness and Control in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Circulation. Cardiovascular quality and outcomes  2011;4(5):10.1161/CIRCOUTCOMES.111.960922.
Background
Individuals living in primary care health professional shortage areas (PC-HPSA) often have difficulty obtaining medical care; however, no previous studies have examined association of PC-HPSA residence with prevalence of CVD risk factors.
Methods and Results
To examine this question, the authors used data from the Multi-Ethnic Study of Atherosclerosis baseline exam (2000–2002). Outcomes included the prevalence of diabetes, hypertension, hyperlipidemia, smoking and obesity as well as the awareness and control of diabetes, hypertension, and hyperlipidemia. Multivariable Poisson models were used to examine the independent association of PC-HPSA residence with each outcome. Models were sequentially adjusted for demographics, acculturation, socioeconomic status, access to health care and neighborhood socioeconomic status. Similar to the national average, 16.7% of MESA participants lived in a PC-HPSA. In unadjusted analyses, prevalence rates of diabetes (14.8% vs 11.0%), hypertension (48.2% vs 43.1%), obesity (35.7% vs 31.1%) and smoking (15.5% vs 12.1%) were significantly higher among residents of PC-HPSAs. There were no significant differences in the awareness or control of diabetes, hypertension, or hyperlipidemia. After adjustment, residence in a PC-HPSA was not independently associated with CVD risk factor prevalence, awareness or control.
Conclusions
This study suggests that increased prevalence of CVD risk factors in PC-HPSAs are explained by the demographic and socioeconomic characteristics of their residents. Future interventions aimed at increasing the number of primary care physicians may not improve cardiovascular risk without first addressing other factors underlying healthcare disparities.
doi:10.1161/CIRCOUTCOMES.111.960922
PMCID: PMC3857032  PMID: 21878669
epidemiology; prevention; risk factors
6.  The Association Between Physical Activity and Subclinical Atherosclerosis 
American Journal of Epidemiology  2008;169(4):444-454.
Prior reports regarding the association between physical activity and subclinical cardiovascular disease have not been consistent. The authors assessed physical activity and walking pace via questionnaire among 6,482 US adults aged 45–84 years without prior clinical cardiovascular disease participating in the Multi-Ethnic Study of Atherosclerosis from 2000 to 2002. Ankle-brachial index (ABI), coronary artery calcification, and internal and common carotid intima-media thickness (IMT) were measured. Metabolic equivalent-hours/week of physical activity were calculated. These data were analyzed by using multivariable linear or relative prevalence regression in gender-specific strata. After adjustment for age, race/ethnicity, clinic site, education, income, and smoking (model 1), increasing total, moderate + vigorous, and intentional-exercise physical activity were not associated with IMT or coronary artery calcification in either gender. These factors were associated with increased ABI (P < 0.05) in women only. Walking pace was associated favorably with common carotid IMT, ABI, and coronary artery calcification in men and with common carotid IMT and ABI in women (all P < 0.05) after adjustment for model 1 variables. These associations were attenuated and, for common carotid IMT, no longer significant when lipids, hypertension, diabetes, and body mass index were added to the model. These data suggest that walking pace is associated with less subclinical atherosclerosis; these associations may be mediated by cardiovascular disease risk factors.
doi:10.1093/aje/kwn350
PMCID: PMC2726643  PMID: 19075250
atherosclerosis; carotid arteries; coronary vessels; exercise; motor activity; peripheral vascular diseases
7.  A Multilevel Assessment of Barriers to Adoption of Dietary Approaches to Stop Hypertension (DASH) among African Americans of Low Socioeconomic Status 
Background
We examined perceptions of Dietary Approaches to Stop Hypertension (DASH) and the food environment among African Americans (AA) with high blood pressure living in two low-income communities and objectively assessed local food outlets.
Methods
Focus groups were conducted with 30 AAs; participants discussed DASH and the availability of healthy foods in their community. Sessions were transcribed and themes identified. Fifty-four stores and 114 restaurants were assessed using the Nutrition Environment Measures Survey (NEMS).
Results
Common themes included poor availability, quality, and cost of healthy foods; tension between following DASH and feeding other family members; and lack of congruity between their preferred foods and DASH. Food outlets in majority AA census tracts had lower NEMS scores (stores: −11.7, p=.01, restaurants: −8.3, p=.001) compared with majority White areas.
Conclusions
Interventions promoting DASH among lower income AAs should reflect the food customs, economic concerns, and food available in communities.
doi:10.1353/hpu.2011.0142
PMCID: PMC3769217  PMID: 22080704
Hypertension; diet; food deserts; African American
8.  Value of Recruitment Strategies Used in a Primary Care Practice-based Trial 
Contemporary clinical trials  2006;28(3):258-267.
Purpose
“Physicians-recruiting-physicians” is the preferred recruitment approach for practice-based research. However, yields are variable; and the approach can be costly and lead to biased, unrepresentative samples. We sought to explore the potential efficiency of alternative methods.
Methods
We conducted a retrospective analysis of the yield and cost of 10 recruitment strategies used to recruit primary care practices to a randomized trial to improve cardiovascular disease risk factor management. We measured response and recruitment yields and the resources used to estimate the value of each strategy. Providers at recruited practices were surveyed about motivation for participation.
Results
Response to 6 opt-in marketing strategies was 0.40% (53/13290), ranging from 0% to 2.86% by strategy; 33.96% (18/53) of responders were recruited to the study. Of those recruited from opt-out strategies, 8.68% joined the study, ranging from 5.35% to 41.67% per strategy. A strategy that combined both opt-in and opt-out approaches resulted in a 51.14% (90/176) response and a 10.80% (19/90) recruitment rate. Cost of recruitment was $613 per recruited practice. Recruitment approaches based on in-person meetings (41.67%), previous relationships (33.33%), and borrowing an Area Health Education Center’s established networks (10.80%), yielded the most recruited practices per effort and were most cost efficient. Individual providers who chose to participate were motivated by interest in improving their clinical practice (80.5%); contributing to CVD primary prevention (54.4%); and invigorating their practice with new ideas (42.1%).
Conclusions
This analysis provides suggestions for future recruitment efforts and research. Translational studies with limited funds could consider multi-modal recruitment approaches including in-person presentations to practice groups and exploitation of previous relationships, which require the providers to opt-out, and interactive opt-in approaches which rely on borrowed networks. These approaches can be supplemented with non-relationship-based opt-out strategies such as cold calls strategically targeted to underrepresented provider groups.
doi:10.1016/j.cct.2006.08.009
PMCID: PMC3760001  PMID: 17030154
9.  Diurnal Salivary Cortisol and Urinary Catecholamines Are Associated With Diabetes Mellitus: The Multi-Ethnic Study of Atherosclerosis 
Metabolism  2011;61(7):986-995.
Objective
To examine the cross-sectional association of diurnal salivary cortisol curve components and urinary catecholamines with diabetes status.
Methods
Up to 18 salivary cortisol samples over 3 days and overnight urinary catecholamines were collected from 1,002 participants in the Multi-Ethnic Study of Atherosclerosis. Diabetes was defined as a fasting blood glucose ≥126 mg/dL or medication use. Cortisol curve measures included awakening cortisol, cortisol awakening response (CAR), early decline, late decline, and cortisol area under the curve (AUC). Urinary catecholamines included epinephrine, norepinephrine, and dopamine.
Results
Participants with diabetes had significantly lower CAR (β=−0.19; 95% CI: −0.34 to −0.04) than those without diabetes in multivariable models. While men with diabetes had a non-significant trend toward lower total AUC (β=−1.56; 95% CI: −3.93 to 0.80), women with diabetes had significantly higher total AUC (β=2.62; 95% CI: 0.72 to 4.51) (p=0.02 for interaction) compared to those without diabetes. Men but not women with diabetes had significantly lower urinary catecholamines, compared to those without diabetes (p<0.05).
Conclusions
Diabetes is associated with neuroendocrine dysregulation, which may differ by sex. Further studies are needed to determine the role of the neuroendocrine system in the pathophysiology of diabetes.
doi:10.1016/j.metabol.2011.11.006
PMCID: PMC3319636  PMID: 22209664
diabetes; hypothalamic-pituitary-adrenal (HPA) axis; salivary cortisol; catecholamines; epidemiology
10.  Prediction of Incident Heart Failure in General Practice: The ARIC Study 
Circulation. Heart failure  2012;5(4):422-429.
Background
A simple and effective Heart Failure (HF) risk score would facilitate the primary prevention and early diagnosis of HF in general practice. We examined the external validity of existing HF risk scores, optimized a 10-year HF risk function, and examined the incremental value of several biomarkers, including NT-proBNP.
Methods and Results
During 15.5 years (210,102 person-years of follow-up), 1487 HF events were recorded among 13,555 members of the bi-ethnic Atherosclerosis Risk in Communities (ARIC) Study cohort. The area under curve (AUC) from the Framingham-published, Framingham-recalibrated, Health ABC HF recalibrated, and ARIC risk scores were 0.610, 0.762, 0.783, and 0.797, respectively. Upon addition of NT-pro-BNP, the optimism corrected AUC of the ARIC HF risk score increased from 0.773 (95% CI: 0.753 – 0.787) to 0.805 (95% CI: 0.792 – 0.820). Inclusion of NT-proBNP improved the overall classification of re-calibrated Framingham, re-calibrated Health ABC, and ARIC risk scores by 18%, 12%, and 13%, respectively. In contrast, Cystatin C or hs-CRP did not add towards incremental risk prediction.
Conclusions
The ARIC HF risk score is more parsimonious yet performs slightly better than the extant risk scores in predicting 10-year risk of incident HF. The inclusion of NT-proBNP markedly improves HF risk prediction. A simplified risk score restricted to a patient’s age, race, gender, and NT-proBNP performs comparably to the full score (AUC = 0.745), and is suitable for automated reporting from laboratory panels and electronic medical records.
doi:10.1161/CIRCHEARTFAILURE.111.964841
PMCID: PMC3412686  PMID: 22589298
heart failure; risk prediction; external validation; NT-proBNP; Cystatin C; hs-CRP; biomarkers
11.  Diurnal Salivary Cortisol is Associated With Body Mass Index and Waist Circumference: The Multi-Ethnic Study of Atherosclerosis 
Obesity (Silver Spring, Md.)  2013;21(1):E56-E63.
Neuroendocrine abnormalities, such as activation of the hypothalamic-pituitary-adrenal (HPA) axis, are associated with obesity; however, few large-scale population-based studies have examined HPA axis and markers of obesity. We examined the cross-sectional association of the cortisol awakening response (CAR) and diurnal salivary cortisol curve with obesity. The Multi-Ethnic Study of Atherosclerosis (MESA) Stress Study includes 1,002 White, Hispanic, and Black men and women (mean age 65±9.8 years) who collected up to 18 salivary cortisol samples over 3 days. Cortisol profiles were modeled using regression spline models that incorporated random parameters for subject-specific effects. Cortisol curve measures included awakening cortisol, CAR (awakening to 30 minutes post-awakening), early decline (30 minutes to 2 hours post-awakening), late decline (2 hours post-awakening to bedtime), and the corresponding areas under the curve (AUC). Body-mass-index (BMI) and waist circumference (WC) were used to estimate adiposity. For the entire cohort, both BMI and WC were negatively correlated with awakening cortisol (p<0.05), AUC during awakening rise and early decline and positively correlated to the early decline slope (p<0.05) after adjustments for age, race/ethnicity, gender, diabetes status, socioeconomic status, beta blockers, steroids, hormone replacement therapy and smoking status. No heterogeneities of effects were observed by gender, age, and race/ethnicity. Higher BMI and WC are associated with neuroendocrine dysregulation, which is present in a large population sample, and only partially explained by other covariates.
doi:10.1002/oby.20047
PMCID: PMC3602310  PMID: 23404865
adiposity; hypothalamic-pituitary-adrenal (HPA) axis; salivary cortisol; diurnal cortisol; cortisol awakening response; epidemiology; obesity; body mass index; waist circumference; epidemiology
12.  Metabolic Syndrome, Diabetes, and Incidence and Progression of Coronary Calcium: The Multiethnic Study of Atherosclerosis (MESA) 
Jacc. Cardiovascular Imaging  2012;5(4):358-366.
Objectives
The purpose of the study was to examine and compare the incidence and progression of coronary artery calcium (CAC) among persons with metabolic syndrome (MetS) and diabetes mellitus (DM), compared to those with neither condition.
Background
MetS and DM are associated with subclinical atherosclerosis as evidenced by coronary artery calcium (CAC).
Methods
The Multiethnic Study of Atherosclerosis included 6,814 African-American, Asian, Caucasian, and Hispanic adults aged 45–84 free of cardiovascular disease at baseline. 5,662 subjects (51% female, mean age 61.0 ± 10.3 years) received baseline and follow-up (mean 2.4 years) cardiac CT scans. We compared the incidence of CAC in 2,927 subjects without CAC at baseline and progression of CAC in 2,735 subjects with CAC at baseline in those with MetS without DM (25.2%), DM without MetS (3.5%), or both DM and MetS (9.0%), compared to neither MetS nor DM (58%). Progression of CAC was also examined in relation to coronary heart disease events over an additional 4.9 years.
Results
Relative to those with neither MetS nor DM, adjusted relative risks (95% confidence intervals) for incident CAC were 1.7 (1.4–2.0), 1.9 (1.4–2.4), and 1.8 (1.4–2.2) (all p<0.01) and absolute differences in mean progression (volume score) were 7.8 (4.0–11.6; p<0.01), 11.6 (2.7–20.5; p<0.05), and 22.6 (17.2–27.9; p<0.01) for those with MetS without DM, DM without MetS, and both DM and MetS, respectively. Similar findings were seen in analysis using Agatston calcium score. In addition, progression predicted CHD events in those with MetS without DM (adjusted hazard ratio 4.1, 95% CI=2.0–8.5, p<0.01) and DM (4.9 [1.3–18.4], p<0.05) among those in highest tertile of CAC increase vs. no increase).
Conclusions
Individuals with MetS and DM have a greater incidence and absolute progression of CAC compared to individuals without these conditions, with progression also predicting CHD events in those with MetS and DM.
doi:10.1016/j.jcmg.2011.12.015
PMCID: PMC3327555  PMID: 22498324
atherosclerosis; diabetes; risk factors; calcification
13.  Electrocardiographic Abnormalities Associated with the Metabolic Syndrome and Its Components: The Multi-Ethnic Study of Atherosclerosis 
Abstract
Background
The association between metabolic syndrome and electrocardiographic (ECG) abnormalities is not well established.
Methods
ECG tracings of 6,765 men and women aged 45–84 years, free of clinical cardiovascular disease, from the Multi-Ethnic Study of Atherosclerosis were obtained (2000–2002) and classified as normal or having major or minor abnormalities. We evaluated the associations of metabolic syndrome and its components with ECG abnormalities, adjusting for age, ethnicity, and gender and testing for effect modification by ethnicity and gender.
Results
The associations of metabolic syndrome, hypertension, and high triglycerides with ECG abnormalities varied significantly by gender. In males, metabolic syndrome and hypertension were significantly associated with major ECG abnormality [1.69 (1.33–2.13), and 2.22 (1.72–2.86), respectively] after adjusting for ethnicity and gender. Hypertension was also associated significantly with minor ECG abnormality in males after adjusting for age and ethnicity. In females, metabolic syndrome and hypertension were significantly associated with major [1.84 (1.44–2.37), and 1.68 (1.27–2.22), respectively] and minor [1.38 (1.19–1.59), and 1.53 (1.32–1.79), respectively] ECG abnormalities after adjusting for age and ethnicity. High triglycerides were only significantly associated with major ECG abnormality in females after adjusting for age and ethnicity. After adjusting for age, ethnicity, and gender, central obesity and high fasting blood glucose were significantly associated with major and minor ECG abnormalities, whereas low high-density lipoprotein cholesterol was significantly associated with major ECG abnormality only.
Conclusions
Metabolic syndrome and its components are associated with major and/or minor ECG abnormalities. The relationship of metabolic syndrome, hypertension, and high triglycerides with ECG abnormalities varied according to gender.
doi:10.1089/met.2011.0090
PMCID: PMC3339381  PMID: 22053762
14.  Classification of Heart Failure in the Atherosclerosis Risk in Communities (ARIC) Study: A Comparison of Diagnostic Criteria 
Circulation. Heart Failure  2012;5(2):152-159.
Background
Population-based research on heart failure (HF) is hindered by lack of consensus on diagnostic criteria. Framingham (FRM), National Health and Nutrition Examination Survey (NHANES), Modified Boston (MBS), Gothenburg (GTH), and International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) code criteria do not differentiate acute decompensated heart failure (ADHF) from chronic stable HF. We developed a new classification protocol for identifying ADHF in the Atherosclerosis Risk in Communities (ARIC) Study and compared it with these other schemes.
Methods and Results
A sample of 1180 hospitalizations with a patient address in four study communities and eligible discharge codes were selected. After assessing whether the chart contained evidence of possible HF signs, 705 were fully abstracted. Two independent reviewers classified each case as ADHF, chronic stable HF or no HF using ARIC classification guidelines. Fifty-nine percent of cases met ARIC criteria for ADHF and 13.9% and 27.1% were classified as chronic stable HF or no HF, respectively. Among events classified as HF by FRM criteria, 68.4% were validated as ADHF, 9.6% as chronic stable HF and 21.9% as no HF. However, 92.5% of hospitalizations with a primary ICD-9-CM 428 “heart failure” code were validated as ADHF. Sensitivities of comparison criteria to classify ADHF ranged from 38 to 95%, positive predictive values from 62 to 92%, and specificities from 19 to 96%.
Conclusions
Although comparison criteria for classifying HF were moderately sensitive in identifying ADHF, specificity varied when applied to a randomly selected set of suspected HF hospitalizations in the community.
doi:10.1161/CIRCHEARTFAILURE.111.963199
PMCID: PMC3326579  PMID: 22271752
heart failure; epidemiology
15.  Retinal microvascular calibre and risk of incident diabetes: The multi-ethnic study of atherosclerosis 
Aim
To prospectively examine the association of retinal microvascular signs with incident diabetes and impaired fasting glucose (IFG) in a multi-ethnic population-based cohort.
Methods
The multi-ethnic study of atherosclerosis comprised Caucasians, African-Americans, Hispanics and Chinese aged 45–84 years. Retinal vascular calibre and retinopathy were quantified from baseline retinal photographs. Incident diabetes and IFG were ascertained prospectively.
Results
After a median follow-up of 3 years, 243 (4.9%) people developed diabetes and 565 (15.0%) developed IFG. After adjusting for known risk factors, participants with wider retinal arteriolar calibre had a higher risk of developing diabetes [HR: 1.60; 95% CI: 1.12–2.29, p = 0.011 comparing highest with lowest arteriolar calibre tertile]. In ethnic subgroup analysis, the association between wider retinal arteriolar calibre and incident diabetes was stronger and statistically significant only in Caucasians [HR: 2.78; 95% CI: 1.37–5.62, p = 0.005]. Retinal venular calibre and retinopathy signs were not related to risk of diabetes or IFG.
Conclusion
Wider retinal arteriolar calibre is independently associated with an increased risk of diabetes, supporting a possible role for early arteriolar changes in diabetes development. This effect was largely seen in Caucasians, and not in other ethnic groups, and may reflect ethnic differences in susceptibility to diabetes from microvascular pathways.
doi:10.1016/j.diabres.2011.10.027
PMCID: PMC3269503  PMID: 22088792
Retinal microvascular calibre; Retinopathy; Diabetes; Impaired fasting glucose
16.  Sedentary Behavior and Adiposity-Associated Inflammation The Multi-Ethnic Study of Atherosclerosis 
Background
Sedentary behavior is associated with adiposity and cardiometabolic risk.
Purpose
To determine the associations between sedentary behavior and measures of adiposity-associated inflammation.
Methods
Between 2002 and 2005, a total of 1543 Multi-Ethnic Study of Atherosclerosis participants completed detailed health history questionnaires, underwent physical measurements and had blood assayed for adiponectin, leptin, tumor necrosis factor – alpha (TNF - α) and resistin. Analyses included linear regression completed in 2010. The mean age was 64.3 years and nearly 50% were female. Forty-one percent were non-Hispanic white, 24% Hispanic-American, 20% African-American, and 14% Chinese-American.
Results
In linear regression analyses and with adjustment for age, gender, ethnicity, education, BMI, smoking, alcohol consumption, hypertension, diabetes mellitus, dyslipidemia, hormone therapy and waist circumference, sedentary behavior was associated with higher natural log (“ln”) of leptin and ln TNF - α but a lower ln adiponectin-to-leptin ratio (β = 0.07, β = 0.03 and –0.07, p < 0.05 for all). Compared to the first tertile, and after the same adjustment, the second and third tertiles of sedentary behavior were associated with higher levels of ln leptin (β = 0.11and β = 0.12, respectively; p < 0.05 for both) but lower levels of the adiponectin-to-leptin ratio (β = –0.09 and –0.11, respectively; p < 0.05 for both).
Conclusions
Sedentary behavior is associated with unfavorable levels of adiposity-associated inflammation.
doi:10.1016/j.amepre.2011.09.023
PMCID: PMC3244676  PMID: 22176840
17.  Translating the Dietary Approaches to Stop Hypertension (DASH) Diet for Use in Underresourced, Urban African American Communities, 2010 
Introduction
Randomized trials have demonstrated the effectiveness of the Dietary Approaches to Stop Hypertension (DASH) program for lowering blood pressure; however, program participation has been limited in some populations. The objective of this pilot study was to test the feasibility of using a culturally modified version of DASH among African Americans in an underresourced community.
Methods
This randomized controlled pilot study recruited African Americans in 2 North Carolina neighborhoods who had high blood pressure and used fewer than 3 antihypertension medications. We offered 2 individual and 9 group DASH sessions to intervention participants and 1 individual session and printed DASH educational materials to control participants. We collected data at baseline (March 2010) and 12 weeks (June 2010).
Results
Of 152 potential participants, 25 were randomly assigned to either the intervention (n = 14) or the control (n = 11) group; 22 were women, and 21 were educated beyond high school. At baseline, mean blood pressure was 130/78 mm Hg; 19 participants used antihypertension medications, and mean body mass index was 35.9 kg/m2. Intervention participants attended 7 of 9 group sessions on average. After 12 weeks, we observed significant increases in fruit and vegetable consumption and increases in participants’ confidence in their ability to reduce salt and fat consumption and eat healthier snacks in intervention compared with control participants. We found no significant decreases in blood pressure.
Conclusion
Implementation of a culturally modified, community-based DASH intervention was feasible in our small sample of African Americans, which included people being treated for high blood pressure. Future studies should evaluate the long-term effect of this program in a larger sample.
doi:10.5888/pcd10.120088
PMCID: PMC3545703  PMID: 23306077
18.  Impact of the Look AHEAD intervention on NT-pro Brain Natriuretic Peptide in overweight and obese adults with diabetes 
Obesity (Silver Spring, Md.)  2011;20(7):1511-1518.
Look AHEAD is a randomized trial determining whether intensive lifestyle intervention (ILI) aimed at long-term weight loss and increased physical fitness reduces cardiovascular morbidity and mortality in overweight and obese individuals with type 2 diabetes compared to control (diabetes support and education, DSE). We investigated the correlates of NT-proBNP, a biomarker associated with heart failure risk, in a subsample from 15 of 16 participating centers and tested the hypothesis that ILI decreased NT-proBNP levels. Baseline and one-year blood samples were assayed for NT-proBNP in a random sample of 1500 without, and all 628 with, self-reported baseline CVD (N=2128). Linear models were used to assess relationships that logtransformed NT-proBNP had with CVD risk factors at baseline and that 1-year changes in NT-proBNP had with intervention assignment. At baseline, the mean (SD) age, BMI, and hemoglobin A1c were 59.6 (6.8) years, 36.0 kg/m2 (5.8), and 7.2% (1.1), respectively. Baseline geometric mean NT-proBNP was not different by condition (ILI 53.3 vs DSE 51.5, p=0.45), was not associated with BMI, and was inversely associated with hemoglobin A1c. At 1 year, ILI participants achieved an average weight loss of 8.3% compared to 0.7% in DSE. At 1 year, NT-proBNP levels increased to a greater extent in the intervention arm (ILI +21.3% vs. DSE +14.2%, p=0.046). The increased NT-proBNP associated with ILI was correlated with changes in A1c, BMI, and body composition. In conclusion, among overweight and obese persons with diabetes, an intensive lifestyle intervention that reduced weight was associated with an increased NT-proBNP.
doi:10.1038/oby.2011.296
PMCID: PMC3509930  PMID: 21959345
natriuretic peptides; diabetes mellitus; obesity
19.  Association of Weight Status with Mortality in Adults with Incident Diabetes 
Context
Type 2 diabetes in normal weight (body mass index [BMI] <25kg/m2) adults is an intriguing representation of the metabolically obese normal weight phenotype with unknown mortality consequences.
Objective
To minimize the influence of diabetes duration and voluntary weight loss on mortality, we tested the association of weight status with mortality in adults with new onset diabetes.
Design
Pooled analysis of five longitudinal cohort studies: Atherosclerosis Risk in Communities Study, 1990–2006; Cardiovascular Health Study, 1992–2008; Coronary Artery Risk Development in Young Adults, 1987–2011; Framingham Offspring Study, 1979–2007; Multi-Ethnic Study of Atherosclerosis, 2002–2011. Participants contributed 27,125 person-years of follow-up.
Setting
2,625 participants with incident diabetes
Participants
Men and women (age>40 years) who developed incident diabetes based on fasting glucose ≥ 126 mg/dL or newly-initiated diabetes medication and who had concurrent measurements of body mass index (BMI). Participants were classified as normal weight if their BMI was 18.5 to 24.99kg/m2 or overweight/obese if BMI≥25 kg/m2.
Main Outcome Measures
Total, cardiovascular, and non-cardiovascular mortality
Results
The proportion of adults who were normal weight at the time of incident diabetes ranged from 9–21% (overall=12%). Over follow-up, 449 participants died, 178 from cardiovascular causes and 253 from non-cardiovascular causes (18 were not classified). The rate of total, cardiovascular and non-cardiovascular mortality was higher in normal weight participants (248.8, 99.8, and 198.1 per 10,000 person-years, respectively) than overweight/obese participants (152.1, 67.8, and 87.9 per 10,000 person-years, respectively). Following adjustment for demographic characteristics and blood pressure, lipids, waist circumference and smoking status, hazard ratios comparing normal weight participants to overweight/obese participants for total, cardiovascular, and non-cardiovascular mortality were 2.08 (95% confidence interval [CI]: 1.52, 2.85), 1.52 (95% CI: 0.89, 2.58) and 2.32 (95% CI: 1.55, 3.48), respectively.
Conclusions
Adults who are normal weight at the time of incident diabetes have higher mortality than adults who are overweight or obese.
doi:10.1001/jama.2012.9282
PMCID: PMC3467944  PMID: 22871870
type 2 diabetes; obesity; cardiovascular disease; longitudinal studies
20.  Impact of Subclinical Atherosclerosis on Cardiovascular Disease Events in Individuals With Metabolic Syndrome and Diabetes 
Diabetes Care  2011;34(10):2285-2290.
OBJECTIVE
While metabolic syndrome (MetS) and diabetes confer greater cardiovascular disease (CVD) risk, recent evidence suggests that individuals with these conditions have a wide range of risk. We evaluated whether screening for coronary artery calcium (CAC) and carotid intimal-medial thickness (CIMT) can improve CVD risk stratification over traditional risk factors (RFs) in people with MetS and diabetes.
RESEARCH DESIGN AND METHODS
We assessed CAC and CIMT in 6,603 people aged 45–84 years in the Multi-Ethnic Study of Atherosclerosis (MESA). Cox regression examined the association of CAC and CIMT with coronary heart disease (CHD) and CVD over 6.4 years in MetS and diabetes.
RESULTS
Of the subjects, 1,686 (25%) had MetS but no diabetes and 881 (13%) had diabetes. Annual CHD event rates were 1.0% among MetS and 1.5% for diabetes. Ethnicity and RF-adjusted hazard ratios for CHD for CAC 1–99 to ≥400 vs. 0 in subjects with neither MetS nor diabetes ranged from 2.6 to 9.5; in those with MetS, they ranged from 3.9 to 11.9; and in those with diabetes, they ranged from 2.9 to 6.2 (all P < 0.05 to P < 0.001). Findings were similar for CVD. CAC increased the C-statistic for events (P < 0.001) over RFs and CIMT in each group while CIMT added negligibly to prediction over RFs.
CONCLUSIONS
Individuals with MetS or diabetes have low risks for CHD when CAC or CIMT is not increased. Prediction of CHD and CVD events is improved by CAC more than by CIMT. Screening for CAC or CIMT can stratify risk in people with MetS and diabetes and support the latest recommendations regarding CAC screening in those with diabetes.
doi:10.2337/dc11-0816
PMCID: PMC3177707  PMID: 21844289
21.  The Relationship of Insulin Resistance and Extracoronary Calcification in the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2011;218(2):507-510.
OBJECTIVE
We hypothesized that insulin resistance, measured by the homeostatic model assessment of insulin resistance (HOMA), is independently associated with prevalent and incident extra-coronary calcification (ECC).
METHODS
We studied calcium scores of the aortic valve (AVC), mitral valve (MVC), thoracic aorta (TAC) and aortic valve root (AVR) in 6,104 MESA participants not on diabetes medication who had baseline cardiac CT scans; 5,312 had follow-up scans (mean 2.4y). Relative-risk regression modeled prevalent and incident ECC adjusted for baseline demographics (model 1), and additionally for CVD risk factors (model 2).
RESULTS
In model 1, prevalence and incidence risk-ratios for the highest versus lowest quartile of HOMA were 20–30% higher in all ECC locations (p-value for trend ≤0.05 for all but incident-AVC). In model 2, all associations were attenuated, primarily by adjustment for metabolic syndrome components.
CONCLUSIONS
HOMA has a positive and graded association with ECC, but not independently of cardiovascular risk factors—particularly metabolic syndrome components.
doi:10.1016/j.atherosclerosis.2011.06.047
PMCID: PMC3185155  PMID: 21798541
cardiovascular calcification; insulin resistance; atherosclerosis; metabolic syndrome; computed tomography; valvular calcification; thoracic aortic calcification
22.  Lifestyle Change and Mobility in Obese Adults with Type 2 Diabetes 
The New England Journal of Medicine  2012;366(13):1209-1217.
Background
Adults with type 2 diabetes mellitus often have limitations in mobility that increase with age. An intensive lifestyle intervention that produces weight loss and improves fitness could slow the loss of mobility in such patients.
Methods
We randomly assigned 5145 overweight or obese adults between the ages of 45 and 74 years with type 2 diabetes to either an intensive lifestyle intervention or a diabetes support-and-education program; 5016 participants contributed data. We used hidden Markov models to characterize disability states and mixed-effects ordinal logistic regression to estimate the probability of functional decline. The primary outcome was self-reported limitation in mobility, with annual assessments for 4 years.
Results
At year 4, among 2514 adults in the lifestyle-intervention group, 517 (20.6%) had severe disability and 969 (38.5%) had good mobility; the numbers among 2502 participants in the support group were 656 (26.2%) and 798 (31.9%), respectively. The lifestyle-intervention group had a relative reduction of 48% in the risk of loss of mobility, as compared with the support group (odds ratio, 0.52; 95% confidence interval, 0.44 to 0.63; P<0.001). Both weight loss and improved fitness (as assessed on treadmill testing) were significant mediators of this effect (P<0.001 for both variables). Adverse events that were related to the lifestyle intervention included a slightly higher frequency of musculoskeletal symptoms at year 1.
Conclusions
Weight loss and improved fitness slowed the decline in mobility in overweight adults with type 2 diabetes. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT00017953.)
doi:10.1056/NEJMoa1110294
PMCID: PMC3339039  PMID: 22455415
23.  Modification of the Effect of Glycemic Status on Aortic Distensibility by Age in the Multi-Ethnic Study of Atherosclerosis 
Hypertension  2009;55(1):26-32.
Elevated serum glucose from diabetes mellitus (DM) or impaired fasting glucose (IFG) shares many mechanisms with aging that decrease aortic distensibility (AD), such as glycation of the extra-cellular matrix. However, little data compares the simultaneous effects of elevated serum glucose and aging on AD. To study this, we examined the relationship between fasting glucose status, age, and AD in the Multi-Ethnic Study of Atherosclerosis (MESA): a multi-ethnic cohort of individuals aged 45-84 years without clinical cardiovascular disease. In MESA, participants with normal fasting glucose (NFG; n = 2270), IFG (n = 870), and DM (n = 412) underwent MRI assessment of proximal thoracic aortic distensibility. This sample was 46% male, 42% white, 30% AA, 11% Asian, and 17% Hispanic. The relationship between glucose status, age, and AD was analyzed with general linear models by adjusting for factors influential on AD. An interaction term was used to determine if age modified the effect of glucose status on AD. AD was lowest among those with DM. The interaction term was significant (p = 0.024). Comparing participants less than 65 years of age, AD was different between NFG and DM (p < 0.01), and between NFG and IFG (p = 0.02). In those older than 65, fasting glucose group was no longer a significant predictor of AD. Our data indicate that there are overall differences in AD between DM, IFG, and NFG. However, age modified the effect of glucose status such that differences between the groups diminished with advancing age.
doi:10.1161/HYPERTENSIONAHA.109.134031
PMCID: PMC3400507  PMID: 19933927
aging; aorta; diabetes mellitus; glucose; magnetic resonance imaging
24.  Impaired Fasting Glucose And The Risk Of Incident Diabetes Mellitus And Cardiovascular Events In An Adult Population: The Multi-Ethnic Study of Atherosclerosis 
Objective
To assess the cardiovascular risk of impaired fasting glucose (IFG).
Background
The association between IFG, incident type 2 diabetes mellitus (T2DM) and cardiovascular (CV) events remains unclear.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) included participants aged 45–84 free of clinical CV disease at baseline (2000–2002). T2DM was defined as fasting glucose >125mg/dl or anti-diabetes medication at baseline and follow-up exams, IFG as no T2DM and fasting glucose 100–125.mg/dl. Cox proportional hazard analysis was used to assess the association between IFG and incident DM and also with incident CV events.
Results
Of 6753 participants included in these analyses 840 (12.7%) had T2DM, 940 (13.8%) had IFG at the baseline exam. During 7.5 years of follow-up there were 418 adjudicated CV events. T2DM was associated with an increased CV incidence in the univariate [hazard ratio (HR); 2.83(2.25–3.56), p<0.0001] and multivariable models (adjusted for demographics and traditional risk factors) [HR; 1.87(1.47 – 2.37), p<0.0001] compared with subjects without T2DM (IFG + NFG). IFG was associated with increased incidence of T2DM [HR; 13.2 (95%CI 10.8–16.2), p<0.001] that remained after adjusting for demographics, highest educational level, physical activity and BMI [HR; 10.5(8.4–13.1), p<0.001] compared to NFG. IFG was associated with incident CV events in the univariate [HR; 1.64(1.26 – 2.14), p=<0.001] but not in the full multivariable model [HR; 1.16(95% CI 0.88–1.52), p=0.3] compared with NFG.
Conclusion
Having IFG was not independently associated with an increased short-term risk for incident CV events. These data reiterate the importance of intervention in persons with IFG to reduce their incidence of T2DM.
doi:10.1016/j.jacc.2011.03.025
PMCID: PMC3146297  PMID: 21718910
Impaired fasting glucose; diabetes mellitus; cardiovascular events; population
25.  High-Normal Albuminuria and Risk of Heart Failure in the Community 
Background
Albuminuria has been associated with cardiovascular risk, but the relationship of high-normal albuminuria to subsequent heart failure has not been well established.
Study Design
Prospective observational study, the Atherosclerosis Risk in Communities (ARIC) Study.
Setting & Participants
10,975 individuals free from heart failure were followed up from the fourth ARIC Study visit (1996–1998) through January 2006.
Predictor
Urinary albumin-creatinine ratio (UACR), analyzed continuously and categorically as optimal (<5 mg/g), intermediate-normal (5–9 mg/g), high-normal (10–29 mg/g), microalbuminuria (30–299 mg/g), and macroalbuminuria (≥300 mg/g).
Outcomes & Measurements
Incident heart failure was defined as a heart failure–related hospitalization or death. Cox proportional hazard models were used to calculate the HR of heart failure after adjustment for age, race, sex, estimated glomerular filtration rate (eGFR), and other cardiovascular risk factors.
Results
Individuals were followed up for a median of 8.3 years and experienced 344 heart failure events. Compared with normal UACR, albuminuria was associated with a progressively increased risk of heart failure from intermediate-normal (adjusted HR, 1.54; 95% CI, 1.12–2.11) and high-normal UACR (adjusted HR, 1.91; 95% CI, 1.38–2.66) to microalbuminuria (adjusted HR, 2.49; 95% CI, 1.77–3.50) and macroalbuminuria (adjusted HR, 3.47; 95% CI, 2.10–5.72). Results were similar in secondary analyses of participants censored at the time of coronary heart disease event and along a range of eGFRs.
Limitations
UACR was measured as a single random sample.
Conclusions
Albuminuria is associated with subsequent heart failure, even in individuals with few cardiovascular risk factors and UACR within the normal range. Our results suggest that the association between albuminuria and heart failure may not be mediated fully by ischemic heart disease or kidney disease, measured using eGFR.
doi:10.1053/j.ajkd.2011.02.391
PMCID: PMC3119712  PMID: 21549463
Albuminuria; urinary albumin-creatinine ratio; heart failure; epidemiology

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